EP1648453A1 - Synergistische pharmazeutische kombination enthaltend cicletanine zur vorbeugung und behandlung von diabetes - Google Patents

Synergistische pharmazeutische kombination enthaltend cicletanine zur vorbeugung und behandlung von diabetes

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Publication number
EP1648453A1
EP1648453A1 EP04727331A EP04727331A EP1648453A1 EP 1648453 A1 EP1648453 A1 EP 1648453A1 EP 04727331 A EP04727331 A EP 04727331A EP 04727331 A EP04727331 A EP 04727331A EP 1648453 A1 EP1648453 A1 EP 1648453A1
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EP
European Patent Office
Prior art keywords
pharmaceutically suitable
acid addition
cicletanine
addition salt
suitable acid
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Withdrawn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
EP04727331A
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English (en)
French (fr)
Inventor
János EGRI
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.)
Synosens Kutato Es Fejleszto Kft
Original Assignee
Synosens Kutato Es Fejleszto Kft
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
Application filed by Synosens Kutato Es Fejleszto Kft filed Critical Synosens Kutato Es Fejleszto Kft
Publication of EP1648453A1 publication Critical patent/EP1648453A1/de
Withdrawn legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide

Definitions

  • the invention refers to a synergistic pharmaceutical , combination suitable for the prevention or treatment of a prediabetic state, metabolic X-syndrome or diabetes mellitus as well as disorders which are associated with the states listed
  • NIDDM non-insulin-dependent diabetes mellitus
  • the aim of the invention is to provide a pharmaceutical combination which is suitable for the prevention of the development of diabetes or at least the complications that accompany diabetes, or, if such prevention is not possible anymore, for the efficient treatment of said complications.
  • cicletanine [chemical name ( ⁇ )-3-(4- chlorophenyl)-1 ,3-dihydro-6-methylfuro-[3,4-c]pyridin-7-ol], a known active agent having blood pressure lowering activity [US Patent No. 4,383,998 ], exerts an insulin sensitizing effect.
  • this available amount becomes sufficient to bring about the required physiological effect in the presence of cicletanine.
  • the administration of cycletanine enhances the sensitivity of insulin. Consequently, a lower dosage of insulin or an antidiabetic or anti-hyperlipidemic active agent administered to the patient is sufficient to produce the therapeutical effect.
  • a first object of the invention is to provide a synergistic pharmaceutical combination suitable for the prevention or treatment of a prediabetic state, metabolic X- syndrome or diabetes mellitus as well as disorders which are associated with the states listed above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium, polycystic ovary syndrome and/or other diabetic complications.
  • a second object of the invention is to provide the use of cicletanine for the preparation of a pharmaceutical composition having insulin sensitizing effect.
  • a third object of the invention is to provide a method for treating a patient suffering from or threatened by a prediabetic state, metabolic X-syndrome or diabetes mellitus as well as disorders which are associated with the states listed above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium, polycystic ovary syndrome and/or other diabetic complications with cicletanine.
  • the synergistic pharmaceutical combination of the invention comprises
  • a second pharmaceutical composition containing an antidiabetic or anti-hyperlipidemic active agent or, if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof and one or more conventional carrier(s).
  • a pharmaceutical combination is an association of two pharmaceutically active agents in which - either each of the active agents has been converted, one by one, to separate pharmaceutical compositions using one or more conventional carrier(s) and any of the usual processes of drug manufacture, and in this case the two sorts of pharmaceutical composition obtained are administered to the patient simultaneously or one after the other following an interval; or
  • the two active agents have been converted to one single pharmaceutical composition that can be administered to the patient being in need thereof.
  • the pharmaceutical composition may contain a mixture of the two active agents, or each of the active agents may be present at a different site in the pharmaceutical composition, e.g. one of them in the tablet core and the other in a coating of the tablet core.
  • one or more conventional carrier(s) and any of the usual processes of drug manufacture are used to prepare this single pharmaceutical composition.
  • any of the pharmacologically active agents conventionally used in the therapy for the treatment of diabetes is meant. These are mainly the following:
  • insulin in the first place, human insulin prepared by recombinant technology is employed, which is administered, in general, parenterally.
  • the insulin sensitizing active agents enhance the effect of insulin.
