CA1036604A - 1-aryl-uracils - Google Patents

1-aryl-uracils

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Publication number
CA1036604A
CA1036604A CA222,621A CA222621A CA1036604A CA 1036604 A CA1036604 A CA 1036604A CA 222621 A CA222621 A CA 222621A CA 1036604 A CA1036604 A CA 1036604A
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Prior art keywords
phenyl
dichloro
uracil
phenoxy
amino
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CA222,621A
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French (fr)
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CA222621S (en
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Axel Haberkorn
Edgar Enders
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Animal Husbandry (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Fodder In General (AREA)

Abstract

Abstract Uracils substituted in the 1-position by a 4-substituted phenyl group which can have further optional substitution in the phenyl ring and which has as the 4-substituent an aryl group linked through an oxygen, sulfur, sulfinyl or sulfonyl group are prepared by treatment of an aniline derivative substituted in the 4-position by an aryl group with either an acylisocyanate following by cyclization of the resultant urea or an enamine followed by hydrolysis and decarboxylation. The compounds, of which 1-[3,5-dlchloro-4-(4'-chloro-phenoxy)-phenyl]-uracil is a typical embodiment, demonstrate anticoccidial activity.

Description

:";

: 1036604 . . . : , Detailed Description The present invention relates to certain new 1 aryluracils, to processes for their production, to their use ~ -~
as anticoccidial agents and to compositions for such use. -~
It is known that certain 1,2,4-triazines have anti-coccidial activity. Thus 2-(4-phenylthiophenyl)-, 2-(4-phenyl-sulphinyl-phenyl)- and 2 (4-phenylsulphonyl-phenyl)-1,2,4-triazine-3,5(2H,4H)-diones are reported as having a coccidio-static action in Belgian Patents Nos. 740,403 and 773,583, which describ~ such 2-phenyl-as-triazine-3,5-(2H,4H)-diones and the use of these compounds for combating coccidiosis.
: These agents, however, have action only against coccidiosis of poultry.
-- The present inventisn pertains to l-aryluracils of . .
,. . .
~ the formula :,.; ~ , ;
.~, ~r - X ~ 0 wherein "''-1 . , Ar is an aryl group of 6 to 10 ring carbon atoms, unsubstituted or substituted with from one to three like or different substituents, said sub-stituents being selected from the group consisting of alkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenyltnio, nalogenoalkyl, hydroxy, acyloxy, methane-.

1036~iQ~
sulfonyloxy, benzenesulfonyloxy, aryloxy, halogeno, ::-cyano, nitro, -N \ 9, , C0-Z~and S02-Y in which each of R and R9 , independent of the other is hydrogen, ; slkyl, alkenyl or aryl or when taken together with the nitrogen atom to which they are cojoined, a hetero-cyclic ring of 5 to 7 ring members of which up to two .
can be further heteroatoms with the remainder being - carbon atoms;

.~ Z is hydroxy, alkox~ or N \ 9, ;

: 8' ~ R
Y is hydroxy, alkyl, aryl or ~\ 9, ;

; each of R , R , R and R , independent of the .

: others, is hydrogen, alkyl, halogeno, alkoxy, nitro, ~

amino, acylamino, cyano, carboalkoxy, trifluoromethyl, ~ :

. 00-N / g or S02-N\ g wherein R and R9 have the ... same meaning as R and R

` each of R5, R and R , independent o the others, .;............... .. . .
is hydrogen, alkyl or alkenyl; and .~ X is -0-, -S-, -S0- or -S02-;
` or a physiologically acceptable salt thereof.

: 20 In a further embodiment, the invention pertains to l-aryluracils wherein X is -0- or -S-.

-. In a further embodiment, the invention pertains to l-aryluraclls wherein Ar is unsubctituted or a mono-, di-
- 2 -.
'. ' ' ' "

~W6604 ~
or tri-substituted phenyl, naphthyl or 5,6,7,8-tetrahydro-naphthyl group wherein when substituted each substituent, -independent of any other, is alkyl of up to 8 carbon atoms, alkoxy of up to 6 carbon atoms, alkenyl of up to 6 carbon atoms, alkenyloxy of up to 6 carbon atoms, alkylthio of up to 6 carbon atoms, halogenoalkyl of up to 4 carbon atoms and up to 5 halogen atoms, hydroxy, acylo~y of up to 8 carbon atoms, methanesulfonyloxy, benzenesulfonyloxy, phenoxy, halogeno- -phenoxy, phenylhalogeno, cyano, nitro, amino, acylamino of up .-. ., ; .
to ~ carbon atoms, mono- or di-alkylamino wherein each alkyl . contains up to 8 carbon atoms, carboxy, carbalkoxy wherein ;., ~: alkoxy contains up to 8 carbon atoms, amidocarbonyl, mono- or :~ di-alkylamidocarbonyl wherein each alkyl contains up to 8 carbon atoms, arylamidocarbonyl wherein aryl contains from 6 to L0 carbon atoms, sulfo, amidosulfonyl, mono- or di- .
alkylsulfo~yl wherein alkyl contains up to 6 carbon atoms, :;~
.;. arylamidosulfonyl wherein aryl contains 6 to 10 carbon atoms, alkylsulfon.yl wherein alkyl contains up to 8 carbon atoms and arylsulfonyl wherein aryl contains from 6 to 10 carbon .,;
atoms.
In a further embodiment, the invention pertains to l-aryluracils wherein Ar is phenyl or mono-, di- or tri-sub-st~tuted phenyl wherein when substituted each substituent, in-. dependent of any other, is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, tri-fluoromethyl, hydroxy, alkanoyloxy of 2 to 4 carbon atoms, _ ~ _ : - :

l0366a4 alkenyloxy of 2 to 4 carbon atoms, phenoxy, halogenophenoxy, phenylhalogeno, cyano, nitro, amino, monoalkylamino of 1 to 4 carbon atoms, dialkylamino wherein each al~yl group contains 1 to 4 carbon atoms, alkanoylamino of 2 to 4 carbon atoms, al~ylsulfonyl of 1 to 4 carbon atoms, amidosulfonyl, mono-alkylamidosulfonyl of 1 to 4 carbon atoms, aialkylamido~ul-fonyl wherein each alkyl contains 1 to 4 carbon atoms, alkyl-sulfonyl of 1 to 4 carbon atoms or phenylsulfonyl.
In a further embodiment, the invention pertains to l-aryluracils ~lerein ~;
X is -0- or -S-;
each of R , R , R and R , independent of the other, is hydrogen, methyl or halogeno; and each of R5, R and R , independent of the other, is hydrogen or methyl.
In a further embodiment, the invention pertains to l-aryluracils wherein Ar is phenyl or mono~, di- or tri-substituted phenyl wherein when substituted each substituent, independent of any other, is methyl, ethyl, methoxy, methylthio, trifluoromethyl, allyloxy, hydroxy, acetoxy, phenoxy, chlorophenoxy, halogeno, cyano, nitro, amino, methanesulfonyl or ethanesulfonyl;
X is -0- or -S-;
each of * and R , independent of the other, is hydrogen, methyl or halogeno;
R3 and R4 are hydrogen; and eachof R5, R6 and R7 is hydrogen.

4 ~

: . ~ : . ., . . -1Q366~4 .
In a further embodiment, the invention pertains to - l-aryluracils o~ the formula:

R
wherein Ar is phenyl or mono-, di- or tri-substituted ~ phenyl in which when substituted each substituent, ; independent of any other, is chloro, bromo amino, methyl or methylsulfonyl; and each of Rl and R2, independent of the other, is hydrogen, methyl, chloro or bromo.

` In a further embodiment, the invention pertains to l-aryluracils of the formula:
.. ,.,` R~
Ar - S - ~ ~ 0 wherein hr is phenyl or mono-, di- or tri-substituted phenyl in which when substituted each substituent, independent of any other, is chloro, bromo, amino, ~ methyl or me~hylsulfonyl; and ; each of Rl and R2, independent of the other, is hydrogen. methyl, chloro or bromo.

: . -, ; , ... .

1~)36604 The l-aryluracils of the present invention and :. their salts exhibit a strong coccidiocidal action. Of those compounds of the invention which are salts, the salts which are physiologically acceptable are particularly important and among these those which are also pharmaceutically accept-ble are preferred.
The l-aryluracils of the formula (I) are obtained by treating a compound of the formula:

: R~ R4 Ar-X ~ -NH2 (II) . R R3 ~ 10 wherein Ar, X, R , R2, R3 and R4 are as defined above, . (a) with an acyl isocyanate of the formula .^~ Rlo-o-c===c-co-Nco (III) wherein R5 and R are as defined above, and .;; R represents alkyl, ;
~ to yield a compound of the formula:
.~'' ' ~
., , ~ .

Ar-X-~R 9 bl Hb6 R~5 0 (IV)
3 X Rl R2 R3 R4, R5, R6 and R are as above ~elireG~

.. - 6 -.. . .
.. ; , . . . . , . :: ~ -, . : . .

1Q3660~

which is then treated with an alkali metal hydroxide or alkoxide and the alkali metal salt of the corresponding uracil derivative, :-thus obtained, of the formula:

Ar-X~O r~l -R R O

wherein Ar, X, R , R2, R3, R4, R5 and R6 are as defined ~- above, and M ~ represents an alkali metal cation, is converted to the free uracil by acidification and is option-ally isolated or optionally converted by means of alkylating ~` 10 agents cr alkenylating agents into the corresponding N-alkyl or N-alkenyl compounds, or (b) w~th a compound of the formula:
R CN
Rl10-1 C-CO-NH-COOR (VI) wherein R and R represent alkyl, ~: to yield an enamine derivative of the formula:

, ' .

Ar-X ~ -NH-C =C-CO-NH-COOR (VII) 2/~='\R3 1~

X Rl R~ R3 R4, R5 and R are as defined above, : 7 .
; 1036604 which is then heated to yield a uracil derivative of the formula: ~ :

1 4 ~ CN (VIII) R 3 ~ .
; wherein Ar, X, R , R2, R3, R4 and R5 are as defined above, - which optionally is isolated, and converted, by hydrolysis at elevated temperatures, into a compound of the formula:

... .
.,-..................................................................... - .
.. ;;. R1 R4 R3 CONH
Ar-X ~ ~ ~ =O . (IX) ~ R2 ~ 3 ~ NH

.- ' . -wherein Ar, X, R , R , R3, R4 and R5 are as defined above, `;
.. : which also can be optionally isolated and converted, by further hydrolysis and decarboxylation, into a compound of the formula:

: . R1 R4 R5 ~r-X~05~=o (X) ~ :~

.; ~ , , i~ wherein Ar, X, Rl, R2, R3, R4 and R5 are as defined above, which also can be optionally converted by means of alkylating ~ agents or alkenylating agents into N-alkyl or N-alkenyl com-pounds respectively.
The process also comprises the optional after steps '', of converting a nitro group to an amino group through re-duction, alkylating a hydroxy group, acylating a hydroxy or amino group, introducing a nitro group through nitration and hydrolysis of an amide or ester group.
Surprisingly, the l-aryluracils according to the present invention show a far better activity against the poultry coccid E. tenella than commercially available sub-stances known from the state of the art, such as 3,5-dinitro-toluylamide, 1-[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-`4 10 picolinium chloride hydrochloride, 3,5-dichloro-2,5-dimethyl-pyridone-4 and the complex of 4,4'-di-(nitro-phenyl)-urea and
4,6-dimethyl-2-hydroxy-pyrimidine.

In addition, they are distinguished by the fact that they are active both against coccidiosis of poultry and against coccidiosis of mammals. This breadth of action is not known in the case of commercially available agents against coccidiosis.

The compounds according to the invention thus represent an enrichment of veterinary medicine.

If, in process variant (a~, 4',2,6-trichloro-4-amino-diphenyl-ether and 3-ethoxy-acryloyl-isocyanate are used as starting materials~ the course of the reaction can be represented by the following equation:

~036604 ~ Cl- ~ -O- ~ -NH2 + C2H5o-c=c-co-Nco :;'' ~ ,,-.,.

Cl-~3-o-~ NH-c-NH-c-cll=cR-oc2H5 ~
. , .
Cl (CH,,),jC-OK~ C1-<~3-0~;3~=o + H~ ~1 ) Cl~ O- ~ _ ~ =o ~' ' C~ o~
-: ' ' ,:
If, in rcaction ~ariant (b), 4',2,6-trichloro-4- -... .
amino-diphenyl-ether and N-(2-cyano-3-ethoxy-acryloyl)-ethyl~
urethane are used as starting materials, the course of the reaction can be represented by the following equation:
.,~ ''"'' N
C2H50-CH=C-CO-NH-COOC2H5 + Cl- ~ -O-".' C~
.

C~ CN
- C2H50H ~ ,;~3-NH-CH=C-Co-NH-CooC2H5 ~; _ ..
, - 10 -~' . . .

10366~4 .
- Cl C~
> Cl- ~ -O ~ ~ hydrolysls Cl . .
,4 . Cl- ~ -0~ ~ 2 hydrolysi~

~=~J ~ + decarbo~yl-~/ ation '' .

cl- ~3 -o~ =o ,, .
As noted above, Ar is an optionally substituted aryl group, with 6 to 10 ring carbon atoms. Phenyl, naphthyl and tetrahydronaphthyl can be mentioned as examples. This aryl group may be substitu~ed or unsubstituted. When sub-stituted, there can be one, two or three substituents, which ~ may be the same or diferent. These substituents include ; 10 alkyl, preferably with 1 to 8, especially 1 to 4, carbon atoms, such as methyl, ethyl, n- and i-propyl, n-, i- and t-butyl and the like; alkoxy with, preferably, 1 to 6, . ~
; especially 1 ~o 4, carbon atoms, such as methoxy, ethoxy, n- and i-propoxy; and n-, i- and t-butoxy; alkenyloxy with from 2 to 6 carbon atoms, such as allyloxy, crotyloxy and :.' . .

: ~:

... . . . .~ , . . . -, . .. . . .

~Q3~6Q4 : :
methallyloxy; alkylthio with preferably 1 to 6, especially - 1 to 4, carbon atoms, such as methylthio, ethylthio, n- and i-propylthio, allylthio and n-, i- and t-butylthio; alkenyl-thio with from 2 to 6 carbon atoms,such as crotylthio and methallylthio; halogenoalkyl with preferably 1 to 4, and especially 1 or 2, carbon atoms and preferably 1 to 5, ~:
especially 1 to 3, halogen atoms, wherein the halogen atoms are identical or different and are preferably fluorine, chlorine - --- or bromine, especially fluorine, such as trifluoromethyl; ::
10 hydroxyl; acyloxy particularly alkanoyloxy of 2 to 4 carbon .
atoms, such as, for example, acetoxy; methanesulphonyloxy; .
benzenesulphonyloxy; aryIoxy such as phenoxy, 4-chlorophenoxy . : .
and 4-bromophenoxy; acyl, particularly alkanoyl of 2 to 6 carbon atoms, such as acetyl and propionyl as well as benzoyl;
halogeno, preferably fluorine, chlorine, bromine and iodine, especially chlorine, bromine and iodine; cyano; nitro; amino;
acylamino such as acetylamino, propionylamino, benzoylamino and 4-chloroben~oylamino, benzenesulfonylamino and N-acetyl-N-methylamino; monoalkylamino and dialkylamino with preferably 1 to 4, especislly 1 or 2, carbon atoms per alkyl group, such as methylamino, dimethylamino, methylethylamino, n- and i-propylamino and methyl-n-butylamino; carboxyl; carbalkoxy with preerably 2 to 4, especially 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy; amidocarbonyl, monoalkylamido-carbonyl, dialkylamidocarbonyl and arylamidocarbonyl; sul-` fo (-S03H); amidosulfonyl; monoalkylamidosulfonyl; dialkyl-~ amidosulfonyl; arylamidosulfonyl; alkylsulfonyl such as ` - - 12 -.

`~` 1~136604 methylsulfonyl, chloromethylsulfonyl and ethylsulfonyl; and arylsulfonyl such as phenylsulfonyl and 4-chlorophenylsulfonyl.
R , R , R3 and R4 can be the same or different and include: hydrogen; straighL-chain or branched alkyl with preferably 1 to 6, especially 1 to 4, carbon atoms, of which methyl, ethyl, n- and i-propyl and n-, i- and t-butyl can be mentioned as examples; halogeno, especially chlorine, bromine and iodine; alkoxy with 1 to 3 carbon atoms, especially methoxy and ethoxy; nitro; acylamino with preferably 2 to 6, especially with 2 to 4 carbon atoms, of which acetylamino, propionyl-; amino and butyrylamino may be mentioned as examples; cyano;
alkoxycarbonyl with preferably 1 to 6, especially 1 to 4, carbon atoms in the alkoxy part, of which methoxycarbonyl and ethoxy-carbonyl may be men~ioned as examples; and trifluorometllyl.
The radicals R8, R9, R8 and R9 can in each case be identical or different and represent hydrogen, straight-chain or branched alkyl with preferably 1 to 6 carbon atoms; alkenyl with preferably 3 to 4 carbon atoms, of which allyl, methallyl and crotyl may be mentioned as examples, or aryl, particularly ; 20 phenyl and chlorophenyl; alternatively, R8 and R9 and R8 and, 9' R together with the nitrogen atom to which they are co~oined form a saturated or unsaturated heterocyclic ring. The hetero--~ cyclic ring can contain 1 to 3 further hetero-atoms, preferably 1, such as a oxygen, sulfur, nitrogen, S02 or N-alkyl group, wherein alkyl of the N-alkyl group preferably contains 1 to 4, ; especially 1 or 2, carbon atoms. Methyl, ethyl, n- and i-:'. :' ' "`~ " . :.

~' ' , ~ .

...

