CA1069908A - Process for the preparation of anthelmintically active 2-carbalkoxyamino-benzimidazole derivatives - Google Patents
Process for the preparation of anthelmintically active 2-carbalkoxyamino-benzimidazole derivativesInfo
- Publication number
- CA1069908A CA1069908A CA261,424A CA261424A CA1069908A CA 1069908 A CA1069908 A CA 1069908A CA 261424 A CA261424 A CA 261424A CA 1069908 A CA1069908 A CA 1069908A
- Authority
- CA
- Canada
- Prior art keywords
- carbomethoxyamino
- phenyl
- acid
- benzothiadiazine
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention is directed to a process for the preparation of a 2-carbalkoxyamino-benzimidazole derivative of the formula (1)
This invention is directed to a process for the preparation of a 2-carbalkoxyamino-benzimidazole derivative of the formula (1)
Description
2-Carbalkoxy-amino-benzimidazolyl derivative~ ha~ing alkyl, acyl, phenoxy and phenylthio radicals in 5(6)-position are known as anthelmintics (P. Actor et al., Nature ~, 321 (1967); G~rman Of~enlegungs~chri~t NoO 2,0299637; Garma~
Offenlegungsschrift No o 2 ~1 64,690; German Of~enlegungsschri~*
No. 2~363~348)o . ~
The s~bject o~ the in~ention is a process for preparing -CRr~ ox~
anthelminticall~ active 2~ ~ -amino-benzimidazole deri-vatives o~ the formula (1)
Offenlegungsschrift No o 2 ~1 64,690; German Of~enlegungsschri~*
No. 2~363~348)o . ~
The s~bject o~ the in~ention is a process for preparing -CRr~ ox~
anthelminticall~ active 2~ ~ -amino-benzimidazole deri-vatives o~ the formula (1)
3 X _~3 I ~ COOR~
wherein Rl i5 alkyl ha~ing 1 to 4 carbon ato~s, R2 and R3 are, independen~lr Prom each other, hydrogen, alkoxy ha~ing t to 4 carbon atoms, halogen, trifluoromethyl, alkyl ha~ng 1 to 4 carbon atoms or ON and X are the group -O-SO~ or -S02-0-, which co~prises treating a lH-2 5 1 ~ 4-benzothiadiazi~e derivati~e of the formula ~2), wherein R1 to R3 and X ha~e ths sama m~aning as in ~ormula (1), R~ i5 hydrogen, an acetyl or ben zoyl r~dical and n is zero or 1, with an acid or triphenyl-phosphine or, if R4 stands ~or the acetyl- or benzoyl radical, with a base~
~2~ R4~ .
3 X N--S~ ~)n (2)~ ---~- 2 ~ .
6~ H ~
As alkyl radicals in the substituent~ R1, R2 and R3 there are considered~ Methyl, athyl, propyl, isopropyl, butrl, secondary butyl, tertiary butylO As alkoxy groups in the ubstituents R2 and R3 th~re may be considered: msthoxy, ethoxy, propoxy, isopropoxy and butoxy. As halogen atoms in the substituents R2 and R3 th~re ~re conRidared fluorine, chlorine, bromi~e a~d ~odine.
There are e~peciall~ pre~erred compounds o~ the formula (1) wherein R1 i~ methyl, ethyl, propyl or butyl, R2 is hydro-gen and R3 i6 hydrogen, chlorine, bromine, trifluoromethyl,methyl, ethrl, methoxy or ethoxy, R3 being preferably in a 3-po~ition o~ the phenyl ring.
I~ tho procsss o~ the i~Yention i3 carried out by reac-ting a benzothiadiazine deri~ative of the formula (2), wherein ~5 R4 is hydrog0n, with an acid, expedie~tly at least equimolar amounts of the acid are mixed with a solution o~ the compound ~;
of the ~ormula (2), wheroin R~ iB hydrogen. Suitabl~ sol~entQ
are above all polar or~anic solvents such as lower aliphatic alcohols, ethers, dioxane, acetone, acetonitrile, d~0thylene-glycol e~her, tetrahydrofurane, dimethylformamide both in pure form and in mixture with ~ater. In the latter ca~e the pH ~alue ~s expediently below 4. The reaction temperature may range between 0 and 120 C, preferably between 15 and 60C.
Suit ble acids are miner~l acids such as halohydric acids and other ~ineral acids and strong organic acids, as for example sul~onic acids.
If the process o~ the in~ention is carried out by reac-ting a ben~othiadiazine derivatiYe of the fo~mula (2~, wherein -~29 R4 is hydrogen, with triphenyl phosphine, the reactants are - 3 ~
- -. . ., .. :. :, :i .. , ~ i:, ,. ,: ,, ; : . .... .. . .~. :
~IL()69908 expediently heated in a solvent up to a temperature between 40 and 120C, preferably up to the boiling point of the solvent used.
Suitable solvents are especially aprotic solvents such as chloro-form, benzene, methylene dichloride, tetrahydrofurane or dioxane.
If the process is carried out by reacting a benzothiadiazine derivative of the formula (2) J wherein ~4 stands for an acyl radi-cal, with a base, at least equimolar amounts of the base are mixed with a solution of the compound of the formula (2). Suitable solvents are the same as described above in the reaction with acid.
If the solvents mentioned are present as a mixture with water the pH value of the reaction medium shall not exceed 8. Suitable bases are inorganic bases such as alkali metal and alkaline earth metal hydroxides, alkali metal carbonate and -hydrogen carbonates ~
as well as alkali metal phosphates, and organic bases such as ~ j tertlary amines and quaternary ammonium hydroxides.
Especially good results are obtained by reacting benzothia-diazine derivative of the formula (2) with triphenyl phosphine ^~
in~a solvent.
The preparation of the starting materials of the formula (2) !~
is subject of the copending Canadian Patent Application Serial No.
261,426, filed concurrently herewith and is~carried out by reduc-tion of an o-nitro-phenyl-thiono-carbamoyl-carbaminate of the j;
23 formula (3) R2 ~ -~ X - ~ NO2 (3) 3 NH CS-NH-COORl ,-' ~
99~ , in which Rl, R2, R3 and X hava the meanin~ men$ioned for for-mula (2)~ with sodium dithionite in a~ alkaline solution.
Th~ o-nitro-phenyl-thionocarbamoyl-carbaminate i~ ob-tained ~rom a o~nitro-aniline derivativa of the ~ormula (4~ ;
R2 ~ X - ~ 2 (4 --- -- - . .. .. ... . - ~
by reactio~ with alkylisothiocyanato ~ormiate of the formula . S = C = N - COOR
-wherbin the substituents ha~e the abo~e meanings.
~ lH-291,4-benzothiadiazine derivatives of the formula , .
(Z) there are considered the 3-,carbomethoxyamino-7-(lH-2,1,4-benzothiadiazine)-~ul~onic acid phenyl aster 3-carbomethoxyamino-7~ 2,1,4-b6!nzothiadiazine)-sulfonic aoid 4-chloro-phenyl ester 3-carbomethoxya~ino-7-(1H-2,1,4-benzothiadiazi~e)-~ulfonic acid 3 ohloro-phenyl ester 3-carbomethoxyalaino-7-(1H-2,1,4-benzothiadia~lne)-sulf`onic .
acid 2-chloro-phenyl ester -3-carbomethoxyamino-7(l~-2,1,4-benzothi~diazine)-~ul~onic aoid 2,5-dichloro-phenyl ester 3-carbomethoxy~mino-7-~1H-2,1,4-ben~othiadiazine)-sulfonic acid 3,5-dichloro-phe~yl ester 3~carbomethoxyamino-7-(lH-2, 1, 4 benzothiadiazine )-sul~onic acid 4-bromo-phenyl ester 3-carbomethoxyamino-7-(lH-2,1,4-benzothiadiazine~-sulfonic acid 3 bromo-phenyl ester ._ 5 _ .' ' , ;,. . ,, l :` :,. ' ' `, .'. i ~ ' '~ ~ ' ' ' 99~3 3-carbomethoxyamino-7~ 2,1,4-benzothiadiazin~-sulfonic acid 2-bromo-phenyl ~ster 3-carbomethoxyamino-7 (1H-291,4-benzothiadiazine) sul~onic acid 4-methyl-phenyl estar 3-carbometho~yamino 7-(1H-2,1,4-benzothiadiazinc)~sulfonio acid 3-methyl phenyl e~t~r 3-carbomathoxyamino 7-(lH-2,1,4-benzothiadiazine~- 8U~ ~onic acid 2~methyl~phenyl ester 3-carbom~thoxyamino~7-(1H~2,1,4-benzothiadiazine) sulfonic acid 4-t.butyl-phenyl e6ter 3-carbomethoxyamino 7-(lH-2 9 1 ~ 4-benzothiadiazine)-~ulfonic ~ :
acid 2,4Qdimethyl-phenrl ester 3-carbomethoxyamino-7-tl~2,1,4benzothiadiazine)~sulfonic cid 2-chloro~4-methyl~phonyl ester 3-carbomethoxyamino~7-(lH-2,1 9 4-benzothiadiazine)-sulfonic a¢id 2-chloro-6-methyl-phenyl ester 3-c~rbomethoxyamino-7-(lH~2,1,4 benzothiadia~ine)-sul~onic acid 3-chloro-~methyl-phenyl ester 3-carbomethoxyami~o-7-(lH;2,1,4-b~nzothiadiazine)-sulfonic-acid ~=chloro-6-methyl-phenrl ester 3-carbomethox~ami~o-7-(lH-2,1,4-benzothiadiazine)-sulfonic acid 4-chloro-2-methyl-phenyl ester 3 carbomethoxyamino-7-(lH-2,1,4-benzothiadiazine)-sul~onic acid 4Dchloro-3-msthyl-phenyl eRter 3-carbomethoxyamino-7-(1R-2,1,4-benzothiadiazine)-sulfonic acid 3-trlfluoromethyl-phenyl ester 3 carbomethoxyamino~7-(lH-2,1,4-ben~othiadiazine)-sul~onic acid 4-methoxy-phenyl esker 29 3-carbomethoxyamino-7-(lH-2,1,4-b~n~othiadiazine)-~ulfonic ~611G9911 8 ~1~!2 acid 3-methoxy-phenyl ester 3 carbomethoxyamino-7-(lH-2,1,4~benzothiadiazine)-sUlfonic acid 2-methoxy-phenyl est~r 3-carbomethoxyamino-7-(lH-2,1,4benzothiadiazine)-sulfonic acid 4 propoxy-phenyl ester 3-carbomethoxyamino 7-(lH-2,1,4-ben~othiadiazine)-sul~o~lc acid 4-isopropoxy-phenyl e~t~r 3-carbomethoxyamino-7-(lH-Z11,4-bcnzothiadiazine)-~ulfonic acid 4-buto~y-phenyl e~ter 3-carbomethoxyamino-7-~lH-2,1,4-b~nzothiadiazine)-sulfonic acid- 4-isobutoxy~phenyl est~r :.
