WO2013058642A1 - Utilisation des bétaxantines et de leurs dérivés pour préparer un médicament destiné au traitement du prédiabète et du diabète. - Google Patents

Utilisation des bétaxantines et de leurs dérivés pour préparer un médicament destiné au traitement du prédiabète et du diabète. Download PDF

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Publication number
WO2013058642A1
WO2013058642A1 PCT/MX2012/000100 MX2012000100W WO2013058642A1 WO 2013058642 A1 WO2013058642 A1 WO 2013058642A1 MX 2012000100 W MX2012000100 W MX 2012000100W WO 2013058642 A1 WO2013058642 A1 WO 2013058642A1
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WO
WIPO (PCT)
Prior art keywords
derivatives
betaxanthines
diabetes
groups
prediabetes
Prior art date
Application number
PCT/MX2012/000100
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English (en)
Spanish (es)
Inventor
Agustin LUGO RADILLO
Original Assignee
Lugo Radillo Agustin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lugo Radillo Agustin filed Critical Lugo Radillo Agustin
Publication of WO2013058642A1 publication Critical patent/WO2013058642A1/fr

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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
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention consists in using betaxanthines and their derivatives to prepare a medicament for the treatment of prediabetes and diabetes.
  • the present inventor has found for the first time solid scientific evidence that the administration of a betalaine lowers blood or plasma glucose concentrations. Since betaxanthines are part of betalains, as are betacyanins, and share a similar general formula, betaxanthines can also be used to prepare a medication to treat prediabetes and diabetes.
  • the present invention describes the use of betaxanthines and their derivatives, to prepare a medicament for the treatment of diabetes and prediabetes. Betaxanthines and their derivatives can be used individually or incorporated into pharmaceutical compositions to prepare a medicament for the treatment of prediabetes and diabetes.
  • Diabetes or diabetes mellitus is a group of metabolic diseases in which the individuals who suffer from it have blood or plasma glucose concentrations equal to or greater than 126 mg / dL (WHO, 1999 and 2006). Patients with blood glucose concentrations of 100 mg / dL (ADA, 201 1) at 125 mg / dL are considered to suffer from prediabetes 2-8% of the world's population suffers from diabetes.
  • diabetes There are several types of diabetes: type 1 diabetes, type 2 diabetes, gestational diabetes, congenital diabetes, diabetes related to cystic fibrosis, steroid-induced diabetes or steroid diabetes, and monogenic diabetes or caused by monogenic mutations.
  • Type 1 diabetes is caused by deficiency in insulin production.
  • Type 2 diabetes is caused by insulin resistance, which may or may not be combined with a reduction in insulin secretion.
  • Gestational diabetes is when a woman who had not had diabetes has a high blood or plasma glucose level during pregnancy.
  • Congenital diabetes is due to genetic defects in insulin secretion.
  • Diabetes related to cystic fibrosis is caused by damage to the pancreas, which is caused by the alterations present in this disease.
  • Steroid-induced diabetes is generated by high doses of glucocorticoids.
  • Monogenic diabetes refers to several inherited forms of diabetes that are caused by mutations in autosomal dominant genes that alter insulin production. Diabetes can be treated with insulin or drugs. Diabetes is not curable, except for gestational diabetes that can disappear on its own after delivery. Untreated or untreated diabetes causes complications.
  • Acute complications include: diabetic ketoacidosis, hypoglycemia and hyperosmolar non-ketosis. Long-term complications include: cardiovascular disorders, retinopathy, chronic renal failure, diabetic foot and susceptibility to infections.