3660~
propyl and n-, i- and t-butyl may be mentioned as examples i , of alkyl groùps. The heterocyclic ring will contain 5 to 7, preferably 5 or 6, ring members which will be carbon atoms when not a hetero group. The 6-membered heterocyclic ring preferably contains the hetero-atom or the hetero-group in the position para to the amine nitrogen atom or amide nitro-gen atom. Pyrrolidine, piperidine, hexamethyleneimine, morphol~ne, thiomorpholine and N-methylpiperazine may be --mentioned as examples of the heterocyclic ring.
R10, Rll and R 2 preferably rep~esent straight-chain or branched alkyl with preferably 1 to 6, especially ; 1 to 4, carbon atoms, Methyl, ethyl, n- and l-propyl and ;
. n-, i- and t-butyl may be mentioned as examples.
- The compounds of the formula II which can be used according to the invention are known or can be manufactured according to known methods. The following may be mentioned as examples: 4-bromo-4'-amino-diphenyl-ether, 4-~odo-4'-amino-diphenyl-ether, 2,6-dichloro-4-amino-diphenyl-ether, 4',2-dichloro-4-amino-diphenyl-ether, 4',2,6-trichloro-4-amino-di-phenyl-ether, 3',4',2,6-tetrachloro-4-amino-diphenyl-ether, .
4'-bromo-2,6-dichloro-4-amino-diphenyl-ether, 4'-chloro-2,3,5, . ,.
6-tetramethyl-4-amino-diphenyl-ether, 4'-fluoro-2-bromo-4-amino-diphenyl-ether, 4'-iodo-2,6-dimethyl-4-amino-diphenyl-ether, 4'-chloro-2,6-diethyl-4-amino-diphenyl-ether, 4'-tert.-butyl-2,6-dichloro-4-amino-diphenyl-ether, 4'-phenyl-2-iodo-4-amino-diphenyl-ether, 4'-phenoxy-2,6-dichloro-4-amino-diphenyl-ether, 4'-(4"-chloro-phenoxy)-2,6-dichloro-4-amino-diphenyl-ether, 4'-cyano-2,6-dichloro-4-amino-diphenyl-ether, 4'-cyano-; .
', , ': ' .. - . . . . . -. . .. - . ~

2,6-dibromo -4-amino-diphenyl-ether, 4'-cyano-2-chloro-6-iodo-4-amino-diphenyl-ether, ~'-nitro-2,5-dimethyl-4-amino-diphenyl-ether, 2'-isopropoxy-2,~-dichloro-~-amino-diphenyl-ether, 4'-methoxy-2,6-dichloro-4-amino-diphen.yl-ether, 4'-allyloxy-2,6-dibromo-4-amino-diphenyl-ether, 3',4'-diethoxy-2-methyl-6-bromo-4-amino-diphenyl-ether, 2',6'-dichloro-4-amino-diphenyl-ether, 2',6'-dimethyl-2,6-dichloro-4-~mino-diphenyl-ether, 2', 6'-diisopropyl-2-bromo-4-amino-diphenyl-ether, 2',4',6',2,6-. pentachloro-4-amino-diphenyl-ether, 4'-methyl-2'-chloro-2-bromo-4-amino-diphenyl-ether, 4'-d1methyl-amidosulphonyl-2,6-dichloro-4-amino-diphenvl-ether, 4'-pyrrolidinosulphonyl-2,6-dichloro-q-amino-diphenyl-ether, 4'-morpholinosulphonyl-2,6-dimethyl-4-amino-diphenyl-ether, 4'-dimethylamidocarbonyl-2-chloro-6-methyl-~-amino-diphenyl-ether, 4'-methylsulphonyl-2,6-dibromo-~-amino-diphenyl-ether, 4'-bromo-2-methylsulphonyl-4-- amino-diphenyl-ether, 4'-bromo-2-methoxy-6-chloro-4-amino-dip~cnyl-elhe., 4'-~et'.lyl3-ulphu~lyl~y-2,6-diDromo-4-amino-diphenyl-ether, 2',4'-dichloro-2-nitro-4-amino-diphenyl-ether, 4'-bromo-2-dimethylamidosulphonyl-4-amino-diphenyl-ether, 4'-chloro-3',5'-dimethyl-2-trifluoromethyl-4-amino-dipheny] -ether, . 3',4'-dichloro-2-acetyl-amino-4-amino-diphenyl-ether, 4'-chloro-. 2-methoxy-6-chloro-4-amino-diphenyl-ether, 4'-nitro-2-chloro-6-bromo-4-amino-diphenyl-ether, 4'-isooctyl-2,6-dichloro-4-; amino-diphenyl-ether, 2',4'-dichloro-2-methoxycarbonyl-4-amino-diphenyl-ether, 4'-trifluoromethylsulphonyl-2,6-dichloro-4-amino-diphenyl-ether, 4'-phenylthio-2,6-dimethyl-4-amino-di-phenyl-ether, 2',4'-dimethyl-2-chloro-6-bromo-4-amino-diphenyl- .
ether, 2',5'-dichloro-2-isopropyl-4-amino-diphenyl-ether, 4'-chloromethylsulphonyl-2,6-dichloro-4-amino-diphenyl-ether, 4'-bromo-2-cyano-4-amino-diphenyl-ether, 4'-chloro-2-bromo-6-methyl-~-a~l1no-~iphenyl-ether, ~',5',2,6-tetrachloro-4'-hydro~y-~ , : - 15 - -, :

.. . . .. . ... . . . . . . . ..

103660~
4-amino-diphenyl-ether, 3l-methyl-4l-dimethylamino-2~6-dichloro- :

4-amino-diphenyl-ether, 4'-(2"-oxo-pyrrolidinyl-(1"))-2,6-di-chloro-4-amino-diphenyl-ether, 4'-diethylamino-2,6-dichloro-4-amino-diphen~l-ether, 4'-methylsulphonyl-2,6-dichloro-4-amino-diphenyl-ether, 4'-hydroxy-2,6-dichloro-4-1mino-diphenyl-ether, 4'-acetylamino-2,6-dimethyl-4-amino-diphenyl-ether, 2',4'-di- : -nitro-2,6-dichloro-4-amino-diphenyl-ether, 4'-benzoylamino- -2,6-dichloro-4-amino-d phenyl-ether, 4'-(l"-naphthyl)-2,6-di-methyl-4-amino-diphenyl-ether, 4'-(2"-naphthyl)-2,6-dichloro- ~ .

4-amino-diphenyl-ether, 4'-(l"-chloro-2"-naphthyl)-2,6-di-chloro-4~amino-diphenyl-ett~er, 4'2,6-tribromo-4-aminodiphenyl-ether, 4'-iodo-2,6-dibromo-4-aminodiphenyl-ether, 4',2,6-triiodo-4-aminodiphenyl-ether, 4'-bromo-2,6-diiodo-4-aminG-diphenyl-ether, 4'-chloro-2,6-diiodo-4-amino-diphenyl-ether, 4'-fluoro-2,6-diiodo-4-amino-diphenyl-ether, 4'-bromo-4-amino-, . .
diphenyl-sulphide, 4'-nitro-2-chloro-diphenyl-sulphide, 4',2,6-: tlichlor~ -~nino-diphenyl-sulphlde, 4i-methyl-2,6-dibromo-4-:. amino-diphenyl-sulphide, 4'-tert.-butyl-2,6-dichloro-4-amino-diphenyl-sulphide, 4'-acetylamino-2,6 dichloro-4-amino-diphenyl-sulphide, 4l-benzoylamino-2-methyl-6 chloro-4-amino-diphenyl-sulphide, 2'-propionylamino-2,6-dichloro-4-amino-diphenyl-sulphide, 4'-dimethylamidosulphonyl-2-bromo-4-amino-diphenyl-. sulphide, 4'-morpholinosulphonyl-2,6-dibromo-4-amino-diphenyl-sulphide, 4'-chloro-2-trifluoromethyl-4-amino-diphenyl-sulphide, 4'-nitro-2,6-dichloro-4-amino-diphenyl-sulphide, 2',4'-dichloro-. 2-nitro-4-amino-diphenyl-sulphide, 4'-chloro-2-dimethylamino-' sulphonyl-4-amino-diphenyl-sulphide, 4'-methylsulphonyl-2,6-dibromo-4-amino-diphenyl-sulphide, 4'-chloro-2,3,5,6-tetra-methyl-4-amino-diphenyl-sulphide, 4'-methyl-2,6-dichloro-4-amino-diphenyl-sulphoxide, 4'-chloro-2,6-dimethyl-4-amino-di-; phenyl-~ulphoxide, 4'-2,6-tri~hloro-4-amino-diphenyl-sulphoxide, ;.

. .

.. . . ..
.. . . . ~ . :

1~366(~-~
4'-dimethylaminosulphonyl-2,6-dichloro-4-amino-diphenyl-sul-phoxide, 4'-bromo-2,6-dichloro-4-amino-diphenyl-sulphone, 4'-acetylamino-2-bromo-4-amino-diphenyl-sulp~1one, 4',2,6-trichloro-4-amino-diphenyl-sulphone, 4'-bromo-2,6-dichloro-4-amino-di-phenyl-sulphone, 4'-methyl-2,6-dichloro-4-amino-diphenyl-sul-phone and 4'-phenyl-2-chloro-4-amino-diphenyl-sulphone.
The 3-alkoxy-acryloylisocyanates of the general formula III which can be used according to the invention are known or can be manufactured according to known processes, such as, for example, by reaction of the corresponding 3-alkoxy-acrylic acid c~,lorides with silver cyanate or by reaction of the correspond-; in~ 3-alkoxy-acrylic acid amides with oxalyl chloride. The following may be mentioned as examples of 3-alkoxy-acryloyl-isocyanates III: 3-ethoxy-acr,ylic acid isocyanate, 3-methoxy-acrylic acid isocyanate, 3-isopropoxy-acrylic acid isocyanate, 3-methoxy-methacrylic acid isocyanate, ~-ethoxy-methacrylic aciu iso~y~rl~e, J-eihoxy-crotonic acid isocyanate, 3-methoxy-~ crotonic acid isocyanate, 3-butoxy-crotonic acid isocyanate, ;; 3-ethoxy-2-methyl-crotonic acid isocyanate, 3-ethoxy-2-ethyl-crotonic acid isocyanate, 3-ethoxy-2-allyl-crotonic acid iso-cyanate and 3-methoxy-2-butyl-crotonic acid isocyanate.
The compounds of the formula VI which can be used according to t~,e invention in process variant b) are known or can be prepared according to known methods, for example by '; reaction of ortho-formic acid trialkyl esters with cyanoacetyl-, urethanes. N-(2-Cyano-3-ethoxy-acryloyl)-uret~,ane and N-(2-cyano-3-methocy-acryloyl)-urethane may be mentioned as examples.
; In process variant a), compounds of the formula II are reacted with those of the formula III in the molar ratio of l : l, preferably in solvents which are inert towards isocya-nate~, for example in hydrocarbons or chlorinated hydrocarbons '' '- : "

1036f~04 such IS benzene, toluene, white spirit, petroleum ether, di-chloroml~thanc, chloroform or carbon tetrachloride or ethers ~ .
such as diisopropyl ether, tetrahydrorurane, dioxane or 1,2-dimethoxyethane.
If the 3-alkoxy-acryloylisocyanates of the formula III
have been manufactured from ~-alkoxy-acrylic acid chlorides and silver isocyanates, the crude isocycmate solutions, which still contain silver salts, can be used for the reaction. The forma-tion of tlle urea derivatives IV from the components II and III

takec place readily, the reaction being exothermic. In general, temperatures of 20 to 40C are maintained by cooling, ~ut if the reaction is slowed down by the low solubility of the com-ponent II, it can be accelerated by warming, for example to 60 - 120C. The urea derivatives of the general formula IV, thus prepared, are generally sparingly soluble in the solvents -~ state~ and can be isolated in good yields. Silver salts which are also present in the products and originate from the prep-` ~ aration of the 3-alhoxy-acryloylisocyanates can be purified by recrystallisation, if appropriate with conjoint use of weak ; 20 reducing agents such as copper, iron or zinc powder or reducing salts such as sodium sulphite or sodium borohydride, from polar solvents such as dimethylformamide, dimethylsulphoxide, hexamethylphosphoric acid triamide, N-methyl-pyrrolidone or tetramethylurea.
~ ~he cyclization of the l-aryl-3-acryloyl-ureas of the general formula IV, thus obtained, to give the l-aryl-uracil~
., - . , .
i` of the general formula I, according to the invention, can be ` ~ carried out either in alkaline aqueous solution or aqueous-~ alcoholic solution at ~H 8 to pH 12, preferably pH 9 to pH 11.

; 30 Alternatively, cyclisation by treatment with alkali metal alkoxides, preferably with potassium tert.-butylate, i9 al~o .

: , . .. . .

~' 1o36604 possible. For this purpose, the urea derivative IV, in tert.-butanol, is heated with an equivalent amount of potassium tert.-butylate under reflux, the solvent is distilled off completely and the residue is heated to temperatures of up to 150C, preferably up to 120C, in vacuo. The potassium salts of the l-aryl-uracils, thus obtained, are in some cases readily water-soluble and the compounds can be precipitated in the free form by dissolving the salts in hot water and acidifying the solution. However, the salts can also be converted to the l-aryl-~-alkyl-uracils by reaction with alhylating agents or alkenylating agents, such as methyl chloride, -ethyl bromide, isopropyl iodide, allyl bromide or n-butyl iodide, in polar solvents, such as dimethylformamide, acetonitrile, acetone or -~
ethanol.
In process variant b), compounds of the formula II are reacted with cornpounds O r the formula VI hy w~.rmi n~ equim.n1ar ~ . :
amounts of the components, in solvents, to temperatures of 40 -~
to 120C, pr~ferably 60 to 100C. ~uitable solvents are polar organic solvents, for example methanol, ethanol, tetrahydro-furane, acetone and 1,2-dimethoxyethane.
,;
This reaction gives the enamines of the general for-j: .
! ` mula VII.
The compounds of the formula VII are cyclised to ura- ;
cil derivatives of the general formula VIII by heating in sol-vents, or preferably in the melt, to temperature~ of 150 to 280C, preferably to 180 - 250C, with elimination of the ~ alcohol R120H, for example ethanol or methanolO
; The nitrile~ of the formula VIII are then hydroly~ed, and decarboxylated, by treatment with mineral acids at temp-; 30 ~r~ re~ of 1~0 +^ ~0~, pr^4^..a~.y ~ ' tU ^VUO~. rreferably, ~ the hydrolysis and decarboxylation is carried out in one step .' 19 . .
.:

'1~36604 by heatin~ with 60 to ~oo~0 strength sulphuric aeid. However, if desired, the hydrolysis of the nitrile group can also be earried out stepwise, with intermediate isolation of the eorre-- sponding earboxylic acid ami~e or carboxvlic acid. Fer tkis purpose the nitrile VII is warmed, for example with 48C/o strength hydrobromie acid, or hydrobromic acid/phosphoric acid mixtures, to temperatures of 120 to 150C.
~he majority of the starting compounds of the formula (II) employed in reaction variant a) and b) are not previously ~ -~0 known.
However, they can easily be prepared by reduction o~
the correspondin~ nitro compounds (N) R1 R4 R1 ~4 Ar-X ~ NO Reduetion ~ Ar X ~ NH2 (II) R R3 ~2 ~ R3 , ; Customary methods of reduction are here:
l) Catalystic reduetion on Raney niekel or noble metal catalysts.
; 2) Reduetion with tin-II ehloride.
3) Reduetion with iron by the Beehamps method.
Literature: "Methoden der organisehen Chemie" ("Methods of - 20 Organie Chemistry") (Houben-Weyl), volume ll/l, page 360 - 472.
Nitro eompounds of the formula N, in whieh X repre-sents O ot S, are suitable obtained from the eorresponding phenolates or thiophenolates of the formulae Ar-O ~ Me ~ or Ar-S ~ Me~ , respectively, in which Me ~ represents a mono-valent cation, by reaction with 4-nitro-l-halogenobenzenes -~h~rh ~ r+'^na ~y Su~s~ i ~Ut_u îu~ h~r~ bne reaetants pre- ~ ~
; ' , . .

1~)366~)4 ferably bein~ re~cted in the equimolar ratio, in an inert organic solvent, at temperatures between -10 an~ +60C, pre-ferably 0 to 40C.
The followin~ may be mentioned indivi.du~lly as new active compounds: 1-[3-chloro-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point: 217 to 218C; 1-[3,5-dimethyl-4-(4'-chlorophen~lthio)-phenyl]-uracil, meltin~ point: 184 to 1~6C; 1-[3,5-dibromo-4-(4'-chloro-phen~lthio)-phenyl]-uracil, melting point: 265 to 26~C (with decomposition); 1-[3-bromo-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point:
230 to 231C (with decomposition); 1-[3-methyl-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point: 217 to 218C; 1- ~ -[4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point: 207 ~ ~
to 209C; 1-[3,5-dichloro-4-(4'-chloro-phenylthio)-phenyl]- : :
uracil, melting point: 2c2 to 225C; 1-[3-chloro-4-(4'-chloro-phenylthio)-phenyl]-5-methyl-uracil, melting point: 252 to 254 ~ ,5-dichloro-4-~4'-chloro-phenoxy)-phenyl~-uracil, :~:
melti~g point: 271 to 272C; 1-[3-chloro-4-(4'-chloro-phenoxy) -phenyl]-uracil, melting point: 263 to 265C; 1-[3,5-dichloro- :~

4-(4'-chloro-phenoxy)-phenyl]-5-methyl-uracil, melting point:
155 to 156C; 1-[3,5-dichloro-4-(4'-chlorophenoxy)-phenyl]-6-methyl-uracil, melting point 270 to 273 1-[3-ohloro-4-(1'- ~ :
naphthoxy)-phenvl]-uracil, melting point: 200 to 202C; 1-[3-chloro-4-(2'-naphthoxy)-phenyl]-uracil, melting point 208 to 209C; 1-[3-chloro-4-(2',6'-dimethyl-phenoxy)-phenyl]-uracil, melting point: 222 to 224C; 1-~3,5-dichloro-4-(2',6'-dimethyl .
-phenoxy)-phenyl]-uracil, melting point: 212 to 214C; 1-~3-chloro-4-(2',6'-diisopropyl-phenoxy)-phenyl]-uracil, melting `~:

point: 204 to 205C; 1-[3,5-dichloro-4-(2',6'dii~opropyl- .
phenoxy)-phenyl]-uracil, melting point: 210 to 212C; 1-[3- ~
5-dichloro-4-(4'-chloro-3',5'-dimethyl-phenoxy)-phenyl]-uracil, ~`

~ .
.. . - - ,~,.. . : . ~ . :- . . : .. !

melting point: 228 to 230C; 1-[3-chloro-4-(4'-phenyl-pheno~y) -phenyl]-uraeil, melting point: 255 to 256C; 1-[3-chloro-4-(4'-chloro-3',5'-dimethyl-phenoxy)-phen~l]-uracil, melting point: 257 to 258C; 1-~3,5-dichloro-4-(1'-naphtho~y)-phenyl]-uraeil, melting point: 249 to 251C; 1-[3,5-diehloro-4-(2'-naphtho~y)-phenyl~-uraeil, melting point: 247 to 249C; 1-~3, 5-dichloro-4-(4'-bromo-phenoxy)-phenyl]-uracil, melting point 288 to 290C; 1-[3,5-diehloro-4-(4'-<4"-ehloro-pheno~
phenoxy)-phenyl]-ur.~cil, melting point: 250 to 252C; 1-[3,5-dichloro-4-(4'-phenyl-pheno~y)-phenyl]_uracil, melting point:
237 to 238C; 1-[3,5-dichloro-4-(2',6'-dichloro-phenoxy)- :
phenyl]-uracil, melting point: 238 to 240C; 1-[3,5-diehloro- ::
4-(4'-tert-butyl-phenoxy)-phenyl]-uracil, melting point: 249 to 251C; 1-[3,5-dichloro-4-(4'-isooctyl-pheno~y)-phenyl]- :~
uracil, melting point: 215 to 217C; 1-¦3,5-dichloro-4-(2', ~: -.
` 4',6'-trichloro-phenoxy)-phenyl]-uracil, melting point: 282 to : :
-~ 283C; l-l3,5-dichloro-4-(3'-methyl-4-methylmercapto-phenoxy)-~,; .
phenyl]-uraeil, melting point: 240 to 241C; 1-[3,5-dichloro-4-(4'-phenoxy-phenoxy)-phenyl]-uracil, melting point: 272 to -~ 20 278C (with decomposition); 1-[3,5-dichloro-4-(3'-methyl-4'-dimethylamino-pheno~y)-phenyl~-uraeil, melting point: 194 to - 196C; 1-[3,5-diehloro-4-(4'-hydro~y-phenoxy)-phen~l]-uraeil, melting point: 300 to 302C; 1-[3,5-dichloro-4-(4'-bromo-phenoxy)-phenyl]-5-methyl-uraeil, melting point: 258 to 260C;
1-[3,5.dibromo-4-(4'-ehloro-phenoxy)-phenyl]-5-methyl-uraeil, -melting point: 261 to 263C; 1-[3,5-diehloro-4-(4'-dimethyl- ~
amidoisulphonyl-phenoxy)-phenyl]-uraeil, melting point: 286 to ~-289C (with deoomposition); 1-[3,5-diehloro-4-(2',4'-dinitro-phenoxy)-phenyl]-uraeil, melting point: 284 to 286C (with deeomposition); 1-[3-dimethylamidosulphonyl-4-(2',4'-di-ehloro-phenoxy)-phenyl]-uraeil, melting point: rJ 140C (with .,'' .

;..

