CA2182986A1 - Use of insulin sensitisers for treating renal diseases - Google Patents
Use of insulin sensitisers for treating renal diseasesInfo
- Publication number
- CA2182986A1 CA2182986A1 CA002182986A CA2182986A CA2182986A1 CA 2182986 A1 CA2182986 A1 CA 2182986A1 CA 002182986 A CA002182986 A CA 002182986A CA 2182986 A CA2182986 A CA 2182986A CA 2182986 A1 CA2182986 A1 CA 2182986A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- insulin sensitiser
- group
- insulin
- substituted
- 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.)
- Abandoned
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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A method for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria which method comprises the administration of an effective, non-toxic amount of an insulin sensitiser to a human or non-human mammal in need thereof.
Description
0 WO 95/21608 2, ~2 ~ 8~ r~
Use of Insulin sensit~sers for treating renal dlseases This invention relates to a novel method for the treatment of renal diseases.
European Patent Arrlir~tinnc 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 Number 5104888, disclose certain l l; ,. ,l ;.lil-r. 1;. . ~ derivatives which are disclosed as having lly~o~;ly~à~ lic and lly~ln~ activity~ The ll,;~,.,li.l;.,. .1;,."1~ derivatives disclosed in these patent ~ are examples of a class of hypù~lyu~ lic agem generally referred to as 'insulin sensitisers' and hence thcse compounds are referred to herein as 't~ .i;nll~ insulin sensitisers'.
Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in I,.~
Patent ArFiic~tinnc 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 Number5232945andT.~t~ PatentArF~ tinr~c PublicationNumbers W092/03425 and WO91/19702.
Examples of other insulin sensilisers are those disclosed in European Patent Application. Publication Number 0533933, Japanese Patent Application Publication Number ()5271~04 and ~inited States Patent Number 5264451.
We have now discovered that compounds having insulin sensitiser activity can prevent llydlu...,l~lllu~ nd proteinuria, such as :31hllmin--tiR and that they are therefore of potential use in the treatment andlor IJlu~llrla~d~ of renal disease, especially renal disease associated with the uc~,lu~ of Type Il diabeus including diabetic l~ lllupallly, glu~ll.,~ulul~ , glomerular sclerosis, 30 nephrotic syndrome, hypertellsive n~,~,l,lu~h,.u~i~ and end stage renal disease.
The prophylactic action of an insulin sensitiser upon ~ lu~Jallly is also indicative that an insulin sensitising agent can be expected to prevent, reverse, stabilise or relard the l~lu~lu~siu,l of microalbuminuria to ~lhllminl~ri~ This is because micrn:llh~minllri~ is considered to be a predictor of furure ~ Jlllu~alll~, 35 especially in patients with clinical evidence of pre-diabetic insulin resistance WOg5/21608 2182~86 r~
syndrome, alternatively referred to as Syndrome X.
Accordingly, the present invention provides a method for the treatment and/or prophylaxis of renal diseases including diabetic n~l~u~!Jullly, ~;lu~ , glomerular sclerosis, nephrotic syndrome, l~
5 n~Jlllua~ uaia and end stage renal disease, and microalbuminuria which method comprises the ~ ,- of an effective, non-toxic amount of an insulin sensitiser to a human or non-human mammal in need thereof.
Particular insulin sensitisers include rhi~37nli~1in~ n~. insulin sensitisers.
Particular insulin sensitisers include acyclic insulin sensitisers~
One favoured group of insulin sensitisers are the ~ ;.. f.1;.. insulin sensitisers disclosed in EP 0306228 and W094/05659. Thus in a favoured aspect the present invention provides a method for the treatment and/or ~JIu~llyla~da of renal diseases including diabetic ~ lllu~àllly, ~;lul~ , glomerular sclerosis, nephrotic syndrome, hypertensive l~ lua~ ,.ua;S and end stage renal disease, and microalb-lminuna which method comprises the a~ .,.ti~,~ of an effective non-toxic amo~lnt of a compound of fommula (1):
R' R2 R3 A--N--(CH2)n--o~3CH C~
S~NH
(I) or a tautomeric form thereof and/or a pllal 1 ~ lly acceptable salt thereof, and/or a ~llal . ,~ lly acceptable solvate thereof, wherein:
Al represents a substituted or ~ ;1 aromatic h~,t~,~uu~y~,lyl group;
Rl represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group,25 wherein the aryl moiety may be substituted or ,~ .1 or a substituted or rl1 aryl group;
R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond;
A2 represents a benzene ring having in total up to five ,, .l.~, il l.. . ,1~, and n represents an integer in the range of from 2 to 6; to a human or non-human0 mammal in need thereof
Use of Insulin sensit~sers for treating renal dlseases This invention relates to a novel method for the treatment of renal diseases.
European Patent Arrlir~tinnc 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 Number 5104888, disclose certain l l; ,. ,l ;.lil-r. 1;. . ~ derivatives which are disclosed as having lly~o~;ly~à~ lic and lly~ln~ activity~ The ll,;~,.,li.l;.,. .1;,."1~ derivatives disclosed in these patent ~ are examples of a class of hypù~lyu~ lic agem generally referred to as 'insulin sensitisers' and hence thcse compounds are referred to herein as 't~ .i;nll~ insulin sensitisers'.
Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in I,.~
Patent ArFiic~tinnc 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 Number5232945andT.~t~ PatentArF~ tinr~c PublicationNumbers W092/03425 and WO91/19702.
Examples of other insulin sensilisers are those disclosed in European Patent Application. Publication Number 0533933, Japanese Patent Application Publication Number ()5271~04 and ~inited States Patent Number 5264451.
We have now discovered that compounds having insulin sensitiser activity can prevent llydlu...,l~lllu~ nd proteinuria, such as :31hllmin--tiR and that they are therefore of potential use in the treatment andlor IJlu~llrla~d~ of renal disease, especially renal disease associated with the uc~,lu~ of Type Il diabeus including diabetic l~ lllupallly, glu~ll.,~ulul~ , glomerular sclerosis, 30 nephrotic syndrome, hypertellsive n~,~,l,lu~h,.u~i~ and end stage renal disease.
The prophylactic action of an insulin sensitiser upon ~ lu~Jallly is also indicative that an insulin sensitising agent can be expected to prevent, reverse, stabilise or relard the l~lu~lu~siu,l of microalbuminuria to ~lhllminl~ri~ This is because micrn:llh~minllri~ is considered to be a predictor of furure ~ Jlllu~alll~, 35 especially in patients with clinical evidence of pre-diabetic insulin resistance WOg5/21608 2182~86 r~
syndrome, alternatively referred to as Syndrome X.
Accordingly, the present invention provides a method for the treatment and/or prophylaxis of renal diseases including diabetic n~l~u~!Jullly, ~;lu~ , glomerular sclerosis, nephrotic syndrome, l~
5 n~Jlllua~ uaia and end stage renal disease, and microalbuminuria which method comprises the ~ ,- of an effective, non-toxic amount of an insulin sensitiser to a human or non-human mammal in need thereof.
Particular insulin sensitisers include rhi~37nli~1in~ n~. insulin sensitisers.
Particular insulin sensitisers include acyclic insulin sensitisers~
One favoured group of insulin sensitisers are the ~ ;.. f.1;.. insulin sensitisers disclosed in EP 0306228 and W094/05659. Thus in a favoured aspect the present invention provides a method for the treatment and/or ~JIu~llyla~da of renal diseases including diabetic ~ lllu~àllly, ~;lul~ , glomerular sclerosis, nephrotic syndrome, hypertensive l~ lua~ ,.ua;S and end stage renal disease, and microalb-lminuna which method comprises the a~ .,.ti~,~ of an effective non-toxic amo~lnt of a compound of fommula (1):
R' R2 R3 A--N--(CH2)n--o~3CH C~
S~NH
(I) or a tautomeric form thereof and/or a pllal 1 ~ lly acceptable salt thereof, and/or a ~llal . ,~ lly acceptable solvate thereof, wherein:
Al represents a substituted or ~ ;1 aromatic h~,t~,~uu~y~,lyl group;
Rl represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group,25 wherein the aryl moiety may be substituted or ,~ .1 or a substituted or rl1 aryl group;
R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond;
A2 represents a benzene ring having in total up to five ,, .l.~, il l.. . ,1~, and n represents an integer in the range of from 2 to 6; to a human or non-human0 mammal in need thereof
-2-O WO95121608 21 82986 ~ .'C~
Suitable aromatic heterocyclyl groups of the c~ .u~ fl~ of formula (I) include substituted or llncllhsritlllf-fl single or fused ring aromatic l~ u~,y~,lyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
S Favoured aromatic llf,l~,.ul,y~,lyl groups of the ~,u~ Juullda of formula (I) include substituted or ,."~ d single ring aromatic l.ci~,lu~,y~,lyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.
