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

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

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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
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pyrimidine
hydroxyethyl
amino
methyl
recrystallization
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Jacques Mathieu
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    • 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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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

IN WHICH R1 is hydrogen, lower alkyl, aralkyl, R2 is hydrogen, halogen, lower alkyl, hydroxyalkylamino, omegaaryl-omega-hydroxyalkylamino, morpholino, R3 is hydrogen, lower alkyl eventually hydroxyl-substituted, aralkyl, R4 is lower alkyl substituted by at least one hydroxyl group separated from N by at least two carbon atoms, or R3 and R4 together with the extranuclear N are morpholino, as well as their salts with inorganic or organic acids. These compounds are hypotensives, peripheral and coronary vasodilators, diuretics, bronchodilators, spasmolytics and circulatory and respiratory analeptics.

New 2,4,6-trisubstituted pyrimidine derivatives of the general formula

Description

nited States Patent [72] inventor Jacques Mathleu Brussels, Belgium [21 Appl. No. 699,294 [22] Filed Jan. 22, 1968 [45] Patented Nov. 30, 1971 [73] Assignee U.C.B. Societe Anonyrue Saint-Gilles-les Bruxelles, Belgium [32] Priority Jan. 25, 1967 [33] Great Britain [31 3,774/67 [54] 2,4,6-TR1SUBS'11TUTED DERIVATIVES 0F PYRIMIDINE 7 Claims, No Drawings [52] 11.8. CI ..260/256.4 N,
260/246, 260/247.5, 424/248, 424/251 [51] lnt.Cl C07d5l/42,
C07d 87/38 [50] Field of Search 260/256.4'N [5 6] References Cited UNITED STATES PATENTS 2,994,637 8/1961 Bimber 260/2564 N 3,299,067 1/1967 Regnier et al... 260/256.4 N 3,325,496 6/1967 Critchley et al. 260/2564 Primary Examiner-Alex Mazel Asxislan! Examiner-Anne Marie Tighe Anomey- McGlew and Toren ABSTRACT: New 2,4,6-trisubstituted pyrimidine derivatives of the general formula in which R, is hydrogen, lower alkyl, aralkyl,
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.
These compounds are hypotensives. peripheral and coronary vasodilators, diuretics. bronchodilators, spasmolytics and circulatory and respiratory analeptics.
2 ,4,6-TRISUBSTITUTED DERIVATIVES F PYRIMIDINE 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:
in which 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
R and R taken together with the extranuclear nitrogen atom to which they are attached fonn a morpholino radical,
as well as their salts with inorganic and organic acids.
Pharmacological studies have shown that the new compounds according to the present inventionpossess interesting properties, some being hypotensives, peripheral and coronary vasodilators, diuretics, bronchodilators and spasmolytics and some being circulatory and respiratory analeptics.
The following list of compounds according to the invention has been chosen to illustrate the pharmacological activity. This is on the understanding that said list is not restrictive, as all the compounds of the invention have been submitted to the test mentioned below.
A. 2-propyl-4-methyl-6-[bis( 2-hydroxyethyl)amino]- pyrimidine B. 2-methyl-4-propyl-6'morpholino-pyrimidine C. 2-ethyl-4-chloro-6-morpholino-pyrimidine D. 2-ethyl-4-chloro-6-[N,N-( 2-hydroxyethyl((ethyl)amino] -pyrimidine 2-ethyl-4-chloro-6-[ N,N-( 2-hydroxyethyl)(methyDaminol-pyrimidine F. 2-methyl-4-chloro-6-morpholino-pyrimidine G. 2-benzyl-4-m ethyl-6-[bis(2-hydroxyethyl)amino1- pyrimidine H. 2-benzyl-.4-chloro-6-( 2-hydroxyethyl)amino pyrimidine l. 2-propyl-4-(Lhydroxyethyl)amino-6-morpholinopyrimidine J. 2-propyl-4-( 2-phenyl-2-hydroxyethyl )amino-6- bis( 2- hydroxyethyl)amino1-pyrimidine 2-propyl-4-(2phenyl-2-hydroxyethyl)amino-6- morpholino-pyrimidine 2-methyl-4,6-dimorpholino-pyrimidine 2-propyl-4-methyl-6-[N,N-(2-hydroxyethyl)(benzyl)amino]-pyrimidine 2-propyl-4-methyl-6-[N,N-(2-hydroxyethyl)(ethyl)amino]pyrimidine 2-propyl-4-methyl-6-( -hydroxypentyl)aminopyrimidine Doses Thcophylline Product A mfl-lltg. l u l n l0 IO 33 5 lo 20 37.5 I40 i0 20 27.5 30 lo 12.5 20 I4 90 50 30 65 60 20 35 10 77.5 270 I= cardiac output increase in (maximal effect) ll= duration of increase in minutes.
