WO2010100337A1 - Nouveaux promédicaments de la metformine - Google Patents

Nouveaux promédicaments de la metformine Download PDF

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Publication number
WO2010100337A1
WO2010100337A1 PCT/FI2010/050165 FI2010050165W WO2010100337A1 WO 2010100337 A1 WO2010100337 A1 WO 2010100337A1 FI 2010050165 W FI2010050165 W FI 2010050165W WO 2010100337 A1 WO2010100337 A1 WO 2010100337A1
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WO
WIPO (PCT)
Prior art keywords
metformin
prodrugs
pharmaceutically acceptable
carbon atoms
saturated
Prior art date
Application number
PCT/FI2010/050165
Other languages
English (en)
Inventor
Kristiina Huttunen
Jukka LEPPÄNEN
Jarkko Rautio
Jouko Vepsäläinen
Original Assignee
University Of Eastern Finland
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 University Of Eastern Finland filed Critical University Of Eastern Finland
Publication of WO2010100337A1 publication Critical patent/WO2010100337A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/08—Sulfenic acids; Derivatives thereof
    • C07C313/18—Sulfenamides
    • C07C313/26—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C313/30—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel prodrugs of metformin, their pharmaceutically acceptable salts, pharmaceutical compositions containing the prodrugs, and methods of using the prodrugs.
  • the present invention relates to prodrugs wherein sulfur- containing promoieties are attached to metformin to form novel bioreversible sulfenyl guanidine (N-S) prodrugs of metformin with improved oral absorption, and consequently promoted bioavailability.
  • Metformin iV,./V-dimethyl imidodicarbonimidic diamide
  • metformin is used as adjunct therapy to virtually every other antihyperglycemic medicine available today.
  • metformin is highly basic and fully protonated under physiological conditions (pH 1.2-7.4), and therefore, is slowly and incompletely absorbed from the upper intestine after oral administration resulting in the poor bioavailability.
  • formulation strategies for example, extended-release formulations, have been developed attempting to ameliorate the malabsorption of metformin with trivial results (Belcher et al. 2005; Cullen et al. 2004).
  • Prodrugs are pharmacologically inactive or impaired, bioreversible derivatives of drug molecules utilised to improve the unfavourable physicochemical, pharmaceutical or biopharmaceutical properties of a parent drug (Prodrugs: Challenges and Rewards. 2007; Rautio et al. 2008; Stella and Himmelstein 1985). Accomplishing good membrane permeability for high passive transcellular absorption after oral administration by masking hydrogen bonding groups of an active compound is probably one of the most commonly introduced prodrug strategy.
  • metformin prodrugs which are readily bioconverted to metformin in vivo and able to improve oral bioavailability of metformin.
  • the present invention is directed to novel sulfenyl guanidine prodrugs of metformin and their pharmaceutically acceptable salts, as well as to methods of using such prodrugs.
  • the particular embodiments described herein are intended in all respects to be illustrative rather than restrictive. Alternative embodiments will become apparent to those skilled in the art to which the present invention pertains without departing from its scope.
  • the present invention concerns sulfenyl guanidine prodrugs of metformin and the pharmaceutically acceptable salts thereof.
  • sulfenyl guanidine prodrug(s) refers to prodrug(s) having a N-S bond, wherein the S is bivalent.
  • Preferred groups of R in the sulphur-containing moiety include but are not limited to a saturated or unsaturated, straight or branched chain of 1 to 10 carbon atoms or a saturated or unsaturated cyclic ring of 3 to 10 carbon atoms optionally containing a heteroatom, or an aromatic or heteroaromatic ring and all these backbones can optionally be substituted with 1 to 3 groups selected from hydroxyl, amino, mono- or dialkylamino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy and alkenyloxy.
  • R is a saturated or unsaturated straight or branched alkyl chain of 2 to 8 carbon atoms, or a saturated or unsaturated cyclic ring of 4 to 8 carbon atoms optionally containing a heteroatom, said straight or branched alkyl chain or cyclic ring optionally being substituted with 1 to 3 groups selected from amino, mono- or dialkylamino, acylamino, carboxyl or alkylcarboxyl, or a phenyl ring optionally with 1 to 2 substituent groups selected from amino, mono- or dialkylamino, acylamino, carboxyl or alkylcarboxyl.