  • Hyperglycemia present in diabetes mellitus can be diagnosed by one of the following methods: Determination of fasting plasma glucose levels greater than or equal to 7.0 mmol / L (126 mg / dL), determination of glycosylated hemoglobin (HbAlc) greater than or equal to 6.5%, symptoms of hyperglycemia and casual plasma glucose greater than or equal to 1.1 mmol / L (200 mg / dL), plasma glucose greater than or equal to 1.1 mmol / L (200 mg / dL) two hours after 75 g of an oral glucose load (WHO, 1999 and 2006).
  • Constant blood glucose levels above 100 mg / dL can lead to serious complications such as ketoacidosis or diabetic coma, which can be fatal (ADA, 2011).
  • Compounds that lower blood or plasma glucose concentrations are the most commonly used medications to treat diabetes.
  • the pharmaceutical compounds available in the market to treat diabetes are not completely effective in all patients and all of them have side effects. Therefore, new molecules capable of lowering blood or plasma glucose levels are good candidates to be used to prepare medications for the treatment of various types of diabetes, including prediabetes.
  • the present inventor has identified a group of molecules capable of lowering the concentration of blood or plasma glucose with which a medicament for the treatment of prediabetes and diabetes can be prepared.
  • This group of molecules are betaxanthines.
  • plasma glucose concentrations decreased significantly (pO.00001) in mice that were administered betanidine, a semi-conserved molecule of the general betaxanthine formula. .
  • Betanidine is a red to violet betalaine belonging to the betacyanine group.
  • glycosylated is generally found in the form of betanin (Wybraniec, S., et al., 2011). Betanin is generally used as a food and paint dye.
  • Betalains including betanidine, are aromatic derivatives derived from tyrosine. Betalains are produced in almost all plants of the order Caryophyllales and also in fungi of the phylum Basidiomycota, are present in all their tissues, including fruits and seeds. The only families of the order Caryophyllales in which they are not produced are Caryophyllaceae and Molluginaceae, which produce anthocyanins instead of betalains.
  • Betanidine has the following chemical formula:
  • the present invention is based on solid results, demonstrating unambiguously that a betalaine decreases blood or plasma glucose concentration.
  • the mechanism by which it generates this effect is still unknown because this effect Betanidine is a fact that has just been found by the present inventor and whose existence was unknown to science.
  • Betalains are antioxidants (Wybraniec, S., et al., 201 1; Tsai, P.J., et al., 2010) and chemopreventives (Kapadia, GJ, et al. 1996). No betalain regulation activity of blood or plasma glucose concentrations had been reported before this finding (Lugo-Radillo, A., et al., 2012).
  • betanidine derivatives including those of its isobetanidine isomer
  • This semi-preservation of the general formula of betanidine is found in all betaxanthines and therefore also its activity to reduce the concentration of blood or plasma glucose. It is inferred that this activity of reducing the concentration of blood or plasma glucose is also modified by the types and / or number of atoms, radicals or groups that are bound or adhered to this general formula, and therefore, are also included in this invention.
  • Vulgaxanthin I Vulgaxanthin II Indicaxanthin
  • This invention includes the use of betaxanthines and their derivatives, individually or in combination with themselves or with other pharmaceutical compounds to prepare a medicament for the treatment of diabetes and prediabetes, by any route of administration and for use in any organism.
  • eukaryotic including the human.
  • the results presented here clearly indicate - and for the first time - that betaxanthines can be used to lower the concentration of blood or plasma glucose (Lugoadillo, A., et al., 2012).
  • the present invention includes:
  • Vulgaxanthin I, vulgaxanthin II and derivatives of both within the invention share the following general formula:
