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EP0921798A1 - Nouveau traitement contre la resistance a la leptine - Google Patents

Nouveau traitement contre la resistance a la leptine

Info

Publication number
EP0921798A1
EP0921798A1 EP97931945A EP97931945A EP0921798A1 EP 0921798 A1 EP0921798 A1 EP 0921798A1 EP 97931945 A EP97931945 A EP 97931945A EP 97931945 A EP97931945 A EP 97931945A EP 0921798 A1 EP0921798 A1 EP 0921798A1
Authority
EP
European Patent Office
Prior art keywords
leptin
sensitiser
pharmaceutically acceptable
formula
moiety
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97931945A
Other languages
German (de)
English (en)
Inventor
George Henry SmithKline Beecham Pharm. POSTE
Stephen Alistair SmithKline Beecham Pharm. Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9614740.0A external-priority patent/GB9614740D0/en
Priority claimed from GBGB9614751.7A external-priority patent/GB9614751D0/en
Priority claimed from GBGB9616412.4A external-priority patent/GB9616412D0/en
Priority claimed from GBGB9616407.4A external-priority patent/GB9616407D0/en
Priority claimed from GBGB9616409.0A external-priority patent/GB9616409D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0921798A1 publication Critical patent/EP0921798A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to a novel treatment and in particular to a method for the treatment and/or prophylaxis of leptin resistance and/or conditions associated with leptin resistance and/or complications thereof.
  • EP 0306228 discloses that the compounds per se of EP 0306228 are useful for the regulation of appetite and food intake in subjects suffering from disorders associated with under- eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.
  • the compound of example 30 of EP 0306228 is 5-(4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione (or 'BRL49653').
  • Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers WO93/21166 and WO94/01420. These compounds are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers WO92/03425 and WO91/19702.
  • insulin sensitisers examples include those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
  • PP AR ⁇ peroxisome proliferator-activated receptor
  • Kallen et al state that their results indicate that BRL49653 and other antidiabetic thiazolidinediones down-regulate leptin gene expression resulting in lowered plasma leptin concentrations. Kallen et al correlate this effect on leptin with the PPAR ⁇ agonist activity of these thiazolidinediones.
  • BRL 49653 has no effect upon leptin expression in the adipose tissue of the rats and, more importantly, that circulating plasma leptin concentrations are significantly lowered.
  • this reduction occurs in the absence of food intake and body weight gain leading to the proposal that BRL 49653 and hence other similar compounds must sensitise the target cell in its response to leptin. It follows therefore that BRL 49653 and similar compounds would enhance the anorexic and weight loss effects of leptin and agonists thereof and other agents that amplify cellular responses to leptin. This is considered to be of particular importance for the treatment of those individuals who are unable to respond fully to the leptin signal i.e.
  • the invention provides a method for the treatment and/or prophylaxis of leptin resistance and/or conditions associated with leptin resistance and/or complications thereof, in humans or non-human mammals, which method comprises the internal administration of an effective, non-toxic and pharmaceutically acceptable amount of a leptin sensitiser or a pharmaceutically acceptable derivative thereof.
  • the method comprises the use of a selective leptin sensitiser.
  • the leptin sensitiser is administered in combination with leptin and/or an analogue, such as an agonist, thereof.
  • the method comprises the co-administration of an effective, non-toxic and pharmaceutically acceptable amount of a leptin sensitiser and leptin and/or an analogue, such as an agonist, of leptin.
  • Leptin resistance gives rise to obesity and disordered control of food intake and energy expenditure.
  • Conditions and complications associated with leptin resistance include cardiovascular diseases especially athersclerosis, impaired glucose tolerance and non- insulin dependant diabetes.
  • the present invention provides a method for the treatment and/or prophylaxis of obesity in humans or non-human mammals, which method comprises the internal administration of an effective, non-toxic and pharmaceutically acceptable amount of a leptin sensitiser or a pharmaceutically acceptable derivative thereof.
  • the obesity is associated with or is caused by leptin resistance.
