US3320126A - Gastric anti-secretory compositions - Google Patents

Gastric anti-secretory compositions Download PDF

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Publication number
US3320126A
US3320126A US316120A US31612063A US3320126A US 3320126 A US3320126 A US 3320126A US 316120 A US316120 A US 316120A US 31612063 A US31612063 A US 31612063A US 3320126 A US3320126 A US 3320126A
Authority
US
United States
Prior art keywords
gastric
trimethylpyrazine
secretory
rats
hydrochloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US316120A
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English (en)
Inventor
Robert I Meltzer
Wilson B Lutz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Pharmaceutical Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Pharmaceutical Co filed Critical Warner Lambert Pharmaceutical Co
Priority to US316120A priority Critical patent/US3320126A/en
Priority to DK497564AA priority patent/DK106381C/da
Priority to GB41648/64A priority patent/GB1031915A/en
Priority to FR991282A priority patent/FR3929M/fr
Application granted granted Critical
Publication of US3320126A publication Critical patent/US3320126A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms

Definitions

  • This invention relates to new compositions of matter and to methods of using the same. More particularly, this invention relates to therapeutic compositions containing the compound 2-dimethyiamino-3,5,6-trimethylpyrazine or a nontoxic acid addition salt thereof, which compositions are useful as gastric anti-secretory agents.
  • Drugs useful for this therapy are, for example, the antacids which neutralize gastric acidity in vivo and the anticholinergics which nullify the etfects of acetylcholine and are, therefore, depressants of the parasympathetic nervous system.
  • the rationale of the use of the anti-cholinergic drugs is based on the theory that parasympathetic overactivity results in hypersecretion and hyperacidity. Chemically these agents are represented by the belladonna alkaloids such as atropine, tertiary amines, such as dicycloamine hydrochloride, quaternary amines such as methantheline bromine and methscopolamine bromide.
  • a further object of this invention is to provide therapeutic compositions containing anti-secretory agents which can relieve gastric hyperacidity and hypersecretion.
  • N HSCT HaC 3,32h,l26 Patented May 16, 1967 or of its acid addition salts are remarkably effective in inhibiting gastric secretion.
  • This discovery is quite surprising since the above compound -is quite unrelated chemically to any of the known anti-secretory drugs.
  • the administration of the foregoing compound at a dosage level of 4 mg. per kilo of body weight has been found to suppress the volume of gastric secretion to such extent that it is reduced to the levels of about 50% of that of untreated rats.
  • the compound has not been observed to produce the side effects commonly associated with anti-cholinergic medication.
  • the compound Z-dimethylamino-3,5,6-trimethylpyrazine is prepared, for example, by treating 2-chloro-3,5,6- trimethylpyrazine with an excess of dimethylamine.
  • This reaction may be represented by the following equation:
  • the above reaction may be carried out, for example, in a sealed tube employing a reaction temperature of about to 185 C. for about 3 days.
  • the desired reaction product is obtained as a yellow oily base.
  • hydro chloride salt is usually the desired form to be incorporated into dosage forms, the base is converted into the hydrochloride by adding an ethereal solution of hydrogen chloride. The salt is then recovered by filtration techniques.
  • the hydrochloride salt is preferred, other salts such as the sulfate, phosphate, citrate, nitrate, acetate, hydrobromide, and the like may also be prepared by adding the corresponding acid to the free base and recovering the salt so formed by filtration.
  • EXAMPLE 1 Z-dimethylamina-3,5,6-trimethylpymzine hydrochloride A solution of 5.0 g. (0.032 mole) of 2-chloro-3,5,6-trimethylpyrazine in 20 ml. of liquid dimethylamine is heated in a sealed tube at C. for three days. The reaction mixture is cooled and the excess dimethylamine vented. Anhydrous ether (50 ml.) is added to the residue and the by-product dimethylamine hydrochloride which forms is filtered oif. The ethereal filtrate is washed with 50 ml. of 10% KOH and dried over anhydrous potassium carbonate. The desiccant is separated by filtration and the filtrate is treated with 25 ml.
  • the recrystallization may be accomplished also by forming a solution in a minimum of 2-propanol and adding ether to the solution until it becomes just turbid.
  • each group of 12 rats should each be of one sex only and it is preferable that a single study (comparison of a standard with an unknown) be made on one sex.
  • Each group receives a different dose level of the drug, e.g., 1 mg./kg.; mg./kg. and the control receives normal saline solution.
  • the rats are fasted in cages with wide meshed wire bases to minimize coprophagy. The duration of the preoperative fast is 48 hours. During the first 36 hours of this period, the animals are free to drink tap water and Mead Johnsons 5% amigen and 5% dextrose electrolyte solution.
  • amigen-dextrose solution is removed from the cages the evening before the operation and the rat is allowed access to water only. This procedure allows the fasting rat to receive adequate nutrients and electrolytes and avoids the erratic results obtained when inadequate precautions are taken with regard to hydration and nutrition.
  • the rats are deprived of both water and food and confined in individual cages during the three hour collection period.
  • the animals are then killed with ether, the abdomen opened, and the stomach removed.
  • the entire stomach contents are caught in a graduated centrifuge tube and the fluid volume recorded after centrifugation. If the rats have been handled properly during the fast and collection period, the solid portion of the stomach contents will be negligible.
  • the average volume in untreated rats will be from six to eight milliters. If the average volume of the control rats is less than four millilters, the experiment is considered unsatisfactory and is repeated.
  • the pH of the fluid portion of the centrifuged stomach juices is determined with the Beckman pH meter, and exactly two cc. (pipetted) of the stomach contents are titrated with 0.04 normal sodium hydroxide using one drop of two percent phenolphthalein in ethyl alcohol as an indicator.
  • the primary object of the test is to measure the fluid volume of the stomach contents.
  • Logdose-response lines are drawn and an ED is determined for each drug.
  • the ED is that dose of the drug which produces a 50% decrease in fluid volume as compared to the controls.
  • the ED for 2-dimethylamino- 3,5,6-trimethylpyrazine hydrochloride as determined by the above method has been found to be 4 mg./ kg.
  • An anti-secretory composition in dosage unit form comprising an inert pharmaceutical carrier in combination with from about 5 to 200 mg. of a member of the group consisting of 2-dimethylamino-3,5,6-trimethylpyrazine and the non-t0xic pharmaceutically acceptable acid addition salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US316120A 1963-10-14 1963-10-14 Gastric anti-secretory compositions Expired - Lifetime US3320126A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US316120A US3320126A (en) 1963-10-14 1963-10-14 Gastric anti-secretory compositions
DK497564AA DK106381C (da) 1963-10-14 1964-10-09 Fremgangsmåde til fremstilling af 2-dimethylamino-3,5,6-trimethylpyrazin eller syreadditionssalte heraf.
GB41648/64A GB1031915A (en) 1963-10-14 1964-10-12 Pyrazine derivatives
FR991282A FR3929M (fr) 1963-10-14 1964-10-13