In particular, the aromatic ll~t~,~ul,yl,lyl groups of the cnmrf~n~lc of formula (I) comprise 1, 2 or 3 Il~ u...vllla, especially l or 2, selected from 10 oxygen, sulphur or nitrogen.
Suitable values for Al when it represents a 5- membercd aromatic heterocyclyl grollp include thiazolyl and oxazolyl, especially oxazolyl.
Suitable val~les for A l when it represents a 6- membered aromatic lu~y~lyl group include pyridyl or pyrimidinyl, especially pyridyl.
Preferably, Al represents a moiety of formula (a), (b) or (c):
R7XXl R7~ R~
(a) (b) (c) wherein:
R6 and R7 each i".l. ~.~.,.l....ly represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or ~ .1 aryl group or when R6 and R7 are each attached to adjacent carbon atoms, then R6 and R7 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom Clll~;li by R6 alld R7 together is substituted or ,."~.,l,~,il"~, .l and in the moiety of formula (a) Xl represents oxygen or sulphur.
Aptly, A I represents a moiety of the abovedefined formula (a).
Aptly, Al represents a moiety of the abu. ~ formula (b).
Aptly, A l represents a moiety of the ~bu~cl~,r~ ,l formula (c).
A particular form of moiety (c) is a moiety (c'):
Suitable aromatic heterocyclyl groups of the c~ .u~ fl~ of formula (I) include substituted or llncllhsritlllf-fl single or fused ring aromatic l~ u~,y~,lyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
S Favoured aromatic llf,l~,.ul,y~,lyl groups of the ~,u~ Juullda of formula (I) include substituted or ,."~ d single ring aromatic l.ci~,lu~,y~,lyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.
In particular, the aromatic ll~t~,~ul,yl,lyl groups of the cnmrf~n~lc of formula (I) comprise 1, 2 or 3 Il~ u...vllla, especially l or 2, selected from 10 oxygen, sulphur or nitrogen.
Suitable values for Al when it represents a 5- membercd aromatic heterocyclyl grollp include thiazolyl and oxazolyl, especially oxazolyl.
Suitable val~les for A l when it represents a 6- membered aromatic lu~y~lyl group include pyridyl or pyrimidinyl, especially pyridyl.
Preferably, Al represents a moiety of formula (a), (b) or (c):
R7XXl R7~ R~
(a) (b) (c) wherein:
R6 and R7 each i".l. ~.~.,.l....ly represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or ~ .1 aryl group or when R6 and R7 are each attached to adjacent carbon atoms, then R6 and R7 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom Clll~;li by R6 alld R7 together is substituted or ,."~.,l,~,il"~, .l and in the moiety of formula (a) Xl represents oxygen or sulphur.
Aptly, A I represents a moiety of the abovedefined formula (a).
Aptly, Al represents a moiety of the abu. ~ formula (b).
Aptly, A l represents a moiety of the ~bu~cl~,r~ ,l formula (c).
A particular form of moiety (c) is a moiety (c'):
-3-WO gS/2 1608 ~ 1 ~ 2 9 8 ~ P~ l ,~, ~"11 7 N ~\
(c') wherein R6 and R7 are as defined in relation to formula (c).
In one favoured aspect R6 and R7 together represent a moiety of formula (d):
R6b~
(d) wherein R8a and R8b each i "~ ,. . ,. If " 1 Iy represent hydrogen, halogen, substituted or ~ d alkyl or alkoxy.
Suitably, R8a and R8b each i,~ y represent hydrogen, halogen, alkyl or alkoxy. Favourably, R8a represents hydrogen. Favourably, R8b 15 represents hydrogen. Preferably, R8a and R8b both represent hydrogen.
In a funher favoured aspect R6 and R7 each i..,l. l~ ...1f .~lly represent hydrogen, alkyl or a substituted or .~ d phenyl group and more favourably, R6 and R7 each i..~ l. .Illy represent hydrogen, alkyl or phenyl.
Preferably, for the moiety of formula (a), R6 and R7 together represent 20 the moiety of formula (d).
Preferably, for the moieties of formula (b), (c) or (c'), R6 and R7 both repre~sent hydrogen.
It will be ~ppreciated Ihat the five ~.. l~lil.. ~, of A2 include three optional Suitable optional ~ l~l;l, ..l~ for the moiety A2 include halogen, 25 substituted or ~ l alkyl or alkoxy.
Further suit:~ble, favoured and preferred values for variables A2, R l, R2, R3and n are as defined in EP 0306228 and W094/05659.
A preferred compound of formula (I) is 5-[4-[2-(N-methyl-N-(2-pyndyl)amino)ethoxylbenzyl]~h~ in~-2~4-dione or a tautomeric form thereof
(c') wherein R6 and R7 are as defined in relation to formula (c).
In one favoured aspect R6 and R7 together represent a moiety of formula (d):
R6b~
(d) wherein R8a and R8b each i "~ ,. . ,. If " 1 Iy represent hydrogen, halogen, substituted or ~ d alkyl or alkoxy.
Suitably, R8a and R8b each i,~ y represent hydrogen, halogen, alkyl or alkoxy. Favourably, R8a represents hydrogen. Favourably, R8b 15 represents hydrogen. Preferably, R8a and R8b both represent hydrogen.
In a funher favoured aspect R6 and R7 each i..,l. l~ ...1f .~lly represent hydrogen, alkyl or a substituted or .~ d phenyl group and more favourably, R6 and R7 each i..~ l. .Illy represent hydrogen, alkyl or phenyl.
Preferably, for the moiety of formula (a), R6 and R7 together represent 20 the moiety of formula (d).
Preferably, for the moieties of formula (b), (c) or (c'), R6 and R7 both repre~sent hydrogen.
It will be ~ppreciated Ihat the five ~.. l~lil.. ~, of A2 include three optional Suitable optional ~ l~l;l, ..l~ for the moiety A2 include halogen, 25 substituted or ~ l alkyl or alkoxy.
Further suit:~ble, favoured and preferred values for variables A2, R l, R2, R3and n are as defined in EP 0306228 and W094/05659.
A preferred compound of formula (I) is 5-[4-[2-(N-methyl-N-(2-pyndyl)amino)ethoxylbenzyl]~h~ in~-2~4-dione or a tautomeric form thereof
-4-.
O WO95121608 2 1 82986 r~~ 41l and/0 a plldl Illdc~uLi~dlly acceptable salt thereof, especially a maleic acid salt thereof, and/or a l.l, .. Il~A. ~ .lli: ~lly acceptable solvate thereof.
As indicated above, a compound of formula (I) may exist in one of several tautomeric fomms, all of which are ,"~ in the method of the present
O WO95121608 2 1 82986 r~~ 41l and/0 a plldl Illdc~uLi~dlly acceptable salt thereof, especially a maleic acid salt thereof, and/or a l.l, .. Il~A. ~ .lli: ~lly acceptable solvate thereof.
As indicated above, a compound of formula (I) may exist in one of several tautomeric fomms, all of which are ,"~ in the method of the present
5 invention. Tt will be appreciated that the present invention f~ the A~llll;..;~ll~l;Ull of all of the isomeric forms of the culll~uullda of formula (I) and the ~ ", ~ lly acceptable salts thereof, including any ~;...cui~ul~ iC forms thereof, whether as individual isomers or as mixtures of isomers.
