US3624084A - 2,4,6-trisubstituted derivatives of pyrimidine - Google Patents

2,4,6-trisubstituted derivatives of pyrimidine Download PDF

Info

Publication number
US3624084A
US3624084A US699294A US3624084DA US3624084A US 3624084 A US3624084 A US 3624084A US 699294 A US699294 A US 699294A US 3624084D A US3624084D A US 3624084DA US 3624084 A US3624084 A US 3624084A
Authority
US
United States
Prior art keywords
pyrimidine
hydroxyethyl
amino
methyl
recrystallization
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
US699294A
Other languages
English (en)
Inventor
Jacques Mathieu
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.)
UCB SA
Original Assignee
UCB SA
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 UCB SA filed Critical UCB SA
Application granted granted Critical
Publication of US3624084A publication Critical patent/US3624084A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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.

Landscapes

  • 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)
US699294A 1967-01-25 1968-01-22 2,4,6-trisubstituted derivatives of pyrimidine Expired - Lifetime US3624084A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB3774/67A GB1143167A (en) 1967-01-25 1967-01-25 Derivatives of pyrimidine

Publications (1)

Publication Number Publication Date
US3624084A true US3624084A (en) 1971-11-30

Family

ID=9764663

Family Applications (1)

Application Number Title Priority Date Filing Date
US699294A Expired - Lifetime US3624084A (en) 1967-01-25 1968-01-22 2,4,6-trisubstituted derivatives of pyrimidine

Country Status (5)

Country Link
US (1) US3624084A (is")
BE (1) BE709787A (is")
DE (1) DE1695975A1 (is")
FR (2) FR1555900A (is")
GB (1) GB1143167A (is")

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3984411A (en) * 1975-04-10 1976-10-05 Societe Generale De Recherches Et D'applications Scientifiques "Sogeras" Pyrimidines
US4116674A (en) * 1974-08-05 1978-09-26 Imperial Chemical Industries Limited Process of severely damaging or killing unwanted plants with pyrimidine compounds
EP0057440A1 (en) * 1981-01-29 1982-08-11 Sankyo Company Limited Aminopyrimidine derivatives, processes for their preparation, and fungicidal, insecticidal and acaricidal compositions containing them
US5138058A (en) * 1989-02-22 1992-08-11 Hoechst Aktiengesellschaft Piperazine substituted pyrimidine derivatives and physiologically tolerated salts thereof
US5254555A (en) * 1989-10-30 1993-10-19 Beecham Group P.L.C. Amino pyrimidin-7-yl substituted benzopyrans for treatment of hypertension
WO2004111014A1 (en) * 2003-06-06 2004-12-23 Vertex Pharmaceuticals Incorporated Pyrimidine derivatives as modulators of atp-binding cassette transporters
US20060074068A1 (en) * 2002-04-18 2006-04-06 Ucb, S.A. Chemical compounds with dual activity, processes for their preparation and pharmaceutical compositions
US20070244131A1 (en) * 2004-10-15 2007-10-18 Aventis Pharmaceuticals Inc. 2,6-substituted-4-monosubstitutedamino-pyrimidine as prostaglandin d2 receptor antagonists
WO2009105220A1 (en) * 2008-02-19 2009-08-27 Janssen Pharmaceutica N.V. Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2662607B1 (fr) * 1990-05-30 1992-08-28 Oreal Composition destinee a etre utilisee pour freiner la chute des cheveux et pour induire et stimuler leur croissance, contenant des derives d'alkyl-2 amino-4 (ou dialkyl-2-4) pyrimidine oxyde-3 .
JPH09301958A (ja) * 1996-05-09 1997-11-25 Nippon Shoji Kk 新規ピリミジン化合物及び抗ロタウイルス剤
DE60314730T2 (de) * 2002-03-15 2008-06-05 Ciba Specialty Chemicals Holding Inc. Verwendung von 4-aminopyrimidinen zur antimikrobiellen behandlung von oberflächen
WO2011105572A1 (ja) * 2010-02-26 2011-09-01 持田製薬株式会社 新規ヘテロアリール誘導体

