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DE2329399A1 - 4-ALKYL-AMINOURACILE, THE METHOD FOR MANUFACTURING IT AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

4-ALKYL-AMINOURACILE, THE METHOD FOR MANUFACTURING IT AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS

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Publication number
DE2329399A1
DE2329399A1 DE19732329399 DE2329399A DE2329399A1 DE 2329399 A1 DE2329399 A1 DE 2329399A1 DE 19732329399 DE19732329399 DE 19732329399 DE 2329399 A DE2329399 A DE 2329399A DE 2329399 A1 DE2329399 A1 DE 2329399A1
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DE
Germany
Prior art keywords
general formula
branched
hydrogen
straight
chain
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.)
Pending
Application number
DE19732329399
Other languages
German (de)
Inventor
Guenter Dr Brenner
Joachim Dr Goering
York Dr Hartleben
Oskar Dr Rohte
Manfred Dr Tauscher
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.)
WUELFING J A FA
Original Assignee
WUELFING J A FA
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
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Application filed by WUELFING J A FA filed Critical WUELFING J A FA
Priority to DE19732329399 priority Critical patent/DE2329399A1/en
Priority to FI157974A priority patent/FI157974A/fi
Priority to AT430074A priority patent/AT332425B/en
Priority to JP49062447A priority patent/JPS5052077A/ja
Priority to SE7407471A priority patent/SE7407471L/xx
Priority to NL7407611A priority patent/NL7407611A/xx
Priority to BE145190A priority patent/BE816055A/en
Priority to FR7419693A priority patent/FR2232320A1/en
Priority to HUWU000016 priority patent/HU168153B/hu
Priority to DD17905374A priority patent/DD119233A5/xx
Publication of DE2329399A1 publication Critical patent/DE2329399A1/en
Pending legal-status Critical Current

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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
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

11 4-Alkyl-aminouracile, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel " 11 4-Alkyl-aminouracils, process for their preparation and pharmaceuticals containing these compounds "

Gegenstand der vorliegenden Erfindung sind neue 4-Alkylaminouracile der allgemeinen Formel I sowie deren Salze mit pharmakologisch verträglichen anorganischen und organischen Säuren,The present invention relates to new 4-alkylaminouracils of the general formula I and their salts with pharmacologically acceptable inorganic and organic Acids,

(D(D

1 2 1 2

in der R und/oder R Wasserstoff, geradkettige oder verzweigte, gesättigte oder ungesättigte Alkylreste mit bis zu 6 C-Atomen, welche gegebenenfalls durch eine Äther-, Hydroxy- oderin which R and / or R is hydrogen, straight-chain or branched, saturated or unsaturated alkyl radicals with up to 6 carbon atoms, which optionally by an ether, hydroxy or

409881 /1198409881/1198

eine Gruppe -TIR^R-, substituiert sein können, wobei R. und/orb.r R„ Wasserstoff, geradkettige oder verzweigte, gesöttigic oder ungesättigte Alkylreste mit bis zu 4 C-Atomen sind, nov/i.e Cycloalkyl, R Wasserstoff, einen geradkettigon oder vei-zv/e igten, gesättigten oder ungesättigten Alkylrest oder eine Aralkyl-, Aryl-, Cycloalkyl-, Halogen-, Nitro-, Amino-, Acylamino-, Formylgruppe,a group -TIR ^ R-, where R. and / orb.r R "hydrogen, straight-chain or branched, gesöttigic or are unsaturated alkyl radicals with up to 4 carbon atoms, nov / i.e Cycloalkyl, R is hydrogen, a straight-chain or a branched, saturated or unsaturated alkyl radical or an aralkyl, aryl, cycloalkyl, halogen, nitro, amino, acylamino, Formyl group,

R und H Wasserstoff, geradkettige oder verzweigte, gesättigte oder ungesättigte Alkylreste mit bis zu 6 C-Atoruen, die gegebenenfalls noch durch ein Heteroatom unterbrochen sind und einen heterocyclischen Ring bilden können, bedeuten.R and H are hydrogen, straight-chain or branched, saturated or unsaturated alkyl radicals with up to 6 carbon atoms, which are optionally interrupted by a heteroatom and may form a heterocyclic ring.

Die Erfindung betrifft ferner ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I, welches dadurch gekennzeichnet ist, dass manThe invention also relates to a process for the preparation of compounds of the general formula I, which is characterized is that one

a) entsprechend substituierte 4-Halogenuracile der allgemeinen Formel IIa) correspondingly substituted 4-halouracils of the general Formula II

(II) Hai(II) shark

mit entsprechend substituierten Aminen der allgemeinen Formel IIIwith appropriately substituted amines of the general Formula III

409881/1198409881/1198

,R*, R *

HN.HN.

in denen R , R , R , R und R die oben angegebene Bedeutung haben, und Hai ein Halogen, insbesondere Chlor ist, umsetzt oderin which R, R, R, R and R have the meaning given above have, and Hai is a halogen, in particular chlorine, converts or

b) in 4-Allcylaininouracilc der allgemeinen Formel IVb) in 4-Allcylaininouracilc of the general formula IV

IlIl

(IV)(IV)

die entsprechenden Substituenten R , die die oben angegebene Bedeutung haben, in an sich bekannter Weise in die 5-Stellung einführt, oderthe corresponding substituents R, which are those given above Have meaning, introduces into the 5-position in a manner known per se, or

c) die entsprechend substituierten 4-Amino-uracile der allgemeinen Formel V,c) the correspondingly substituted 4-amino-uracils of the general Formula V,

409881/1198409881/1198

mit entsprechend substituierten Aminhydrochloriden der allgemeinen Formel VI,with appropriately substituted amine hydrochlorides of the general Formula VI,

-R5-R5

ClCl

(VI)(VI)

in der R , R , R , R und R die oben genannte Bedeutung haben, umsetzt.in which R, R, R, R and R have the abovementioned meaning have implemented.

