US3466312A - Derivatives of dialkyl-cysteines and allied compounds - Google Patents

Derivatives of dialkyl-cysteines and allied compounds Download PDF

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US3466312A
US3466312A US461855A US3466312DA US3466312A US 3466312 A US3466312 A US 3466312A US 461855 A US461855 A US 461855A US 3466312D A US3466312D A US 3466312DA US 3466312 A US3466312 A US 3466312A
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dimethylcysteine
dialkylcysteine
compounds
compound
therapeutic
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Nicholas Ercoli
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AH Robins Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • 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
    • A61K31/285—Arsenic compounds
    • 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
    • A61K31/29—Antimony or bismuth compounds
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/66—Arsenic compounds
    • C07F9/70—Organo-arsenic compounds
    • C07F9/74—Aromatic 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/90—Antimony compounds
    • C07F9/902—Compounds without antimony-carbon linkages
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/94—Bismuth compounds

Definitions

  • the action of the above mentioned compounds as agents against metal poisoning appears to be related to their activity as metal binding agents, due to the ability of the sulphur atoms they contain to form coordinate bonds with metal, particularly heavy metal, atoms, and in particular to the formation of chelates in which interaction between the metallic compound concerned and the thiol compound results in the incorporation of the metal atom into a heterocyclic ring containing at least one coordinate bond to the metal atom.
  • This improved therapeutic index both increases the patients tolerance of therapeutically elfective metallic compounds, while reducing side elects, and permits a larger amount of a therapeutic preparation containing metallic compounds to be administered thereby improving its therapeutic effectiveness.
  • dialkylcysteine derivatives containing antimony are eifective antiparasitic agents of low toxicity, and it is believed that the dialkylcysteine radical increases the penetration of the metallic radical into the parasite, at the same time facilitating its elimination from the host.
  • dialkylcysteine derivatives of other metals and organo metallic compounds provide a method of introducing these metals and compounds into a patient in an effective and relatively non toxic form, the dialkylcysteine radical improving the availability of the metallic radical and at the same time assisting in its elimination from the patient.
  • the invention relates to novel metal and organo metallic derivatives of dialkylcysteines and related compounds having the following general formula or their acid salts, where y is 0 or ,an integer less than or equal to v-x where v is the valency of the metal, z is 0 (except when y is 0) or an integer less than or equal to w-y, where w is the maximum number of coordinate bonds which can be formed with the metal, x is 0 or an integer up to v, Me is antimony (trivalent or pentavalent) arsenic, bismuth, iron (divalent or trivalent), selenium, or tellurium, or mercury, A is an organic or inorganic radical or radicals or where x is two or more, the remainder of a heterocyclic ring in which Me is included, R1 and R2 are -CH3 or -C2H5 and R3 is H or -CO.CH3.
  • the invention also extends to pharmaceutical products including one or more of the above derivatives or capable of forming such derivatives in solution.
  • the reaction between the metallic starting compound and the dialkylcysteine or analogue may be of one or both of two types. Firstly, a condensation reaction may take place with the elimination of the hydrogen atom from the thiol or analogous group in the dialkylcysteine or analogue and an anion bonded to the metal in the metallic compound, a direct covalent linkage being established between the metal radical and the sulphur, selenium or tellurium atom in the dialkylcysteine or analogue. At the same time a coordinate bond is formed between the nitrogen atom in the latter compound and the metal atom. Secondly, and alternatively or additionally, a wholly coordinate linkage may be established between the metal atom and the sulphur, selenium or tellurium atom and the nitrogen atom in a dialkylcysteine or analogous molecule.
  • the derivatives may be prepared by mixing an appropriate metal oxide or halide, or a hydrohalide of an appropriate organo metallic compound, suspended or dissolved in water, alcohol, glycerol or other suitable polar solvent with the selected dialkylcysteine or diakylcysteine analogue. Condensation compounds formed may be separated if desired by adding ether, acetone or other organic liquid in which the product is insoluble.