Suitable ~ for any heterocyclyl group of the ..., . ,l,u~ of 10 formula (I) include up to 4 ~,.l,~/;ll . ,. ~ selected from the group consisting of:
alkyl, alkoxy, aryl and halogen or any two ~1.l.~1;1.l, .11~ on adjacent carbon atoms, together with the c~rbon atoms to which they are attached, may form an aryl group, preferably a benzene rillg7 ~nd wherein the carbon atoms of the aryl group represented by the s;~id two ~ ;l,.f,..~ may themselves be substituted or 15 ""~l.~.;l,.:~.,~
The suitable, faYoured and preferred I~ f-. insulin sensitisers disclosed in European Patent Applications, Publication Numbers: 0306228, 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; T.~ ~I Patent Application, Publication Numbers 92/18501, g3/02079, 93/22445 and United States Patel~t Number 51()4888 ;~re those uu~ fJulld~ defined as suitable, favoured and preferred in the respective patent p~lhli~-Atif~n~
The suitable, favoured and preferred acyclic insulin sensitisers disclosed in l~ .".Al;~ "Al Patent ~rplirAtion~ Publication Numbers WO91/19702, W092/03425, W093/21166 and WO94/01420 and United States Patent Number 5232945 are those cnmrol-nfl~ defined as suitable, favoured and preferred in therespective patent pllhlirAtir,nc Other suitable, favoured and preferred insulin sensitisers are the suitable, favoured and preferred compounds disclosed in European Patent Application, Publication NLlmber ()533933, lntf rrAtir~nAl Patent Application, Publication Number WO 93/02079, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
Also specifically included in the method of the invention are the specific examples disclosed in the above mentioned patent Alll~
When used herein the temm 'insulin sensitiser' relates to ~,u~ uu~ld~ which WO95/21608 2~ ~q86 P~ [;11 0 increase the biological response to insulin. In addition, based upon the observed effeets in appropriate test animals such as Zucker fatty (fa/fa) rats, insulin sensitisers are indicated to lower elevated fasting plasma insulin c., ..., and improve glycaemic control.
When used herein the term '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, alku,.y~,dll,u..yl, alk~"~y-,dll,u,lylàlkyl, alkyl~albu~yloxy, or alkylearbonyl groups.
When used herein the term 'halogen' refers to fluorine, chlorine, bromine 10 and iodine; preferably ehlorine.
When used herein the terms 'alkyl' and 'alkoxy' relate to groups having straight or branehed carbon ch.qin~,rc ntqining up to 12 carbon atoms.
When used herein the term 'acyl' includes alkylca.~u"yl groups.
Suitable alkyl groups are C1-12 alkyl groups, especially C1-6 alkyl groups 15 e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
Suitable ~llh~titl~l~nt~ for any alkyl group include those indieated above in relation to the term "aryl".
Suitable plla~ dc~ h,dlly aeeeptable salts inelude salts of earboxy groups and aeid addition salts.
Suitable l,l,A""~. {...... ~ y acceptable salts of carboxy groups include metal salts, s~lch as for example aluminium, alkali metal salts such as lithium,sodium or potassium, alkaline canh metal salts such as calcium or II~
and ammr)nil.m or substituted ammonium salts, for example those with lower alkylamines such as L- h,Lllyldlllill~;, hydroxy alkylamines such as 2-hydroxyethylamille, bis-(2-hydroxyethyl)-amine or tri-(2-llydlw-y~,ll,yl)-amine, eyeloalkylamines such as bicyclohexylamine, or with procaine, dib~ yl~ ,idi~e, N-benzyl-b-~ .,.,Ll.yld,~ , dcllydlual,;~iylalll;lle, N,N'-bisdehydroabietylamine, glucamine, N-methylglueamine or bases of the pyridine type such as pyridine, collidine, q~inine or quinoline.
Suitable acid :Lddition salts include IJIldl 11~ - . . .1;. AIIY aeeeptable inorganie salts sueh as the sulphate, nitrate, phosphate, borate, hydroehloride and l~yd~ul:lu~ide and rhA lllA- ~ ,.lly aeceptable organic acid addition salts sueh as aeetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto gllltarate and a-~ly~ ,l"~ , especially the maleate salt.
Suitable ~llalllld~cLlLi~ally accept ble solvates include hydrates.
O WO95/21608 ~182986 I "~l ~r~s~l The active compoLlnds disclosed in ~he above mentioned patent ~,u1,1i. ,.li~."c and referred to herein as insulin sensitisers, including the specific examples disclosed therein, are uu~ lly prepared according to the methods disclosed in the said patent ~ Thus a compound of formula (1), or the 5 tautomeric form thereof, and/or a ~ lly acceptable salt thereof, and/or a pllal l l l - c, ~ lly rLcceptable solvate thereof, may be prepared using the processes described in EP 0306228 and W094/05659.
The salts and/or solvates of the compounds of formula (I) may be prepared and isolated according to conventionai procedures for example sodium 10 salts may be prepared by using sodium methoxide in methanol.
The present invention also provides an insulin s~nCitic~r~s~ r~h as a compound of formula (1), or LL tautomeric form thereof ând/or a ~Jlla llla~ i"ally acceptable Sâlt thereot and/or a plla~ lly Llcceptable solvate thereof, for use in the tre Ltment of and/or prophyl~Lxis of renal diseases including diabetic 15 I~ u~ua~ , glomerulonephrilis, glomerLllar sclerosis, nephrotic syndrome, hypertensive "~ Iuscl~lu~i~ and elld stage renal disease, and microalbuminuria.
The present invention also provides Ln insulin c~nci~ic~r,cll~h as a compound of formula (1), or a tautomeric form thereof and/or a ~ y acceptable salt thereof and/or a 1.l, - 111~ y acceptable solvate thereof, for 20 use in the, lldllL~rnu~ of a 1 1-.. I i~ ..., ... I for the treatment and/or ~JIU~)Il,ylll~i~ of renal diseâses including diabetic ncpllluuall~y~ ~lu~ ulul~ lilis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalb~lminuri;l.
In the above mentioned rre~tment and or prophylaxis the insulin sensitiscr 25 such as a compound of formula (1), or a tautomeric form thereof andlor a IJllal Illa~ uli~ally acceptable salt thereof and/or a plla~ Ally acceptable solvate thereof, may be à~ -i"i~ d ~ se or, preferably, as a ~
also comprising a 1,l, ~ ",~. ~..li. .lly acceptable carrier.
Accordingly, the present invention also provides a 1,l - ".~
30 composition for the tre.ltment and/or prophylaxis of renal diseases includingdiai~etic l~C~ u~.lLlly, glomerulonephriti~, glomerular sclerosis, nephrotic syndrome, hypertensive Ll~JI,Iu.ul~.usi~ and end stage renal disease, and microalbuminuria which r..mrr.citiCm comprises an insulin sensitiser, such as a compound of the formula (1), or a tautomeric form thereof, or a r~ IY
35 a~ eptable salt thereof, or a ~i,a, " ~ lly acceptable solvate thereof, and a WO95121608 7 i 8~8~ P~ l 11 0 ,I,Au " IA. . . I l ir :ll Iy acceptable carrier therefor.
As used herein the term ~rh.1""- ~ 11y acceptable' embraces compounds, .,. ,1 l .ll..~; l i....~ and ingredients for both human and veterinary use: for example the term ~ iy acceptable salt' embraces a ~,t~ lruily 5 acceptable salt.
The rnmrncitinn may, if desired, be in the form of a pack a~ i by written or printed insttuctions for use.
Usually the pl,~ d~,culicdl comrn. ci~ir~.nc of the present invention will be adapted fororal Alll,.;";~l,Alin,~, although cnmrocitinnc forArl".;.,;~ ;.,., by10 other routes, such as by injection and l~ CU~ JU:I absorption are also envisaged.
Particularly suitable C~,lll,.,u .;liulls for oral Alll~ I are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
In accordance wilh conventional ~ ..1 ,lld~,~,ulical practice the carrier may 15 comprise ~I diluent, filler, di~ C~ , wetting agent, lubricant, colourant, flavourant or other conventional adjuvant Typical carriers include, for example, ~ y~ line cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyv;~yl~oly~,y..~lidone~
IllAg,.l. 7;11~11 stearate. sodium lauryl sulphate or sucrose.
Most suitably the cnmro~irinn 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 ~Isually 0 1 to 500 mg, and more especially 0.1 to 250mg.
Conveniently, Ihe active ingredient may be a II..illi~ cd as a 25 I/Il~ 1 rnn1rnCitinn hereinbefore defined, and this forms a particular aspect of the present invention.
In the above mentioned treatments an insulin sensitiser, such as a compound of the formula (1), or a tautomeric form thereof and/or a Au ~ y acceptable salt thereof and/or a rl ~ y acceptable solvate thereof, may be raken in doses, such as those described above, one to six times a day in a ml~nner sLlch th:lt the total daily dose for a 70 kg adult willgenerally be in the r.lnge of froin 0.1 to 6000 mg, and more usually about I to 1500 mg, generally about 0.5 to 10 mg. That is in the range of from 1.429 x 10~3to 85.714 mg/k,/day, more usually about 1.429 x lo-2 îo 21.429 mglkg/day, generally about 7 143 x 10-3 to 0 1429 mg/kg/day ~I WO95/21608 2 ~ 82986 P.,~ .l tll The following Examples illust~ale the invention but do not limit it in any way.
