FR2796940A1 - Metformin salts active in alleviating diabetic metabolic syndromes, such as protein metabolic disorders, hypertension, inflamed joints, obesity and increase in serum triglycerides - Google Patents

Metformin salts active in alleviating diabetic metabolic syndromes, such as protein metabolic disorders, hypertension, inflamed joints, obesity and increase in serum triglycerides Download PDF

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FR2796940A1
FR2796940A1 FR9909649A FR9909649A FR2796940A1 FR 2796940 A1 FR2796940 A1 FR 2796940A1 FR 9909649 A FR9909649 A FR 9909649A FR 9909649 A FR9909649 A FR 9909649A FR 2796940 A1 FR2796940 A1 FR 2796940A1
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metformin
sep
acid
salt according
salts
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FR2796940B1 (en
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Gerard Moinet
Daniel Cravo
Gerard Botton
Didier Mesangeau
Lilianne Doare
Micheline Kergoat
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Merck Sante SAS
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LIPHA SAS
LIPHA Liyonnaise Industrielle Pharmaceutique
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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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • 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
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • 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
    • 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

Abstract

Salts of metformin (N,N-dimethylimidodicarbonimido diamide; I) active in alleviating diabetic metabolic syndromes (SMIR). The salts of (I) are preferably the 2,5-dihydroxy benzene sulfonate (dobesilate), acetyl salicylate, naproxenate, ketoprofenate, 5-(2,5-dimethylphenoxy)-2,2-dimethyl pentanoate, captoprilate, apovincaminate, aminophyllinate, sulfamoyl phenoxy acetate, 6-hydroxy-2,5,7,8-tetramethyl chroman-2-carboxylate, bezafibrate, or alginate.

Description

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NOUVEAUX SELS DE METFORMINE,
LEUR PROCEDE D'OBTENTION
ET LES COMPOSITIONS PHARMACEUTIQUES EN RENFERMANT La présente invention se rapporte au domaine de la chimie organique et plus particulièrement à celui de la chimie thérapeutique. NEW METFORMIN SALTS,
THEIR PROCESS OF OBTAINING
The present invention relates to the field of organic chemistry and more particularly to that of therapeutic chemistry.

La présente invention a plus précisément pour objet de nouveaux sels de metformine, leur procédé d'obtention, leur utilisation en tant qu'agents antidiabétiques et les compositions pharmaceutiques qui les contiennent. The present invention more specifically relates to new metformin salts, their method of production, their use as antidiabetic agents and the pharmaceutical compositions which contain them.

La metformine est un biguanide substitué (N,N-diméthylimidodicarbonimido diamide ou 1,1-diméthylbiguanide), qui est reconnu depuis relativement longtemps comme un agent antihyperglycémiant, notamment en permettant d'améliorer la sensibilité à l'insuline, et qui est utilisé comme tel dans le traitement du diabète. Metformin is a substituted biguanide (N, N-dimethylimidodicarbonimido diamide or 1,1-dimethylbiguanide), which has been recognized for a relatively long time as an antihyperglycemic agent, in particular by improving insulin sensitivity, and which is used as a such in the treatment of diabetes.

Le diabète est marqué essentiellement par une élévation pathologique de la glycémie. Il se peut traduire biologiquement, notamment s' il est de type II, par : - des troubles du métabolisme des protides et des lipides, - de l'hypertension artérielle; - des inflammations de articulations; - une surcharge pondérale importante (obésité), - une augmentation anormale de la teneur des triglycérides dans le sérum sanguin. Diabetes is essentially marked by a pathological rise in blood sugar. It can be translated biologically, especially if it is of type II, by: - disorders of the metabolism of proteins and lipids, - arterial hypertension; - inflammations of joints; - an important overweight (obesity), - an abnormal increase of the triglyceride content in the blood serum.

L'ensemble de ces troubles est défini par l'abréviation SMIR. All of these disorders are defined by the abbreviation SMIR.

La présente invention a pour objet de nouveaux sels de metformine améliorant les syndromes métaboliques du diabète définis par l'abréviation SMIR. The present invention relates to new metformin salts improving metabolic diabetes syndromes defined by the abbreviation SMIR.

On a constaté, en outre, que l'utilisation de ces sels de metformine s'accompagne d'une absence de prolifération cellulaire (hépatique ou pancréatique) et surtout d'une amélioration des syndromes cardio-vasculaires (hypertension, dégénérescence vasculaire), de l'amélioration des phénomènes métaboliques (hyperglycémie, taux élevé de lipoprotéines liés au diabète). It has been found, moreover, that the use of these metformin salts is accompanied by an absence of cellular proliferation (hepatic or pancreatic) and especially by an improvement of the cardiovascular syndromes (hypertension, vascular degeneration), improvement of metabolic phenomena (hyperglycemia, high level of lipoproteins related to diabetes).

