CA2522126A1 - A synergistic pharmaceutical combination comprising cicletanine for the prevention or treatment of diabetes - Google Patents
A synergistic pharmaceutical combination comprising cicletanine for the prevention or treatment of diabetes Download PDFInfo
- Publication number
- CA2522126A1 CA2522126A1 CA002522126A CA2522126A CA2522126A1 CA 2522126 A1 CA2522126 A1 CA 2522126A1 CA 002522126 A CA002522126 A CA 002522126A CA 2522126 A CA2522126 A CA 2522126A CA 2522126 A1 CA2522126 A1 CA 2522126A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutically suitable
- acid addition
- addition salt
- cicletanine
- 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.)
- Abandoned
Links
- CVKNDPRBJVBDSS-UHFFFAOYSA-N Cicletanine Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=C(Cl)C=C1 CVKNDPRBJVBDSS-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960001932 cicletanine Drugs 0.000 title claims abstract description 41
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 19
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 12
- 230000002265 prevention Effects 0.000 title claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 50
- 239000013543 active substance Substances 0.000 claims abstract description 48
- 239000002253 acid Substances 0.000 claims abstract description 44
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 239000003472 antidiabetic agent Substances 0.000 claims abstract description 25
- 230000003178 anti-diabetic effect Effects 0.000 claims abstract description 24
- 230000001315 anti-hyperlipaemic effect Effects 0.000 claims abstract description 19
- 239000012050 conventional carrier Substances 0.000 claims abstract description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 60
- 102000004877 Insulin Human genes 0.000 claims description 32
- 108090001061 Insulin Proteins 0.000 claims description 32
- 229940125396 insulin Drugs 0.000 claims description 31
- 206010022489 Insulin Resistance Diseases 0.000 claims description 15
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 14
- -1 nicomof Chemical compound 0.000 claims description 12
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 229960003105 metformin Drugs 0.000 claims description 9
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 9
- 230000001235 sensitizing effect Effects 0.000 claims description 9
- 201000004384 Alopecia Diseases 0.000 claims description 8
- 208000002249 Diabetes Complications Diseases 0.000 claims description 8
- 206010012655 Diabetic complications Diseases 0.000 claims description 8
- 231100000360 alopecia Toxicity 0.000 claims description 8
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 8
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 208000030159 metabolic disease Diseases 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 6
- 229960004580 glibenclamide Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 6
- 229960001641 troglitazone Drugs 0.000 claims description 6
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 6
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims description 6
- ZILVNHNSYBNLSZ-UHFFFAOYSA-N 2-(diaminomethylideneamino)guanidine Chemical class NC(N)=NNC(N)=N ZILVNHNSYBNLSZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 claims description 4
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 claims description 4
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 claims description 4
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 claims description 4
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 claims description 4
- NMWQEPCLNXHPDX-UHFFFAOYSA-N Glybuzole Chemical compound S1C(C(C)(C)C)=NN=C1NS(=O)(=O)C1=CC=CC=C1 NMWQEPCLNXHPDX-UHFFFAOYSA-N 0.000 claims description 4
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims description 4
- 229940100389 Sulfonylurea Drugs 0.000 claims description 4
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 claims description 4
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 claims description 4
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 claims description 4
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims description 4
- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 claims description 4
- NSJYMFYVNWVGON-UHFFFAOYSA-N glisentide Chemical compound COC1=CC=CC=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCC2)C=C1 NSJYMFYVNWVGON-UHFFFAOYSA-N 0.000 claims description 4
- GZKDXUIWCNCNBJ-UHFFFAOYSA-N glisolamide Chemical compound O1C(C)=CC(C(=O)NCCC=2C=CC(=CC=2)S(=O)(=O)NC(=O)NC2CCCCC2)=N1 GZKDXUIWCNCNBJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229960000698 nateglinide Drugs 0.000 claims description 4
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims description 4
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001467 thiazolidinediones Chemical class 0.000 claims description 4
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 3
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 3
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 3
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 3
- 229920001268 Cholestyramine Polymers 0.000 claims description 3
- 229920002911 Colestipol Polymers 0.000 claims description 3
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 claims description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 3
- KUEUWHJGRZKESU-UHFFFAOYSA-N Niceritrol Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 KUEUWHJGRZKESU-UHFFFAOYSA-N 0.000 claims description 3
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 3
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 3
- JLRNKCZRCMIVKA-UHFFFAOYSA-N Simfibrate Chemical compound C=1C=C(Cl)C=CC=1OC(C)(C)C(=O)OCCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 JLRNKCZRCMIVKA-UHFFFAOYSA-N 0.000 claims description 3
- 229960002632 acarbose Drugs 0.000 claims description 3
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims description 3
- 229960001466 acetohexamide Drugs 0.000 claims description 3
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 claims description 3
- 229960003526 acipimox Drugs 0.000 claims description 3
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- 229960004111 buformin Drugs 0.000 claims description 3
- 229960001761 chlorpropamide Drugs 0.000 claims description 3
- 229950009226 ciglitazone Drugs 0.000 claims description 3
- 229960002174 ciprofibrate Drugs 0.000 claims description 3
- 229960001214 clofibrate Drugs 0.000 claims description 3
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 claims description 3
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 claims description 3
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- XXRVYAFBUDSLJX-UHFFFAOYSA-N etofibrate Chemical compound C=1C=CN=CC=1C(=O)OCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 XXRVYAFBUDSLJX-UHFFFAOYSA-N 0.000 claims description 3
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- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 claims description 3
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- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims description 3
- 229960001381 glipizide Drugs 0.000 claims description 3
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 3
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—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
Landscapes
- 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)
Abstract
The invention refers to a synergistic pharmaceutical combination which comprises (a) a first pharmaceutical composition containing cicletanine or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier(s), and (b) 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). The pharmaceutical combination is suitable for the prevention or treatment of, among others, diabetes mellitus.