  • the method is also of particular benefit to patients suffering from the insulin resistant diabetes syndrome, including the pre-diabetic impaired glucose tolerance phase of the syndrome.
  • Prophylaxis is of particular benefit in the pre-diabetic, impaired glucose tolerance phase of the syndrome.
  • a suitable leptin sensitiser is an insulin sensitiser, including thiazolidinedione and acyclic insulin sensitisers.
  • a suitable leptin sensitiser is a PPAR ⁇ agonist.
  • Suitable PPAR ⁇ agonists include thiazolidinediones.
  • a particular leptin sensitiser is that which has both insulin sensitiser and PPAR ⁇ agonist activity.
  • a suitable thiazolidinedione is a thiazolidine-2,4-dione derivative, that is a compound comprising a moiety of formula (A):
  • Suitable compounds comprising a moiety of formula (a) include compounds of formula (I):
  • T represents an aryl or heterocyclyl group optionally substituted with one or more alkyl groups, aralkyl groups or heterocyclylalkyl groups, the said alkyl, aralkyl and heterocyclylalkyl groups themselves being optionally substituted.
  • the carbon atom marked with an asterisk (*) in formula (I) is a chiral carbon.
  • T represents a moiety selected from the list consisting of (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (Im), (In), (Io) and (Ip):
  • a ⁇ , A ⁇ , R! and n are as defined below and in relation to formula (I) of EP 0306228; or
  • L] and L 2 are the same or different and each represents hydrogen or lower alkyl or Li and L 2 are combined to form an alkylene group;
  • L 3 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 sulphur, or a group or the formula
  • R 13 and R l4 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 form the group consisting of nitrogen, oxygen or sulphur to form a 5- or 6- membered ring;
  • R 2 is a bond or a lower alkylene group or a pharmaceutically acceptable salt thereof (providing compounds as defined in EP8203); or
  • R ⁇ , R ⁇ are the same or different and each represents a hydrogen atom or a
  • R3 represents a hydrogen atom a C*. 6 aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a (C )-6 alkoxy)carbonyl group, or an aralkyloxycarbonyl group;
  • R4 and R ⁇ are the same or different and each represents a hydrogen atom, a Ct. 5 alkyl group or a C 1-5 alkoxy group, or R ⁇ and R ⁇ together represent C ) - alkylenedioxy group; n is 1 ,2 or 3 ;
  • R ⁇ , R ⁇ and R ⁇ are as defined in relation to formula (I) of EP 0032128; or
  • R is cycloalkyl of three to seven carbon atoms, naphthyl, thienyl, furyl, phenyl, or substituted phenyl wherein said substitutent is alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, trifluoromethyl, chloro or bis(trifluoromethyl;
  • R is alkyl of one to three carbon atoms
  • A is O or S; and B is N or CH;
  • R' is as defined in relation to formula (I) of EP 0489663;
  • Rl, R ⁇ , R3 and n are as defined in relation to formula (I) of EP 0155845; or
  • R! is C]_6 alkyl, especially ethyl, as defined in EP 0257781 ; or
  • a and B each independently CH or N, with the proviso that when A or B is N, the other is CH;
  • X is S, SO, SO 2 , CH 2 , CHOH or CO;
  • n is 0 or 1 ;
  • Y is CHR 20 or R 21 , with the proviso that when n is 1 and Y, is NR 21 , X j is SO 2 or CO;
  • R 19 , R 20 , R 2 ) and R 22 are each indendently hydrogen or methyl
  • X 2 and X 3 are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromo, chloro, or fluoro; or a pharmaceutically acceptable cationic salt thereof, or a pharmaceutically acceptable acid addition salt thereof where A or B is N, (providing compounds as defined in relation to formula (I) of EP 0332331); or
  • Y is CH or N;
  • Z is hydrogen, (C,. 7 )alkyl, (C 1 . 7 )cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, phenyl, mono- or disubstituted with the same or different groups which are(C ⁇ .