3-carboethoxyamino-7-(lH-2,1,4-benzothiadiazlne) sulfonic acid phenyl ester 3 carbopropoxyami~o-7-(lH-2,1,4-b~nzothiadiazine~-~ulfonic acid ph~nyl e~tar 3-carbi~opropoxyamino-7-(lH~2~1,4~-b~nzothiadiazine)-sulfonic acid ph~nyl est~r 3 carbbutoxyami~o-7-(lH~2,1p4;benseothiadiazine)-sulfonic acid phenyl ester 3~carbiaobuto~yami~o7 (1~-2,1,4-benzothiadiazina~-sulfonic acid phenyl ester 3-carbo-t.-butoxyamino-7-(lH-2,1,4-benzothiadiazine)-sulfonic - acid phen~l ester 3-carbom~thoxyamino 7-phenyl~ul~onyloxy-lH-2,1,4-benzothia-diazine 3-carbom~thoxyamino-7-(4-chloroophenylsulfonyloxy)~lH~2,1,4 benzothiadiazine 3-carbom0thoxyamino-7-(3-chloro-phenylsulfonyloxy)-1H-2,1,4-29 ben20thiadiazine :- . ' : ' ''' :" '' ` ' :'"',. :'";' " ' ' :' : '-"' . '.' :' ': ' ':,: ''' , :' ~ , , ,' : :':: : : : ,, ,:, .:. ::, ':~: ': ,., " ' :, ' , '.,'', .,, . ::,: : :' ': :
': . . ~ ' ' ' : . : , ., ',:::: ,' ', :' ': ,' :'.: ' ' :, , , :,~ ' . " "; '' ' , ' ': :
~6~
3-carbomethoxyamino-7-(2-chloro-phenyl~ulfonyloxy)-lH-2,1,4-benzothiadiazine 3-carbome thoxyamino- 7-(2,5-dichloro-phenylsul~onyloxy)-lH-2,1,4-benzothiadiazine 3-carbomethoxyamino-7-(3,4~dichloro-phenylsu~fonyloxy)-1H-2,1,4-benzothiadiazin0 3-carbomethoxyamino-7-(3,5-dichloro-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine ~.
3-carbomethoxyamino-7-(4-bromo-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine 3-carbometho~yamino-7-(3-bromo-phenylsulfonyloxy)-lH-2,1,4-benzothiadlazine 3-carbomethoxyamino-7-(2-bromo-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine 3-carbomcthoxyamino 7-(4-methyl-phenyl~ulfonyloxy)-tH-2,1,4-benzothiadiazine 3-cQrbomethoxyamino-7-(3-methyl-phanylsulfonyloxy~-lH-2,1,4-bcnzothiadiazine 3-oarbometho~ya~ino-7-(2-methrl-phenylsulfonyloxy)-lH-2,1,4 benzot~iadiazine 3-carbomethoxyamino-7~(4-tert.butyl phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine 3-carbomethoxyamino-7-(2-ohloro-4-methyl-phenylsul~onyloxy)-1H-2,1,4-benzothiadiazino 3-carbomethoxyamino-7-(2-chloro-6-methyl-phenylsulfonyloxy)-lH-2,1,4-benzothiadia~ine 3-carbomethoxyamino-7-(3~chloro-4-methyl-phenylsulfonyloxy)-lH-2,1,4-benzothiadiazine 29 3-carbomethoxyamino-7 (3-chloro-6-methyl-phenylsulfonyloxy)-: - 8 - :
:: : : . . . : ~ ': ' ' ; :, ~. ' . ! . `
~L~69~
1H 2,1,4-benzuthiadiazi~e ~; :
3-carbomethoxyamino-7-(4-chloro-2-methyl-phenylsulfonyloxy) 1~ 2,1,4-benzothiadia~ine 3-carbomethoxyamino-7-(4-chloro-3-methyl-phenyl~ulfonyloxy)-lH-2,1,4-benzothiadia%ine 3-carbomethoxyamino-743-trifluoromethyl-phenylsulfonyloxy)-lH-2,1,4-bo~zothiadiazine 3-carbomethoxyamino-7-(4-methoxyph~nyleulfonyloxy)-1H-2,1,4-benzothiadiazine : .
3-carbomethoxyamino-7-(3-methox~-phenylsulfonyloxy)-lH-2,1,4 benzothiadiazine 3-carbomethoxyamino-7-(2-methoxy-phenyl~ul~onyloxy) lH-2,1,4 benzothiadiazine 3-carbomethoxyamino-7-(4 propoxy-phenylsul~onyloxy)-1H-2,1,4-.
benzothiadiazine 3-carbomethoxramino-7-(4-isopropo:~y,-phenylsulfo~yloxy)-lH-2,1,4-benzothiadiazine 3-carbomethoxyamino-7-(4-butoxy-phenyl~ulfonyloxy)-lH-2,1,4-benzothiadiazine 3-oarbomsthoxyamino~7-(4-isobutoxy-phenyl~ul~onyloxy)-lH-2,1,4-b~n~othiadiazine 30carboethoxyamino-7-phenylsul~onyloxy 1H-2,1,4-b0n~othia-diazlne 3-carbopropoxyamino-7-phenyl~ulfonyloxy-lH~2,1,4-benzothia-diazine3-carboisopropoxya~ino-7-phenylsul~onyloxy~lH-2 9 1 ~ 4-benzo-thiadiazine 3-carbobutoxyamino-7-phenylsulfonyloxy~lH-2,1,4-benzothia- ~:
.. . .
29 diazine _ 9 _ ~:
~0699~ HOE ~
_., :
3-carbisobutoxyamino-7-phenylsulfonyloxy 1H-2,1,4-b0nzothia-dlazin~ ~
3-carbo-t.butoxyamino-7-phenyl~ulfo~yloxy~ 2,1,4-benzothia- :
diazine 3-carboethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy) lH-2,1,4-benzothiadia~ine 3-carbisopropoxyamino-7~(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazi~o 3-carbisobu~tox~amino-7-(3-trifluoromethyl-phenyl~ulfonyloxy)-10 lH 2,1,4-benzothiadiazine.
According to the proces~ described the following 2-carb- ;
alkoxy-amino-benzimidazole derivativas are obtained for example:
2-carbomethoxyamino-5-b2nzimidazol-sul~onic aoid-phenyl o~ter 2-carbomethoxyamino-5-benzimidazol-4-chloro-sulfonic acid-phenyl ester 2-carbomethoxyamlno-5-benzimidazol-3-chloro-sulfonic acid-phenyl eæter 2-carbomethoxyamino-5-benzimidazol-2-chloro-sulfonic acid-20 phenyl ester ~ .