  • R examples include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, phenyl, cysteine (without double S in the structure, -N-Cys), branched -CHR' 2 or -CR' 3 , in which R' is straight or branched chain of 1 to 5 carbon atoms, such as i-propyl, sec-butyl, £-butyl, optionally substituted with 1 to 3 groups selected from amino, mono- or dialkylamino, acylamino, carboxyl or alkylcarboxyl.
  • a straight or branched alkyl chain preferably contains 1 to 10 carbon atoms, even more preferably 2 to 8 carbon atoms.
  • Aromatic or heteroaromatic groups include but are not limited to groups such as phenyl, naphthelenyl, benzyl, benzoyl, pyridyl, furanyl, pyrronyl, thiophenyl, thiazol, imidazolyl, indolyl, benzofuranyl.
  • Heteroatoms are selected from the group consisting of N, O and S.
  • a suitable pharmaceutical composition according to the invention comprises a metformin prodrug of the invention and a pharmaceutical acceptable vehicle, with which the compound is administered to a patient.
  • Water is a preferred vehicle when the compound is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles also include excipients such starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, ethanol, and the like.
  • the present pharmaceutical compositions if needed, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used.
  • compositions according to the invention can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquid, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for pharmaceutical use.
  • the present prodrug and/or pharmaceutical compositions thereof may be administered through a variety of routes of administration. Administration can be systemic or local.
  • Methods for administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, topical (e.g., skin, eyes, nose, ears), or by inhalation.
  • Various delivery systems can be used for administration (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules).
  • a further object of the invention is the use of the novel sulfenyl guanidine prodrugs of metformin for the preparation of a medicament for the treatment of type 2 diabetes.
  • a still further object of the invention is a method for treating type 2 diabetes in a mammal, preferably in a human, which comprises administering to said mammal an effective amount of a compound according to the invention to provide therapeutically effective amount of metformin suitable for the desired treatment and management of type 2 diabetes.
  • An effective amount of metformin refers to an amount which is effective in achieving the desired antidiabetic and antihyperglycemic effects.
  • a typical dose of metformin for an adult human is 500 mg 2 to 3 times a day, total daily doses of for example 0.5 to 3 g per day being possible.
  • the improved bioavailability of metformin ascribed to the novel prodrugs of the present invention may result in improved efficacy, reduced gastro-intestinal adverse effects and/or lower required daily orally administered therapeutic doses.
  • the invention is also directed to a method for increasing oral bioavailability of metformin, comprising the step of preparing a metformin prodrug of the formula
  • novel sulfenyl guanidine prodrugs of the invention are readily absorbed from the gastrointestinal tract either by passive and/or carrier-mediated absorption and/or any other permeation mechanism and bioconverted to metformin in vivo.
  • the bioavailability of the novel prodrugs of metformin is improved compared to the bioavailability of metformin. Consequently, lower doses of orally administered metformin are necessary to achieve and maintain the required therapeutical effects. This means less side effects and better patient compliance.
  • Reaction conditions a) Acetonitrine (ACN), microwave irradiation (MW) 100 0 C, 10 min, b) metformin (1,1- dimethyl imidodicarbonimidic diamide), dimethylformamide (DMF), room temperature (RT), 24 h.
  • Metformin (/VyV-dimethyl imidodicarbonimidic diamide hydrochloride) (1.0 g, 6.0 mmol) in 10 ml of 1 M NaOH was stirred at room temperature for 30 min. Water was evaporated in vacuo and the residue was dissolved in 30 ml of MeOH. The solvent was evaporated and the residue was redissolved in 20 ml of MeOH. NaCl was filtered out of the solution and the filtrate was evaporated to yield basic metformin as white solid (0.77 g, 99%).
  • the compound 2b was synthesized as example 2 above.
  • the compound 2c was synthesized as example 2 above.
  • the compound 2d was synthesized as example 2 above.
  • the rates of chemical stability of the metformin sulfenyl guanidine prodrugs were determined at 37 0 C in 50 mM (ionic strength 0.15) HCl buffer at pH 1.0, acetate buffer at pH 4.0, phosphate buffer at pH 7.4 and borate buffer at pH 9.0.
  • the incubation mixtures were prepared by dissolving 5-10 mM stock solutions of prodrugs in H 2 O in preheated buffer solutions.