WO95121608 2;3 8~ r~l~ 5 ~
Example 1: Studies Into Tlle Effects Of Tl~e Test Compound Upon Renal Patholo~y Obese Zucker rals are known to develop chronic ~ U~JGLIly in addition to lly~ ;d, hyperin~ nq~miq and peripheral insulin resistance (Kasiske e~ al 1985).
5-[4-[2-(N-methyl-N-(2-pyridyl)aminoh,lllu,,y]~ yl]~ -2~4-dione (herein after referred to as 'test compound') was adl~ ;aL~lcd to 2-3 month old obese Zucker fa/fa rats by dietary ~ to proYide a daily dose over 1 û a period of 3 months rr nging from 2.0 - 7.0 ~Lmole/kg body weight. A group of age-matched obese Zucker fa/fa rats were given the same diet without the addition of the test compound, as WL~S L~ group of lean Fa/? rats. At the end of t~3e study, all of the control Zucker fa/fa rats had chronic r..,~lllulJaLlly which involved dilated tubules, atrophied or hyperplastic tubular epithelial cells, thickened tubular basement ~ lblall~s, segmented glomeruli or global ~IUIII.,I ulual,L,Iu~In the cullca~ dil~g leL3n rnimals, 3/15 animals, a minimal degree of chronic llc~311lu~,all,y was seen.
Treatment with test compound resulted in a reduction in the incidence and degree of chronic 13C~IIIU~LnIIY compL~red to the control group of Zucker fa/fa rats.
In the kidneys of the control Zucker fa/fa rats, mild-moderdte ll~dlull~,i)lllusis was seen in 4/9 animals. Cll~u~u~ ;al;.,dlly this involved dilation of the kidney pelvis. Islo llydlul~clullluaia was seen in the rats treated with test compound.
~ WO 95/21608 2 1 8 2 9 8 6 r~ . 3. . ~ ~I
TABLE OF SlGNrFlCANT HISTOPATHOLOGICAL
FINDINGS IN THE KIDNEY OF FAI'I`Y ZUCKER RATS
Group/Tre~tment Hydronephrosis Chronic Nephropathy Animal Number Group 1 Test Compound in diet 1~ 0 ++
17 0 +
21 0 +
24 0 +
Group Z
Diet only 3 ++ +
5 +++ +
13 0 +
1 4 ++ ++
18 0 +
23 +++ ++
26 0 +
29 0 +
0 ++
, 5 Severity Key 0 None see~
W095/21608 = 21 329~6 P~
Minim~l + Mild ++ Moder~te +++ M~rked 21 ~2986 WO 95/21608 r~
Example 2: Studies Into Tlle Effect Of Test C~ Upon Systolic Blood Pressure, Urinnry Totnl Protein And Urinary N-Acetyl n-D-(" ' ' (NAG~ ActiYity l\q~.,~...
5 A second study was performed in Zucker rats over a period of 9 months to investigate the l~nvirll~in~1 effects of the drug on systolic blood pressure andvarious indices of renal function, two of which are . Al-l I ~ ;r~ here. In one arm of the study, the drug was given in the diet (~0 ,umole/kg of diet) from aged 6-7weeks in Zucker fatty (fa/fa) rats, whilst in a second artn of the study, drug 10 treatment as above was delayed unti~ proteinuria had become established after 4 months, indicative of structural damage .llready present in the kidneys. A thirdgroup of Zucker fatty rats and a further group of lean rats were given diet alone throughout the period of study.
15 After dosing with the test con1pound, at monthly intervals l~I~,a.~UlCIII~ l were made of systolic blood pressure, urinary total protein and urinary N-acetyl 3-D-~,I",.,~.";"i~ (NAG) activity.
Me~su, ~ of S~ tolic Blood Pre.~sure 20 Rats were enclosed in custom-built restrainers and placed on a shelf in a warming cabinet, whose LC~ IUIC was controlled at a~ 'y 30~C. An inflatable cuff with integral plllse sensor WQS attached to the tail of each rat. After warrning for 20-30 min the tail cuff was inflated and deflated A~ . "~ y and a Ill~.a:~Ull..~ lL of systolic blood pressure made using an IITC Non-Invasive Blood 25 Pressure Monitor. This cycle w~s repeated sever~l times for each rat until stable values of blood pressure were obtained.
Meus~ of Urinar~ Paramerers Twenty-four hour urine collections, made in m~r~h~ nn cages, were aliquoted 30 and frozen at -70"C until re4~1ired for assay.
(i) Urinary Protein Urinary protein c., ~, l,..li."~ was measured using the Bio-Rad protein assay nsmodified for use in a 96-well microtitre plate. The assay is a dye-binding assay35 based on the differential colour change of ~ dye in response IO various WO95121608 218~986 r~ V
~1~ .. ~ .1 l 1.1 l 1. .1~C of pro~ein (Bradford, Anal. Biochem.,72, ~48, 1976). After a period of incubation with Dye Re~gent, diluted urine samples are read at an optical density of 595 nm using a Molecular Devices multiplate reader.
5 (ii) Urinar~v NAG Aclivir~
NAG activity was assayed using a reagent kit on a Hitachi 717 analyser (both suppied by Boehringer Mannheim UK, Lewes). Enzyme activity was measured by monitoring the rate of chlorophenol (570 nm) released from the substrate chlorophenol red-~-D-pl.,. .,~ -..1:.,..l..
J;~esults al~d Statistics In the tables below, les~llts ~re given as mean values for the group + the standard error of the mean. Res-~lts have been analysed by one way ANOVA and significant differences from the Zucker fatty rat control group have been 15indicated by an asterisk.
Conclusion The results of Example ~ ,J.. ~ .. that treatment of Zucker fatty (falfa) rats from the age of 6-7 weeks, for a period of 9 months, with BRL 49653 given via 20 the diet, prevented Ihe development of hypertension and markedly reduced boththe elevation of urinar)~ NAG activity ;md the rate of dcvclvl.. ,~,l of proteinuria.
When drug treatment was - .,. , .~ ,.( cd after proteinuria had become ~-c~llhli~
both systolic blood pressure and urinary NAG activity were prevented from risingfurther and again there was a marked reduction of the rate of increase in the 25 urinary protein ~,ullC~ aliOll.
21 ~2986 WO 95/21608 r~,l/~ 3!1~ 11 Effects of starting treatment with Test Compound prior to the dc~,_lop",~,~l of renal c~ r~ S-SYSTOLIC BLOOD PRESSURE (mm Hg) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 umol/kg of diet) (powdered chow) (powdered chow) 0102i3 106i3 123i3-110i3- 120i4 128i3 2122i4- 137i4 132i4 3122i4- 142i6 134i3 4126i6' 146i4 132i4-5131 i4- 157i6 138i4-6128i3' 150i6 133i2-7125i6' 157i6 128i6' 8133$5' 155i4 130i3-g143i4' 164+4 136i3' 10ffects of starting treatment with Test Compound prior to the d~ J~lopl"a"l of renal ~ -s URINARY PROTEIN CONCENTRATION (llg/hour) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 umollko of diet) (powdered chow) (powdered chow) 0226i15' 287i17 198i19' 373 i 22 355 i 1 8 321 i 23' 2402 i 22 ' 509 i 28 396 i 20' 3221 i 32 ' 874 i 102 393 i 25' 4376 i 54 ' 3965 i 731 613 i æ~
51573 i 105 5823 i 809 1395 i 88' 61585 i 147 8946 i 1171 1192 i 92' 72124 i 293 12052 i 1535 1176 i 96-82664 i 370` 14534 i 1540 1409 i 9Z' 93152 i 515- 16182 i 1581 1373 i 113-WO 9~/21608 2 1 8 2 '~ d P~
Effects of starting ~ "~:,)l with Test Compound prior to the d~J~l~pl"~n~ of renal complications.
URINAFIY N-ACETYL-B- D-GLUCOSAMINIDASE ACTIVITY
(mU/hour) Treatment Duration Zucker ~atty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 pmol/k~ of diet) (powdered chow) (powdered chow) 05.7iO.4 5.9iO.3 4.4iO.3' 7.5 $ 0.7 9.1 i O.8 5.1 i O.5-23.8i1.1' 8.2i1.5 6.5iO.3 34.5iO9 8.2i1.0 5.2iO.4' 45.1 i 1.2 ' 9.3 i 0.5 6.9 i 0.5-565iO.7` 10.7iO.4 7.6iO.7-66.5i1.1- 10.8i1.7 7.4iO.5 78.9 i 0.8' 11.7 i 0.7 7.1 i 0.5-86.2 i 1.2- 11.8 i 1.3 7.4 i 0.5-99.1 i 1.2- 13.4 i 0.8 7.7 i 0.6-Effects of starting l,~al",e"l with Test Compound once renal co"" s~ ticns have become e~ ',ed.