Entsprechende Reaktionsmechanismen sind z.B. aus den folgenden Literaturstellen an sich bereits bekannt : J. Org. Chem. 1£» C9^1) S. 1879 bis 1890 und J. Liebigs A. £9£ (1966), S. 134 bis 150.Corresponding reaction mechanisms are already known per se, for example from the following literature references: J. Org. Chem. 1 £ »C9 ^ 1 ) pp. 1879 to 1890 and J. Liebigs A. £ 9 £ (1966), pp. 134 to 150.

Die Herstellung von Salzen mit pharmakologisch zulässigen anorganischen und oi'ganischen Säuren kann in üblicher Weise durch Lösen der Base in organischen Lösungsmitteln (z.B. Äthanol) und Zugabe der erforderlichen Säuremenge durchgeführt werden.The manufacture of salts with pharmacologically acceptable inorganic and organic acids can be used in the customary manner by dissolving the base in organic solvents (e.g. ethanol) and adding the required amount of acid will.

Die nachstehenden Beispiele erläutern die Erfindung.The following examples illustrate the invention.

Beispiel 1 1,3-Di-n-butyl-4-(ß-hydroxyäthyl)-amino-uracilExample 1 1,3-Di-n-butyl-4- (β-hydroxyethyl) -amino-uracil

a) 181,0 g (0,71 Mol) 1,3-Di-n-butyl-4-chloruracil werden mit 256,5 g (4,? Mol) Äthanolamin 40 Minuten in 500 ml Äthanola) 181.0 g (0.71 mol) of 1,3-di-n-butyl-4-chloruracil are mixed with 256.5 g (4.? mol) of ethanolamine in 500 ml of ethanol for 40 minutes

409881/1198409881/1198

unter Rückfluss gekocht. Die aus der abgekühlten Lösung ausgefallenen Kristalle werden abgesaugt und aus Wasser umkristallisiert. refluxed. The precipitated from the cooled solution Crystals are suctioned off and recrystallized from water.

Man erhält 191,6 g (97 Prozent der Theorie) 1,3-Di-n-butyl-4-(ß-hydroxyäthyl)-amino-uracil vom Schmelzpunkt 115 bis 117,5°C191.6 g (97 percent of theory) of 1,3-di-n-butyl-4- (β-hydroxyethyl) amino uracil are obtained from melting point 115 to 117.5 ° C

Analyse ^ c H NAnalysis ^ c H N

ber.: 59,30 8,90 14,82 gef.: .59,22 8,84 14,73calc .: 59.30 8.90 14.82 found: .59.22 8.84 14.73

NMR : 6^5 ppm (Triplett, 1 Proton)NMR: 6 ^ 5 ppm (triplet, 1 proton)

4,8 ppm (Triplett, 2 Protonen) 3,0 - 3,7 ppm (Multiplett, 8 Protonen) 0,9-1,5 ppm (Multiplett, 14 Protonen)4.8 ppm (triplet, 2 protons) 3.0 - 3.7 ppm (multiplet, 8 protons) 0.9-1.5 ppm (multiplet, 14 protons)

IR : 3250, 1682, 1610, 1575, 1540 cm"1 IR: 3250, 1682, 1610, 1575, 1540 cm " 1

UV__: 268^, E J ^ = 784,0 (CH3OH)UV__: 268 ^, EJ ^ = 784.0 (CH 3 OH)

A09881/1198A09881 / 1198

b) 4,78 g (O,02 Mol) 1,3-Di-n-butyl-4-aminouracil werden mit 0,24 g (0,04 Mol) Aminoäthanol und 0,19 g (0,02 Mol) Aminoäthanol-hydrochlorid 17 Stunden bei 150°C geschmolzen. Das Ende der Reaktion wird daran erkannt, days kein Ammoniak mehr entweicht.b) 4.78 g (0.02 mol) of 1,3-di-n-butyl-4-aminouracil become with 0.24 g (0.04 mol) of aminoethanol and 0.19 g (0.02 mol) Aminoethanol hydrochloride melted at 150 ° C for 17 hours. The end of the reaction is recognized by the absence of ammonia more escapes.

Nach dem Erkalten werden die Kristalle abgesaugt und aus Wasser oder Benzol/Petroläther umkristallisiert.After cooling, the crystals are suctioned off and recrystallized from water or benzene / petroleum ether.

Schmelzpunkt: 115 bis 117°CMelting point: 115 to 117 ° C

Ausbeute: 4,0 g = 71 Prozent der Theorie.Yield: 4.0 g = 71 percent of theory.

In diesem Beispiel entspricht die Ausführungsform geniäss Abschnitt a) der Variante a) des beanspruchten Verfahrens, während die Ausführungsform von Abschnitt b) die Variante c) des beanspruchten Verfahrens erläutert.In this example, the embodiment corresponds to enjoyment Section a) of variant a) of the claimed method, while the embodiment of section b) the variant c) of the claimed method explained.