  • Ri, R 2 , R 3 , R4, R5, Re, R7, R «, R9, Rio, Rn can vary independently from each other in terms of the group or atom that forms them, these groups or atoms can be: hydrogen , sulfur, oxygen, halogen atoms, hydroxy, amino, amide, carboxy, carbonyl, keto, aldehyde, nitroso, nitro, cyano, acyl, thiol groups, (Ci-C 6 ) alkyl, (C 2 -C) groups 6 ) Alkyl, (C 2 -C) Alcinyl, halogen chyl, (Ci-Ce) alkoxy, (Ci-C 6 ) thioalkoxy, (Ci-C 6 ) halogenoalkoxy, di (Ci-Ce) alkylamino or alkylcarbonyl, any saccharide, any polysaccharide, any glycoside, any alkane, any alkene , any al
  • Ri, R 2 , R 3 , R4, R 5 , R ⁇ , R 7 , R 8 , R9, Rio, Rn can vary independently from each other in terms of the group or atom that forms them, these groups can be or Atoms: hydrogen, sulfur, oxygen, halogen atoms, hydroxy, amino, amide, carboxy, carbonyl, keto, aldehyde, nitroso, nitro, cyano, acyl, thiol groups, (CI-CU) alkyl groups, (C 2 -C6) alkylenyl, (C 2 -C 6 ) alcinyl, (C] -C 6 ) halogenoalkyl, (Ci-C 6 ) alkoxy, (Ci-C 6 ) thioalkoxy, (Ci-C 6 ) halogenoalkoxy, di (Ci -C 6 ) alkylamino or alkylcarbonyl, any saccharide, any polysaccharide, any
  • Miraxanthin I and its derivatives within the invention share the following general formula:
  • Ri, R 2 , R 3 , R4, R 5 , R ⁇ , R7, Re, R9, Rio, Rn > R12 can vary independently from each other in terms of the group or atom that forms them, and these groups or atoms can be : hydrogen, sulfur, oxygen, halogen atoms, hydroxy groups, amino, amide, carboxy, carbonyl, keto, aldehyde, nitroso, nitro, cyano, acyl, thiol, groups (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkylenyl, (C 2 -C 6 ) alcinyl, (Ci-C 6 ) halogenoalkyl, (Ci-C 6 ) alkoxy, (Ci-C 6 ) thioalkoxy, (Ci-C 6 ) halogenoalkoxy, di (Ci -C 6 ) alkylamino or alkylcarbonyl, any saccharide, any poly
  • miraxanthin III and miraxanthin V and derivatives thereof to prepare a medication for the treatment of prediabetes and diabetes.
  • Miraxanthin III miraxanthin V and derivatives of both within the invention share the following general formula:
  • Ri, R 2 , R 3 , R4, R5, R ⁇ , R7, R 8 , R9, Rio, R11 » R12, R13 can vary independently of each other in terms of the group or atom that forms them, these groups can be or atoms: hydrogen, sulfur, oxygen, halogen atoms, hydroxy, amino, amide, carboxy, carbonyl, keto, aldehyde, nitroso, nitro, cyano, acyl, thiol groups, (Ci-C 6 ) alkyl groups, ( C 2 -C 6 ) alkylenyl, (C2-C 6 ) alcinyl, (C] -C 6 ) halogenoalkyl, (Ci-C 6 ) alkoxy, (Ci-C 6 ) thioalkoxy, (Ci-C 6 ) halogenoalkoxy, di (Ci-C 6 ) alkylamino or alkylcarbonyl, any saccharide, any polys
  • Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ , R7, R 8 , R9, Rio can vary independently from each other in terms of the group or atom that forms them, these groups or atoms can be: hydrogen, sulfur, oxygen, halogen atoms, hydroxy groups, amino, amide, carboxy, carbonyl, keto, aldehyde, nitroso, nitro, cyano, acyl, thiol, groups (Ci-C 6 ) alkyl, (C 2 - C 6 ) alkylenyl, (C 2 -C 6 ) alcinyl, (Ci-C 6 ) halogenoalkyl, (Ci-C 6 ) alkoxy, (Ci- C 6 ) thioalkoxy, (CJ-C ⁇ ) halogenoalkoxy, di (Ci- C 6 ) alkylamino or alkylcarbonyl, any saccharide, any polysacc
  • Betaxanthines or any of its derivatives can be extracted from a plant source that contains them and / or, with or without subsequent purification. Subsequently they can be used alone or in combination with each other or in combination with other pharmaceutical products to prepare a drug for the treatment of prediabetes or diabetes. This medicine can be administered orally directly or added to any type of food or liquid to decrease the concentration of blood or plasma glucose.
  • Betaxanthines or any of its derivatives can be synthesized artificially. Subsequently they can be used alone or in combination with each other or in combination with other pharmaceutical products to prepare a drug for the treatment of prediabetes or diabetes. This medicine can be administered orally directly or added to any type of food or liquid to decrease the concentration of blood or plasma glucose.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Obesity (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
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  • Mycology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Child & Adolescent Psychology (AREA)
  • Endocrinology (AREA)
  • Alternative & Traditional Medicine (AREA)
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Abstract

