Hydrogen sulfide donor in organic salt form and preparation method therefor

Abstract

A hydrogen sulfide donor in an organic salt form and a preparation method thereof. The hydrogen sulfide donor exists as a salt formed by organic compounds with an alkaline motif and hydrogen sulfide with weak acidity. The hydrogen sulfide donor features with a simple structure, and an easy preparation method. Moreover, hydrogen sulfide donors in different forms can be prepared according to research and development needs. After the hydrogen sulfide donor enters an organism, the process of in vivo dissociation and hydrogen sulfide supply is simple, rapid, and effective, and there is no requirement for enzyme or any other complicated condition, and thus, the hydrogen sulfide donor has a great application prospect and value.

Claims

1. A hydrogen sulfide donor in organic salt form, comprising a compound containing a guanidino group and hydrogen sulfide.

2. The hydrogen sulfide donor in organic salt form according to claim 1, wherein the compound is metformin.

3. The hydrogen sulfide donor in organic salt form according to claim 1, wherein the compound is guanethidine.

4. The hydrogen sulfide donor in organic salt form according to claim 1, wherein the compound is arginine.

5. A preparative method for hydrogen sulfide donor in organic salt form according to claim 1, comprising: mixing the compound containing a guanidino group and hydrogen sulfide in a solvent to form a reaction mixture; and separating the solvent from the reaction mixture to obtain the hydrogen sulfide donor in organic salt.

6. The preparative method for hydrogen sulfide donor in organic salt form according to claim 5, wherein the compound is in a free base form.

7. The preparative method for hydrogen sulfide donor in organic salt form according to claim 5, wherein the solvent is water or alcohol.

Description

DESCRIPTION OF FIGURE

(1) FIG. 1 is the schematic diagram showing the in vivo metabolic process of sulfur amino acids reported in literature.

EXAMPLES

Example 1 Preparation of Guanidine Free Base (1)

(2) At room temperature, to a 1000 mL round-bottom long-neck flask with the dry tube of anhydrous calcium chloride (or other suitable drying agents), was added absolute ethanol (500 mL), then the cut metal sodium (2.53 g, 110 mmol) was added in portions, and sodium ethoxide solution was obtained after complete dissolution of sodium. Metformin hydrochloride (18.10 g, 110 mmol) was added to the solution of sodium ethoxide in portions, and then lots of white solid suspended in the solution. After finishing the addition, the mixture was heated to 60° C. and allowed to react for 1 h, and then cooled to room temperature and filtered, to obtain the white solid (6.0 g). After dried in phosphorus pentoxide dryer, the crude product (13.88 g) was obtained as white solid. The crude product (5 g) was dissolved in acetone under sonication for desalting, and the filtrate was concentrated to dry, to obtain guanidine free base as white solid. m.p. 108-110° C.

(3) .sup.1H NMR (400 MHz, D.sub.2O): δ 2.87 (s, 6H);

(4) .sup.13C NMR (100 MHz, D.sub.2O): δ 37.14 (2C), 158.44, 161.55. The structure is:

(5) ##STR00002##

Example 2 Preparation of Guanidine Free Base (2)

(6) At room temperature, metformin hydrochloride (1.65 g, 10 mmol) was dissolved in 10 mL water, to which was added aq. odium hydroxide solution (5 mL, 2 mol/L), and the mixture was stirred at room temperature for 1 h. The water was removed by concentration under reduced pressure, to obtain the white solid, that was desalted using acetone to provide metformin free base with strong alkaline as white solid. M.p. of crude product was 90-100° C., and after recrystallization, m.p. of the product was 110-112° C.

Example 3 Preparation of Guanidine Free Base (3)

(7) At 50° C., to the suspension of metformin hydrochloride (16.6 g, 100 mmol) in isopropanol (70 mL), was added potassium hydroxide (5.88 g, 105 mmol) under stirring, and the mixture was kept at 50° C. and allowed to react for 2 h, then cooled to room temperature and filtered. The filter cake was washed with isopropanol and acetone, and the washing solution and the filtrate were combined and concentrated. The resultant solid was desalted using acetone to provide metformin free base with strong alkaline as white solid. M.p. of crude product was 90-100° C., and after recrystallization, m.p. of the product was 110-112° C.