2-carbomethoxyamino-5-benzimidazol-2,5-dichlorD-3ulfonic acid- -ph~nyl e~ter :~
2-carbomethoxyamino-5-benzimidazol-3,5~diohloro~sul~onio acid-phen~l e 9 ter 2-carbomethoxyamlno-5-benzimidazol 4-bromo-sulfonic a~id-phenyl ester 2-carbomethoxyami~o-5-benzimidazol~3-bromo-sulfonic aoid- ~:
phenyl ester 29 2-carbomethoxyamino-5-benzimidazols2-bromo-sulfonic acid-1[3~99~
phenyl 9 ~ ter 2-carbom6thoxyamlno-5~benzimidazol~4-methyl-sul~onic acid-phenyl ester 2-carbomethoxramino-5-b6nzimidazol-3-methyl~sulfonic acid-phenyl ester 2-carbomethoxyamino-5-benzimidazol-2-methrl sulfonic acid~
phenyl cster 2-carbomethoxyamino-5-benzimidazol-4-tert.butyl-~ulfonic acid-ph~nyl ester 2-carbometho~yamino-5-benzimidaæol-2,~-dimethyl-sulfonio acid-phenyl ester~
2 carbomethoxyaml~o05-benzimidazol-2-chloro-4-methyl-~ulfonic acid-phenyl e~ter 2-carbomethoxramino-5-benzimidazol-2-chloro-6-methyl-sulf`onic ~.
acid~phenyl ester 2-~arbomethoxyamino-5-benzimidazol-3-chloro-4-methyl-~ulfonic acid-phenyl e~ter 2- arbomethoxyamino-5-benzimidazol-3~chloro-6-m~thyl-~ulfonic aoid-phenyl n~tor 2-carbom~thoxyamino-5-benzlmidazol-3-chloro-4-carbethoxy-sul~onic acid-phenyl ester 2~carbomethox~mino-5-benzimid~zol 4-chloro-2-methyl-6ulfonic acid-phenyl est~r 2~carbomethoxyamino-5-benzimidazol-4-chloro-3~msthyl-~ul~onic acid-phenyl ester 2-carbomethoxyamino 5-benzimidazol-3-trifluoromethyl-~ul~onic ~ .
acid phenyl e~ter 2-carbomethoxyamino-5-benzimidazol-3,5-bistrifluoromethyl-29 sulfonic acid phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-methoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-3-methoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-2-methoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-propoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-isobutoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-butoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-isobutoxy-phenyl ester 2-carboethoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbopropoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbisopropoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbobutoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbisopropoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbo-tert.-butoxyamino-5-benzimidazol-sulfonic acid-phenyl ester ester 2-carbomethoxy-5(6)-phenylsulfonyloxy-benzimidazole 2-carbomethoxy-5-(6)-(4-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(3-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(2-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(2,5-chloro-phenylsulfonyloxy)-benzimid-dazole 2-carbomethoxy-5-(6)-(3,5-chloro-phenylsulfonyloxy)-benzimi-dazole 2-carbomethoxy-5-(6)-(3,4-dichloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(4-bromo-phenylsulfonyloxy)-benzimi-dazole 2-carbomethoxy-5-(6)-(3-bromo-phenylsulfonyloxy)-benzimi-dazole 1~:1169908 H~
2-carbometho~cyamino-5(6~-(2-bromo phenylsulfonyloxy)wbenzimi-dazole 2~çarbomethoxyamino~5(6)~(4 m~thyl-phenylsul~onyloxy) benzimi- -dazole 2-earbomethoxramiIlo-5(6)-(3-methyl-phenylsul~onyloxy)~benzimi~ ~:
dazole 2-earbomethoxyamino-5(6~-(2-methyl-phenyl~ulfonyloxy)-benzimi-dazole 2-carbo~ethoxya~ino-5(6)-(4-tert.butyl-phenylsul~onyloxy)-~0 benzimidazole 2-carbo~ethoxyamino-5(6)-~2-chloro-4-methyl-phenyl~ulfo~yloxy)-benzimidazol~
2-carbomethoxyamino-5(6)-(Z-chloro-6-methyl phenylsulfonyl- :
oxy)-benzimidazole 2-carbomethoxy~mino-5(6)-(3-chloro-4-methrl-phenylsulfonyl-oxy)-benzlmidazole 2-carbomethoxyamlno,5(6)~(3-chloro-6-methyl-phenyl~ulfonyl-oxy~ -benzimidazsle 2-carbomethoxyamino-5(6)-(4-chloro-2-methy~-phenylsulfonylw oxy)-benzimidazole 2-carbomethoxyamino-5(6)-(4-chloro 3~methyl-phenylsulfonyl- -o~y) benzi~idazole 2-carbomathoxyamino-5~6)-(4-chloro-3,5-dimethyl-phenyl-sulfonyl~- )-ben~imidazole 2 carbomethoxyamino-5~6) (3-tri~luoro~ethyl-phenylsul~onyl)-benzimidazole -carbomethoxyamino-5(6)~(4-methoxy phenylsul~onyl)-benzimi- -I, dazole i 29 2-carbomethoxyamino-5~6)-(3-methoxy-phenylsulfonyl)~benzi~i-, - 13 -dazole 2 carbomethoxyamino-5(6)-(2-methoxy-phenyl~ulfonyl)~benzimi-dazole 2-carbomethoxyamino-5(6)-(4~propoxy-ph~nyl~ul~onyl)-be~imi dazole 2 carbomethoxyamino 5(6)-(4-is3propoxy-phenylsulfonyl)-benzimidazole 2-carbomethoxyamino-5(6~-(4-buto~y-phenylsulfon~ benzimi-dazole 2-carbomethoxyamino-5(6)-(4-isobutoxy-phenylsulfonyl)-benzimidazole 2--carbetho~yamino 5(6)-phenyl6ulfonyl-benzimidazols 2-carbopropoxyamino-5(6)-phenylsul~onyloxy-benzimidazole 2-carbisopropoxyamino-5(6) phenyl~ul~onyloxy-benzimidazole ;~i~
2-carbobutoxyamino-5(6~-phenylsulf'onyloxy-bengimida~ole 2-carbisobutoxyamino-5(6)-phenylstllfonyloxy-benzimidazole 2-carbDtart.butoxyamino-5~6)-phenylsul~onyloxy-b2nzimida~ole 2-carbethoxyamiMo-5(6)~(3-trifluoromathyl-phenylsulfonyloxy 3 - :
benzimidazole 2-oarbi~opropoxyamino-5(6)-~3~trifluoromethyl-pheny~sul~onyl)-benzimidazole 2-carbi~obutoxyamino-5(6)-(2-tri~luoromethyl-phenylsulfonyl)~ :~
benzimidazoleO
The 2-carbalkoxyamino-benzimida~ole deriYatiYe~ o~ the invention are valusble chemoth2rapeutics and are suitable for combating parasitic diseases in humans and animals.
They are particularly acti~e against a great number of c~ helminth~, for example Haemonchus~ Trichostrongylus, O~ter-29 tagia, Strongyloides, Cooperia, Chabertia, Oesophagostomum, 14 ~ ~ -~69~8 ~
Hyostrongylus, Ankylostoma, Ascaris and Heterakis. The com-pounds have a particularly pronounced activity against gastric and inte~tinal strongylide~ which attack above all ruminant~
and cau~e considerable sconomic losses; for that reason the compounds of the invention ars especially used in veteri~ary medicine .
Depending on the ca~e the active substance~ of the for~
mula (1) are administered in dosage units between 0.5 and 50 mg per kg of body weight.
For oral application tablets, dragees, capsules, powders, granules or paste6 are considered, which contain tha acti~e substance~ together with u~ual auxiliaries and carrier~ such as t~rch, ccllulose powder~ talc, magnasium stearate, ~ugar, gelatine.9 calcium carbonate, finely divided silicic Aoid, carboxymathyl cellulo6e or similar substances.
~or parenteral application thore are considered solutions, for example oily sclutions which are prepar0d while using sesame oil, c~stor oil or synthetic trigl~rcerides, if desired ~ -with addition of t~kopherol as antioxydating agent and/or while using ~urface~acti~e ~ubstances ~uch as sorbitane-fat*y acid ester. Aqueou~ suspension are co~sidered, which are pre pared while usi~g ethoxylatsd serbitane-~atty acid ester, if desired with addition or thickening agsnts, such as polyethy-lene glycol or carboxymethyl cellulose.
The concentrations of the active subs*ances accordi~g to the invention in the compositio~ prepared with these ~ub-stances are preferablr between 2 and 20 percent by wsight for being u~ed as veterinary medicament; ~or use as human ~edi-29 cament the concentrations o~ the active substanoes preferably , ..... ~......... - . . ~ ,, ,. , ,~; . . .
'. ,, :;" :: ' ' ' ' . ' ' "' '' ' . .; ,. ' " ' ' . ' : : ' ' ~, i~ - .. ~ ' ' ., .. . ' ' ' ,',,' '- ". '.' '. , '.. ... ~.. , .. :.. ' , :: ' ': ~ ' , ': ' : ' .1, .: ,:, . , :' ': ,.'.: .: .' ' : ,, , '`, ""' ' ' ' ' ' . ' : .:
': ' . ' ' ' : . ' :: ' ;: : ' : . . ' ': ' , , ; .. .. ' ' ' : ' : ,: . '. ' ., . : :
. . ' : . ':: ":: . , ' ,,: , :, , .: . ~
':,: ' ' . ' :. ': .. ' .. ''' :,, "',' ' " "''' '' ' ' ',' " '' ' ' ' ":
~6~
range between 20 and 80 perc0nt by weight.
The products of the process hav~ not only ~n excellent actiYity with oral admini~tratio~, but the~ act also paren-terally in do~age units down to 2 mg/kg. Thus, they are much superior to co~parable banzimidazole derivatives, especially to all know~ 5(6)-~ubstituted 2 be~zimidazole carbaminat~s.