~036604 decomposition); 1-[3,5-dibromo-4-(4'-chloro-phenoxy)-phenyl]-: uracil, melting point: 288 to 290C; 1-[3,5-dibromo-4-(4'-bromo-phenoxy)-phenyl]-uracil, melting point: 302 to 304C;
1-[3-cyano-4-(2',4'-dichlorophenoxy)-ph~nyl]-uracil, melting point: 28G to 282C; 1-[3,5-dimethyl-4-(4'-chloro-phenoxy)- :.
: phenyl]-uracil, melting point: 231 to 233C; 1-[3-chloro-5-methyl-4-(4'--chloro-phenoxy)--phenyl]-ura~il9 melting point:
. 216 to 218C; l-L3,5-dichloro-4-(4'-iodo-phenoxy)-phenyl]- ' ;
uracil, melting point: 291 to 293C (with decomposition); ~ ~
1-[3,5-dichloro-4-(4'-acetyl-phenoxy)-phenyl]-uracil, melting ~ :
~: point: 243 to 245C; 1-[3,5-diiodo-4-(4'-iodo-phenoxy)~
phenyl]-uracil, m~lting point: 297 to 298C; 1-[3,5-dibromo-4-(4'-iodo-phenoxy)-phenyl]-uracil, melting point: 308 to :~
. 310C (with decomposition); 1-[3,5-dichloro-4-(4'-phen!rl~
sulphonyl-phenoxy)-phenyl]-uracil, melting point: 153 to 155C;
1-[3,5-diiodo-4-(4'-brQm.o-pher.o~y)-pha.. yl~--url~ii, melting :~
; point: 285 to 287C; 1-[3,5-dibromo-4-(4'-fluoropheno~y)-phenyl]-uracil, melting point: 269 to 271C; 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-3-methyl-uracil, melting point:

178 to 179C; 1-[3,5-diiodo-4-(4'-chloro-pheno~y)-phenyl]-. uracil, melting point: 294 to 296C; 1-~3,5-dichloro-4-(4'-chloro-2'-nitro-phenoxy)--phenyl]-uracil, melting point: 182 to :
184C; 1-[3,5-dichloro-4-(4'-methyl-~ulphonyl-pheno~y)-phenyl]-:; uracil, melting point: 296 to 297C (~ith decompo~ition), 1-[3,5-dichloro-4-(4'-bromo-3'-chloro-pheno~y)-phenyl]-uracil, melting point: 256 to 258C; 1-[3,5-dichloro-4-(3',5'-di-chloro-phenoxy)-phenyl]-uracil, melting point: 193 to 196C;
1-[3,5-dibromo-4-(3'-chloro-5'-methyl-pheno~cyl-phenyl]-uracil, melting point: 206 to 208C; 1-[3-chloro-5-bromo-4-~4'-chloro-30 nhc~nr~y ~-~h.C.~ J-5-me:'~.hj'i-UraCil ~ l-L3-iOdO-4- ( 4 ~ -chloro-.''~'' ' ~
- 23 - ;
~;: . ~' ''' 1g366Q4 phenoxy)-phenyl]-uracil; 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-5~6-dimethyl-uracil; 1-[3,5-dichloro-4-(4'-bromo-phenoxy)-phenyl]-3-methyl-uracil; 1-~3,5-dibromo-4-(3',4'-dichloro-phenoxy)-phenyl]-3,5-dimethyl-uracil; 1-[3,5-dibromo-4-(2',4'-dichloro-phenoxy)-phenyl]-3,6-dimethyl-uracil; 1-[3, 5-dimethyl-4-~4'-bromo-phenoxy)-phenyl]-uracil; 1-[3-methyl-4-(3',5'-dimethyl-phenoxy)-phenyl]-uracil; 1-[2-methyl-5-bromo-4-(2',4'-dichloro-phenoxy)-phenyl]-uracil; 1-[3,5-di- :
bromo-4-(4'-fluoro-phenoxy)-phenyl]-3-allyl-uracil; 1-[3-ethyl-4-(2'-tert.-butyl-phenoxy)-phenyl]-uracil; 1-~3-isopropyl-4~
(4'-chloro-3'-methyl-phenoxy)-phenyl]-uracil; 1-[3,5-dichloro- ~: :.
4-(4'-methylsulphonyloxy-phenoxy)-phenyl]-uracil; 1-[3-bromo-4-(4'-n-butyl-phenoxy)-phenyl]-uracil; 1-[3-chloro-4-(4'-..
: hydro~y-3l,5'-dichloro-phenoxy)-phenyl]-uracil; 1-[3,5-di-. ; , bromo-4-(4'-nitro-phenoxy)-phenyl~-uracil; 1-[3,6-dimethyl-4-(3'-chloro-phenoxy)-phenyl]-uracil; 1-[3-chloro-5-methyl-4-(4'-cy~no-nhPnoY.y)-rhcny']-ulacil, i-~3-cnioro-5-bromo-4-(4~
dimethylamido-sulphonyl-phenoxy)-phenyl]-uracil; 1-[3-dimethyl-amido-sulphonyl-4-(2',4',5'-trichloro-phenoxy)-phenyl]-uracil;
1-[3-acetylamino-4-(2',4'-dimethyl-phenoxy)-phenyl]-uracil;
1-[3-nitro-4-(4'-methyl-phenoxy)-phenyl]-uracil; 1-[3-dimethyl-amidocarbonyl-4-(4'-bromophenoxy)-phenyl]-uracil; 1-[3-tri-fluoromethyl-4-(4'-methyl~ulphonyloxy-phenoxy)-phenyl]-uracil; ;~-1-[3,5-dibromo-4-(4'-diethylaminophenoxy)-phenyl]-uracil; 1-[3, 5-dichloro-4-(4'-allylthio-phenoxy)-phenyl]-uracil; 1-[3,5-di-. "., ! ~ ~
~ chloro-4-(4'methylsulphinyl-pheno~y)-phenyl]-uracil; 1-[3,5-., dibromo-4-(4'-dimethylamino-3'-methyl-phenoxy)-phenyl]-uracil;
1-[3-bromo-5-methyl-4-(4'-diethylamidocarbonyl-phenoxy)-phenyl]-uracil; 1-[3-bromo-5-ethyl-4-(2'-i~opropoxy-phenoxy)-phenyl]-uracil; 1-[2-chloro-4-(4'-phenoxy-phenoxy)-phenyl]-uracil;
. ., 2 -me ~hy ~ 4 ' - <4 -cnloro-phenoxy> -pheno~y)-phenyl]-uracil;
. 1-[3,5-dibromo-4-(1'-naphthoxy)-phenyl]-uracil; 1-[3-chloro- ~:

., lQ36604 5-methyl-4-(2'-naphtho~y)-phenyl]-uracil; 1-[3-chloro-4-(1'-chloro-2'-naphthoxy)-phenyl.]-uracil; 1-[3-bromo-5-iodo-4-(4'- .
phenyl-phenoxy)-phenyl]-uracil; 1-~3-chloro-4-(4'-phenylthio-. phenoxy)-phenyl]-uracil; 1-[3,5-dichloro-4-(4'-benzoylamino- ~;
pheno~y)-phenyl]-uracil; l-[~-bromo-4-(4'-benzenesulphonyl-amino-phenoxy)-phenyl]-uracil; 1-[3-bromo-4-(4'anilidocarbonyl-ph~no~y)-phenyl]-uracil; 1-[3,5-dichloro-4-(4'-fluoro-pheno~y)~
phenyl]-uracil; 1-[3,5-dichloro-4-pheno~y-phenyl]-uracil;

,5-dichloro-4-(2',4',5'-trichloro-phenoxy)-phenyl]-uracil;

1-[3,5-dichl~ro-4-~2',4'-dimethyl-phenoxyj-phenyl]-uracil;
1-[3,5-dichloro-4-(3',5'-dichloro-4'-hydroxy-pheno~y)-phenyl]- ... .
uracil; 1-[~,5-dichloro-4-(4'-propionyl-amino-pheno~y)-phenyl]~
. ur~cil; 1-[3,5-dichloro-4-(4'-nitro-2'-chloro-phenoxy)-phenyl]- `:
ur~cil; 1-[3-chloro-5-meth~1-4-(4'-methyl~ulphonyl-o~y-pheno~y)- .-~
. phen~l.]~uracil; 1-[3,5-dichloro-4-(4'-piperidyl3ulphonyl- :
: phenoxy)-phenyl]-uracil; 1-[3,5-dichloro-4-(4'-~im.ethyl-~mido-carbonyl-amino-phenoxy)-phenyl]-ur3cil; 1-[3,5-dichloro-4-(4'-. cyano-2'-chloro-phenoxy)-phen~-1]-uracil; 1-[3,5-dibromo-4-(4'- ..
phenylsulphonyl-pheno~y)-phenyl]-ura.cil; 1-[3,5-dichloro-4-(1'-; chloro-2'-naphtho~y)-phenyl]-uracil; 1-[3,5-diiodo-4-(4'-.. ~ fluoro-phenoxy)-phenyl]-uracil; 1-[3,5-dichloro-4-(4'-methoxy-phenoxy)-phenyl]-uracil; 1-[3-bromo-5-methyl-4-(4'-ethylsul-phonyl-pheno~y)-phenyl]-uracil; 1-[3,5-dibromo-4-(3'-chloro-phenoxy?-phenyl]-uracil; 1-[3,5-dichloro-4-(3',4'-dimethoxy-phenoxy)-phenyl]-uracil; 1-~3,5-dichloro-4-(4'-pyrrolidinyl-~'~ -pheno~y)-phenyl]-uracil; 1-[3,5-dichloro-4~(4'- <2"-o~o-pyrrolidinyl- ~ -pheno~y3-phenyl]-uracil; 1-(3,5-dibromo-4-phenoxy-phenyl)-ur~cil; 1-[3,5-dibromo-4-(2',4'-dichloro~
. pheno~y)-phenyl]-uracil; 1-[3,5-dibromo-4-(2',4'-dimethyl- .:
30 phenoxy)- phenyl[-uracil: 1-c~;5-dibr^m^-A-(4'-n-uulyi-pnenoxyj-phenyl]-uracil; 1-[3,5-dibromo-4-(4'-dimethylamidosulphonyl- :

: - 25 -, .

` 1036604 phenoxy)-phenyl]-uracil; 1-[3,5-dibromo-4-(4'-dimethylamido-carbonyl-phenoxy)-phenyl]-uracil; 1-[3,5-dibromo-4-(4'-ethoxy- ..
pheno~y)-phenyl]-uracil; 1-[3,5-dibromo-4-(4'-allyl-oxO-phe-noxy)-phenyl]-uracil; 1-[3,5-dibromo-4-(4'-phenoxy-phenoxy)-phenyl]-uracil; 1-[3,5-dibromo-4-(4'-nitro-2'-methyl-phenoxy)- :~ ~
phen\l]-uracil; 1-[3,5-dimethyl-4-(4'-bromo-phenoxy)-phenyl]- ~ .
3-methyl-uracil; 1-[3,5-dimethyl-4-(4'-chloro-phenoxy)-phenyl]- .
5-methyl-ura.cil; 1-[3,5-dimethyl-4-(4'-cyano-phenoxy)-phenyl]-uracil; 1-[3,5-dimethyl-4-(4'-acetylaminophenoxy)-phenyl]-ura.cil; 1-[3,5-dimethyl-4-(1'-naphthoxy)-phenyl]-uracil; 1-[3, 5-dimethyl-4-(4'-phenyl-phenoxy)-phenyl]-uracil; 1-[3,5-di-methyl-4-(4'-nitro-2'-chloro-phenoxy)-phenyl]-uracil; 1-[3,5-dimethyl-4-(2',4'-dimethyl-phenoxy)-phenyl]-uracil; 1-[3,5-dimethyl-4-(3',5'-dimethyl-phenoxy~-phenyl]-uracil; 1-[3,5-dimethyl-4-(3'-methyl-4'-dimethylamidosulphonyl-phenoxy)-phenyl}
uracil; 1-[3,5-dimethyl-4-(4'-phenoxy-phenoxy)-phenyl]-ura.cil; ~.
l-l3,5-dimethyl-4-(3',5'-dichloro-4'-hydroxy-phenoxy)-phenyl]- ;~
uracil; 1-[3,5-dimethyl-4-(2'-isopropoxy-phenoxy)-phenyl]-uracil; 1-~3-chloro-5-methyl-4-(4'-bromo-~henoxy)-phenyl]-uracil; 1-[3-chloro-5-methyl-4-(4'-chloro-phenoxy)-phenyl]-5-methyl-uracil; 1-~3-chloro-5-methyl-4-(2'-chloro-phenoxy)-phenyl-]-3-methyl-uracil; 1-[3-bromo-5-methyl-4-(4'-chloro-phenoxy)-phenyl]-uracil; 1-[3-bromo-5-methyl-4-(4'-diethylamido-sulphonyl-phenoxy)-phenyl}uracil; 1-[3-bromo-5-chloro-4-(4'-bromo-phenoxy)-phenyl]-uracil; 1-[3-bromo-5-chloro-4-(4'- ::
cyano-phenoxy)-phenyl]-uracil; 1-[3-bromo-5-chloro~4-(4'-methyl-ulphonyl-pheno~y)-phenyl]-uracil; 1-(3-bromo-5-chloro-4-... . .
phenoxy)-phenyl-uracil; 1-[3-chloro-5-dimethylamidosulphonyl-. 4-(4'-chloro-phenoxy)-phenyl]-uracil; 1-[3-methoxy-5-chloro-4-.; 30 (4'bromo-pheno~y)-phenyl]-uracil; 1-~3-bromo-5-chloro-4-(4'-. phenoxy-phenoxy)-phenyl]-uracil; 1-~3,5-diiodo-4-(4'-fluoro-' -: - - . .

`` 10366Q4 phenoxy)phenyl]-uracil; 1-[3,5-diiodo-4-(4'-nitro-pheno~y)~
phenyl]-uracil; 1-[3,5-diiodo-4-(4'-cyano-phenoxy)-phenyl]- ;.
. uracil; 1-~3,5-diiodo-4-(4'-methylsulphonyl-phenoxy)-phenyl]-~ uracil; 1-[3,5-diiodo-4-(4'-dimethylamino-3-methyl-phenoxy)- ~ :~
phenyl]-uracil; 1-~3-iodo-5-bromo-4-(4'-cyano-phenoxy)-phenyl]-uracil; 1-~3-chloro-4-(4'-bromo-phenylthio-phenyl]-uracil; ~ :
1-[3-chloro-4-(4'-chloro-phenvlthio)-phenyl]-5-methyl-uracil; .. .
; 1-[3-chloro-4-(4'-cyano-phenylthio)-phenyl]-uracil; 1-[3-- chl~ro-4-(3'-methyl-4-dimethyla.minosulphonyl-phenylthio)-phenyl]-uracil; 1-[3-bromo-4-(4'-methyl-phenylthio)-phenyl]-3-methyl-ur~cil; 1-[3-bromo-4-(2',4'-dichloro-phenylthio)-phenyl]-uracil; 1-[3-methyl-4-(4'-nitro-phenylthio)-phenyl]-uracil;
3-dimethylamidosulphonyl-4-(4'-chloro-phenylthio)-phenyl]-uracil; 1-~3-chloro-4-(4'-acetylamino-phenylthio)-phenyl]-. , .
uracil; 1-[3-chloro-4-(2'-propionylamino-phenylthio)-phenyl]- .. .
uracil; 1-~3-trifluoromethyl-4-(4'-chloro-phenylthio)-phenyl]- .
.. .
ura~il, 1- [ 3-hr~m~-4- ( 4 ' -m~?thyl -ph~ny:l th i o ~ -ph ~n,vl ~-uracil ~
..
. 1-~3,5-dichloro-4-(4'-chloro-phenylthio)-phenyl]-6-methyl- .
. uracil; 1-[3,5-dichloro-4-(4'-methyl-phenylthio)-phenyl]-. 20 uracil; 1-~3,5-dichloro-4-(4'-dimethylamidosulphonyl-phenyl-.' thio)-phenyl]-ura.cil; 1-~3,5-dibromo-4-(4'-methyl-phenylthio)-. phenyl]-uracil; 1-[3,5-dibromo-4-(3'-methyl-phenylthio)-phenyl]- .
.. ` 3,5-dimethyl-uracil; 1-~3-methyl-5-chloro-4-phenylthio]-3-. methyl-uracil; 1-~3-methyl-5-chloro-4-(4'-phen-lthio-phenyl- .; .
I thio)-phen.yl]-uracil; 1-[3-methyl-5-bromo-4-(4'-chloro-phenyl- ::~
thio)-phenyl]-uracil; 1-[3-methyl-5-chloro-4-(4'-phenyl-phenyl-'. thio)-phenyl]-uracil; 1-[3-methyl-5-chloro-4-(1'-naphthylthio)- - .
phenyl]-uracil; 1-(3,5-dichloro-4-phenylsulphinyl-phenyl)- .
. uracil; 1-[3,5-dimethyl-4-(4'-chloro-phenylsulphinyl)-phenyl]-- 30 uracil; 1-~3-methyl-5-chloro-4-(4'-methyl-phenyl~ulphinyl)-' J--U.,~ L ~--~----' ' V L ~ '--'t--~ ~ --U L ~:~: V--r'~

. - 27 -.
, ~036604 phenyl]-uracil; 1-[3,5-dichloro-4-(4'-chloro-phenylsulphonyl)- -phenyl]-uracil; 1-~3,5-dibromo-4-(4'-methyl-phenylsulphonyl)- -phenyl]-uracil and 1-[3-methyl-5-chloro-4-(4'-chloro-phenyl-sulphonyl)-phenyl]-uracil.
The compounds of this invention and their salts exhibit powerful coccidiocidal effects. They are highly active against the species of coccidia of poultry, such as, for example, Eimeria tenella (coccidiosis of the appendix in chickens), E. acer w lina, E. brunett~, E. maxima, E. mitis, E. mivati, E. necatrix and E. praecox (coccidiosis of the small intestine in chickens), and can accordingly be used for the prophylaxis and treatment of coccidiosis infections ; of poultry. In addition, the new active compounds are dis-tinguished by a very powerful activity in coccidial infections of other animals, particularly mammals, such as, for example, ` of rabbits such as E. stiedae (coccidiosis of the liver), E.
ma~na, E. media, E. irresidua and E. perforans (coccidiosis of the intestine), of sheep, cattle and other domestic animals, including dogs and cats, and of laboratory animals such as white mice ~. falciformis) and rats.
In addition, the compounds have activity against toxoplasmosis and can be employed bo~h for the treatment of the cats which excrete the infectious stages (oocysts) and for the treatment of the infected humans.
Coccidial infections can lead to severe losses in the case of domestic animals and represent a significant problem, especially in raising poultry and mammals such as cattle~ sheep, rabbits and dogs. The action of the previously - ~8 -known agents against coccidiosis in poultry is, in mos~ cases, restricted to but a few species. The treatment and prophy- ;~
laxis of coccidiosis in mammals hitherto represents a largely unsolved problem.
The compounds of this invention can be adminis-tered to livestock in a variety of formulations, such as in premixes for administration with the feed, in drinking water, and in pour-on formulations. While the compounds are, as a ;
rule, most suitably administered in this fashion, namely with the feed or in the drinking water, the compou~ds can also be administered to individual animals in the form of tablets, medicinal drinks, capsules or the like, or by in-~ ~ection? These last-mentioned methods of administration are, ; of course, less suitable for the treatment of a large number ` of animals than for the treatment of a limited number of ;-animals; however, they are very suitable for administration to a small number of animals or to individual animals.
,.;. . ,~ ' ! .
The invention thus includes compositions contain-ing the l-aryluracil and a carrier. This includes a medi-cated fodder comprising the compound and a nutri~ious mater-ial. A medicated fodder according to the invention is usually prep~red by thoroughly mixing about 10 to 2,000, preferably about 25 to 250, ppm of active compound with a nutritionally balanced feed, for example with the chick feed described below.
To prepare a concentrate of a premix which is in-tended Ior ultlmate dilution witn the feed to the above-.