  • Z is hydrogen or (C ⁇ -3 )alkyl
  • R 17 and R 18 are each independently hydrogen or methyl; and n is 1,2 or 3; or a pharmaceutically acceptable cationic salt thereof, or a pharmaceutically acceptable acid addition salt thereof when the compound contains a basic nitrogen, (providing compounds as defined in relation to formula (I) of EP 0332332; and
  • T represents a moiety of the above defined formula (la), (Ic), (le),
  • T represents a moiety selected from the list consisting of (a), (b),(c),(d),(e),(f),(g),(h)and(i):
  • thiazolidinediones and /or PPAR ⁇ agonists disclosed in European Patent Applications, Publication Numbers:0008203, 0139421 , 0032128, 0428312, 0489663, 0155845, 0257781 , 0208420, 0177353, 0319189, 0332331, 0332332, 0528734 and 0508740, International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852. The contents of these publications are included herein by reference.
  • thiazolidinediones are those disclosed in EP 0306228 and WO94/05659.
  • the compounds of EP 0306228 and WO94/05659 particularly include the compounds of formula (II):
  • A represents a substituted or unsubstituted aromatic heterocyclyl group
  • 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
  • R2 and R ⁇ each represent hydrogen, or R ⁇ and R ⁇ together represent a bond
  • a ⁇ represents a benzene ring having in total up to five substituents
  • n represents an integer in the range of from 2 to 6; to a human or non-human mammal in need thereof.
  • Suitable values for A I when it represents a 5- membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
  • Suitable values for A I when it represents a 6- membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.
  • a ⁇ represents a moiety of formula (j), (k) or (1):
  • R6 and R? each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R ⁇ and R? are each attached to adjacent carbon atoms, then R ⁇ and R ⁇ together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R6 and R 7 together is substituted or unsubstituted; and in the moiety of formula (j) ⁇ l represents oxygen or sulphur.
  • a I represents a moiety of the above defined formula (j).
  • A represents a moiety of the above defined formula (k).
  • a I represents a moiety of the above defined formula (1).
  • a particular form of moiety (1) is a moiety (I 1 ):
  • R ⁇ and R 7 are as defined in relation to formula (1).
  • R ⁇ > and R 7 together represent a moiety of formula (m):
  • R ⁇ a and R ⁇ b each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R ⁇ a and R ⁇ each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R ⁇ a represents hydrogen.
  • R**b represents hydrogen.
  • R ⁇ a and R**b both represent hydrogen.
  • R ⁇ and R 7 each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R and R 7 each independently represent hydrogen, alkyl or phenyl.
  • R ⁇ and R 7 together represent the moiety of formula (m).
  • R 6 and R 7 both represent hydrogen.
  • the five substituents of A ⁇ include three optional substituents.
  • Suitable optional substituents for the moiety A ⁇ include halogen, substituted or unsubstituted alkyl or alkoxy.
  • a specific example of a compound of formula (II) is 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, including those salts disclosed in WO94/05659 and most especially a maleic acid salt thereof, and/or a pharmaceutically acceptable solvate thereof.
  • a compound of formula (I) may exist in one of several tautomeric forms, all of which are encompassed in the method of the present invention. It will be appreciated that the present invention encompasses the administration of all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.
  • thiazolidenediones are those disclosed in EPO 139421 and USP5478852, being of formula (I) as defined above wherein moiety T represents the above defined moiety (Ic), especially, (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H- 1 -benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(l-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazol
  • Patent Applications Publication Numbers: 0306228, 0008203, 0139421 , 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740, International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852 are those compounds defined as suitable, favoured and preferred in the respective patent publications.
  • the suitable, favoured and preferred acyclic insulin sensitisers disclosed in International Patent Applications, Publication Numbers WO91/19702, WO92/03425, W093/21 166 and WO94/01420 and United States Patent Number 52329452 are those compounds defined as suitable, favoured and preferred in the respective patent publications.