  • a variation of this method consists in dissolving in alkaline solution stoichiometric amounts of a metallic salt and the dialkylcysteine or dialkycysteine analogue, and then if desired isolating the reaction product with ether or the like, as above.
  • An alternative method consists in the electrolysis of an inorganic salt of the desired metal dissolved in a solution containing water along with the dialkylcysteine or dialkylcysteine analogue: the metal ions will enter into a condensation reaction with the dialkylcysteine or dialkylcysteine analogue, the product then being isolated if desired.
  • racemic and dextro rotary dialkylcysteines may be used for the synthesis, the dextro forms providing compounds of greater therapeutic index.
  • the invention is particularly applicable to compounds of arsenic, antimony, and bismuth containing an organic group or groups.
  • the ratio of the metallic compound to the dialkylcysteine ligand is adjusted to provide the greatest increase in therapeutic index.
  • the resulting compound or complex may be utilized in the form of mixtures, solutions, and/or products obtained by the precipitation of solutions of the constituent compounds.
  • a lethal dose (LDQO) of 3-amino 4- hydroxyphenylarsenoxide (arsenoxide) reacted according to the invention with the same amount of dimethylcysteine is completely detoxified (in each case 50 mg./kg. given subcutaneously to mice).
  • dimethylcysteine or ethyl-methyl-cysteine substitution of the oxygen or chlorine atoms of aromatic arsenoxides or dichlorarsines increases their therapeutic index by decreasing their toxicity, while maintaining or improving the effectiveness of known effective preparations.
  • Other therapeutically insignificant substituted aryl compounds assume useful properties by the introduction of this new As-:R2 radical (where R is a dialkylcysteine radical).
  • This substitution is particularly advantageous for 3- acetamino-4-hydroxy-arsinoxide to obtain a product of low toxicity for the treatment of amoebiasis and for -arsenobenzamide to obtain an antifilarial drug with better therapeutic index.
  • dimethyl or -ethyl--methylcysteine detoxifes organic antimony preparations (e.g. antimony alkali tartrates, antimony gluconate) when reacted therewith without interfering with their therapeutic efficiency.
  • organic antimony preparations e.g. antimony alkali tartrates, antimony gluconate
  • a similar effect was noted when using the N-acetyl derivatives of these dialkylcysteines, though to a lower degree.
  • cysteine itself reduces toxicity to the same extent as the antiparasitic effect of the antimonials.
  • cysteine itself reduces toxicity to the same extent as the antiparasitic effect of the antimonials.
  • its positive antidotal action becomes counterbalanced by its negative effect on therapeutic efficiency and the combined treatment is not practicable.
  • Similar results were obtained with a number of other antidotes of metal poisoning containing -SH and -NH- groups (benzoylamino--dimethyl acrylic thiol acid and a-benzoylamino--mercapto isovaleric thiol acid) structurally close to the dialkylcysteines (Ercoli et al. Archiv. Internat.
  • Example 1 One part of potassium antimonyl tartrate (tartar emetic) is mixed with 1.5 or 2 parts of dl. dimethylcysteine or d. dimethylcysteine hydrochloride in powder form, and is heat sterilized and vialed as dry powder, which is stable over a period of years.
  • the product obtained is soluble up to 6.15% in bidistilled water; the 5-6% solution indicated for treatment has a pH of ca. 6.4.
  • Example 2 One part of sodium antimonyl tartrate is mixed with 1.66 parts of dl. dimethylcysteine and is heat sterilized and vialed as dry powder, as in Example 1.
  • the degree of detoxification is considerably higher than in the previous example (TP and TF2), reaching a toxicity decrease in the order of 1:10.
  • This highly detoxified complex compound has been used clinically, under the name of NaP, for intensive treatment (short term therapy over 5-8 days) of bilharzia patients.
  • the comparative results with other drugs obtained in the same Bilharzia Service Centre as far as tolerance and therapeutic effect are contained in Table Il.
  • the preparation comprises the compound sodium antimonyl-dimethylcysteinyl tartrate having the probable structure.
  • Example 3 One gram of K-antimonyl tartrate and 1.5 grams of dl. dimethylcysteine are dissolved in 40 cc. distilled water 40. The addition of 300 cc. of acetone or 400 cc. ethylalcohol forms a crystalline deposit with an Sb content of 14-15 and a LD50 corresponding to 40-50 Ing/kg. Sb injected subcutaneously in mice (ca. 3 times that of antimonyl tartrate) with a curative index in trypanosomiasis 10C-150% higher than that of the Sb tartrate used for the preparation.