SYSTOLIC BLOOD PRESSURE (mm Hg) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Controi Control (50 IJmol/ks oi diet) (powdered chow) (powdered chow) -4106i3 106i3 123i3--3123i5 120i4 128i3 -2138~7 137i4 132i4 -1141 i6 142i6 134i3 0146i4 146i4 132i4-140i5 157i6 138i4-2134i3 150i6 133i2-3144i3` 157i6 128i6-4139i3' 155i4 130i3' 5146i6' 164i4 136i3' 2~ 829 Wo 95/21608 8 6 r~
Effects of starting l~ l,--e,ll with Test Compound once renal complications have become e_ ' )ecl.
URINARY PROTEIN CONCENTRATION (~g/hour) Trea;ment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 umol/kg of diet) (powdered chow) (powdered chow) 4220 i 13 287 i 17 198 i 19--3347 i 32 355 i 18 321 i 23' -2457 i 21 509 i 28 396 i 21--1958 i 194 874 i 102 393 i 25' 03520 i 905 3965 i 731 613 i 52' 3692 i 386 5823 i 809 1395 i 88-Z5326i967 8946i1171 1192i92' 36230 i 835' 12052 i 1535 1178 i 96' 45379 i 708- 14534 i 1540 1409 i 92' 57677 i 825' 16182 + 1581 1373 ~ 113' Effects of starting l-~al."~"l with Test Compound once renal cu",plicalions have become s ,ed.
URINARY N-ACETYL-B-D-GLUCOSAMINIDASE ACTIVITY
(mU/hour) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (5û umollkg of diet) (powdered chow) (powdered chow) -45.4 i 0.2 5.9 i 0.3 4.4 i 0.3' -38.3 i 0.5 9.1 i 0.8 5.1 i 0.5' -29.5i1.1 8.2i1.5 6.5iO.3 -17.8 i 0.6 8.2 i 1.0 5.2 i 0.4' 07.6iO.7 9.3iO.5 6.9iO.5' 7.6iO.7 10.7iO.4 7.6io.r 25.7iO.9 10.8i1.7 7.4iO.5 37.4iO.9' 11.7iO.7 7.1 iO.5' 45.4 i 1.0' 11.8 i 1.3 7.4 i 0.5' 58.0i1.1' 13.4iO.8 7.7iO.6'
Suitable ~ for any heterocyclyl group of the ..., . ,l,u~ of 10 formula (I) include up to 4 ~,.l,~/;ll . ,. ~ selected from the group consisting of:
alkyl, alkoxy, aryl and halogen or any two ~1.l.~1;1.l, .11~ on adjacent carbon atoms, together with the c~rbon atoms to which they are attached, may form an aryl group, preferably a benzene rillg7 ~nd wherein the carbon atoms of the aryl group represented by the s;~id two ~ ;l,.f,..~ may themselves be substituted or 15 ""~l.~.;l,.:~.,~
The suitable, faYoured and preferred I~ f-. insulin sensitisers disclosed in European Patent Applications, Publication Numbers: 0306228, 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; T.~ ~I Patent Application, Publication Numbers 92/18501, g3/02079, 93/22445 and United States Patel~t Number 51()4888 ;~re those uu~ fJulld~ defined as suitable, favoured and preferred in the respective patent p~lhli~-Atif~n~
The suitable, favoured and preferred acyclic insulin sensitisers disclosed in l~ .".Al;~ "Al Patent ~rplirAtion~ Publication Numbers WO91/19702, W092/03425, W093/21166 and WO94/01420 and United States Patent Number 5232945 are those cnmrol-nfl~ defined as suitable, favoured and preferred in therespective patent pllhlirAtir,nc Other suitable, favoured and preferred insulin sensitisers are the suitable, favoured and preferred compounds disclosed in European Patent Application, Publication NLlmber ()533933, lntf rrAtir~nAl Patent Application, Publication Number WO 93/02079, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
Also specifically included in the method of the invention are the specific examples disclosed in the above mentioned patent Alll~
When used herein the temm 'insulin sensitiser' relates to ~,u~ uu~ld~ which WO95/21608 2~ ~q86 P~ [;11 0 increase the biological response to insulin. In addition, based upon the observed effeets in appropriate test animals such as Zucker fatty (fa/fa) rats, insulin sensitisers are indicated to lower elevated fasting plasma insulin c., ..., and improve glycaemic control.
When used herein the term '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, alku,.y~,dll,u..yl, alk~"~y-,dll,u,lylàlkyl, alkyl~albu~yloxy, or alkylearbonyl groups.
When used herein the term 'halogen' refers to fluorine, chlorine, bromine 10 and iodine; preferably ehlorine.
When used herein the terms 'alkyl' and 'alkoxy' relate to groups having straight or branehed carbon ch.qin~,rc ntqining up to 12 carbon atoms.
When used herein the term 'acyl' includes alkylca.~u"yl groups.
Suitable alkyl groups are C1-12 alkyl groups, especially C1-6 alkyl groups 15 e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
Suitable ~llh~titl~l~nt~ for any alkyl group include those indieated above in relation to the term "aryl".
Suitable plla~ dc~ h,dlly aeeeptable salts inelude salts of earboxy groups and aeid addition salts.
Suitable l,l,A""~. {...... ~ y acceptable salts of carboxy groups include metal salts, s~lch as for example aluminium, alkali metal salts such as lithium,sodium or potassium, alkaline canh metal salts such as calcium or II~
and ammr)nil.m or substituted ammonium salts, for example those with lower alkylamines such as L- h,Lllyldlllill~;, hydroxy alkylamines such as 2-hydroxyethylamille, bis-(2-hydroxyethyl)-amine or tri-(2-llydlw-y~,ll,yl)-amine, eyeloalkylamines such as bicyclohexylamine, or with procaine, dib~ yl~ ,idi~e, N-benzyl-b-~ .,.,Ll.yld,~ , dcllydlual,;~iylalll;lle, N,N'-bisdehydroabietylamine, glucamine, N-methylglueamine or bases of the pyridine type such as pyridine, collidine, q~inine or quinoline.
Suitable acid :Lddition salts include IJIldl 11~ - . . .1;. AIIY aeeeptable inorganie salts sueh as the sulphate, nitrate, phosphate, borate, hydroehloride and l~yd~ul:lu~ide and rhA lllA- ~ ,.lly aeceptable organic acid addition salts sueh as aeetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto gllltarate and a-~ly~ ,l"~ , especially the maleate salt.
Suitable ~llalllld~cLlLi~ally accept ble solvates include hydrates.
O WO95/21608 ~182986 I "~l ~r~s~l The active compoLlnds disclosed in ~he above mentioned patent ~,u1,1i. ,.li~."c and referred to herein as insulin sensitisers, including the specific examples disclosed therein, are uu~ lly prepared according to the methods disclosed in the said patent ~ Thus a compound of formula (1), or the 5 tautomeric form thereof, and/or a ~ lly acceptable salt thereof, and/or a pllal l l l - c, ~ lly rLcceptable solvate thereof, may be prepared using the processes described in EP 0306228 and W094/05659.
The salts and/or solvates of the compounds of formula (I) may be prepared and isolated according to conventionai procedures for example sodium 10 salts may be prepared by using sodium methoxide in methanol.
The present invention also provides an insulin s~nCitic~r~s~ r~h as a compound of formula (1), or LL tautomeric form thereof ând/or a ~Jlla llla~ i"ally acceptable Sâlt thereot and/or a plla~ lly Llcceptable solvate thereof, for use in the tre Ltment of and/or prophyl~Lxis of renal diseases including diabetic 15 I~ u~ua~ , glomerulonephrilis, glomerLllar sclerosis, nephrotic syndrome, hypertensive "~ Iuscl~lu~i~ and elld stage renal disease, and microalbuminuria.
The present invention also provides Ln insulin c~nci~ic~r,cll~h as a compound of formula (1), or a tautomeric form thereof and/or a ~ y acceptable salt thereof and/or a 1.l, - 111~ y acceptable solvate thereof, for 20 use in the, lldllL~rnu~ of a 1 1-.. I i~ ..., ... I for the treatment and/or ~JIU~)Il,ylll~i~ of renal diseâses including diabetic ncpllluuall~y~ ~lu~ ulul~ lilis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalb~lminuri;l.
