US2849369A - Therapeutic compositions of cyanacetic acid hydrazide and acid addition salts thereof, and processes employing the same - Google Patents

Therapeutic compositions of cyanacetic acid hydrazide and acid addition salts thereof, and processes employing the same Download PDF

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US2849369A
US2849369A US381117A US38111753A US2849369A US 2849369 A US2849369 A US 2849369A US 381117 A US381117 A US 381117A US 38111753 A US38111753 A US 38111753A US 2849369 A US2849369 A US 2849369A
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hydrazide
acid
cyanacetic
addition salts
acid addition
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Muset Pedro Puig
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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
    • A61K31/275—Nitriles; Isonitriles

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  • My invention relates to therapeutic compositions of cyanacetic acid hydrazide and acid addition salts thereof, and processes employing the same. More particularly, my invention relates to such compositions in which the active ingredient is cyanacetic acid hydrazide or an acid addition salt thereof, such as hydrochloride, hydroiodide, phosphate, sulfinate.
  • the properties of a substance do not only depend on the number of its atoms, but rather on their position in the molecule, on the distances separating them, on the angles formed by their valencies, all data which it is easy to determine accurately by means of to-days refractometric techniques.
  • the linear chain of carbon atoms that binds these two atoms replaces the pyridine ring (which only plays the part of a simple support) and situates these two atoms at the same distance as that existing in the case of the hydrazide of isonicotinic acid between the two analogous nitrogen atoms.
  • the molecular weight of the hydrazide of cyanacetic acid (99) being lower than that of the hydrazide of isonicotinic acid (137.15), a larger quantity of active functional groups is administered at even weight.
  • the substitution of the pyridine ring by an aliphatic chain decreases the toxicity and facilitates the diffusion of the product in the organism.
  • the hydrazide of cyanacetic acid has proved active against the Mycobacterium tuberculosis in laboratory as well as clinically.
  • the hydrazide of cyanacetic acid is extremely unstable and loses its activity after a short time owing to various chemical transformations. Moreover, it is very quickly destroyed under the influence of heat. It follows, as a consequence, that the values of the antibacillary activity obtained in vitro are necessarily much lower than the real abilities of the product.
  • the toxicity has been studied on white mice by intraperitoneal injection and per es; the lethal dose LD (which kills 50% of the animals) has been 283.4 mg./l g. and respectively 350 mg./ kg. These doses are higher than those obtained in the case of the same tests with the hydrazide of isonicotinic acid, thus resulting in a wider tolerance margin in favor of the hydrazide of cyanacetic acid.
  • the hydrazide of cyanacetic acid is also active in extrapulmonary tuberculosis, such as tuberculosis of the skin, genital and urinary tuberculosis.
  • My invention may be applied to the treatment of tuberculosis in veterinary medicine as well as to man.
  • the product may take the form of tablets, sterile powder, capsules or of any other way of administration by oral route.
  • the hydrazide of cyanacetic acid may take the form of sterile powder to be diluted at the time of use, or possibly in solution.
  • the product in addition to the above-mentioned forms, may take the form of animal feed, in which there will be not less than 1% (one part per thousand) of active ingredient.
  • the hydrazide of cyanacetic acid may be mixed with various substances in order to facilitate administration.
  • the quantities of active product going into the various compositions may vary according to need; they may be comprised between 10 mg. and mg. per dosage unit (tablet) for human medicine, and between 20 mg. and 200 mg. per dosage unit for animal medicine.
  • the active product may be used under the form of its acid addition salts (hydrochloride, hydroiodide, phosphate, sulfinate, etc.)
  • Example 1 Composition of tablet dosage for human medicine:
  • Example 2 Composition of a tablet dosage for human medicine:
  • Example 3 Composition of tablet dosage for animal medicine:
  • the lactose is mixed with starch paste, then granulated by means of a 2 mm. mesh sieve and afterwards dried and screened.
  • the other components are then added to the granule; the mass thus obtained is mechanically stirred during at least one hour and compressed into 0.255 g. tablets. Within the 24 hours. which follow the compression, the tablets disintegrate in to seconds when put into water. Exposing the active substance to dampness or to a temperature exceeding 30 C. must be avoided.
  • Example 4 Preparation of ampules of hydrazide of cyanacetic acid in sterile powder for injections.
  • a concentrated solution (20%) of hydrazide of cyanac etic acid in distilled water is prepared. This is filtered under vacuum through a sterilizing filter (Cham- The'filtered liquid is collected in a sterile container.
  • the precipitate is collected and placed in a sterile crystalliz er.
  • the latter is placed in a desiccator under vacuum in the presenceof phosphoric anhydride.
  • the hydrazide is removed from the desiccator after 48 hours and is aseptically pulverized in a sterile glass mortar. The powder is placed in a dry and sterile flask.
  • the quantity required for filling the ampules istaken from the flask and the filled ampules will be sealed by 4 means of a blow-pipe or closed with a sterile rubber stopper.
  • the method of combatting tuberculosis which comprises the step of administering to a human being infected with tubercle bacilli a compound selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
  • the method for combatting tuberculosis which comprises the step of' adminstering to a human being infected with tubercle bacilli a composition comprising not less than ten percent of a compound selected from th group of cyanacetic acid hydrazide and acid addition salts thereof as an active ingredient.
  • the method for combatting tuberculosis which comprises the step of administering to a human being infected with tubercle bacilli a composition containingas an active ingredient not less than twenty percent of a compound selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
  • the method for combatting tuberculosis which comprises the step of adminstering to a human being infected with tubercle bacilli a composition containing as an active ingredient between ten milligramsand one hundred milligrams per dosage unit of a compound selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
  • the method for combatting tuberculosis which. comprises the step of administering to a human being infected with tubercle bacilli a composition containing as an active ingredient between twenty milligrams and two hundred milligrams per dosage unit of acompound selected, from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
  • a therapeutic composition in dosage unit form comprising between ten milligrams and one hundred milligrams per dosage unit of an active ingredient selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof, and a solid pharmaceutical carrier.
  • a therapeutic composition in dosage unit form comprising between. twenty milligrams and two hundred milligrams per dosage unit of anactive ingredient selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereofiand a solid pharmaceutical carrier.
  • a therapeutic composition according to claim 10, in which said solid pharmaceutical carrier; is at least partly starch,
  • a veterinary feed for combatting tuberculosis comprising not lessthan one part per thousand of a compound selected. from the group consisting of cyanacetic acid hydrazide and acid addition saltsthereof.
  • a solid and sterile preparationin dosage unit form intended for dissolving in a suitable quantity'of sterilized and buffered water in order to prepare a liquid for treating, by parenteral route, hurnan tuberculosis, comprising between ten milligrams and one hundred milligrams per dosage unit of a member selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof, as an active ingredient.

