US2847437A - Process for the preparation of ferriferro cobaltochloroaminoacetate - Google Patents
Process for the preparation of ferriferro cobaltochloroaminoacetate Download PDFInfo
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- US2847437A US2847437A US550858A US55085855A US2847437A US 2847437 A US2847437 A US 2847437A US 550858 A US550858 A US 550858A US 55085855 A US55085855 A US 55085855A US 2847437 A US2847437 A US 2847437A
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- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 14
- MPMSMUBQXQALQI-UHFFFAOYSA-N cobalt phthalocyanine Chemical compound [Co+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 MPMSMUBQXQALQI-UHFFFAOYSA-N 0.000 claims description 9
- 229960002449 glycine Drugs 0.000 claims description 9
- 235000013905 glycine and its sodium salt Nutrition 0.000 claims description 9
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 claims description 6
- 229940097268 cobaltous chloride hexahydrate Drugs 0.000 claims description 6
- 229940044631 ferric chloride hexahydrate Drugs 0.000 claims description 6
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000011876 fused mixture Substances 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 24
- 150000003839 salts Chemical class 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 15
- 239000010941 cobalt Substances 0.000 description 13
- 229910017052 cobalt Inorganic materials 0.000 description 13
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 12
- 238000011282 treatment Methods 0.000 description 10
- 208000007502 anemia Diseases 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 229910052742 iron Inorganic materials 0.000 description 9
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 8
- 229940032296 ferric chloride Drugs 0.000 description 8
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 5
- 229940097267 cobaltous chloride Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 4
- 159000000014 iron salts Chemical class 0.000 description 4
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- FQMNUIZEFUVPNU-UHFFFAOYSA-N cobalt iron Chemical compound [Fe].[Co].[Co] FQMNUIZEFUVPNU-UHFFFAOYSA-N 0.000 description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 2
- 229940045032 cobaltous nitrate Drugs 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229940060367 inert ingredients Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000019629 palatability Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- KTVIXTQDYHMGHF-UHFFFAOYSA-L cobalt(2+) sulfate Chemical compound [Co+2].[O-]S([O-])(=O)=O KTVIXTQDYHMGHF-UHFFFAOYSA-L 0.000 description 1
- IEXXNGVQCLMTKU-UHFFFAOYSA-H cobalt(2+);2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Co+2].[Co+2].[Co+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O IEXXNGVQCLMTKU-UHFFFAOYSA-H 0.000 description 1
- GICLSALZHXCILJ-UHFFFAOYSA-N ctk5a5089 Chemical compound NCC(O)=O.NCC(O)=O GICLSALZHXCILJ-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
Definitions
- the present invention relates to novel compounds or complexes which are adapted to promote erythrogenesis (erythrocyte production) and hemoglobin formation in the prevention or treatment of anemia including anemia accompanying pregenancy. More specifically the present invention is directed to improved means for the administration of iron and cobalt when iron and cobalt are indicated in the treatment of anemia.
- the principal object of the present invention is to provide improved means for administering cobalt and iron in the treatment of anemias substantially free from the disadvantages discussed above.
- a more specific object of the present invention isto provide a cobalt-iron complex which is less irritating to the gastro-intestinal tract andmore readily acceptable on the basis of palatability than mixtures of cobalt and iron salts previously employed in the treatment of anemias.
- Still another object is to provide a process for preparing the cobalt-iron complex characterized by the advantages specified above. 7 l
- the complexes or compounds of the present invention can be readily prepared by heating and fusing a mixture made up of a water-soluble, non-toxic cobaltous salt, a water-soluble, non-toxic ferric salt and an amino acid, particularly the a-amino acids such as aminoacetic acid (glycine) and equivalents thereof including alanine, sarcorates Patent sine, lysine, glutaminic acid and the like.
- Suitable cobalt salts include cobaltous chloride, cobaltous nitrate, cobaltous sulfate, cobaltous acetate, cobaltous citrate, etc.
- suitable ferric salts include ferric chloride, ferric nitrate, etc.
- the salts Where available are preferably employed in their hydrate from, a preferred combination being made up of cobaltous chloride hexahydrate and ferric chloride hexahydrate.
- the cobaltous and ferric salts and amino acid are employed in amounts to provide a CozFezamino acid ratio of about 1:1:3 to 1:8:24 with about a 1:1:6 to 1:4:17 ratio of Co:Fe:amino acid being generally in the preferred range.
- acid to cobalt can be employed if desired but are ordinarily not accompanied by an appreciable beneficial result.
