1. A process for the recovery and refining of rhodium starting from a mixture containing rhodium and other transition metals, including those of the platinum Group as well as metals of the main Groups, said process being characterized by the following passages:
a) formation of an adduct between rhodium trichloride and a halide of a metal selected from metals of Groups IIA, IIIA, IVA, IVB, VB and VIB;
b) carbonylation of the precipitated adduct, deriving from passage a) with the formation of rhodium halogen carbonyls;
c) sublimation of the carbonylated product obtained in the previous passage.
2. The process according to claim 1, characterized in that it further comprises the following passages:
d) oxidation to rhodium trichloride hydrate of the complex Rh2CO)4Cl2 obtained at the end of passage c), the halide of the metal in passage a) being a chloride;
e) reduction with hydrogen, at a high temperature, of the rhodium trichloride hydrate deriving from the oxidation of passage d).
3. The process according to claim 1, characterized in that the formation of the adduct between rhodium trichloride and halide of a metal selected from metals of Groups IIA, IIIA, IVA, IVB, VB and VIB, is effected in the presence of free hydrochloric acid and by the addition of a quantity of metal halide sufficient to cause the precipitation of the adduct.
4. The process according to claim 1, characterized in that the halide of the metal selected from metals of Groups IIA, IIIA, IVA, IVB, VB and VIB is a chloride.
5. The process according to claim 1, characterized in that the halide of the metal selected from metals of Groups IIA, IIIA, IVA, IVB, VB and VIB is anhydrous aluminum trichloride or anhydrous vanadium trichloride.
6. The process according to claim 3, characterized in that the free hydrochloric acid is concentrated.
7. The process according to claim 6, characterized in that the concentrated hydrochloric acid is hydrochloric acid at 37%.
8. The process according to claim 1, characterized in that the adduct deriving from passage a) is washed with alcohols before being subjected to passage b).
9. The process according to claim 1, characterized in that the carbonylation reaction is carried out in an aqueous solution with a concentration of rhodium varying from 5 gl to 300 gl, under vigorous stirring, the partial CO pressure being kept within a range of 300 hPa to 5.065 MPa, at a temperature ranging from 10 C. to 100 C.
10. The process according to claim 9, characterized in that the concentration of rhodium varies from 50 gl to 200 gl.
11. The process according to claim 9, characterized in that the partial CO pressure is kept within a range of 400 to 2000 hPa and the temperature within a range of 20 C. to 50 C.
12. The process according to claim 1, characterized in that the carbonylated product at the end of passage b) consisting of rhodium halogen carbonyl, is extracted with an organic solvent, and concentrated to dryness, before sublimation.
13. The process according to claim 12, characterized in that the organic solvent is selected from ethers, esters, carboxylic acids, alcohols, alkyl halides and hydrocarbons.
14. The process according to claim 12, characterized in that the organic solvent is an ether or an alkyl halide.
15. The process according to claim 12, characterized in that the organic solvent is MTBE or CH2Cl2.
16. The process according to claim 1, characterized in that the sublimation reaction is carried out under vacuum, at pressures lower than 10 mmHg, and at a temperature lower than 110 C.
17. The process according to claim 1, characterized in that the carbonylation reaction is carried out by heating the adduct deriving from passage a) to 100 C., in a Pyrex tube, in a stream of CO.
18. The process according to claim 17, characterized in that the sublimation of the carbonylated product takes place directly on the cold part of the Pyrex tube.
19. The process according to claim 2, characterized in that the oxidation reaction is carried out with HNO3 or H2O2 in hydrochloric acid.
20. The process according to claim 2, characterized in that the reduction reaction is carried out in a quartz tube, in a stream of hydrogen at 500 C.
21. Rhodium (I) chlorocarbonyl dimer, Rh2(CO)4Cl2, obtainable by means of the process according to any of claims 1, 3-18, the metal halide in passage a) being a chloride.
22. Use of the rhodium (I) chlorocarbonyl dimer Rh2CO)4Cl2, according to claim 21, for the synthesis of rhodium derivatives.