Description

United States Patent O THERAPEUTIC COMPOSITIONS OF CYANACETIC ACID HYDRAZIDE AND ACID ADDITION SALTS THEREOF, AND PROCESSES EMPLOY- ING THE SAME Pedro Puig Muset, Molins de Rey, Spain, assignor to Laboratoires O M, Socit Anonyme, Geneva, Switzerland, a Swiss corporation N Drawing. Application September 18, 1953 Serial No. 381,117
17 Claims. (Cl. 167-65) My invention relates to therapeutic compositions of cyanacetic acid hydrazide and acid addition salts thereof, and processes employing the same. More particularly, my invention relates to such compositions in which the active ingredient is cyanacetic acid hydrazide or an acid addition salt thereof, such as hydrochloride, hydroiodide, phosphate, sulfinate.
Having studied the pharmacological action of the hydrazide of isonicotinic acid, I have reached the conclusion that its action cannot be compared to that of nicotinic acid, as several authors have contended. I have refuted this comparison (see Torax, Montevideo, vol. I, pages 5-16, May 1952), basing myself on the works of MacKenzie (J. Lab. and Clin. Med. 33, 1249, 1948) as well as on those of Brun and Vellier (Lyon Medical, 48, 1946), or Morellini and Montani (Rf. Min. Med. 37, 442, 1946) and of Jouin and Buu-Hoi (Ann. Inst. Pasteur, 72, 580, 1946).
On the contrary, I have established that the superiority of the hydrazide of isonicotinic acid must be sought for in the highly advantageous structure of the molecule of this compound, in which certain atoms are arranged and bound together according to a configuration which gives an intensive and efiicacious pharmacological effect.
In fact, the properties of a substance do not only depend on the number of its atoms, but rather on their position in the molecule, on the distances separating them, on the angles formed by their valencies, all data which it is easy to determine accurately by means of to-days refractometric techniques.
Basing myself on my above-mentioned theory, I have searched for the compounds possessing active groupings similar to those of the hydrazide of isonicotinic acid, situated at the same spatial distance and not presenting the drawbacks of the pyridine ring. I have found that the hydrazide of cyanacetic acid fulfilled the desired conditions, taking into account the distance existing between its nitrogen atom (corresponding to that of the pyridine ring of the hydrazide of isonicotinic acid) and its nitrogen atom of the hydrazinic group. The linear chain of carbon atoms that binds these two atoms replaces the pyridine ring (which only plays the part of a simple support) and situates these two atoms at the same distance as that existing in the case of the hydrazide of isonicotinic acid between the two analogous nitrogen atoms.
The clinical tests have fully confirmed my hypothesis and shown that the hydrazide of cyanacetic acid has an action similar to that of the hydrazide of isonicotinic acid while being better tolerated.
The molecular weight of the hydrazide of cyanacetic acid (99) being lower than that of the hydrazide of isonicotinic acid (137.15), a larger quantity of active functional groups is administered at even weight. Moreover, the substitution of the pyridine ring by an aliphatic chain decreases the toxicity and facilitates the diffusion of the product in the organism.
The hydrazide of cyanacetic acid has already been synthetized at the end of the last century (R. von Rothen- 2,849,369 Patented Aug. 26, 1958 ice burg: Berichte des Deutschen Chem. Gesellsch. 27, 687, 1894) but has not heretofore been the object of any therapeutic application.
The hydrazide of cyanacetic acid has proved active against the Mycobacterium tuberculosis in laboratory as well as clinically.
In vitro, the product inhibits the growth of the Mycobacterium tuberculosis in concentrations of 1 l0=' in Lowenstein and Youmans medium. In solution, the hydrazide of cyanacetic acid is extremely unstable and loses its activity after a short time owing to various chemical transformations. Moreover, it is very quickly destroyed under the influence of heat. It follows, as a consequence, that the values of the antibacillary activity obtained in vitro are necessarily much lower than the real abilities of the product.
The toxicity has been studied on white mice by intraperitoneal injection and per es; the lethal dose LD (which kills 50% of the animals) has been 283.4 mg./l g. and respectively 350 mg./ kg. These doses are higher than those obtained in the case of the same tests with the hydrazide of isonicotinic acid, thus resulting in a wider tolerance margin in favor of the hydrazide of cyanacetic acid.