- a particularly stable complex is one in which the ingredients are mixed and fused to provide a complex with a ratio of about 1:2:9 of Co:Fe:amino acid.-
- the following examples will serve to illustrate the invention.
- Example II A mixture made up of 726 grams of ferric chloride hexahydrate, 150 grams of cobaltous chloride hexahydrate and 804 grams of aminoacetic acid is heated between -130 C. for a period of from 3 to 5 minutes so that the mass melts and becomes dark green or blackish in color. If the reaction product or complex does not form a solid on cooling, it is reheated until it turns to a solid on cooling.
- the complex produced by this process has a Co:Fe:amino acid ratio of about 1:4:17.
- Example III This complex is prepared in accordance with Example II by heating and fusing a mixture made up of 150 grams of cobaltous chloride hexahydrate, 340.3 grams of ferric chloride hexahydrate and 425.4 grams of aminoactic acid. This complex has a Co:Fe:aminoacetic acidratio of 1:229.
- Example IV This complex is prepared in accordance with Example I by heating and fusing a mixture of hydrate salts made up of 107 grams of cobaltous acetate, 116, grams of ferric chloride and 200 grams of aminoacetic acid. This complex has a Co:Fe:amino acid ratio of 1:1 :6.
- Example V This complex is prepared in accordance withExample IV by heating and fusing grams of cobaltous nitrate, 116 grams of ferric chloride and 200 grams of aminoacetic acid.
- Example VI This complex is prepared inaccordance with Example IV by heating and fusing 102 grams of cobaltous chloride, grams of ferric nitrate and 200 grams of aminoacetic acid.
- Example VII This complex is prepared in accordance with Example IV by heating and fusing 90 grams of cobaltous chlo- Larger ratios of iron and amino.
- Example VIII This product is prepared in accordance with Example IV by heating and fusing 90 grams of cobaltous chloride, 100 grams of ferric chloride and 200 grams of sarcosine.
- the order of mixing of the ingredients is of no consequence and the reaction can be carried out by heating and fusing any one or twocomponents prior to the addition of the other components. Ordinarily, it is preferred to fuse the salts and then add the amino acid or to fuse all three ingredients simultaneously.
- the heating or fusing temperature should be sufficient to fuse (melt) the mass and should be carried out with stirring for a sufficient time to provide a complex which forms a solid on cooling.
- the salts or at least one salt is preferably in hydrate form the temperature employed should be sufiicient to drive off the water of hydration. Temperatures of around 100-250 C. can be employed in many instances with a temperature of about 125 C. being generally preferred. In all cases, however, the temperature employed should be below the decomposition temperature as evidenced by the charring of the amino acid. The optimum fusing temperature and time for a particular mixture can be readily ascertained by preliminary test.
- the products perpared in accordance with the present invention can be powdered and combined with inert ingredients according to the practice of the art and compressed into tablets for administration. Such tablets can, if desired, be enteric coated to delay their disintegration in the gastro-intestinal tract where patients are unusually susceptible to gastric irritation.
- the products can likewise be mixed with inert ingredients according to the practice of the art and filled into hard or soft gelatin capsules for administration to patients.
- the products can also be dissolved in suitable quantities of water or other common pharmaceutical vehicle in appropriate concentration for administration as a flavored or unflavored elixir, solution, tincture or other liquid product.
- the complexes produced in accordance with the present invention are water soluble and have toxicities of the same order as mixtures of the individual cobalt and iron salts used heretofore in the treatment of anemia.
- the complexes are not mere mixtures of the original ingredients or simple salts of amino acids. This has been established by solubility, freezing point and electrical conductance determinations as well as by chromatographic investigations. oxidation-reduction reaction apparently takes place during fusion as evidenced by the fact that the iron introduced in ferric form is present in both ferric and ferrous forms in the final complex.
- ferriferrocobalto 'chloroaminoacetate has been proposed for the complex made by fusing cobaltous chloride, ferric chloride and aminoacetic acid, although the formula of this complex as well as the other complexes, is extremely complicated and remains undetermined and unknown.
- the complexes or fusion compositions produced by the process of the present invention may contain small amounts of inorganic components. These contaminants can be removed, if desired, by the following purification procedure.
- Example IX It'has also been determined that an y added until no further precipitation occurs.
- the precipitate is allowed to settle and the supernatant liquid decanted.
- the oily brownish liquid residue is next dissolved in a minimum of water.
- Methanol is then added to the solution until no further precipitation takes place.