To determine the action o~ the compounds according to the invention, chemotherapautic investigations o~ sheep having a weight of about 30 kg were carried.Qut, which had been experiment~lly infected with larvae of Haemonohus con-tortus and Trichostrongylus colubriformis. The test animals were kept in tiled boxes which were thoroughly cleaned daily.
At the end of the pre-patency period (time between infection and sexual maturity of the parasites, with incipie~t elimina-'io~ of eggs or larvae), the number of egg~ per gram of faeces (EpG) were determined by a modi~ied McMaster procesR ~ :
according to Wetzel (see Tierart~iche Umschau 6, 209-210;
1951)o Immediately therea~ter, the sheep (in genera} com-prising ~our to eight animals per active substance, but at least two) were treated. The dosage units of the products of ths process ~ere administered to the animals as a suspension in each case i~ 10 ml of a tylose suspension (1% streng~
aqueouo su3pension). On the 7th, 14th and 28th day after the treatment, ths number of eggs per gram of faeces wa~ again determined in accorda~ce with the abovementioned proces~ and its changa in percentage terms relatlve to the tnitial value be~ore treatment is determined.
The following Table lists the results of these testsO
29 The numbers indicated under ~e~fsct" are t~e decrease in ~L~6~ 8 ~!~
percent of the number of eggs in the faeces.
Ex. ~ ~ r~ rt~
1 5 mg/kg peroral 100 %
t5 mg/kg peroral ~90 %
wherein Rl i5 alkyl ha~ing 1 to 4 carbon ato~s, R2 and R3 are, independen~lr Prom each other, hydrogen, alkoxy ha~ing t to 4 carbon atoms, halogen, trifluoromethyl, alkyl ha~ng 1 to 4 carbon atoms or ON and X are the group -O-SO~ or -S02-0-, which co~prises treating a lH-2 5 1 ~ 4-benzothiadiazi~e derivati~e of the formula ~2), wherein R1 to R3 and X ha~e ths sama m~aning as in ~ormula (1), R~ i5 hydrogen, an acetyl or ben zoyl r~dical and n is zero or 1, with an acid or triphenyl-phosphine or, if R4 stands ~or the acetyl- or benzoyl radical, with a base~
~2~ R4~ .
3 X N--S~ ~)n (2)~ ---~- 2 ~ .
6~ H ~
As alkyl radicals in the substituent~ R1, R2 and R3 there are considered~ Methyl, athyl, propyl, isopropyl, butrl, secondary butyl, tertiary butylO As alkoxy groups in the ubstituents R2 and R3 th~re may be considered: msthoxy, ethoxy, propoxy, isopropoxy and butoxy. As halogen atoms in the substituents R2 and R3 th~re ~re conRidared fluorine, chlorine, bromi~e a~d ~odine.
There are e~peciall~ pre~erred compounds o~ the formula (1) wherein R1 i~ methyl, ethyl, propyl or butyl, R2 is hydro-gen and R3 i6 hydrogen, chlorine, bromine, trifluoromethyl,methyl, ethrl, methoxy or ethoxy, R3 being preferably in a 3-po~ition o~ the phenyl ring.
I~ tho procsss o~ the i~Yention i3 carried out by reac-ting a benzothiadiazine deri~ative of the formula (2), wherein ~5 R4 is hydrog0n, with an acid, expedie~tly at least equimolar amounts of the acid are mixed with a solution o~ the compound ~;
of the ~ormula (2), wheroin R~ iB hydrogen. Suitabl~ sol~entQ
are above all polar or~anic solvents such as lower aliphatic alcohols, ethers, dioxane, acetone, acetonitrile, d~0thylene-glycol e~her, tetrahydrofurane, dimethylformamide both in pure form and in mixture with ~ater. In the latter ca~e the pH ~alue ~s expediently below 4. The reaction temperature may range between 0 and 120 C, preferably between 15 and 60C.
Suit ble acids are miner~l acids such as halohydric acids and other ~ineral acids and strong organic acids, as for example sul~onic acids.
If the process o~ the in~ention is carried out by reac-ting a ben~othiadiazine derivatiYe of the fo~mula (2~, wherein -~29 R4 is hydrogen, with triphenyl phosphine, the reactants are - 3 ~
- -. . ., .. :. :, :i .. , ~ i:, ,. ,: ,, ; : . .... .. . .~. :
~IL()69908 expediently heated in a solvent up to a temperature between 40 and 120C, preferably up to the boiling point of the solvent used.
Suitable solvents are especially aprotic solvents such as chloro-form, benzene, methylene dichloride, tetrahydrofurane or dioxane.
If the process is carried out by reacting a benzothiadiazine derivative of the formula (2) J wherein ~4 stands for an acyl radi-cal, with a base, at least equimolar amounts of the base are mixed with a solution of the compound of the formula (2). Suitable solvents are the same as described above in the reaction with acid.
If the solvents mentioned are present as a mixture with water the pH value of the reaction medium shall not exceed 8. Suitable bases are inorganic bases such as alkali metal and alkaline earth metal hydroxides, alkali metal carbonate and -hydrogen carbonates ~
as well as alkali metal phosphates, and organic bases such as ~ j tertlary amines and quaternary ammonium hydroxides.
Especially good results are obtained by reacting benzothia-diazine derivative of the formula (2) with triphenyl phosphine ^~
in~a solvent.
The preparation of the starting materials of the formula (2) !~
is subject of the copending Canadian Patent Application Serial No.
261,426, filed concurrently herewith and is~carried out by reduc-tion of an o-nitro-phenyl-thiono-carbamoyl-carbaminate of the j;
23 formula (3) R2 ~ -~ X - ~ NO2 (3) 3 NH CS-NH-COORl ,-' ~
99~ , in which Rl, R2, R3 and X hava the meanin~ men$ioned for for-mula (2)~ with sodium dithionite in a~ alkaline solution.
Th~ o-nitro-phenyl-thionocarbamoyl-carbaminate i~ ob-tained ~rom a o~nitro-aniline derivativa of the ~ormula (4~ ;
R2 ~ X - ~ 2 (4 --- -- - . .. .. ... . - ~
by reactio~ with alkylisothiocyanato ~ormiate of the formula . S = C = N - COOR
-wherbin the substituents ha~e the abo~e meanings.
~ lH-291,4-benzothiadiazine derivatives of the formula , .
(Z) there are considered the 3-,carbomethoxyamino-7-(lH-2,1,4-benzothiadiazine)-~ul~onic acid phenyl aster 3-carbomethoxyamino-7~ 2,1,4-b6!nzothiadiazine)-sulfonic aoid 4-chloro-phenyl ester 3-carbomethoxya~ino-7-(1H-2,1,4-benzothiadiazi~e)-~ulfonic acid 3 ohloro-phenyl ester 3-carbomethoxyalaino-7-(1H-2,1,4-benzothiadia~lne)-sulf`onic .
acid 2-chloro-phenyl ester -3-carbomethoxyamino-7(l~-2,1,4-benzothi~diazine)-~ul~onic aoid 2,5-dichloro-phenyl ester 3-carbomethoxy~mino-7-~1H-2,1,4-ben~othiadiazine)-sulfonic acid 3,5-dichloro-phe~yl ester 3~carbomethoxyamino-7-(lH-2, 1, 4 benzothiadiazine )-sul~onic acid 4-bromo-phenyl ester 3-carbomethoxyamino-7-(lH-2,1,4-benzothiadiazine~-sulfonic acid 3 bromo-phenyl ester ._ 5 _ .' ' , ;,. . ,, l :` :,. ' ' `, .'. i ~ ' '~ ~ ' ' ' 99~3 3-carbomethoxyamino-7~ 2,1,4-benzothiadiazin~-sulfonic acid 2-bromo-phenyl ~ster 3-carbomethoxyamino-7 (1H-291,4-benzothiadiazine) sul~onic acid 4-methyl-phenyl estar 3-carbometho~yamino 7-(1H-2,1,4-benzothiadiazinc)~sulfonio acid 3-methyl phenyl e~t~r 3-carbomathoxyamino 7-(lH-2,1,4-benzothiadiazine~- 8U~ ~onic acid 2~methyl~phenyl ester 3-carbom~thoxyamino~7-(1H~2,1,4-benzothiadiazine) sulfonic acid 4-t.butyl-phenyl e6ter 3-carbomethoxyamino 7-(lH-2 9 1 ~ 4-benzothiadiazine)-~ulfonic ~ :
acid 2,4Qdimethyl-phenrl ester 3-carbomethoxyamino-7-tl~2,1,4benzothiadiazine)~sulfonic cid 2-chloro~4-methyl~phonyl ester 3-carbomethoxyamino~7-(lH-2,1 9 4-benzothiadiazine)-sulfonic a¢id 2-chloro-6-methyl-phenyl ester 3-c~rbomethoxyamino-7-(lH~2,1,4 benzothiadia~ine)-sul~onic acid 3-chloro-~methyl-phenyl ester 3-carbomethoxyami~o-7-(lH;2,1,4-b~nzothiadiazine)-sulfonic-acid ~=chloro-6-methyl-phenrl ester 3-carbomethox~ami~o-7-(lH-2,1,4-benzothiadiazine)-sulfonic acid 4-chloro-2-methyl-phenyl ester 3 carbomethoxyamino-7-(lH-2,1,4-benzothiadiazine)-sul~onic acid 4Dchloro-3-msthyl-phenyl eRter 3-carbomethoxyamino-7-(1R-2,1,4-benzothiadiazine)-sulfonic acid 3-trlfluoromethyl-phenyl ester 3 carbomethoxyamino~7-(lH-2,1,4-ben~othiadiazine)-sul~onic acid 4-methoxy-phenyl esker 29 3-carbomethoxyamino-7-(lH-2,1,4-b~n~othiadiazine)-~ulfonic ~611G9911 8 ~1~!2 acid 3-methoxy-phenyl ester 3 carbomethoxyamino-7-(lH-2,1,4~benzothiadiazine)-sUlfonic acid 2-methoxy-phenyl est~r 3-carbomethoxyamino-7-(lH-2,1,4benzothiadiazine)-sulfonic acid 4 propoxy-phenyl ester 3-carbomethoxyamino 7-(lH-2,1,4-ben~othiadiazine)-sul~o~lc acid 4-isopropoxy-phenyl e~t~r 3-carbomethoxyamino-7-(lH-Z11,4-bcnzothiadiazine)-~ulfonic acid 4-buto~y-phenyl e~ter 3-carbomethoxyamino-7-~lH-2,1,4-b~nzothiadiazine)-sulfonic acid- 4-isobutoxy~phenyl est~r :.