  • the Sb content of the crystalline preparations so obtained can be varied according to the ratio of antimonial and dialkylcysteine used, all having an increased therapeutic index in yrelation toxicity referred to Sb content.
  • the optimal preparations for therapeutic use are those containing l0 to 20% Sb, obtained fby the method described from the original organic compounds containing 36 to 39.5% Sb (antimony potassium tartrate 36.5%: antimony sodium tartrate 39.4%: sodium antimonyl gluconate 36%
  • Sb antimony potassium tartrate 36.5%: antimony sodium tartrate 39.4%: sodium antimonyl gluconate 36%
  • These materials are suitable for the preparation, purification and isolation of chemical compounds of defined structural formula containing Sb and two organic radicals, one of them the dialkylcysteine, the other re spectively tartaric or gluconic acid for example.
  • Example 4 (a) One gram of 3amino-4-hydroxyphenylarsenoxide (arsenoxide) was uniformly mixed with 2 grams of d. dimethylcysteine hydrochloride, 3.0 grams sucrose, 0.18 gram sodium carbonate and 0.03 gram ascorbic acid. The preparation was vialed to contain 60 mg. arsenoxide for single adult dose (162 mg. of the mixture), dissolved in distilled water before use. The LD50 for mice of the arsenoxide-dimethylcysteine derivative in the preparation was 150 mg./kg.: i.e. the preparation decreased 2.7 fold in toxicity with an activity identical to the starting product, which represents a corresponding I(2.7)() increase in safety. Improvement of the safety factor, to varying degrees, is obtained using 1 part arsenoxide and 0.5 to 6 parts of d. dimethylcysteine hydrochloride.
  • the lower toxicity of the product extends not only to the systemic but even to the local action of the arsenical, which in the form of the present composition can be utilized by intramuscular injection also. While arsenoxide caused severe necrotic lesions on rabbit skin in 1-2 mg./ml. concentrations (given intradermally), 20 nig/ml. of the arsenical in presence of the dialkylcysteine induced no lesions.
  • mice The minimal lethal dose of this compound for mice is 200 mg./kg., while it clarifies Tiypanosoma equipardum infection of the same species in 2.5-3.0 nig/kg. subcutaneous doses and induces permanent cure with 12. mg./kg.
  • the therapeutic index has been increased by not less than 100%. The improvement of the therapeutic index is even greater with the dextrorotatory compound.
  • the therapeutic properties of the product can be ac- Ecient, products of reduced toxicity ae prepafed (a) counted by the formation in solution of 3-amino-4-hyby d1 S501Vmg 1"3 Paffs meflylehylfystelne or dimethyldroxyphcnttrsinodioimcthylcystcinc'
  • This compound cysteine powder kept m sterile vials in a commercial 'soluhas a tolerated dose corresponding to 18 mg./kg.
  • As, but 35 non 0f afsenamlde Just beffe I lse- A V131.
  • composition is used in the form of capsules (500 mg.) for the treatment of amebiasis.
  • Example 8 (a) One part of antimony trichloride is mixed with 2.4 parts dl. dimethylcysteine and 2 parts of sodium carbonate under careful conditions of dryness. The resulting snowy powder dissolves rapidly in water with libera- 9 tion of CO2. The solution of the mixture has a pH of 6.8 and can be injected without causing lesions. Its LD50 for mice (subcutaneous) corresponds to slightly over 100 mg./kg. Sb (Table 4).
  • DMC Sb
  • the product a white solid, was readily soluble in water at neutral 1 1 logical characteristics as the mono-hydrochloride. In doses of 200 mg./kg. it killed 75% of the mice to which it was administered (i.e. its LD75 was 200 mg./kg.), while 12.5 mg./kg. cleared T rypanosoma equperdum ⁇ from all infected animals treated.
  • Example 10 Antimony-D-dimethylcysteine hydrochloride
  • a The reduced toxicity of the product of mixing antimony trioxide with d.dimethylcysteine hydrochloride was found to be due to the formation of antimony-d-dimethylcysteine-hydrochloride. The tolerance of this compound was the highest encountered, corresponding to an LD50 (mouse) of 245 mg./kg. Sb, with a favourable therapeutic index in trypanosomiasis, infected mice being cleared by 1/0 of the lethal dose, i.e., 25 ing/kg. of the preparation, corresponding to 6.2 mg./kg. Sb.