23. A rhodium sponge obtainable by means of a process which, starting from a mixture containing rhodium and other transition metals, including those of the platinum Group as well as those of the main Groups, comprises the following passages:
a) formation of an adduct between rhodium trichloride and a chloride of a metal selected from metals of Groups IIA, IIIA, IVA, IVB, VB and VIB;
b) carbonylation of the precipitated adduct, deriving from passage a) with the formation of rhodium chloro carbonyls;
C) sublimation of the carbonylated product obtained in the previous passage.
d) oxidation to rhodium trichloride hydrate of the complex Rh2(CO)4Cl2 obtained at the end of passage c);
e) reduction with hydrogen, at a high temperature, of the rhodium trichloride hydrate deriving from the oxidation of passage d).
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A pharmaceutical composition comprising a compound having the following structure
andor a compound having the following structure
or a pharmaceutically acceptable salt thereof in combination with at least one second therapeutic agent 2 which is suitable in the treatment of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), atherosclerose, glaucoma and hyperglycemia; wherein the at least one second therapeutic agent (2) is selected from the group consisting of:
2.a) biguanides,
2.b) sulfonylureas,
2.c) meglitinides,
2.d) thiazolidindiones,
2.e) alpha-glucosidase inhibitors,
2.f) insulins and insulin analogues,
2.g) dipeptidyl peptidase IV inhibitors (DPP IV inhibitors)
2.h) SGLT 2 inhibitors,
2.i) PPAR gammaalpha modulators,
2.j) glucose-dependent insulinotropic polypeptide agonists,
2.k) beta-3 agonists,
2.l) GLP1 and GLP1 analogues,
2.m) PPAR gamma modulators,
2.n) HMG-CoA reductase inhibitors, and
2.o) PPAR delta modulators.
2. The pharmaceutical composition according to claim 1 characterized in that the at least one second therapeutic agent 2 is selected from the groups consisting of 2.a), 2.g) and 2.h).
3. A pharmaceutical composition comprising a compound having the following structure
andor a compound having the following structure
or a pharmaceutically acceptable salt thereof in combination with at least one second therapeutic agent 2 which is suitable in the treatment of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), atherosclerose, glaucoma and hyperglycemia; characterized in that the at least one second therapeutic agent 2 is selected from the group consisting of metformin (2.a1), phenformin (2.a2), buformin (2.a3), chlorpropamide (2.b1), acetohexamide (2.b2), tolazamide (2.b3), glibenclamide (2.b4), tolbutamide (2.b5), glimepiride (2.b6), glipizide (2.b7), gliquidone (2.b8), glibornurid (2.b9), glyburide (2.b10), gliclazide (2.b11), nateglinide (2.c1), repaglinide (2.c2), mitiglinide (2.c3), pioglitazone (2.d1), rosiglitazone (2.d2), troglitazone (2.d3), ciglitazone (2.d4), miglitol (2.e1), acarbose (2.e2), voglibose (2.e3), insulin lispro (Humalog\xae) (2.f1), insulin aspartat (Novorapid\xae) (2.f2), insulin glulisine (Apidra\xae) (2.f3), regular insulin (2.f4), intermediate acting insulins like NPH-insulins and long acting insulins like lente (2.f5) and ultralente insulin (2.f6), insulin glargine (Lantus\xae) (2.f7), insulin detemir (Levemir\xae) (2.f8), denagliptin (2.g1), carmegliptin (2.g2), melogliptin (2.g3) sitagliptin (2.g4), vildagliptin (2.g5), saxagliptin (2.g6), linagliptin (2.g7), dutogliptin (2.g8), gemigliptin (2.g9), alogliptin (2.g10), 6-(4-ethylbenzyl)-4-(\u03b2-D-glucopyranos-1-yl)-2-methoxy-benzonitrile (2.h1), 2-(4-ethylbenzyl)-4-(\u03b2-D-glucopyranos-1-yl)-5-methoxy-benzonitrile (2.h2), 1-cyano-2-(4-ethylbenzyl)-4-(\u03b2-D-glucopyranos-1-yl)-5-methyl-benzene (2.h3), 2-(4-ethylbenzyl)-4-(\u03b2-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile (2.h4), 2-(4-ethyl-benzyl)-4-(\u03b2-D-glucopyranos-1-yl)-benzonitrile (2.h5), 2-(4-cyclopropyl-benzyl)-4-(\u03b2-D-glucopyranos-1-yl)-benzonitrile (2.h6), 1-chloro-4-(\u03b2-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene (2.h7), 1-chloro-4-(\u03b2-D-glucopyranos-1-yl)-2-4-((R)-tetrahydrofuran-3-yloxy)-benzyl-benzene (2.h8), 1-chloro-4-(\u03b2-D-glucopyranos-1-yl)-2-4-((S)-tetrahydrofuran-3-yloxy)-benzyl-benzene (2.h9), 1-methyl-2-4-((R)-tetrahydrofuran-3-yloxy)-benzyl-4-(\u03b2-D-glucopyranos-1-yl)-benzene (2.h10), 1-methyl-2-4-((S)-tetrahydrofuran-3-yloxy)-benzyl-4-(\u03b2-D-glucopyranos-1-yl)-benzene (2.h11), dapagliflozin (2.h12), atigliflozin (2.h13), remogliflozin (2.h14), sergliflozin (2.h15), canagliflozin (2.h16), tesaglitazar (2.i1), muraglitazar (2.i2), KRP297 (2.i3), pramlintide (2.j1), amlyin (2.j2), ritobegron (2.k1), YM 178 (2.k2), solabegron (2.k3), talibegronb (2.k4), N-5984 (2.k5), GRC-1087 (2.k6), rafabegron (2.k7), FMP825 (2.k8), exenatide (2.l1), liraglutide (2.l2), taspoglutide (2.l3), metaglidasen, (2.m1) simvastatin (2.n1), lovastatin (2.n2), provastatin (2.n3), GW 501516 (2.o1), GW 0742 (2.o2), L165041 (2.o3), LY 465608 (2.o4), and L-796449 (2.o5).