- the precipitate is recovered by filtering rapidly through a sintered glass. funnel. After washing with two small portions of methanol, the complex is obtained as a grayish, hygroscopic relatively pure product.
- the complexes of the present invention provide as noted above improved means of administering cobalt and iron when assimilable cobalt and iron are indicated in the treatment of anemia. As they tend to be less irritating and are more palatable than mixtures of cobalt and iron salts used heretofore, the complexes can be used to advantage in place of such mixtures and in the similar dosage units to provide the desired Co :Fe ratio in accordance with established practices in this art.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
United PROCESS FOR THE PREPARATION OF FERRIF- ERRO COBALTOCHLOROAIVDNOACETATE Application December 5, 1955 Serial No. 550,858
2 Claims. (Cl. 260-439) No Drawing.
The present invention relates to novel compounds or complexes which are adapted to promote erythrogenesis (erythrocyte production) and hemoglobin formation in the prevention or treatment of anemia including anemia accompanying pregenancy. More specifically the present invention is directed to improved means for the administration of iron and cobalt when iron and cobalt are indicated in the treatment of anemia.
It is recognized in the treatment of anemias, that cobalt will promote erythrogenesis and that the presence of available iron is necessary, in addition to cobalt, for the synthesis of hemoglobin by erythrocytes or their precursors in the body. See Kato, K., Journal of Pediatrics, pages 385-396 (1937); Rohn, R. 1., Bond, W. H., Klotz, L. 1., The Journal of the Indiana State Medical Assn. 46, pages 1253-1260 (1953); Coles, B. L., James, U., The Journal- Lancet, 75, page 79 (1955 In the past, anemias of the types specified have been treated by conjoint administration of cobaltous and ferrous salts such as cobaltous chloride and ferrous sulfate. Such treatments have been elfective in many cases but treatment has some times been handicapped by the patients reaction to these inorganic ionic salts which tend to be irritating to the gastro-intestinal tract. The degree of this irritability is an idiosyncrasy of the individual and therefore interferes with treatment in some patients more than others. With patients with low tolerances proper dosages cannot be administered without undue discomfort and the unfavorable action seems in some cases to impair optimum assimilation of cobalt and iron.
The taste or palatability of mixtures of cobalt and iron salts is also nauseating and astringent Where liquid preparationsare required as in the case of infants or in patients who cannot swallow tablets or capsules. This, coupled with gastro-intestinal irritation poses problems as mixtures of salts in certain instances have proven so unpalatable or so irritating as to prevent patients from accepting this type of medication.
The principal object of the present invention is to provide improved means for administering cobalt and iron in the treatment of anemias substantially free from the disadvantages discussed above.
A more specific object of the present invention isto provide a cobalt-iron complex which is less irritating to the gastro-intestinal tract andmore readily acceptable on the basis of palatability than mixtures of cobalt and iron salts previously employed in the treatment of anemias.
Still another object is to provide a process for preparing the cobalt-iron complex characterized by the advantages specified above. 7 l
Other objects of the present invention will be apparent as the description proceeds.
The complexes or compounds of the present invention can be readily prepared by heating and fusing a mixture made up of a water-soluble, non-toxic cobaltous salt, a water-soluble, non-toxic ferric salt and an amino acid, particularly the a-amino acids such as aminoacetic acid (glycine) and equivalents thereof including alanine, sarcorates Patent sine, lysine, glutaminic acid and the like. Suitable cobalt salts include cobaltous chloride, cobaltous nitrate, cobaltous sulfate, cobaltous acetate, cobaltous citrate, etc., and suitable ferric salts include ferric chloride, ferric nitrate, etc. The salts Where available are preferably employed in their hydrate from, a preferred combination being made up of cobaltous chloride hexahydrate and ferric chloride hexahydrate. The cobaltous and ferric salts and amino acid are employed in amounts to provide a CozFezamino acid ratio of about 1:1:3 to 1:8:24 with about a 1:1:6 to 1:4:17 ratio of Co:Fe:amino acid being generally in the preferred range. acid to cobalt can be employed if desired but are ordinarily not accompanied by an appreciable beneficial result. A particularly stable complex is one in which the ingredients are mixed and fused to provide a complex with a ratio of about 1:2:9 of Co:Fe:amino acid.- The following examples will serve to illustrate the invention.
Example I Example II A mixture made up of 726 grams of ferric chloride hexahydrate, 150 grams of cobaltous chloride hexahydrate and 804 grams of aminoacetic acid is heated between -130 C. for a period of from 3 to 5 minutes so that the mass melts and becomes dark green or blackish in color. If the reaction product or complex does not form a solid on cooling, it is reheated until it turns to a solid on cooling. The complex produced by this process has a Co:Fe:amino acid ratio of about 1:4:17.
