CA2924682A1 - Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the prevention and treatment of diabetes - Google Patents
Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the prevention and treatment of diabetes Download PDFInfo
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- CA2924682A1 CA2924682A1 CA2924682A CA2924682A CA2924682A1 CA 2924682 A1 CA2924682 A1 CA 2924682A1 CA 2924682 A CA2924682 A CA 2924682A CA 2924682 A CA2924682 A CA 2924682A CA 2924682 A1 CA2924682 A1 CA 2924682A1
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- Prior art keywords
- carboxy
- ethyl
- dimethylpropan
- aminium
- pharmaceutically acceptable
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- 150000003839 salts Chemical class 0.000 title claims abstract description 16
- ISMYCKWHOZKHNJ-UHFFFAOYSA-O 3-carboxypropyl-ethyl-dimethylazanium Chemical compound CC[N+](C)(C)CCCC(O)=O ISMYCKWHOZKHNJ-UHFFFAOYSA-O 0.000 title claims abstract description 6
- 206010012601 diabetes mellitus Diseases 0.000 title claims description 12
- 230000002265 prevention Effects 0.000 title claims description 7
- PPDPFXLNXLDRNM-WLHGVMLRSA-N (e)-but-2-enedioate;3-carboxypropyl-ethyl-dimethylazanium;hydron Chemical group OC(=O)\C=C\C([O-])=O.CC[N+](C)(C)CCCC(O)=O PPDPFXLNXLDRNM-WLHGVMLRSA-N 0.000 claims description 3
- DQSCWIHGBKJVRY-UHFFFAOYSA-N 3-carboxypropyl-ethyl-dimethylazanium;dihydrogen phosphate Chemical group OP(O)([O-])=O.CC[N+](C)(C)CCCC(O)=O DQSCWIHGBKJVRY-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 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 abstract description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 11
- 239000008103 glucose Substances 0.000 abstract description 11
- 102000004877 Insulin Human genes 0.000 abstract description 9
- 108090001061 Insulin Proteins 0.000 abstract description 9
- 229940125396 insulin Drugs 0.000 abstract description 9
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 abstract description 4
- 230000037058 blood plasma level Effects 0.000 abstract description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 16
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 9
- JHPNVNIEXXLNTR-UHFFFAOYSA-N 4-(trimethylammonio)butanoate Chemical compound C[N+](C)(C)CCCC([O-])=O JHPNVNIEXXLNTR-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 6
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- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
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- 238000002560 therapeutic procedure Methods 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- PHIQHXFUZVPYII-LURJTMIESA-O (S)-carnitinium Chemical compound C[N+](C)(C)C[C@@H](O)CC(O)=O PHIQHXFUZVPYII-LURJTMIESA-O 0.000 description 1
- WOTYQFCDMFUXPG-UHFFFAOYSA-N 2-acetyloxybenzoate;3-carboxypropyl-ethyl-dimethylazanium Chemical compound CC[N+](C)(C)CCCC(O)=O.CC(=O)OC1=CC=CC=C1C([O-])=O WOTYQFCDMFUXPG-UHFFFAOYSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical group OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
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- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- -1 carboxy-N-ethyl-N,N-dimethylpropan-1-aminium 3-carboxypropanoate Chemical compound 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FIIMLTIASNPROL-UHFFFAOYSA-N dihydrogen phosphate;2-methylbutan-2-ylazanium Chemical group OP(O)([O-])=O.CCC(C)(C)[NH3+] FIIMLTIASNPROL-UHFFFAOYSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229940127004 drugs for type 2 diabetes Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
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- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-M orotate Chemical compound [O-]C(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-M 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium and its pharmaceutically acceptable salts to decrease blood plasma levels of insulin and glucose.
Description
Description Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the prevention and treatment of diabetes Technical Field The present invention relates to 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof for use in the prevention and treatment of diabetes. Examples of pharmaceutically acceptable salts of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium are: 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate.