Example 4 Preparation of Guanidine Free Base (4)

(8) At room temperature, silver oxide (460 mg, 2 mmol) was suspended in 8 ml distilled water under vigorously stirring, to which was drop added 10 times diluted concentrated ammonia (9.5 mL). After the reaction solution was clear, to the freshly prepared solution of silver ammonia ([Ag(NH.sub.3).sub.2].sup.+OH.sup.−), was added metformin hydrochloride (660 mg, 4 mmol), and lots of white precipitation appeared. At room temperature, the mixture was stirred for additional 30 min and filtered, and the filtrate was concentrated to dry under reduced pressure, to provide the product.

Example 5 Preparation of Guanidine Free Base (5)

(9) At room temperature, guanidine sulfate (1.21 g, 10 mmol) was dissolved in 10 mL distilled water, to which was added freshly prepared aqueous solution of barium hydroxide (5 mL, 2 mol/L). After stirring at room temperature for 30 min, water was evaporated under reduced pressure to obtain the pale yellow oil, that was placed at room temperature overnight and became solid, to provide the target compound.

(10) .sup.13C NMR (100 MHz, D.sub.2O): δ 160.98, 162.45.

Example 6 1,1-dimethylbiguanide hydrogen sulfide salt (C.SUB.4.H.SUB.11.N.SUB.5..H.SUB.2.S, MW: 163.24)

(11) 1,1-Dimethylbiguanide (26 g, 0.2 mol) in one of examples 1-4 was taken and mixed with 100 mL water, and under the conditions that the temperature was kept at 2° C., 100 ml aqueous solution of 6.8 g hydrogen sulfide was added and mixed. The mixed solution was freeze-dried for 24 h, to provide the white solid that was collected to obtain the target compound.

(12) .sup.1H NMR (400 MHz, D.sub.2O): δ 3.01 (s, 6H);

(13) .sup.13C NMR (100 MHz, D.sub.2O): δ 37.45 (2C), 158.39, 160.15.

(14) Elemental analysis: for C.sub.4H.sub.15N.sub.5OS; Cacld: C, 29.43%, H, 8.03%, N, 42.90%, S, 19.64%;

(15) Found: C, 28.16%, H, 8.36%, N, 41.39%, S, 17.46%.

(16) The water content in sample was 11.58%.

(17) The content of reducing substance was 88.2% by iodometric titration. The structure is:

(18) ##STR00003##

Example 7 L-Arginine Hydrogen Sulfide Salt (C.SUB.6.H.SUB.14.N.SUB.4.O.SUB.2..H.SUB.2.S, MW: 208.28)

(19) L-arginine monohydrate (38.4 g, 0.2 mol) was mixed with 100 mL water, and under the conditions that the temperature was kept at 25° C., hydrogen sulfide was added 0.5 h. Then, the mixed solution was freeze-dried for 24 h, to provide the white solid, that was collected to obtain the product.

(20) .sup.1H NMR (400 MHz, D.sub.2O): δ 1.54-1.74 (m, 4H), 3.17 (t, J=6.7 Hz, 2H), 3.43 (t, J=6.0 Hz, 1H);

(21) .sup.13C NMR (100 MHz, D.sub.2O): δ 24.44, 31.58, 40.73, 54.94, 156.70, 179.27.

(22) The water content in sample was 12.9%.

(23) The content of reducing substance was 69.2% by iodometric titration. The structure is:

(24) ##STR00004##

Example 8 Morpholine Biguanide Hydrogen Sulfide Salt (C.SUB.6.H.SUB.13.N.SUB.5.O.H.SUB.2.S, MW: 205.28)

(25) Morpholine biguanide (34.2 g, 0.2 mol) was mixed with 100 mL water, and under the conditions that the temperature was kept at 25° C., hydrogen sulfide was added 0.5 h. Then, the mixed solution was rotatory evaporated at 50° C. to remove water and provide the white solid (46 g), that was collected to obtain the target compound.

(26) .sup.1H NMR (400 MHz, D.sub.2O): δ 3.35 (t, J=4.0 Hz, 1H), 3.46 (t, J=4.0 Hz, 2H), 3.67 (t, J=4.0 Hz, 1H), 3.71 (t, J=4.0 Hz, 2H);

(27) .sup.13C NMR (100 MHz, D.sub.2O): δ 45.08, 65.99, 158.86, 160.33;

(28) Elemental analysis: for C.sub.6H.sub.15N.sub.5OS, Cacld: C, 35.11%, H, 7.37%, N, 34.12%, S, 15.62%;

(29) Found: C, 29.31%, H, 8.36%, N, 27.29%, S, 12.46%.