~ , :

` 1036604 . mentioned values, generally about 1 to 30%, preferably about 10 to 30 per cent by weight, of active compound are mixed with an edible organic or inorganic excipient, as for example corn flour, a mixture of corn and soya bean meal or mineral salts which contain a small amount of an edible dust-suppres-sant oil, for example corn oil or soya bean oil. The premix is then added to an otherwise complete feed before the latter is made a~ailable to the livestock. The following composition :
is an example of the use of the compounds according to the invention in poultry feed:
52.000% of s'nredded cereal feed ; 17.995% of shredded soya 5.000% of corn gluten feed 5.000% of wheat wholemeal 3 ~ ûuû ;o u i I LS I.I iut:~ l ., .
- . 3.û00% of tapioca meal . .
. 3.0ûû% of green lucerne meal , 2.û00% of comminuted wheat germ . 2.000% of soya oil .~ .!0 1.600% of fishbone meal -. 1.500% of whey powder .~ , 1.4ûC% of carbonated feed lime l~OOû% of feed line phosphate l.ûOOZ of molasses 0.500% of brewer's yeast û . û05% of 1-13~5-dichloro-4-(4'-chloro-phenoxy)-rh^"'^'~T~ g"' 1 100 . 000%

' ?

~Q366~

Such a feed is suitable both for curative and for prophylactic use.

In the mass treatment and prophylaxis of cocci- -- diosis of poultry, above all of coccidiosis o~ chickens, ducks, geese and turkeys, suitable dosages in practice are obtained by admixture of 10 to 100 ppm, preferably 50 to 100 ppm, to the feed; in special cases, because of good toleration, these amounts can be increased. A lowering of the dose can be achieved by combination with imidazole-4,5-dicarboxylic acid amide or sulphonamides, such as, for example, the p-amino-benzenesulphonamides of 2-amino-4,6-dimethylpyrimid~ne, of 2-~minoquinoxaline, of 2-amino-5-methoxy-pyrimidine and of 2-amino-4-methyl-pyrimidine, because these boost the activity.
On an individual treatment basis, generally a dose of from 5 to 250 mg/kg of body weight is administered, which may be -; divided between several administrations.
.The coccidiocidal activity of some compounds accord-ing to the invention is shown, by way of examples, in Tables 1 and 2, Eimeria tenella (coccidiosis of ~he appendix in chickens) is given as an example of the activity against poul-try coccidia and Eimeria falciformis (mice) is given as an ~` example of a coccid ln mammals.

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; . : ' . - - 33 -1()366~4 If, for example, 11 day old chicks are infected with 30,000 sporulated occysts or Eimeria tenella, the pathogen of coccidiosis of the appendix, 30 to 70% of the animals die in the case of the untreated controls. The surviving chicks excrete 300,000 to 500,000 oocysts per gram (opg) of faeces daily from the 7th to the 9th day after the infection. In the course of the illness, the weight increase is considerably impaired and there are pronounced macroscopially detectable ~ pathological changes in the appendices, which lead tc severe haemorrhages. In ~esting the activity against E. tenella, the compounds according to the invention were administered with the feed from 3 days before infection to 9 days after infection (end of the experiment).
The number of oocysts was de~ermined with the aid of the Mc-Master chamber (on this subject, see Engelbrecht et al., Parasitologische Arbeitsmethoden in Medizin und Veterina'r-medizin (Parasitological procedures in Medicine and Veterinary Medicine), page 172, Akademie-Verlag Berlin (1965)).
The treatment of the Eimeria falciformis infection of mice, mentioned as an example of coccidia in mammals, took place on the 1st, 2nd, 3rd, 6th, 7th and 8th day after infec-tion. The infection was brought about with 10,000 sporulated oocysts per mouse (weighing 15 g). In the case of the un-treated controls, from the 7th day after infection onwards massive excretion of oocysts and diarrhoea containing blood are observed, and 30% of the animals die of the infection.
These compounds can also be used medicinally in humans, as for the treatment of toxoplasmosis, as noted above. For thls use, and for individual treatment of .
; - 34 -:'''. . .
;. .

lQ36604 animals other than humans, the compounds are administered parenterally or orally in any of the usual pharmaceutical forms.
These include solid and liquid oral unit dosage forms such as tablets, capsules, powders, suspensions, solut ons, syrups and the like, including sustained release preparations, and fluid .; ~ - ~,, .
injectable forms such as sterile solutions and suspensions.
The term unit dosage form as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosage to animals, each unit containing a lt~ predetermined quantity of active material in association with s the required diluent, carrier or vehicle. The quantity of sctive material is tha~ calculated to produce the desired thera-peutic effect upon administration of one or more of such units.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted d~luent pharmaceutical carrier such as an edible carbohydrate materlal as for example, starch. Sweetening, flavoring, .
; preservative, dispersing and coloring agents can also be pres~nt.Capsules are made by preparing a powder mixture as ; 20 described above and filling formed gelatin sheaths. A lubricant ~uch as talc, magnesium stearate and calcium stearate can be added to the powder mixture as an adjuvant before the filling operation; a glidant such as colloidal silica may be added to , ~ . . .
improve flow properties; a disintegrating or solubilizing agent may be added to improve the availability of the medicament when ; the capsule is ingested.

.

;.
:

10366l:)4 Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base such as starch, sucrose, kaolin,dicalcium phosphate and -the like. The powder mixture can be granulated by wetting . .
with a binder such as syrup, starch paste, ~cacia mucilage or solutions of cellulosic or polymeric materials and forcing ~; through a screen. As an alternative to granulating, the powder -mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A
protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as syrups and elixirs can be prepared in unit dosage form so that a given quantity, e.g., a teaspoon-; ful, contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored ; aqueous sucrose solution while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formu-' .
.

:.' ' .

~ 036~04 lated by dispersing the compound in a non-toxic vehicle in which it ls insoluble.
, . - . . . .
Fluid unit dosage forms for parenteral administration can be prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and steriliz-- ing the suspension or solution. Alternatively a meas~red amount of ~he compound is placed in a vial and the vial and its con-tents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to adm~nistration.
The following examples will serve to further typify the nature of the invention without being a limitation on the scope thereof, the invention being defined only by the appended claims.
Example 1 1-[3]Chloro-4-(4'-chloro-~hen~lthio~-phen~l]-uracil a) N-12-CYano-3-(3-chloro-4-(4'-chloro-PhenYlthio?-phenY

. . .
amino)-acryloyl]-urethane :.' Cl CN ' ' ' Cl-~S--~N-CS-C-CO-~-COOCz115 18 g of N-(2-cyano-3-ethoxy-acryloyl)-urethane and 23 g of 2,4'-dichloro-4-amino-diphenyl-sulphide in 300 ml of ethanol are heated for 2 hours under reflux. The batch is then boiled to 0C and the reaction product which has precipi-;. ' , : - 37 -" ' . . .

- -., . , . ~ ~ .
.. . . . .
, . .

~0366Q4 18 g of N-(2-cyano-3-ethoxy-acryloyl)-urethane and - 23 g of 2,4'-dichloro-4-amino-diphenyl-sulphide in 300 ml of ethanol are heated for 2 hours under reflux. The batch is then cooled to 0C and the reaction product which has precipi-tated is filtered off. Yield: 34 g of the co~ound N-12- -cyano-3-(3-chloro-4-(4'-chloro-phenylthio)-phenylamino)-acryloyl]-urethane. Melting point: 177 to 178C
(decomposition).
~ b) 1- ~ hloro-4-~4~-chloro-phenylthio~-phenyl]-5-cyan uracil C~

Cl- ~ S ~ ~ ~ ~ - 0 0~ . ' .

33 g of N-[2-cyano-3-(3-chloro-4-(4'-chloro-phenyl-thio)-phenyl-amino)-acryloyl]-urethane are heated to 250C in a distillation apparatus for about 15 minutes, during which approx. 3.0 g of ethanol are eliminated. The melt ~s then recrystallised from d~methylformamide-ethanol.
Yield: 28 g of 1-[3-chloro-4-(4'-chloro-phenylthio)-phenyl]-5-cyano-uracil. Melting Point: 213 to 217C.
c) 1-[3 Chloro-4-(4'-chloro-P;~en~lthio~-phenyl]-uracil `~ 20 Cl- ~ - S - ~ - ~ =0 0~ ' 27 g of the 1-[3-chloro-4-(4'-chloro-phenylthio)-- phenyl]-uracil prepared according to b), in 150 ml of 78%
strength sulphuric acid, are heated to 170-180C for approx.

; - 38 -.''' ' ' ' ': ' -: . , , . . . . . .. . . . , . .. . _ 3~6Q4 15 to 20 mlnutes, until the evolution of CO2 has ceased. The -batch is then poured into ice water and the product which has precipitated is filtered off, washed and dried.
Yield: 20 g of 1-~3-chloro-4-(4'-chloro-phenylthio)-phenyl~-uracil. Melting point: 217 to 218C (from dilute acetic acid).
Example 2 1-[3~5-Dichloro-4-(4'-chloro-phPnYlthio)phenvl uracil a) N-[2-Cyano-3-(3~5-dichloro-4-<4t-chloro-phenylthio\ -' phenylamino)-acrylovl]-urethane .: .
, C\ C~' C~ ~--- 5~7~ CH=C-CO-NH-COOC2~5 , ~ ' '' Cl j, ' ::

15 g of N-(2-cyano-3-ethoxy-acryloyl)-urethane and 21.5 g of 2,6,4'-trichloro-4-amino-diphenyl-sulphide in 200 ml of tetrahydrofurane are heated for 1 hour under reflux, during which time a solution forms. The bulk of the solvent is then distilled off in vacuo and the residue is stirred with ethanol.
; The crystalline precipitate is filtered off and dried.
Yield: 28 g o N-~2-cyano-3-(3,5-dichloro-4-<4'-chloro-phenylthio~-phenylamino)-acrylovll-urethane. Melting point:
20 191 to 193C (decomposition).
b) 1-[3,5-Dichloro-4-(4'-chloro-phen~lthio)-phenYl]-~-cyano-- uracil 27 g of the N-12-cyano-3-(3,5-dichloro-4-<~'-chloro-.'.! phenylthio> -phenylamino)-acryloyl]~urethane prepared under a) are heated to 250C in a distillation apparatus for approx.
: 15 minutes, until the elimination of ethanol has ceased. The melt which remains is then recrystallised from glacial ace~ic : . .

. ~ .

` acid. Yield: 22 g of 1-[3,5-dichloro-4-(4'-chloro-phenylthio)-phenyl]-5-cyano-uracil. Melting point: 210 to 212C.
c ) 1- r3 . 5-Dichloro-4-(4'-chloro-phenylthio)phenvll-5-carbamido-uracil CO~H2 Cl- ~ -S ~ - ~ --0 22 g of the cyano-uracil prepared under b) and 250 ml of 48% strerlgth hydrobromic acid are heated for 2 hours under reflux. Hereupon, the product first softens without dissolving, and later again ~olidifies to crystals. The mixture i~ diluted with water and the product is filtered off and recrystallised from glacial acetic acid. Yield: 12 g of 1-[3~5-dichloro-4-(4'-chlorophenylthio)-phenyl]-5-carbamido-uracil. Melting ;~ point: 261 to 262C (decomposition).
d) 1-[3,5-Dichloro-4-(4'-chloro-Phenylthio)-phen~ racil ,", ~ ' .

Cl- ~ -S- ~ - ~ =o . .

10 g of the 1-[3,5-dichloro-4-(4'-chloro-phenylthio)-phenyl]-5-carbamido-uracil prepared under c), in 100 ml of 78~o strength ~ulphuric acid, are warmed to 180C for 15 minutes, until the evolution of C02 has ceased. The batch i~ then poured onto ice and the reaction product is filtered off, washed, dried and recrystallised from dimethylformamide-water.
; Yield: 6 g of 1-[~,5-dichloro-4-(4'-chloro-phenylthio)-phenyl]-:

, -uracil. Melting point: 222 to 225C.
Analogou~ly to Example 2, 1-[3-chloro-4-(4'-chloro-phenoxy)-~henyl]-uracil can be prepared starting from N-(2-cyano-3-ethoxy-acryloyl)-urethane and 2,4'-dichloro-4-amino-diphenyl-ether.
N-(2-Cyano-~-ethoxy-acryloyl)-urethane and 2,4'-di-- chloro-4-amino-diphenyl-ether give N-[2-cyano-3-(3-chloro-4-<4'-chloro-phenoxy-phenylamino)-acryloyl]-urethane.
' C~ Ç~ :
Cl- ~ _o_ ~ _~-cN=c-cc-~-cccc2~5 Yield: 75% of theory; melting point: 160 to 162C
(decompo~i~ion3.
A cyclisation reaction of this compound gives 1-[3-chloro-4-(4'-chloro-phenoxy)-phenyl]-5-cyano-uracil :
C~ ~ N

Cl- ~ -0- ~ _ ~ =o Yield: 83~o of theory; melting point: 197 to 198C.
Partial ~aponification of the abovementioned compound gives 1-[3-chloro-4-(4'-chloro-phenoxy)-ph~nyl]-5-carbamido-uracil O-~H2 ~: Cl-~3-o-~ =0 ., ~ ' .
. .
Yield: 63% of theory; melting point: 260 to 265C
(decomposition).

Further saponification and decarbo~ylation gives 1~ -; - 41 -.: . . . - . ~ .............. .. . . . .
. - . .. . : . : .
.. .. . . . . . ~

chloro-4-(4'-chloro-phenoxy)-phenyl]-uracil Cl C~ _o-~ =o Yield: 71~ of theory; melting point: 263 to 265C.
ExamPle 3 1-~3.5-Dichloro-4-(4~-chloro-phenoxy)-phenyll-uracil a) 1-[3,5-Dichloro-4-(4'-chloro-phenoxy2-phen~1]-3-(3-ethox~-acryloyl)-urea (11-~-0~ -R-~ C~=C~-00~5 Cl .~` ' ' .' : 22.6 g of silver cyanate and 14.0 g of 3-ethoxyacrylic acid chloride in 250 ml of dry benzene are ~tirred for 1 hour at 40C. 27.5 g of 3,5,4'-trichloro-4-amino-diphenyl-ether are added to the resulting solution of 3-ethozy-acryloyl-isocyanate, without removing the suspended silver salts.
After the slightly exothermic reaction ha~ subsided, the mix-... . .
ture is additionally warmed to 40C for 1 hour. The batch is - then diluted with 300 ml of petroleum ether and filtered, and the filte~ residue is dried. For purification, the product - obtained is stirred in 300 ml of dimethylformamide at 130 to - 140C, the silver salts are reduced by addition of 10 part~
by weight of zinc dust and the solution is clarified by filtra-tion and cooled. Yield: 25 g of 1-~3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloylhlrea; melting point:
252 to 254C.

,, Q366~4 `

`::
b) 1- r 3 . 5-Dichloro-4-(4~-chloro-phenoxy)-phenyll-uracil . . . -.

C~ 3 -o~ > =o -, 1 " ~'' ' 10 g of the urea derivative obtained under a), 150 ml of tert.-butanol and 2.8 g of potassium tert.-butylate are heated under reflux for 30 minutes. The solvent is then di-stilled off and the residue is heated to 120C in vacuo for 20 minutes. The residue is then dissolved in 500 ml of water at 90C, the solution is clarified by filtration and the uracil deriva~ive is precipitated by acidification with dilute acetic -` 10 acid. The product is filtered off, dried and recrystallised ~, from acetic a¢id. Yield: 6 g of 1-~3,5-dichloro-4-(4'-chlorophenoxy)-phenyl]-uracil; melting point: 271 to 272C.
Analogously to Example 3, 1-[4-(4'-chloro-phenylthio)-phenyl]-uracil can be prepared startinG from 4-amino-4'-chloro-diphenyl-sulphide:
c) 1-~4-(4'-chlorophenylthio)phenyl]-3-(3-ethoxy-` acryloyl)-urea :'. ' Cl- ~ -S- ~ -NH-C-NH-C-CH=CH-OC2H5 .` :

Yield: 72% of theory; mslting point: 216 to 217C, and from this d) 1-[4-(4'-chloro-phenylthio)-phenyl]-uracil .; ~ ~ ` .
` Cl- ~ -S- ~ - ~ =0 `

:. d'' .
-~ ` ~ 43 ~

-` ` 1t)3~;6(~
~ield: 68% of theory; melting point: 205 to 206C can be obtained.
Example 4 1-[3 5-Dibromo-4-(4'-chloro-phenylthio)-phenyl]-uracil .
a) l-13~5-Dibromo-4-(4'-chloro-phenvlthio)-phenyl]-3-~3-ethoxy-acryloyl)-urea Br o 0 Cl - ~ -S - ~ NH-c-NH-c-cH=cH-oc2~s Br 12.0 g of silver cyanate and 7.6 g of 3-ethoxyacrylic acid chloride in 150 ml of benzene are stirred for 1 hour at 40C and 20.0 g of 3,5-dibromo-4'-chloro-4-amino-diphenyl-sulphide are added. The mixture is stirred for a further hour at 40C and diluted with 200 ml of petroleum ether, and the ; product is filtered off and dried. To remove the silver salts, it is recrystallised from dimethylformamide with addition of zinc dust.
Yield: 18.0 g of 1-[3,5-dibromo-4-(4'-chloro~phenyl-. .
thio)-phenyl]-3-(3-ethoxy-acryloyl)-urea; melting point:
246 to 247C (decompositio~.
b) 1-l3~5-Dibromo-4-t4~-chloro-phen~lthio)-phenvl]-uraci ~-. B\r ` Cl - ~ - S ~ ~ 0 .
10 g of the urea derivative obtained under a) are stirred wlth 150 ml of ethanol at 60C and dissolved by drop-wise addition of 15% strength sodium hydroxide solution ~pH

.

' ' , ' ' ~ 1~3~6t)~

10). The mixture is ~tirred for 15 minutes at 60C and acidifie~ with dilute acetic acid. The uracil derivati~e which precipitate~ i9 filtered off, dried and recrystallised from dimeth!~lformamide~water. Yield: 6,0 g of ~ 3,5-dibromo-4-(4'-chloro-phenylthio~phenyl]-uracil; melting point: 265 to 268C (decomposition).
Analogously to Example 4, 1-r3-bromo-4-(4'-chloro-phenvlthio)-~henvll-uracil can be prepared from 3-bromo-4'-c~loro-4-amino-diphenyl-sulphide.

1-~3-Bromo-4-(4'-chloro-phenylthio)-phenyl~-3-(3-ethoxy-acryloyl)-urea B~ 0 Cl- ~ -S- ~ -NH-C-NH-C-CH=CH-OC2H5 ~ . , .
~ Yield: 76% of theory; melting point: 219 to 221C (decompo-`.......... ,,itio.n~, and frGm t.. i.Y l-L3-biu~iu-4-(4~ hiUrO-prlenylbniO~-phenyl]-uracil Br Cl- ~ ~ -S~ =0 ' Yield: 62% of theory; melting point: 230 to 231C
(decompo~ition).
The following l-aryl-uracils can be prepared analo-gou~ly to Example 3~ 3-chloro-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point: 217 to 218C; 1-[3,5-di-methyl-4-(4'-chlorophenylthio)-Phenyl]-uracil, melting point:
184 to 186 C; 1-~3,5-dibromo-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point: 265 to 268C (with decompos~tion):
1-[3-bromo-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting - ~5 -. "
.' .

.. . . . .
.