Background Art 3-Carboxy-/V,/V,N-trimethylpropan-1-aminium (GBB) is known mostly as a bio-precursor of carnitine, a key molecule in the regulation of myocardial energy metabolism. It was primarily characterised as a toxic substance, which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and cardiac arrest in diastole LINNEWEH W. Gamma- Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Seylers Zeitschrift fur physiologLsche Chemle. 1929, vol.181, p.42-53. In later publications it has been shown 3-carboxy-/V,/V,N-trimethylpropan-1-aminium has extremely low toxicity (LD50 7000 mg/kg, s.c.)
Background Art 3-Carboxy-/V,/V,N-trimethylpropan-1-aminium (GBB) is known mostly as a bio-precursor of carnitine, a key molecule in the regulation of myocardial energy metabolism. It was primarily characterised as a toxic substance, which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and cardiac arrest in diastole LINNEWEH W. Gamma- Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Seylers Zeitschrift fur physiologLsche Chemle. 1929, vol.181, p.42-53. In later publications it has been shown 3-carboxy-/V,/V,N-trimethylpropan-1-aminium has extremely low toxicity (LD50 7000 mg/kg, s.c.)
2 ROTZSCH. W. Uber die Toxizitat des Carnitins und einiger verwandter Stoffe.
Acta biol. med. germ. 1959, vol.3, p.28-36.
Methods for preparation of a new compound with cardioprotective activity - 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium has been disclosed in WO 2011/048201 A
(GRINDEKS, JSC) 28/04/2011 . Salts of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium as well as their use in the treatment of cardiovascular diseases has been disclosed in patent publication WO 2012/146736 A (GRINDEKS, JSC) 27/12/2012.
Diabetes mellitus is one of the leading causes of morbidity and mortality globally, and despite medical breakthroughs and treatment innovations, the number of adults with this condition has been increasing at a faster pace than previously expected DANAEI
G., et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants.
Lancet.
2011, vol.378, p.31-40. Type 2 diabetes mellitus (T2DM) comprises about 90% of all diabetes cases throughout the world. T2DM is a metabolic disorder characterized by elevated blood glucose levels in the context of insulin resistance and relative insulin deficiency. Insulin resistance contributes to hyperinsulinaemia which is often seen in early stages of T2DM. Furthermore, hyperinsulinaemia is predictive of development of T2DM, as it is known to precede T2DM by decades. T2DM causes dysfunctions in multiple organs and tissues leading to disability and premature death of T2DM
patients. Diabetes-related expenses to healthcare systems and patients are projected to increase twice during next 25 years HUANG E.S., et al. Projecting the future
Acta biol. med. germ. 1959, vol.3, p.28-36.
Methods for preparation of a new compound with cardioprotective activity - 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium has been disclosed in WO 2011/048201 A
(GRINDEKS, JSC) 28/04/2011 . Salts of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium as well as their use in the treatment of cardiovascular diseases has been disclosed in patent publication WO 2012/146736 A (GRINDEKS, JSC) 27/12/2012.
Diabetes mellitus is one of the leading causes of morbidity and mortality globally, and despite medical breakthroughs and treatment innovations, the number of adults with this condition has been increasing at a faster pace than previously expected DANAEI
G., et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants.
Lancet.
2011, vol.378, p.31-40. Type 2 diabetes mellitus (T2DM) comprises about 90% of all diabetes cases throughout the world. T2DM is a metabolic disorder characterized by elevated blood glucose levels in the context of insulin resistance and relative insulin deficiency. Insulin resistance contributes to hyperinsulinaemia which is often seen in early stages of T2DM. Furthermore, hyperinsulinaemia is predictive of development of T2DM, as it is known to precede T2DM by decades. T2DM causes dysfunctions in multiple organs and tissues leading to disability and premature death of T2DM
patients. Diabetes-related expenses to healthcare systems and patients are projected to increase twice during next 25 years HUANG E.S., et al. Projecting the future
3 diabetes population size and related costs for the U.S.. Diabetes Care. 2009, vol.32, p.2225-2229. , therefore anti-diabetes drugs are of high necessity and economical value.