(30) The water content in sample was 16.26%.

(31) The content of reducing substance was 76.3% by iodometric titration. The structure is:

(32) ##STR00005##

Example 9 P-Guanidinobenzoic Acid Hydrogen Sulfide Salt (C.SUB.8.H.SUB.9.N.SUB.3.O.SUB.2..H.SUB.2.S, MW: 213.26)

(33) P-guanidinobenzoic acid (35.8 g, 0.2 mol) was mixed with 100 mL absolute ethanol, and under the conditions that the temperature was kept at 10° C., hydrogen sulfide was added 1 h. Then, the mixed solution was rotatory evaporated at 45° C. to remove the solvent and provide the white solid (41 g), that was collected to obtain the target compound.

(34) Elemental analysis: for C.sub.8H.sub.11N.sub.3O.sub.2S, Cacld: C, 45.06%, H, 5.20%, N, 19.70%, S, 15.04%;

(35) Found: C, 38.99%, H, 5.56%, N, 17.29%, S, 13.03%.

(36) The water content in sample was 3.72%.

(37) The content of reducing substance was 85.5% by iodometric titration. The structure is:

(38) ##STR00006##

Example 10 Cyanoguanidine Hydrogen Sulfide Salt (C.SUB.2.H.SUB.4.N.SUB.4..H.SUB.2.S, MW: 118.16)

(39) Cyanoguanidine (16.8 g, 0.2 mol) was mixed with 100 mL absolute ethanol, and under the conditions that the temperature was kept at 2° C., 100 mL ethanol solution of 6.8 g hydrogen sulfide was added 1 h. Then, the mixed solution was rotatory evaporated at 45° C. to remove the solvent and provide the white solid (23 g), that was collected to obtain the target compound.

(40) Elemental analysis: for C.sub.2H.sub.6N.sub.4S, Cacld: C, 20.33%, H, 5.12%, N, 47.42%, S, 27.14%;

(41) Found: C, 16.59%, H, 5.59%, N, 38.68%, S, 22.14%.

(42) The water content in sample was 5.36%.

(43) The content of reducing substance was 86.2% by iodometric titration. The structure is:

(44) ##STR00007##

Example 11 Guanidine Acetate Hydrogen Sulfide Salt (C.SUB.3.H.SUB.7.N.SUB.3.O.SUB.2..H.SUB.2.S, MW: 151.19)

(45) Guanidine acetate (23.4 g, 0.2 mol) was mixed with 100 mL dichloromethane, and at room temperature, the solution was drop added to a three-necked bottle filled with hydrogen sulfide. The mixture was stirred 3 h at room temperature, and white solid precipitated, that was filtered and dried in vacuum, to provide the white solid (26 g), that was collected to obtain the target compound.

(46) Elemental analysis: for C.sub.3H.sub.9N.sub.3O.sub.2S, Cacld: C, 23.83%, H, 6.00%, N, 27.79%, S, 21.21%;

(47) Found: C, 20.68%, H, 6.43%, N, 24.26%, S, 18.41%.

(48) The water content in sample was 3.58%.

(49) The content of reducing substance was 90.2% by iodometric titration. The structure is:

(50) ##STR00008##

Example 12 Famotidine Hydrogen Sulfide Salt (C.SUB.8.H.SUB.5.N.SUB.7.O.SUB.2.S.SUB.3..H.SUB.2.S, MW: 371.53)

(51) Famotidine (6.74 g, 0.02 mol) was mixed with 100 mL tetrahydrofuran, and under the conditions that the temperature was kept at 30° C., hydrogen sulfide was added 2 h. Then, the mixed solution was rotatory evaporated at 40° C. to remove the solvent and provide the white solid (7.3 g), that was collected to obtain the target compound.

(52) Elemental analysis: for C.sub.8H.sub.17N.sub.7O.sub.2S.sub.4, Cacld: C, 25.86%, H, 4.61%, N, 26.39%, S, 34.52%;

(53) Found: C, 23.18%, H, 5.03%, N, 23.58%, S, 30.85%.

(54) The water content in sample was 4.62%.

(55) The content of reducing substance was 93.7% by iodometric titration. The structure is:

(56) ##STR00009##

Example 13 Guanethidine Hydrogen Sulfide Salt (C.SUB.9.H.SUB.21.N.SUB.5..H.SUB.2.S, MW: 233.38)

(57) Guanethidine (4.00 g, 0.02 mol) was mixed with 100 mL tetrahydrofuran, and at room temperature, the solution was drop added to a reaction bottle filled with hydrogen sulfide. The mixture was allowed to react 12 h at room temperature, and solid was produced after freeze-drying at 0-5° C., then filtered and provided the white solid (3.6 g), that was collected to obtain the target compound.