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US316120A US3320126A (en) 1963-10-14 1963-10-14 Gastric anti-secretory compositions

Publications (1)

Publication Number Publication Date
US3320126A true US3320126A (en) 1967-05-16

Family

ID=23227553

Family Applications (1)

Application Number Title Priority Date Filing Date
US316120A Expired - Lifetime US3320126A (en) 1963-10-14 1963-10-14 Gastric anti-secretory compositions

Country Status (4)

Country Link
US (1) US3320126A (fr)
DK (1) DK106381C (fr)
FR (1) FR3929M (fr)
GB (1) GB1031915A (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4692527A (en) * 1984-09-15 1987-09-08 Basf Aktiengesellschaft 2-amino-3,5-di-(halomethyl)-pyrazines and their preparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155663A (en) * 1962-11-15 1964-11-03 Warner Lambert Pharmaceutical Aminopyrazines
US3249503A (en) * 1963-10-22 1966-05-03 Warner Lambert Pharmaceutical Euphoriant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155663A (en) * 1962-11-15 1964-11-03 Warner Lambert Pharmaceutical Aminopyrazines
US3249503A (en) * 1963-10-22 1966-05-03 Warner Lambert Pharmaceutical Euphoriant

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4692527A (en) * 1984-09-15 1987-09-08 Basf Aktiengesellschaft 2-amino-3,5-di-(halomethyl)-pyrazines and their preparation

Also Published As

Publication number Publication date
DK106381C (da) 1967-01-30
FR3929M (fr) 1963-02-14
GB1031915A (en) 1966-06-02

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