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Parmi les sels de metformine à composante cardio-vasculaire conformes à l'invention, on pourra citer plus particulièrement à titre de sels actuellement préférés : - le 2,5-dihydroxybenzènesulfonate de metformine ; - l'acétylsalicylate de metformine ; - le naproxénate de metformine ; - le kétoprofènate de metformine ; - le 5-(2,5-dimethylphenoxy)-2,2-diméthylpentanoate de metformine (gemfibrozilate) ; - le captoprilate de metformine ou le (S)-1-(3-mercapto-2-méthyl-1-oxo- propyl)-l-prolinate de metformine ; - l'apovincaminate de metformine ; - l'aminophyllinate de metformine ; - le sulfamoylphénoxyacétate de metformine ; - le 6-hydroxy-2,5,7,8-tétraméthyl-chroman-2-carboxylate de metformine ; - le bezafibrate de metformine ; - l'alginate de metformine ; L'invention comprend, en outre, les compositions pharmaceutiques renfermant au moins un sel de metformine à composante cardio-vasculaire, comme principe actif, en association avec des excipients acceptables pharmaceutiquement, et appropriés à leur administration, principalement par voie orale, mais également par voie parentérale. Among the metformin salts with a cardiovascular component according to the invention, mention may be made more particularly as currently preferred salts: metformin 2,5-dihydroxybenzenesulphonate; metformin acetylsalicylate; metformin naproxenate; metformin ketoprofenate; metformin 5- (2,5-dimethylphenoxy) -2,2-dimethylpentanoate (gemfibrozilate); metformin captoprilate or metformin (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -1-prolinate; metformin apovincaminate; metformin aminophyllinate; metformin sulfamoylphenoxyacetate; metformin 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate; metformin bezafibrate; metformin alginate; The invention furthermore comprises pharmaceutical compositions containing at least one metformin salt of cardiovascular component, as active ingredient, in association with pharmaceutically acceptable excipients, and suitable for their administration, mainly orally, but also by parenteral route.

De manière avantageuse, en ce qui concerne le mode d'administration par voie orale, on pourra utiliser toutes les formes usuelles appropriées à cette voie, telles que, par exemple, les comprimés, dragées, gélules ou capsules. A titre indicatif, le poids unitaire de principe actif peut varier entre 50 et 500 mg, et la posologie quotidienne pourra être, par exemple, de 1 à 3 comprimés par jour. Advantageously, as regards the mode of oral administration, it will be possible to use all the usual forms appropriate for this route, such as, for example, tablets, dragees, capsules or capsules. As an indication, the unit weight of active ingredient may vary between 50 and 500 mg, and the daily dosage may be, for example, 1 to 3 tablets per day.

Les compositions pharmaceutiques, conformes à l'invention, sont particulièrement utiles dans le traitement des formes de diabète, permettant notamment de réduire, The pharmaceutical compositions, in accordance with the invention, are particularly useful in the treatment of forms of diabetes, which make it possible in particular to reduce,

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voire d'éviter, le syndrome métabolique d'insulinorésistance que l'on peut observer lors de certaines thérapeutiques antidiabétiques. En effet, ces dernières stimulant essentiellement la sécrétion d'insuline, sans pour autant améliorer l'insulinorésistance, aboutissent, à plus ou moins long terme, à l'aggravation du diabète par épuisement des cellules-(3, pancréatiques.  to avoid, the metabolic syndrome of insulin resistance that can be observed during certain antidiabetic therapeutics. Indeed, the latter essentially stimulating the secretion of insulin, without improving insulin resistance, lead, in the more or less long term, to aggravation of diabetes by depletion of pancreatic (3) cells.

En outre, les sels, objet de la présente invention, contribuent à traiter les phénomènes d'hypertension ou d'hyperlipémie associés au diabète L'invention concerne, également, le procédé d'obtention d'un sel de metformine tel que décrit précédemment, caractérisé en ce qu'il consiste, essentiellement, à salifier la metformine base avec un acide minéral ou organique, dans un solvant inerte approprié, puis à isoler ledit sel ainsi obtenu par les méthodes usuelles. In addition, the salts which are the subject of the present invention contribute to treating the phenomena of hypertension or hyperlipemia associated with diabetes. The invention also relates to the process for obtaining a metformin salt as described above, characterized in that it essentially consists of salifying the base metformin with an inorganic or organic acid in a suitable inert solvent and then isolating said salt thus obtained by the usual methods.

De manière préférentielle, la metformine base et l'acide sont en quantités sensiblement équimolaires. Preferably, the base metformin and the acid are in substantially equimolar amounts.

La metformine base est un produit instable que l'on ne trouve pas dans le commerce et qu'il est nécessaire de préparer préalablement à toutes utilisations. Metformin base is an unstable product that is not commercially available and needs to be prepared before use.

La préparation de la metformine base est connue de l'homme de l'art (voir par exemple les brevets FR 2. 243.684 et FR 2. 264.525) et on s'y référera à titre d'état de la technique. The preparation of metformin base is known to those skilled in the art (see, for example, FR 2 243 684 and FR 2 264 520) and reference will be made to it as a prior art.