Description
A SYNERGISTIC PHARMACEUTICAL COMBINATION COMPRISING CICLETANINE FOR THE
PREVENTION OR TREATMENT OF DIABETES
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 above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium, polycystic ovary syndrome and/or other diabetic complications.
In the industrially developed countries more and more human being suffers from diabetes. The frequency of the disease is growing especially rapidly in the population above 50 of age. For example, the development of type 2 diabetes (i.e. non-insulin-dependent diabetes mellitus, NIDDM) is promoted by the defects in both the production and use of insulin. Genetic and environmental factors equally contribute to the formation of this wide-spread serious disease accompanied by significant mortality. The patient treated with insulin or another antidiabetic or anti-hyperlipidemic agent obtains, as a matter of fact, only a palliative treatment that improves the life quality, however, the complications which accompany the diabetes appear unavoidably. A significant part of the antidiabetic agents only enhances the production of insulin in the organism.
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.
It has been found that cicletanine [chemical name (~)-3-(4-chlorophenyl)-1,3-dihydro-6-methylfuro-[3,4.-c]pyridin-7-of], a known active agent having blood pressure lowering activity [US
Patent No. 4,383,998 ], exerts an insulin sensitizing effect. For example, in cases when insulin is produced by the organism in a decreased amount, this available amount becomes sufficient to bring about the required physiological effect in the presence of cicletanine. Also in patients suffering from insulin resistance, 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.
Thus, 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 sensitising 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) a first pharmaceutical composition containing"cicletanine or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier(s), and (b) 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).
Definition of expressions used in the description and claims 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 carriers) and any of the usual processes of drug manufacture, and in this case the two sorts of pharmaceutical composition obtained are administered fio the patient simulfianeously or one after the other following an interval; or - the two active agents have been converfied to one single pharmaceutical composition that can be administered to the patient being in need fihereof. In the latter case, the pharmaceutical composition may contain a mixiure 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. Of course, one or more conventional carriers) and any of the usual processes of drug manufacture are used to prepare this single pharmaceutical composition.
Under an antidiabetic active agent (b~) any of the pharmacologically active agents conventionally used in the therapy for the treatment of diabetes is meant. These are mainly the following:
- insulin, - insulin sensitizing active agents, - active agents that enhance the production of insulin, - sulfonamides, - biguanidine derivatives and - a-glucosidase inhibitors.
As 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 PP~R
(peroxisome proliferator-activated receptor) y-agonists, for example the thiazolidinedione derivatives such as pioglitazone [(~)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-5 thiazolidinedione], troglitazone [(~)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,3-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-[4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]benzyl]-2,4-thiazolidinedione] and other 2,4-thiazolidinedione derivatives as well as pharmaceutically suitable acid addition salts thereof.
The active agents that enhance the production of insulin are, for example, as follows: mitiglinide [(ocS,3aR,7aS)-octahydro-y-oxo-a-(phenylmethyl)-2H-isoindole-2-butanoic acid), repaglinide [(S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]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.