The therapeutic tests on animals show the efliciency of the hydrazide of cyanacetic acid against the Mycobacterium tuberculosis in vivo. Batches of six guinea-pigs infected in the thigh according to the Steenken and Wolinsky technique and simultaneously treated with hydrazide of cyanacetic acid showed no tuberculous lesions after having been sacrificed at the end of 50 days. All control animals showed tuberculous lesions.
in clinic, the action of hydrazide of cyanacetic acid on patients suffering from pulmonary tuberculosis may be summarized as follows:
Improvement of subjective state, disappearance of fever, cough and expectoration, recovery of appetite, progressive and regular increase in weight, decrease or disappearance of bacilli in sputum, lowering of erythrocyte sedimentation rate, radiological improvements have been observed in certain cases. Tolerance, at therapeutic doses, is perfect, even with certain patients who do not stand the hydrazide of isonicotinic acid. Moreover, the hydrazide of cyanacetic acid is efficacious even with cer tain patients who have become resistant to hydrazide of isonicotinic acid (F. G. Valdecasas, J. A. Salva, P.
Puig Muset; Medicina clinica No. 4, Tome XIX, page The hydrazide of cyanacetic acid is also active in extrapulmonary tuberculosis, such as tuberculosis of the skin, genital and urinary tuberculosis.
My invention may be applied to the treatment of tuberculosis in veterinary medicine as well as to man. the product may take the form of tablets, sterile powder, capsules or of any other way of administration by oral route. For parenteral route, the hydrazide of cyanacetic acid may take the form of sterile powder to be diluted at the time of use, or possibly in solution. in veterinary medicine, in addition to the above-mentioned forms, the product may take the form of animal feed, in which there will be not less than 1% (one part per thousand) of active ingredient.
The hydrazide of cyanacetic acid may be mixed with various substances in order to facilitate administration.
' The quantities of active product going into the various compositions may vary according to need; they may be comprised between 10 mg. and mg. per dosage unit (tablet) for human medicine, and between 20 mg. and 200 mg. per dosage unit for animal medicine. The active product may be used under the form of its acid addition salts (hydrochloride, hydroiodide, phosphate, sulfinate, etc.)
berlain bougie or porous glass G).
Example 1 Composition of tablet dosage for human medicine:
G. Hydrazide of cyanacetic acid 0.051 Lactose 0.l70 Starch 0.030 Stearin 0.004
Example 2 Composition of a tablet dosage for human medicine:
G. Hydrazide of cyanacetic acid 0.101 Lactose 0.120
Starch 0.030
Stearin 0.004
Example 3 Composition of tablet dosage for animal medicine:
G. Hydrazide of cyanacetic acid 0.151 Calcium carbonate 1.200 Aluminum silicate 1 .800 Starch 0.500
The method for preparing tablets in accordance with the above Examples 1 and 2 is the following:
The lactose is mixed with starch paste, then granulated by means of a 2 mm. mesh sieve and afterwards dried and screened. The other components are then added to the granule; the mass thus obtained is mechanically stirred during at least one hour and compressed into 0.255 g. tablets. Within the 24 hours. which follow the compression, the tablets disintegrate in to seconds when put into water. Exposing the active substance to dampness or to a temperature exceeding 30 C. must be avoided.
Example 4 Preparation of ampules of hydrazide of cyanacetic acid in sterile powder for injections.
All the material which will be used for the various following manipulations must be perfectly dry and sterile.
A concentrated solution (20%) of hydrazide of cyanac etic acid in distilled water is prepared. This is filtered under vacuum through a sterilizing filter (Cham- The'filtered liquid is collected in a sterile container.
1 liter of this solution is poured, immediately after having been prepared and filtered, into 5.liters of absolute alcohol which has also been filtered by means of a bougie and kept in a sterile container. The hydrazide of cyanacetic acid. precipitates. It is left at rest for two hours, in order that the product should precipitate to the maximum, then the solution is filtered through a sterilized porous glass.