4. The pharmaceutical composition according to claim 3 characterized in that the at least one second therapeutic agent 2 is (2.a1), (2.d1), (2.g7) and (2.h9).
5. The pharmaceutical composition according to claim 3 characterized in that the composition is suitable for combined or simultaneous or sequential use of 1.a andor 1.b and the at least one second therapeutic agent 2.
6. The pharmaceutical composition according to claim 3 characterized in that 1.a andor 1.b and the at least one second therapeutic agent 2 are present in a single dosage form.
7. The pharmaceutical composition according to claim 1 characterized in that 1.a andor 1.b and the at least one second therapeutic agent 2 are present each in a separate dosage form.
8. A method of using a compound having the following structure:
andor a compound having the following structure
or a pharmaceutically acceptable salt thereof, for
slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome, or
improving glycemic control andor for reducing of fasting plasma glucose, of postprandial plasma glucose andor of glycosylated hemoglobin HbA1c, or
slowing, delaying or reversing progression from impaired glucose tolerance, impaired fasting blood glucose, insulin resistance andor from metabolic syndrome to type 2 diabetes mellitus, or
slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, or
reducing the weight or facilitating a reduction of the weight, or
slowing, delaying or treating the degeneration of pancreatic beta cells andor the decline of the functionality of pancreatic beta cells andor for improving andor restoring the functionality of pancreatic beta cells andor restoring the functionality of pancreatic insulin secretion, or
slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat, or
maintaining andor improving the insulin sensitivity andor for treating hyperinsulinemia andor insulin resistance, or
slowing progression of delaying or treating athersclerosis and complications of atherosclerosis, or
slowing progression of delaying or treating glaucoma and complications of glaucoma, or
slowing progression of delaying or treating dyslipidemiahyperlipidemia and complications of dyslipidemiahyperlipidemia;
improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise, or
improving glycemic control in patients with type 2 diabetes
in a patient in need thereof characterized in that 1.a andor 1.b is administered in combination or alternation with at least one second therapeutic agent with at least one second therapeutic agent 2 which is suitable in the treatment of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), atherosclerose, glaucoma and hyperglycemia.
9. A second therapeutic agent 2 according to claim 1, or a pharmaceutically acceptable salt thereof, for
slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome, or
improving glycemic control andor for reducing of fasting plasma glucose, of postprandial plasma glucose andor of glycosylated hemoglobin HbA1c, or
slowing, delaying or reversing progression from impaired glucose tolerance, impaired fasting blood glucose, insulin resistance andor from metabolic syndrome to type 2 diabetes mellitus, or
slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, or
reducing the weight or facilitating a reduction of the weight, or
slowing, delaying or treating the degeneration of pancreatic beta cells andor the decline of the functionality of pancreatic beta cells andor for improving andor restoring the functionality of pancreatic beta cells andor restoring the functionality of pancreatic insulin secretion, or
slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat, or
maintaining andor improving the insulin sensitivity andor for treating hyperinsulinemia andor insulin resistance, or
slowing progression of delaying or treating athersclerosis and complications of atherosclerosis, or
slowing progression of delaying or treating glaucoma and complications of glaucoma, or
slowing progression of delaying or treating dyslipidemiahyperlipidemia and complications of dyslipidemiahyperlipidemia;
improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise, or
improving glycemic control in patients with type 2 diabetes
in a patient in need thereof characterized in that second therapeutic agent 2 is administered in combination or alternation with 1.a andor 1.b or a pharmaceutically acceptable salt thereof.