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.
b. Peripheral vasodilator effect on dogs leg Thedogs leg is perfused with a constant blood output according to the technique described by D. WELLENS (Arch.int.Pharmacodyn. l 5 l, (l964),28 1-285 The products are injected in the perfusion circuit and their vasodilator effect is manifested by a decrease in perfusion pressure.
Vasodilator action in of that of theophylline Product B=370 Product D=530 Product H= Product M=900 Product C=300 Product E=300 Product L=l00 Product P=3 10 Product Dose 2p.g.lml. 50ng.lml. l00 .g./ml.
Theophylline Product B Product C Product F Product G Product H Product I Product J Product L Product N Product 0 Product Dose 2 ,g./ml. Dose ZO g/ml.
Theophyllinc 2.3 mm. H 25 mm. H,O Product A l l Product G Product I 9 Product 0 l4 e. 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.
The following table gives the results of comparative tests between theophylline and certain products of the invention.
Compound Bronchospasm Doses Maximum Effect mgJkg. effect after (at 2 min.) l2 min.
Theophylline Acetylcholine 2 18 3.7
Histamine 2 30 4.6
I6 93.7 92.7 S-hydroxy- 2 20.5 2 tryptamine 4 48.4 20
Product A Acctylcholinc 0.4 17.2 0.4 0.8 37.2 9.6
3.2 84 57.2 50 Histamine 0.4 l8.3 L5
3.2 71.5 40 S-hydroxy- 0.4 6.6 3.6 tryptamine 0.8 26 ll.7 L6 53.6 l9.7
Product K 5-hydroxy- 3 SS 9 tryptamine 9 I0 98 Product P Acctylcholine l 2 l 3 22 5 9 36 I5 S-hydroxy- I l6 l0 tryptamine 3 48 22 9 79 43 With reference to the eflicaceous dose, Product A appears to be four to five times more active than theophylline. 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).
f. Spasmolytic effect on isolated organs.
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-
151). The eflicaceous dose DE 50 is determined (in micrograms/ml.) that antagonizes 50 percent of the convulsivant effect (induced by barium chloride or acetylcholine).
The found DE 50 value is given in the following table for both theophylline and the Product A according to the invention:
Product A BaClZ Acetylcholine Product A proves to be more than twice as active as theophylline.
g. 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.).
Product DL 50 Theophyllinc 176 Product A 240 Product 8 1 l0 Product C 240 Product D 200 Product E 350 Product F 364 From the pharmacological tests (a) to (3) it appears that the products of the invention have analogous effects to those of theophylline, besides pronounced advantages over that substance.
Consequently, 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.
In particular, they may be prepared by the following methods:
a. when 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;
b. when 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.
0. when 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.
The following examples are given for the purpose of illustrating the present invention.
EXAMPLE 1 2-propyl-4-methyl-6-[bis( Z-hydroxyethyl )amino 1- pyrimidine.
A mixture of 371 g. (2.17 mol) 2-propyl-4-methyl--chloropyrimidine, 457 g. (4.45 mol) diethanolamine and 1,500 cc. anhydrous dioxan is boiled under reflux for 30 hours. The reaction mixture is cooled and the upper layer is separated from the lower layer which consists of diethanolamine hydrochloride. By the addition of ether to the dioxan solution, 2-propyl-4-methyl-6-[bis(2-hydroxyethyl)aminol-pyrimidine crystallizes out. It is recrystallized from dioxan, ethyl acetate or ethanol. Yield 430.5 g. (1.8 mol), which is 83 percent of theory. M.p. lO2-l03 C.
There is given below a list of compounds which have been prepared by the same process, starting from the appropriate 6- chloropyrimidine and from the appropriate amine. Some of the compounds were isolated by concentration of the dioxan solution and distillation of the residue or by conversion into the hydrochloride:
2-propyl-6-morpholino-pyrimidine; m.p. of the hydrochloride 183l84 C., after recrystallization from isopropanol-ether.