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2994637A (en) * 1957-11-13 1961-08-01 Diamond Alkali Co Aminopyrimidines as fungicides
US3299067A (en) * 1963-11-19 1967-01-17 Science Union & Cie 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives
US3325496A (en) * 1963-11-12 1967-06-13 Geigy Chem Corp 2, 4, 6-tri-amino-substituted pyrimidines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2994637A (en) * 1957-11-13 1961-08-01 Diamond Alkali Co Aminopyrimidines as fungicides
US3325496A (en) * 1963-11-12 1967-06-13 Geigy Chem Corp 2, 4, 6-tri-amino-substituted pyrimidines
US3299067A (en) * 1963-11-19 1967-01-17 Science Union & Cie 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4116674A (en) * 1974-08-05 1978-09-26 Imperial Chemical Industries Limited Process of severely damaging or killing unwanted plants with pyrimidine compounds
US3984411A (en) * 1975-04-10 1976-10-05 Societe Generale De Recherches Et D'applications Scientifiques "Sogeras" Pyrimidines
EP0057440A1 (en) * 1981-01-29 1982-08-11 Sankyo Company Limited Aminopyrimidine derivatives, processes for their preparation, and fungicidal, insecticidal and acaricidal compositions containing them
US5138058A (en) * 1989-02-22 1992-08-11 Hoechst Aktiengesellschaft Piperazine substituted pyrimidine derivatives and physiologically tolerated salts thereof
US5254555A (en) * 1989-10-30 1993-10-19 Beecham Group P.L.C. Amino pyrimidin-7-yl substituted benzopyrans for treatment of hypertension
US7544675B2 (en) * 2002-04-18 2009-06-09 Ucb, S.A. Chemical compounds with dual activity, processes for their preparation and pharmaceutical compositions
US20060074068A1 (en) * 2002-04-18 2006-04-06 Ucb, S.A. Chemical compounds with dual activity, processes for their preparation and pharmaceutical compositions
US20050059687A1 (en) * 2003-06-06 2005-03-17 Makings Lewis R. Modulators of ATP-Binding Cassette transporters
WO2004111014A1 (en) * 2003-06-06 2004-12-23 Vertex Pharmaceuticals Incorporated Pyrimidine derivatives as modulators of atp-binding cassette transporters
US8642609B2 (en) 2003-06-06 2014-02-04 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20070244131A1 (en) * 2004-10-15 2007-10-18 Aventis Pharmaceuticals Inc. 2,6-substituted-4-monosubstitutedamino-pyrimidine as prostaglandin d2 receptor antagonists
US8193183B2 (en) * 2004-10-15 2012-06-05 Aventis Pharmaceuticals Inc. 2,6-substituted-4-monosubstitutedamino-pyrimidine as prostaglandin D2 receptor antagonists
WO2009105220A1 (en) * 2008-02-19 2009-08-27 Janssen Pharmaceutica N.V. Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase
US20090264429A1 (en) * 2008-02-19 2009-10-22 Richard Apodaca Aryl - Hydroxyethylamino - Pyrimidines and Triazines as Modulators of Fatty Acid amide Hydrolase
US8598202B2 (en) 2008-02-19 2013-12-03 Janssen Pharmaceutica Nv Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase

Also Published As

Publication number Publication date
GB1143167A (en) 1969-02-19
FR7383M (is") 1969-10-27
FR1555900A (is") 1969-01-31
BE709787A (is") 1968-07-24
DE1695975A1 (de) 1971-05-19

Similar Documents

Publication Publication Date Title
US3624084A (en) 2,4,6-trisubstituted derivatives of pyrimidine
KR100359676B1 (ko) 벤조일구아니딘및이의제조방법
US4430343A (en) Benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containing the same
DE69523462T2 (de) Substituierte o6-benzylguanine
US4599338A (en) Antimigraine 8-[3-(4-aminocarbonyl piperazino and piperidino) propyl[xanthines
US4886807A (en) Novel pyrimidopyrimidine derivative, process for producing it and pharmaceutical composition
US4289776A (en) Xanthine derivatives
US4548820A (en) Xanthine compounds
NO115800B (is")
GB1576351A (en) Xanthine derivatives
EP0682027A1 (de) Pyrrolopyrimidinderivate mit antiproliferativer Wirkung
US3631043A (en) Di- and triphenylpropyl piperazine compounds
JPH05310731A (ja) イミダゾール−５−カルボン酸誘導体の新規なアシラール、それらの製造方法及び利用方法
US3930006A (en) Antiparkinsonism compositions and method
US4980350A (en) Piperazinylalkylpyrimidines as hypoglycemic agents
DE69201559T2 (de) Pyrimidinderivate zur erhöhung der antitumoraktivität.
US4511557A (en) Pharmaceutical composition
US4535080A (en) Derivatives of 2-piperazino-pyrimidine, methods for their preparation and their utilization as drugs or intermediates for drugs
US3497307A (en) Method of preventing oxidation of 6-substituted purines with 4-hydroxy-1h-pyrazolo(3,4-d)pyrimidine and 4,6 - dihydroxy-1h-pyrazolo(3,4-d)pyrimidine
US3757017A (en) 4,5 polymethylene pyrimidine derivatives
US3819612A (en) 2-substituted adenosine derivatives and the production thereof
DD236928A5 (de) Verfahren zur herstellung neuer 1,2,4-triazolo-carbamate
NZ206906A (en) Substituted pyridazines and pyrimidines and pharmaceutical compositions
US3574212A (en) Quinazolinylureas
EP0330263A1 (en) Piperazinylalkylpyrimidines as hypoglycemic agents