In the above mentioned rre~tment and or prophylaxis the insulin sensitiscr 25 such as a compound of formula (1), or a tautomeric form thereof andlor a IJllal Illa~ uli~ally acceptable salt thereof and/or a plla~ Ally acceptable solvate thereof, may be à~ -i"i~ d ~ se or, preferably, as a ~
also comprising a 1,l, ~ ",~. ~..li. .lly acceptable carrier.
Accordingly, the present invention also provides a 1,l - ".~
30 composition for the tre.ltment and/or prophylaxis of renal diseases includingdiai~etic l~C~ u~.lLlly, glomerulonephriti~, glomerular sclerosis, nephrotic syndrome, hypertensive Ll~JI,Iu.ul~.usi~ and end stage renal disease, and microalbuminuria which r..mrr.citiCm comprises an insulin sensitiser, such as a compound of the formula (1), or a tautomeric form thereof, or a r~ IY
35 a~ eptable salt thereof, or a ~i,a, " ~ lly acceptable solvate thereof, and a WO95121608 7 i 8~8~ P~ l 11 0 ,I,Au " IA. . . I l ir :ll Iy acceptable carrier therefor.
As used herein the term ~rh.1""- ~ 11y acceptable' embraces compounds, .,. ,1 l .ll..~; l i....~ and ingredients for both human and veterinary use: for example the term ~ iy acceptable salt' embraces a ~,t~ lruily 5 acceptable salt.
The rnmrncitinn may, if desired, be in the form of a pack a~ i by written or printed insttuctions for use.
Usually the pl,~ d~,culicdl comrn. ci~ir~.nc of the present invention will be adapted fororal Alll,.;";~l,Alin,~, although cnmrocitinnc forArl".;.,;~ ;.,., by10 other routes, such as by injection and l~ CU~ JU:I absorption are also envisaged.
Particularly suitable C~,lll,.,u .;liulls for oral Alll~ I are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
In accordance wilh conventional ~ ..1 ,lld~,~,ulical practice the carrier may 15 comprise ~I diluent, filler, di~ C~ , wetting agent, lubricant, colourant, flavourant or other conventional adjuvant Typical carriers include, for example, ~ y~ line cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyv;~yl~oly~,y..~lidone~
IllAg,.l. 7;11~11 stearate. sodium lauryl sulphate or sucrose.
Most suitably the cnmro~irinn 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 ~Isually 0 1 to 500 mg, and more especially 0.1 to 250mg.
Conveniently, Ihe active ingredient may be a II..illi~ cd as a 25 I/Il~ 1 rnn1rnCitinn hereinbefore defined, and this forms a particular aspect of the present invention.
In the above mentioned treatments an insulin sensitiser, such as a compound of the formula (1), or a tautomeric form thereof and/or a Au ~ y acceptable salt thereof and/or a rl ~ y acceptable solvate thereof, may be raken in doses, such as those described above, one to six times a day in a ml~nner sLlch th:lt the total daily dose for a 70 kg adult willgenerally be in the r.lnge of froin 0.1 to 6000 mg, and more usually about I to 1500 mg, generally about 0.5 to 10 mg. That is in the range of from 1.429 x 10~3to 85.714 mg/k,/day, more usually about 1.429 x lo-2 îo 21.429 mglkg/day, generally about 7 143 x 10-3 to 0 1429 mg/kg/day ~I WO95/21608 2 ~ 82986 P.,~ .l tll The following Examples illust~ale the invention but do not limit it in any way.
WO95121608 2;3 8~ r~l~ 5 ~
Example 1: Studies Into Tlle Effects Of Tl~e Test Compound Upon Renal Patholo~y Obese Zucker rals are known to develop chronic ~ U~JGLIly in addition to lly~ ;d, hyperin~ nq~miq and peripheral insulin resistance (Kasiske e~ al 1985).
5-[4-[2-(N-methyl-N-(2-pyridyl)aminoh,lllu,,y]~ yl]~ -2~4-dione (herein after referred to as 'test compound') was adl~ ;aL~lcd to 2-3 month old obese Zucker fa/fa rats by dietary ~ to proYide a daily dose over 1 û a period of 3 months rr nging from 2.0 - 7.0 ~Lmole/kg body weight. A group of age-matched obese Zucker fa/fa rats were given the same diet without the addition of the test compound, as WL~S L~ group of lean Fa/? rats. At the end of t~3e study, all of the control Zucker fa/fa rats had chronic r..,~lllulJaLlly which involved dilated tubules, atrophied or hyperplastic tubular epithelial cells, thickened tubular basement ~ lblall~s, segmented glomeruli or global ~IUIII.,I ulual,L,Iu~In the cullca~ dil~g leL3n rnimals, 3/15 animals, a minimal degree of chronic llc~311lu~,all,y was seen.
Treatment with test compound resulted in a reduction in the incidence and degree of chronic 13C~IIIU~LnIIY compL~red to the control group of Zucker fa/fa rats.
In the kidneys of the control Zucker fa/fa rats, mild-moderdte ll~dlull~,i)lllusis was seen in 4/9 animals. Cll~u~u~ ;al;.,dlly this involved dilation of the kidney pelvis. Islo llydlul~clullluaia was seen in the rats treated with test compound.
~ WO 95/21608 2 1 8 2 9 8 6 r~ . 3. . ~ ~I
TABLE OF SlGNrFlCANT HISTOPATHOLOGICAL
FINDINGS IN THE KIDNEY OF FAI'I`Y ZUCKER RATS
Group/Tre~tment Hydronephrosis Chronic Nephropathy Animal Number Group 1 Test Compound in diet 1~ 0 ++
17 0 +
21 0 +
24 0 +
Group Z
Diet only 3 ++ +
5 +++ +
13 0 +
1 4 ++ ++
18 0 +
23 +++ ++
26 0 +
29 0 +
0 ++
, 5 Severity Key 0 None see~
W095/21608 = 21 329~6 P~
Minim~l + Mild ++ Moder~te +++ M~rked 21 ~2986 WO 95/21608 r~
Example 2: Studies Into Tlle Effect Of Test C~ Upon Systolic Blood Pressure, Urinnry Totnl Protein And Urinary N-Acetyl n-D-(" ' ' (NAG~ ActiYity l\q~.,~...
5 A second study was performed in Zucker rats over a period of 9 months to investigate the l~nvirll~in~1 effects of the drug on systolic blood pressure andvarious indices of renal function, two of which are . Al-l I ~ ;r~ here. In one arm of the study, the drug was given in the diet (~0 ,umole/kg of diet) from aged 6-7weeks in Zucker fatty (fa/fa) rats, whilst in a second artn of the study, drug 10 treatment as above was delayed unti~ proteinuria had become established after 4 months, indicative of structural damage .llready present in the kidneys. A thirdgroup of Zucker fatty rats and a further group of lean rats were given diet alone throughout the period of study.
15 After dosing with the test con1pound, at monthly intervals l~I~,a.~UlCIII~ l were made of systolic blood pressure, urinary total protein and urinary N-acetyl 3-D-~,I",.,~.";"i~ (NAG) activity.
Me~su, ~ of S~ tolic Blood Pre.~sure 20 Rats were enclosed in custom-built restrainers and placed on a shelf in a warming cabinet, whose LC~ IUIC was controlled at a~ 'y 30~C. An inflatable cuff with integral plllse sensor WQS attached to the tail of each rat. After warrning for 20-30 min the tail cuff was inflated and deflated A~ . "~ y and a Ill~.a:~Ull..~ lL of systolic blood pressure made using an IITC Non-Invasive Blood 25 Pressure Monitor. This cycle w~s repeated sever~l times for each rat until stable values of blood pressure were obtained.
Meus~ of Urinar~ Paramerers Twenty-four hour urine collections, made in m~r~h~ nn cages, were aliquoted 30 and frozen at -70"C until re4~1ired for assay.
(i) Urinary Protein Urinary protein c., ~, l,..li."~ was measured using the Bio-Rad protein assay nsmodified for use in a 96-well microtitre plate. The assay is a dye-binding assay35 based on the differential colour change of ~ dye in response IO various WO95121608 218~986 r~ V
~1~ .. ~ .1 l 1.1 l 1. .1~C of pro~ein (Bradford, Anal. Biochem.,72, ~48, 1976). After a period of incubation with Dye Re~gent, diluted urine samples are read at an optical density of 595 nm using a Molecular Devices multiplate reader.