  • the most important sorts of them are the PPAR (peroxisome proliferator-activated receptor) ⁇ -agonists, for example the thiazolidinedione derivatives such as pioglitazone [( ⁇ )-5-[[4-[2-(5-ethyl-2-pyridinyI)ethoxy]phenyl]methyl]-2,4- thiazolidinedione], troglitazone [( ⁇ )-5-[[4-[(3,4-dihydro-6- hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]- phenyl]methyl]-2,4-thiazolidinedione], ciglitazone [5-[[4-[(1- methylcyclohexyl)methoxy]phenyl]methyl]-2,4-thiazolidine- dione, rosiglitazone [(+)-5-
  • the active agents that enhance the production of insulin are, for example, as follows: mitiglinide [( ⁇ S,3aR,7aS)- octahydro- ⁇ -oxo- ⁇ -(phenylmethyl)-2H-isoindole-2-butanoic acid], repaglinide [(S)-2-ethoxy-4-[2 ⁇ [[3-methyl-1-[2-(1- piperidinyl)phenyl]butyl]amino]-2-oxoethyI]benzoic acid], senaglinide (i.e. nateglinide) [N-[[(trans-4-(1-methylethyl)- cyclohexyl]carbonyl]-D-phenylalanine] or pharmaceutically suitable acid addition salts or pharmaceutically suitable salts thereof.
  • mitiglinide [( ⁇ S,3aR,7aS)- octahydro- ⁇ -oxo- ⁇ -(phenylmethyl)-2H
  • sulfonylurea derivatives e.g. tolbutamide [N-f(butylamino)- carbonyl]-4-methylbenzenesulfonamide], chlorpropamide [4- chloro-N-[(propylamino)carbonyl]benzenesulfonamide], tolazamide [N-[[(hexahydro-1 H-azepin-1-yl)amino]carbonyl]-4- methylbenzenesulfonamide], acetohexamide [4-acetyl-N- [(cyclohexylamino)carbonyl]benzenesulfonamide] etc.
  • tolbutamide N-f(butylamino)- carbonyl]-4-methylbenzenesulfonamide
  • chlorpropamide 4- chloro-N-[(propylamino)carbonyl]benzenesulfonamide]
  • tolazamide N-[[(hexahydro-1 H-a
  • glibenclamide [5-chloro-N-[2-[4-[[[(cyclohexylamino)carbonyl]- amino]sulfonyl]phenyl]ethyl]-2-methoxybenzamide]
  • glipizide [N-[2-[4-[[[(cyclohexyl-amino)carbonyl]amino]su!fonyl]phenyl]- ethyl]-5-methylpyrazine-carboxamide]
  • gliclazide [N-[[(hexa- hydrocyclopenta[c]pyrrol-2(1 H)-yl)amino]carbonyl]-4-methyl- benzenesulfonamide]
  • glimepiride [trans-3-ethyl-2,5-dihydro-4- methyl-N-[2-[4-[[[[[[(4-methylcyclohexylamino)carbonyl]- amino]sul
  • the most important biguanidine derivatives can be characterized by the formula R 1 R 3 ⁇ / N -C - NH - - C - N
  • R 1 , R 2 , R 3 and R 4 represent, independently, a hydrogen atom, a C- ⁇ - 1 0 alkyl group, a naphthyl group, a phenyl group or a phehyl(C ⁇ - alkyl) group, wherein in both former cases the phenyl group is optionally substituted by 1-3 substituents which can be, independently, a halo atom, a C ⁇ - 4 alkyl group . or a C ⁇ - 4 alkoxy group, with the proviso that one of R 1 , R 2 , R 3 and R 4 is other than a hydrogen atom, or
  • R 1 and R 2 together with the adjacent nitrogen atom and/or R 3 and R 4 together with the adjacent nitrogen atom form a 5- or 6-membered, saturated, unsaturated or aromatic ring that can be fused with a further 5- or 6-membered saturated, unsaturated or aromatic ring optionally containing also a nitrogen atom, and pharmaceutically suitable acid addition salts thereof.
  • Especially preferred biguanidine derivatives are metformin [N.N-dimethylimidocarbonimidic diamide], buformin [N- butylimidodicarbonimidic diamide] and phenformin [N-(2- phenylethyl)imidodicarbonimidic diamide].
  • the ⁇ -glucosidase inhibitors inhibit the enzyme ⁇ - glucosidase.
  • Important representants thereof are, for example, miglitol [1 ,5-dideoxy-1 ,5-[(2-hydroxyethyl)imino]-D-glucitol], acarbose [0-4,6-dideoxy-4-[[[1 S-(1 ⁇ ,4 ⁇ ,5 ⁇ ,6 ⁇ )]-4,5,6- trihydroxy-(3-hydroxymethyl)-2-cyclohexen-1 -yI]amino]- ⁇ -D- glucopyranosyl-(1 - 4)-0- ⁇ -D-glucopyranosyl-(1 -»4)-D- glucose], voglibose [3,4-dideoxy-4-[[2-hydroxy-1- (hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epiinositol] etc.
  • any of the pharmacologically active agents conventionally used in the therapy for the treatment of high blood-lipid level is meant. These are compounds that can be classified mainly as follows: aryloxyalkanoic acid derivatives, HMG coenzyme reductase inhibitors, nicotinic acid derivatives, antacids for bile acids. Out of the aryloxyalkanoic acid derivatives, preferred active agents are e.g.
  • lovastatin [[1S- [1 ⁇ (R * ),3 ⁇ ,7 ⁇ ,8 ⁇ (2S * ,4S * ),8 ⁇ ]]-2-methylbutanoic acid 1 ,2, 3,7,8, 8 ⁇ -hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester], fluvastatin [[R * ,S * -(E)]-(+)-7-[3-(4-fluorophenyl)-1 -(1 -methyl- ethyl)- 1 H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid], pravastatin [[1 S-[1 ⁇ ( ⁇ S * , ⁇ S*),2 ,6 ⁇ ,
  • nicotinic acid derivatives for example, the following ones are used: acipimox [5-methylpyrazinecarboxylic acid 4-oxide], niceritrol [3-pyridinecarboxylic acid 2,2-bis[[(3- pyridinylcarbonyl)oxy]methyl]-1 ,3-propanediyl ester], nicomol [3-pyridinecarboxylic acid (2-hydroxy-1 ,3-cyclohexane- diylidene)-tetrakis(methylene) ester], nicoclonate [3-pyridinecarboxylic acid 1-(4-chlorophenyl)-2-methylpropyl ester] etc.
  • colestipol a basic anion exchange resin: N- (2-aminoethyl)-N'-[2-[(2-aminoethyl)amino]-ethyl]-1 ,2-ethane- diamine polymer with (chloromethyl)oxirane]
  • cholestyramine a synthetic, strongly basic anion exchange resin containing quaternary ammonium functional groups which are attached to a styrene-divinylbenzene copolymer
  • polidexide an anion exchange resin containing quaternary ammonium groups which bind the bile acids in the intestine] etc.
  • the antidiabetic and anti-hyperlipidemic active agents are known from the literature. If desired and chemically possible, these active agents can be used in the form of the pharmaceutically suitable acid addition salts thereof or in the form of the salts formed with pharmaceutically suitable bases. Under a pharmaceutically suitable acid addition salt, an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrogen chloride or sulfuric acid and the like, or with a pharmaceutically suitable organic acid such as acetic acid, fumaric acid, lactic acid and the like is meant.