Out of the sulfonamides, the most important ones are the sulfonylurea derivatives e.g. tolbutamide [N-[(butylamino)-carbonyl]-4-methylbenzenesulfonamide], chlorpropamide [4-chloro-N-[(propylamino)carbonyl]benzenesulfonamide], fiolazamide [N-[[(hexahydro-1 H-azepin-1-yl)amino]carbonyl]-4-methylbenzenesulfonamide], acetohexamide [4-acetyl-N-[(cyclohexyfamino)carbonyl]benzenesulfonamide] etca as first generation sulfonylureas or, for example, glyburide (glibenclamide) [5-chloro-N-[2-[4-[[[(cyclohexylamino)carbonyl]_ amino]sulfonyl]phenyl)ethyl]-2-methoxybenzamide], glipizide [N-[2-[4-[[[(cyclohexyl-amino)carbonyl]amino]sulfonyl]phenyl]-ethyl]-5-methylpyrazine-carboxamide], gliclazide [N-[[(hexa-hydrocyclopenta[c]pyrrol-2(1 H)-yl)amino]carbonyl]-4-methyl-- benzenesulfonamide], glimepiride [traps-3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]-sulfonyl]phenyl]ethyl]-2-oxo-1 H-pyrrole-1-carboxamide], gfiquidone [N-[(cyclohexyl-amino)carbonyl]-4-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2(1 H)-isoquinolinyl)ethyl]-benzenesulfonamide], glibornuride [N-[[(3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]-4-methyl-benzenesulfonamide], glisoxepid [N-[2-[4-[[[[(hexahydro-1 H-azepin-1-yl)amino]carbonyl]amino]-sulfonyl]phenyl]ethyl]-5-methyl-3-isoxazolecarboxamide], glisentide [N-[2-[4-[[[(cyclo-pentylamino)-carbonyl]amino]sulfonyl]phenyl]-ethyl]-2-methoxybenzamide], glisolamide [N-[2-[4[[[(cyclohexyl-amino)carbonyl]amino]-sulfonyl]phenyl]ethyl]-5-methyl-3-isoxazolecarboxamide], glybuzole [N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide], glyclopyramide [4-chloro-N-[(1-pyrrolidinylamino)carbonyl]benzenesulfonamide]
etc. as second generation sulfonylureas and pharmaceutically suitable acid addition salts thereof.
The most important biguanidine derivatives can be characterized by the formula ~1 ~3 2 ~~ ~~ \ ~
I~ N H ~l H (~
wherein R~, R2, R3 and R4 represent, independently, a hydrogen atom, a C~_~o alkyl group, a naphthyl group, a phenyl group or a phenyl(C~_4 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~, R2, R3 and R4 is other than a hydrogen atom, or R~ and R2 together with the adjacent nitrogen atom and/or R3 and R4 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].
PREVENTION OR TREATMENT OF DIABETES
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 above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium, polycystic ovary syndrome and/or other diabetic complications.
In the industrially developed countries more and more human being suffers from diabetes. The frequency of the disease is growing especially rapidly in the population above 50 of age. For example, the development of type 2 diabetes (i.e. non-insulin-dependent diabetes mellitus, NIDDM) is promoted by the defects in both the production and use of insulin. Genetic and environmental factors equally contribute to the formation of this wide-spread serious disease accompanied by significant mortality. The patient treated with insulin or another antidiabetic or anti-hyperlipidemic agent obtains, as a matter of fact, only a palliative treatment that improves the life quality, however, the complications which accompany the diabetes appear unavoidably. A significant part of the antidiabetic agents only enhances the production of insulin in the organism.
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.
It has been found that cicletanine [chemical name (~)-3-(4-chlorophenyl)-1,3-dihydro-6-methylfuro-[3,4.-c]pyridin-7-of], a known active agent having blood pressure lowering activity [US
Patent No. 4,383,998 ], exerts an insulin sensitizing effect. For example, in cases when insulin is produced by the organism in a decreased amount, this available amount becomes sufficient to bring about the required physiological effect in the presence of cicletanine. Also in patients suffering from insulin resistance, 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.
Thus, 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 sensitising 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) a first pharmaceutical composition containing"cicletanine or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier(s), and (b) 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).
Definition of expressions used in the description and claims 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 carriers) and any of the usual processes of drug manufacture, and in this case the two sorts of pharmaceutical composition obtained are administered fio the patient simulfianeously or one after the other following an interval; or - the two active agents have been converfied to one single pharmaceutical composition that can be administered to the patient being in need fihereof. In the latter case, the pharmaceutical composition may contain a mixiure 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. Of course, one or more conventional carriers) and any of the usual processes of drug manufacture are used to prepare this single pharmaceutical composition.
Under an antidiabetic active agent (b~) any of the pharmacologically active agents conventionally used in the therapy for the treatment of diabetes is meant. These are mainly the following:
- insulin, - insulin sensitizing active agents, - active agents that enhance the production of insulin, - sulfonamides, - biguanidine derivatives and - a-glucosidase inhibitors.