The precipitate is collected and placed in a sterile crystalliz er. The latter is placed in a desiccator under vacuum in the presenceof phosphoric anhydride.
The hydrazide is removed from the desiccator after 48 hours and is aseptically pulverized in a sterile glass mortar. The powder is placed in a dry and sterile flask.
The quantity required for filling the ampules istaken from the flask and the filled ampules will be sealed by 4 means of a blow-pipe or closed with a sterile rubber stopper.
All these manipulations must be performed aseptically and preferably under sterilizing rays.
What I claim is:
1. The method of combatting tuberculosis which comprises the step of administering to a human being infected with tubercle bacilli a compound selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
2. The method for combatting tuberculosis which comprises the step of' adminstering to a human being infected with tubercle bacilli a composition comprising not less than ten percent of a compound selected from th group of cyanacetic acid hydrazide and acid addition salts thereof as an active ingredient.
3. The method for combatting tuberculosis which comprises the step of administering to a human being infected with tubercle bacilli a composition containingas an active ingredient not less than twenty percent of a compound selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
4. The method for combatting tuberculosis which comprises the step of adminstering to a human being infected with tubercle bacilli a composition containing as an active ingredient between ten milligramsand one hundred milligrams per dosage unit of a compound selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
5. The method for combatting tuberculosis which. comprises the step of administering to a human being infected with tubercle bacilli a composition containing as an active ingredient between twenty milligrams and two hundred milligrams per dosage unit of acompound selected, from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof.
6 A therapeutic composition in dosage unit form comprising between ten milligrams and one hundred milligrams per dosage unit of an active ingredient selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof, and a solid pharmaceutical carrier.
7. A therapeutic composition according to claim 6, in which said solid pharmaceutical carrier is at least partly starch.
8. A therapeutic composition according to claim 6, in which said solid pharmaceutical carrier is at least partly lactose.
9. A therapeutic composition according to claim 6, in which saidsolidpharmaceutical carrier is at least partly stearin.
10. A therapeutic composition in dosage unit form comprising between. twenty milligrams and two hundred milligrams per dosage unit of anactive ingredient selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereofiand a solid pharmaceutical carrier.
11. A therapeutic composition. according to claim 10, in which said solid pharmaceutical carrier; is at least partly starch,
12. Atherapeutic compositionaccording to claim 10, in which said solidpharmaceutical carrier is at least partly lactose.
13. A therapeutic composition according to claim 10, in which. said solid pharmaceutical carrier is at leastpartly stearin.
14. A veterinary feed for combatting tuberculosis comprising not lessthan one part per thousand of a compound selected. from the group consisting of cyanacetic acid hydrazide and acid addition saltsthereof.
15. A solid and sterile preparationin dosage unit form intended for dissolving in a suitable quantity'of sterilized and buffered water in order to prepare a liquid for treating, by parenteral route, hurnan tuberculosis, comprising between ten milligrams and one hundred milligrams per dosage unit of a member selected from the group consisting of cyanacetic acid hydrazide and acid addition salts thereof, as an active ingredient.
16. A solid and sterile preparation in dosage unit form intended for dissolving in a suitable quantity of sterilized .5
References Cited in the file of this patent UNITED STATES PATENTS 2,596,069 Fox May 6, 1952 OTHER REFERENCES I. A. M. A., 162:6, page 595, Oct. 6, 1956. Valdecasas et a1., Medicina Clinica, vol. 17, No. 4, pp.
Shavel, I. Am. Pharm. Assn., vol. XLII, July 1953, Sc. Ed., pp. 402-403.
Rathenburg, Berichte des Deutschen Chem., Gesellsch. 27, 687 (1894).