  • a pharmaceutically suitable inorganic acid such as hydrogen chloride or sulfuric acid and the like
  • a pharmaceutically suitable organic acid such as acetic acid, fumaric acid, lactic acid and the like
  • the antidiabetic or anti-hyperlipidemic active agent has a chemical structure that can form a salt with a base
  • the salt of the active agent formed with a pharmaceutically suitable inorganic or organic base can be used.
  • said active agent can form an acid addition salt with an acid
  • a pharmaceutically suitable acid addition salt of the active agent can be employed, too.
  • the CM alkyl group can be a methyl, ethyl, n- propyl, isopropyl, n-butyl, sec,-butyl, tert.-butyl, or isobutyl group.
  • the C-MO alkyl group may be, in addition to the ones • listed above, for example, a pentyl, hexyl, heptyl, octyl, nonyl or decyl group, too.
  • a C ⁇ - alkoxy group can be, for example, a methoxy, ethoxy, n-propoxy or n-butoxy group.
  • a halo atom is, for example, a fluoro, chloro, bromo or iodo atom.
  • a 5- or 6- membered, saturated, unsaturated or aromatic ring containing a nitrogen atom is, for example, a pyrrole, isopyrrole, dihydro- pyrrole, pyrrolidine, pyridine, piperidine, dihydropyridine, tetra- hydropyridine ring or the like.
  • the mass (or weight) ratio of the cicletanine or a pharmaceutically suitable acid addition salt thereof and the antidiabetic or ahti-hyperlipidemic active agent or, if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof is, in general, (1 -100):(100-1 ).
  • the one or two pharmaceutical composition(s) of the pharmaceutical combination is/are suitable for peroral or parenteral administration and is/are solid or liquid composition(s).
  • the suitable dosage forms and manufacture thereof as well as the useful carriers are known from the literature e.g. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, USA.
  • each active agent can be present in a separate pharmaceutical composition or both cicletanine and the antidiabetic or anti-hyperlipidemic active agent are present in a single common pharmaceutical composition.
  • the antidiabetic or anti-hyperlipidemic active agent can be, for example, one of the species listed above.
  • the preferred synergistic pharmaceutical combination of the invention may contain cicletanine or a pharmaceutically suitable acid addition salt thereof such as the hydrochloride as well as (b-i) an antidiabetic active agent e.g.
  • insulin or an insulin sensitizing active agent such as a thiazolidinedione derivative, for example, pioglitazone, troglitazone, ciglitazone, rosiglitazone, or an active agent that enhances the production of insulin such as mitiglinide, repaglinide, senaglinide, or a sulfonamide such as tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyburide, glipizide, gliclazide, glimepiride, gliquidone, glibornuride, glisoxepid, glisentide, glisolamide, glybuzole, glyclopyramide, or a biguanidine derivative of the formula I, preferably metformin, buformin, phenformin, or an - glucosidase inhibitor such as miglitol, acarbose or voglibose, or (b 2 ) an anti
  • an aryloxyalkanoic acid derivative such as clofibrate, gemfibrozil, simfibrate, etofibrate, ciprofibrate, ronifibrate, or a HMG coenzyme reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, or a nicotinic acid derivative such as acipimox, niceritrol, nicomol, nicoclonate, or an antacid for bile acids such as colestipol, cholestyramine, polidexide, or, if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base of the species given under (b-i) and (b 2 ).
  • Human regular insulin was infused at a constant rate (13 mU/kg, NOVO Nordisk, Copenhagen) via one of the venous catheters over 120 min. This insulin infusion yielded plasma insulin immunoreactivity of 100+5 ⁇ U/ml in the steady state. This value corresponds to five times the value of the normal upper limit. Blood samples (0.3 ml) were taken from the arterial cannula for blood glucose concentration at 10 min intervals.
  • Blood glucose concentration was maintained constant (5.5+0.5 mmol/litre) by a variable rate of glucose infusion via the second venous cannula.
  • this condition we defined this condition as steady state.
  • additional blood samples 0.5 ml
  • the glucose infusion rate (mg/kg/min) during steady state was used to characterize insulin sensitivity [DeFronzo R.A. et al., Am. J. Of Physiol., 237, E214-223 (1979)].
  • test compound(s) was/were administered to healthy and hypercholesterolaemic animals, respectively, perorally, in a single dose, daily, for five days, and the glucose infusion rates determined on the 6 th day were averaged within each test group consisting of 6 animals.
  • One group of the healthy and one of the hypercholesterolaemic animals was used as the control. The results obtained are shown in Tables 1 , 2, and 3.
  • Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state
  • Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state
  • HC hypercholesterolaemic animals were used in the test.
  • Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state
  • HC hypercholesterolaemic animals were used in the test.