As 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 PP~R
(peroxisome proliferator-activated receptor) y-agonists, for example the thiazolidinedione derivatives such as pioglitazone [(~)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-5 thiazolidinedione], troglitazone [(~)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,3-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-[4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]benzyl]-2,4-thiazolidinedione] and other 2,4-thiazolidinedione derivatives as well as pharmaceutically suitable acid addition salts thereof.
The active agents that enhance the production of insulin are, for example, as follows: mitiglinide [(ocS,3aR,7aS)-octahydro-y-oxo-a-(phenylmethyl)-2H-isoindole-2-butanoic acid), repaglinide [(S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]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.
Out of the sulfonamides, the most important ones are the sulfonylurea derivatives e.g. tolbutamide [N-[(butylamino)-carbonyl]-4-methylbenzenesulfonamide], chlorpropamide [4-chloro-N-[(propylamino)carbonyl]benzenesulfonamide], fiolazamide [N-[[(hexahydro-1 H-azepin-1-yl)amino]carbonyl]-4-methylbenzenesulfonamide], acetohexamide [4-acetyl-N-[(cyclohexyfamino)carbonyl]benzenesulfonamide] etca as first generation sulfonylureas or, for example, glyburide (glibenclamide) [5-chloro-N-[2-[4-[[[(cyclohexylamino)carbonyl]_ amino]sulfonyl]phenyl)ethyl]-2-methoxybenzamide], glipizide [N-[2-[4-[[[(cyclohexyl-amino)carbonyl]amino]sulfonyl]phenyl]-ethyl]-5-methylpyrazine-carboxamide], gliclazide [N-[[(hexa-hydrocyclopenta[c]pyrrol-2(1 H)-yl)amino]carbonyl]-4-methyl-- benzenesulfonamide], glimepiride [traps-3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]-sulfonyl]phenyl]ethyl]-2-oxo-1 H-pyrrole-1-carboxamide], gfiquidone [N-[(cyclohexyl-amino)carbonyl]-4-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2(1 H)-isoquinolinyl)ethyl]-benzenesulfonamide], glibornuride [N-[[(3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]-4-methyl-benzenesulfonamide], glisoxepid [N-[2-[4-[[[[(hexahydro-1 H-azepin-1-yl)amino]carbonyl]amino]-sulfonyl]phenyl]ethyl]-5-methyl-3-isoxazolecarboxamide], glisentide [N-[2-[4-[[[(cyclo-pentylamino)-carbonyl]amino]sulfonyl]phenyl]-ethyl]-2-methoxybenzamide], glisolamide [N-[2-[4[[[(cyclohexyl-amino)carbonyl]amino]-sulfonyl]phenyl]ethyl]-5-methyl-3-isoxazolecarboxamide], glybuzole [N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide], glyclopyramide [4-chloro-N-[(1-pyrrolidinylamino)carbonyl]benzenesulfonamide]
etc. as second generation sulfonylureas and pharmaceutically suitable acid addition salts thereof.
The most important biguanidine derivatives can be characterized by the formula ~1 ~3 2 ~~ ~~ \ ~
I~ N H ~l H (~
wherein R~, R2, R3 and R4 represent, independently, a hydrogen atom, a C~_~o alkyl group, a naphthyl group, a phenyl group or a phenyl(C~_4 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~, R2, R3 and R4 is other than a hydrogen atom, or R~ and R2 together with the adjacent nitrogen atom and/or R3 and R4 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 a-glucosidase. Important representants thereof are, for example, miglitol [1,5-dideoxy-1,5-[(2-hydroxyethyl)imino]-D-glucitol], acarbose [O-4.,6-dideoxy-4-[[[1 S-(1 a,4cc,5(3,6a,)]-4,5,6-trihydroxy-(3-hydroxymethyl)-2-cyclohexen-1-yl]amino]-a,-D-g1 ucopyranosyl-( 1-~4)-O-a.-D-glucopyranosyl-( 1-~4.)-D-glucose], voglibose [3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epiinositol]
etc.
Under an anti-hyperlipidemic active agent (b2) 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. clofibrate [2-(4-chlorophenoxy)-2-methyl=
propanoic acid ethyl ester], gemfibrozil [5-(2,5-dimethyl-phenoxy)-2,2-dimethylpentanoic acid], sirnfibrate [2-(4-chloro-phenoxy)-2-methylpropanoic acid 1,3-propanediyl ester], etofibrate [3-pyridinecarboxylic acid 2-[2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy]ethyl ester], ciprofibrate [2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid], ronifibrate [3-pyridinecarboxylic acid 3-[2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy]propyl ester] etc.
etc.