De manière préférentielle, l'acide utilisé est choisi parmi : - l'acide 2,5-dihydroxybenzènesulfonique ; - l'acide acétylsalicylique ; - le naproxène ; - l'acide alginique; - l'acide 2-(3-benzoylphényl)-propionique ; - l'acide 2-[4-[2-[(4-chlorobenzoyl)amino]éthyl]phenoxy]-2-méthylpropanoïque ou acide bezafibrique ; - l'acide 5-(2,5-dimethylphenoxy)-2,2-diméthylpentanoïque ou acide gemfibrozique ; Preferably, the acid used is chosen from: - 2,5-dihydroxybenzenesulphonic acid; acetylsalicylic acid; - naproxen; alginic acid; 2- (3-benzoylphenyl) -propionic acid; 2- [4- [2 - [(4-chlorobenzoyl) amino] ethyl] phenoxy] -2-methylpropanoic acid or bezafibric acid; 5- (2,5-dimethylphenoxy) -2,2-dimethylpentanoic acid or gemfibrozic acid;

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- l'acide apovincaminique ; - l'aminophylline ; - l'acide sulfamoylphénoxyacétique; - l'acide 6-hydroxy-2,5,7,8-tétraméthyl-chroman-2-carboxylique.  - Apovincaminic acid; aminophylline; sulfamoylphenoxyacetic acid; 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.

Le solvant inerte utilisé lors de la salification est choisi, de préférence, parmi l'éthanol, l'isopropanol, l'acétone, le N,N-diméthyl-formamide, le diméthylsulfoxyde ou l'acétonitrile. The inert solvent used during the salification is preferably chosen from ethanol, isopropanol, acetone, N, N-dimethylformamide, dimethylsulfoxide or acetonitrile.

Les exemples suivants illustrent l'invention sans pour autant la limiter. The following examples illustrate the invention without limiting it.

EXEMPLE Dobésilate de metformine (ou 2,5-dihydroxybenzènesulfonate de metformine) 1 Dans une fiole de 500 ml contenant une solution à 50 C de 2,5dihydroxybenzènesulfonate de potassium (57 g, 0.25 mol), dans 150 ml d'eau déminéralisée, on ajoute ,sans refroidir, une solution extemporanée préparée à partir de metformine base (32.5 g, 0. 25 mol), d'eau déminéralisée (150 ml) et d'acide D,L-tartrique (37. 5 g, 0.25 mol). Il se forme un précipité qui est filtré dès que la température du mélange revient à 20 C. Le solide blanc obtenu est recristallisé de l'éthanol (250 ml). On obtient 67,7 g du sel désiré (sous la forme d'un solide blanc cristallin), soit un rendement de 87 %. EXAMPLE Metformin dobesilate (or metformin 2,5-dihydroxybenzenesulfonate) 1 In a 500 ml flask containing a 50 C solution of potassium 2,5dihydroxybenzene sulphonate (57 g, 0.25 mol) in 150 ml of demineralized water, add, without cooling, an extemporaneous solution prepared from metformin base (32.5 g, 0.25 mol), demineralized water (150 ml) and D, L-tartaric acid (37.5 g, 0.25 mol) . A precipitate forms which is filtered as soon as the temperature of the mixture returns to 20 ° C. The white solid obtained is recrystallized from ethanol (250 ml). 67.7 g of the desired salt (in the form of a crystalline white solid) is obtained, ie a yield of 87%.

Pf (banc Kôfler) : 150-152 C [1H] RMN-60 Mhz. DMSO. TMS : # (ppm) : 2. 85 (6H, s); 6. 45 (6H, m); 6.85 (1 H, m); 7. 10 (2H, s); 8.75 (1H, s);
9.65 (1 H, s) IR (KBr) cm-': 3442 v OH ; v NH ; v C=N Pf (Kofler bench): 150-152 [1H] NMR-60 Mhz. DMSO. TMS: # (ppm): 2.85 (6H, s); 6. 45 (6H, m); 6.85 (1H, m); 7. 10 (2H, s); 8.75 (1H, s);
9.65 (1H, s) IR (KBr) cm- ': 3442; OH; v NH; v C = N

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EXEMPLE II Acétylsalicylate de metformine 2 Un mélange de metformine base (7,8 g, 60 mmol) et d'acide acétylsalicylique (10,8 g, 60 mmol) est dissout dans de l'isopropanol (70 ml). Après 15 minutes d'agitation, un précipité se forme. Il est essoré et rincé au pentane. On obtient 17 g du sel désiré, soit un rendement de 91 %.  EXAMPLE II Metformin Acetylsalicylate 2 A mixture of metformin base (7.8 g, 60 mmol) and acetylsalicylic acid (10.8 g, 60 mmol) was dissolved in isopropanol (70 ml). After stirring for 15 minutes, a precipitate forms. It is drained and rinsed with pentane. 17 g of the desired salt are obtained, ie a yield of 91%.