  • the prodrug mixtures of about 200 ⁇ M were incubated in a water bath at 37 0 C and the samples were withdrawn at appropriate intervals.
  • ACN was added to the samples (1: 1, v/v) to hinder further degradation during the high-performance liquid chromatography (HPLC) analyses.
  • HPLC high-performance liquid chromatography
  • the bioconversion of the metformin sulfenyl guanidine prodrugs were determined in 80% human serum, rat serum and 20% rat liver homogenate diluting with phosphate buffer (pH 7.4) at 37 0 C.
  • Prodrugs were dissolved in 50 mM phosphate buffer pH 7.4 (ionic strength 0.15) and the stock solutions as well as the biological material were preheated in a water bath. The reactions were initiated by adding the stock solutions to serum/liver homogenate. The mixtures were placed in a water bath at 37 0 C and the samples were withdrawn at appropriate intervals.
  • Ice-cold ACN was added to the samples (4:1, v/v) to precipitate proteins and hinder further degradation and the samples were centrifuged for 10 min at 12 000 rpm and kept on ice until injected into the HPLC system.
  • the concentration of the prodrugs and metformin were analyzed from the supernatants by the HPLC.
  • the prodrug 2b released metformin extremely fast with the half-lives ranging from 4 seconds to 40 minutes, whereas the prodrug 2a released hardly any metformin in vitro during 24 hours (Table 1). Due to possible involvement of free radicals in the bioconversion in vitro, the prodrug 2b was activated more readily compared to the prodrug 2a.
  • the distribution coefficients (log D) of metformin and metformin sulfenyl guanidine prodrugs were determined at room temperature from the distribution of the compounds between a mixture of 1-octanol and 50 mM acetate/phosphate buffer (pH 4.0 or 7.4) system. 1 mL of metformin or prodrug solution (150 ⁇ g/mL) in 50 mM buffer was added to 4 ml of 1-octanol saturated with desired buffer. The mixtures were shaken for 1 h and the phases were separated. The concentration of metformin or the metformin sulfenyl guanidine prodrugs in the buffers before and after the shaking were analyzed by HPLC.
  • the log D values of the prodrugs 2a and 2b as well as metformin are shown in Table 2.
  • the log D values of the prodrugs were significantly higher than those of metformin.
  • the calculated logP of 2c is 1.74 (ChemBioDraw Ultra 11.0).
  • the compounds were dissolved either in 0.9% NaCl solution or 10% HP- ⁇ -CD in 0.6% NaCl solution and orally administered (total injection volume of 1.0 ml) to the rats using a feeding tube.
  • An approximately 200 ⁇ l aliquot of blood sample was collected via the jugular vein at regular time intervals after the start of the oral administration to micro test tubes containing 3% EDTA in 0.7% NaCl solution.
  • the drawn blood volume was substituted by 0.9 % NaCl immediately after each blood sampling.
  • Plasma samples were centrifuged 5 min at 14 000 rpm immediately after each blood sampling and 100 ⁇ l aliquot of each plasma sample and 20 ⁇ l of 5.2 mg/ml 1,1,3,3- tetramethylguanidine as an internal standard were vortexed with ice-cold ACN (1:4, v/v) to precipitate proteins and hinder further degradation.
  • the samples were centrifuged 5 min at 14 000 rpm and kept on ice until injected into the HPLC system.
  • the pharmacokinetic analysis was performed by GraphPad Prism software, version 4.03 (GraphPad Software, Inc., San Diego, CA, USA).
  • the area under the plasma concentration - time curve (AUC) was calculated using the linear trapezoidal method.
  • the maximum plasma concentration (C max ) and the time to reach the maximum plasma concentration (t max ) were read directly from the plasma concentration - time data.
  • the bioconversion of sulfenyl guanidine prodrugs of metformin is expected to occur from a nucleophilic substitution reaction by endogenous nucleophiles (glutathione, cysteine, etc.) (Guarino, Karunaratne, and Stella 2007).
  • the prodrugs 2a and 2b were readily and quantitatively converted to metformin in rats after intravenous administration in vivo and only metformin was detected in rat blood.
  • Tables 3 and 4 show the AUC and C max values of both metformin and prodrug 2a after i.v. and oral administration, respectively.
  • the AUC and C max values after oral administration of the prodrug 2a (274.97 ⁇ g* min/ml, 1.34 ⁇ g/ml, respectively) was almost equal to the AUC and C max after oral administration of metformin (289.37 ⁇ g* min/ml, 1.65 ⁇ g/ml, respectively) although 25 mg (0,1 mmol) of prodrug 2a was given compared to 35 mg (0,2 mmol) of metformin.
  • the bioavailability (F%) of the prodrug 2a (63.1%) was improved compared to the bioavailability of metformin (42.7%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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)