  • suitable, favoured and preferred insulin sensitisers are the suitable, favoured and preferred compounds disclosed in European Patent Application, Publication Number 0533933, International Patent Application, Publication Number WO 93/02079 , Japanese Patent Application Publication Number 05271204 and United States Patent Number 52644515 and 5478852.
  • Suitable pharmaceutically acceptable forms of leptin and/or an analogue, such as an agonist, thereof and/or agents which mimic or increases the pharmacological effect of leptin are as described in GB 2292382.
  • the disclosures of GB 2292382 are incorporated herein by reference.
  • the treatment of the invention does not include treatment of disorders associated with overeating, such as obesity caused by overeating and bulimia when such treatment includes the administration as the sole medicament of a compound of the above defined compound of formula (II), including 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
  • the term 'leptin sensitiser' relates to a substance which increases the pharmacological response of, for example, a target cell, to a given plasma concentration of leptin.
  • a 'selective leptin sensitiser' functions so as to be substantially free from certain effects, such as the reduction of plasma concentrations of leptin or the reduction in the expression or secretion of leptin, especially when these effects arise from action in adipose tissue.
  • 'leptin resistant' relates to the condition wherein an individual has a lower than normal pharmacological response to leptin, for example due to a decreased response of target cells to a given plasma concentration of leptin.
  • An 'analogue of leptin' includes an agonist thereof and the analogues disclosed in GB 2292382.
  • 'PPAR ⁇ agonist' relates to an agonist, such as a small molecular weight agonist, of the peroxisomal proliferator-activated receptor of the gamma subtype, this nuclear receptor is a member of the ligand activated transcription factor family that include the steroid, retinoid and thyroid receptors.
  • PPAR ⁇ agonist activity may be assessed by use of the methodology disclosed by Lehmann et al : Journal of Biological Chem., 270, 12953-12956 (1995).
  • 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • Suitable heterocyclyl groups are aromatic and non-aromatic heterocylic groups.
  • Suitable non-aromatic heterocylic groups include groups comprising single or fused ring heterocyclic groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen, optionally fused to one or more aryl groups.
  • Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • aromatic heterocyclyl groups comprise 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable substituents for the heterocyclyl include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two 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 two substituents may themselves be substituted or unsubstituted.
  • '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.
  • acyl' includes alkylcarbonyl groups.
  • Suitable alkyl groups are Cj-i 2 alkyl groups, especially C1 -6 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 pharmaceutically acceptable salts include salts of carboxy groups and acid addition salts.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate and a-glycerophosphate, especially the maleate salt.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • PPAR ⁇ agonists referred to herein are conveniently prepared according to the methods disclosed in the above mentioned patent publications in which they are disclosed:
  • a compound of formula (I), or the tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof may be prepared using the processes described in EP 0306228 and WO94/05659.
  • troglitazone may be prepared as described in EP0139421 or USP 5478852.
  • the salts and or solvates of the thiazolidinediones may be prepared and isolated according to conventional procedures for example those disclosed in the, above mentioned, patent publications.
  • the present invention also provides a leptin sensitiser or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of leptin resistance and/or conditions associated with leptin resistance and/or complications thereof.
  • the present invention also provides a leptin sensitiser or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of leptin resistance and/or conditions associated with leptin resistance and/or complications thereof.
  • the leptin sensitiser may be administered per ⁇ e or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the leptin sensitisers mentioned herein are formulated and administered in accordance with the methods disclosed in the above mentioned patent applications and patents.
  • the present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of obesity, which composition comprises a leptin sensitiser, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
  • medicament or also comprises an effective, non-toxic and pharmaceutically acceptable amount of leptin and/or an analogue, such as an agonist, thereof and/or an agent which mimics or increases the pharmacological effect of leptin.
  • an analogue such as an agonist, thereof and/or an agent which mimics or increases the pharmacological effect of leptin.
  • the term 'pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.
  • the composition will be formulated in unit dose form.
  • Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg, preferably 0.5 to 10 mg.
  • the active ingredient may be administered as a pharmaceutical composition herein before defined, and this forms a particular aspect of the present invention.