Pf (banc Kôfler) : 101-103 C [1H] RMN-200 Mhz, DMSO : # (ppm) : 2. 20 (s, 3H); 2. 95 (s, 6H); 6.92 (d, 1 H); 7. 20 (t, 1 H); 7. 35 (t, 1 H);
7. 80 (t, 1 H) [13C] RMN - 50 Mhz, DMSO : # (ppm) : 23.59, 39.60 (CH3); 124. 79, 127. 12, 131. 49, 133. 32 (CH) ; 135.32,
151. 75 (C=C) ; 161. 05, 161. 61 (C=N) ; 170.57, 171. 71 (C=O) IR (KBr) cm-1: 1748 v c=o ; v c=o Ce produit se différencie complètement du produit décrit sous ce nom dans la littérature (voir le brevet FR 2.243.684). Pf (Kofler bench): 101-103 [1H] NMR-200 Mhz, DMSO: # (ppm): 2. (s, 3H); 2. 95 (s, 6H); 6.92 (d, 1H); 7. (t, 1H); 7. 35 (t, 1H);
7. 80 (t, 1H) [13C] NMR - 50 Mhz, DMSO: # (ppm): 23.59, 39.60 (CH3); 124. 79, 127. 12, 131. 49, 133. 32 (CH); 135.32,
151. 75 (C = C); 161. 05, 161. 61 (C = N); 170.57, 171. 71 (C = O) IR (KBr) cm-1: 1748; vc = 0; vc = o This product is completely different from the product described under this name in the literature (see patent FR 2,243,684).

EXEMPLE III Naproxénate de metformine (ou 2(S)-méthyl-2-(6-méthoxynaphtyl)-acétate de metformine) 3 Dans une fiole de 250 ml, on ajoute de la metformine base (6. 45 g, 50 mmol), de l'acide 2(S)-méthyl-2-(6-méthoxynaphtyl)-acétique (11. 5 g, 50 mmol) et de l'isopropanol (100 ml). Le tout est chauffé à reflux et un précipité se forme au bout de 30 minutes. Celui-ci est essoré et lavé au pentane. On obtient 16. 5 g du sel désiré, soit un rendement de 94%. EXAMPLE III Metformin Naproxenate (or metformin 2 (S) -methyl-2- (6-methoxynaphthyl) acetate) In a 250 ml vial, metformin base (6. 45 g, 50 mmol) was added, 2 (S) -methyl-2- (6-methoxynaphthyl) -acetic acid (11.5 g, 50 mmol) and isopropanol (100 ml). The whole is heated to reflux and a precipitate is formed after 30 minutes. It is drained and washed with pentane. 16 g of the desired salt are obtained, ie a yield of 94%.

Pf (banc Kôfler): 231-233 C [1H] RMN-200 Mhz, DMSO : Pf (Kofler bench): 231-233 ° C [1H] NMR-200 Mhz, DMSO:

<Desc/Clms Page number 6><Desc / Clms Page number 6>

# (ppm) : 1. 20 (d, 3H); 2. 80 (s, 6H); 3. 35 (q, 1 H); 3. 75 (s, 3H); 6.45 (d, 1 H);
7. 15 (s, 1 H); 7. 40 (d, 1 H); 7. 54 (s, 1 H); 7. 61 (d, 1 H) [13C] RMN - 50 Mhz, DMSO : # (ppm) : 20. 85, 39. 09 (CH3); 49. 63 (CH) ; 55. 92 (CH3); 106.45, 118.90,
125.75, 126.68, 128. 42 (CH); 129. 36 (C=C) ; 129. 75 (CH) ; 133.45, 141. 77,
157. 32 (C=C) ; 159.23, 161.21 (C=N) ; 178. 74 (C=O) IR (KBr) cm-1: 1655 v c=o EXEMPLE IV Captoprilate de metformine 4 Dans une fiole de 250 ml, on ajoute de la metformine base (6 g, 46 mmol), du captopril (10 g, 46 mmol) et de l'acétonitrile (50 ml). Le tout est chauffé à reflux pendant 3 heures et le solvant est éliminé. Le résidu est trituré dans un mélange d'acétonitrile et de pentane (1/1 en volume) et le solide formé est essoré. On obtient 16 g du sel désiré, soit un rendement de 100 %. # (ppm): 1. (d, 3H); 2. 80 (s, 6H); 3.35 (q, 1H); 3.75 (s, 3H); 6.45 (d, 1H);
7. 15 (s, 1H); 7. 40 (d, 1H); 7. 54 (s, 1H); 7. 61 (d, 1H) [13C] NMR - 50 Mhz, DMSO: # (ppm): 20. 85, 39.09 (CH3); 49. 63 (CH); 55. 92 (CH3); 106.45, 118.90,
125.75, 126.68, 128. 42 (CH); 129. 36 (C = C); 129. 75 (CH); 133.45, 141. 77,
157. 32 (C = C); 159.23, 161.21 (C = N); 178. 74 (C = O) IR (KBr) cm-1: 1655 vc = EXAMPLE IV Metformin Captoprilate 4 In a 250 ml flask was added metformin base (6 g, 46 mmol), captopril ( 10 g, 46 mmol) and acetonitrile (50 ml). The whole is refluxed for 3 hours and the solvent is removed. The residue is triturated in a mixture of acetonitrile and pentane (1/1 by volume) and the solid formed is drained. 16 g of the desired salt are obtained, ie a yield of 100%.