3-carboethoxyamino-7-(lH-2,1,4-benzothiadiazlne) sulfonic acid phenyl ester 3 carbopropoxyami~o-7-(lH-2,1,4-b~nzothiadiazine~-~ulfonic acid ph~nyl e~tar 3-carbi~opropoxyamino-7-(lH~2~1,4~-b~nzothiadiazine)-sulfonic acid ph~nyl est~r 3 carbbutoxyami~o-7-(lH~2,1p4;benseothiadiazine)-sulfonic acid phenyl ester 3~carbiaobuto~yami~o7 (1~-2,1,4-benzothiadiazina~-sulfonic acid phenyl ester 3-carbo-t.-butoxyamino-7-(lH-2,1,4-benzothiadiazine)-sulfonic - acid phen~l ester 3-carbom~thoxyamino 7-phenyl~ul~onyloxy-lH-2,1,4-benzothia-diazine 3-carbom~thoxyamino-7-(4-chloroophenylsulfonyloxy)~lH~2,1,4 benzothiadiazine 3-carbom0thoxyamino-7-(3-chloro-phenylsulfonyloxy)-1H-2,1,4-29 ben20thiadiazine :- . ' : ' ''' :" '' ` ' :'"',. :'";' " ' ' :' : '-"' . '.' :' ': ' ':,: ''' , :' ~ , , ,' : :':: : : : ,, ,:, .:. ::, ':~: ': ,., " ' :, ' , '.,'', .,, . ::,: : :' ': :
': . . ~ ' ' ' : . : , ., ',:::: ,' ', :' ': ,' :'.: ' ' :, , , :,~ ' . " "; '' ' , ' ': :
~6~
3-carbomethoxyamino-7-(2-chloro-phenyl~ulfonyloxy)-lH-2,1,4-benzothiadiazine 3-carbome thoxyamino- 7-(2,5-dichloro-phenylsul~onyloxy)-lH-2,1,4-benzothiadiazine 3-carbomethoxyamino-7-(3,4~dichloro-phenylsu~fonyloxy)-1H-2,1,4-benzothiadiazin0 3-carbomethoxyamino-7-(3,5-dichloro-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine ~.
3-carbomethoxyamino-7-(4-bromo-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine 3-carbometho~yamino-7-(3-bromo-phenylsulfonyloxy)-lH-2,1,4-benzothiadlazine 3-carbomethoxyamino-7-(2-bromo-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine 3-carbomcthoxyamino 7-(4-methyl-phenyl~ulfonyloxy)-tH-2,1,4-benzothiadiazine 3-cQrbomethoxyamino-7-(3-methyl-phanylsulfonyloxy~-lH-2,1,4-bcnzothiadiazine 3-oarbometho~ya~ino-7-(2-methrl-phenylsulfonyloxy)-lH-2,1,4 benzot~iadiazine 3-carbomethoxyamino-7~(4-tert.butyl phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine 3-carbomethoxyamino-7-(2-ohloro-4-methyl-phenylsul~onyloxy)-1H-2,1,4-benzothiadiazino 3-carbomethoxyamino-7-(2-chloro-6-methyl-phenylsulfonyloxy)-lH-2,1,4-benzothiadia~ine 3-carbomethoxyamino-7-(3~chloro-4-methyl-phenylsulfonyloxy)-lH-2,1,4-benzothiadiazine 29 3-carbomethoxyamino-7 (3-chloro-6-methyl-phenylsulfonyloxy)-: - 8 - :
:: : : . . . : ~ ': ' ' ; :, ~. ' . ! . `
~L~69~
1H 2,1,4-benzuthiadiazi~e ~; :
3-carbomethoxyamino-7-(4-chloro-2-methyl-phenylsulfonyloxy) 1~ 2,1,4-benzothiadia~ine 3-carbomethoxyamino-7-(4-chloro-3-methyl-phenyl~ulfonyloxy)-lH-2,1,4-benzothiadia%ine 3-carbomethoxyamino-743-trifluoromethyl-phenylsulfonyloxy)-lH-2,1,4-bo~zothiadiazine 3-carbomethoxyamino-7-(4-methoxyph~nyleulfonyloxy)-1H-2,1,4-benzothiadiazine : .
3-carbomethoxyamino-7-(3-methox~-phenylsulfonyloxy)-lH-2,1,4 benzothiadiazine 3-carbomethoxyamino-7-(2-methoxy-phenyl~ul~onyloxy) lH-2,1,4 benzothiadiazine 3-carbomethoxyamino-7-(4 propoxy-phenylsul~onyloxy)-1H-2,1,4-.
benzothiadiazine 3-carbomethoxramino-7-(4-isopropo:~y,-phenylsulfo~yloxy)-lH-2,1,4-benzothiadiazine 3-carbomethoxyamino-7-(4-butoxy-phenyl~ulfonyloxy)-lH-2,1,4-benzothiadiazine 3-oarbomsthoxyamino~7-(4-isobutoxy-phenyl~ul~onyloxy)-lH-2,1,4-b~n~othiadiazine 30carboethoxyamino-7-phenylsul~onyloxy 1H-2,1,4-b0n~othia-diazlne 3-carbopropoxyamino-7-phenyl~ulfonyloxy-lH~2,1,4-benzothia-diazine3-carboisopropoxya~ino-7-phenylsul~onyloxy~lH-2 9 1 ~ 4-benzo-thiadiazine 3-carbobutoxyamino-7-phenylsulfonyloxy~lH-2,1,4-benzothia- ~:
.. . .
29 diazine _ 9 _ ~:
~0699~ HOE ~
_., :
3-carbisobutoxyamino-7-phenylsulfonyloxy 1H-2,1,4-b0nzothia-dlazin~ ~
3-carbo-t.butoxyamino-7-phenyl~ulfo~yloxy~ 2,1,4-benzothia- :
diazine 3-carboethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy) lH-2,1,4-benzothiadia~ine 3-carbisopropoxyamino-7~(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazi~o 3-carbisobu~tox~amino-7-(3-trifluoromethyl-phenyl~ulfonyloxy)-10 lH 2,1,4-benzothiadiazine.
According to the proces~ described the following 2-carb- ;
alkoxy-amino-benzimidazole derivativas are obtained for example:
2-carbomethoxyamino-5-b2nzimidazol-sul~onic aoid-phenyl o~ter 2-carbomethoxyamino-5-benzimidazol-4-chloro-sulfonic acid-phenyl ester 2-carbomethoxyamlno-5-benzimidazol-3-chloro-sulfonic acid-phenyl eæter 2-carbomethoxyamino-5-benzimidazol-2-chloro-sulfonic acid-20 phenyl ester ~ .