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. (Also prepared from 4-chloro-6-morpholinopyrimidine by catalytic dehalogenation suing palladiated carbon. 2,4-dimethyl-6-[bis(2-hydroxyethyl)amino]-pyrimidine; m.p. l48l49 C., after recrystallization from dioxan. 2,4-dimethyl-6-morpholino-pyrimidine; b.p. l0l-l03 C./0.0l mm.Hg. 2-ethyl-4-methyl-6-[bis(2-hydroxyethyl)amino]- pyrimidine; m.p. 93-94 C., after recrystallization from propanol-ether. 2-ethyl-4-methyl-6-morpholino-pyrimidine; b.p. l09-l 10 C./0.0()l mm. Hg. 2-propyl-4-methyl-6-(2-hydroxyethyl)amino-pyrimidine;
m.p. l06-l07 C., after recrystallization from dioxa nether.
2-propyl-4-methyl-6-( 3-hydroxypropyl)amino-pyrimidine; m.p. of the hydrochloride ll6-l l7 C., after recrystallization from alcohol.
2-propyl-4-methyl-6-(2,3-dihydroxypropyl)aminopyrimidine; m.p. l07-l08 C., after recrystallization from ethyl acetate-hexane.
2-propyl-4-methyl-6-morpholino-pyrimidine; m.p. of the hydrochloride l8l-l82 C., after recrystallization from alcohol-ether.
2-propyl-4-methyl-6-[ bis( 2-hydroxypropyl )amino]- pyrimidine; nondistillable and noncrystallizable oil which gives only a spot on electrophoresis; analysis: calculated molecular weight 267, found molecular weight 267; nitrogen calculated 15.73 percent, nitrogen found 15.58 percent.
2-propyl-4-methyl-6-[N,N-(2-hydroxyethyl)(ethyl)amino]- pyrimidine; b.p. l30-l32 C./0.00l mm. Hg.
2-propyl-4-methyl-6-[N,N-(2-hydroxyethyl)(methyl)amino ]-pyrimidine; b.p. l24l26 C./0.00l mm. Hg.
2-propyl-4-methyl-6-( S-hydroxypentyl )amino-pyrimidine;
m.p. 7374 C., after recrystallization from ethyl acetate.
2-propyl-4-methyl-6-[ N ,N-( 2-hydroxyethyl benzyl )amino l-pyrimidine; m.p. 73-74 C., after recrystallization from ethanol-water.
2-isopropyl-4-methyl-6-(2-hydroxyethyl)amino-pyrimidine; m.p. l56-l57 C., after recrystallization from ethyl acetate-hexane.
2-isopropyl-4-methyl-6-morpholino-pyrimidine; m.p. of the hydrbchloride 2i l2l2 C., after recrystallization from ether.
2-isopropyl-4-methyl-6-[ bis( 2-hydroxyethyl )amino pyrimidine; m.p. ll8-l 19 C., after recrystallization fromacetone.
4-methyl-6-[ bis( Z-hydroxyethyl )amino ]-pyrimidine; m .p.
l04l05 C., after recrystallization from ethyl acetatehexane.
2-butyl-4-methyl-6-[ bis( 2-hydroxyethyl )amino pyrimidine; m.p. 5354 C., after recrystallization from ethyl acetate.
2-isobutyl-4-methyl-6-[bis(2-hydroxyethyl)amino]- pyrimidine; m.p. 65 C., after recrystallization from ethyl acetate.
2-butyl-4-methyl-6-morpholino-pyrimidine; m.p. of the hydrochloride l02103 C.
2-isobutyl-4-methyl-6-morpholino-pyrimidine; m.p. of the hydrochloride l-l86 C.
2-methyl-4-propyl-6-morpholino-pyrimidine; lap. 12 1 1 22 C./0.00l mm. Hg.
2-methyl-4-propyl-6-[ bis( 2-hydroxyethyl )amino pyrimidine; m.p. l00-l0l C., after recrystallization from ethyl acetate.
2-4-dipropyl-fi-morpholino-pyrimidine;
C./0.00l mm. Hg.
2-4-dipropyl-6-[ bis( 2-hydroxyethyl )amino]-pyrimidine;
m.p. 6364 C., after recrystallization from ethyl acetate.
2-pentyl-4-methyl-6-(2-hydroxyethyl)amino-pyrimidine;
m.p. 71 C., after recrystallization from ether.
2-pentyl-4-methyl-6-[bis-(2-hydroxyethyl)amino]- pyrimidine; m.p. of the hydrochloride l20l2l C., after recrystallization from ether.
2-pentyl-4-methyl-6-morpholino-pyrimidine; m.p. of the hydrochloride l7l-l72 C., after recrystallization from ether.
2-benzyl-4methyl-6-[ bis( 2-hydroxyethyl )amino pyrimidine; m.p. 78-79 C., after recrystallization from ethyl acetate-hexane.
2-benzyl-6-morpholino-pyrimidine; m.p. of the hydrochloride C., after recrystallization from isopropanol-ether.
EXAMPLE 2 2-propyl-4-chloro-6-morpholino-pyrimidine 17.4 g. (0,2 mol) morpholine are added to l9.l g. (0.1 mol) 2-propyl-4,6-dichloro-pyrimidine in [00 cc. dioxan. During the course of the addition, there is observed an increase of the temperature to about 70 C. At the end of the addition, the reaction mixture is heated to 80 C. for 10 hours. After cooling the reaction mixture, morpholine hydrochloride formed during the reaction is filtered off. The filtrate is then evaporated to dryness and the residue recrystallized from water. There are finally isolated 23.3 g. (0,096 mol) 2-propyl- 4-chloro-6-morpholino-pyrimidine, the yield being 96 percent of theory; m.p. 5960 C.
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.
4-chloro-6-morpholino-pyrimidine; m.p. ll-l52 after recrystallization from ethyl acetate-hexane. 4-chloro-6-[bis(2-hydroxyethyl)aminol-pyrimidine; m.p. of hydrochloride l22l23 C., after recrystallization from isopropanol-ether. 4-chloro-6-(2-hydroxyethyl)amino-pyrimidine; m.p.