Under an anti-hyperlipidemic active agent (b2) 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. clofibrate [2-(4-chlorophenoxy)-2-methyl=
propanoic acid ethyl ester], gemfibrozil [5-(2,5-dimethyl-phenoxy)-2,2-dimethylpentanoic acid], sirnfibrate [2-(4-chloro-phenoxy)-2-methylpropanoic acid 1,3-propanediyl ester], etofibrate [3-pyridinecarboxylic acid 2-[2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy]ethyl ester], ciprofibrate [2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid], ronifibrate [3-pyridinecarboxylic acid 3-[2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy]propyl ester] etc.
Out of the HMG coenzyme reductase inhibitors, the most important active agents are the following: lovastatin [[1 S-[1a(R''),3a,7~,8[i(2S*,4S~'),8a[i]]-2-methylbutanoic acid 1,2,3,7,8,8a-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 a(aS*,8S*),2a,6a,8~(R*),8aa]]-1,2,6,7,8,8a-hexahydro-[i,b,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid monosodium salt], simvastatin [[1 S-[1 a,3a,7[i,8[i(2S*,4S*),8a[i]]-2,2-dimethylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester], atorvastatin [[R-(R*,R*)]-2-(4-fluorophenyl)-[3,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid] etc.
Out of the 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-pyridine-carboxylic acid 1-(4-chlorophenyl)-2-methylpropyl ester] etc.
Out of the antacids that bind the bile acids, important ones are the following: 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-divinylben~ene copolymer], polidexide [an anion exchange resin containing quaternary ammonium groups 5 which bind the bile acids in the intestine] etc.
The antidiabefic 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 10 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.
When the antidiabetic or anti-hyperlipidemic active agent has a chemical structure that can form a salt with a base, also the salt of the active agent formed with a pharmaceutically suitable inorganic or organic base can be used. When 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.
In formula I, the C~_4 alkyl group can ~be a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec,-butyl, tert.-butyl, or isobutyl group. The C~_~o 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~_4 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.
In the synergistic pharmaceutical combination of the invention, the mass (or weight) ratio of the,cicletanine or a pharmaceutically suitable acid addition salt thereof and the 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 is, in general, (1-100):(100-1). In general, the one or two pharmaceutical compositions) 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.
In the synergistic pharmaceutical combination of the invention, 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. Thus, 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~) an anti-diabetic 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 a-glucosidase inhibitor such as miglitol, acarbose or voglibose, or (b2) an anti-hyperlipidemic active agent e.g. 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~) and (b2).
The influence of the combination of the invention on the glucose sensitivity was studied using the following tests. All experiments performed conform to the European Community guiding principles for the care and use of experimental animals.
Adult male New Zealand white rabbits weighing 3-3.2 kg, housed in an animal room (12-hour light/darl< periods a day, temperature of 22-25 °C, relative humidity of 50-70 %) with one animal per pen, fed commercial laboratory chow and tap water ad libitum, were used throughout. The animals underwent surgery after a two-week adaptation period [Szilvassy Z. et al., Br. J. Pharmacol., 112, 999-1001 (1994)].
Surgery was performed under aseptic conditions. The rabbits were anaesthetized with an intravenous bolus of 10 mg/kg diazepam (Sigma, St. Louis, MO, USA) and 5 mg/kg ketamine (EGIS Pharmaceuticals Ltd., Budapest, Hungary).
Lidocaine (EGIS Pharmaceuticals Ltd., Budapest, Hungary) was administered subcutaneously for local pain relief. Poly-ethylene catheters were inserted into two major branches of the jugular vein and the left carotid artery. The catheters were exteriorised through the back of the neck. These lines were kept patent by filling with sodium heparin solution (100 IU/ml).
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 p,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. i-0.5 mmol/litre) by a variable rate of glucose infusion via the second venous cannula. When blood glucose had stabilized for at least 30 min, we defined this condition as steady state. In the steady state, additional blood samples (0.5 ml) were taken for plasma insulin determination at 10-min intervals. The glucose infusion rate (mg/kg/min) during steady state was used to characterise insulin sensitivity [DeFronzo R.A. et al., Am. J. Of Physiol., 237, E214-223 (1979)]. The 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 6t" 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. , Table 1 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Group Control CicletanineMetforminCicletanine of (30 mg/kg)(100 (30 mg/kg) animals p.o. mg/kg) +
p.o. metformin (100 mg/kg) p.o.
normal 13,81,11 16,21,35 14,41,03 19,41,32 7,91,3 14,21,31 10,71,01 15,61,12 normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
Table 2 5 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Group Control CicletanineTroglitazoneCicletanine of (30 mg/kg)(75 mg/kg) (30 mg/kg) animals p.o. p.o. +
troglitazone (75 mg/kg) p.o.
normal 13,20,9816,91,13 14,30,08 19,82,00 ...._....................._...........__..._..........................._.......