Although several classes of anti-diabetic drugs are currently available, there is a significant need for novel therapies with added medical value and improved side-effect profile. Achieving and maintaining long-term glycaemic control by existing drugs in T2DM patients is often challenging, also due to insufficient insulinaemic control MANNINO G.C., SESTI G. Individualized Therapy for Type 2 Diabetes: Clinical Implications of Pharmacogenetic Data. Mol Diagn Ther. 2012, vol.16, p.285-302.
, SAFAVI M., et al. The importance of synthetic drugs for type 2 diabetes drug discovery. Expert Opih Drug DiScov. Ahead of Print (doi:10.1517/17460441.2013.837883). 19.09.2013, p.1-25. Normalizing insulin levels is of particular preventive and therapeutic importance since uncontrolled insulin resistance and subsequent hyperinsulinaemia are major contributors in development of T2DM. Therefore, new pharmacotherapy targeting hyperglycaemia, insulin resistance and hyperinsulinaemia could be of particular interest for effective prevention and treatment of T2DM.
Summary of invention The present invention is directed to prevention and treatment of diabetes by decreasing blood plasma levels of insulin and glucose.
Although several classes of anti-diabetic drugs are currently available, there is a significant need for novel therapies with added medical value and improved side-effect profile. Achieving and maintaining long-term glycaemic control by existing drugs in T2DM patients is often challenging, also due to insufficient insulinaemic control MANNINO G.C., SESTI G. Individualized Therapy for Type 2 Diabetes: Clinical Implications of Pharmacogenetic Data. Mol Diagn Ther. 2012, vol.16, p.285-302.
, SAFAVI M., et al. The importance of synthetic drugs for type 2 diabetes drug discovery. Expert Opih Drug DiScov. Ahead of Print (doi:10.1517/17460441.2013.837883). 19.09.2013, p.1-25. Normalizing insulin levels is of particular preventive and therapeutic importance since uncontrolled insulin resistance and subsequent hyperinsulinaemia are major contributors in development of T2DM. Therefore, new pharmacotherapy targeting hyperglycaemia, insulin resistance and hyperinsulinaemia could be of particular interest for effective prevention and treatment of T2DM.
Summary of invention The present invention is directed to prevention and treatment of diabetes by decreasing blood plasma levels of insulin and glucose.
4 During our research to find new active substances to treat hyperglycaemia an unexpected glucose- and insulin- reducing effect of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium salts has been discovered.
The reduction of glucose and insulin concentration in blood is achieved by treatment with 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or its pharmaceutically acceptable salts, for example but not limited to: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium 2-(acetyloxy)benzoate, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate, carboxy-N-ethyl-N,N-dimethylpropan-1-aminium 3-carboxypropanoate, preferably 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate or 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate.
3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium can be used in pharmaceutical preparations containing the compound, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. Thus, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable solutions can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt therefore can also be prepared for transdermal application, for example, in a form of adhesive plaster.
A therapeutically effective amount of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or its pharmaceutically acceptable salt is about 0.01 to 500 mg/kg/day, preferably 0.1 to 100 mg/kg/day.
Example Female ApoE-/- mice weighing 18 - 20 g were maintained on a 12 h dark/12 h light cycle in air-conditioned rooms (22.5 0.5 C, 50 5% humidity) with unlimited access to food and water.
Mice were adapted to local conditions for one week before the beginning of the study.
At the age of 8 weeks, mice were randomly assigned to five equally sized groups (n =
10). Experimental animals of all groups were fed with WESTERN RD (P) diet (Cat 82316) from Special Diets Services (Great Britain) for 4 months. During these months, mice from different experimental groups received following treatment:
Control group - drinking water;
GBB group - GBB 10mg/kg;
3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate group - 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate 17.5 mg/kg;
3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate group - 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate 16.8 mg/kg.
GBB, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate or 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate were added to the drinking water. The doses of GBB, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate were equimolar to the 10 mg/kg dose (62.5 inium d4-(ethyl(dimethyl)ammonio)butanoate. The dosing of the test compounds was confirmed by measuring the consumption of drinking water every 2 days and adjusting the concentration of supplemented substances.