Beispiel 2 1,3-Di-n-butyl-4-(ß-p-toluolsulfonyl-äthyl)-amino-uracilExample 2 1,3-di-n-butyl-4- (β-p-toluenesulfonyl-ethyl) -amino-uracil

10 g (0,0354 Mol) 1,3-Di-n-butyl-4-chloruracil und 7,4 g (0,0388 Hol) p-Toluolsulfochlorid werden in 100 ml Pyridin gelöst und längere Zeit (ca. 72 Stunden) bei -2o°C stehengelassen. Die Reaktionsmischung wird wie üblich aufgearbeitet Der Toluolsulfonsäureester fällt auf Zugabe von Wasser aus, wird abgesaugt und aus Methanol/F^O umkristallisiert.10 g (0.0354 mole) 1,3-di-n-butyl-4-chlorouracil and 7.4 g (0.0388 Hol) p-Toluenesulfochlorid are in 100 ml of pyridine dissolved and left to stand for a long time (approx. 72 hours) at -2o ° C. The reaction mixture is worked up as usual. The toluenesulphonic acid ester precipitates on the addition of water, is suctioned off and recrystallized from methanol / F ^ O.

Man erhält 7,5 g (49 Prozent der Theorie) 1,3-Di-n-butyl-4-(ß-p-toluolsulfonyläthyl)-amino-uracil vom Schmelzpunkt 1 027.5 g (49 percent of theory) of 1,3-di-n-butyl-4- (β-p-toluenesulfonylethyl) -amino-uracil are obtained from melting point 1 02

bis 1O3,5°Cup to 1O3.5 ° C

409881/1198409881/1198

Analyse :Analysis: CC. HH N νN ν SS. ber.:ber .: 57,6357.63 7,147.14 9,609.60 ·. 7,33·. 7.33 gef.:found: 57,1157.11 7,187.18 9,269.26 7,357.35 57,2057.20 7,057.05 9,219.21 7,377.37

NMR: .. 7,8 - 7,3 ppm (2 Dubletts, 4 Protonen)NMR: .. 7.8 - 7.3 ppm (2 doublets, 4 protons)

• 5,9 ppm (Singulett, 1 Proton)• 5.9 ppm (singlet, 1 proton)

4,7 ppm (Singulett, 1 Proton)4.7 ppm (singlet, 1 proton)

4,3 - 3,4 ppra (Multiplett, 8 Protonen)4.3 - 3.4 ppra (multiplet, 8 protons)

" 2,5 ppm (Singulett, 3 Protonen)"2.5 ppm (singlet, 3 protons)

1,5-0,9 ppm (Multiplett, 14 Protonen)1.5-0.9 ppm (multiplet, 14 protons)

IR : 3260, 1682, 1610, 1575, 1540, 1350, 1170 cm~IR: 3260, 1682, 1610, 1575, 1540, 1350, 1170 cm ~

Beispiel 3 1 , 3-Dimethyl-4-/J*2 -hydroxy äthyl-piperazinyl-( 127-uracilExample 3 1,3-Dimethyl-4- / J * 2 -hydroxyethyl-piperazinyl- (127-uracil

87,3 g (0,5 Mol) 1,3-Di-methyl-4-chloruracil und 180,0 g (1,30 Mol) 1-(2-Hydroxyäthyl)-piperazin v/erden in 300 ml Äthanol gelöst und 2 Stunden unter Rückfluss erhitzt. Nach dem Abkühlen fallen Kristalle aus, die abgesaugt werden. Das Rohprodukt wird aus Äthanol/Petroläther umkristallisiert.87.3 g (0.5 mole) 1,3-dimethyl-4-chlorouracil and 180.0 g (1.30 mol) 1- (2-hydroxyethyl) piperazine v / earth in 300 ml Dissolved ethanol and refluxed for 2 hours. After cooling, crystals precipitate and are filtered off with suction. That The crude product is recrystallized from ethanol / petroleum ether.

Man erhält 107 g (80 Prozent der Theorie) 1,3-Dimethyl-4- ^~2-hydroxyäthyl-piperazinyl-(1)_7~uracil vom Schmelzpunkt107 g (80 percent of theory) 1,3-dimethyl-4- ^ ~ 2-hydroxyethyl-piperazinyl- (1) _7 ~ uracil of the melting point

120 bis 121°C.120 to 121 ° C.

409881 /1198409881/1198

Analyse: C H NAnalysis: C H N

ber.: 53,72 7,49 20,82 gef.: 53,86 7,35 20,82calc .: 53.72 7.49 20.82 found: 53.86 7.35 20.82

NHR j 5,2 ppm (Singulett, 1 Proton)NHR j 5.2 ppm (singlet, 1 proton)

3,6 - 3,8 ppm (Triplett, 2 Protonen)3.6 - 3.8 ppm (triplet, 2 protons)

3.4 - 3,5 ppm (2 Singuletts, 6 Protonen)3.4 - 3.5 ppm (2 singlets, 6 protons)

2.5 - 3,2 ppm (Multiplctt, 11 Protonen)2.5 - 3.2 ppm (Multiplctt, 11 protons)

IR : 3140, 2990, 2890,, 2830, 2815, 1690, 1635,IR: 3140, 2990, 2890, 2830, 2815, 1690, 1635,

: ι: ι

1590 cm"1590 cm "

Beispiel ,3-Düsoprop.vl-4-/~2-hydroxyäthyl-piperazinyl-(Example, 3-Diisoprop.vl-4- / ~ 2-hydroxyethyl-piperazinyl- (

23,0 g (0,1 Mol) 1,3-Diisopropyl-4-chloruracil werden in 20 ml abs. Äthanol Gelöst, 32,5 g (0,25 Mol) 1-(2-Hydro>:yäthyl)-piperaain zugetropft und das Gemisch noch 4 5 Minuten unter Rückfluss gekocht. Nach dem Abkühlen v/ird das Reaktions-Gemisch langsam init Essigester versetzt und das ausgefallene Rohprodukt abg€:saugt. !lach Urakristallisation aus Eosigester/ Petroläther v/ird 1 ,3-Diisopropy] -4-^~2-hydroxyäthylpiperazinyl-(1)_J7-uracil in 62prozentiger Ausbeute erhalten.23.0 g (0.1 mol) of 1,3-diisopropyl-4-chloruracil are in 20 ml abs. Dissolved ethanol, 32.5 g (0.25 mol) 1- (2-Hydro>: yethyl) -piperaain added dropwise and the mixture boiled under reflux for a further 4 5 minutes. After cooling, the reaction mixture becomes slowly mixed with ethyl acetate and the precipitated crude product is sucked off. ! laugh Uracrystallization from Eosigester / Petroleum ether for 1,3-diisopropy] -4- ^ ~ 2-hydroxyethylpiperazinyl- (1) _J7-uracil obtained in 62 percent yield.