Example III This complex is prepared in accordance with Example II by heating and fusing a mixture made up of 150 grams of cobaltous chloride hexahydrate, 340.3 grams of ferric chloride hexahydrate and 425.4 grams of aminoactic acid. This complex has a Co:Fe:aminoacetic acidratio of 1:229.
Example IV This complex is prepared in accordance with Example I by heating and fusing a mixture of hydrate salts made up of 107 grams of cobaltous acetate, 116, grams of ferric chloride and 200 grams of aminoacetic acid. This complex has a Co:Fe:amino acid ratio of 1:1 :6.
Example V This complex is prepared in accordance withExample IV by heating and fusing grams of cobaltous nitrate, 116 grams of ferric chloride and 200 grams of aminoacetic acid.
' Example VI This complex is prepared inaccordance with Example IV by heating and fusing 102 grams of cobaltous chloride, grams of ferric nitrate and 200 grams of aminoacetic acid.
Example VII This complex is prepared in accordance with Example IV by heating and fusing 90 grams of cobaltous chlo- Larger ratios of iron and amino.
' 3 ride, 100 grams of ferric chloride and 200 grams of alanine.
Example VIII This product is prepared in accordance with Example IV by heating and fusing 90 grams of cobaltous chloride, 100 grams of ferric chloride and 200 grams of sarcosine.
The order of mixing of the ingredients (cobaltous salt, ferric salt and amino acid) is of no consequence and the reaction can be carried out by heating and fusing any one or twocomponents prior to the addition of the other components. Ordinarily, it is preferred to fuse the salts and then add the amino acid or to fuse all three ingredients simultaneously. The heating or fusing temperature should be sufficient to fuse (melt) the mass and should be carried out with stirring for a sufficient time to provide a complex which forms a solid on cooling. As the salts or at least one salt is preferably in hydrate form the temperature employed should be sufiicient to drive off the water of hydration. Temperatures of around 100-250 C. can be employed in many instances with a temperature of about 125 C. being generally preferred. In all cases, however, the temperature employed should be below the decomposition temperature as evidenced by the charring of the amino acid. The optimum fusing temperature and time for a particular mixture can be readily ascertained by preliminary test.
The products perpared in accordance with the present invention can be powdered and combined with inert ingredients according to the practice of the art and compressed into tablets for administration. Such tablets can, if desired, be enteric coated to delay their disintegration in the gastro-intestinal tract where patients are unusually susceptible to gastric irritation. The products can likewise be mixed with inert ingredients according to the practice of the art and filled into hard or soft gelatin capsules for administration to patients. The products can also be dissolved in suitable quantities of water or other common pharmaceutical vehicle in appropriate concentration for administration as a flavored or unflavored elixir, solution, tincture or other liquid product.
The complexes produced in accordance with the present invention are water soluble and have toxicities of the same order as mixtures of the individual cobalt and iron salts used heretofore in the treatment of anemia. The complexes, however, are not mere mixtures of the original ingredients or simple salts of amino acids. This has been established by solubility, freezing point and electrical conductance determinations as well as by chromatographic investigations. oxidation-reduction reaction apparently takes place during fusion as evidenced by the fact that the iron introduced in ferric form is present in both ferric and ferrous forms in the final complex. The name ferriferrocobalto 'chloroaminoacetate has been proposed for the complex made by fusing cobaltous chloride, ferric chloride and aminoacetic acid, although the formula of this complex as well as the other complexes, is extremely complicated and remains undetermined and unknown.
The complexes or fusion compositions produced by the process of the present invention may contain small amounts of inorganic components. These contaminants can be removed, if desired, by the following purification procedure.
Example IX It'has also been determined that an y added until no further precipitation occurs. The precipitate is allowed to settle and the supernatant liquid decanted. The oily brownish liquid residue is next dissolved in a minimum of water. Methanol is then added to the solution until no further precipitation takes place. The precipitate is recovered by filtering rapidly through a sintered glass. funnel. After washing with two small portions of methanol, the complex is obtained as a grayish, hygroscopic relatively pure product.