  • the amount of glucose infused to obtain constant blood glucose level has been measured in the above tests. It is favourable that a higher amount of glucose should be needed at the given constant blood glucose level which indicates the enhanced effect of insulin. Consequently, the higher glucose infusion rate is measured, the higher efficiency is obtained with the compound tested.
  • the especially preferred synergistic pharmaceutical combination of the invention contains (a) cicletanine or a pharmaceutically suitable acid addition salt thereof and (b) a biguanidine derivative of the formula I, suitably metformin, or a pharmaceutically suitable acid addition salt thereof, or a sulfonylurea, suitably glyburide, or a pharmaceutically suitable acid addition salt thereof, or a thiazolidinedione derivative, suitably troglitazone, or a pharmaceutically suitable acid addition salt thereof, wherein the active agents are present in separate pharmaceutical compositions or in a single pharmaceutical composition.
  • the invention includes also the use of cicletanine or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition having insulin sensitizing effect.
  • the pharmaceutical composition is a unit dosage form, in general, suitable for peroral or ' parenteral administration, and contains 30 to 100 mg of cicletanine or cicletanine hydrochloride.
  • the suitable dosage forms and manufacture thereof as well as the useful carriers are known from the literature e.g. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, USA.
  • the insulin sensitizing effect of various doses of cicletanine was studied using similar tests employed in the study of glucose sensitivity of the synergistic pharmaceutical combination of the invention.
  • the animals were treated with 10 mg/kg, 30 mg/kg or 100 mg/kg of cicletanine, perorally, once daily, for 5 days.
  • the glucose infusion rate was determined on the 6 th day. The results obtained are shown in Table 4.
  • Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state
  • HC hypercholesterolaemic animals were used in the test.
  • the invention includes also a method for the treatment or the prevention of a prediabetic state, metabolic X-syndrome or diabetes mellitus as well as disorders which are associated with the states listed above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium, polycystic ovary syndrome and/or other diabetic complications, in which the patient suffering from or threatened by said states is treated with a therapeutically effective amount of cicletanine or a pharmaceutically suitable acid addition salt thereof.
  • the therapeutically effective amount of cicletanine is an amount that produces insulin sensitizing effect.
  • an antidiabetic or anti- hyperlipidaemic active agent can be administered to the patient suffering from or threatened by the states listed above.
  • the antidiabetic or anti-hyperlipidemic active agent and the cicletanine or a pharmaceutically suitable acid addition salt thereof can be administered simultaneously or one after the other following a shorter interval lasting for e.g. some seconds or minutes or a longer interval lasting for e.g. 10-30 minutes.
  • the daily dose of the antidiabetic or anti-hyperlipidemic agent is lower than the usual daily dose thereof employed in the conventional treatment when no cicletanine is administered.
  • the daily dose of cicletanine is, in general 30 to 100 mg, preferably about 50 mg for an adult person having a body weight of 70 kg.
  • - prediabetic state such as glucose intolerance or insulin resistance
  • IDDM IDDM
  • NIDDM NIDDM
  • a pharmaceutical composition containing cicletanine or a pharmaceutically suitable acid addition salt thereof can be administered to a patient that is treated or conventionally should be treated with an antidiabetic or anti-hyperlipidemic active agent in order to prevent or treat a prediabetic state, metabolic X-syndrome or diabetes mellitus as well as disorders which are associated with the states listed above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium, polycystic ovary syndrome and/or other diabetic complications.
  • the pharmaceutical composition containing cicletanine or a pharmaceutically suitable acid addition salt thereof As a result of the administration of the pharmaceutical composition containing cicletanine or a pharmaceutically suitable acid addition salt thereof, either no further treatment with an antidiabetic or anti-hyperlipidemic active agent is required, or a lower dosage of the antidiabetic or anti-hyperlipidemic active agent is sufficient.
  • a pharmaceutical composition containing cicletanine or a pharmaceutically suitable acid addition salt thereof as the active agent is administered to a patient suffering from diabetes and obtaining a regular insulin treatment, then the daily insulin dose can be reduced, thus, avoiding the development of insulin resistance.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP04727331A 2003-04-15 2004-04-14 Synergistische pharmazeutische kombination enthaltend cicletanine zur vorbeugung und behandlung von diabetes Withdrawn EP1648453A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0300990A HUP0300990A2 (hu) 2003-04-15 2003-04-15 Szinergista gyógyszer-kombináció a diabetesz megelőzésére vagy kezelésére
PCT/HU2004/000037 WO2004091612A1 (en) 2003-04-15 2004-04-14 A synergistic pharmaceutical combination comprising cicletanine for the prevention or treatment of diabetes