At the age of 8 and 16 weeks blood was collected into EDTA/diamide- and protease inhibitor (PMSF, pepstatin, leupeptin, aprotinin)-containing tubes. Blood glucose concentration was measured using a MediSense Optium Xceed blood glucose meter and strips. Plasma was obtained by centrifugation at 3000 x g and stored frozen (-80 C) until analysis. Plasma insulin concentrations were determined with a RIA
kit (Biotrend, Germany).
Treatment-effect on plasma glucose level is presented in Table 1. Both 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate reduced plasma glucose levels in a statistically significant manner, while GBB lacked an effect.
Table 1 Effects of test compounds at a dose of 10mg/kg on plasma glucose concentration in fed and fasted ApoE-/- mice Week 8 Week 16 Fed Fasted Fed Fasted Control group 8,0 0,42 5,1 0,28 10,0 0,55 5,4 0,33 3-carboxy-N-ethyl-N,Ab dimethylpropan-1-aminium dihydrogen phosphate group 8,2 0,61 3,7 0,18* 8,2 0,39* 4,3 0,16*
3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate group 7,6 0,27 3,9 0,08* 9,2 0,34 4,0 0,22*
GBB group 8,1 0,25 4,4 0,39 8,4 0,29 4,5 0,31 Each value represents the mean S.E.M. of 8-10 animals. *Significantly different from the control group (Tukey's test P< 0.05).
Insulin levels were decreased by 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate (Table 2).
Table 2 Effects of test compounds at a dose of 10mg/kg on plasma insulin concentration in fasted ApoE-/- mice Week 8 Week 16 Control group 1,39 0,13 1,26 0,05 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate group 0,60 0,06* 0,97 0,11*
3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate group 0,62 0,06* 0,85 0,06*
GBB group 1,30 0,11 1,20 0,10 Each value represents the mean S.E.M. of 8-10 animals. *Significantly different from the control group (Tukey's test P< 0.05).
Results presented in Table 1 and Table 2 show that 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate have a glucose and insulin level lowering properties, thus demonstrating efficacy in prevention and treatment of diabetes.
The reduction of glucose and insulin concentration in blood is achieved by treatment with 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or its pharmaceutically acceptable salts, for example but not limited to: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium 2-(acetyloxy)benzoate, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate, carboxy-N-ethyl-N,N-dimethylpropan-1-aminium 3-carboxypropanoate, preferably 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate or 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate.
3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium can be used in pharmaceutical preparations containing the compound, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. Thus, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable solutions can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt therefore can also be prepared for transdermal application, for example, in a form of adhesive plaster.
A therapeutically effective amount of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium or its pharmaceutically acceptable salt is about 0.01 to 500 mg/kg/day, preferably 0.1 to 100 mg/kg/day.
Example Female ApoE-/- mice weighing 18 - 20 g were maintained on a 12 h dark/12 h light cycle in air-conditioned rooms (22.5 0.5 C, 50 5% humidity) with unlimited access to food and water.
Mice were adapted to local conditions for one week before the beginning of the study.
At the age of 8 weeks, mice were randomly assigned to five equally sized groups (n =
10). Experimental animals of all groups were fed with WESTERN RD (P) diet (Cat 82316) from Special Diets Services (Great Britain) for 4 months. During these months, mice from different experimental groups received following treatment:
Control group - drinking water;
GBB group - GBB 10mg/kg;
3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate group - 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate 17.5 mg/kg;
3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate group - 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate 16.8 mg/kg.
GBB, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate or 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate were added to the drinking water. The doses of GBB, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate were equimolar to the 10 mg/kg dose (62.5 inium d4-(ethyl(dimethyl)ammonio)butanoate. The dosing of the test compounds was confirmed by measuring the consumption of drinking water every 2 days and adjusting the concentration of supplemented substances.
At the age of 8 and 16 weeks blood was collected into EDTA/diamide- and protease inhibitor (PMSF, pepstatin, leupeptin, aprotinin)-containing tubes. Blood glucose concentration was measured using a MediSense Optium Xceed blood glucose meter and strips. Plasma was obtained by centrifugation at 3000 x g and stored frozen (-80 C) until analysis. Plasma insulin concentrations were determined with a RIA
kit (Biotrend, Germany).