  • the active compound is be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg, generally about 0.5 to 10 mg. That is in the range of from 1.429 x 10" 3 to 85.714 mg/kg/day, more usually about 1.429 x 10" 2 to 21.429 mg/kg/day, generally about 7.143 x 10" 3 to 0.1429 mg/kg/day.
  • the invention provides a novel leptin sensitiser, in particular a leptin sensitiser which does not include any of the compounds disclosed in the abovementioned patents and patent applications, such as the specific examples thereof.
  • BRL 49653 The effects of the thiazolidinedione insulin sensitiser, BRL 49653, on plasma leptin concentrations and on epididymal fat ofonRNA expression were examined in high fat-fed and high carbohydrate-fed adult Wistar rats. Feeding rats a high fat diet is known to induce insulin resistance (Storlein et al 1991, Diabetes 40:280-289). Diets were given for 4 weeks, with BRL 49653 (lO ⁇ mol/kg/day) administered by an oral gavage for the last 4 days. Treatment with BRL 49653 reduced plasma leptin concentrations in high fat-fed rats from 2.34 ⁇ 0.19 to 1.42 ⁇ 0.09 ng/ml (pO.OOl).
  • Plasma leptin was unaffected by BRL 49653 in the high-carbohydrate fed rats. There was no difference in ob mRNA expression between high fat-fed and high carbohydrate-fed rats with or without treatment. BRL 49653 had no effect on body weight gain or food intake (Table 1). The observation that BRL 49653 reduces circulating leptin but has no effect on food intake and body weight gain in insulin resistant rats suggests that the compound enhances cellular responses to leptin
  • Table 1 Body weights and food intakes of rats fed HF or HC diet ⁇ treatment.
  • Table 2 Fasting plasma measurements of rats fed HF or HC diet ⁇ treatment.
  • Control BRL 49653 Control BRL 49653 leptin (ng/ml) 2.34 ⁇ 0.19 1.42 ⁇ 0.09 2.10 ⁇ 0.11 1.91 ⁇ 0.09
  • Rats were divided into two groups, one group were fed on a HF diet for 4 weeks and one group were fed on a high carbohydrate (HC) diet for 4 weeks.
  • the HF diet contained (by weight) 30.7% casein, 7.5% fibre, 7.2% polyunsaturated fat, 35.2% saturated fat and 10.4% corn starch.
  • the HC diet contained 21.2% casein, 3.3% fibre, 5.0 % polyunsaturated fat and 61.8% corn starch.
  • the metabolisable energy of the HF diet was 4440 Kcals/kg and for the HC diet was 3210 Kcals/kg.
  • the % metabolisable energies were 20% from protein, 12 % from carbohydrate and 68% from fat.
  • the corresponding values for the HC diet were 20% from protein, 68% from carbohydrate and 12% from fat.
  • the rats fed the HC diet were similarly divided into two groups. The rats continued to receive their respective diets during the four day treatment period. Body weight and food and water intakes were recorded. On the 5th day, rats were fasted for 6 hours starting at 08:00 and at 14:00 they were anaesthetised with sodium pentobarbitone. Blood was collected from the dorsal aorta, anticoagulated with EDTA and plasma was stored at - 20 °C for leptin determination. The rats were killed, the epididymal fat pads were removed, immediately freeze clamped and stored at -80 °C.
  • Leptin concentrations were measured by immunoassay using recombinant murine leptin as standard, (rabbit anti-leptin IgG was raised to recombinant murine leptin, biotinylated and detected by incubation with europium- streptavidin and subsequent fluorescence).
  • Total RNA extraction and northern analysis Total RNA was extracted (17) and the integrity of the RNA was checked on a 1.1 % agarose gel before northern analysis was performed. 20 ug total RNA was loaded on to a 1.1% denaturing formaldehyde gel and separated by electrophoresis at 150mA for 3 hours.
  • RNA was blotted by capillary transfer onto a positively charged nylon membrane overnight. After the transfer the RNA samples were fixed to the membrane by UV- crosslinking.