10. A method of using a compound having the following structure:
andor a compound having the following structure
or a pharmaceutically acceptable salt thereof, for
slowing progression of delaying or treating athersclerosis and complications of atherosclerosis, or
slowing progression of delaying or treating athersclerosis and complications of glaucoma,
slowing progression of delaying or treating dyslipidemiahyperlipidemia and complications of dyslipidemiahyperlipidemia;
improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise, or
improving glycemic control in patients with type 2 diabetes
in a patient in need thereof.
11. A method of using the pharmaceutical composition according to claim 1 for
slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or
improving glycemic control andor for reducing of fasting plasma glucose, of postprandial plasma glucose andor of glycosylated hemoglobin HbA1c; or
slowing, delaying or reversing progression from impaired glucose tolerance, insulin resistance andor from metabolic syndrome to type 2 diabetes mellitus; or
slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or
reducing the weight or facilitating a reduction of the weight; or
slowing, delaying or treating the degeneration of pancreatic beta cells andor the decline of the functionality of pancreatic beta cells andor for improving andor restoring the functionality of pancreatic beta cells andor restoring the functionality of pancreatic insulin secretion; or
slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat; or
maintaining andor improving the insulin sensitivity andor for treating hyperinsulinemia andor insulin resistance; or
slowing progression of delaying or treating athersclerosis and complications of atherosclerosis, or
slowing progression of delaying or treating athersclerosis and complications of glaucoma, or
slowing progression of delaying or treating dyslipidemiahyperlipidemia and complications of dyslipidemiahyperlipidemia;
improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise, or
improving glycemic control in patients with type 2 diabetes in a patient in need thereof.
12. The method according to claim 8 wherein, the patient is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.
13. The method according to claim 8, wherein the patient is an individual who shows one, two or more of the following conditions:
(a) a fasting blood glucose or serum glucose concentration greater than 110 mgdL, in particular greater than 125 mgdL;
(b) a postprandial plasma glucose equal to or greater than 140 mgdL;
(c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 8.0%.
14. The method according to claim 8, wherein the patient is an individual wherein one, two, three or more of the following conditions are present:
(a) obesity, visceral obesity andor abdominal obesity,
(b) triglyceride blood level \u2267150 mgdL,
(c) HDL-cholesterol blood level <40 mgdL in female patients and <50 mgdL in male patients,
(d) a systolic blood pressure \u2267130 mm Hg and a diastolic blood pressure \u226785 mm Hg,
(e) a fasting blood glucose level \u2267110 mgdL,
(f) LDL-cholesterol blood levels \u2267130 mgdL.
15. The method according to claim 8, wherein the patient is an individual for whom monotherapy with metformin is contraindicated andor who has an intolerance against metformin at therapeutic doses.
16. The method according to claim 8, wherein the patient is an individual with insufficient glycemic control despite treatment with one or more antidiabetic drugs selected from the groups 2a) to 2n)
2.a) biguanides,
2.b) sulfonylureas,
2.c) meglitinides,
2.d) thiazolidindiones,
2.e) alpha-glucosidase inhibitors,
2.f) insulins and insulin analogues,
2.g) dipeptidyl peptidase IV inhibitors (DPP IV inhibitors)
2.h) SGLT 2 inhibitors,
2.i) PPAR gammaalpha modulators,
2.j) glucose-dependent insulinotropic polypeptide agonists,
2.k) beta-3 agonists,
2.l) GLP1 and GLP1 analogues,
2.m) PPAR gamma modulators, and
2.n) HMG-CoA reductase inhibitors.
17. The method according to claim 8, wherein the at least one second therapeutic agent 2 is selected from (2.a1), (2.d1), (2.g7) and (2.h9).