1l4-l15 C., after recrystallization from ethyl acetatehexane. 2-propyl-4-chloro-6-(2-hydroxyethyl)amino-pyrimidine;
m.p. of the hydrochloride 108 C., after recrystallization from alcohol-ether. 2-propyl-4-chloro-6-[bis(2-hydroxyethyl)amino]- pyrimidine; m.p. 7980 C., after recrystallization from ethyl acetate. 2-methyl-4-chloro-6-( 2-hydroxyethyl )amino-pyrimidine;
m.p. 96-97 C.. after recrystallization from toluene-hexane. 2-methyl-4-chloro-6-[bis(Z-hydroxyethyl)amino1- pyrimidine; m.p. l34l35 C., after recrystallization from ethyl acetate. 2-methyl-4-chloro-6-morpholino-pyrimidine; m.p. 94-95 C.. after recrystallization from water. 2-ethyl-4-chloro-6-[bis(2-hydroxyethyl)aminol-pyrimidine;
m.p. 109 C., after recrystallization from ethyl acetate. 2-ethyl-4-chloro-6-morpholino-pyrimidine; m.p. 7980 C.. after recrystallization from water. 2-ethyl-4-chloro-6-[ N,N-( 2-hydroxyethyl methyl )amino pyrimidine;b.p. 145-147 C./0.00l mm.Hg. 2-ethyl-4-chloro-6-[N,N-(2-hydroxyethyl)(ethyl)aminolpyrimidine; b.p. l4ll42 C./0.00l mm. Hg. 2-propyl-4-chloro-6-[ N,N-( 2-hydroxyethyl methyl )amino l-pyrimidine; b.p. l45l47 C./0.00l mm. Hg. m.p. of the hydrochloride 128-l 29 C. 2-isopropyl-4-chloro--morpholino-pyrimidine; m.p. 74 C.,
after recrystallization from isopropanol-water. 2-isopropyl-4-chloro-6-[bis(Z-hydroxyethyl)amino]- pyrimidine; m.p. 76-77 C., after recrystallization from ethyl acetate-hexane. 2-isopropyl-4-chloro-6-(2-hydroxyethyl)amino-pyrimidine; m.p. 57-58 C., after recrystallization from ethyl acetatehexane. 2-isobutyl-4-chloro-6-morpholino-pyrimidine; b.p. 135l3 7 C./0.005 mm. Hg; n"- =l .5498. 2-isobutyl-4-chloro-6-[ bis( 2-hydroxyethyl)amino]- pyrimidine; m.p. 9394 C., after recrystallization from ethyl acetate-hexane. 2-isobutyl-4-chloro-6-( 2-hydroxyethyl)amino-pyrimidine;
m.p. l23-l24 C., after recrystallization from isopropanol-ether. 2-benzyl-4-chloro-6-morpholino-pyrimidine; m.p. l4ll42 C., after recrystallization from ethyl acetate-hexane. 2-benzyl-4-chloro-6-( Z-hydroxyethyl)amino-pyrimidine;
m.p. of the hydrochloride 126l28 C., after recrystallization from isopropanol-ether. 2-benzyl-4-chloro-6-[bis(2-hydroxyethyl)amino]- pyrimidine; m.p. of the hydrochloride 129 C., after recrystallization from isopropanol-ether.
EXAMPLE3 2-propyl-4-( 2-hydroxyethyl )amino-6-morpholinopyrimidine.
24.15 g. (0.1 mol) 2-propyl-4-chloro-6-morpholinopyrimidine and g. (1.64 mol) monoethanolamine are heated to C. for 20 hours. The excess ethanolamine is then distilled off in a vacuum and the residue taken up in dioxan. The ethanolamine hydrochloride formed during the reaction is separated by filtration through Hyfiocel" or norite. The filtrate is then evaporated to dryness. The residue (29 g.) is dissolved, with heating, in the minimum amount of ethyl acetate and hexane then added until the appearance of a slight cloudiness. After cooling, crystallization ta es place. By filtra- EXAMPLE 4 2-propyl-4,6-dimorpholino-pyrimidine 87 g. (1 mol) morpholine are carefully added to 19.1 g. (0.1 mol) 2-propyl-4,6-dichloropyrimidine. During the course of the addition, the temperature increases to l40 C. Subsequently, the temperature is maintained at l30-l40 C. for 25 hours. The reaction mixture is then cooled and water and ether added. The ethereal layer is separated, washed with water, dried and evaporated to dryness. The residue is recrystallized from hexane.
There are finally obtained 26 g. (0.089 mol) 2-propyl-4,6- dimorpholino-pyrimidine. Yield 89 percent of theory; m.p. 102 C.
The 2-methyl-4,6-dimorpholino-pyrimidine has also been prepared by this method; m.p. I70l7l C., after recrystallization from ethyl acetate-hexane.
lclaim:
l. 2-propyl-4-methyl-6-[bis( 2-hydroxyethyl)amino]- pyrimidine.
2. 2-pentyl-4-methyl-6-( 2-hydroxyethyl)amino-pyrimidine.
3. 2-propyl-4-chloro-6-( 2-hydroxyethyl)amino-pyrimidine.
4. 2-propyl-4-chloro-6-[ bis( 2-hydroxyethyl )amino pyrimidine.
2-ethyl-4-chloro-6-[N,N-( 2-hydroxyethyl)(methyl)amino]-pyrimidine.
6. 2-ethyl-4-chloro-6-[N,N-(Z-hydroxyethyl)(ethyl)amino] -pyrimidine.
7. 2-propyl-4-( 2-phenyl-2-hydroxyethyl )amino-6-( 2- hydroxyethyl)amino-pyrimidine.
t I t t t