Schmelzpunkt: 128 bis 129°C.Melting point: 128 to 129 ° C.

409881/1198409881/1198

Anolyse: C H NAnolysis: C H N

ber.: 59,23 8,70 17,27calc .: 59.23 8.70 17.27

gef.: 59,05 8,48 16,85Found: 59.05 8.48 16.85

59,04 8,52 16,9959.04 8.52 16.99

In entsprechender Weise wurden nach der Variante a) des beanspruchten Verfahrens die in der nachstehenden Tabelle I aufgeführten Verbindungen hergestellt.In a corresponding manner, according to variant a) of the claimed Process the compounds listed in Table I below were prepared.

409881/1198409881/1198

Tabelle ITable I.

Nr. des BeispielsNo. of the example

R1 R 1

"XX/"XX /

RSRS

R'1 + RSR ' 1 + RS

Schmp. in 0C (Lösungsmittel f. U-mkri s tall isation)M.p. in 0 C (solvent for U-mkri s tallization)

Ausbeute yield

6.)6.)

8.)8th.)

10.) 11.)10.) 11.)

CHjCHj

CIIjCIIj

CH3 CH 3

CHjCHj

CIIjCIIj

CHjCHj

CIIjCIIj

CHjCHj

CIIjCIIj

CIIjCIIj

CHjCHj

CIIjCIIj

CIIjCIIj

CTTCTT

II;II;

IIII

CH2 -CII2N.CH 2 -CII 2 N.

TK-CILTK-CIL

/CIl, -/ CIl, -

CTICTI

N-CIL^ -CII2 -GHjN-CIL ^ -CII 2 -GHj

/CH2 -CIL,./ CH 2 -CIL ,.

^N-CH2 ^ N-CH 2

/CIi2 -CH2^/ CIi 2 -CH 2 ^

CII2 -CII 2 -

-CH.-CH.

N-CPI2 -CH-CII3
OHN-CPI 2 -CH-CII 3
OH

-CII2 · CAU -011-CII 2 · CAU -011

N-CII2 -CIT2 -NH2 N-CII 2 -CIT 2 -NH 2

N-CIL, -ClI2 -CIU -NITN-CIL, -ClI 2 -CIU -NIT

Äthanol/ PetrolätherEthanol / petroleum ether

kristallin Äthanolcrystalline ethanol

123,0-124,0 Äthanol123.0-124.0 ethanol

137,0-138,0 Äthanol137.0-138.0 ethanol

120.0-121,0120.0-121.0

Äthanol/ PetrolätherEthanol / petroleum ether

kristallin Äthanol/ petroläthercrystalline ethanol / petroleum ether

123,0-124,0 Äthanol123.0-124.0 Ethanol

5454

7676

7777

8080

7070

50 £50 pounds

CO Γ\3 COCO Γ \ 3 CO

CO CD CDCO CD CD

FortGCFortGC tzung von Tby T CH3 CH 3 a b e 1 1 ca b e 1 1 c CH3 CH 3 ϊ Iϊ I ί
R" + R3 ί
R "+ R3 - Seite 11 -- page 11 - Aus-
b eu t eThe end-
prey << 78 1» 78 1 » Nr. dos
nci.3p.iclsNo. dos
nci.3p.icls R1 R 1 CH3 CH 3 R2 R 2 CH3 CH 3 »»»» ^CH2 -CH2,. ^O^ CH 2 -CH 2,. ^ O
^CIT2 -CIL5% ,OC2H5 ^ CIT 2 -CIL 5 %, OC 2 H 5 Schrr.p. m C
(Lösungsmittel f.
U:r.kristal 1 isati on)Schrr.p. m C
(Solvent f.
U: r.kristal 1 isati on) 77 #77 # 62 $, $ 62, 12.)12.) CII3 CII 3 CH3 . CH 3 . HH _ , ^^ O_, ^^ O 149,0-150,0
Äthanol149.0-150.0
Ethanol 44 i> 44 i> 56 4 56 4 13.)13.) CH3 CH 3 CH3 CH 3 IIII o-o ■o-o ■
^iJ2 -ViJ2 Jirr=/^ iJ 2 -ViJ 2 Jirr = / 249,0-251,0
Äthanol249.0-251.0
Ethanol 29 5629 56 Ξ 14.)Ξ 14.)
OOOO 1-C3H7 ^1-C 3 H 7 ^ X-C3H7 XC 3 H 7 HH kristallin
Äthanolcrystalline
Ethanol OOOO 1-C3H7 1-C 3 H 7 1-C3II7 1-C 3 II 7 ΉΉ 2 |J
CTT3
^CII2 -CIL,. 2 | J
CTT 3
^ CII 2 -CIL ,. kristallin
Äthanol/
Essigestercrystalline
Ethanol /
Ethyl acetate COCO
OOOO
16.)16.) 1-C3II7 1-C 3 II 7 1-C3II7 1-C 3 II 7 1
H 1
H ρ« —CTT
^ 2 2^N-CiI2 -CH2 -CH3
CiL, -CIi2 ρ «- C T T
^ 2 2 ^ N-CiI 2 -CH 2 -CH 3
CiL, -CIi 2 128,5-130,0
Benzin 40/60
" 100/140128.5-130.0
Gasoline 40/60
"100/140 17.)17.) X-C3H7 XC 3 H 7 X-C3II7 XC 3 II 7 HH 98,0- 99,0
Benzin 40/60
Äther98.0- 99.0
Gasoline 40/60
ether 18.)18.) IIII C^ 2 nN^:N-CIL, -CH-CH3 C ^ 2 nN ^: N-CIL, -CH-CH 3 122,0-123,0
Sssigester 1
Äthanol " 122.0-123.0
Sssigester 1
Ethanol " 19.)19.) II
ιII
ι 147,0-148,5
Aceton 8
Äthanol 2147.0-148.5
Acetone 8
Ethanol 2