1(J36604 point: 230 to 231C (with decomposition); 1-[3-methyl-4-(4'-ehloro-phenylthio)-phenyl]-uracil~ melting point: 217 to 218C;
1-[4-(4'-chloro-phenylthio)-phenyl]-uracil, meltin~ point:
2G7 to 209C; 1-[3,5-dichloro-4-(4'-chloro-phenylthio)-phenyl]-uracil, melting point: 222 to 225C; 1-[3-chloro-4-(4'-chloro-phenylthio)-phenyl]-5-methyl-uraeil, melting point: 252 . to 254C; 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-uraeil, melting point: 271 to 272C; 1-[3-ehloro-4-(4'-chloro-phenoxy)-phenyl]-uracil, melting point: 263 to 265C; 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-5-methyl-uracil, melting point:
155 to 156C; 1-[3,5-dichloro-4-(4'-chloropheno~y)-phenyl]-6- ;
.~ meth~yl-uracil, melting point: 270 to 273C; 1-[3-ehloro-4-(1-naphthoxy?-phenyl]-uracil, melting point: 200 to 202C; 1-[3-,~ ehloro-4-(2'-naphthoxy)-phenyl]-uraeil, melting point: 208 to 209C; l-~-chloro-4-(2',6'-dimethyl-pheno~y)-phenyl]-uracil, ,! melting point: 222 to 224C; 1-[3,5-diehloro-4-(2',6'-di- .

~eth~l-phenG-~y)-~l.eilyl]-ura~ii, meiting point: 212 to 214-C;
; 1-[3-ehloro-4-(2',6'-diisopropyl-pheno~y)-phenyl]-uraeil, melting point: 204 to 205C; 1-[3,5-diehloro-4-(2';6'-diiso-2CI propyl-phenoxy)-phenyl]-uraeil, melting point: 210 to 212C;
1-[3,5-diehloro-4-(4'-ehloro-3',5'-dimethyl-pheno~y)-phenyl]-uraeil, melting point: 228 to 230C; 1-~3-ehloro-4-(4'-phenyl-., .
~ phenoxy)-phenyl]-uraeil, melting point: 255 to 256et 1-[3-ehloro-4-(4'-chloro-3',5'-dimethyl-phenoxy)-phenyl]-uraeil, ; melting point: 257 to 258C; 1-[3,5-dichloro-4-(1'-naphtho~y)-phenyl]-uraeil, melting point: 249 to 251C; 1-~3,5-diehloro-4-(2'-naphthoxy)-phenyl]-uraeil, melting point: 247 to 249C;
3,5-diehloro-4-(4'- <4"-ehloro-phenoxy> -pheno~y)-phenyl~-uraeil, melting point; 250 to 252C; 1-[3,5-diehloro-4-(4'-30 phenyl-pheno~y~-phenyl]-uraeil, melting point: 237 to 238C;
5-~lcnloro-4-~2l~6~-dichloro-pheno~y)-phenyl3-uracil~
., -~ ' ~: - 46 -... - .. . . . ~... - - . .: . ~

~36604 melting point: 238 to 240C; 1-[3,5-dichloro-4-(4'-tert-butyl-phenoxy)-phenyl]-uracil, melting point: 249 to 251C;
1-[3~5-dlchloro-4-(4l-i~ooctyl-phenoxy)-phenyl]-uracil~ melting point: 215 to 217C; 1-[3,5-dichloro-4-(2'~4',6'-trichlOrO-phenoxy)-phen~yl]-uracil, melting point: 282 to 283C; 1-[3,5-dichloro-4-(3'-methyl-4-methylmercapto-phenoxy)-phenyl]-uracil, melting point: 240 to 241C; 1-~3,5-dichloro-4-(4'-phenoxy-phenoxy)-phenyl]-uracil, melting point: 275 to 278C ~with de-composition); 1-[3,5-dichloro- 4-(3'-methyl-4'-dimethylamino-phenoxy)-phenyl]-uracil, melting point: 194 to 196C; 1-[3,5-dichloro-4-(4'-hydroxy-phenoxy)-phenyl]-uracil, melting point:
300 to 302C; 1-[3,5-dichloro-4-(4'-bromo-phenoxy)-phenyl]-5-methyl-uracil, melting point: 258 to 260C; 1-[3,5-dibromo-4-(4'-chloro-pheno~y)-phenyl]-5-methyl-uracil, melting point:
261 to 263C; 1-[3,5-dichloro-4-(4'-dimethylamidosulphonyl- . :
phenoxy)-phenyl]-uracil, melting point: 286 to 289C (with de-composition); l-l3,5-dichloro-4-(2',4'-dinitro-pheno2y)-phenyl uracil, melting point: 284 to 286C (with decomposition); 1-[3- :~
dimethylamidosulphonyl-4-(2',4'-dichloro-phenoxy)-phenyl]-uracil, melting point: 140C (with decomposition); 1-[3,5-dibromo-4-(4'-chloro-phenoxy)-phenyl]-uracil, melting point:
288 to 290C; 1-[3,5-dibromo-4-(4'-bromo-phenoxy)-phenyl]-uracil, melting point: 302 to 304C; 1-[3-cyano-4-(2',4'-di-chloro-phenoxy~-phenyl]-uracil, melting point: 280 to 282C;
1-[3,5-dimethyl-4-(4'-chloro-pheno~y)-phenyl]-uracil, melting point: 231 to 233C; 1-[3-chloro-5-methyl-4-(4'-chloro-phe-noxy)-phenyl]-uracil, melting point: 216 to 218a; 1-[3,5-dichloro-4-(4'-iodo-phenoxy)-phenyl]-uracil, melting point:
291 to 293C (with decomposition); 1~[3,5-dichloro-4-(4'- ;
acetyl-pheno~y)-phenyl]-uracil, melting point: 243 to 245C;
1-[3,5-diiodo-4-(4'-iodo-pheno~y)-phenyl]-uracil, melting "

.~ 47 _ ,' 1Q366~4 point: .297 to 298C; 1-[3,5-dibromo-4-(4'-iodo-pheno~y)-phenyl]-uracil, melting point: 308 to 310C (with decomposi-tion); 1-[3,5-dichloro-4-(4'-phenylsulphonyl-pheno~y)-phenyl]-ur~cil, melting point: 153 to 155C; 1-[3,5-diiodo-4-(4'-bromo-phenoxy)-~henyl]-uracil, melting point: 285 to 287C;
:. 1-[3,5-dibromo-4-(4'-flu.oro-phenoxy)-phenyl]-uracil, melting point: 269 to 271C; 1-[3,5-dichloro-4-(4'-chloro-pheno~y)-- phenyl~-3-methyl-uracil, melting point: 178 to 179C; 1-[3,5-- diiodo-4-(4'-chloro-phenoxy)-phenyl]-uracil, melting point:
294 to 296C; 1-~3,5-dichloro-4-(4'-chloro-2'-nitro-phenoxy)- :~
phenyl]-uracil, melting point: 182 to 184C; 1-[3,5-dichloro-4-(4'-methylsulphonyl-phenoxy)-~henyl]-uracil, melting point:
296 to 2q7C (with decomposition); 1-[3,5-dichloro-4-(4'-bromo-3'-chloro-pheno~y)-phenyl]-uracil, melting point: 256 to 258C;
1-[3,5-dichloro-4(3',5'-dichloro-phenoxy)-phenyl]-uracil, :
~.
melting point: 193 to 196C and 1-~3,5-dibromo-4-(3'-chloro-~ 5'-methyl-phenoxy)-phenyl]-uracil, melting point: 206 to 208C.
E~ample 5 . ~ :
r~ -DimethYl-4-(4'-chloro-Phenvlthio)-Phenvll-uracil 20 a) l r~.5-DimethYl-4-(4'-chloro-phenvlthio)-Phenyl~
~ ethoxv-acrvloyl)-urea Cl- ~ -S ~ -NH-C-NH-C-CH=CH-OC2H5 ~ I
'~ 3 .
."' ' ~ ' 16.0 g of silver cyanate and 10.5 of 3-etho~yacrylic .--: acid chloride in 150 ml of dry benzene are stirred for 1 hour At 40C. 1 g of 3,5-dimethyl-4'-chloro-4-amino-diphenyl-~ulphide is then added and the mi~ture is ~tirred for a further . hour at 40~C. It is then diluted with 200 ml of petroleum .
:: - 4~ - .~
. .
, `~ 10366Q4 ether and the product is filtered off and dried. To remove the sil~er salts, it is recrystallised from dimethylformamide with addition of zinc dust.
Yield: 15 g of 1-[3,5-dimethyl-4-(4'-chloro-phenyl-;` thio)-phenyl]-3-(3-ethoxy-acryloyl)-urea; melting point: 236 to 238C.
b) 1- r3 . 5-Dimethyl-4-(4'-chloro-phenylthio)-phenyll-uracil C~3 Cl- ~ .-S- ~ - ~ =0 10 g of the 1-[3,5-dimethyl-4-(4'-chloro-phenylthio)-phenyl]-3-(3-ethoxy-acryloyl)-urea prepared under a) are dis-solved in 150 ml of ethanol and 2.5 g of 44~o strength sodium hydroxide solution at 60C and the mixture is left to stand for 15 hours at 20C. It is then acidified with dilute acetic acid and the product is filtered off and dried.
Yield: 8.0 g of 1-~3,5-dimethyl-4-(4'-chloro-phenyl-thio)-phenyl]-3-(3-ethoxy-acryloyl)-urea; melting point: 184 to 186C (from acetonitrile).
Example 6 _-~3~5-Dichloro-4-(4l-chloro-phenox~)-Phenyll-5-methyl-uraci . . - ' Cl\ ~ CH3 Cl ~ o ~ ~ 0 Cl 0 , .
a) 1- r~,5-Dichloro-4-(4'-chloro-~henoxy)-phen~ -(3-methox~-.
meth~lacr~loyl)-ure R

"' ,: ' ' ' ' Q366~4 Cl ~ 0 ~ NH-C-NH-C-C - J_OCH3 - Cl 13.5 of silver cyanate and 8.9 g of 3-methoxy-meth-acrylic acid chloride in 200 ml of dry benzene are stirred for 1 hour at 40C. 17.0 g of 2,6,4'-trichloro-4-amino-diphenyl-ether are then added and the mixture is stirred for a further hour at 40C. The batch is then diluted with an equal volume of petroleum ether and the product is filtered off and dried. ¦
- Recrystallisation from dimethylformamide, with addition of small amounts of zinc dust, gives the compound 1-[3,5-dichloro- ~ I
4-(4'-chloro-phenoxy)-phenyl]-3-(3-methoxymethacryloyl)-urea in the pure form; yield 15.0 g; melting point: 215 to 216C.
b) 1-[3.~-Dichloro-4-(4'-chloro-Phenoxv)-Phenyl]-5-meth~l-uracil ~ ~
;I C ~ CH3 :~ . Cl~o~O
.. . ., Cl , , 13. 0 g of the urea derivative prepared under a) and 4.5 g of potassium tert.-butylate in 200 ml of tert.-butanol are heated ~or 30 minutes under reflux. ~he solvent is then . . , distil~`ed off and the residue i~ heated to 120C (bath temper-ature) for 20 minute~ at 15 mm Hg. The reaction product i~
dissolved in 600 ml of water at 80C, precipitated with dilute acetic acid, filtered off and dried. Recrystallisation from glacial acetic acid-methanol gives 8.0 g of 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phen~ 5-meth~l-uracil of mQl t.i ng nn~ n+.
155 to 156C.
.' l .

.
,' .

;...................................................... . . .

36604 :' .

Analogously, 3-ethoxy-crotonic acid chloride and silver cyanate give 2-ethox~-crotonoyl-isocyanate and thi~, with 2,6, 4'-trichloro-4-amino_diphenyl_ether, gives 1-~3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-3(3-ethoxy-crotonoyl)-urea (melting point: 244 - 246C, with decomposition). From this, 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-6-methyl-uracil (melting point: 270-272C) i~ o'btained by cyclisation with potassium tert.-butylate.
Example 7 . .
'` l-r3,5-Dichloro-4-(4'-chloro-phenox~-phen~1]-3-meth~l-uracil ."~

C1 ~ 0 ~ N ~

~' - Cl ~ H3 8.0 g Ol l-L3~5-uicrl;oro-4-(4:-chloro-phenoxyj-phenyl 3-uracil are dissolved in 200 ml of dimethylformamide, 2.4 g of potassium tert.-butylate are added and 3.5 g of methyl iodide are introduced in small portions over the course of 15 minutes, '' "~ at 50 - 60C. The mixture is stirred for a further 30 min-utes at the same temperature and the product is preclpitated by adding water, filtered off and dried. After recrystallisa-tion from dilute acetic acid, 6.0 g of 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl] 3-methyl-uracil of melting point:

'' 178 - 179C are obtained.
ExamPle 8 : ~- r3 . 5-Dichloro-4-(4~-bromophenox~)-phen~ll-uracil.,, - . .
. , .
-; . . Cl .. .
~A -\,~;/--V~ U
.,,, ''' C~

~ 51 . , .

, .

10366~4 a) 1- r3 . 5-Dichloro 4-(4'-bromo-~henoxy)-phen~11-3-(3-ethox~-acrylovl)-urea Cl 0 0 Br~O~NH-C-NH-C-CH=CH-OC2H5 - Cl 13.5 g of silver cyanate and 8.8 g of 3-etho~y-acrylic acid chloride in 200 ml of dry benzene are stirred for 1 hour at 40C. 20.0 g of 2,6-dichloro-4'-bromo-4-amino-diphenyl-ether are then added and the mixture i~ stirred for a further hour at 40C. It i~ then diluted with an equ?l volume o~
petroleum ether and the product is filtered of~ and dried.
Recrystallisation from dimethylformamide with the addition of a little zinc du~t give~ the compound l-t3,5-dichloro-4-(4'-bromo-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-urea in the pure form. Yield 22 g; melting point: 260 - 262~C, with decompo-ition.
The following urea derivative~ can be prepared analo-gously, using the 4-amino-diphenyl-ether deri~atives li~ted under Ex~mple C)~ 3,5-dichloro-4-(4'-iodo-phenoxy)-phenyl]-3-(3-etho~y-acryloyl)-urea, melting point: 250 - 252; 1-[3, 5-dichloro-4-(2',6'-dlmethyl-pheno~y)-phenyl]-3-(3-etho~y-... .
~cryloyl)-urea, melting point: 205 - 206C, with decompositlon;
1-[3,5-dichloro-4-(2',6'-dichloro-pheno~y)-phenyl]-3-(3-etho~y-acryloyl)-urea, melting point: 230 - 232C; 1-[3,5-dichloro-;~ 4-(2',4',6'-trichloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-. .
'. urea, melting point: 229 - 230C, with decompo6ition; 1-t3,5-dichloro-4~(3'-methyl-4'-methylmercapto-pheno~y)-phenyl]-3-t3-i~ etho~y~acryloyl)-urea, melting point: 238-239C, with decompo-s ~ition; 1 ~3,5-dichloro-4-(3'-methyl-4'-dimethylamino-phenoxy)-1~?366(~
phenyl]-3-(3-etho~y-acryloyl)_urea, melting point: 229-230G, with decompoqition; 1-[3,5-dichloro-4-(4'-methylsulphOnyl-pheno~y)-phenyl]-3-(3-etho~y-acryloyl)-urea~ melting point:
261 - 262C, with decomposition; 1-[3,5-dichloro-4-(4'-bromo-- 3'-chloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-ure~, melting point: 257C, with decomposition; 1-[3,5-dichloro-4~
- naphthoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point:
250-252C, with decomposition; 1-[3,5-dichloro-4-(4-~4'-chloro-phenoxy>-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 242-244C, with decomposition; 1-[3,5-dichloro-4-(4'-acetyl-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting poin~
244-246C, with decomposition; 1-~3,5-dibromo-4-(4'-chloro-phenoxy)-phenyl]-3-(3-etho~y-acryloyl)-urea, melting point:
246-247C; 1-[3,5-dibromo-4-(4'-bromo-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 247-248C; 1-[3,5-di-- bromo-4-(4'-iodo-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-ureaJ
melting point: 263-264C, with decomposition; 1-~3,5-dibromo-4-(3'-chloro-5'-methyl-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 243-245C, with decomposition; 1-[3,5-dilodo-4-(4'-bromo-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 268-270C, with decomposition; 1-[3,5-diiodo-4-(4'-iodo-pheno~y)-phenyl~-3-(3-ethoxy-acryloyl)-u~ea, melting point: 27;-273C, with decompo~ition, 1-[395-dimethyl-4-(4'-chloro-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: `216-218C; 1-[3-chloro-5-methyl-4-(4'-chloro-phenoxy)-` phenyl]-3-(3-etho~y-acryloyl)-urea, melting point: 232-233C.
b) l-r~,~-Dichloro-4-(4'-bromoPheno~v)-~hen~ll-uracil ~ 10 g of the urea derivative prepared under a) are - heated with 150 ml of tert.-butanol and 2.4 g of potas8ium tert.-butylate for 30 minute~ under re~ h~ ~A~
then distilled of~ and the re~idue i~ heated in vacuo to 120C

-.

: :

1~366(~4 .for 20 minutes. The residue ls then taken up with 500 ml of water at 90C and the mixture i~ neutralised with dilute acetic acid. The product is filtered off, dried and recrystal].ised . from acetic acid. Yield: 6 g of 1-[3,5-dichloro-4-(4'-bromo-. phenoxy)-phenyl]-uracil; melti.ng point: 288-290C.
ExamPle 9 l-r~.~-Dichloro-4-(2'.4'-dichloro-phenox~)-phenvll-ura.cil .