Abstract

La présente invention concerne de nouveaux promédicaments de la metformine, leurs sels de qualité pharmaceutique, des compositions pharmaceutiques contenant les promédicaments et les procédés d'utilisation des promédicaments. En particulier, la présente invention concerne des promédicaments, les profractions contenant du soufre étant attachées à de la metformine pour former de nouveaux promédicaments sulfénylguanidines (N-S) bioréversibles de la metformine qui présentent une absorption orale améliorée et, par conséquent, une biodisponibilité favorisée.
PCT/FI2010/050165 2009-03-03 2010-03-03 Nouveaux promédicaments de la metformine WO2010100337A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20095208A FI20095208A0 (fi) 2009-03-03 2009-03-03 Metformiinin uudet aihiolääkkeet
FI20095208 2009-03-03

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012061165A2 (fr) * 2010-10-25 2012-05-10 Lu Xiandan Sharon Procédés et compositions d'amélioration de propriétés admet
WO2016025725A1 (fr) * 2014-08-14 2016-02-18 The Medical College Of Wisconsin, Inc. Composés de mito-metformine et leurs procédés de synthèse et d'utilisation
WO2016044433A2 (fr) 2014-09-16 2016-03-24 Biopharma Works Dérivés de la metformine
CN106748941A (zh) * 2016-11-28 2017-05-31 武汉福山生物科技有限公司 含硒化合物及其用途
US9827222B2 (en) 2013-07-01 2017-11-28 Emory University Treating or preventing nephrogenic diabetes insipidus
EP3950673A1 (fr) 2014-04-30 2022-02-09 Inspirna, Inc. Inhibiteurs de transport de créatine et leurs utilisations

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2696740A1 (fr) * 1992-10-13 1994-04-15 Dospharma Sa Dérivés prodrogués de la diméthylbiguanide et applications comme médicaments.
WO2003032908A2 (fr) * 2001-10-16 2003-04-24 University Of Kansas Nouveaux promedicaments de composes contenant des liaisons n-h et leurs procedes de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2696740A1 (fr) * 1992-10-13 1994-04-15 Dospharma Sa Dérivés prodrogués de la diméthylbiguanide et applications comme médicaments.
WO2003032908A2 (fr) * 2001-10-16 2003-04-24 University Of Kansas Nouveaux promedicaments de composes contenant des liaisons n-h et leurs procedes de preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUTTUNEN K.M. ET AL.: "Determination of metformin and its prodrugs in human and rat blood by hydrophilic interaction liquid chromatography.", J. PHARM BIOMED. ANAL., vol. 50, 2009, pages 469 - 474 *
HUTTUNEN K.M. ET AL.: "The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption.", J. MED. CHEM., vol. 52, 2009, pages 4142 - 4148 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012061165A2 (fr) * 2010-10-25 2012-05-10 Lu Xiandan Sharon Procédés et compositions d'amélioration de propriétés admet
WO2012061165A3 (fr) * 2010-10-25 2012-07-12 Lu Xiandan Sharon Procédés et compositions d'amélioration de propriétés admet
US9827222B2 (en) 2013-07-01 2017-11-28 Emory University Treating or preventing nephrogenic diabetes insipidus
US10596144B2 (en) 2013-07-01 2020-03-24 Emory University Treating or preventing nephrogenic diabetes insipidus
EP3950673A1 (fr) 2014-04-30 2022-02-09 Inspirna, Inc. Inhibiteurs de transport de créatine et leurs utilisations
WO2016025725A1 (fr) * 2014-08-14 2016-02-18 The Medical College Of Wisconsin, Inc. Composés de mito-metformine et leurs procédés de synthèse et d'utilisation
CN107205968A (zh) * 2014-08-14 2017-09-26 威斯康星州医药大学股份有限公司 修饰的线粒体‑二甲双胍化合物及其合成和使用方法
US11274114B2 (en) 2014-08-14 2022-03-15 The Medical College Of Wisconsin, Inc. Modified mito-metformin compounds and methods of synthesis and use thereof
WO2016044433A2 (fr) 2014-09-16 2016-03-24 Biopharma Works Dérivés de la metformine
WO2016044433A3 (fr) * 2014-09-16 2016-06-16 Biopharma Works Dérivés de la metformine
US10017529B2 (en) 2014-09-16 2018-07-10 BioPharma Works LLC Metformin derivatives
CN106748941A (zh) * 2016-11-28 2017-05-31 武汉福山生物科技有限公司 含硒化合物及其用途

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Publication number Publication date
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