2-carbomethoxyamino-5-benzimidazol-2,5-dichlorD-3ulfonic acid- -ph~nyl e~ter :~
2-carbomethoxyamino-5-benzimidazol-3,5~diohloro~sul~onio acid-phen~l e 9 ter 2-carbomethoxyamlno-5-benzimidazol 4-bromo-sulfonic a~id-phenyl ester 2-carbomethoxyami~o-5-benzimidazol~3-bromo-sulfonic aoid- ~:
phenyl ester 29 2-carbomethoxyamino-5-benzimidazols2-bromo-sulfonic acid-1[3~99~
phenyl 9 ~ ter 2-carbom6thoxyamlno-5~benzimidazol~4-methyl-sul~onic acid-phenyl ester 2-carbomethoxramino-5-b6nzimidazol-3-methyl~sulfonic acid-phenyl ester 2-carbomethoxyamino-5-benzimidazol-2-methrl sulfonic acid~
phenyl cster 2-carbomethoxyamino-5-benzimidazol-4-tert.butyl-~ulfonic acid-ph~nyl ester 2-carbometho~yamino-5-benzimidaæol-2,~-dimethyl-sulfonio acid-phenyl ester~
2 carbomethoxyaml~o05-benzimidazol-2-chloro-4-methyl-~ulfonic acid-phenyl e~ter 2-carbomethoxramino-5-benzimidazol-2-chloro-6-methyl-sulf`onic ~.
acid~phenyl ester 2-~arbomethoxyamino-5-benzimidazol-3-chloro-4-methyl-~ulfonic acid-phenyl e~ter 2- arbomethoxyamino-5-benzimidazol-3~chloro-6-m~thyl-~ulfonic aoid-phenyl n~tor 2-carbom~thoxyamino-5-benzlmidazol-3-chloro-4-carbethoxy-sul~onic acid-phenyl ester 2~carbomethox~mino-5-benzimid~zol 4-chloro-2-methyl-6ulfonic acid-phenyl est~r 2~carbomethoxyamino-5-benzimidazol-4-chloro-3~msthyl-~ul~onic acid-phenyl ester 2-carbomethoxyamino 5-benzimidazol-3-trifluoromethyl-~ul~onic ~ .
acid phenyl e~ter 2-carbomethoxyamino-5-benzimidazol-3,5-bistrifluoromethyl-29 sulfonic acid phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-methoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-3-methoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-2-methoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-propoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-isobutoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-butoxy-phenyl ester 2-carbomethoxyamino-5-benzimidazol-4-isobutoxy-phenyl ester 2-carboethoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbopropoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbisopropoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbobutoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbisopropoxyamino-5-benzimidazol-sulfonic acid-phenyl ester 2-carbo-tert.-butoxyamino-5-benzimidazol-sulfonic acid-phenyl ester ester 2-carbomethoxy-5(6)-phenylsulfonyloxy-benzimidazole 2-carbomethoxy-5-(6)-(4-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(3-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(2-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(2,5-chloro-phenylsulfonyloxy)-benzimid-dazole 2-carbomethoxy-5-(6)-(3,5-chloro-phenylsulfonyloxy)-benzimi-dazole 2-carbomethoxy-5-(6)-(3,4-dichloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxy-5-(6)-(4-bromo-phenylsulfonyloxy)-benzimi-dazole 2-carbomethoxy-5-(6)-(3-bromo-phenylsulfonyloxy)-benzimi-dazole 1~:1169908 H~
2-carbometho~cyamino-5(6~-(2-bromo phenylsulfonyloxy)wbenzimi-dazole 2~çarbomethoxyamino~5(6)~(4 m~thyl-phenylsul~onyloxy) benzimi- -dazole 2-earbomethoxramiIlo-5(6)-(3-methyl-phenylsul~onyloxy)~benzimi~ ~:
dazole 2-earbomethoxyamino-5(6~-(2-methyl-phenyl~ulfonyloxy)-benzimi-dazole 2-carbo~ethoxya~ino-5(6)-(4-tert.butyl-phenylsul~onyloxy)-~0 benzimidazole 2-carbo~ethoxyamino-5(6)-~2-chloro-4-methyl-phenyl~ulfo~yloxy)-benzimidazol~
2-carbomethoxyamino-5(6)-(Z-chloro-6-methyl phenylsulfonyl- :
oxy)-benzimidazole 2-carbomethoxy~mino-5(6)-(3-chloro-4-methrl-phenylsulfonyl-oxy)-benzlmidazole 2-carbomethoxyamlno,5(6)~(3-chloro-6-methyl-phenyl~ulfonyl-oxy~ -benzimidazsle 2-carbomethoxyamino-5(6)-(4-chloro-2-methy~-phenylsulfonylw oxy)-benzimidazole 2-carbomethoxyamino-5(6)-(4-chloro 3~methyl-phenylsulfonyl- -o~y) benzi~idazole 2-carbomathoxyamino-5~6)-(4-chloro-3,5-dimethyl-phenyl-sulfonyl~- )-ben~imidazole 2 carbomethoxyamino-5~6) (3-tri~luoro~ethyl-phenylsul~onyl)-benzimidazole -carbomethoxyamino-5(6)~(4-methoxy phenylsul~onyl)-benzimi- -I, dazole i 29 2-carbomethoxyamino-5~6)-(3-methoxy-phenylsulfonyl)~benzi~i-, - 13 -dazole 2 carbomethoxyamino-5(6)-(2-methoxy-phenyl~ulfonyl)~benzimi-dazole 2-carbomethoxyamino-5(6)-(4~propoxy-ph~nyl~ul~onyl)-be~imi dazole 2 carbomethoxyamino 5(6)-(4-is3propoxy-phenylsulfonyl)-benzimidazole 2-carbomethoxyamino-5(6~-(4-buto~y-phenylsulfon~ benzimi-dazole 2-carbomethoxyamino-5(6)-(4-isobutoxy-phenylsulfonyl)-benzimidazole 2--carbetho~yamino 5(6)-phenyl6ulfonyl-benzimidazols 2-carbopropoxyamino-5(6)-phenylsul~onyloxy-benzimidazole 2-carbisopropoxyamino-5(6) phenyl~ul~onyloxy-benzimidazole ;~i~
2-carbobutoxyamino-5(6~-phenylsulf'onyloxy-bengimida~ole 2-carbisobutoxyamino-5(6)-phenylstllfonyloxy-benzimidazole 2-carbDtart.butoxyamino-5~6)-phenylsul~onyloxy-b2nzimida~ole 2-carbethoxyamiMo-5(6)~(3-trifluoromathyl-phenylsulfonyloxy 3 - :
benzimidazole 2-oarbi~opropoxyamino-5(6)-~3~trifluoromethyl-pheny~sul~onyl)-benzimidazole 2-carbi~obutoxyamino-5(6)-(2-tri~luoromethyl-phenylsulfonyl)~ :~
benzimidazoleO
The 2-carbalkoxyamino-benzimida~ole deriYatiYe~ o~ the invention are valusble chemoth2rapeutics and are suitable for combating parasitic diseases in humans and animals.
They are particularly acti~e against a great number of c~ helminth~, for example Haemonchus~ Trichostrongylus, O~ter-29 tagia, Strongyloides, Cooperia, Chabertia, Oesophagostomum, 14 ~ ~ -~69~8 ~
Hyostrongylus, Ankylostoma, Ascaris and Heterakis. The com-pounds have a particularly pronounced activity against gastric and inte~tinal strongylide~ which attack above all ruminant~
and cau~e considerable sconomic losses; for that reason the compounds of the invention ars especially used in veteri~ary medicine .
Depending on the ca~e the active substance~ of the for~
mula (1) are administered in dosage units between 0.5 and 50 mg per kg of body weight.
For oral application tablets, dragees, capsules, powders, granules or paste6 are considered, which contain tha acti~e substance~ together with u~ual auxiliaries and carrier~ such as t~rch, ccllulose powder~ talc, magnasium stearate, ~ugar, gelatine.9 calcium carbonate, finely divided silicic Aoid, carboxymathyl cellulo6e or similar substances.
~or parenteral application thore are considered solutions, for example oily sclutions which are prepar0d while using sesame oil, c~stor oil or synthetic trigl~rcerides, if desired ~ -with addition of t~kopherol as antioxydating agent and/or while using ~urface~acti~e ~ubstances ~uch as sorbitane-fat*y acid ester. Aqueou~ suspension are co~sidered, which are pre pared while usi~g ethoxylatsd serbitane-~atty acid ester, if desired with addition or thickening agsnts, such as polyethy-lene glycol or carboxymethyl cellulose.
The concentrations of the active subs*ances accordi~g to the invention in the compositio~ prepared with these ~ub-stances are preferablr between 2 and 20 percent by wsight for being u~ed as veterinary medicament; ~or use as human ~edi-29 cament the concentrations o~ the active substanoes preferably , ..... ~......... - . . ~ ,, ,. , ,~; . . .
'. ,, :;" :: ' ' ' ' . ' ' "' '' ' . .; ,. ' " ' ' . ' : : ' ' ~, i~ - .. ~ ' ' ., .. . ' ' ' ,',,' '- ". '.' '. , '.. ... ~.. , .. :.. ' , :: ' ': ~ ' , ': ' : ' .1, .: ,:, . , :' ': ,.'.: .: .' ' : ,, , '`, ""' ' ' ' ' ' . ' : .:
': ' . ' ' ' : . ' :: ' ;: : ' : . . ' ': ' , , ; .. .. ' ' ' : ' : ,: . '. ' ., . : :
. . ' : . ':: ":: . , ' ,,: , :, , .: . ~
':,: ' ' . ' :. ': .. ' .. ''' :,, "',' ' " "''' '' ' ' ',' " '' ' ' ' ":
~6~
range between 20 and 80 perc0nt by weight.
The products of the process hav~ not only ~n excellent actiYity with oral admini~tratio~, but the~ act also paren-terally in do~age units down to 2 mg/kg. Thus, they are much superior to co~parable banzimidazole derivatives, especially to all know~ 5(6)-~ubstituted 2 be~zimidazole carbaminat~s.