~1 Cl C l~

. a) l-r~.5-Dichloro-4-~2',4'-dichloro-PhenoxY)-~hen.Y
; 10 etho~-acr.vlovl)-urea : Cl ~ O ~ N~;-C~ CH=CR-OC~
Cl .
'.. ''' ' ' ' .` 15 g of silver cyanate and 7.8 g of 3-ethoxy-acrylic; acid chloride in 200 ml of dry benzene are stirred for 1 hour at 40C and the silver salts are then filtered off, wlth es-clusion of moisture. 17.0 g of 2,6,2',4'-tetrachloro-4-amino-- diphenyl-ether are introduced ~lowly, at 10C, lnto the solu-. tion of 3-et~o~y-acryloyl-isocyanate, obtained above, and the mi~ture is then stirred for 1 hour at 40C. Thereafter it is - diluted with an equal volume of petroleum ether and the product is ~iltered off and dried. Recrystallisation from dimethyl-formamide gives 20 g of 1-[3,5-dichloro-4-(2',4'-dichloro-pheno~y)-phenyl]-3-(3-etho~y-acryloyl)-urea. Melting point:
. 263 - 264C, with decomposition. ..
The following urea derivatives can be prepared analo-:` :

' ~36604 .
: ~ously, using the 4-amino-diphenyl-ether derivative~ listed under Example D: 1-[3,5-dichloro-4-(4'-methoxy-phenoxy)-phe-nyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 232 - 234C, with decomposition; l-~3,5-dibromo-4-(4'-bromo-3'-c~.loro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, m~lting point:
252 - 253C, with decomposition; 1-[3,5-dichloro-4-(4'-ethyl-sulphonyl-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 236 - 237C, with decomposition; 1-[3,5-dibromo-4-(4-methoxy-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 231 - 23~C; 1-[3-bromo-5-methyl-4-(4'-chloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 228 - 233C;
1-[3-bromo-5-chloro-4-(4'-iodophenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, meltin~ point: 260 - 261C, with decomposition;
1-[3,5-dibromo-4-(4'-methylsulphonyl-phenoxy)-phenyl]-3-(3-- ethoxy-acryloyl)-urea, melting point: 260 - 261C, with de-. composition; 1-[3,5-dichloro-4-(2',4',5'-trichloro-phenoxy)-~henyl]-3-(3-ethoxy-acryloyl)-urea~ melting point: 252 - 253C, . with decomposition; 1-[3,5-dichloro-4-(4'-chloro-2'-methyl-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point:

: 20 269 - 270C, with decomposition; 1-[3,5-dichloro-4-(4'-acetyl-: amino-phehoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 259 - 260C, with decomposition; 1-~3,5-dichloro-4-(4'- <2"-oxo-pyrrolidinol~ -phenoxy)-phenyl]-3-(3-ethoxy-acryl-oyl)-urea, meltlng point: 237 - 240C, with decomposition;
1-[3-bromo-5-chloro-4-(4'-chloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 248 - 250G, with decomposition;
1-[3-chloro-5-iodo-4-(4'-chloro-phenoxy)-phenyl]-3-(3-etho~y-acryloyl)-urea, melting point: 257 - 258C, with decomposition, 1-[3,5-dichloro-4-(3-dimethylamino-4-(methyl-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 235 - 236C; 1-[3, . 5-dichloro-4-(4'-fluoro-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-1036604 ~ ~

urea, melting point: 244 - 245C, with decompo~ition; 1-~3,5-dichloro-4-t4'- <2",5"-dimethyl-pyrryl> -phenoxy)-phenyl]-3-(3-etho~y-acryloyl)-urea, melting point: 240 - 242C, with decom-position; 1-~3,5-dichloro-4-(4'-cyano-pheno~y)-phenyl]-3-(3-etho~y-acryloyl)-urea, melting point: 243 - 244C, with decom-position; 1-[3,5-dichloro-4-(2',4',6'-trichloro-3'-methyl-phenoxy)-phenyl]-~-(3-ethoxy-acryloyl)-urea, melting point: ~
249 - 251C, with decomposition; 1-[3,5-dichloro-4-(2',3'- :
dimethyl-pheno~y)-phenyl]-3-(3-ethoxy-acryl o~rl ) -urea, melting point: 248 - 249C, with decomposition; 1-[3,5-dichloro-4- ~ ~:
(5',6',7',8'-tetrahydro-1'-naphthoxy)-phenyl]-3-(3-ethoxy- ~:
acryloyl)-urea, melting point: 247 - 248C, with decomposition;
1-[3,5-dichloro-4-(3'-chloro-2'-methyl-pheno~y)-phenyl]-3-(3- .
etho~y-acryloyl)-urea, melting point: 246 - 249C, with decom-position; 1-[3,5-dichloro-4-(5'-metho~y-1'-naphthoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 243 - 244C; 1-(3, ~
5-dichloro-4-pheno~y)-phenyl)-3-(3-etho~y-acryloyl)-urea, mel- :.
ting point: 237 - 239C; 1-[3,5-dichloro-4-(4'-chloro-2',3'-, .~ dimethyl-pheno~y)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting ;;: .20 point: 247 - 248C; 1-[3,5-dichloro-4-(2'-chloro-4'-methyl-.. sulphonyl-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting :.
point: 273 - 275C, with decomposition; 1-[3,5-dichloro-4-(4'-methylmercapto-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, : melting point: 265 - 267C; 1-~3,5-dichloro-4-(2'-chloro-4'- .
acetylamino-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting : :
. .
;~ point: 244 - 246C, with decompo~ition; 1-[3,5-dichloro-4-(2',3'-dichloro-4'-acetylamino-phenoxy)-phenyl]-3-(3-etho~y- ~:.
acryloyl)-urea, melting point: 250 - 252C, with decompo~ition; -. 1-[3,5-dichloro-4-(3'-chloro-4'-acet~lamino-~heno~y)-phenylj- - .
. 30 3-(3-etho~-acrYlo~l)-urea~ melting point: 267C, with decompo-: 8ition; 1-[3,5-dichloro-4-(4'-acetylamino-naphthoxy-(1~

~ ' :;

:
- `

1~6604 phenyl]-3-(3-ethoxy-acryloyl)-ureat melting point: 234 - 236C, with decomposition; l-[3,5-dichloro-~-(4'-chloro-naphthoxy-phenyl]-3-(3-ethoxy-acryloyl)-urea, melting point: 265 -267C, with decomposition.
b) l-r~.~-Dichloro-4-(2',4'-dichloro-rhenoxv)-~henvll-uracil 16.0 g of the urea derivative prepared under a) and 4.3 g of ~otassium tert.-butylate (90~ strength) in 200 ml of tert.-butanol are heated for 20 minutes under reflux, the sol-~ent is then distilled off and the residue is warmed to 100C
:
at 15 mm Hg for 20 minutes. The batch i9 then ~tirred into 400 ml of water at 90, the mixture is acifified with dilute acetic acid and the product is filtered off, washed and dried.
; Recrystallisation from glacial acetic acid gives 12 g of uracil ; derivative of melting point: 180 - 184C.
' ~he following uracils are obtained analogously from `1 the urea derivative~ ted under a): 1-[3,5-dichloro-4-(4'-methoxy-phenoxy)-phenyl]-uracil, melting point: 256 0 257C;
[3,5-dibromo-4-(4'-bromo-3'-chloro-phenoxy)-phenyl]-uracil, melting point: 268 to 270C; 1-[3,5-dichloro-4-(4'-ethyl~ul-phonyl-phenoxy)-phenyl]-uracil, melting point: 243 - 245C;
1-[3,5-dibromo-4-(4'-methoxy-phenoxy)-phenyl]-uracil, melting point: 258 - 260C; 1-[3-bromo-5-methyl-4-(4'-chloro-phenoxy)-phenyl]-uracil, melting point: 231 - 233C; 1-[3-bromo-5-chloro-4-(4'-iodo-phenoxy)-phenyl]-uracil, melting point: 304 -306C; 1-[3,5-dibromo-4-(4'-methyl~ulphonyl-phenoxy)-phenyl]-uracil, melting point: 305 - 307C; 1-[3,5-dichloro-4-(2', 4',5'-trichloro-phenoxy)-phenyl]-uracil, melting point: 233 -234C; 1-[3,5-dichloro-4-(4'-chloro-2'-methyl-phenoxy)-phenyl]-uracil, melting point: 237 - 239 C; 1-[3,5-dichloro-4-(4'-acetylamino-phenoxy)-phenyl~-uracil, mslting point: 32~ - ~27~
with decomposition; 1-[3,5-dichloro-4-~4'-~2n-o~o-pyrrolidinol>
..
_ 57 _ . .
.

: -pheno~y)-phenyl]-uracil, melting point: 278 - 279C; 1-[3-bromo-5-chloro-4-(4'-chloro-phenoxy)-phenyl]-uracil, melting point: 274 - 276C; 1-[3-chloro-5-iodo-4-(4'-chloro-pheno~y)-phenyl]-uracil, melting point: 265 - 266C; 1-[3,5-dichloro-4-(3'-dim~thylamino-4'-methyl-phenoxy)-pht~nyl]-uracil, melting point: 128 - 130C; 1-[3,5-dichloro-4-(4'-fluoro-phenoxy)-phenyl]-uracil, melting point: 248-250C; 1-~3,5-dichloro-4- :
(4'- ~2",5"-dimethyl-pyrryl> -phenoxy)-phenyl]-uracil, melting point: 210-212C; 1-[3,5-dichloro-~-(4'-cyano-phenoxy)-::~ lt) phenyl]-uracil, melting point: 247 - 248C; 1-~3,5-dichloro-4-(2',4',6'-trichloro-3'-methyl-pheno~y)- phenyl]-uracil, mel-. ting point: 2~2 - 233C; 1-[3,5-dichloro-4-(2',3'-dimethyl-phenoxy)-phen~l]-uracil, melting point: 256 - 257C; 1-[3,5-: dichloro-4-(5',6',7',8'-tetrahydro-1'-naphtho~y)-phenyl]-uracil, ... melting point: 237 - 240C; 1-[3,5-dichloro-4-(~'-chloro-2'-meth~l-phen^~y)-phc,lyll-ulacil, n-leith~ int; 24~ - 24~
1-[3,5-dichloro-4-(5'-methoxy-1'-naphthoxy)-phenyl]-uracil, melting point: 288 - 289C; 1-[3,5-dichloro-4-pheno~y-phenyl]-uracil, melting point: 229 - 231C; 1-[3,5-dichloro-4-(4'-chloro-2',3'-dimethyl-phenoxy)-phenyl]--uracil, melting point:
223 - 225C; 1-[3,5-dichloro-4-(2'-chloro-4'-methylsulphonyl-pheno~y)-phenyl]-uracil, melting point: 315 - 317C; 1-[3,5-dichloro-4-(4'-methylmercapto-pheno~y)-phenyl]-uracil, melting .. point: 265 - 267C; 1-[3,5-dichloro-4-(2'-chloro-4'-acetyl-amino-phenoxy)-phenyl]-uracil, melting point: 332 - 334C, with :
decomposition; 1-[3,5-dichloro-4-(2',3'-dichloro-4'-acetylamino- :
pheno~y)-phenyl]-uracil, melting point: 334 - 335C, with de-~ composition; 1-[3,5-dichloro-4-(3'-chloro-4'-acetylamino-phe- .
: no~y)-phenyl]-uracil, melting point: 280 - 282C, with decom-- 30 yu~i ~iu.~ [3, 5-aicnloro-4-(4'-acetylamino-naphtho~y-~1> )-phenyl]-uracil, melting point: 311 - 312C, with decomposition;

1~136604 1-[3,5-dichloro-4-(4'-chloro-naphthoxy-~1> )-phenyl]-uracil, - melting point: 188 - 191C~ ¦

Exam~le 10 ' :
l-r~.~-Dichloro-4-(4'-amino-phenox~)-phen,yll-uracil ,~ .

H N ~ 0~ ~ ~ ~ 0 2 y ~ H
Cl 0 ... .
8 g of 1-[3,5-dichloro-4-(4'-acetylamino-pheno~y)-phenyl]-uracil in 100 ml of 48% strength hydrobromic acid are heated for 1 hour under reflu~; hereupon, solution fir~t occurs and after a short time the reaction product precipiate~.
The mixture is concentrated in vacuo, diluted with water and neutrali~ed by adding dilute ammonia, and the product 1~ fil-tered of~ and dried. Yield 6 g, melting point: 265 - 266C.
; Analogously, the following uracile are obtained from the corresponding acetylamino derivative~ by hydrolysis with 48% strength hydrobromic acid: 1-[3,5-dichloro-4-(2'-chloro-4'-amino-phenoxy)-phenyl]-uracil, melting point: 194 -198C; 1-~3,5-dichloro-4-(2',3'-dichloro-4'-amino-pheno~y)-` phenyl]-uracil, melting point: 277 - 279PC, with decompo8i-tion; 1-[3,5-dichloro-4-(3'-chloro-4'-amino-pheno~y)-phenyl]-uracil, melting point: 247 - 249C; 1-[3,5-dichloro-4-(4'-amino-haphtho~y-~l) )-phenyl]-uracil, melting point: 252 -255C.
, E~camPle 11 ,' -r~,5-Dichloro-4-(4'-allyloxy-Phenox:s)-phenyll-uracil "

:. CH2-CH-C~I2-0~=~0~ _0 ',' . 1 o , ,, ' .

:.............. : -lQ36604 ~
6.0 g of 1-[3,5-dichloro-4-(4'-hydroxy-phenoxy)-phenyl~-uracil are dissolved in 100 ml of dimethylformamide and 2.5 g of potassium tert.-butylate (90% strength) are introduced at 0; hereupon, the potassium salt of the uracil deri~ative cry-stallises out. 2.0 g of allyl bromide are then added and the ;- mixture i~ stirred for 12 hours at 20, whereupon ~olution occurs. The product is precipitated by adding water, filtered off, dried and recrystallised from toluene. Yield, 4.0 g;
melting point: 186 - 187 (after drying at 100C/10 mm Hg).
Analogously, 1-[3,5-dichloro-4-(4' <2"-oxo-propoxy> -phenoxy)-phenyl]-uracil, melting point: 275 - 280C, is obtai-ned with chloroacetone, and 1-[3,5-dichloro-4-(4'- <2"-dimethyl-amino-ethoxy> -phenoxy)-phenyl]-uracil, melting pOillt: 196 -199C, is obtained with ~,N-dimethyl-2-chloro-ethylamine.
Exam~le 12 l-r3.~-Dichloro-4-(4'-nitro-~henox:r)-Phenyll-uracil : ~ C~L `
.. o ~3 ~ ~ ,-10.0 g of 1-(3,5-dichloro-4-phenoxy-phenyl)-uracil are -~ dissolved in 80 ml of concentrated sulphuric acid and 5 - 10C
2 and 3.3 g of finely powdered potassium nitrate are introduced, The mixture is stirred for 1 hour at 15 - 20 and p~red onto ice. It is then rendered neutral with ammonia ~olution and the product is filtered off, washed and dried. It iB purified by recrystallisation from acetic acid. Yield 8 g; melting point: 273 - 275C, with decomposition.
Example 1~
'' ~

, ,. : .

NH2 Cl ~/ ~I ~ ~
'': . .
31.0 g of 1-[3,5-dichloro-4-(2',4'-dinitro-pheno~y)-phenyl]-uracil are dissolved in 200 ml of dimeth~lformamide, 5,0 g of Raney nickel are added and hydrogenation is carried ,~ out at 20 - 40C, under 40 atmospheres gauge hydrogen pre~ure, until the absorption of hydrogen ha~ ceased. The catalyst is filtered off, the filtrate is concentrated in vacuo, 200 ml of absolute ether are added to the residue and the mixture i~
allowed to crystallise.
Yield, 20.0 g of 1-[3,5-dichloro-4-(2',4'-diamino-phenoxy)-phenyl]-uracil of melting point: 244 - 245C after ` dryin~ at 140C/10 mm Hg.
Example 14 .~ l-r75.~-,Dichloro-4-(2'.4'-bi~-acetvlamino-Pheno~cY)-~henvll-uracil CH~C0 ~ Cl cH3cO-NH ~o ~ o o .., ~
4.0 g o~ 1-[3,5-dichloro-4-(2',4'-diamino-phenoxy)-phenyl]-uracil and 20 ml of dioxane are heated to the reflux temperature and 3.0 g of acetic anhydride are added. Here-upon, solution occurs, accompanied by an exothermic reaction.
After 15 minutes at 90, water i~ added until the mi~ture - turn~ turbid, and crystalli~ation is then allowed to take place.
.
Yield, 4.5 g of 1-[3,5-dichloro-4-(2',4'-bis-acetyl-amino-pheno~y)-phenyl]-uracil; melting point: 322 - 234C, with decompogition.

, ' ' .

1C~3~6~4 If, in the above instruction, the acetic anhydride is ;~
replaced by 4.0 g of pyrocarbonic acid diethyl ester and in other respects the procedure indicated is followed, 4.5 g of ~ 1-[3,5-dichloro-4-(2',4'-bis-carbethoxyamino-phenoxy)-phenyl]-uracil, melting point: 247 - 249C, with decompos~tion, are ;~
obtained.
.
; Preparation of starting materials.

Example A

2~6-Dibromo-4'-chloro-4-amino-diphenyl-sulphide - Br ` `
\` - :' Cl ~ - S _ ~ - NH2 ,~
Br a) 2,6-Dibromo-4'-chloro-4-nitro-diphenYl-sulphide.
162 g of 4-chloro-thiophenol are dissolved in 250 ml of dimethylsulphoxide and 450 ml of benzene, 72 g of potassium hydroxide powder (88% strength) are added and the water is eliminated from the system under reflux, by means of a separa- - -... . .
tor,whilst passing nitrogen over the mixture. The benzene is then distilled off at 20 mm Hg until the temperature reaches ., 80C. The remaining solution of potassium 4-chloro-thiopheno-~: late in dimethylsulphoxide is added dropwise, at 0 - $C, to a solution of 400 g of 3,4,5-tribromo-nitrobenzene in 600 ml of dimethylformamide and the batch is stirred for 12 hours at 20C. It is then stirred into 5 1 of water and the reaction product is filtered off, washed and dried. Yield 460 g of .
` 2,6-dibromo-4'-chloro-4-nitro-diphenyl-sulphide, melting point:

104 - 106C (from acetone).

The following can be obtained analogously: from 4-: chloro-thiophenol and 3,4-dibromo-nitrobenzene, 2-bromo-4'-.. ,,~ .

- . . . : ~ . - - . ~ .

' lV366~

chloro-4-nitro-diphenyl-sulphide, melting point: 125 - 126C;
from 4-chloro-thiophenol and 4-bromo-~-methyl-nitrobenzene, 2-l~ethyl-4'-chloro-4-nitro-diphenyl-sulphide, melting point:
95 - 97C.
b) 2.6-Dibromo-4'-chloro-4_amino-diphenyl-sulphide 250 g of 2,6-dibromo-4'-chloro-4-nitro-diphenyl-sul-phide are dissolved in 500 ml of tetrahydroiurane, 10 g of an-hydrous Raney nickel catalyst are added and the batch is hydro-genated at 50 - 60C and 50 atmospheres gauge hydrogen pressure until the absorption of hydrogen has ceased. ~he catalyst is then filtered off, the solvent is distilled off and the residue is recrvstallised from toluene. Yield: 175 g; melting point:
129 - 132C.
Example B
2-Bromo-4'-chloro-4-amino-diphen~l-sulphide . ~ .
Cl~ S~NH2 /
Br 150 g of 2-bromo-4'-chloro-4-nitro-diphenyl-sulphide are introduced into a solution of 335 g of tin-II chloride dihydrate in 400 ml of concentrated hydrochloric acid and 100 ml o~ dioxane at 70 - 80C. The reduction takes place exo-thermically; thereafter, the mixture is additionally warmed to 100C for 30 minutes and poured into a mixtur~ of 1.2 1 of 40~0 strength sodium hydroxide solution and 1.2 kg of ice.
The amino compound which precipitate~ is filtered off, washed until neutral and dried. It i~ purified by recrystallisation ,., from acetone or toluene; yield 105 g; melting point: 60 -2C.

Analogously, 2-2-methyl-4'-chloro-4-amino-diphenyl-.:.
- 63 - ~
', --` 1036604 `sulphide, of melting point: 65 - 66C, obtained from 2-methyl-4'-chloro-4-nitro-diphenyl-sulphide.
Example C
2~6-Dichloro-4'-bromo-4-amino-diphenyl-ether _~- ~ ~

a~ 2 6-Dichloro-4'-bromo-4-nitro-diphenyl-ether 60 g of 4-bromo-phenol are dissolved in a mixture of 120 ml of dimethylsulphoxide and 300 ml of benzene, 24 g of potassium hydroxide powder (88% pure) are added and the water is eliminated azeotropically from the system via a separator.
The benzene is then distilled off at 20 mm Hg and 60C. The remaining solution of potassium 4-bromo-phenolate in dimethyl-sulphoxide is added dropwise, at 10C, to a solution of 79 g ~ -of-3,4,5-trichloro-n~trobenzene in 300 ml of dimRthylformamide.
The batch is subsequently stirred for a further 12 hours at 20C and then stirred into S 1 of water, and the reaction product is filtered off, washed and dried. Yield: 120 g;
melting point: 121 122C.
The following can be obtalned analogously: from 4-iodo-phenol and 3,4,5-trichloro-nitrobenzene, 2,6-dichloro-4'-iodo-4-nitro-diphenyl-ether, melting point: 135 - 137C;
from 2,6-dimethyl-phenol and 3,4,5-trichloro-nitrobenzene, 2,6-dichloro-2'~6'-dimethyl-4-nitro-diphenyl-ether, melting point. 109 - 111C; from 2,6-dichloro-phenol and 3,4,5-tri-chloro-nitrobenzene, 2,6,2',6-tetrachloro-4-nitro-diphenyl-ether, melting point: 141 - 143C; from 2,4,6-trlchloro-.
- phenol and 3,4,5-trichloro-nitrobenzene, 2,6,2',4',6'-penta-. , ~ , .
-. , ,. : ;., .. , .... . ~ .. . . . . .