5 (ii) Urinar~v NAG Aclivir~
NAG activity was assayed using a reagent kit on a Hitachi 717 analyser (both suppied by Boehringer Mannheim UK, Lewes). Enzyme activity was measured by monitoring the rate of chlorophenol (570 nm) released from the substrate chlorophenol red-~-D-pl.,. .,~ -..1:.,..l..
J;~esults al~d Statistics In the tables below, les~llts ~re given as mean values for the group + the standard error of the mean. Res-~lts have been analysed by one way ANOVA and significant differences from the Zucker fatty rat control group have been 15indicated by an asterisk.
Conclusion The results of Example ~ ,J.. ~ .. that treatment of Zucker fatty (falfa) rats from the age of 6-7 weeks, for a period of 9 months, with BRL 49653 given via 20 the diet, prevented Ihe development of hypertension and markedly reduced boththe elevation of urinar)~ NAG activity ;md the rate of dcvclvl.. ,~,l of proteinuria.
When drug treatment was - .,. , .~ ,.( cd after proteinuria had become ~-c~llhli~
both systolic blood pressure and urinary NAG activity were prevented from risingfurther and again there was a marked reduction of the rate of increase in the 25 urinary protein ~,ullC~ aliOll.
21 ~2986 WO 95/21608 r~,l/~ 3!1~ 11 Effects of starting treatment with Test Compound prior to the dc~,_lop",~,~l of renal c~ r~ S-SYSTOLIC BLOOD PRESSURE (mm Hg) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 umol/kg of diet) (powdered chow) (powdered chow) 0102i3 106i3 123i3-110i3- 120i4 128i3 2122i4- 137i4 132i4 3122i4- 142i6 134i3 4126i6' 146i4 132i4-5131 i4- 157i6 138i4-6128i3' 150i6 133i2-7125i6' 157i6 128i6' 8133$5' 155i4 130i3-g143i4' 164+4 136i3' 10ffects of starting treatment with Test Compound prior to the d~ J~lopl"a"l of renal ~ -s URINARY PROTEIN CONCENTRATION (llg/hour) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 umollko of diet) (powdered chow) (powdered chow) 0226i15' 287i17 198i19' 373 i 22 355 i 1 8 321 i 23' 2402 i 22 ' 509 i 28 396 i 20' 3221 i 32 ' 874 i 102 393 i 25' 4376 i 54 ' 3965 i 731 613 i æ~
51573 i 105 5823 i 809 1395 i 88' 61585 i 147 8946 i 1171 1192 i 92' 72124 i 293 12052 i 1535 1176 i 96-82664 i 370` 14534 i 1540 1409 i 9Z' 93152 i 515- 16182 i 1581 1373 i 113-WO 9~/21608 2 1 8 2 '~ d P~
Effects of starting ~ "~:,)l with Test Compound prior to the d~J~l~pl"~n~ of renal complications.
URINAFIY N-ACETYL-B- D-GLUCOSAMINIDASE ACTIVITY
(mU/hour) Treatment Duration Zucker ~atty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 pmol/k~ of diet) (powdered chow) (powdered chow) 05.7iO.4 5.9iO.3 4.4iO.3' 7.5 $ 0.7 9.1 i O.8 5.1 i O.5-23.8i1.1' 8.2i1.5 6.5iO.3 34.5iO9 8.2i1.0 5.2iO.4' 45.1 i 1.2 ' 9.3 i 0.5 6.9 i 0.5-565iO.7` 10.7iO.4 7.6iO.7-66.5i1.1- 10.8i1.7 7.4iO.5 78.9 i 0.8' 11.7 i 0.7 7.1 i 0.5-86.2 i 1.2- 11.8 i 1.3 7.4 i 0.5-99.1 i 1.2- 13.4 i 0.8 7.7 i 0.6-Effects of starting l,~al",e"l with Test Compound once renal co"" s~ ticns have become e~ ',ed.
SYSTOLIC BLOOD PRESSURE (mm Hg) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Controi Control (50 IJmol/ks oi diet) (powdered chow) (powdered chow) -4106i3 106i3 123i3--3123i5 120i4 128i3 -2138~7 137i4 132i4 -1141 i6 142i6 134i3 0146i4 146i4 132i4-140i5 157i6 138i4-2134i3 150i6 133i2-3144i3` 157i6 128i6-4139i3' 155i4 130i3' 5146i6' 164i4 136i3' 2~ 829 Wo 95/21608 8 6 r~
Effects of starting l~ l,--e,ll with Test Compound once renal complications have become e_ ' )ecl.
URINARY PROTEIN CONCENTRATION (~g/hour) Trea;ment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (50 umol/kg of diet) (powdered chow) (powdered chow) 4220 i 13 287 i 17 198 i 19--3347 i 32 355 i 18 321 i 23' -2457 i 21 509 i 28 396 i 21--1958 i 194 874 i 102 393 i 25' 03520 i 905 3965 i 731 613 i 52' 3692 i 386 5823 i 809 1395 i 88-Z5326i967 8946i1171 1192i92' 36230 i 835' 12052 i 1535 1178 i 96' 45379 i 708- 14534 i 1540 1409 i 92' 57677 i 825' 16182 + 1581 1373 ~ 113' Effects of starting l-~al."~"l with Test Compound once renal cu",plicalions have become s ,ed.
URINARY N-ACETYL-B-D-GLUCOSAMINIDASE ACTIVITY
(mU/hour) Treatment Duration Zucker fatty rats Zucker fatty rats Lean rats (months) Test Compound Control Control (5û umollkg of diet) (powdered chow) (powdered chow) -45.4 i 0.2 5.9 i 0.3 4.4 i 0.3' -38.3 i 0.5 9.1 i 0.8 5.1 i 0.5' -29.5i1.1 8.2i1.5 6.5iO.3 -17.8 i 0.6 8.2 i 1.0 5.2 i 0.4' 07.6iO.7 9.3iO.5 6.9iO.5' 7.6iO.7 10.7iO.4 7.6io.r 25.7iO.9 10.8i1.7 7.4iO.5 37.4iO.9' 11.7iO.7 7.1 iO.5' 45.4 i 1.0' 11.8 i 1.3 7.4 i 0.5' 58.0i1.1' 13.4iO.8 7.7iO.6'
Claims (10)
- Claims:
l. A method for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease and microalbuminuria which method comprises the administration of an effective, non-toxic amount of an insulin sensitiser to a human or non-human mammal in need thereof. - 2. A method according to claim 1, wherein the insulin sensitiser is a thiazolidinedione insulin sensitiser.
- 3. A method according to claim 1, wherein the insulin sensitiser is an acyclic insulin sensitiser.
- 4. A method according to claim 1, wherein the insulin sensitiser is a compound of formula (I):
-(I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
A1 represents a substituted or unsubstituted aromatic heterocycyl group;
R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiely may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond;
A2 represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6; to a human or non-human mammal in need thereof. - 5. A method according to claim 4, wherein in the compound of formula (I) A1 represents a moiety of formula (a), (b) or (c):
(a) (b) (c) wherein:
R6 and R7 each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R6 and R7 are each attached to adjacent carbon atoms, then R6 and R7 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R6 and R7 together is substituted or unsubstituted; and in the moiety of formula (a) X1 represents oxygen or sulphur. - 6. A method according to claim 5, wherein in the compound of formula (I) A1 represents a moiety of the above defined formula (c).
(c') wherein R6 and R7 are as defined in claim 5. - 7. A method according to claim 1, wherein the insuiin sensitiser 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 and/or a pharmaceutically acceptable solvate thereof.
- 8. A method according to claim 7, wherein the insulin sensitiser is a maleic acid salt of 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 solvate thereof.
- 9. The use of an insulin sensitiser for the manufacture of a medicament for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease and microalbuminuria.