Although purification is not required, it has been found when making large commercial batches that traces of some unreacted ferric chloride or like caustic salt may be present as a contaminant in the final complex. To take care of this possibility it is generally preferred in commercial operations to routinely add about l-5% of sodium citrate to the complexes as sodium salts of this type form harmless, non-irritating compounds with irritating salts such as ferric chloride. In commercial operations it has also been found advantageous to include ascorbic acid (vitamin C) with the cobalt-iron-amino-acid complexes of the present invention to provide a daily dosage of 5 mg. to 1 gram of ascorbic acid.
The complexes of the present invention provide as noted above improved means of administering cobalt and iron when assimilable cobalt and iron are indicated in the treatment of anemia. As they tend to be less irritating and are more palatable than mixtures of cobalt and iron salts used heretofore, the complexes can be used to advantage in place of such mixtures and in the similar dosage units to provide the desired Co :Fe ratio in accordance with established practices in this art.
It will be understood that while the invention for the most part has been illustrated with the cobaltous chlorideferric chloride-aminoacetic acid complex, that other equivalent cobaltous and ferric salts (non-toxic in the amounts employed) and equivalent amino acids can be used as pointed out above in place of chloride salts and aminoacetic acid. Various other equivalent combinations falling within the scope of the invention will be apparent to those skilled in the art.
The present application is a continuation-in-part of our prior application Serial No. 466,692, filed on Novemher 3, 1954, and now abandoned.
We claim:
1. The process of preparing a cobalt-iron-amino-acid complex which comprises fusing a mixture of cobaltous chloride hexahydrate, ferric chloride hexahydrate and aminoacetic acid at a temperature of about 1l0130 C. and for a sufficient time to provide a reaction product which turns to a solid on cooling, the amounts of cobaltous and ferric salts and amino acid in said fused mixture being such as to provide a complex with a CozFezamino acid ratio of 121:3 to 118124.
2. The process of preparing a cobalt-iron-arnino-acid complex which comprises fusing a mixture of cobaltous chloride hexahydrate, ferric chloride hexahydrate and aminoacetic acid at a temperature of about 125 C. for a sufficient time to provide a complex which turns to a solid on cooling, the proportion of ingredients being such as to provide a complex with a CozFezarnino acid ratio of about 1:2:9.
References Cited in the file of this patent FOREIGN PATENTS
Claims (1)
1. THE PROCESS OF PREPARING A COBALT-AMINO-ACID COMPLEX WHICH COMPRISES FUSING A MIXTURE OF COBALTOUS CHLORIDE HEXAHYDRATE, FERRIC CHLORIDE HEXAHYDRATE AND AMINOACETIC ACID AT A TEMPERATURE OF ABOUT 110-130*C. AND FOR A SUFFICIENT TIME TO PROVIDE A REACTION PRODUCT WHICH TURNS TO A SOLID ON COOLING, THE AMOUNTS OF COBALTOUS AND FERRIC SALTS AND AMINO ACID IN SAID FUSED MIXTURE BEING SUCH AS TO PROVIDE A COMPLEX WITH A CO:FE:AMINO ACID RATIO OF 1:1:3: TO 1:8:24.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US550858A US2847437A (en) | 1955-12-05 | 1955-12-05 | Process for the preparation of ferriferro cobaltochloroaminoacetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US550858A US2847437A (en) | 1955-12-05 | 1955-12-05 | Process for the preparation of ferriferro cobaltochloroaminoacetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2847437A true US2847437A (en) | 1958-08-12 |
Family
ID=24198856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US550858A Expired - Lifetime US2847437A (en) | 1955-12-05 | 1955-12-05 | Process for the preparation of ferriferro cobaltochloroaminoacetate |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2847437A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2936316A (en) * | 1955-02-25 | 1960-05-10 | Chicopee Mfg Corp | Chelated metal compounds |
| US3095297A (en) * | 1960-05-27 | 1963-06-25 | Cros Sa | Process for the preparation of nu, nu'-ethylene-bis-[2-(omicron-hydroxyaryl) glycine] ferric chelates |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB673063A (en) * | 1947-06-23 | 1952-06-04 | Medical Res Proprietary Ltd | Metallic compounds of amino acids and preparation thereof |
-
1955
- 1955-12-05 US US550858A patent/US2847437A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB673063A (en) * | 1947-06-23 | 1952-06-04 | Medical Res Proprietary Ltd | Metallic compounds of amino acids and preparation thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2936316A (en) * | 1955-02-25 | 1960-05-10 | Chicopee Mfg Corp | Chelated metal compounds |
| US3095297A (en) * | 1960-05-27 | 1963-06-25 | Cros Sa | Process for the preparation of nu, nu'-ethylene-bis-[2-(omicron-hydroxyaryl) glycine] ferric chelates |
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