Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom

Definitions

• R is hydrogen, halogen, lower alkyl, hydroxyalkylamino, omega-aryl-omega-hydroxyalkylamino, morpholino,
• R is hydrogen, lower alkyl eventually hydroxyl-substituted, aralkyl
• R is lower alkyl substituted by at least one hydroxyl group separated from N by at least two carbon atoms, or
• R and R together with the extranuclear N are morpholino, as well as their salts with inorganic or organic acids.
• peripheral and coronary vasodilators diuretics.
• bronchodilators spasmolytics and circulatory and respiratory analeptics.
• the present invention is concerned with new 2,4,6-trisubstituted derivatives of pyrimidine and their addition salts with pharmaceutically acceptable acids, as well as with the preparation thereof and their therapeutic use.
• the new 2,4,6-trisubstituted pyrimidine derivatives according to the present invention are compounds of the general formula:
• R is a member selected from the group consisting ofv hydrogen, alkyl containing up to five carbon atoms and aralkyl,
• R is a member selected from the group consisting of hydrogen, halogen, alkyl containing up to five carbon atoms, hydroxyalkylamino, omega-aryl-omega-hydroxyalkylamino and morpholino,
• R taken separately is a member selected from the group consisting of hydrogen, alkyl containing upto five carbon atoms which may be substituted by at least one-hydroxyl group and aralkyl, 7
• R taken separately, is alkyl containing from to two to five carbon atoms, substituted by at least one hydroxyl group separated from the N atom by at least two carbonatoms, and
• Product A proves to be considerably superior to theophylline both as to the increase in cardiac output and as to the duration of that increase.
• This circulatory analeptic action manifests itself, among other features, by an increase in renal output which may result in an interesting diuretic power.
• a respiratory analeptic power has also been observed.
• Protective effect against bronchospasm induced in guineapigs The method of H. KONZE'IT and R. ROESSLER (Arch.exp.Path.Pharmakol.l95, (1940),7174) is applied on masculine and feminine albino guinea-pigs weighing between 300 and 500 g.
• Product K 5-hydroxy- 3 SS 9 tryptamine 9 I0 98
• the properties put forward are such that they preconise a therapeutical application in the treatment of spastic states of the bronchial unstriated muscles (asthma. bronchitis, emphysema).
• lsolated intestine preparations (of rat or guinea-pig) are placed in a survival bath according to the known method described by R. MAGNS (P flueger Arch. I02, (1904),!23-
• the eflicaceous dose DE 50 is determined (in micrograms/ml.) that antagonizes 50 percent of the convulsivant effect (induced by barium chloride or acetylcholine).
• spasmolytic effects in situ The spasmolytic effect observed in vitro on an isolated organ (test 1) is also observed in situ” in the animal (anesthetized dog).
• the Product A e.g., at doses of 0.5 to 5 mg./kg., obviously inhibits spasms induced by the injection of morphine (0.25 mg./kg.).
• the products of the invention show, in intravenous toxicity tests on rats, a mean toxicity which is less than that of theophylline, as can be seen from the following table (DL 50 expressed in mg./kg.).
• the products of the invention can be used in the therapeutical applications wherever theophylline is used.
• the new compounds of the present invention may be prepared by the known methods of preparing substituted pyrimidines.
• R is a member selected from the group consisting of hydrogen and alkyl, reacting a member selected from the group consisting of 2-R,-6-halo-pyrimidine and 2-R,- 4-alkyl-6-halo-pyrimidine with an organonitrogen compound selected from the group consisting of primary and secondary hydroxyalkylamines and morpholine;
• R is a member selected from the group consisting of halogen, hydroxyalkylamino and morpholino
• reacting a 2-R -4,6-dihalo-pyrimidine with an organonitrogen compound selected from the group consisting of primary and secondary hydroxyalkylamines and morpholine in such quantities and under such working conditions that a member of the group consisting of 2-R -4-halo-6-hydroxyalkylamino-pyrimidine, 2-R -4-halo-6-morpholinopyrimidine, 2-R -4,6-bis-hydroxyalkylamino-pyrimidine and 2-R 4,6-dimorpholino-pyrimidine is isolated.
• R is a member selected from the group consisting of hydroxyalkylamino and morpholino, reacting a member selected from the group consisting of 2-R -halo- 6-hydroxyalkylamino-pyrimidine and 2-R,-4-halo-6- morpholino-pyrimidine with an organonitrogen compound selected from the group consisting of primary and secondary hydroxyalkylamines and morpholine.
• the 2,4,6-trisubstituted pyrimidine derivatives thus obtained may subsequently be converted into their salts with mineral and organic acids.
• 2-isobutyl-6-morpholino-pyrimidine m.p. of the hydrochloride 2l8-2l9 C. after recrystallization from ethanol-ether.
• This product may also be prepared from 2-isobutyl-4-chloro-6-morpholino-pyrimidine described in example 2 by the known catalytic dehalogenation method using palladiated carbon. 6morpholino-pyrimidine; m.p. of the hydrochloride 193-l94 C, after recrystallization from isopropanolether.
• the corresponding hydrochloride may be prepared in ether; m.p. l39-l40 C.
• the following compounds are also prepared by this process. Some of them are purified by distillation. In the syntheses in which diethanolamine is used, the diethanolamine hydrochloride formed in the course of the reaction is separated by decantation.
• the 2-methyl-4,6-dimorpholino-pyrimidine has also been prepared by this method; m.p. I70l7l C., after recrystallization from ethyl acetate-hexane.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (9)

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Citations (3)

• 1967
  • 1967-01-25 GB GB3774/67A patent/GB1143167A/en not_active Expired
• 1968
  • 1968-01-08 FR FR1555900D patent/FR1555900A/fr not_active Expired
  • 1968-01-22 US US699294A patent/US3624084A/en not_active Expired - Lifetime
  • 1968-01-23 DE DE19681695975 patent/DE1695975A1/de active Pending
  • 1968-01-24 BE BE709787D patent/BE709787A/xx unknown
  • 1968-03-25 FR FR145321A patent/FR7383M/fr not_active Expired

Patent Citations (3)

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