(58) Elemental analysis: for C.sub.9H.sub.23N.sub.5S, Cacld: C, 46.32%, H, 9.93%, N, 30.01%, S, 13.74%;

(59) Found: C, 41.31%, H, 10.93%, N, 26.69%, S, 12.22%.

(60) The water content in sample was 3.93%.

(61) The content of reducing substance was 92.6% by iodometric titration. The structure is:

(62) ##STR00010##

Example 14 Clonidine Hydrogen Sulfide Salt (C.SUB.9.H.SUB.9.C.SUB.12.N.SUB.3..H.SUB.2.S, MW: 264.17)

(63) Clonidine (4.58 g, 0.02 mol) was mixed with 50 mL dichloromethane, to which was added 50 ml ethanol solution of 3.9 g hydrogen sulfide at 0° C. Under the conditions that the temperature was kept at 0° C., the mixture was allowed to react 2 h, and then solid was produced after freeze-drying at 0-5° C., filtered and provided the white solid (3.6 g), that was collected to obtain the target compound.

(64) Elemental analysis: for C.sub.9H.sub.11Cl.sub.2N.sub.3S, Cacld: C, 40.92%, H, 4.20%, Cl, 26.84%, N, 15.91%, S, 12.14%;

(65) Found: C, 37.16%, H, 4.33%, Cl, 24.34%, N, 14.65%, S, 11.02%.

(66) The water content in sample was 2.72%.

(67) The content of reducing substance was 93.3% by iodometric titration. The structure is:

(68) ##STR00011##

Example 15 Cimetidine Hydrogen Sulfide Salt (C.SUB.10.H.SUB.16.N.SUB.6.S.H.SUB.2.S, MW: 286.42)

(69) Cimetidine (5.04 g, 0.02 mol) was mixed with 50 mL ethyl acetate, to which was added 50 ml ethyl acetate solution of 3.9 g hydrogen sulfide at 0° C. Under the conditions that the temperature was kept at 0° C., the mixture was allowed to react 3 h, and then solid was produced after freeze-drying at 0-5° C., filtered and provided the white solid (2.9 g), that was collected to obtain the target compound.

(70) Elemental analysis: for C.sub.10H.sub.18N.sub.6S.sub.2, Cacld: C, 41.93%, H, 6.33%, N, 29.34%, S, 22.39%;

(71) Found: C, 36.11%, H, 6.76%, N, 25.51%, S, 19.26%.

(72) The water content in sample was 6.52%.

(73) The content of reducing substance was 91.9% by iodometric titration. The structure is:

(74) ##STR00012##

Example 16 Guanoclor Hydrogen Sulfide Salt (C.SUB.9.H.SUB.12.Cl.SUB.2.N.SUB.4.O.H.SUB.2.S, MW: 297.20)

(75) Guanoclor (5.25 g, 0.02 mol) was mixed with 100 mL dichloromethane, and under the conditions that the temperature was kept at 0° C., hydrogen sulfide was added 5 h. Then, the mixture was placed at 0-5° C., and the solid precipitated, was filtered and provided the white solid (2.6 g), that was collected to obtain the target compound.

(76) Elemental analysis: for C.sub.9H.sub.14Cl.sub.2N.sub.4OS, Cacld: C, 36.37%, H, 4.75%, Cl, 23.86%, N, 18.85%, S, 10.79%;

(77) Found: C, 33.36%, H, 5.07%, Cl, 21.93%, N, 17.29%, S, 9.92%.

(78) The water content in sample was 3.37%.

(79) The content of reducing substance was 95.2% by iodometric titration. The structure is:

(80) ##STR00013##

Example 17 1,8-diazabicycloundec-7-ene (DBU) hydrogen sulfide salt (C.SUB.9.H.SUB.16.N.SUB.2..H.SUB.2.S, MW: 186.32)

(81) DBU (30.4 g, 0.2 mol) was mixed with 100 mL water, and under the conditions that the temperature was kept at 25° C., 100 ml aqueous solution of 6.8 g hydrogen sulfide was added and mixed. Then, the mixed solution was rotatory evaporated at 50° C. and provided the solid (39 g), that was collected to obtain the target compound.