  • Probe labelling Digoxigenin-1 1-UTP was incorporated into cDNA for ob and b-actin via PCR. b-actin was used to normalise the RNA in each sample.
  • Hybridisation Prehybridisation was carried out for one hour at 42 °C in prehybridisation buffer (DIG Easy Hyb, Boehringer Mannheim). The cDNA probe was denatured by boiling for 5 minutes, cooled on ice then added to fresh hybridisation buffer (DIG Easy Hyb, Boehringer Mannheim).

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Abstract

L'invention concerne un procédé de traitement et/ou de prophylaxie contre la résistance à la leptine et/ou d'états associés à la résistance à la leptine, et/ou de complications affectant des mammifères humains ou non humains. Ce procédé consiste à administrer par voie interne une quantité efficace, non toxique et pharmaceutiquement acceptable d'un sensibilisant à la leptine ou d'un dérivé pharmaceutiquement acceptable de celle-ci.
EP97931945A 1996-07-12 1997-07-14 Nouveau traitement contre la resistance a la leptine Withdrawn EP0921798A1 (fr)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
GB9614740 1996-07-12
GB9614751 1996-07-12
GBGB9614740.0A GB9614740D0 (en) 1996-07-12 1996-07-12 Novel treatment
GBGB9614751.7A GB9614751D0 (en) 1996-07-12 1996-07-12 Novel treatment
GBGB9616412.4A GB9616412D0 (en) 1996-08-05 1996-08-05 Novel treatment
GB9616407 1996-08-05
GB9616409 1996-08-05
GBGB9616407.4A GB9616407D0 (en) 1996-08-05 1996-08-05 Novel treatment
GBGB9616409.0A GB9616409D0 (en) 1996-08-05 1996-08-05 Novel treatment
GB9616412 1996-08-05
PCT/GB1997/001928 WO1998002159A1 (fr) 1996-07-12 1997-07-14 Nouveau traitement contre la resistance a la leptine

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GB9711683D0 (en) * 1997-06-05 1997-08-06 Smithkline Beecham Plc Composition
AU2893199A (en) * 1998-03-03 1999-09-20 Board Of Regents, The University Of Texas System Fatty acid-induced beta-cell apoptosis
KR100610578B1 (ko) 1999-04-28 2006-08-09 닥터 레디스 레보러터리즈 리미티드 치환된 이원 헤테로고리, 비만증 및 고콜레스테롤증치료제로서의 그 용도
ES2248581T3 (es) 2001-03-12 2006-03-16 Intercept Pharmaceuticals, Inc. Esteroides como agonistas de fxr.
CN100577175C (zh) 2001-04-04 2010-01-06 奥索-麦克尼尔药品公司 包括葡萄糖重吸收抑制剂和ppar调节剂的联合疗法
US6987123B2 (en) 2001-07-26 2006-01-17 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US7618940B2 (en) * 2002-12-06 2009-11-17 Fibrogen, Inc. Fat regulation
ES2609395T5 (es) 2004-03-12 2021-08-06 Intercept Pharmaceuticals Inc Tratamiento de la fibrosis usando ligandos de Fxr
US10987362B2 (en) 2004-03-12 2021-04-27 Intercept Pharmaceuticals, Inc. Treatment of fibrosis using FXR ligands
ITMI20050912A1 (it) 2005-05-19 2006-11-20 Erregierre Spa Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici
CA2676417C (fr) 2007-01-19 2016-06-28 Intercept Pharmaceuticals, Inc. Modulateurs de tgr5 et leurs procedes d'utilisation
BRPI0916735B8 (pt) 2008-07-30 2021-05-25 Intercept Pharmaceuticals Inc compostos moduladores de tgr5, composições farmacêuticas compreendendo os mesmos e seus usos
EA030681B1 (ru) 2008-11-19 2018-09-28 Интерсепт Фармасьютикалз, Инк. Модуляторы tgr5 и способы их применения
US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
IN2014MN02561A (fr) 2012-06-19 2015-09-04 Intercept Pharmaceuticals Inc

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