Pf (banc Kôfler): 94-96 C [1H] RMN-200 Mhz. DMSO : # (ppm) : 0.65 (d, 3H); 1. 13 (t, 3H);2.00 (m, 4H); 2.66 (m, 2.94 (s, 6H);
3. 39 (m, 3H); 3. 99 (m, 3H) [13C] RMN - 50 Mhz. DMSO : # (ppm) : 15. 14 (CH3); 21. 27 (CH2) ; 1. 64 (CH3); 26. 18 (CH2) ; 30. 20 (CH2);
36. 17 (CH3); 38. 00 (CH) ; 44. 80 (CH2); 60. 74 (CH); 157. 43 (C=N) ; 158. 73 (C=N) ; 172. 00 (C=O); 177. 47 (C=O) IR (KBr) cm-': 3340 v NH EXEMPLE V Kétoprofènate de metformine (ou 2-(3-benzoylphényl)-propionate de metformine) 5 Dans une fiole de 250 ml, on ajoute de metformine base (6. 45 g, 50 mmol), du kétoprofène (acide 2-(3-benzoylphényl)-propionique) (12. 7 g, 50 mmol) et de Pf (Kofler bench): 94-96 [1H] NMR-200 Mhz. DMSO: # (ppm): 0.65 (d, 3H); 1. 13 (t, 3H) 2.00 (m, 4H); 2.66 (m, 2.94 (s, 6H);
3.39 (m, 3H); 3. 99 (m, 3H) [13C] NMR - 50 Mhz. DMSO: # (ppm): 15.14 (CH3); 21. 27 (CH2); 1. 64 (CH3); 26. 18 (CH2); 30. (CH2);
36. 17 (CH3); 38.00 (CH); 44. 80 (CH2); 60. 74 (CH); 157. 43 (C = N); 158. 73 (C = N); 172. 00 (C = O); 177. 47 (C = O) IR (KBr) cm- ': 3340 v EXAMPLE V Metformin ketoprofenate (or metformin 2- (3-benzoylphenyl) propionate) In a 250 ml vial, metformin was added base (6. 45 g, 50 mmol), ketoprofen (2- (3-benzoylphenyl) propionic acid) (12.7 g, 50 mmol) and

<Desc/Clms Page number 7><Desc / Clms Page number 7>

l'isopropanol (100 ml). Le tout est chauffé à reflux pendant 1 heure et le solvant est éliminé sous vide. Le résidu sec est trituré dans de l'acétonitrile et le solide obtenu est essoré. On obtient 21 g du sel désiré, soit un rendement de 92%.  isopropanol (100 ml). The whole is refluxed for 1 hour and the solvent is removed under vacuum. The dry residue is triturated in acetonitrile and the solid obtained is drained. 21 g of the desired salt are obtained, ie a yield of 92%.

Pf (banc Kôfler) . 159-161 C [1H] RMN -200 Mhz, DMSO :
5 (ppm) : 1. 35 (d, 3H); 2. 93 (s, 6H); 3. 47 (q, 1 H); 7. 75 (m, 14H) [13C] RMN - 50 Mhz, DMSO : # (ppm) : 20.89, 38. 27 (CH3); 49. 70, 127.93, 129. 52, 129. 75, 130.58,
133.12, 133.52 (CH) ; 137. 35, 138.27, 147. 09 (C=C) ; 159. 39, 161. 25 (C=N) ;
178.19, 297.06 (C=O) IR (KBr) cm-': 1668 v c=o EXEMPLE VI 6-hydroxy-2,5,7,8-tétraméthyl-chroman-2-carboxylate de metformine 6 Dans une fiole de 250 ml, on ajoute de metformine base (7. 74 g, 60 mmol), du Trolox # (acide 6-hydroxy-2,5,7,8-tétraméthyl-chroman-2-carboxylique) (15 g, 60 mmol) et de l'isopropanol (100 ml). Le tout est chauffé à reflux et un précipité se forme au bout de 30 minutes. Celui-ci est essoré et lavé au pentane. On obtient 21 g du sel désiré, soit un rendement de 85%. Pf (Kofler bench). 159-161 ° C [1H] NMR -200 MHz, DMSO:
(Ppm): 1.35 (d, 3H); 2.93 (s, 6H); 3. 47 (q, 1H); 7. 75 (m, 14H) [13C] NMR - 50 Mhz, DMSO: # (ppm): 20.89, 38. 27 (CH3); 49, 70, 127.93, 129. 52, 129. 75, 130.58,
133.12, 133.52 (CH); 137. 35, 138.27, 147. 09 (C = C); 159. 39, 161. (C = N);
178.19, 297.06 (C = O) IR (KBr) cm -1: 1668 vc = EXAMPLE VI Metformin 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate 6 In a 250 ml flask metformin base (7. 74 g, 60 mmol), Trolox # (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) (15 g, 60 mmol), and isopropanol (100 ml). The whole is heated to reflux and a precipitate is formed after 30 minutes. It is drained and washed with pentane. 21 g of the desired salt are obtained, ie a yield of 85%.

Pf (banc Kôfler) : 169-171 C [1H] RMN-200 Mhz, DMSO : # (ppm) : 1. 40 (s, 3H); 1.50 (m, 1 H); 2. 00 (3s, 9H); 2. 42 (m, 3H); 2.95 (s,
6H); 7.15 (s, 6H) [13C] RMN - 50 Mhz, DMSO : # (ppm) : 14.16, 14. 42, 15. 09 (CH3) ; 23. 75 (CH2) ; 28. 48 (CH3) ; 33. 52 (CH2) ; 39. 59 (CH3) ; 80. 04 (C quaternaire); 119. 50, 122.15, 122.60,
124. 16, 146. 81, 148. 841 (C=C) ; 160. 72, 162. 43 (C=N) ; 179. 12 (C=O) IR (KBr) cm-': 1652 v c=o Pf (Köfer bench): 169-171 ° C [1 H] NMR-200 Mhz, DMSO: δ (ppm): 1. 40 (s, 3H); 1.50 (m, 1H); 2.00 (3s, 9H); 2.42 (m, 3H); 2.95 (s,
6H); 7.15 (s, 6H) [13 C] NMR - 50 Mhz, DMSO: δ (ppm): 14.16, 14.42, 15.09 (CH3); 23. 75 (CH2); 28. 48 (CH3); 33. 52 (CH2); 39.59 (CH3); 80. 04 (quaternary C); 119. 50, 122.15, 122.60,
124. 16, 146. 81, 148. 841 (C = C); 160, 72, 162. (C = N); 179. 12 (C = O) IR (KBr) cm- ': 1652 vc = o

<Desc/Clms Page number 8><Desc / Clms Page number 8>

EXEMPLE VII Etude pharmacologique des compositions selon l'invention.  EXAMPLE VII Pharmacological Study of the Compositions According to the Invention

Dans les tableaux qui suivent, on a rassemblé les résultats d'essais comparatifs in vitro entrepris pour montrer l'intérêt, dans le traitement du diabète, des différents sels de metformine conformes à l'invention par rapport au produit le plus couramment utilisé, à savoir le chlorhydrate de metformine. In the following tables, the results of comparative in vitro tests undertaken to show the interest, in the treatment of diabetes, of the different metformin salts according to the invention compared with the most commonly used product, have been gathered. know metformin hydrochloride.

Tableau I: Effet antidiabétique du dobésilate de metformine 1

Figure img00080001
Table I: Antidiabetic Effect of Metformin Dobesilate 1
Figure img00080001

<tb>
<tb> dose <SEP> durée <SEP> glycémie <SEP> p
<tb> chlorhydrate <SEP> de <SEP> metformine <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 30 <SEP> % <SEP> < <SEP> 0.001
<tb> 1 <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 32 <SEP> % <SEP> < <SEP> 0.001
<tb>
Tableau Il : Effet antidiabétique de l'acétylsalicylate de metformine 2

Figure img00080002
<Tb>
<tb> dose <SEP> duration <SEP> blood glucose <SEP> p
<tb> hydrochloride <SEP> of <SEP> metformin <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 30 <SEP>% <SEP><SEP> 0.001
<tb> 1 <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 32 <SEP>% <SEP><SEP> 0.001
<Tb>
Table II: Antidiabetic Effect of Metformin Acetylsalicylate 2
Figure img00080002

<tb>
<tb> dose <SEP> durée <SEP> glycémie <SEP> p
<tb> chlorhydrate <SEP> de <SEP> metformine <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 27 <SEP> % <SEP> < <SEP> 0.001
<tb> 2 <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 34 <SEP> % <SEP> < <SEP> 0. <SEP> 001
<tb>
Remarque : le composé 2 présente en outre une action antiischémique se traduisant notamment par une amélioration de la vie cellulaire. <Tb>
<tb> dose <SEP> duration <SEP> blood glucose <SEP> p
<tb> hydrochloride <SEP> of <SEP> metformin <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 27 <SEP>% <SEP><SEP> 0.001
<tb> 2 <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 34 <SEP>% <SEP><<SEP> 0. <SEP> 001
<Tb>
Note: Compound 2 also has an anti -ischemic action resulting in particular by an improvement in cell life.

Tableau III: Effet antidiabétique du naproxénate de metformine 3

Figure img00080003
Table III: Antidiabetic Effect of Metformin Naproxenate 3
Figure img00080003

<tb>
<tb> dose <SEP> durée <SEP> glycémie <SEP> p
<tb> chlorhydrate <SEP> de <SEP> metformine <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 27 <SEP> % <SEP> < <SEP> 0.001
<tb> 3 <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 62 <SEP> % <SEP> < <SEP> 0.001 <SEP>
<tb> <Tb>
<tb> dose <SEP> duration <SEP> blood glucose <SEP> p
<tb> hydrochloride <SEP> of <SEP> metformin <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 27 <SEP>% <SEP><SEP> 0.001
<tb> 3 <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 62 <SEP>% <SEP><SEP> 0.001 <SEP>
<Tb>

<Desc/Clms Page number 9><Desc / Clms Page number 9>

Remarque : le composé 3 présente en outre une action antiischémique se traduisant notamment par une amélioration de la vie cellulaire.  Note: Compound 3 also has an anti -ischemic action resulting in particular by an improvement in cell life.

Tableau IV: Effet antidiabétique du captoprilate de metformine 4

Figure img00090001
Table IV: Antidiabetic effect of metformin captoprilate 4
Figure img00090001

<tb>
<tb> dose <SEP> durée <SEP> glycémie <SEP> p
<tb> chlorhydrate <SEP> de <SEP> metformine <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 38 <SEP> % <SEP> < <SEP> 0.001
<tb> 4 <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 36 <SEP> % <SEP> < <SEP> 0.01 <SEP>
<tb>
Tableau V : Effet antidiabétique du kétoprofènate de metformine 5

Figure img00090002
<Tb>
<tb> dose <SEP> duration <SEP> blood glucose <SEP> p
<tb> hydrochloride <SEP> of <SEP> metformin <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 38 <SEP>% <SEP><SEP> 0.001
<tb> 4 <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 36 <SEP>% <SEP><<SEP> 0.01 <SEP>
<Tb>
Table V: Antidiabetic Effect of Metformin Ketoprofenate 5
Figure img00090002

<tb>
<tb> dose <SEP> durée <SEP> glycémie <SEP> p
<tb> chlorhydrate <SEP> de <SEP> metformine <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 29 <SEP> % <SEP> < <SEP> 0.001
<tb> 5 <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 61 <SEP> % <SEP> < <SEP> 0.01
<tb>
Tableau VI: Effet antidiabétique du 6-hydroxy-2,5,7,8-tétraméthyl-chromane-2-carboxylate de metformine 6

Figure img00090003
<Tb>
<tb> dose <SEP> duration <SEP> blood glucose <SEP> p
<tb> hydrochloride <SEP> of <SEP> metformin <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 29 <SEP>% <SEP><<SEP> 0.001
<tb> 5 <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 61 <SEP>% <SEP><SEP> 0.01
<Tb>
Table VI: Antidiabetic effect of metformin 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylate 6
Figure img00090003

<tb>
<tb> dose <SEP> durée <SEP> glycémie <SEP> p
<tb> chlorhydrate <SEP> de <SEP> metformine <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 27 <SEP> % <SEP> < <SEP> 0.001
<tb> 6 <SEP> 200 <SEP> mg <SEP> 4 <SEP> jours <SEP> - <SEP> 14 <SEP> % <SEP> < <SEP> 0.05
<tb> <Tb>
<tb> dose <SEP> duration <SEP> blood glucose <SEP> p
<tb> hydrochloride <SEP> of <SEP> metformin <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 27 <SEP>% <SEP><SEP> 0.001
<tb> 6 <SEP> 200 <SEP> mg <SEP> 4 <SEP> days <SEP> - <SEP> 14 <SEP>% <SEP><SEP> 0.05
<Tb>

Claims (17)