(82) Elemental analysis: for C.sub.9H.sub.18N.sub.2S, Cacld: C, 58.02%, H, 9.74%, N, 15.04%, S, 17.21%;

(83) Found: C, 29.11%, H, 11.67%, N, 7.51%, S, 8.56%.

(84) The water content in sample was 18.33%.

(85) The content of reducing substance was 62.6% by iodometric titration. The structure is:

(86) ##STR00014##

Example 18 4-Dimethylaminopyridine (DMAP) hydrogen sulfide salt (C.SUB.7.H.SUB.10.N.SUB.2..H.SUB.2.S, MW: 156.25)

(87) DMAP (24.4 g, 0.2 mol) was dissolved in 100 mL dichloromethane, and the solution was drop added to a three-necked bottle filled with hydrogen sulfide and reacted for 1.5 h. The color of reaction solution gradually became dark, and after stayed overnight, pale yellow solid precipitated, that was filtered and collected, to obtain the target compound (8.6 g).

(88) Elemental analysis: for C.sub.7H.sub.12N.sub.2S, Cacld: C, 53.81%, H, 7.74%, N, 17.93%, S, 20.52%;

(89) Found: C, 43.82%, H, 8.68%, N, 14.61%, S, 16.72%.

(90) The water content in sample was 5.62%.

(91) The content of reducing substance was 85.9% by iodometric titration. The structure is:

(92) ##STR00015##

Example 19 Piperazidine Hydrogen Sulfide Salt (C.SUB.4.H.SUB.10.N.SUB.2..H.SUB.2.S, MW: 120.22)

(93) Piperazidine (17.2 g, 0.2 mol) was dissolved in 100 ml absolute ethanol, to which was added dry hydrogen sulfide at room temperature, and white needle solid precipitated at once. The mixture was stirred 5 min, filtered, and collected, to obtain the target compound (2.9 g).

(94) Elemental analysis: for C.sub.4H.sub.12N.sub.2S, Cacld: C, 39.96%, H, 10.06%, N, 23.30%, S, 26.67%;

(95) Found: C, 36.02%, H, 8.68%, N, 20.91%, S, 23.92%.

(96) The water content in sample was 2.98%.

(97) The content of reducing substance was 92.9% by iodometric titration. The structure is:

(98) ##STR00016##

Example 20 Tryptamine Hydrogen Sulfide Salt (C.SUB.10.H.SUB.12.N.SUB.2..H.SUB.2.S, MW: 194.30)

(99) Tryptamine (3.2 g, 0.02 mol) was dissolved in 30 ml absolute ethanol, to which was added dry hydrogen sulfide, and white solid precipitated at once. The mixture was stirred 30 min, filtered, and collected, to obtain the target compound (0.8 g).

(100) .sup.1H NMR (400 MHz, D.sub.2O): δ 2.96 (t, J=9.0 Hz, 2H), 3.11 (t, J=8.8 Hz, 2H), 7.03 (t, J=4.0 Hz, 1H), 7.08-7.13 (m, 2H), 7.34 (d, J=4.0 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H);

(101) .sup.13C NMR (100 MHz, D.sub.2O): δ 22.93, 40.10, 109.39, 112.35, 118.58, 119.71, 122.48, 124.53, 126.75, 136.71;

(102) Elemental analysis: for C.sub.10H.sub.14N.sub.2S, Cacld: C, 61.82%, H, 7.26%, N, 14.42%, S, 16.50%;

(103) Found: C, 55.82%, H, 8.12%, N, 13.02%, S, 15.02%.

(104) The water content in sample was 3.65%.

(105) The content of reducing substance was 93.7% by iodometric titration. The structure is:

(106) ##STR00017##

INDUSTRIAL APPLICABILITY

(107) The present invention provides one new structural form of hydrogen sulfide (H.sub.2S) donor that may have research and/or medicinal developmental values, i.e. hydrogen sulfide donor in organic salt form, and further provides the preparative method thereof. The structure of hydrogen sulfide donor according to the present invention is simple, and the preparative method thereof is also simple and feasible. Moreover, according to the requirement of research and development, various types of hydrogen sulfide donors can be obtained. After the hydrogen sulfide donor enters an organism, the in vivo dissociation and supply process of hydrogen sulfide is simple, rapid, and effective, and there is no requirement for enzyme or any other complicated conditions, thus the hydrogen sulfide donor has a great application prospect and value.