366(~4 chloro-4-nitro-diphenyl-ether, meltin~ point: 100 - 101C;
from 3-rnethyl-4-methylmercapto-phenol and 3,4,5-trichloro-nitro-benzene, 2,6-dichloro-3'-methyl-4'-methylmercapto-4-nitro-diphenyl-ether, meltin~ point: 83 - ~6C; from 3-methyl-4- -dimethylamino-phenol and 3,4,5-trichloro-nitrobenzene, 2,6-dichloro-3'-methyl-4'-dimethylamino-4-nitro-diphenyl-ether, meltin~ point: 65 - 66C; from 4-methylsulpho~yl-phenol and 3,4,5-trichloro-nitrobenzene, 2,6-dichloro-4'-methylsulphonyl-4-nitro-diphenyl-ether, melting point: 163 - 165C; from 4-bromo-3-chloro-phenol and 3,4,5-trichloro-nitrobenzene, 2,6, 3'-trichloro-4'-bromo-4-nitro-diphenyl-ether, melting point:
110 - 112C; from l-hydroxy-naphthalene and 3,4,5-trichloro-nitrobenzene, 3,5-dichloro-4-(1'-naphthoxy)-nitrobenzene, mel.ting point: 100 - 102C; from 4'-chloro-4-hydroxy-diphenyl-ether and 3,4,5-trichloro-nitrobenzene, 3,5-dichloro-4-(4-(4'-chloro-phenoxy)-phenoxy)-nitrobenzene, melting point: 182 -184~C; from 4-chloro-phenol and 3,4,5-trichloro-nitrobenzene, 2,6-4'-trichloro-4-nitro-diphenyl-ether, melting point: 101 -103C; from 4-hydroxy-acetophenone and 3,4,5-trichloro-nitro-benzene, 2,6-dichloro-4'-acetyl-4-nitro-diphenyl-ether, melting point: 123 - 125C; from 4-chloro-phenol and 3,4,5-tribromo-nitrobenzene, 2,6-dibromo-4'-chloro-4-nitro-diphenyl-ether, melting point: 128 - 130C; from 4-bromo-phenol and 3,4,5-tribromo-nitrobenzene, 2,6,4'-tribromo-4-nitro-diphenyl-ether, melting point: 126 - 128C; from 4-iodo-phenol and 3,4,5-tri-bromo-nitrobenzene, 2,6-dibromo-4'-iodo-4-nitro-diphenyl-ether, melting point: 135 - 137C; from ~-chloro-5-methyl-phenol and 3,4,5-tribromo-nitrobenzene, 2,6-dibromo-3'-chloro-5'-methyl-:;. , .. 4-nitrodiphenyl-ether, melting point: 177 - 179C; from 4-.~ 30 bromo-phenol and 4-bromo-3,5-diiodo-nitrobenzene, 2,6-diiodo-4'- :
bromo-4-nitro-diphenyl-ether, melting point: 138 - 140C;

; - 65 -". ' , ` - :

1(~366(~4 from 4-iodo-phenol and 4-bromo-3,5-diiodo-nitrobenzene, 2,6, 4'-triiodo-4-nitro-diphenyl-ether, melting point: 147 - 149C;
from 4-chloro-phcnol and 4-chloro-3,5-dimethyl-nitrobenzene, -~
2,6-dimethyl-4'-chloro-4-nitro-diphen~l-ether, melting point:
137 - 13~C;. from 4-chlorophenol and 3,4-dichloro-5-methyl-nitrobenzene, 2,4'-dichloro-6-methyl-4-nitro-diphenyl-ether, melting point: 113 - 114C.
b) 2 ! 6-Dichloro-4'-bromo-4-amino-diphen~l-ether 110 g of 2,6-dichloro-4'-bromo-4-nitro-diphenyl-ether, prepared according to a), are introduced at 80C into a solu-tion of 226 g of tin-II chloride dihydrate in 200 ml of concen-trated hydrochloric acid and 150 ml of dioxane. The mixture i9 ~ -then he~ted additionally for 30 minutes under reflux. There-; after, the batch i9 poured into 1 1 of 40% strength sodium hydroxide solution and 1 1 of ice water and the product is filtered off, washed until neutral and dried. Yield, 90 g;
melting point: 149 - 150~C (from toluene).
The following can be obtained analogously, 2,6-dichloro-4'-iodo-4-amino-diphenyl-ether, melting point: 148 - 149C;
` 20 2,6-dichloro-2',6'-dimethyl-4-amino-diphenyl-ether, melting point: 168 - 169C; 2,6,2',6'-tetrachloro-4-amino-diphenyl-ether, melting point: 170 - 172C; 2,6,2',4'~6'-pentachloro-4_am1no-diphenyl-ether, melting point: 177 - 178C; 2,6-di-; chloro-3'-methyl-4'-methylmercapto-4-amino-diphenyl-ether, mel-ting point: 136 - 137C; 2,6-dichloro-3'-methyl-4'-dimethyl-amino-4-amino-diphenyl-ether, melting point: 139 - 140C;
2,6-dichloro-4'-methylsulphonyl-4-amino-diphenyl-ether, melting . .
point: 204 - 206C; 2,6-3'-trichloro-4'-bromo-4-amino-di-phenyl-ether, melting point: 144 - 146C; 3,5-dichlo~o-4-(1'-30 naphthoxy)-aniline, melting point: 106 - 107C; 3,5-dichloro-4-(4-(4'-chloro-phenox.y)-phenoxy)-aniline, melting poin+: 115 -. .

1036~(~4 117C; 2~6,4'-trichloro-4-amino-diphenyl-ether, melting point:
158 - 160C; 2,6-dichloro-4'-acetyl-4-amino-diphenyl-ether, melting point: 116 - 119C; 2,6-d~bromo-4'-chloro-4-amino-diphenyl-ether, melting point: 136 - 138C; 2,6-4'-tribromo-4-amino-diphenyl-ether, melting point: 146 - 147C; 2,6-di-bromo-4'-iodo-4-amino-diphenyl-ether, melting point: 170 -171C; 2,6-dibromo-3'-chloro-5'-methyl-4-amino-diphenyl-ether, melting point: 157 - 158C; 2,6-diiodo-4'-bromo-4-amino-di-phenyl-ether, melting point: 147 - 149C; 2,6-4'-triiodo-4-amino-diphenyl-ether, mel~ing point: 196 - 197C; 4'-chloro-2,6-dimethyl-4-amino-diphenyl-ether, melting point: 100 - 101C;
2,4'-dichloro-6-methyl-4-amino-diphenyl-ether, melting point:
140 - 141C.
Example D
2,6,2',4'-Tetrachloro-4-amino-diphenyl-ether Cl C\
C~- 0-~-NH2 Cl a) 2.6,2',4'-Tetrachloro-4-nitro-diphenyl-ether 65 g of 2,4-dichloro-phenol and 50 g of potassium tert.-butylate (90% strength) are dissolved in 200 ml of dimethyl-sulphoxide and the solution is added dropwise, at 20 to 30C, to a solution of 91 g of 3,4,5-trichloroni~robenzene in 200 ml of dim~thylformamide. Thereafter the batch is warmed to 80 for 1 hour and then stirred into 4 litres of water at 80. The crystalline reaction produc~ is filtered off, rinsed with warm water and dried. Yield 137 g. Melting point: 141 - 144C.
The product is sufficiently pure for further processing; the thin layer chromatogram does not show any impurities.

~ - 67 - ~ ~

: :

. .. , . . ,, : .:

The following can be prepared analogously: 2,6-di-chloro-4'-methoxy-4-nitro-diphenyl-ether, melting point:
141 - 143C; 2,6,4'-tribromo-3'-chloro-4-nitro-diphenyl-ether, melting point: 129 - 132C; 2,6-dichloro-4'-ethyl-sulphonyl-4-nitro-diphenyl-ether, melting point: 125 - 128C; 2,6-dibromo-4'-methoxy-4-nitro-diphenyl-ether, melting point: 150 -151C; 2-bromo-6-methyl-4'-chloro-4-nitro-diphenyl-ether, melt-ing point: 120 - 124C; 2-bromo-6-chloro-4'-iodo-4-nitro-diphenyl-ether, melting point: 128 - 129C; 2,6-dibromo-4'- ~ ~.
methylsulphonyl-4-nitro-diphenyl-ether, melting point: 176 -178C; 2,6,2',4',5'-trichloro-4-nitro-diphenyl-ether, melting point: 101 - 104C; 2,6,4'-trichloro-2'-methyl-4-nitro-di-phenyl-ether, melting point: 124 - 127C; 2,6-dichloro-4'-acetylamino-4-nitro-diphenyl-ether, melting point.: 206 - 208C;
2,6-dichloro-4'-(2"-oxo-pyrrolidinyl)-4-nitro-diphenyl-ether, melting point: 181 - 182C; 2-bromo-4',6-dichloro-4-nitro-diphenyl-ether, melting point: 108 - 110C; 2,4'-dichloro-6-iodo-4-nitro-diphenyl-ether, melting point: 114 - 116C; 2,6-dichloro-3'-dimethylamino-4'-methyl-4-nitro-diphenyl-ether, melting point: 93 - 96C; 2,6-dichloro-4'-fluoro-4-nitro-di- .
phenyl-ether, melting point: 117 - 119C; 2,6-dichloro-4'-(2",5"-dimethyl-pyrryl)-4-nitro-diphenyl-ether, melting point:
179 - 181C; 2,6-dichloro-4'-cyano-4-nitro-diphenyl-ether, melting point: 138 - 140C; 2,6,2',4',6'-pentachloro-3'-methyl-4-nitro-diphenyl-ether, melting point: 141 - 145C; 2,6-di-chloro-2',3'-dimethyl-4-nitro-diphenyl-ether, melting point:
101 - 104C; 2,6-dichloro-5',6',7',8'-tetrahydro-4-nitro-phenyl-naphthyl-(l')-ether, melting point: 132 - 134C; 2,6, 3'-trichloro-2'-methyl-4-nitro-diphenyl-ether, melting point:
102 - 104C; 2,6-dichloro-5'-methoxy-4-nitro-phenyl-naphthyl-(l')-ether, melting point: 1~0 - 142C; 2,6,4'-trichloro-2', . .- , .
6~ .

.

1~366Q4 3'-dimethyl-4-nitro_diph~nyl_etheI~, melting point: 157 - 158C;
2,6,2'-trichloro-4'-methylsulphonyl 4-nitro-diphenyl-ether, melting point: 208 - 210C; 2,6-dichloro-4'-methylmercapto-4-nitro-diphenyl-ether, melting point: 90 - 93C; 2,6,2'-tri-~hloro-4'-acetylamino-4-nitro-diphenyl-ether, melting point:
159 - 161C; 2,6,2',3'-tetrachloro-4'-acetylamino-4-nitro-diph-enyl-ether, melting point: 173 - 174C; 2,6,3'-trichloro-4'-acetylamino-4-nitro-diphenyl-ether, melting ~oint: 188 - 191 C;
2,~,4'-trichloro-4-nitro-phenyl-naphthyl- (l')-ether, melting point: 118 - 119C; 2,6-dichloro-4'-nitro-phenyl-naphthyl-(l')-ether, melting point: 232 - 234C.
b) 2,6,2',4'-Tetrachloro-4-amino-di~henyl-ether 135 g of the nitro compound prepared under a) are introduced into a mixture of 285 g of tin-II chloride dihydrate, 250 ml of concentrated hydrochlorid acid and 80 ml of dioxane at ~0. Her~upon, the temperature ri~e~ to 105C. The mix-ture is ~dditionally stirred ~or S~ minutes at lOu C, cooled ~- to 50C and poured into a mixture of 1.2 litres o~ 44~ strength sodium hydroxide solution and 1.2 litres of water. After ~o cooling, the product is filtered off, washed with water until neutral and dried. Yield, 114 g; melting point: 147 - 150C
.
after recrystallisation from petroleum ether.

The following can be prepared analogou~ly, 2,6-dichloro-4'-methoxy-4-amino-diphenyl-ether, melting point: 139-142C;

2,6,4'-tribromo-3'-chloro-4-amino-diphenyl-ether, melting point:

143 - 144C; 2,6-dichloro-4'-ethyl-sulphonyl-4-amino-diphenyl-ether, melting point: 147 - 148C; 2,6-dibromo-4'-methoxy-4-amino-diphenyl~ether, melting point: 115 - 116C; 2-bromo-6-methyl-4'-chloro-4-amino-diphenyl-ether, melting point: 122-123C; 2-bromo-6-chloro-4'-iodo-4-amino-dip~;enyl-ether, mel-ting point: 153 - 155 C; 2,6-dibromo-4'-methylsulphonyl-4-- 69 ~

.

lQ3f~6Q4 amino-diphenyl-ether, meltin~ point: 243 - 245C; 2,6,2',4', .~
5'-pentachloro-4-amino-diphenyl-ether, melting point: 132 - . . .
134C; 2,6,4'-1;richloro-2'-methyl-4-amino-diphenyl-ether, melting point: 104 - 106C; 2~6-dichloro-4l-acetylamino-4-amino-diphenyl-ether, melting point: 240 - 241C; 2,6-dichloro-4'- -(2"-oxo-pyrrolidinyl)-4-amino-diphenyl-ether, melting point:
198 - 199 C; 2-bromo-4',6-diGhloro-4-amino-diphenyl-ether, meltin~ noint: 1~8 - 140C; 2,4'-dichloro-6-iodo-4-amino-di-phenyl-ether, meltin~ point: 113 - 114C; 2,6-dichloro-3'-dimethylamino-4'-methyl-4-amino-diphenyl-ether, melting point: .
88 - 90C; 2,6-dichloro-4'-fluoro-4-amino-diphenyl-ether, melting point: 140 - 143C; 2,6-dichloro-4'-(2",5"-dimethyl-pyrryl)-4-amino-diphenyl-ether, melting point: 188 - 192C;
2,6-dichloro-4'-cyano-4-amino-diphenyl-ether, melting point:
164 - 167C; 2,6,2',4',6'-pentachloro-3'-methyl-4-amlno-di-phenyl-ether, melting point: 1~0 ~ C; 2,6-dichloro-2'.3'-dimethyl-4-amino-diphenyl-ether, melting point: 104 - 107C;
2,6-dichloro-5',6',7',8'-tetrahydro-4-amino-phenyl-naphthyl-(l')-ether, melting point: 108 - 110C; 2,6,3'-trichloro-2'-methyl-4-amino-diphenyl-ether, melting Point: 81 - 82C;
2,6-dichloro-5'-methoxy-4-amino-phenyl-naphthyl-(1')-ether, melting point: 146 - 148C; 2,6,4'-trichloro-2',3'-dimethyl-4-amino-diphenyl-ether, melting point: 142 - 145C; 2,6,2'-.,. . ~
~ trichloro-4'-methylsulphonyl-4-amino-diphenyl-ether, melting . ',~: .
:; point: 166 - 168C; 2,6-dichloro-4'-methylmercapto-4-amino-diphenyl-ether, melting point: 125 - 127C; 2,6,4'-trichloro-; 4-amino-phenyl-naphthyl-(1')-ether, melting Point: 140 - 142C.

~ ExamPle E

:~ 2.6.2'-Trichloro-4'-acet~lamino-4-amino-di en~l-ether :
.

. - 70 -~ .
.. .

... : . . .:

--366~4 . .
Cl Cl C~l CO ~ O ~ N~
~1 ' 110 g of 2,6,2'-trichloro-4'-acetylamino-4-nitro-di-phenyl-ether are ~tirred with ~00 ml of methanol and 5.0 g of ~aney nickel are added. 'l'he mixture is then hydrogenated at 40 to 60C and a hydrogen pressure of ~)0 atmospheres gauge until the absorption ~f hydrogen has ceased. The warm ~olution is freed from the catalyst by filtration, warm water i~ added to the flltrate until it turns turbid, and crystallisation i~
allowed to take place.
.. . . ~ .
Yield, 85 ~; meltin, point: 180 - 183C.
The following 4-amino-diphenyl derivatives can be obtained analogously from the corresponding r.i'ro compour.ds:
2,6,3'-trichloro-4'-acetylamino-4-amino-diphenyl-ether, melting point: 177 - 178C; 2,6,2',3'-tetrachloro-4'-acetylamino-4-' amino-diphenyl-ether, melting point: 223 - 225C; 2,6-chloro-~ 4'-acetylamino-4-amino-diphenyl-ether, melting point: 240 -~, .
241C, 2,6-dichloro-4'-acetylamino-4-amino-phenyl-naphthyl-(l')-ether, melting point: 202 205C.
. . . . :
.'.
SUPPLEMENTAL DISCLOSURE
, Example 15 .
1-l3,5-Dichloro-4-(4'-N-ethoxycarbonYi-N-ethoxycarbonyl-N
,' methylamino]-pheno ~)-phenyl]-uraci :': .' ,:

\
:
- 1~366~4 5 2 ~ Cl~

N ~ O
., a) 4-(N-ethoxvcarbonvl-N-methvlamino~-~he~o H5C200C-N ~ OH

... .
100 g of 4-methylaminophenol sulphate are dissolved in 100 ml of dimethylforrr.amide and 100 ml of triethylamine and 100 g .~ . .
#';':~, of pyrocarbonic acid diethyl ester are added slowly. The ~ mixture is left to ~tand for 70 hours, the solvent is ., ~ . . .- distilled off in vaouo and the residue is stirred with dilute ~, acetic acid. The compound solidifies on prolonged standing.
~he dried crude product is used for further nroce~sing~ Y~eld 95 g-. ,~ . . .
. . . ..
b) 2,6-Dichloro-4-nitro-4'-~N-ethoxycarbonyl-N-methylamino)-diphenyl-ether ' .

!~
.~, , H5a200a~ ~

.. . . . .

' ' ' ' ' , ' ' ': ' .
50.0 g of 4-ethoxycarbonyl-N-methylamino-phenol are stirred with 32 g of potassiurn tert.-butylate (90~, strength) in 120 ~1 o~ dimethyl-sulphoxide until a solution has formed. ~ 'r . .

': ~,. :
., .
.: . .
; - 72 - -,,. ~d.~,. ;' ' --~ - - , , ~ : . ;

1~366~4 This solution is added dropwise, at 15-20C, to a solution of 58 g of 3,4,5-trichloronitrobenzene in 120 ml of dimethyl-forrnamide. The mixture is stirred for 12 hours at 20C and poured into 4 1 of water and the product is filtered off, washed and dried. Yield: 95 g; melting point: 114-115 C
after recrystallisation from ethanol.
c) 2.6-~)ichloro-4-amino-4'-(N-ethoxycarbonvl-N-methYiamino) di~hen~l-ether . . - . .

;~ ~ 0~3 ~ ~ ~ C ~ ~H2 Cl 68 g of the nitrodiphenyl-ether obtained according to b) are ætirred into 350 ml o~ ethanol, 5.0 g of Raney nickel are added and the batch i~ hydrogenated at 60C and 60 atmos-pheres gauge hydrogen pressure until the absorption of hydrogen has ceased. The mixture is filtered hot to remove the catalyst and the product is precipitated from the filtrate with water. Yield: 55 g, melting point: 140-142C.

d) 1-[3,5-dichloro-4-(4'-[N-ethoxycarbonyl-N-methylamino]-phenoxy)-phenyl-3-(3-ethoxy-acryloyl)-urea ': ' C~ '' ll CN > ~ ~ NH-C-NH-C-CH=CH-OC2H5 C - .