Claims (1)

  1. 6. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM COMPRISING BETWEEN TEN MILLIGRAMS AND ONE HUNDRED MILLIGRAMS PER DOSAGE UNIT OF AN ACTIVE INGREDIENT SELECTED FROM THE GROUP CONSISTING OF CYANACETIC ACID HYDRAZIDE AND ACID ADDITION SALTS THEREOF, AND A SOLID PHARMACEUTICAL CARRIER.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899356A (en) * 1956-09-21 1959-08-11 Cyanacethydrazide compositions for
US3053732A (en) * 1957-01-30 1962-09-11 Ici Ltd Lungworm control composition and method of using same
US3116312A (en) * 1960-03-31 1963-12-31 American Cyanamid Co Substituted-2-cyanoacetanilides
US3214467A (en) * 1957-02-26 1965-10-26 Boehringer & Soehne Gmbh Sulfonyl urea compounds and a process of making same
US3320236A (en) * 1963-03-07 1967-05-16 Miles Lab Reaction products of polymeric dialdehyde polysaccharides with p-aminosalicylates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2596069A (en) * 1952-03-07 1952-05-06 Hoffmann La Roche Compositions for combating tuberculosis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2596069A (en) * 1952-03-07 1952-05-06 Hoffmann La Roche Compositions for combating tuberculosis

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899356A (en) * 1956-09-21 1959-08-11 Cyanacethydrazide compositions for
US3053732A (en) * 1957-01-30 1962-09-11 Ici Ltd Lungworm control composition and method of using same
US3214467A (en) * 1957-02-26 1965-10-26 Boehringer & Soehne Gmbh Sulfonyl urea compounds and a process of making same
US3116312A (en) * 1960-03-31 1963-12-31 American Cyanamid Co Substituted-2-cyanoacetanilides
US3320236A (en) * 1963-03-07 1967-05-16 Miles Lab Reaction products of polymeric dialdehyde polysaccharides with p-aminosalicylates

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