._.._....._........._.._.........._...._...M.__...._..._......_...._.......__..
.................__............._............._._..._............_.............
_.._..................._.............._......_............
HC 8,20,76 13,51,41 13,21,06 15,70,99 normal = healthy animals were used in the test;
10 HC = hypercholesterolaemic animals were used in the test.
Table 3 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Gr~uia ~~ntr~I Cicletanine ~aride Ci~lefanirre ~f (30 mg/kg) (1 mg/kg) (30 mg/kg) anirr~als p.o. p.o. +
glyburide (1 mg/kg) p.o.
normal 13,44~0,86 15,9~0,89 11,8~1,3g 16,4.~2,22 HC 8,4~1,09 12,9~1,06 7,0~1,00 14,91~0,78 normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
As a matter of fact, 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.
As seen in Table 1, in healthy animals, of course, higher values are obtained than in hypercholesterolaemic ones. In the control groups, lower glucose infusion rates are experienced than in the groups treated with either cicletanine or metformin.
Anyway, in both healthy and cholesterolaemic animals, the glucose infusion rates are significantly higher when the animals has been treated with both cicletanine and metformin than in the case when only one of the test compounds has been administered. Thus, synergism is observed between cicletanine and metformin.
The situation is the same with cicletanine and troglitazone as well as cicletanine and glyburide as shown by Table 2 and Table 3, respectively.
Thus, 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. Preferably, 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~h day. The results obtained are shown in Table 4.
Table 4 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Group Control CicletanineCicle Cicletanine of (10 mg/kg) (30 mglkg)(100 mg/kg) animalsp.o. p.o. p.o.
normal 13,440,86 14, 91,1116, 81, 15, 90,83 HC 8,41,09 11,21,21 13,51,41 14,261,16 normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
As a matter of fact, in the latter test the influence of various doses of cicletanine on the utilization of insulin produced by the pancreas was studied. From tha data of Table 4 it can be seen that, relative to the control group, even a peroral dosage of as low as 10 mg/kg of cicletanine enhances the utilization of insulin produced by the organism in both healthy and hyper-cholesterolaemic animals. (The control data indicate the amount of glucose to be administered by infusion which amount is required to produce an euglycaemic state in hyper-insulinaemic animals.) Of course, the higher doses of cicletanine produced still favourable utilizations of insulin.
The invention includes also a method for the treatment or the prevention of a prediabetic state, metabolic ?~-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 andlor 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.
In addition to cicletanine or a pharmaceutically suitable acid addition salt thereof, if desired, also an antidiabetic or anti-hyperlipidaemic active agent can be administered to the patient suffering from or threatened by the states listed above. In this case 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.
Since the cicletanine synergistically enhances the therapeutical effect of the antidiabetic or anti-hyperlipidemic active agent, 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, 5 preferably about 50 mg for an adult person having a body weight of 70 kg.
Using the process of the invention, the development of especially the following clinical patterns can be prevented, or, when once developed, they can be influenced advantageously:
10 - prediabetic state such as glucose intolerance or insulin resistance, - metabolic X-syndrome, - both types of diabetes (IDDM and NIDDM), - diabetic complications with special regards to retinopathy, 15 neuropathy, nephropathy, polycystic ovary syndrome (PCOS), alopecia, diffuse effluvium, gestation diabetes mellitus (GDM), arterial hypertonia, dislipidemia, arterio-sclerosis, obesitas, cardial ischemia associated with diabetes etc.
20 Thus, 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. 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. When 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.
Out of the 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-pyridine-carboxylic acid 1-(4-chlorophenyl)-2-methylpropyl ester] etc.
Out of the antacids that bind the bile acids, important ones are the following: 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-divinylben~ene copolymer], polidexide [an anion exchange resin containing quaternary ammonium groups 5 which bind the bile acids in the intestine] etc.
The antidiabefic 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 10 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.
When the antidiabetic or anti-hyperlipidemic active agent has a chemical structure that can form a salt with a base, also the salt of the active agent formed with a pharmaceutically suitable inorganic or organic base can be used. When 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.
In formula I, the C~_4 alkyl group can ~be a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec,-butyl, tert.-butyl, or isobutyl group. The C~_~o 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~_4 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.
In the synergistic pharmaceutical combination of the invention, the mass (or weight) ratio of the,cicletanine or a pharmaceutically suitable acid addition salt thereof and the 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 is, in general, (1-100):(100-1). In general, the one or two pharmaceutical compositions) 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.
In the synergistic pharmaceutical combination of the invention, 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. Thus, 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~) an anti-diabetic 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 a-glucosidase inhibitor such as miglitol, acarbose or voglibose, or (b2) an anti-hyperlipidemic active agent e.g. 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~) and (b2).