- 10. A pharmaceutical composition for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease and microalbuminuria which composition comprises an insulin sensitiser and a pharmaceutically acceptable carrier therefor.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9402624.2 | 1994-02-10 | ||
| GB9402624A GB9402624D0 (en) | 1994-02-10 | 1994-02-10 | Novel method |
| GB9410214A GB9410214D0 (en) | 1994-05-21 | 1994-05-21 | Novel method |
| GB9410214.2 | 1994-05-21 | ||
| GBGB9426019.7A GB9426019D0 (en) | 1994-12-22 | 1994-12-22 | Novel method |
| GB9426019.7 | 1994-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2182986A1 true CA2182986A1 (en) | 1995-08-17 |
Family
ID=27267046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002182986A Abandoned CA2182986A1 (en) | 1994-02-10 | 1995-02-07 | Use of insulin sensitisers for treating renal diseases |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0777469A1 (en) |
| JP (1) | JPH09512249A (en) |
| CN (2) | CN1083715C (en) |
| AP (1) | AP553A (en) |
| AU (1) | AU700826B2 (en) |
| CA (1) | CA2182986A1 (en) |
| IL (1) | IL112590A (en) |
| MX (1) | MX9603338A (en) |
| SG (1) | SG47100A1 (en) |
| TW (1) | TW475896B (en) |
| WO (1) | WO1995021608A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA973850B (en) * | 1996-05-06 | 1997-12-02 | Reddy Research Foundation | Novel antidiabetic compounds having hypolipidaemic, anti-hypertensive properties, process for their preparation and pharmaceutical compositions containing them. |
| ZA973848B (en) * | 1996-05-06 | 1997-12-02 | Reddy Research Foundation | Novel heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them. |
| US5919782A (en) * | 1996-05-06 | 1999-07-06 | Dr. Reddy's Research Foundation | Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them |
| US5885997A (en) * | 1996-07-01 | 1999-03-23 | Dr. Reddy's Research Foundation | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases |
| US6114526A (en) * | 1996-07-01 | 2000-09-05 | Dr. Reddy's Research Foundation | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases |
| US6372750B2 (en) | 1996-07-01 | 2002-04-16 | Dr. Reddy's Research Foundation | Heterocyclic compounds, process for their preparation and pharmaceutical compounds containing them and their use in the treatment of diabetes and related diseases |
| USRE39266E1 (en) * | 1996-07-01 | 2006-09-05 | Dr. Reddy's Laboratories, Limited | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases |
| US5985884A (en) * | 1996-07-01 | 1999-11-16 | Dr. Reddy's Research Foundation | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases |
| US6313113B1 (en) | 1997-04-15 | 2001-11-06 | Reddy-Cheminor, Inc. | Heterocyclic compounds having antidiabetic, hypolipidemic and antihypertensive properties, process for their preparation and pharmaceutical compositions containing them |
| US6011031A (en) * | 1997-05-30 | 2000-01-04 | Dr. Reddy's Research Foundation | Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them |
| GB9711683D0 (en) * | 1997-06-05 | 1997-08-06 | Smithkline Beecham Plc | Composition |
| US20020137940A1 (en) | 1997-12-16 | 2002-09-26 | Smithkline Beecham P.L.C. | 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical |
| GB9726563D0 (en) * | 1997-12-16 | 1998-02-11 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB9726566D0 (en) * | 1997-12-16 | 1998-02-11 | Smithkline Beecham Plc | Novel pharmaceutical |
| OA11871A (en) | 1999-04-23 | 2006-03-27 | Smithkline Beecham Plc | Novel pharmaceutical. |
| BR0013375A (en) * | 1999-08-17 | 2002-07-23 | Smithkline Beecham Plc | Pharmaceutical compositions containing thiazolidinedione derivatives and process for their preparation |
| EP1284291A4 (en) * | 2000-05-25 | 2005-06-08 | Yamanouchi Pharma Co Ltd | Human pgc-1 promoter |
| GB0019223D0 (en) * | 2000-08-04 | 2000-09-27 | Smithkline Beecham Plc | Novel pharmaceutical |
| JP2008531707A (en) | 2005-03-03 | 2008-08-14 | スミスクライン ビーチャム コーポレーション | Medicine |
| EP2155769B1 (en) | 2007-05-04 | 2012-06-27 | Katholieke Universiteit Leuven KU Leuven Research & Development | Tissue degeneration protection |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0842925A1 (en) * | 1987-09-04 | 1998-05-20 | Beecham Group Plc | Substituted thiazolidinedione derivatives |
| GB9023584D0 (en) * | 1990-10-30 | 1990-12-12 | Beecham Group Plc | Novel compounds |
| FR2680512B1 (en) * | 1991-08-20 | 1995-01-20 | Adir | NOVEL 2,4-THIAZOLIDINEDIONE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| JPH05310719A (en) * | 1992-04-28 | 1993-11-22 | Terumo Corp | Thiazolidine-2,4-dione derivative |
-
1995
- 1995-02-07 SG SG1996007235A patent/SG47100A1/en unknown
- 1995-02-07 CN CN95192362A patent/CN1083715C/en not_active Expired - Fee Related
- 1995-02-07 AU AU15783/95A patent/AU700826B2/en not_active Ceased
- 1995-02-07 JP JP7520956A patent/JPH09512249A/en not_active Ceased
- 1995-02-07 WO PCT/EP1995/000441 patent/WO1995021608A1/en not_active Application Discontinuation
- 1995-02-07 MX MX9603338A patent/MX9603338A/en unknown
- 1995-02-07 CA CA002182986A patent/CA2182986A1/en not_active Abandoned
- 1995-02-07 EP EP95907653A patent/EP0777469A1/en not_active Withdrawn
- 1995-02-08 AP APAP/P/1995/000717A patent/AP553A/en active
- 1995-02-09 IL IL11259095A patent/IL112590A/en not_active IP Right Cessation
- 1995-02-10 TW TW084101155A patent/TW475896B/en not_active IP Right Cessation
-
2001
- 2001-03-30 CN CN01112436A patent/CN1318372A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CN1083715C (en) | 2002-05-01 |
| EP0777469A1 (en) | 1997-06-11 |
| CN1318372A (en) | 2001-10-24 |
| IL112590A (en) | 2002-08-14 |
| WO1995021608A1 (en) | 1995-08-17 |
| AP553A (en) | 1996-11-06 |
| AP9500717A0 (en) | 1995-04-30 |
| SG47100A1 (en) | 1998-03-20 |
| JPH09512249A (en) | 1997-12-09 |
| IL112590A0 (en) | 1995-06-29 |
| AU1578395A (en) | 1995-08-29 |
| MX9603338A (en) | 1997-03-29 |
| TW475896B (en) | 2002-02-11 |
| CN1145027A (en) | 1997-03-12 |
| AU700826B2 (en) | 1999-01-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2182986A1 (en) | Use of insulin sensitisers for treating renal diseases | |
| Connor et al. | Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase | |
| ES2197213T3 (en) | USE OF PRAMIPEXOL AS A NEUROPROTECTOR AGENT. | |
| US20040053989A1 (en) | Dithiolthione compounds for the treatment of neurological disorders and for memory enhancement | |
| CZ198296A3 (en) | Preparations for treating arteriosclerosis and xanthoma | |
| EP0695183B1 (en) | Use of thiazolidinediones for the treatment of atherosclerosis and eating disorders | |
| US5424301A (en) | Starch stabilized o-substituted tetrahydropyridine oxime cholinergic agents | |
| JPS63264421A (en) | Remedy for hyperlipemia | |
| EP0921798A1 (en) | Novel treatment of leptine resistance | |
| AU2018219213A1 (en) | Treatment of diabetes and associated metabolic conditions with epigenetic modulators | |
| CA1261272A (en) | Dihydropyridine combination product | |
| CN101272805A (en) | Pharmaceutical composition containing PPAR gamma agonist | |
| US20030109552A1 (en) | Use of insulin sensitisers for treating renal diseases | |
| US20020115699A1 (en) | Method for treating renal disease | |
| WO2001052849A1 (en) | Remedies for diabetes | |
| AU2001261409A1 (en) | Prevention of insulin-dependent diabetes, complications thereof, or allograft rejection by inhibition of cyclooxygenase-2 activity with NS398 or PDTC | |
| HU229425B1 (en) | Use of thiazole derivatives for preparing a medicine for protecting mitochondria | |
| CZ32998A3 (en) | Preparation of medicament for reducing amount of exogenous insulin | |
| US20040266833A1 (en) | Novel use of certain insulin sensitizers or ppar-gamma agonists | |
| CA2417883A1 (en) | Pharmaceutical composition comprising metformin and a 5-phenoxyalkyl-2,4-thiazolidinedione-type derivative | |
| WO1999012548A1 (en) | Treatment of inflammatory conditions | |
| NZ506200A (en) | Use of a leptine sensitiser in combination with leptin to treat leptine resistance conditions (e.g. obesity) | |
| HU224436B1 (en) | Use of 5-[4-{2-[n-methyl-5-(2-pyridyl)amino]ethoxy}benzyl]thiazolidine-2,4-dione for the preparation of pharmaceutical compositions | |
| AU7217000A (en) | Novel treatment of leptin resistance | |
| WO2000047209A1 (en) | Methods of modulating uric acid levels |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |