METFORMIN COMPLEXES WITH TRANSITION METALS AND P GROUP ELEMENTS

Abstract

Disclosed herein is an invention that refers to hydrochloride metformin complexes with transition metals and group P elements, such as cobalt (II), nickel (II), copper (II), zinc (III), iron (II), bismuth (III) and their preparation method. Additionally, the present invention offers crystalline forms of the metformin-cobalt (II) complex, metformin-nickel complex and metformin-copper complex as well as methods for therapeutic use in patient treatment and their preparation method.

Claims

1. A metformin-transition metal complex of any of the following formulas (a), (b) (c) or (d): ##STR00003## wherein M.sup.n+ (n+=positive charge) corresponds to metals with tetrahedral or square planar conformations for nickel (II), copper (II) and zinc (III) (formula (a), formula (c) or formula (d)) or octahedral conformations for cobalt (II), copper (II), iron (II) and bismuth (III) (formula (b)).

2. The complex according to claim 1, wherein the metallic cations (M.sup.2+) tetrahedral conformation (formula (a)) and for the square conformation (formula (c) and (d)) are selected from nickel (II), copper (II) and zinc (III).

3. The complex according to claim 1, wherein the metallic cations (M.sup.2+) octahedral conformation (formula (b)) are selected from cobalt (II), copper (II), iron (II) and bismuth (III).

4. The complex according to claim 1, wherein the complex is selected from metformin-copper complex, metformin-iron complex, metformin-bismuth complex, metformin-nickel complex, metformin-zinc complex.

5. The complex according to claim 1, wherein the complex is in a crystalline form.

6. The complex according to claim 5, wherein a crystalline form of metformin-cobalt complexes is characterized by powder X-ray diffraction that comprises the following 2⊖ values: 9.82; 10.31; 10.59; 10.67; 11.62; 12.12; 12.66; 13.04; 14.11; 14.53; 15.07; 15.39; 15.57; 16.06; 16.24; 16.59; 17.11; 17.47; 17.99; 18.47; 19.12; 19.71; 20.05; 20.72; 20.99; 21.28; 21.46; 21.69; 22.08; 22.94; 23.16; 23.31; 23.67; 24.03; 24.50; 25.21; 25.51; 25.87; 26.25; 26.87; 27.19; 27.47; 27.87; 28.09; 28.39; 28.64; 28.86; 29.48; 30.11; 30.41; 31.03; 31.31; 31.68; 32.19; 32.37; 32.53; 32.74; 33.20; 33.52; 33.99; 34.44; 34.63; 35.02; 35.23; 35.85; 36.16; 36.66; 37.17; 37.81; 38.07; 38.49; 38.72; 38.95; 39.24; 39.48; 39.70; 39.90; 40.03; 40.14; 40.38; 40.87; 41.36; 41.66; 42.21; 42.37; 42.59; 42.80; 43.16; 43.35; 44.00; 44.19; 44.41; 44.79; 45.11; 45.38; 45.55; 45.79; 46.06; 46.63; 47.37; 48.05; 48.45; 48.67; 49.00; 49.35; 49.81.

7. The complex according to claim 5, wherein a crystalline form of metformin-Nickel complexes is characterized by powder X-ray diffraction that comprises the following 2⊖ values: 9.78; 11.62; 14.24; 15.60; 16.86; 19.13; 20.14; 20.85; 23.25; 23.34; 23.64; 23.97; 24.68; 25.80; 26.33; 26.71; 27.53; 28.85; 30.83; 31.36; 31.96; 32.69; 33.61; 34.09; 34.45; 34.82; 34.99; 35.44; 35.76; 36.14; 36.44; 36.75; 37.17; 37.75; 37.98; 38.32; 38.46; 38.66; 38.83; 39.44; 39.76; 40.32; 40.90; 41.36; 41.74; 41.84; 41.96; 42.08; 42.30; 42.44; 42.79; 43.19; 43.65; 44.15; 44.53; 44.83; 45.31; 45.64; 45.83; 46.11; 46.39; 46.53; 46.97; 47.52; 47.74; 48.06; 48.26; 48.47; 48.76; 49.04; 49.47; 49.62.

8. The complex according to claim 5, wherein a crystalline form of metformin-Copper complexes is characterized by powder X-ray diffraction that comprises the following 2⊖ values: 9.65; 11.78; 14.05; 15.31; 16.42; 18.79; 18.90; 19.37; 20.31; 21.40; 23.15; 23.49; 23.82; 24.33; 24.80; 24.92; 25.25; 26.03; 26.82; 28.22; 29.07; 29.22; 30.33; 30.68; 31.48; 31.81; 32.00; 32.08; 33.02; 33.19; 33.61; 33.94; 34.59; 35.73; 36.04; 36.42; 36.72; 36.89; 37.07; 37.95; 38.21; 38.33; 38.58; 38.91; 39.19; 39.39; 40.54; 40.64; 40.80; 40.95; 41.30; 41.57; 41.79; 42.39; 42.86; 43.05; 43.23; 43.41; 43.59; 44.10; 44.23; 44.78; 45.10; 45.27; 45.86; 46.07; 46.94; 47.14; 47.33; 47.54; 48.02; 48.20; 48.45; 48.63; 48.84; 49.12; 49.52; 49.72.

9. The complex according to claim 5, wherein a crystalline form of metformin-zinc complexes is characterized by powder X-ray diffraction that comprises the following 2⊖ values: 7.68; 13.71; 14.07; 14.41; 14.79; 15.39; 16.25; 17.26; 18.11; 18.49; 18.94; 19.20; 19.42; 22.04; 22.88; 23.66; 24.44; 24.82; 25.12; 25.24; 26.89; 27.45; 27.71; 28.00; 28.35; 28.63; 28.93; 29.06; 29.58; 29.73; 30.14; 30.65; 30.88; 31.06; 31.30; 31.48; 32.16; 32.71; 33.36; 33.75; 34.11; 34.93; 35.69; 36.85; 37.15; 37.46; 37.68; 37.85; 38.11; 38.39; 38.53; 38.79; 38.97; 39.11; 39.44; 39.74; 40.30; 40.40; 40.71; 40.85; 41.61; 42.08; 42.17; 42.58; 42.79; 43.11; 43.41; 43.74; 44.22; 44.54; 44.85; 44.94; 45.20; 45.48; 45.60; 45.85; 46.22; 46.46; 46.63; 47.08; 47.28; 47.36; 47.58; 48.23; 48.42; 48.73; 48.99; 49.12; 49.48; 49.44.

10. A preparation procedure of a crystalline form of a metformin-transition metal complex according to formulas (a), (b) (c) or (d): ##STR00004## where M.sup.n+ (n+=positive charge) corresponds to metals with tetrahedral or square planar conformations for nickel (II), copper (II) and zinc (III) (formula (a), formula (c) or formula (d)) or octahedral conformations for cobalt (II), copper (II), iron (II) and bismuth (III) formula (b)), the method comprising: de-protonating the amine nitrogen with the help of a strong base; or adding a base for formation of a neutral metformin.

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. (canceled)

17. A pharmaceutical composition comprising the metformin-metal complex of claim 1.

18. A method to treat a disease in which a patient is given a therapeutically effective dose of the metformin-transition metal complex of claim 1 or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the disease is diabetes, obesity, hypertriglyceridemia, hyperglycemia, atherosclerosis, cancer or related illnesses.

20. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0074] FIG. 1. Illustrates photographs of the nine complexes of metformin-metal of the present invention.

[0075] FIG. 2. Illustrates the structures of the obtained compounds a) [Co(C.sub.4H.sub.12N.sub.5).sub.3]Cl.sub.2.nH.sub.2O, b) [Cu(C.sub.4H.sub.12N.sub.5).sub.2]Cl.sub.2.H.sub.2O, c) [Ni(C.sub.4H.sub.11N.sub.5).sub.2]Cl.H.sub.2O and d) [Zn(C.sub.4H.sub.11N.sub.5)Cl.sub.3]

[0076] FIG. 3. Illustrates the powder X-ray diffraction pattern for the compound MfnCo (a).

[0077] FIG. 4. Illustrates the powder X-ray diffraction pattern for the compound MfnNi (f).

[0078] FIG. 5. Illustrates the powder X-ray diffraction pattern for the compound MfnCu (e).

[0079] FIG. 6. Illustrates the powder X-ray diffraction pattern for the compound MfnZn (h).

[0080] FIG. 7. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of metformin hydrochloride.

[0081] FIG. 8. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of cobalt (II) with method 1 (a).

[0082] FIG. 9. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of cobalt (II) with method 2 (b).

[0083] FIG. 10. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of copper (II) with method 1 (c).

[0084] FIG. 11. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of copper (II) with method 1 (d).

[0085] FIG. 12. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of copper (II) with method 2 (e).

[0086] FIG. 13. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of copper (II) with method 1 (f).

[0087] FIG. 14. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of nickel (II) with method 2 (g).

[0088] FIG. 15. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of zinc (II) (h).

[0089] FIG. 16. Illustrates the Fourier transform infrared (FTIR) spectroscopic chart of the coordination compound of bismuth (III) (i).

[0090] FIG. 17. Illustrates the thermogravimetric analysis (TGA) chart and the differential scanning calorimetry (DSC) for the hydrochloride metformin ligand.

[0091] FIG. 18. Illustrates the thermogravimetric analysis (TGA) chart and the differential scanning calorimetry (DSC) for the metformin-cobalt (II) complex with method 1 (a).

[0092] FIG. 19. Illustrates the thermogravimetric analysis (TGA) chart and the differential scanning calorimetry (DSC) for the metformin-nickel (II) complex with method 1 (c).

[0093] FIG. 20. Illustrates the thermogravimetric analysis (TGA) chart and the differential scanning calorimetry (DSC) for the metformin-copper (II) complex with method 1 (f).

[0094] FIG. 21. Illustrates the thermogravimetric analysis (TGA) chart and the differential scanning calorimetry (DSC) for the metformin-zinc (II) (h).

[0095] FIG. 22. Illustrates the thermogravimetric analysis (TGA) chart and the differential scanning calorimetry (DSC) for the metformin-bismuth (III) (i).

[0096] FIG. 23. Illustrates the cytotoxicity of different molecules on cell lines C2C12 and HepG2.

EXAMPLES

[0097] Preparation Procedure of the Metformin-Transition Metals Complexes

[0098] The first procedure for the preparation of the hydrochloride-metformin-cobalt complex is now described:

[0099] In a flat-bottomed flask, 10 mL of methanolic solutions of the Mfn ligand (C.sub.4H.sub.12N.sub.5Cl) (33 mg, 0.2 mmol) were mixed with 1.2 equivalents of NaOH and 5 mL of cobalt (II) chloride (CoCl.sub.2.6H.sub.2O) (23 mg, 0.1 mmol). The reaction mixture was refluxed for 60 minutes. The resulting solution was concentrated and cooled to room temperature. Cubic reddish crystals were obtained by slow evaporation after 4 weeks (yield=61.57%) %). Elemental Anal. Calcd for [Co(C.sub.4H.sub.11N.sub.5).sub.3]Cl.sub.2.2H.sub.2O (C12H.sub.37N15O2Cl2Co): C, 26.05; H, 6.74; N, 37.97. Found: C, 25.86; H, 6.02; N, 37.21.

[0100] A second procedure for the preparation of the metformin-cobalt complex is the following:

[0101] In a flat bottom flask, 10 mL of methanolic solutions the Metformin ligand (C.sub.4H.sub.12N.sub.5Cl) (33 mg, 0.2 mmol) were mixed with 1.2 equivalents of NaOH and 5 mL of the cobalt (II) chloride salt (II) (CoCl.sub.2.6H.sub.2O) (23 mg, 0.1 mmol). It was taken to reflux and stirred for 60 minutes at 100° C. The resulting solution was cooled at room temperature allowing its evaporation in an evaporator, leading to a reddish solid.

[0102] In one embodiment, the first procedure for the preparation of a metformin-nickel complex is now described:

[0103] In a flat-bottomed flask, 4 mL of a solution of the Mfn ligand (C.sub.4H.sub.12N.sub.5Cl) (66 mg 0.4 mmol) were mixed with 4 mL of aqueous nickel (II) sulfate solution (NiSO.sub.4.6H.sub.2O) (47 mg, 0.2 mmol) and 53 mg of NaOH (1.3 mmol). The reaction mixture was stirred for 60 minutes at room temperature. The resulting solution was cooled to room temperature and filtered to separate the orange solid (crystalline powder) obtained. The obtained solid was dissolved in water, and HCl was added dropwise until dissolution. The compound was recrystallized by slow evaporation to obtain prism orange crystals (yield=53.70%). Elemental Anal. Calcd for [Ni(C.sub.4H.sub.11N.sub.5)(C.sub.4H.sub.10N.sub.5)]Cl.H.sub.2O (C8H.sub.23N10OClNi): C, 26.01; H, 6.27; N, 37.91. Found: C, 25.67; H, 5.81; N, 37.03.

[0104] In another embodiment, the second procedure for the preparation of a metformin-nickel complex is the following:

[0105] In a flat bottom flask, (66 mg, 0.4 mmol) of the ligand, Mfn (C.sub.4H.sub.12N.sub.5Cl) are dissolved in 4 mL of an aqueous solution of nickel sulfate (NiSO.sub.4.6H.sub.2O) (47 mg, 0.2 mmol) to which (53 mg, 1.33 mmols) of NaOH is added. It was magnetically stirred for 60 minutes. The resulting precipitate was filtered and washed with water (orange solid).

[0106] In another embodiment, the procedure for the preparation of a metformin-copper complex is the following:

[0107] In a flat-bottomed flask, 4 mL of an aqueous solution of the Mfn ligand (C.sub.4H.sub.12N.sub.5Cl) (33 mg, 0.2 mmol) were mixed with 4 mL of an aqueous solution of copper (II) chloride (CuCl.sub.2.2H.sub.2O) (200 mg, 1.17 mmol) and 1.2 equivalents of NaOH. The reaction mixture was stirred for 60 minutes at room temperature. The resulting solution was concentrated, cooled to room temperature, and filtered to obtain a purple solid. The solid was dissolved in water and recrystallized by slow evaporation to obtain purple needless crystals (yield=88.02%). Elemental Anal. Calcd for [Cu(C.sub.4H.sub.11N.sub.5).sub.2]Cl.sub.2.2H.sub.2O (C8H.sub.26N10OCl2Cu): C, 22.41; H, 6.11; N, 32.66. Found: C, 22.15; H, 6.21; N, 32.41.

[0108] In another embodiment, the procedure for the preparation of a metformin-iron complex is the following:

[0109] In a flat-bottomed flask, 4 mL of an aqueous solution of the Mfn ligand (C.sub.4H.sub.12N.sub.5Cl) (33 mg, 0.2 mmol) were mixed with 4 mL of an aqueous solution of iron (II) chloride (FeCl.sub.2.6H.sub.2O) (200 mg, 0.74 mmol) and 1.2 equivalents of NaOH. The reaction mixture was stirred for 60 minutes at room temperature. The resulting solution was concentrated, cooled to room temperature, and filtered to obtain a deep red solid.

[0110] In another embodiment, the procedure for the preparation of a metformin-bismuth complex is the following:

[0111] In a flat bottom flask, 4 mL of the aqueous solution of the ligand Mfn (C.sub.4H.sub.12N.sub.5Cl) (204 mg, 1.23 mmols) were mixed with 4 mL of the methanol-based solution of bismuth (III) nitrate (200 mg, 0.41 mmols) to which 1.2 equivalents of NaOH were added. It was taken to reflux for 60 minutes. After it cooled off, it was filtered by separating the obtained solid (cream color solid).

[0112] Hence, the invention based on the synthesis of metal-metformin complexes (metal=Fe.sup.2+, Cu.sup.2+, Co.sup.2+, Zn.sup.2+, Bi.sup.3+, Ni.sup.2+) was carried out in one single step, through the use of reflux heating. According to the present invention, nine different compounds were obtained for which the physiochemical properties were obtained, and analyzed through different spectroscopic, thermal and X-ray diffraction techniques, which are presented later on for each compound.

[0113] Furthermore, the reaction products were analyzed through optical microscopy, thus detecting crystals for compounds (a), (b), (e), (f) and (g), with irregular shapes of cubes, blocks, and plates.

TABLE-US-00001 TABLE 1 Physio-chemical properties of the obtained coordination compounds. Melting point Compound Color Texture Solubility (° C.) MfnCo (a) reddish Solid DMSO/MeOH/water 270 orange (partially soluble) MfnCo (b) reddish Solid water/methanol 246 orange MfnCu (c) pale Dusty Insoluble 245 Pink MfnCu (d) fucsia cotton-like DMSO 225 Pink MfnCu (e) Persian Dusty Water 255 red MfnNi (f) Orange Dusty methanol 316 (partially soluble) MfnNi (g) Orange Dusty DMSO/chloroform 314 MfnZn (h) White Dusty DMSO 229 MfnBi (i) White Solid —

[0114] The reported metformin-metal complexes were full characterized by single crystal X-ray diffraction, presenting the follow cell parameters and crystallographic information. Particularly, table 2 shows the crystallographic data of the metformin-metal complexes (M=Co, Ni, Cu and Zn) as shown:

TABLE-US-00002 TABLE 2 Crystallographic data and refinement parameters for (1) [Co(C.sub.4H.sub.11N.sub.5).sub.3]Cl.sub.2•2H.sub.2O, (2) [Ni(C.sub.4H.sub.11N.sub.5)(C.sub.4H.sub.10N.sub.5)]Cl•H.sub.2O, (3) [Cu(C.sub.4H.sub.11N.sub.5).sub.2]Cl.sub.2•H.sub.2O and (4) [Zn(C.sub.4H.sub.12N.sub.5)Cl.sub.3] compounds. Compound (1) (2) (3) (4) Emp. Formula C.sub.12H.sub.33N.sub.15Co, C.sub.16H.sub.42N.sub.20Ni.sub.2, C.sub.8H.sub.22N.sub.10Cu, C.sub.4H.sub.12Cl.sub.3N.sub.5Zn 2(Cl), H.sub.2O 2(Cl), 2H.sub.2O 2(Cl), 2(H.sub.2O) FW (g/mol) 535.38 739.05 428.83 301.91 Crystal system Monoclinic Space Group C2/c P2.sub.1/c P2.sub.1/n P2.sub.1/c Unit cell a (Å) 36.470 (2) 13.3863 (6) 5.1596 (14) 12.5200 (12) b (Å) 8.5892 (6) 7.4187 (5) 11.562 (2) 7.5140 (6) c (Å) 17.3656 (13) 15.7512 (9) 15.091 (4) 13.0298 (13) β (°) 99.376 (6) 104.757 (5) 95.63 (3) 113.199 (12) Volume (Å.sup.3) 5367.1 (6) 1512.64 (15) 895.9 (4) 1126.7 (2) Z 4 4 2 2 ρ calcd (mg/m.sup.3) 1.325 1.618 1.590 1.780 Abs. Coeff (mm.sup.−1) 0.872 1.476 1.541 2.856 F(000) 2248 772 446 608 θ range (°) 2.7-28.0 2.7-34.5 2.7-26.5 3.2-29.0 Ref. collected/ 38196, 6485 4364, 2843 5415, 1863 5154, 2966 Unique [R(int)] [0.120] [0.019] [0.091] [0.025] Completeness (%) 99.6 98.8 99.9 99.2 Data/rest./ 6485/0/323 2843/0/111 1863/0/119 2966/0/120 param. Gof on F.sup.2 1.01 1.09 1.04 1.09 R1 [I > 2σ(I)] 0.0601 0.0512 0.0585 0.0373 wR2 [I > 2σ(I)] 0.1598 0.1314 0.1570 0.0928

[0115] The [Co(C.sub.4H.sub.11N5).sub.3]Cl.sub.2.2H.sub.2O (MfnCo compound (b)) crystallizes within the monoclinic crystalline system with a space group C2/c. This compound is comprised of three molecules of ligand Mfn coordinated to the Co.sup.2+ cation, two Cl anions and two molecules of crystallization water per asymmetric unit. The ligand is coordinated to the metallic cation through the nitrogen of the amino group forming a chelate. This coordination mode gives stability to the molecule and allows its formation. The cation is coordinated to six atoms of nitrogen, forming a compound with octahedral geometry. The new compound is an ionic compound where [CO(C.sub.4HN.sub.11N.sub.5).sub.3].sup.2+ is the cation, and the chloride ions act as counter ions.

[0116] The [Ni(C.sub.4H.sub.11N.sub.5).sub.2]Cl.H.sub.2O (MfnNi compound (f)) compound was obtained as yellow crystals that crystallized in the C2/c monoclinic space group. The compound contains two cationic complexes, two chloride anions, and two water molecules in the asymmetric unit. The complexes are formed by one metformin ligand and one deprotonated metformin coordinated to the Ni.sup.2+ center, forming a four-coordinated arrangement (NiN.sub.4) with a distorted square planar polyhedron or parallelepiped.

[0117] The [Cu(C.sub.4H.sub.12N.sub.5).sub.2]Cl.sub.2.H.sub.2O (MfnCu compound (e)) was obtained as purple crystals. The asymmetric unit is formed by a half Cu′ metallic cation located in a symmetry center, which is coordinated by one chelate metformin ligand, one chloride anion as a counter-ion, and one free water molecule. The complex is formed by the coordination of two chelate metformin ligands to generate a four-coordinated rectangular polyhedron (CuN.sub.4).

[0118] The [Zn(C.sub.4H.sub.11N.sub.5)Cl.sub.3] (MfnZn compound (h)) was obtained as colorless crystals with one Zn.sup.2+ metal coordinated by three chloride anions and one protonated metformin molecule in the asymmetric unit. The final complex presents a tetrahedral (ZnNCl.sub.3) arrangement around the Zn center.

[0119] FIG. 5 shows the infrared spectrum of the hydrochloride metformin ligand; the molecule is comprised by various types of bonds such as C—N, N—H, C—H, and C═N, corresponding to different functional groups that absorb radiation under specific wavelengths.

[0120] The characteristic bands of the functional groups in the spectrum: (C—N): 1053 cm.sup.−1 and 1163 cm.sup.−1; (C═N): 1562 cm.sup.−1 and 1629 cm.sup.−1; (C—H): 2811 cm.sup.−1 and (N—H): 3168 cm.sup.−1, 3293 cm.sup.−1 and 3377 cm.sup.−1. Additionally, a large intensity band is observed at 2358 cm.sup.−1 that is due to the presence of CO.sub.2 during the measuring process.

[0121] FIG. 6 shows the obtained infrared spectrum for the metformin coordination compound of Co (II) (a) with the characteristic bands of the functional groups: (C—N): 1049 cm.sup.−1 and 1226 cm.sup.−1, where a slight displacement is evident under a higher wavelength in this last absorption band; (C═N): 1575 cm.sup.−1; (C—H): 2859 cm.sup.−1 and 2937 cm.sup.−1. For the (N—H) group, a largely intense bandwidth is observed at 3336 cm.sup.−1 and 3624 cm.sup.−1. Finally, a band is present at 2358 cm.sup.−1 due to the presence of CO.sub.2 during the measuring process of the coordination compound.

[0122] FIG. 7 shows the infrared spectrum for the cobalt coordination compound obtained for method 2, where the characteristic bands of the functional groups can be detailed: (C—N): 1062 cm.sup.−1, 1192 cm.sup.−1 and 1245 cm.sup.−1, while a slight displacement is also evident under a higher wavelength in this last absorption band; (C═N): 1512 cm.sup.−1 and 1673 cm.sup.−1, with the latter having a large intensity. For (N—H) and (O—H): 3406 cm.sup.−1, a large and intense bandwidth is observed due to the overlapping of the respective bands of each functional group since the reaction environment of the compound (b) was methanol. Additionally, no bands were detected for the functional group (C—, whose absorption range is 2960-2850 cm.sup.−1, since the bands can also be overlapped with the large band (N—H) and (O—H), as a consequence of their size and absorption intensity.

[0123] FIG. 8 shows the infrared spectrum for the copper coordination compound. The characteristic bands of the functional groups can be seen: (C—N): 1278 cm.sup.−1; (C═N): 1676 cm.sup.−1; (C—H): 3164 cm.sup.−1 and (N—H): 3216 cm.sup.−1, 3358 cm.sup.−1 and 3398 cm.sup.−1.

[0124] FIG. 9 shows the infrared spectrum for the copper (II) coordination compound method 1 (d); the characteristic bands of the functional groups are seen: (C—N): 1266 cm.sup.−1; (C═N): 1519 cm.sup.−1 y 1645 cm.sup.−1; (C—H): 3254 cm.sup.−1 and for (N—H): a 3372 cm.sup.−1 and 3431 cm.sup.−1.

[0125] FIG. 10 shows the spectrum obtained for the copper (II) coordination compound through method 2 (e). The characteristic bands for the functional groups were: (C—N): 1058 cm.sup.−1 and 1277 cm.sup.−1; (C═N): 1567 cm.sup.−1 and 1621 cm.sup.−1; (C—H): 2851 and 2941 cm.sup.−1; (N—H) a 3285 cm.sup.−1; 3381 cm.sup.−1 and 3464 cm.sup.−1. An intense band is observed at 2335 cm.sup.−1 that is caused by the presence of CO.sub.2 when samples are measured.

[0126] FIG. 11 corresponds to the infrared spectrum of the nickel (II) coordination compound method 1 (f). The characteristic bands of the functional groups are: (C—N): 1041 cm.sup.−1 and 1372 cm.sup.−1 for the complex, showing a displacement in higher wavelengths in this last band; (C═N): 1572 cm.sup.−1; (C—H): 2801 cm.sup.−1 and (N—H): 3227 cm.sup.−1, 3344 cm.sup.−1 and 3458 cm.sup.−1.

[0127] FIG. 12 corresponds to the infrared spectrum of the nickel (II) coordination compound method 2 (g). The characteristic bands of the functional groups are: (C—N): 1058 cm.sup.−1 and 1306 cm.sup.−1; (C═N): 1572 cm.sup.−1. A strong band is present at 1469 cm.sup.−1, which corresponds to the two methyl radical groups combined with the tertiary amine. For (C—H): 2803, 2864, 2936 and 3001 cm.sup.−1; (N—H): 3248, 3342 cm.sup.−13431 and 3496 cm.sup.−1.

[0128] FIG. 13 corresponds to the infrared spectrum of the zinc (II) coordination compound (h). The characteristic bands of the functional groups are: (C—N): 1076 cm.sup.−1, 1180 cm.sup.−1 and 1240 cm.sup.−1, with a slight displacement under higher wavelengths in this last absorption band; (C═N): 1666 cm.sup.−1, which is the highest absorption in the entire spectrum. A band is also detected at 1491 cm.sup.−1 which corresponds to two radical metal groups combined with the tertiary amine. (C—H): 2831 cm.sup.−1, and 2940 cm.sup.−1 and (N—H): 3272 cm.sup.−1, 3350 cm.sup.−1 and 3437 cm.sup.−1.

[0129] FIG. 14 corresponds to the infrared spectrum of the bismuth (III) coordination compound. The characteristic bands of the functional groups are: (C—N): 1058 cm.sup.−1 and 1377 cm.sup.−1, with a slight displacement under higher wavelengths in this last absorption band; (C═N): 1585 y 1628 cm.sup.−1; (C—H): 2948 cm.sup.−1 and finally (N—H): 3172 cm.sup.−1 and 3365 cm.sup.−1.

[0130] Table 3 shows a summary of the absorption values for each compound.

[0131] The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), delivered the following results:

[0132] FIG. 16 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the cobalt (II) metformin complex with method 1 (a). Two losses of mass can be evidenced. They are marked in the TGA curve as 1 and 2, with the mass loss percentages presented in Table 4. It is noteworthy to mention that possible molecular structures can be proposed that match the mass of the compound.