To determine the action o~ the compounds according to the invention, chemotherapautic investigations o~ sheep having a weight of about 30 kg were carried.Qut, which had been experiment~lly infected with larvae of Haemonohus con-tortus and Trichostrongylus colubriformis. The test animals were kept in tiled boxes which were thoroughly cleaned daily.
At the end of the pre-patency period (time between infection and sexual maturity of the parasites, with incipie~t elimina-'io~ of eggs or larvae), the number of egg~ per gram of faeces (EpG) were determined by a modi~ied McMaster procesR ~ :
according to Wetzel (see Tierart~iche Umschau 6, 209-210;
1951)o Immediately therea~ter, the sheep (in genera} com-prising ~our to eight animals per active substance, but at least two) were treated. The dosage units of the products of ths process ~ere administered to the animals as a suspension in each case i~ 10 ml of a tylose suspension (1% streng~
aqueouo su3pension). On the 7th, 14th and 28th day after the treatment, ths number of eggs per gram of faeces wa~ again determined in accorda~ce with the abovementioned proces~ and its changa in percentage terms relatlve to the tnitial value be~ore treatment is determined.
The following Table lists the results of these testsO
29 The numbers indicated under ~e~fsct" are t~e decrease in ~L~6~ 8 ~!~
percent of the number of eggs in the faeces.
Ex. ~ ~ r~ rt~
1 5 mg/kg peroral 100 %
t5 mg/kg peroral ~90 %
4 5 mg/kg subcutaneous 75
5 15 mg/k~ peroral 95 11 5 mg/kg peroral 80 %
12 2,5 mg~kg subcutaneous ~90 %
13 5 mg/kg peroral >95 %
14 5 mg/kg peroral 90 %
19 5 mg/~g peroral 100 %
20 15 mg/kg peroral 80 ~ , .
21 5 Mg/kg peroral 100 23 5 mg~kg peroral >95 %
24 5 mg~kg subcutaneous >95 ~ .-The following Examples illustrate the inventio~
X A ~_Y L ~ II -A mixture of 5.0 g of 3~cArbomethoxyamino-7-(1H-2,1,4 benzothiadiazine)-sul~onic acid phenyl esters and 7.5 g of triphenyl phosphine arc refluxed for three hours in 600 ml o~
chloroform. Then the solution is conoentrated to a large extent and the deposit precipitated is ~iltered. After washi~g out and drying the yield is 3.2 g o~ 2-carbomethoxyami-no-5(6)-benzimidazol-s~l~onic acid phenyl ester having a mel-ting point of 242~C (decomposition).
~~- There are obtained with good yields while using the equi-_ 17 -- .
,, . . ' .' :'. : :'.:.: :: ': ':-: .::,: :. : ,:.': :.. :.. . ~: :.:.. ':': ,: , ~q~69~
valent amount in ea~h casa of th~ corresponding 3-carbalkoxy- -amino-lH-2,1,4 benzothiadiazine derivative from 2. 3-~arbomethoxyamino~7~ -2,1,4-benzothiadiazine)-sulfonic -acid-4-chlorophenyl ester the 2-carbomethoxyamino-5(6)-benzimida~ol-sulfonic acid-4^chloro-phenyl ester having a melting point of 250 C
(decomposition).
3~ 3 Carbomethoxyamino7-(lH-2,1,4-benzothiadiazine)-sulfonic acid 3-chloro-phenyl ester -~the 2-carbomethoxyamino-5~6)-benzi~idazol-sulfonic acid-3-chloro~phenyl ester ha~ing a melting poi~t of 234C
(decomposition)~
4. 3 Carbomethoxyamino-7-(lH-2,1,4-benzothiadia~ine)-sul~onic acid-3,5-dichlorophenyl ester the 2-carbomethoxyamino-5(6)-benzimida~ol~sulfonic aoid-3,5-dlchloro-phenyl ester having a melting point of 250C
(decomposition).
5. 3-Carbomethoxyamino-7-(lH-2,1,4-benzothiadiazin~ ulfon~c acid-3-bromo phenyl e~ter the 2-carbomethoxyamino-5(6)-b2n~imidazol sulronic acido 3-bromo-phenyl ester ha~ing a melting point of 242C
(decomposition).
12 2,5 mg~kg subcutaneous ~90 %
13 5 mg/kg peroral >95 %
14 5 mg/kg peroral 90 %
19 5 mg/~g peroral 100 %
20 15 mg/kg peroral 80 ~ , .
21 5 Mg/kg peroral 100 23 5 mg~kg peroral >95 %
24 5 mg~kg subcutaneous >95 ~ .-The following Examples illustrate the inventio~
X A ~_Y L ~ II -A mixture of 5.0 g of 3~cArbomethoxyamino-7-(1H-2,1,4 benzothiadiazine)-sul~onic acid phenyl esters and 7.5 g of triphenyl phosphine arc refluxed for three hours in 600 ml o~
chloroform. Then the solution is conoentrated to a large extent and the deposit precipitated is ~iltered. After washi~g out and drying the yield is 3.2 g o~ 2-carbomethoxyami-no-5(6)-benzimidazol-s~l~onic acid phenyl ester having a mel-ting point of 242~C (decomposition).
~~- There are obtained with good yields while using the equi-_ 17 -- .
,, . . ' .' :'. : :'.:.: :: ': ':-: .::,: :. : ,:.': :.. :.. . ~: :.:.. ':': ,: , ~q~69~
valent amount in ea~h casa of th~ corresponding 3-carbalkoxy- -amino-lH-2,1,4 benzothiadiazine derivative from 2. 3-~arbomethoxyamino~7~ -2,1,4-benzothiadiazine)-sulfonic -acid-4-chlorophenyl ester the 2-carbomethoxyamino-5(6)-benzimida~ol-sulfonic acid-4^chloro-phenyl ester having a melting point of 250 C
(decomposition).
3~ 3 Carbomethoxyamino7-(lH-2,1,4-benzothiadiazine)-sulfonic acid 3-chloro-phenyl ester -~the 2-carbomethoxyamino-5~6)-benzi~idazol-sulfonic acid-3-chloro~phenyl ester ha~ing a melting poi~t of 234C
(decomposition)~
4. 3 Carbomethoxyamino-7-(lH-2,1,4-benzothiadia~ine)-sul~onic acid-3,5-dichlorophenyl ester the 2-carbomethoxyamino-5(6)-benzimida~ol~sulfonic aoid-3,5-dlchloro-phenyl ester having a melting point of 250C
(decomposition).
5. 3-Carbomethoxyamino-7-(lH-2,1,4-benzothiadiazin~ ulfon~c acid-3-bromo phenyl e~ter the 2-carbomethoxyamino-5(6)-b2n~imidazol sulronic acido 3-bromo-phenyl ester ha~ing a melting point of 242C
(decomposition).
6. 3-Carbo~e~hoxyamino-7-(lH-2,1,4-banzothiadia~ine)-sulfonic ~ .
acid 4-m-thyl-phenyl est~r 2-carbometho~yamino 5(6~-bsnzimidazol-sulfonio acid-4-methyl-phenyl e~ter ha~ing a melting point of 240 C
(decomposition).
acid 4-m-thyl-phenyl est~r 2-carbometho~yamino 5(6~-bsnzimidazol-sulfonio acid-4-methyl-phenyl e~ter ha~ing a melting point of 240 C
(decomposition).
7. 3-Carbomethoxyamino 7-(lH~2,1,4-benzothiadiazine)-sulfonic 29 acid-3-methyl-phenyl ester . , . .... ,... , . ,, -, - ... . .
~63 699(~8 ~!~
2~carbomethoxyamino-5~6)-benzimidazol-sulfonic acid-3-methyl-phenyl ester ha~lng a m~lting point of 234C
(decomposition).
~63 699(~8 ~!~
2~carbomethoxyamino-5~6)-benzimidazol-sulfonic acid-3-methyl-phenyl ester ha~lng a m~lting point of 234C
(decomposition).
8~ 3-Carbomethoxyamino-7-(1H-2,1,4-benzothiadia~ine) sul ;.
fonic acid-4-methoxy-phenyl ester 2-carbomethoxyamino-5(6)-benzimidazol-sul~onic acid-4-methoxy-phenyl ester ha~ing a melting point of 228 C
( docompositio~ ) .
fonic acid-4-methoxy-phenyl ester 2-carbomethoxyamino-5(6)-benzimidazol-sul~onic acid-4-methoxy-phenyl ester ha~ing a melting point of 228 C
( docompositio~ ) .
9. 3-Carbomethoxyamino-7-~lH-2,1,4-benzothiadiazi~)-sul-fonlc acid-3-methoxr-phenyl ~ster 2-carbome thoxyamino- 5 ( 6 ) -benzimidazol-sul~onic acid-3-methoxy-phenyl ester ha~ing a melting point of 227C
(decomposition).
(decomposition).
10. 3-Carbom~thoxyamino-7-(lH-2,1~4-benzothiadiazine)~ul-~o~ic acid 3-ethoxy-phenyl es1;er `:
2~carbomethoxyamino-$(6)-benzimida~ol-sulfonic acid-3-ethoxy-phenyl ester haYing a melting p~int of 210C
(docompo ition).