  • Example 1l.-Mercury-d-dimethylcysteine hydrochloride Two grams of HgClZ were dissolved in 100 ml. distilled water and 16 ml. NaOH solution added. The insoluble HgO precipitated was repeatedly washed with distilled water on a filter, then resuspended in ml. distilled water. This suspension was slowly added to 60 ml. of a solution containing 1.5 grams d-dimethylcysteine hydrochloride heated at 70 C.; the mercury oxide immediately dissolved. The reaction product can be recrystallised by gradual cooling or recovered quantitatively by the addition of 2-3 volumes of a mixture of butyl alcohol and ether, or by adding ethyl alcohol.
  • Example l2.-Mercury -dldimethylcysteine hydrochloride 2.01 grams of HgCl2 were dissolved in 30 ml. absolute alcohol and 2.3 grams of DL. dimethylcysteine were sii-spended in 105 ml. of the same medium in an Erlenmeyer flask. The HgClz solution was heated on water bath while the alcoholic dimethylcysteine suspension was slowly added to it. The suspension went immediately into solution as a result of the reaction with the HgCl2. The reaction product could be collected by slow crystallization after cooling or by precipitation with ether. The white crystals formed, observed on a heated plate under the microscope, started to volatilize at 170 C.
  • HgS was precipitated by the addition of H28 in acid solution. Its formula was Hg(SC5H10O2N.HCl)2 (Hg, 35.2%; H, 3.85%; C, 21.2%; S, 11.3%; Cl, 12.4%). Microanalysis gave the following 12 experimental values: Hg, 38.75%; H, 4.17%; C, 22.26%; S, 11.18%; Cl, 12.45%.
  • the material, alone or in cornbination with dialkylcysteine, can be used as an antibacterial and/or diuretic agent.
  • Example l3.-Ferrous and ferric dand dl. dimethylcysteine (a) 1 gram ferrie sulphate was dissolved by heating in 200 ml. water and ferric oxide precipitated with 10 ⁇ ml. 5% NH4.OH. The ferric oxide formed was washed until neutral on the filter, then suspended in 60 m1. water. To this suspension 600 mg. of DL-Cimethylcysteine hydrochloride (or the free amine) dissolved in 45 ml. water were added. The mixture on being heated to boiling for 10 minutes took on a dark violet colour; it was filtered and 100 ml. ethanol and 200 ml. ether were added to the filtrate.
  • dialkylcysteines soluble in organic solvents for example D-dimethylcysteine hydrochloride, which is soluble in ethanol
  • a practical method of preparation consists in placing the dialkylcysteine over a layer of the same weight of ferrie hydroxide, freshly prepared as in Example 5a, but washed with alcohol after precipitation, in the extractor chamber of a Soxhlet apparatus.
  • the alcohol vapour condensed in the chamber dissolves the dialkylcysteine and passing through the oxide, forms the reaction product, which drops continuously into the bottle generating the alcohol vapour. Under these conditions, a brownish product, soluble in water, is formed, which on heating decomposes leaving a black residue (FeS).
  • Both the ferrous and ferric dialkylcysteine derivatives can be used as hematopoietic agents.
  • Selenium and tellurium derivatives of dialkylcysteines may be prepared by similar methods. It is believed that they may be effective as cytotoxic agents to inhibit excess cell growth.
  • Example 14 Further examples of dialkylcysteine derivatives of metallo-orgamc compounds are given below: Diphenylethylmethyl-chlorarsine te cm-otm-ornCHVAe-oi reacting with the dialkylcysteine gives an arylalkyl 13 (alkyl) (mono dialkylcysteine)arsine.
  • the arylstibonous halides (ArSbCl2) or the aroxostibines (NH2C6H4-SbO) form di-dialkylcysteine compounds.
  • Chlorodiphenylstibine (C6H5)2.SbCl forms a diaryl(mono)dialkylcysteine-stibine.
  • 2.ch1oro1,3 dithia-Z-arsacyclopentane CHT-S AsCl CH2-S forms a 2 dialkylcysteinyl-1,3dithia-2-arsacycl0pentane, as does the stibiacyclopentane derivative of dimercaptopropanol (BAL) in which 2 bonds of 3-valent Sb are linked in an internal dithiol ring, the third to the dialkylcysteine selected.
  • BAL dimercaptopropanol
  • heterocyclic organo-metallic compounds containing for example arsindole, 1,3-dithiaarsacyclopentane, 1,3-stibiacyclopentane, phenothiarsine, or dimercaptopropanol-cyclic-bismuth rings may also be used.
  • Triphenylbismuth dichloride (C6H5)3BiCl2 gives a triaryl-bis (dia1ky1cysteine)Bi compound.
  • Alkali metal salts of antimonyl-dialkyl cysteinyl tartaric acids and complexes thereof with dialkyl cysteines 1.
  • Chemical A-bstracts vol. 25, p. 740 (1931). Chemical Abstracts, Vol. 49, p. 118702. (1955). Chemical Abstracts, vol. 50, pp. 3134i-3135a (1956). Chemical Abstracts, vol. 50, p. 6234e (1956). Chemical Abstracts, vol. 55, p. 5467a (1961). Chemical Abstracts, vol. 57, p. 5578a (1962). Chemical Abstracts, v01. 54, p. 22131a (1960). Chemical Abstracts, vol. 53, p. 101811 (1959). Chemical Abstracts, vol. 24, p. 3991 (1930). Chemical Abstracts, vol. 29, p. 80175 (1935). Chemical Abstracts, vol. 41, p. 3758g59( 1947). Chemical Abstracts, vol. 49, p. 87246 (1955 Chemical Abstracts, vol. 50, p. 5038c (1956).