TABLE-US-00003 TABLE 3 Absorptions in the IR spectrum of the obtained coordination compounds. functional Vibration Compound Group (cm.sup.−1) Metformin C—N 1053, 1163 C═N 1562, 1629 C—H 2811 N—H 3168, 3293, 3377 MfnCo (a) C—N 1049, 1226 C═N 1575 C—H 2859, 2937 N—H 3336, 3624 MfnCo (b) C—N 1062, 1192, 1245 C═N 1512, 1673 C—H N—H 3406 MfnCu (c) C—N 1278 C═N 1676 C—H 3164 N—H 3216, 3358, 3398 MfnCu (d) C—N 1266 C═N 1519, 1645 C—H 3254 N—H 3372, 3431 MfnCu (e) C—N 1058, 1277 C═N 1567, 1621 C—H 2851, 2941 N—H 3285, 3381, 3464 1041, 1372 MfnNi (f) C—N 1572 C═N 2801 C—H 3227, 3344, 3458 N—H 1058, 1306 1572 MfnNi (g) C—N 2803, 2864, 3001 C═N 3248, 3342, 3431, C—H 3496 1076, 1180, 1240 N—H 1666 2831, 2940 MfnZn (h) C—N 3272, 3350, 3437 1058, 1377 C═N 1585, 1628 C—H 2948 N—H 3172, 3365. MfnBi (i) C—N C═N C—H N—H

[0133] For this compound, the molecular formula [Co(C.sub.4H.sub.11N.sub.5)](Cl).sub.2.1/2H.sub.2O is proposed, and, according to the calculations, the theoretical mass loss percentages corresponding to the experimental mass losses (marked as 1 and 2 in the TGA curve) are related with the loss of % of the water molecule and the loss of the ligand molecule, respectively.

[0134] FIG. 17 corresponds to the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the cobalt (II) metformin complex with method 2, where two mass losses can be observed, marked as 1 and 2 in the TGA curve, whose experimental mass loss percentages are presented in Table 4.

[0135] For this compound, the molecular formula is [Co (C.sub.4H.sub.11N.sub.5).sub.3](Cl).sub.2.(H.sub.2O).sub.2 according to the characterization by single crystal XRD, and hence, the calculation of the theoretical mass loss percentage was carried out (see Annexes). According to the calculations, the experimental mass losses, corresponding to the TGA curve (marked as 1 and 2), are tied to the loss of two crystallization water molecules and the loss of two ligand molecules.

[0136] FIG. 18 reveals the thermogravimetric analysis (TGA) and differential scanning calorimetry for the copper (II) metformin complex with method 1 (c), where two significantly different mass loss intervals are appreciated, marked as 1 and 2 in the curve, whose theoretical mass loss percentages are shown in Table 4.

[0137] For this compound, the proposed molecular formula is [Cu(C.sub.4H.sub.11N.sub.5) (Cl).sub.2].1/4H.sub.2O and the calculation of the theoretical mass loss percentage was carried out (see Annexes). According to the calculations, the experimental mass losses, corresponding to the TGA curve marks 1 and 2, are caused by the loss of the water molecule and the ligand molecule, respectively.

[0138] FIG. 19 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the copper (II) metformin complex with method 1 (d). The compound (d) was obtained from the same reaction environment than the compound (c); However, when calculating the mass loss percentages, it was determined that the proposed molecular formulas for both compounds do not match. Hence, the molecular formula [Cu(C.sub.4H.sub.11N.sub.5)(Cl).sub.2].2H.sub.2O is proposed for compound (d).

[0139] The thermogram shows two significantly different mass losses, signaled as 1 and 2 in the TGA curve, whose experimental mass loss percentages are shown in Table 4. According to the proposed molecular formula, the corresponding calculations were carried out (see Annexes). Hence, the experimental mass losses marked as 1 and 2 are related to the loss of water molecules of the compound, followed by the loss of the ligand molecule.

[0140] FIG. 20 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the copper (II) metformin complex with method 2 (e), where three significantly different masses are evidenced and marked as 1, 2 and 3, whose experimental mass loss percentages are shown in Table 4.

[0141] For this compound, the molecular formula [Cu(C.sub.4H.sub.11N.sub.5) (Cl).sub.2].H.sub.2O is proposed, and the theoretical mass loss percentage was calculated (see Annexes). According to calculations, the experimental mass losses marked as 1, 2 and 3, are caused by the loss of the water molecule present in its formula, loss of the ligand and elimination of the two Cl molecules, respectively.

[0142] FIG. 21 corresponds to the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the nickel (II) metformin complex method 1 (f). The thermogravimetric analysis was carried out, thus revealing two significantly different mass losses (marked as 1 and 2) whose experimental mass loss percentage is presented in Table 4.

[0143] For this compound, the following molecular formula was proposed: [Ni(C.sub.4H.sub.11N.sub.5)(C.sub.4H.sub.10N.sub.5)]Cl. The theoretical mass percentage was calculated, and accordingly, it was determined that the mass losses correspond to the initial loss of a ligand molecule, followed by the loss of a second ligand molecule.