The influence of the combination of the invention on the glucose sensitivity was studied using the following tests. All experiments performed conform to the European Community guiding principles for the care and use of experimental animals.
Adult male New Zealand white rabbits weighing 3-3.2 kg, housed in an animal room (12-hour light/darl< periods a day, temperature of 22-25 °C, relative humidity of 50-70 %) with one animal per pen, fed commercial laboratory chow and tap water ad libitum, were used throughout. The animals underwent surgery after a two-week adaptation period [Szilvassy Z. et al., Br. J. Pharmacol., 112, 999-1001 (1994)].
Surgery was performed under aseptic conditions. The rabbits were anaesthetized with an intravenous bolus of 10 mg/kg diazepam (Sigma, St. Louis, MO, USA) and 5 mg/kg ketamine (EGIS Pharmaceuticals Ltd., Budapest, Hungary).
Lidocaine (EGIS Pharmaceuticals Ltd., Budapest, Hungary) was administered subcutaneously for local pain relief. Poly-ethylene catheters were inserted into two major branches of the jugular vein and the left carotid artery. The catheters were exteriorised through the back of the neck. These lines were kept patent by filling with sodium heparin solution (100 IU/ml).
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 p,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. i-0.5 mmol/litre) by a variable rate of glucose infusion via the second venous cannula. When blood glucose had stabilized for at least 30 min, we defined this condition as steady state. In the steady state, additional blood samples (0.5 ml) were taken for plasma insulin determination at 10-min intervals. The glucose infusion rate (mg/kg/min) during steady state was used to characterise insulin sensitivity [DeFronzo R.A. et al., Am. J. Of Physiol., 237, E214-223 (1979)]. The 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 6t" 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. , Table 1 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Group Control CicletanineMetforminCicletanine of (30 mg/kg)(100 (30 mg/kg) animals p.o. mg/kg) +
p.o. metformin (100 mg/kg) p.o.
normal 13,81,11 16,21,35 14,41,03 19,41,32 7,91,3 14,21,31 10,71,01 15,61,12 normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
Table 2 5 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Group Control CicletanineTroglitazoneCicletanine of (30 mg/kg)(75 mg/kg) (30 mg/kg) animals p.o. p.o. +
troglitazone (75 mg/kg) p.o.
normal 13,20,9816,91,13 14,30,08 19,82,00 ...._....................._...........__..._..........................._.......
._.._....._........._.._.........._...._...M.__...._..._......_...._.......__..
.................__............._............._._..._............_.............
_.._..................._.............._......_............
HC 8,20,76 13,51,41 13,21,06 15,70,99 normal = healthy animals were used in the test;
10 HC = hypercholesterolaemic animals were used in the test.
Table 3 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Gr~uia ~~ntr~I Cicletanine ~aride Ci~lefanirre ~f (30 mg/kg) (1 mg/kg) (30 mg/kg) anirr~als p.o. p.o. +
glyburide (1 mg/kg) p.o.
normal 13,44~0,86 15,9~0,89 11,8~1,3g 16,4.~2,22 HC 8,4~1,09 12,9~1,06 7,0~1,00 14,91~0,78 normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
As a matter of fact, 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.
As seen in Table 1, in healthy animals, of course, higher values are obtained than in hypercholesterolaemic ones. In the control groups, lower glucose infusion rates are experienced than in the groups treated with either cicletanine or metformin.
Anyway, in both healthy and cholesterolaemic animals, the glucose infusion rates are significantly higher when the animals has been treated with both cicletanine and metformin than in the case when only one of the test compounds has been administered. Thus, synergism is observed between cicletanine and metformin.
The situation is the same with cicletanine and troglitazone as well as cicletanine and glyburide as shown by Table 2 and Table 3, respectively.
Thus, 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. Preferably, 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~h day. The results obtained are shown in Table 4.
Table 4 Insulin sensitivity as characterized by the glucose infusion rate in mg/kg/min during steady state Group Control CicletanineCicle Cicletanine of (10 mg/kg) (30 mglkg)(100 mg/kg) animalsp.o. p.o. p.o.
normal 13,440,86 14, 91,1116, 81, 15, 90,83 HC 8,41,09 11,21,21 13,51,41 14,261,16 normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
As a matter of fact, in the latter test the influence of various doses of cicletanine on the utilization of insulin produced by the pancreas was studied. From tha data of Table 4 it can be seen that, relative to the control group, even a peroral dosage of as low as 10 mg/kg of cicletanine enhances the utilization of insulin produced by the organism in both healthy and hyper-cholesterolaemic animals. (The control data indicate the amount of glucose to be administered by infusion which amount is required to produce an euglycaemic state in hyper-insulinaemic animals.) Of course, the higher doses of cicletanine produced still favourable utilizations of insulin.