; 20 31 E 0~ ver cyan~te ~nd 17 ~ 3-ethc,xy-ac~yli~
acid chloride in 300 ml of dry benzene are stirred for one ." ~7~ _ 73 _ ' hour at 40C and the sil~er salts are then filtered off from the solution of the 3-ethoxyacryloyl-isocyanate. The filtrate is added slowly dropwise, at 15C, to a solution of 40.0 g of the 4-amino-diphenyl-ether, obtained according to c), in 300 ml of dioxane. The mixture is stirred for a *urther hour at 40C and diluted with petroleum ether and the product is ~iltered off and dried.
Yield: 48.0 g; melting point: 210-211C.

e) 1-[3,5-Dichloro-4-(4~-[N-ethoxycarbonyl--N-methylæmino]
phenoxy)-phenyl]-uracil .

CH > ~ ~ ~ ~ ~
,: Cl o 4~.0 g o~ trle urea àerivative obtained according to d) and 12.0 g of potassi~m tert.-butylate in 4C0 .~.' of tert.-butanol are stirred for 12 hours. Most of the solvent is then distilled off and the residue is stirred with 400 ~1 o~ water and 30 ml of acetic acid. The product is filtered off, washed and dried. Yield: 43.0 g; melting point: 160-162C after recrystallisation from toluene.
~lementary analysis and the ~ ~ spectrum agree with the assumed structure.
Example 16 -r~ - chl ~ lamino-phenoxv)-~henyl1-uracil : CJ~
CH3NH ~ 0 ~ N ~ 0 ~1 o~

:
~ 74 -,, ~ . . :

~366Q4 26.0 g of the uracil derivative obtained according to Exa~ple 15 are heated in 100 ml of acetic acid and 100 ~1 of 48% strength hydrobromic acid for 30 minutes under reflux.
The ~ixture is then highly concentrated in vacuo and the resi-- due is stirred with dilute a~monia. The reaction product is ; filtered off, washed and dried. Yield: 17.0 g; melting point: 227-22qC after recrystallisatlon from ortho-dichloro-- benzene.
Elementary analysis and the ~ spectrum agree with the assu~ed structure.
,~ ' ~ ' ' .

., , ~ .
'~

.~ : .
': ' , ':
, "
: ' .
~' . '' " '.:
:.

'' ' , .' :
,,' :

. ~
., . - . ..
.. ;: . -', ~>

. -

Claims (36)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a 1-aryluracil of the formula:

wherein Ar is an aryl group of 6 to 10 ring carbon atoms, unsubstituted or substituted with from one to three like or different substituents, said substituents being selected from the group con-sisting of alkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenylthio, halogenoalkyl, hydroxy, acyloxy, methanesulfonyloxy, benzenesulfonyloxy, aryloxy, halogeno, cyano, nitro, , CO-Z

and SO2-Y in which each of R8 and R9 , independent of the other is hydrogen, alkyl, alkenyl or aryl or when taken together with the nitrogen atom to which they are cojoined, a heterocyclic ring of 5 to 7 ring members of which up to two can be fur-ther heteroatoms with the remainder being carbon atoms;

Z is hydroxy, alkoxy or ;

Y is hydroxy, alkyl, aryl or ;
each of R1 and R2, independent of the other, is hydrogen, alkyl, halogeno, alkoxy, nitro, amino, acylamino, cyano, carboalkoxy, trifluoromethyl, or wherein R8 and R9 have the same meaning as R8 and R9 ;
each of R5, R6 and R7, independent of the others, is hydrogen or alkyl; and X is -O-, -S-, -SO- or -SO2-;
or a physiologically acceptable salt thereof which comprises treating a compound of the formula:
(II) wherein Ar, X, R1 and R2 are as defined above.
(a) with an acyl isocyanate of the formula:
(III) wherein R5 and R6 are as defined above, and R10 represents alkyl, to yield a compound of the formula:
(IV) wherein Ar, X, R1, R2, R5, R6 and R10 defined which is then treated with an alkali metal hydroxide or alkoxide to yield an alkali metal salt of a uracil of the formula:

(V) wherein Ar, X, R1, R2, R5 and R6 are as defined above, and M? represents an alkali metal cation, and converting said salt to said 1-aryluracil by acidification, or (b) with a compound of the formula:

(VI) wherein R11 and R12 represent alkyl, to yield an enamine of the formula:

(VII) wherein Ar, X, R1, R2, R5 and R12 are as defined above, heating said enamine to yield a cyanouracil of the formula:

(VIII) wherein Ar, X, R1, R2 and R5 are as defined above, hydrolyzing said cyanouracil at elevated temperatures into an amide of the formula:

(IX) wherein Ar, X, R1, R2 and R5 are as defined above, and subjecting said amide to hydrolysis and decarboxylation, to yield said 1-aryluracil wherein R7 is hydrogen, and, (i) when R7 is alkyl, treating said 1-aryluracil wherein R7 is hydrogen with an alkylating agent, (ii) optionally introducing a nitro group through nitration, (iii) option-ally reducing any nitro groups to amino groups, (iv) option-ally alkylating any hydroxy group, (v) optionally acylating any hydroxy group, (vi) optionally acylating any amino group, (vii) optionally hydrolyzing any amide group, (viii) option-ally hydrolyzing any ester group, and/or (ix) in the case of the salts forming a physiologically acceptable salt thereof.
2. A 1-aryluracil of the formula:

wherein Ar is an aryl group of 6 to 10 ring carbon atoms, unsubstituted or substituted with from one to three like or different substituents, said substituents being selected from the group con-sisting of alkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenylthio, halogenoalkyl, hydroxy, acyloxy, methanesulfonyloxy, benzenesulfonyloxy, aryloxy, halogeno, cyano, nitro, , CO-Z
and SO2-Y in which each of R8' and R9', independent of the other is hydrogen, alkyl, alkenyl or aryl or when taken together with the nitrogen atom to which they are cojoined, a heterocyclic ring of 5 to 7 ring members of which up to two can be fur-ther heteroatoms with the remainder being carbon atoms;

Z is hydroxy, alkoxy or ;

Y is hydroxy, alkyl, aryl or ;

each of R1 and R2, independent of the other, is hydrogen, alkyl, halogeno, alkoxy, nitro, amino, acylamino, cyano, carboalkoxy, trifluoromethyl, or wherein R8 and R9 have the same meaning as R8 and R9 each of R5, R6 and R7, independent of the others, is hydrogen or alkyl; and X is -O-, -S-, -SO- or -SO2-;

or a physiologically acceptable salt thereof, whenever prepared according to the process of claim 1 or an obvious chemical equivalent thereof.
3. The process as defined in claim 1 wherein Ar is unsubstituted or a mono-, di- or tri-substituted phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl group wherein when substituted each substituent, independ-ent of any other, is alkyl of up to 8 carbon atoms, alkoxy of up to 6 carbon atoms, alkenyl of up to 6 carbon atoms, alkenyloxy of up to 6 carbon atoms, alkylthio of up to 6 carbon atoms, halogenoalkyl of up to 4 carbon atoms and up to 5 halogen atoms, hydroxy, acyloxy of up to 8 carbon atoms, methane-sulfonyloxy, benzenesulfonyloxy, phenoxy, halogeno-phenoxy, phenylhalogeno, cyano, nitro, amino, acyl-amino of up to 8 carbon atoms, mono- or dialkyl-amino wherein each alkyl contains up to 8 carbon atoms, carboxy, carbalkoxy wherein alkoxy contains up to 8 carbon atoms, amidocarbonyl, mono- or di-alkylamidocarbonyl wherein each alkyl contains up to 8 carbon atoms, arylamidocarbonyl wherein aryl con-tains from 6 to 10 carbon atoms, sulfo, amidosulfonyl, mono- or dialkylsulfonyl wherein alkyl contains up to 6 carbon atoms, arylamidosulfonyl wherein aryl con-tains 6 to 10 carbon atoms, alkylsulfonyl wherein alkyl contains up to 8 carbon atoms and arylsulfonyl wherein aryl contains from 6 to 10 carbon atoms;
each of R1 and R2 is hydrogen, alkyl, halogeno, alkoxy, nitro, amino, cyano, carbalkoxy or trifluoromethyl;
each of R5, R6 and R7 is hydrogen or alkyl; and X is -O- or -S-
4. A compound of the formula:

wherein Ar is unsubstituted or a mono-, di- or tri-substituted phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl group wherein when substituted each substituent, independ-ent of any other, is alkyl of up to 8 carbon atoms, alkoxy of up to 6 carbon atoms, alkenyl of up to 6 carbon atoms, alkenyloxy of up to 6 carbon atoms, alkylthio of up to 6 carbon atoms, halogenoalkyl of up to 4 carbon atoms and up to 5 halogen atoms, hydroxy, acyloxy of up to 8 carbon atoms, methane-sulfonyloxy, benzenesulfonyloxy, phenoxy, halogeno-phenoxy, phenylhalogeno, cyano, nitro, amino, acyl-amino of up to 8 carbon atoms, mono- or dialkyl-amino wherein each alkyl contains up to 8 carbon atoms, carboxy, carbalkoxy wherein alkoxy contains up to 8 carbon atoms, amidocarbonyl, mono- or di-alkylaminocarbonyl wherein each alkyl contains up to 8 carbon atoms, arylamidocarbonyl wherein aryl con-tains from 6 to 10 carbon atoms, sulfo, amidosulfonyl, mono- or dialkylsulfonyl wherein alkyl contains up to 6 carbon atoms, arylamidosulfonyl wherein aryl con-tains 6 to 10 carbon atoms, alkylsulfonyl wherein alkyl contains up to 8 carbon atoms and arylsulfonyl wherein aryl contains from 6 to 10 carbon atoms;
each of R1 and R2 is hydrogen, alkyl, halogeno, alkoxy, nitro, amino, cyano, carbalkoxy or trifluoromethyl;
each of R5, R6 and R7 is hydrogen or alkyl; and X is -O- or -S-, or a physiologically acceptable salt thereof, whenever prepared according to the process of claim 3 or an obvious chemical equivalent thereof.
5. The process as defined in claim 1 wherein Ar is phenyl or mono-, di- or tri-substituted phenyl wherein when substituted each substituent, independ-ent of any other, is methyl, ethyl, methoxy, methyl-thio, trifluoromethyl, allyloxy, hydroxy, acetoxy, phenoxy, chlorophenoxy, halogeno, cyano, nitro, amino, methanesulfonyl or ethanesulfonyl;
X is -O- or -S-;
each of R1 and R2, independent of the other, is hydrogen, methyl or halogeno; and each of R5, R6 and R7 is hydrogen.
6. A compound of the formula:
wherein Ar is phenyl or mono-, di- or tri-substituted phenyl wherein when substituted each substituent, independent of any other, is methyl, ethyl, methoxy, methylthio, trifluoromethyl, allyloxy, hydroxy, acetoxy, phenoxy, chlorophenoxy, halogeno, cyano, nitro, amino, methanesulfonyl or ethane-sulfonyl;
X is -O- or -S-; and each of R1 and R2, independent of the other, is hydrogen, methyl or halogeno;
or a physiologically acceptable salt thereof, whenever prepared according to the process of claim 5 or an obvious chemical equivalent thereof.
7. The process as defined in claim 1 wherein Ar is phenyl or mono-, di- or tri-substituted phenyl in which when substituted each substituent, independent of any other, is chloro, bromo, amino, methyl or methylsulfonyl;
each of R1 and R2, independent of the other, is hydrogen, methyl, chloro or bromo;
each of R3, R6 and R7 is hydrogen; and X is oxygen.
8. A compound of the formula:

wherein Ar is phenyl or mono-, di- or tri-substituted phenyl in which when substituted each substituent, independent of any other, is chloro, bromo, amino, methyl or methylsulfonyl; and each of R1 and R2, independent of the other, is hydrogen, methyl, chloro or bromo;

or a physiologically acceptable salt thereof, whenever prepared according to the process of claim 7 or an obvious chemical equivalent thereof.
9. The process for the preparation of 1-[3,5-dichloro-4-(2',4'-dichloro-phenoxy)-phenyl]-uracil which comprises treating 3,5,4'-trichloro-4-amino-diphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-chloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide, and acidifying the product.
10. 1-[3,5-dichloro-4-(2',4'-dichloro-phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 9 or an obvious chemical eauivalent thereof.
11. The process for the preparation of 1-[3,5-dichloro-4-(2',4',5'-trichloro-phenoxy)-phenyl]-uracil which comprises treating 2,6,2',4',6'-pentachloro-4-amino-diphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the re-sultant 1-[3,5]dichloro-4-(2',4',5'-trichloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
12. 1-[3,5-dichloro-4-(2',4',5'-trichloro-phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 11 or an obvious chemical equivalent thereof.
13. The process for the preparation of 1-[3,5-dichloro-4-(2'-chloro-4'-methylsulphonyl-phenoxy)-phenyl]-uracil which comprises treating 2,6,2'-trichloro-4'-methyl-sulphonyl-4-amino-diphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(2'-chloro-4'-methylsulphonyl-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
14. 1-[3,5-dichloro-4-(2'-chloro-4'-methylsulphonyl-phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 13 or an obvious chemical equivalent thereof.
15. The process for the preparation of 1-[3,5-dichloro-4-(2',4'-dichloro-phenoxy)-phenyl]-uracil which comprises treating 2,6,2',4'-tetrachloro-4-amino-diphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the re-sultant 1-[3,5-dichloro-4-(2',4'-dichloro-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
16. 1-[3,5-dichloro-4-(2',4'-dichloro-phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 15 or an obvious chemical equivalent thereof.
17. The process for the preparation of 1-[3,5-dichloro-4-(4'-acetylamino-phenoxy)-phenyl]-uracil which comprises treating 2,6-dichloro-4'-acetylamino-4-amino-diphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-acetylamino-phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
18. 1-[3,5-dichloro-4-(4'-acetylamino-phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 17 or an obvious chemical equivalent thereof.
19. The process as defined in claim 17 including the step of subjecting 1-[3,5-dichloro-4-(4'-acetylamino-phenoxy)-phenyl]-uracil to acidic hydrolysis to yield 1-[3,5-dichloro-4-(4'-amino-phenoxy)-phenyl]-uracil.
20. 1-[3,5-dichloro-4-(4'-amino-phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 19 or an obvious chemical equivalent thereof.
21. The process for the preparation of 1-[3,5-dichloro-4-(2'-naphthoxy)-phenyl]-uracil which comprises treating 3,5-dichloro-4-naphthoxy-aniline with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(2-naphthoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
22. 1-[3,5-dichloro-4-(2'-naphthoxy)-phenyl]-uracil whenever prepared according to the process of claim 21 or an obvious chemical equivalent thereof.
23. The process for the preparation of 1-[3,5-dichloro-4-(4'-acetylphenoxy)-phenyl]-uracil which comprises treating 2,6-dichloro-4'-acetyl-4-aminodiphenyi-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-acetylphenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
24. 1-[3,5-dichloro-4-(4'-acetylphenoxy)-phenyl]-uracil whenever prepared according to the process of claim 23 or an obvious chemical equivalent thereof.
25. The process for the preparation of 1-[3,5-dichloro-4-(4'-methylsulphonylphenoxy)-phenyl]-uracil which comprises treating 2,6-dichloro-4'-methylsulfonyl-4-amino-diphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-methylsulfonylphenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
26. 1-[3,5-dichloro-4-(4'-methylsulphonylphenoxy)-phenyl]-uracil whenever prepared according to the process of claim 25 or an obvious chemical equivalent thereof.
27. The process for the preparation of 1-[3-bromo-4-(4'-chlorophenylthio)-phenyl]-uracil which comprises treating 2-bromo-4'-chloro-4-aminodiphenylthio-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3-bromo-4-(4'-chlorophenylthio)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidify-ing the product.
28. 1-[3-bromo-4-(4'-chlorophenylthio)-phenyl]-uracil whenever prepared according to the process of claim 27 or an obvious chemical equivalent thereof.
29. The process for the preparation of 1-[3,5-dichloro-4-(4'-chlorophenoxy)-phenyl]-uracil which comprises treating 2,6-dichloro-4'-chloro-4-aminodiphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-chlorophenoxy)-phenyl]-3-(3-ethoxy-acryloxy)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
30. 1-[3,5-dichloro-4-(4'-chlorophenoxy)-phenyl]-uracil whenever prepared according to the process of claim 29 or an obvious chemical equivalent thereof.
31. The process for the preparatlon of 1-[3,5-dichloro-4-(4'-bromophenoxy)-phenyl]-uracil which comprises treating 2,6-dichloro-4'-bromo-4-aminodiphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-bromophenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
32. 1-[3,5-dichloro-4-(4'-bromophenoxy)-phenyl]-uracil whenever prepared according to the process of claim 31 or an obvious chemical equivalent thereof.
CLAIMS SUPPORTED BY THE SUPPLEMENTAL DISCLOSURE
33. The process for the preparation of 1-[3,5-dichloro-4-(4'-[N-carbethoxy-N-methylamino]phenoxy)-phenyl]-uracil which comprises treating 2,6-dichloro-4'-[N-carb-ethoxy-N-methylamino]-4-aminodiphenyl-ether with 3-ethoxy-acryloyl-isocyanate, treating the resultant 1-[3,5-dichloro-4-(4'-[N-carbethoxy-N-methylamino]phenoxy)-phenyl]-3-(3-ethoxy-acryloyl)-urea with an alkali metal hydroxide or alkoxide and acidifying the product.
34. 1-[3,5-dichloro-4-(4'-[N-carbethoxy-N-methylamino]phenoxy)-phenyl]-uracil whenever prepared according to the process of claim 33 or an obvious chemical equivalent thereof.
35. The process as defined in claim 33 in-cluding the step of subjecting 1-[3,5-dichloro-4-(4'-[N-carbethoxy-N-methylamino]phenoxy)-phenyl]-uracil to acidic hydrolysis to yield 1-[3,5-dichloro-4-(4'-methylaminophenoxy)-phenyl]-uracil.
36. 1-[3,5-dichloro-4-(4'-methylaminophenoxy)-phenyll-uracil whenever prepared according to the process of claim 35 or an obvious chemical equivalent thereof.
CA222,621A 1974-03-26 1975-03-20 1-aryl-uracils Expired CA1036604A (en)

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CN108530310A (en) * 2017-03-02 2018-09-14 中国科学院上海药物研究所 2- (the miscellaneous base of substituted benzene) fragrance formic acid class FTO inhibitor, preparation method and its application

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DE10040174A1 (en) 2000-08-17 2002-02-28 Bayer Ag Use of triazinetrione sulfones to combat coccidioses
KR20210097148A (en) 2018-11-30 2021-08-06 오츠카 세이야쿠 가부시키가이샤 Heterocyclic compounds for the treatment of epilepsy

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CN108530310A (en) * 2017-03-02 2018-09-14 中国科学院上海药物研究所 2- (the miscellaneous base of substituted benzene) fragrance formic acid class FTO inhibitor, preparation method and its application
CN108530310B (en) * 2017-03-02 2025-01-28 中国科学院上海药物研究所 2-(substituted benzyl)aromatic formic acid FTO inhibitor, preparation method and application thereof

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DK139138B (en) 1978-12-27
AT336039B (en) 1977-04-12
LU72124A1 (en) 1976-02-04
ATA223675A (en) 1976-08-15
NL7503630A (en) 1975-09-30
HU170782B (en) 1977-09-28
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ZA751883B (en) 1976-02-25
GB1456964A (en) 1976-12-01
ES436034A1 (en) 1977-01-01
PH12431A (en) 1979-02-22
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CS188945B2 (en) 1979-03-30
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BE827119A (en) 1975-09-25
FR2265388B1 (en) 1978-08-04
IE41222L (en) 1975-09-26
DE2414612A1 (en) 1975-10-16
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SE7503470L (en) 1975-09-29

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