[0144] FIG. 22 illustrates the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the nickel (II) metformin complex with method 2, where two significantly different mass losses, marked in the TGA curve as 1 and 2, whose experimental mass loss percentages are shown in Table 4.

[0145] For this compound, it is assumed that the molecular formula is [Ni(C.sub.4H.sub.11N.sub.5).sub.2](Cl.sup.−)(OH.sup.−). However, it is noteworthy to mention that, although the same molecular formula is assumed, there are different phases according to the XRD powder analysis. Hence, the theoretical mass loss percentages (see Annexes) were computed which led to state that the first mass loss is caused by the loss of a ligand molecule and the OH.sup.− anion, while the second loss corresponds to the ligand molecule.

[0146] FIG. 23 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the zinc (II) metformin complex (h), where a single mass loss is evidenced and marked in the TGA curve as 1 (see FIG. 36), whose experimental mass loss percentage is shown in Table 4.

[0147] For this compound, the molecular formula [Zn(C.sub.4H.sub.11N.sub.5)Cl.sub.3] was proposed, and the theoretical mass loss was calculated accordingly. The mass loss corresponds to the total decomposition of the molecule.

[0148] FIG. 24 corresponds to the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) for the bismuth (III) (i) metformin complex. It shows two mass losses marked as 1 and 2 in the TGA curve, whose experimental mass loss percentages are presented in Table 4. Furthermore, the TGA curve shows that the decomposition is incomplete since the decline of the curve reaches the 75-80% interval, where it remains constant until the experiment is concluded.

[0149] For this compound, the molecular formula [Bi(C.sub.4H.sub.11N.sub.5).sub.3](NO.sub.3) is proposed, and the theoretical mass loss was calculated accordingly. The mass losses correspond to the loss of the nitrate anion and the elimination of one ligand molecule.

TABLE-US-00004 TABLE 4 Theoretical and experimental mass loss percentages and proposed formula for the obtained coordination compounds obtained. % % Theoretical Experimental Sample mass loss mass loss Proposed formula Ligand  95.4% (C.sub.4H.sub.12N.sub.5)Cl MfnCo (a)  3.3%   3.2% [Co(C.sub.4H.sub.11N.sub.5)](Cl).sub.2•½H.sub.2O  48.1%  46.05% MfnCo (b)  6.51%  6.87% [Co(C.sub.4H.sub.11N.sub.5).sub.3](Cl).sub.2•(H.sub.2O).sub.2 46.68%  49.74% MfnCu (c)  1.67%   1.5% [Cu(C.sub.4H.sub.11N.sub.5)Cl.sub.2]•.sub.1/4H.sub.2O 48.17%  49.46% MfnCu (d) 12.01%  13.63% [Cu(C.sub.4H.sub.11N.sub.5)Cl.sub.2]•2H.sub.2O 43.11%  41.77% MfnCu (e)  8.4%   8.1% [Cu(C.sub.4H.sub.11N.sub.5).sub.2](Cl).sub.2•H.sub.2O  60.2%  64.3% MfnNi (f)  4.9%   5.8% [Ni(C.sub.4H.sub.11N.sub.5)(C.sub.4H.sub.10N.sub.5)]Cl•H.sub.2O  69.6%  73.2% MfnNi (g)  39.5% 35.199% [Ni(C.sub.4H.sub.11N.sub.5).sub.2](Cl)(OH) 34.96% 32.827% MfnZn (h) 82.03%  86.65% [Zn(C.sub.4H.sub.11N.sub.5)(Cl).sub.3] MfnBi (i)  9.41%  7.14% [Bi(C.sub.4H.sub.11N.sub.5).sub.3](NO.sub.3)  19.6%  14.5%

[0150] The obtained metformin-metal complexes of Co(II), Ni(II) and Cu(II) were cell viability evaluated in C2C12 (ATCCCRL-1772TM) mouse muscle cells and HepG2 (ATCC HB-8065TM) human liver carcinoma cells by the MTT assay after the treatment of the three different compounds for 4 hours (C2C12) or 48 hours (HepG2), to determine the potential of the compounds as new safe drugs. The results demonstrate that the compounds exhibit low cytotoxicity at doses less than 250 μg/ml with a cell viability greater than 80%.

[0151] Cell viability was evaluated using the MTT assay, as is showed in FIG. 25.

[0152] FIG. 25 shows the cytotoxicity of different molecules on cell lines C2C12 and HepG2. Cells seeded in 96-well plates were treated with the molecules for 4 h (C2C12) or 48H (HepG2). The cytotoxicity was evaluated by MTT assay. Values are expressed as mean±SEM. ANOVA with post-hoc Tukey for multiple comparisons was performed. **: p<0.01; *: p<0.05. n=3. Insulin 0.3 mM (INS) and metformin 5 mM (MET) are used as positive control.