The invention includes also a method for the treatment or the prevention of a prediabetic state, metabolic ?~-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 andlor 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.
In addition to cicletanine or a pharmaceutically suitable acid addition salt thereof, if desired, also an antidiabetic or anti-hyperlipidaemic active agent can be administered to the patient suffering from or threatened by the states listed above. In this case 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.
Since the cicletanine synergistically enhances the therapeutical effect of the antidiabetic or anti-hyperlipidemic active agent, 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, 5 preferably about 50 mg for an adult person having a body weight of 70 kg.
Using the process of the invention, the development of especially the following clinical patterns can be prevented, or, when once developed, they can be influenced advantageously:
10 - prediabetic state such as glucose intolerance or insulin resistance, - metabolic X-syndrome, - both types of diabetes (IDDM and NIDDM), - diabetic complications with special regards to retinopathy, 15 neuropathy, nephropathy, polycystic ovary syndrome (PCOS), alopecia, diffuse effluvium, gestation diabetes mellitus (GDM), arterial hypertonia, dislipidemia, arterio-sclerosis, obesitas, cardial ischemia associated with diabetes etc.
20 Thus, 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. 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. When 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.
Claims (10)
1. 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 comprising (a) a first pharmaceutical composition containing cicletanine or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier(s), and (b) 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).
2. A pharmaceutical combination of Claim 1 in which a single pharmaceutical composition comprises both the cicletanine or a pharmaceutically suitable acid addition salt thereof and the 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.
3. A pharmaceutical combination of Claim 1 or 2 comprising a thiazolidinedione derivative or a pharmaceutically suitable acid addition salt thereof as the antidiabetic active agent.
4. A pharmaceutical combination of Claim 1 or 2 comprising a sulfonylurea or a pharmaceutically suitable acid addition salt thereof as the antidiabetic active agent.
5. A pharmaceutical combination of Claim 1 or 2 comprising a biguanidine derivative of the formula I, wherein wherein R1, R2, R3 and R4 represent, independently, a hydrogen atom, a C1-10 alkyl group, a naphthyl group, a phenyl group or a phenyl(C1-4 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 C1-4 alkyl group or a C1-4 alkoxy group, with the proviso that one of R1, R2, R3 and R4 is other than a hydrogen atom, or R1 and R2 together with the adjacent nitrogen atom and/or R3 and R4 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, or a pharmaceutically suitable acid addition salt thereof as the antidiabetic active agent.
6. A pharmaceutical combitanion of Claim 5 comprising metformin or a pharmaceutically suitable acid addition salt thereof as the antidiabetic active agent.
7. A pharmaceutical combination of Claim 1 or 2 comprising insulin, pioglitazone, troglitazone, ciglitazone, rosiglitazone, mitiglinide, repaglinide, senaglinide, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyburide, glipizide, gliclazide, glimepiride, gliquidone, glibornuride, glisoxepid, glibenclamide, glisentide, glisolamide, glybuzole, glyclopyramide, metformin, buformin, phenformin, miglitol, acarbose or voglibose, clofibrate, gemfibrozil, simfibrate, etofibrate, ciprofibrate, ronifibrate, lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, acipimox, niceritrol, nicomof, nicoclonate, colestipol, cholestyramine, polidexide or, if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof as the antidiabetic or anti-hyperlipidemic active agent.
8. Use of cicletanine or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition having insulin sensitizing effect.
9. The use of Claim 5 in which each pharmaceutical composition contains 30 to 100 mg of cicletanine or cicletanine hydrochloride.
10. 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.
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HU0300990A HUP0300990A2 (en) | 2003-04-15 | 2003-04-15 | Synergistic combination for the prophylaxis and treatment of diabetes |
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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US20050054731A1 (en) * | 2003-09-08 | 2005-03-10 | Franco Folli | Multi-system therapy for diabetes, the metabolic syndrome and obesity |
US20070275996A1 (en) * | 2003-12-16 | 2007-11-29 | Michele Bortolini | Use of Statins For The Treatment Of Metabolic Syndrome |
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 |
TWI513462B (en) | 2009-11-13 | 2015-12-21 | Toray Industries | Therapeutic or preventive agents for diabetes |
CN103827083B (en) | 2011-08-08 | 2016-03-09 | 伊谬诺米特医疗有限公司 | N1-cyclammonium-N5-substituted-phenyl Biguanide derivative and preparation method thereof and the pharmaceutical composition containing this derivative |
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---|---|---|---|
FZDE | Discontinued |