REVENDICATIONS 1. Les sels de metformine améliorant les syndromes métaboliques du diabète définis par l'abréviation SMIR. 1. Metformin salts improving the metabolic syndromes of diabetes defined by the abbreviation SMIR. 2. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est le dobésilate de metformine.  2. A metformin salt according to claim 1, characterized in that it is metformin dobesilate. 3. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est le naproxénate de metformine.  3. A metformin salt according to claim 1, characterized in that it is metformin naproxenate. 4. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est le kétoprofènate de metformine.  4. A metformin salt according to claim 1, characterized in that it is metformin ketoprofenate. 5. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est le bezafibrate de metformine.  5. A metformin salt according to claim 1, characterized in that it is metformin bezafibrate. 6. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est le 5- (2,5-dimethylphenoxy)-2,2-diméthylpentanoate de metformine.  6. A metformin salt according to claim 1, characterized in that it is metformin 5- (2,5-dimethylphenoxy) -2,2-dimethylpentanoate. 7. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est le (S)-1-(3-mercapto-2-méthyl-1-oxo-propyl)-L-prolinate de metformine.  7. A metformin salt according to claim 1, characterized in that it is metformin (S) -1- (3-mercapto-2-methyl-1-oxo-propyl) -L-prolinate. 8. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est l'apovincaminate de metformine.  8. A metformin salt according to claim 1, characterized in that it is metformin apovincaminate. 9. Un sel de metformine selon la revendication 1, caractérisé en ce qu'ilest l'aminophyllinate de metformine. 9. A metformin salt according to claim 1, characterized in that it is metformin aminophyllinate. 10. Un sel de metformine selon la revendication 1, caractérisé en ce qu'ilest le sulfamoylphénoxyacétate de metformine. 10. A metformin salt according to claim 1, characterized in that it is metformin sulfamoylphenoxyacetate. <Desc/Clms Page number 11><Desc / Clms Page number 11> 11. Un sel de metformine selon la revendication 1, caractérisé en ce qu'ilest le 6- hydroxy-2,5,7,8-tétraméthyl-chroman-2-carboxylate de metformine.  11. A metformin salt according to claim 1, characterized in that metformin 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylate is used. 12. Un sel de metformine selon la revendication 1, caractérisé en ce qu'il est l'acétylsalicylate de metformine12. A metformin salt according to claim 1, characterized in that it is metformin acetylsalicylate 13. Compositions pharmaceutiques renfermant à titre de principe actif au moins un des sels de metformine selon l'une quelconque des revendications 1 à 12, en association avec des excipients acceptables pharmaceutiquement. 13. Pharmaceutical compositions containing as active ingredient at least one of the metformin salts according to any one of claims 1 to 12, in association with pharmaceutically acceptable excipients. 14. Procédé d'obtention d'un sel de metformine selon l'une quelconque des revendications 1 à 12, caractérisé en ce qu'il consiste, essentiellement, à salifier la metformine base avec un acide minéral ou organique dans un solvant inerte approprié, puis à isoler le sel ainsi obtenu selon les méthodes connues. 14. Process for obtaining a metformin salt according to any one of claims 1 to 12, characterized in that it consists essentially in salifying the base metformin with a mineral or organic acid in a suitable inert solvent, and then isolating the salt thus obtained according to the known methods. 15. Procédé selon la revendication 14, caractérisé en ce que la metformine base et l'acide sont en quantités équimolaires. 15. Process according to claim 14, characterized in that the base metformin and the acid are in equimolar amounts. 16. Procédé selon la revendication 15, caractérisé en ce que l'acide est choisi parmi les acides suivants : - l'acide 2,5-dihydroxybenzènesulfonique; - l'acide acétylsalicylique ; - le naproxène; - l'acide alginique ; - l'acide 2-(3-benzoylphényl)-propionique; - l'acide 2-[4-[2-[(4-chlorobenzoyl)amino]éthyl]phenoxy]-2-méthylpropanoïque ou acide bezafibrique ; - l'acide 5-(2,5-dimethylphenoxy)-2,2-diméthylpentanoïque ou acide gemfibrozique ; - le (S)-1-1-(3-mercapto-2-méthyl-1-oxo-propyl)-L-proline ou captopril, - l'acide apovincaminique; - l'aminophylline; - l'acide sulfamoylphénoxyacétique; 16. The method of claim 15, characterized in that the acid is selected from the following acids: - 2,5-dihydroxybenzènesulfonique acid; acetylsalicylic acid; - naproxen; alginic acid; 2- (3-benzoylphenyl) -propionic acid; 2- [4- [2 - [(4-chlorobenzoyl) amino] ethyl] phenoxy] -2-methylpropanoic acid or bezafibric acid; 5- (2,5-dimethylphenoxy) -2,2-dimethylpentanoic acid or gemfibrozic acid; (S) -1-1- (3-mercapto-2-methyl-1-oxo-propyl) -L-proline or captopril, - apovincaminic acid; aminophylline; sulfamoylphenoxyacetic acid; <Desc/Clms Page number 12><Desc / Clms Page number 12> - l'acide 6-hydroxy-2,5,7,8-tétraméthyl-chroman-2-carboxylique.  6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. 17. Procédé selon la revendication 15, caractérisé en ce que ledit solvant est choisi parmi l'éthanol, l'isopropanol, l'acétone, le N,N-diméthyl-formamide, le diméthylsulfoxyde ou l'acétonitrile.17. The method of claim 15, characterized in that said solvent is selected from ethanol, isopropanol, acetone, N, N-dimethylformamide, dimethylsulfoxide or acetonitrile.
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WO2005041923A1 (en) * 2003-10-31 2005-05-12 Alza Corporation Compositions and dosage forms for enhanced absorption of metformin
WO2010146604A2 (en) 2009-06-18 2010-12-23 Exemed Pharmaceuticals Processes for preparing metformin hydrochloride
CN102391160A (en) * 2011-11-23 2012-03-28 黎波 Metformin and 2,5-dihydroxybenzene sulfonate, and compound recipe composition thereof
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