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EP1648453A1 true EP1648453A1 (de) 2006-04-26

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EP (1) EP1648453A1 (de)
JP (1) JP2006523668A (de)
CA (1) CA2522126A1 (de)
HU (1) HUP0300990A2 (de)
RS (1) RS20050776A (de)
WO (1) WO2004091612A1 (de)

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US20050113314A1 (en) * 2003-08-29 2005-05-26 Fong Benson M. Cicletanine in combination with oral antidiabetic and/or blood lipid-lowering agents as a combination therapy for diabetes and metabolic syndrome
US20050054731A1 (en) * 2003-09-08 2005-03-10 Franco Folli Multi-system therapy for diabetes, the metabolic syndrome and obesity
CN1889948A (zh) * 2003-12-16 2007-01-03 诺瓦提斯公司 他汀用于治疗代谢综合征的用途
WO2006034510A2 (en) * 2004-09-22 2006-03-30 Glenn Cornett Enantiomeric compositions of cicletanine, alone and in combination with other agents, for the treatment of disease
US20080096915A1 (en) * 2005-01-13 2008-04-24 Greenberg Traurig LLP Compositions for the treatment of metabolic disorders
CN102655866B (zh) 2009-11-13 2013-11-13 东丽株式会社 糖尿病的治疗或预防药
JP5927518B2 (ja) * 2011-08-08 2016-06-01 イムノメット セラピューティクス インク Ｎ１−環状アミン−ｎ５−置換フェニルビグアニド誘導体、それの調製方法及びそれを含む医薬組成物

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IN156817B (de) * 1981-02-10 1985-11-09 Scras

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Title
See references of WO2004091612A1 *

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HUP0300990D0 (en) 2003-06-28
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HUP0300990A2 (hu) 2005-05-30
CA2522126A1 (en) 2004-10-28
JP2006523668A (ja) 2006-10-19

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