ro co ro co coro co ro co co

Fortsetzung von Tabelle Continuation from table

Nr. desNo. of

BeispielsExample

R1 R 1

R=R =

J Schnp. in C (Lösungsmittel f.J Schnp. In C (solvent f.

Uakristall isation)Uacrystallization)

Ausbeute yield

CjO
OO
OOCjO
OO
OO

■Ό.) 21.) 22.) 23·) 24.) 250 ■ Ό.) 21.) 22.) 23 ·) 24.) 250

26 O 27.)26 O 27.)

1-C3IT7 1-C 3 IT 7

1-C3H7 1-C 3 H 7

1-C3H7 1-C 3 H 7

1-C3H7 1-C 3 H 7

"9"9

1-C3IT7 1-C 3 IT 7

1-C3 IT7 1-C 3 IT 7

1-C3H7 1-C 3 H 7

1-C3H7 1-C 3 H 7

C, H9 C, H 9

CII2-CII2" ■ X-=,CII 2 -CII 2 "■ X- =,

/CH8-CIT8n^/ CH 8 -CIT 8n ^

CH2 -CII2 /CII2 -CIT2 CIL, -CII2 CII2 -CH8 CH 2 -CII 2 / CII 2 -CIT 2 CIL, -CII 2 CII 2 -CH 8

CII2 -CH2 CII2 -CILCII 2 -CH 2 CII 2 -CIL

CH2 -CIT2 CH2 -ClU CH 2 -CIT 2 CH 2 -ClU

N-CH3 N-CH 3

N-CH2 N-CH 2

IH, 0-116,0 Benzin 1OO/HO~9»5 Methanol ~ 0,5IH, 0-116.0 gasoline 100 / HO ~ 9 »5 Methanol ~ 0.5

158,5-^59,5158.5- ^ 59.5

ÄthanolEthanol

157,0-158,0157.0-158.0

ÄthanolEthanol

136,0-188,0 Methanol 8
Benzin 40/60136.0-188.0 methanol 8
Gasoline 40/60

H2,0-U4,0 Essigester/ PetrolätherH2.0-U4.0 ethyl acetate / petroleum ether

Hydrochloricl: 208,0-210,0Hydrochloricl: 208.0-210.0

Äthanol/
PetrolätherEthanol /
Petroleum ether

Öl
dest.oil
least.

140.0-141,0 Methanol 4 / Äther 6140.0-141.0 Methanol 4 / ether 6

6363

6262

51 9&51 9 &

3030th

6363

6060

Portsetzung von Tabelle I Portion of Table I

Nr. dos BeispiolsNo. dos Beispiols

R2,R2,

R3 Schmp. in C (Lösungsmittel f. Umkristallisation)R3 m.p. in C. (Solvent for recrystallization)

Ausbeute yield

28.)28.)

29.)29.)

30.) 31.) 32.)30.) 31.) 32.)

330330

1-C3II7 1-C 3 II 7

1-C3II7 1-C 3 II 7

1-C3II7 1-C 3 II 7

1-C3H7 1-C 3 H 7

.1-C3H7 .1-C 3 H 7

1-C3H7 1-C 3 H 7

1-C3H7 1-C 3 H 7

1-C3H7 1-C 3 H 7

1-C3II7 1-C 3 II 7

1-C3II7 1-C 3 II 7

H'H'

IIII

IIII

(CH2J3-OH(CH 2 J 3 -OH

120,0-122,0 Äthanol/V/asser120.0-122.0 ethanol / v / water

125,0-127,0 Äthanol/Äther125.0-127.0 ethanol / ether

181,0-183,0 Äthanol181.0-183.0 ethanol

156,0-157,5 Essigester156.0-157.5 ethyl acetate

140,0-141,0 Benzin140.0-141.0 gasoline

171,0-172,0 Isqpropanol/ Äther171.0-172.0 isopropanol / ether

41 fi 41 fi

6565

75 #75 #

6868

6060

65 5t65 5t

ro co coro co co

Portsetzung von Tabelle I Portion of Table I

Nr. des neispioXa Schmp. in C
(Lösungsmittel.f.No. of neispioXa m.p. in C
(Solvent.f.

Umkristal!isation)Recrystallization)

Ausbeuteyield

ο co oo ooο co oo oo

3h.) 35.) 3h.) 35.)

36.) 37.) 36.) 37.)

38.)38.) 39.)39.)

CH3 CH 3

CH3 CH 3

CH-CH-

CIl9 CIl 9

CIt,CIt,

J-C3II7 JC 3 II 7

CiI3 CiI 3

CH-CH-

CH3 CH 3

CII.CII.