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BR (1) BR6570245D0 (fr)
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DE (2) DE1301003B (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2150705A1 (fr) * 1971-07-20 1973-04-13 Friedheim Ernst Ah
US4167564A (en) * 1974-09-23 1979-09-11 Albion Laboratories, Inc. Biological assimilation of metals
US4487780A (en) * 1979-09-18 1984-12-11 Scheinberg Israel H Method of treatment of rheumatoid arthritis
EP0262346A1 (fr) * 1986-09-27 1988-04-06 Licentia Patent-Verwaltungs-GmbH Diode IMPATT

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1672615A (en) * 1927-06-29 1928-06-05 Kharasch Morris Selig Alkyl mercuric sulphur compound and process of producing it
US1684920A (en) * 1928-01-24 1928-09-18 Lilly Co Eli Water-soluble organic compound of antimony and process of producing it
US2559061A (en) * 1946-07-15 1951-07-03 Parke Davis & Co Phenylcyanamides and methods for obtaining the same
US2701812A (en) * 1951-06-26 1955-02-08 Dainippon Pharmaceutical Co Diarylarsenious acid derivatives and the preparation thereof
US3002985A (en) * 1958-12-22 1961-10-03 Tanabe Seiyaku Co Ferrous chelates of amino acids
US3281461A (en) * 1963-11-07 1966-10-25 Squibb & Sons Inc Process for preparing penicillamine
US3297531A (en) * 1963-12-11 1967-01-10 Ernst A H Friedheim Complexes of trivalent antimony with penicillamine, and admixtures of excess penicillamine with said complexes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1672615A (en) * 1927-06-29 1928-06-05 Kharasch Morris Selig Alkyl mercuric sulphur compound and process of producing it
US1684920A (en) * 1928-01-24 1928-09-18 Lilly Co Eli Water-soluble organic compound of antimony and process of producing it
US2559061A (en) * 1946-07-15 1951-07-03 Parke Davis & Co Phenylcyanamides and methods for obtaining the same
US2701812A (en) * 1951-06-26 1955-02-08 Dainippon Pharmaceutical Co Diarylarsenious acid derivatives and the preparation thereof
US3002985A (en) * 1958-12-22 1961-10-03 Tanabe Seiyaku Co Ferrous chelates of amino acids
US3281461A (en) * 1963-11-07 1966-10-25 Squibb & Sons Inc Process for preparing penicillamine
US3297531A (en) * 1963-12-11 1967-01-10 Ernst A H Friedheim Complexes of trivalent antimony with penicillamine, and admixtures of excess penicillamine with said complexes

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2150705A1 (fr) * 1971-07-20 1973-04-13 Friedheim Ernst Ah
US3974148A (en) * 1971-07-20 1976-08-10 Friedheim Ernst A H Filaricidal and trypanocidal phenylarsenodithio compounds
US4167564A (en) * 1974-09-23 1979-09-11 Albion Laboratories, Inc. Biological assimilation of metals
US4487780A (en) * 1979-09-18 1984-12-11 Scheinberg Israel H Method of treatment of rheumatoid arthritis
EP0262346A1 (fr) * 1986-09-27 1988-04-06 Licentia Patent-Verwaltungs-GmbH Diode IMPATT

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FR5051M (fr) 1967-05-08
GB1118187A (en) 1968-06-26
OA01742A (fr) 1969-12-15
BR6570245D0 (pt) 1973-08-28
DE1793545A1 (de) 1972-03-09
DE1301003B (de) 1969-08-14

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