L'invention concerne l'utilisation des bétaxantines et de leurs dérivés pour préparer un médicament destiné au traitement du prédiabète et du diabète. Le médicament susmentionné permet de réduire la concentration de glucose plasmatique après son administration. Ce médicament peut contenir une ou plusieurs bétaxantines ou l'un de leur dérivés individuellement ou dans de multiples combinaisons. En outre, le médicament peut contenir des combinaisons d'autres produits pharmaceutiques. De la même manière, le médicament peut être administré par n'importe quelle voie. Ce médicament qui contient une ou plusieurs bétaxantines ou l'un de leurs dérivés et qui est destiné au traitement du prédiabète et du diabète peut être administré à n'importe quel organisme eucaryote, y compris, l'être humain.
PCT/MX2012/000100 2011-10-17 2012-10-15 Utilisation des bétaxantines et de leurs dérivés pour préparer un médicament destiné au traitement du prédiabète et du diabète. WO2013058642A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2011011879A MX2011011879A (es) 2011-10-17 2011-10-17 Uso de las betaxantinas y sus derivados para preparar un medicamento para el tratamiento de la prediabetes y diabetes.
MXMX/A/2011/011879 2011-10-17

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WO2013058642A1 true WO2013058642A1 (fr) 2013-04-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109295123A (zh) * 2018-09-12 2019-02-01 天津大学 一种甜菜黄素的生物生产方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026792A1 (fr) * 1996-12-19 1998-06-25 State Of Israel - Ministry Of Agriculture Compositions contenant des antioxydants et procede de preparation desdits antioxydants
JP2005336069A (ja) * 2004-05-25 2005-12-08 Masaki Sato 抗糖尿病用組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026792A1 (fr) * 1996-12-19 1998-06-25 State Of Israel - Ministry Of Agriculture Compositions contenant des antioxydants et procede de preparation desdits antioxydants
JP2005336069A (ja) * 2004-05-25 2005-12-08 Masaki Sato 抗糖尿病用組成物

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"A database on antidiabetic plants", 19 August 2011 (2011-08-19), Retrieved from the Internet <URL:http://herbalmedicinalplants.org/Herbs.php?disp=Betavulgaris&herblist=B> [retrieved on 20130301] *
ALARCON-AGUILAR, F. J. ET AL.: "Hypoglycemic Activity of Two Polysaccharides Isolated from Opuntia ficus-indica and O. streptacantha", PROCEEDINGS OF THE WESTERN PHARMACOLOGY SOCIETY'S, vol. 46, 2003, pages 139 - 142 *
FERNANDEZ-LOPEZ, J. A. ET AL.: "Application of high-performance chromatography to the characterization of the betalain pigments in prickly pear fruits", JOURNAL OF CHROMATOGRAPHY A, vol. 913, 2001, pages 415 - 420, XP004232807, doi:10.1016/S0021-9673(00)01224-3 *
SALEEM, M. ET AL.: "Secondary metabolites from Opuntiajicus-indica var. saboten", PHYTOCHEMISTRY, vol. 67, 2006, pages 1390 - 1394 *
XIANG, L. ET AL.: "Alkaloids from Portulaca oleácea L.", PHYTOCHEMISTRY, vol. 66, 2005, pages 2595 - 2601 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109295123A (zh) * 2018-09-12 2019-02-01 天津大学 一种甜菜黄素的生物生产方法

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