CII3 CII 3

-Oil-Oil

CH2 -CII -^ \ CH 2 -CII - ^ \

CII3 CII 3

-CIi2 CII2 -CIl1 -CIi 2 CII 2 -CIl 1

ClCl

Γ CII,Γ CII,

-CITj-CITj

CH2 -CIi2 CH 2 -Cli 2

175,0-176,0
Äthanol175.0-176.0
Ethanol

205,0-206,0
Methanol205.0-206.0
Methanol

189,0-191,0
Methanol189.0-191.0
Methanol

175,0
Methanol175.0
Methanol

193,0-*94,0193.0- * 94.0

MethanolMethanol

164,0-165,0164.0-165.0

"ethanol"ethanol

9494

ro co roro co ro

Die neuen Verbindungen zeigen pharmakologisch ein vielfältiges V/irkungsbild, aus dem als ausgeprägte Eigenschaften der Einfluss auf die Cholerese und Diurese zu nennen sind. Darüber hinaus greifen diese Verbindungen durch Senkung der, Cholesterinspiegels im Blutserum in den Cholesterinstoffwechsel ein.The new compounds are pharmacologically diverse Effect picture from which the distinctive properties of the Influence on cholerese and diuresis are to be mentioned. About that In addition, these compounds attack by lowering cholesterol levels in the blood serum in the cholesterol metabolism.

Wegen'ihrer geringen Toxizität stellen die neuen Verbindungen daher einen Fortschritt gegenüber Stoffen gleicher Wirkungsrichtung dar. Because of their low toxicity, the new compounds therefore represents an advance compared to substances with the same direction of action.

Dengernäss betrifft die Erfindung auch Ar&neiiuil eel, welche durch den Gehalt an einer Verbindung nach Formel (i) oder einen pharinakologisch zulässigen Salz einer solchen Verbindung al α Wirkstoff gekennzeichnet sind.Dengernäss the invention also relates, which are characterized by the content of a compound according to formula (i) an pharinakologisch acceptable salt of such a compound or drug al α Ar & neiiuil eel.

Derartige Arzneimittel können ausserdem übliche Trägerstoffe uv:Q sonstige Hilfnstoffe, wie Geschmacksstoffe, Gleitmittel und Farbstoffe, enthalten.Such drugs can also be conventional carriers uv: Q other additives, such as flavorings, lubricants and dyes.

In der nachstehenden Tabelle II sind wichtige phannakologische Eigenschaften einiger erfindungsgenässer 4-Alkylarcinouracile zusammengestellt.In Table II below are important phannacological Properties of some 4-alkylarcinouracils according to the invention compiled.

409881/1198 409881/1198

Tabelle IITable II

Beispiel
Iexample
I. vorläufige Toxizität
(LD50 /LD5)
mg / kg Maus
p.o. i.v.preliminary toxicity
(LD 50 / LD 5 )
mg / kg mouse
poiv Choler. Effekt
p.o. Ratte kle
Ete signif.wirk
Dosis rag/kgCholer. effect
po rat small
Ete signif. Effective
Dose rag / kg •• <r8o<r8o i.n-in- Diuret.
Dosis
mg / kgDiuret.
dose
mg / kg ■■ -- -- Effekt
Ratteeffect
rat 77th > 500 62/38> 500 62/38 <32<32 -- -- Menge: +Quantity: + 1616 - >1000/>1000 74/51-> 1000 /> 1000 74/51 8080 3232 -- 2020th >500> 500 3232 <5 '<5 ' nach 80
Menge+ 26
*after 80
Quantity + 26
* 1010 >1000/>1000 250/l52> 1000 /> 1000 250 / l52 -- 2323 >1000/>1000 270/l65> 1000 /> 1000 270 / l65 Na+ + 25
K+ -Na + + 25
K + - 44th >1000 354/276> 1000 354/276 22 • >1000/>1000 200•> 1000 /> 1000 200 27 % 27 % 99 >1000/>1000 1300/795> 1000 /> 1000 1300/795 11 >1000/>1000 142/110> 1000 /> 1000 142/110 mg/k 3 ρ
% mg / k 3 ρ
%

4098817 11984098817 1198

Es v/urden weiterhin verschiedene biochemische Untersuchungen der nachstehenden Art durchgeführt :Various biochemical studies of the following types were also carried out:

1.) Einfluss der Substanz auf den Serura-Cholesterin-Spiegel nüchterner Ratten1.) Influence of the substance on the serural cholesterol level sober rats

Die Verbindung von Beispiel 1 senkt in einer Dosis von 100 mg/kg oral nach einmaliger Applikation den Serium-Cholesterin-Spiegel von 24 Stunden nüchtern gehaltenen Ratten signifikant gegenüber der Kontrollreihe.The compound of Example 1 lowers the serium cholesterol level in a dose of 100 mg / kg orally after a single application of rats kept fasted for 24 hours were significantly compared with the control series.

Dieser Effekt erstreckt sich über den gesamten Beobachtungszeitraum von 26 Stunden. This effect extends over the entire observation period of 26 hours.

Die erhaltenen Ergebnisse sind in der nachstehenden Tabelle III zusammengestellt und in Fig. 1 graphisch wiedergegeben.The results obtained are shown in Table III below compiled and shown graphically in FIG.