Claims (6)

  1. 2. 2-pentyl-4-methyl-6-(2-hydroxyethyl)amino-pyrimidine.
  2. 3. 2-propyl-4-chloro-6-(2-hydroxyethyl)amino-pyrimidine.
  3. 4. 2-propyl-4-chloro-6-(bis(2-hydroxyethyl)amino)-pyrimidine.
  4. 5. 2-ethyl-4-chloro-6-(N,N-(2-hydroxyethyl)(methyl)amino)-pyrimidine.
  5. 6. 2-ethyl-4-chloro-6-(N,N-(2-hydroxyethyl)(ethyl)amino)-pyrimidine.
  6. 7. 2-propyl-4-(2-phenyl-2-Hydroxyethyl)amino-6-(2-hydroxyethyl)amino -pyrimidine.
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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

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FR2662607B1 (en) * 1990-05-30 1992-08-28 Oreal COMPOSITION FOR USE IN BRAKING HAIR LOSS AND INDUCING AND STIMULATING THEIR GROWTH, CONTAINING ALKYL-2 AMINO-4 (OR DIALKYL-2-4) PYRIMIDINE OXIDE-3 DERIVATIVES.
JPH09301958A (en) * 1996-05-09 1997-11-25 Nippon Shoji Kk New pyrimidine compound and antirotavirus agent
ES2290436T3 (en) * 2002-03-15 2008-02-16 Ciba Specialty Chemicals Holding Inc. USE OF 4-AMINOPIRIDINS FOR ANTIMICROBIAL SURFACE TREATMENT.
WO2011105572A1 (en) * 2010-02-26 2011-09-01 持田製薬株式会社 Novel heteroaryl derivative

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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)

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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

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FR1555900A (en) 1969-01-31

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