Treatment-effect on plasma glucose level is presented in Table 1. Both 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate reduced plasma glucose levels in a statistically significant manner, while GBB lacked an effect.
Table 1 Effects of test compounds at a dose of 10mg/kg on plasma glucose concentration in fed and fasted ApoE-/- mice Week 8 Week 16 Fed Fasted Fed Fasted Control group 8,0 0,42 5,1 0,28 10,0 0,55 5,4 0,33 3-carboxy-N-ethyl-N,Ab dimethylpropan-1-aminium dihydrogen phosphate group 8,2 0,61 3,7 0,18* 8,2 0,39* 4,3 0,16*
3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate group 7,6 0,27 3,9 0,08* 9,2 0,34 4,0 0,22*
GBB group 8,1 0,25 4,4 0,39 8,4 0,29 4,5 0,31 Each value represents the mean S.E.M. of 8-10 animals. *Significantly different from the control group (Tukey's test P< 0.05).
Insulin levels were decreased by 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate (Table 2).
Table 2 Effects of test compounds at a dose of 10mg/kg on plasma insulin concentration in fasted ApoE-/- mice Week 8 Week 16 Control group 1,39 0,13 1,26 0,05 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate group 0,60 0,06* 0,97 0,11*
3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate group 0,62 0,06* 0,85 0,06*
GBB group 1,30 0,11 1,20 0,10 Each value represents the mean S.E.M. of 8-10 animals. *Significantly different from the control group (Tukey's test P< 0.05).
Results presented in Table 1 and Table 2 show that 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate have a glucose and insulin level lowering properties, thus demonstrating efficacy in prevention and treatment of diabetes.
Claims (3)
1. 3-Carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or pharmaceutically acceptable salts thereof for use in method of the prevention and treatment of diabetes.
2. 3-Carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or pharmaceutically acceptable salts for use according to claim 1, wherein a pharmaceutically acceptable salt is 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate.
3. 3-Carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or pharmaceutically acceptable salts for use according to claim 1, wherein a pharmaceutically acceptable salt is 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13186201 | 2013-09-26 | ||
| EP13186201.3 | 2013-09-26 | ||
| PCT/IB2014/064514 WO2015044828A1 (en) | 2013-09-26 | 2014-09-15 | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the prevention and treatment of diabetes |
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| CA2924682A1 true CA2924682A1 (en) | 2015-04-02 |
| CA2924682C CA2924682C (en) | 2018-02-27 |
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| AR (1) | AR099638A1 (en) |
| BR (1) | BR112016004211B1 (en) |
| CA (1) | CA2924682C (en) |
| JO (1) | JO3333B1 (en) |
| MX (1) | MX368505B (en) |
| TN (1) | TN2016000064A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2067474A1 (en) * | 2007-12-05 | 2009-06-10 | Grindeks, a joint stock company | Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate |
| LV14345B (en) | 2009-10-22 | 2011-07-20 | Grindeks, A/S | 4-[ethyl(dimethyl)ammonio]butanoate and their use in the treatment of cardiovascular diseases |
| CA2832693C (en) | 2011-04-27 | 2018-10-02 | Grindeks, A Joint Stock Company | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
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| BR112016004211B1 (en) | 2022-09-06 |
| JO3333B1 (en) | 2019-03-13 |
| CN105530929A (en) | 2016-04-27 |
| MX368505B (en) | 2019-10-04 |
| AR099638A1 (en) | 2016-08-10 |
| CA2924682C (en) | 2018-02-27 |
| ZA201600894B (en) | 2017-05-31 |
| TN2016000064A1 (en) | 2017-07-05 |
| MX2016003347A (en) | 2016-06-24 |
| BR112016004211A2 (en) | 2017-08-01 |
| CN105530929B (en) | 2018-03-02 |
| WO2015044828A1 (en) | 2015-04-02 |
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