409881/1198409881/1198

Tabelle IIITable III

ηη Stunden nach ApplikationHours after application 44th 88th 2626th *) ρ ^. 0,05*) ρ ^. 0.05 00 **) wässrige Lösung von Methylcellulose (0,6 Prozent**) aqueous solution of methyl cellulose (0.6 percent Vorbindung vonPre-binding of Gewicht/Volumen), die ausserdem 0,9 Prozent GeWeight / volume), which is also 0.9 percent Ge Beispiel 1example 1 2929 82,6*82.6 * 79,579.5 75,375.3 wicht/Volumen NaCl und 0,5 Prozent Gev/icht/Volumenweight / volume NaCl and 0.5 percent weight / volume 100 mg/kg (Methocel-
oral Susp.)100 mg / kg (Methocel-
oral susp.) 94,094.0 eines Netzmittels (Polyadditionsprodukte vonof a wetting agent (polyadducts of CholesterinsenkungLowering cholesterol Äthylenoxid) enthält.Ethylene oxide). bei # der Gesamtat # the total 92,692.6 84,684.6 84,084.0 tierzahlanimal number -- MethocelMethocel (Kontrollprobe ohne
Wirkstoff)(Control sample without
Active ingredient) 2929 90,790.7 84,484.4 78,478.4 4 ml/kg oral4 ml / kg orally 97,097.0

409881/1198409881/1198

2.) Einfluss der Verbindung von Beispiel 1 auf den Serum-Cholesterin-Spiegel bei hypercholesterinämischen Ratten (prophylaktischer VersuSh)2.) Influence of the compound of Example 1 on the serum cholesterol level in hypercholesterolemic rats (prophylactic VersuSh)

Die Substanz senkt einen durch Pett-Pütterung (Cholesteringehalt 2 Prozent) überhöhten Serum-Cholesterin-Spiegel bei prophylaktischer Gabe über die gesamte Versuchsdauer von 11 Tagen.The substance lowers you by Pett feeding (cholesterol content 2 percent) increased serum cholesterol levels prophylactic administration over the entire duration of the experiment 11 days.

Die erhaltenen Ergebnisse sind in der nachstehenden Tabelle IV zusammengestellt und in Pig. 2 graphisch wiedergegeben.The results obtained are summarized in Table IV below and in Pig. 2 graphically reproduced.

Tabelle IVTable IV

ηη ChoiesterinsenkungChoiesterin subsidence FettdiätfütterungFat diet feeding 0 Tage0 days 3 Tage3 days 7 Tage7 days 11 Tage11 days Verbindung vonconnection of in Prozentin percent Beispiel 1example 1 gegenüber Kontrolleversus control 100 mg/kg (Methocel-
Sucp.) 1 χ pro die
oral100 mg / kg (Methocel-
Sucp.) 1 χ per die
orally 1010 89,489.4 470,9470.9 1360,31360.3 1452,51452.5 MothocelMothocel (Kontrollprobe ohne(Control sample without Wirkstoff)Active ingredient) 4 ml/kg
1 χ pro die
oral4 ml / kg
1 χ per the
orally 1010 89,489.4 518,7518.7 1577,81577.8 1709,51709.5 -- 9,29.2 13,713.7 15,015.0

409881/1198409881/1198

Claims (2)

PatentansprücheClaims 1 21 2 in der R und/oder R Wasserstoff, geradkettige oder verzweigte, gesättigte oder ungesättigte Alkylrefite mit bis zu 6 C-Atomen, welche gegebenenfalls durch eine Äther-, Hydroxy- oder eine Gruppe -NR6R7 substituiert sein können, wobei R6 und/oder R7 Wasserstoff, geradkettige oder verzweigte, gesättigte oder ungesättigte Alkylreste mit bis zu 4 C-Atomen sind, sowie Cycloalkyl,in which R and / or R is hydrogen, straight-chain or branched, saturated or unsaturated alkyl radicals with up to 6 carbon atoms, which can optionally be substituted by an ether, hydroxyl or a group -NR 6 R 7 , where R 6 and / or R 7 are hydrogen, straight-chain or branched, saturated or unsaturated alkyl radicals with up to 4 carbon atoms, as well as cycloalkyl, R Wasserstoff, einen geradkettigen oder verzweigten, gesättigten oder ungesättigten Alkylrest oder eine Aralkyl-, Aryl-, Cycloalkyl-, Halogen-, Nitro-, Amino-, Acylamino-, Formyl-Gruppe,R is hydrogen, a straight-chain or branched, saturated one or unsaturated alkyl radical or an aralkyl, aryl, cycloalkyl, halogen, nitro, amino, acylamino, Formyl group, A 5 A 5 R und R Wasserstoff, geradkettige oder verzweigte, gesättigte oder ungesättigte Alkylreste mit bis zu 6 C-Atomen, die gegebenenfalls noch durch ein Heteroatom unterbrochen sind und einen heterocyclischen Ring bilden können,R and R hydrogen, straight-chain or branched, saturated or unsaturated alkyl radicals with up to 6 carbon atoms, which are optionally interrupted by a heteroatom and can form a heterocyclic ring, bedeuten. 409881/1198mean. 409881/1198 2. Verfahren zur Herstellung von Verbindungen gemäss2. Process for the preparation of compounds according to Anspruch 1, Formel (I), dadurch gekennzeichnet, dass manClaim 1, formula (I), characterized in that one a) entsprechend substituierte 4-Halogenuracile der allgemeinen Formel (II)a) correspondingly substituted 4-halouracils of the general Formula (II) (II) Hal(II) Hal mit entsprechend substituierten Aminen der allgemeinen Formel (III)with appropriately substituted amines of the general formula (III) 1 ? "*> A R1 ? "*> A R in denen R ,R ,R1R und R die oben angegebene Bedeutung haben und Hai ein Halogen, insbesondere Chlor ist, umsetzt oderin which R, R, R 1, R and R have the meaning given above and Hal is a halogen, in particular chlorine, reacts or b) in 4-Alkylaminouracile der allgemeinen Formel (IV)b) in 4-alkylaminouracils of the general formula (IV) /»09881/1 198/ »09881/1 198 die entsprechenden Substituenten R , die die oben angegebene Bedeutung haben, in an sich bekannter Weise in die 5-Stellung einführt, oderthe corresponding substituents R, which have the meaning given above, in a manner known per se into the 5 position introduces, or c) die entsprechend substituierten 4-Amino-uracile der allgemeinen Formel (V),c) the correspondingly substituted 4-amino uracils of general formula (V), mit entsprechend substituierten Aminhydrochloriden der allgemeinen Formel (VI),with appropriately substituted amine hydrochlorides of the general formula (VI), ClCl in der R ,R ,R1R und R die oben genannte Bedeutung haben, umsetzt. in which R , R , R 1, R and R are as defined above . 3· Arzneimittel, gekennzeichnet durch den Gehalt an einer Ver bindung nach Anspruch 1, Formel (I), oder deren pharmakologisch zulässigen Salzen als Wirkstoff. 3 · Medicines, characterized by the content of a compound according to claim 1, formula (I), or their pharmacologically permissible salts as active ingredient. 409881/1198409881/1198 LeerseiteBlank page
DE19732329399 1973-06-08 1973-06-08 4-ALKYL-AMINOURACILE, THE METHOD FOR MANUFACTURING IT AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS Pending DE2329399A1 (en)

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DE19732329399 DE2329399A1 (en) 1973-06-08 1973-06-08 4-ALKYL-AMINOURACILE, THE METHOD FOR MANUFACTURING IT AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
FI157974A FI157974A (en) 1973-06-08 1974-05-23
AT430074A AT332425B (en) 1973-06-08 1974-05-24 PROCESS FOR THE PREPARATION OF NEW 6-AMINOURACILS AND THEIR SALT
JP49062447A JPS5052077A (en) 1973-06-08 1974-06-01
SE7407471A SE7407471L (en) 1973-06-08 1974-06-06
NL7407611A NL7407611A (en) 1973-06-08 1974-06-06
BE145190A BE816055A (en) 1973-06-08 1974-06-07 4-ALCOYL-AMINO-URACILS
FR7419693A FR2232320A1 (en) 1973-06-08 1974-06-07 4-Amino-uracil derivs - hypocholesterolemiant having diuretic activity
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3222914A1 (en) * 1982-06-18 1983-12-22 Beiersdorf Ag, 2000 Hamburg SUBSTITUTED 5-PHENYLTHIO-6-AMINO-PYRIMIDINONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE, AND PREPARATIONS CONTAINING THESE COMPOUNDS
US5008267A (en) * 1988-10-29 1991-04-16 Mitsui Toatsu Chemicals, Incorporated Pyrimidinedione compounds, method of producing the same and antiarrythmic agents containing the same
RU2449994C1 (en) * 2011-03-10 2012-05-10 Светлана Алексеевна Мещерякова 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride showing biological activity

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Publication number Priority date Publication date Assignee Title
JPH0688982B2 (en) * 1988-10-29 1994-11-09 三井東圧化学株式会社 Novel pyrimidinedione derivative and antiarrhythmic agent containing the compound
FR2659656B1 (en) * 1990-03-15 1994-09-09 Sanofi Sa PYRIMIDINEDIONE-2,4 DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THEM.
DE59903953D1 (en) * 1998-06-26 2003-02-13 Crompton Vinyl Additives Gmbh New NH2-modified 6-aminouracils as stabilizers for halogen-containing polymers
WO2003000664A1 (en) * 2001-06-22 2003-01-03 Bayer Aktiengesellschaft Uracil derivatives and the use thereof for treating bacterial diseases

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US3147257A (en) * 1959-03-24 1964-09-01 Robugen Gmbh New substituted 4-aminouracil derivatives
GB1110734A (en) * 1966-11-10 1968-04-24 Interpharm G M B H & Co K G 9-substituted isotheophyllines
BE755015A (en) * 1969-08-20 1971-02-01 Byk Gulden Lomberg Chem Fab PIPERAZINYL-ALCOYLAMINO-URACILS SUBSTITUTED BY AN ARYL GROUP, THEIR ETHERS AND THIOETHERS, AND THEIR PREPARATION PROCESS
DE2150686A1 (en) * 1971-10-12 1973-04-19 Basf Ag 6-amino-uracil-5-carboxylic acid thioamides - inters for dyestuffs and pharmaceuticals

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3222914A1 (en) * 1982-06-18 1983-12-22 Beiersdorf Ag, 2000 Hamburg SUBSTITUTED 5-PHENYLTHIO-6-AMINO-PYRIMIDINONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE, AND PREPARATIONS CONTAINING THESE COMPOUNDS
US4594419A (en) * 1982-06-18 1986-06-10 Beiersdorf Aktiengesellschaft Substituted 5-phenylthio-6-amino-pyrimidinones, a process for their preparation and their use, and formulations containing these compounds
US4686223A (en) * 1982-06-18 1987-08-11 Beiersdorf Aktiengesellschaft Substituted 5-phenylthio-6-amino-pyrimidinones, a process for their preparation and their use, and formulations containing these compounds
US5008267A (en) * 1988-10-29 1991-04-16 Mitsui Toatsu Chemicals, Incorporated Pyrimidinedione compounds, method of producing the same and antiarrythmic agents containing the same
RU2449994C1 (en) * 2011-03-10 2012-05-10 Светлана Алексеевна Мещерякова 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride showing biological activity

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