2~carbomethoxyamino-$(6)-benzimida~ol-sulfonic acid-3-ethoxy-phenyl ester haYing a melting p~int of 210C
(docompo ition).
11. 3-Carbo~ethoxyQ~ino-7-(lH 2,1,4;bQ~zothiadiazine)-sul-fonic acid-3-cyano-ph0nyi ester 2-c&rbomethnxyamino-5(6~-b~nzimida~ol-~ulfonic acid-3-cyano-phenyl ester ha~ing a melting point o~ 265C
(decomposition)0
(decomposition)0
12. 3~Carbomethoxyamino-7-(lE-2,1,4 benzothiadiazine)-sul-- 25 fonic acid-3-trifluoromethyl-phenyl ester 2-carbomethoxyamino-5(6)-benzimidazol-sulfonic acid 3-tri~luoromethylphenyl ester having a melting point of 250C (decomposition). :~
29 13. 3-Carbomethoxyamino-7-ph~nylsulfo~loxy-lH 2,1,4-.
. , .. . . . . , ,, . , , , , . ,.,, , ", ,, , , , . , , . . . ., ~ . . .
`` 3L06990~
benzothiadiazine th~ 2-carbomethoxyamino-5(6)wphenylsulfonyloxy-benzimi dazol having a melting point of 242C (decompoaition). :~
14. 3-~arbo~etho~yamino-7-(4-chloro-phenylsul~onyloxy)-1H- ~^
2,1,~-benzothiadiazin~ -the 2-carbo~thoxyamino-5(6)~(4-chloro-phenyl~ulfonyloxy)-benzimidazole haYi~g a melting point of 230C (decompo sit~o~).
15~ 3-Carbomethoxyamino-7(3 chlorv-phenyl~ulfonyloxy)-lH-2,1,4~benzothiadiazine 2-carbomethoxyamino-5(6)-(3-chloro-phenylsulfonylo~y3 ~ :
benæimidazole ha~ing a melting point of 250C (decompo-sition).
~6. 3Carbomethoxyamino-7-(3,.4-dichloro-phenyl~ul~onyloxy)- ;
lH-2,1,4-benzothiadiazine 2-carbomethoxyamino-5(6)-(3,4-~dichloro-phenyl~ulfonylo~y) benzimidazole having a meltin~ point of 255C (decompo-sition).
. 17. 3!Carbometho~yamino-7 (3,5-dlchloro-phenylsulfonyloxy)-: 20 1H~2,1,4-benzothiadiazine .
2-carbo~ethoxyamino-5(6)-(3,5-dichloro-phenylsulfonyloxy)-benzimidazole having a melting point of 280~G (de-composition~. -18. 3-Carbomethoxyamino-7-(3-bromo-phenylsulfonyloxy)-1E-2,1,4-benzothiadiazine 2-carbomet~oxyamino-5(6)-(3-bromo-phenylsulfonyloxy)~
benzimidazole having a malting point of 242C (de-composition).
29 1~. 3-Carbomethoxyamino-7-(4methyl-phenyl~ulfonyloxy)-lH-- 20 - .
.. , . . . . . : . . ::
~699(~
2,1,4~benzothiad~azine 2~carbomethoxyamino-5(6) (4 methyl-phanylsulfonyloxy)-ben~imidazol~ having a melting point of 237 C (de-composition).
20. 3-Carbomethoxyamino-7-(3-methyl-phenylsulfonyloxy)-lH-2,1,4-benzothiadiazine 2-carbomethoxyamino-5(6)-(3-methyl-phenylsulfonyloxy)- -benzimidazole having a melting point of 250a (de- `;~.compositi.on).
21. 3-CarbomQthoxyamino-7-(3-tri~luoromethyl-phenylsulfonyloxy)-~lH-2 t 1 9 4-benzothiad~azine 2 carbomethoxyamino-5(6)-(3-tri~luoromethyl-phenylsul~
fonyloxy)-bonzimid`azole ha~ing a melting point of 215 C
(decomposition).
22. 3-Carbethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy,)-lH-2,1,4-benzothiadiazino 2-carbetho~yamino-5(6)-(3-trif`luoromethyl-phenylsulfonyl-oxy)-benzimidazole hav~ng a melting point o~ 227 C
(d~composition).
23. 3-Carbisopropoxyamino-7-(3-trifluoromethyl-ph0nylsulfo_ nyloxy)~lH-2,1,4-ben~othiadiazin0 2~carbisopropoxyamino-5(6)-(3-trifluoromethyl-phenyl sulfonyloxy)-benzimidazole having ~ m~lting point of 205C
(decomposition~.
24~ 3-Carbisobutoxyamino-7-(3-trifluoromethyl-phenylsulfonyl-oxy)~lH-2,1,4-benzothiadiazine 2-carbisobutoxyamino-5(6)-(3-trifluoromethyl-phenyl-sulfonyloxy)-benzimidazole having a melting point of 243 C
29 (decomposition), - ~OG9908 ., .;~*
25. 3-Carbom0thoxyamino-7-(3-cyano-ph~nylsulfonyloxy)-1H-2,1,4-benzothiadiazine 2-carbo~ethoxyami~o-5(6)-(3-cyano-phenylsul~onyloxy)-bcnzimidazol having a m01ting point of 275 C ~de- :
compositio~.
.:: , - ':
": .
-- ~2
29 13. 3-Carbomethoxyamino-7-ph~nylsulfo~loxy-lH 2,1,4-.
. , .. . . . . , ,, . , , , , . ,.,, , ", ,, , , , . , , . . . ., ~ . . .
`` 3L06990~
benzothiadiazine th~ 2-carbomethoxyamino-5(6)wphenylsulfonyloxy-benzimi dazol having a melting point of 242C (decompoaition). :~
14. 3-~arbo~etho~yamino-7-(4-chloro-phenylsul~onyloxy)-1H- ~^
2,1,~-benzothiadiazin~ -the 2-carbo~thoxyamino-5(6)~(4-chloro-phenyl~ulfonyloxy)-benzimidazole haYi~g a melting point of 230C (decompo sit~o~).
15~ 3-Carbomethoxyamino-7(3 chlorv-phenyl~ulfonyloxy)-lH-2,1,4~benzothiadiazine 2-carbomethoxyamino-5(6)-(3-chloro-phenylsulfonylo~y3 ~ :
benæimidazole ha~ing a melting point of 250C (decompo-sition).
~6. 3Carbomethoxyamino-7-(3,.4-dichloro-phenyl~ul~onyloxy)- ;
lH-2,1,4-benzothiadiazine 2-carbomethoxyamino-5(6)-(3,4-~dichloro-phenyl~ulfonylo~y) benzimidazole having a meltin~ point of 255C (decompo-sition).
. 17. 3!Carbometho~yamino-7 (3,5-dlchloro-phenylsulfonyloxy)-: 20 1H~2,1,4-benzothiadiazine .
2-carbo~ethoxyamino-5(6)-(3,5-dichloro-phenylsulfonyloxy)-benzimidazole having a melting point of 280~G (de-composition~. -18. 3-Carbomethoxyamino-7-(3-bromo-phenylsulfonyloxy)-1E-2,1,4-benzothiadiazine 2-carbomet~oxyamino-5(6)-(3-bromo-phenylsulfonyloxy)~
benzimidazole having a malting point of 242C (de-composition).
29 1~. 3-Carbomethoxyamino-7-(4methyl-phenyl~ulfonyloxy)-lH-- 20 - .
.. , . . . . . : . . ::
~699(~
2,1,4~benzothiad~azine 2~carbomethoxyamino-5(6) (4 methyl-phanylsulfonyloxy)-ben~imidazol~ having a melting point of 237 C (de-composition).
20. 3-Carbomethoxyamino-7-(3-methyl-phenylsulfonyloxy)-lH-2,1,4-benzothiadiazine 2-carbomethoxyamino-5(6)-(3-methyl-phenylsulfonyloxy)- -benzimidazole having a melting point of 250a (de- `;~.compositi.on).
21. 3-CarbomQthoxyamino-7-(3-tri~luoromethyl-phenylsulfonyloxy)-~lH-2 t 1 9 4-benzothiad~azine 2 carbomethoxyamino-5(6)-(3-tri~luoromethyl-phenylsul~
fonyloxy)-bonzimid`azole ha~ing a melting point of 215 C
(decomposition).
22. 3-Carbethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy,)-lH-2,1,4-benzothiadiazino 2-carbetho~yamino-5(6)-(3-trif`luoromethyl-phenylsulfonyl-oxy)-benzimidazole hav~ng a melting point o~ 227 C
(d~composition).
23. 3-Carbisopropoxyamino-7-(3-trifluoromethyl-ph0nylsulfo_ nyloxy)~lH-2,1,4-ben~othiadiazin0 2~carbisopropoxyamino-5(6)-(3-trifluoromethyl-phenyl sulfonyloxy)-benzimidazole having ~ m~lting point of 205C
(decomposition~.
24~ 3-Carbisobutoxyamino-7-(3-trifluoromethyl-phenylsulfonyl-oxy)~lH-2,1,4-benzothiadiazine 2-carbisobutoxyamino-5(6)-(3-trifluoromethyl-phenyl-sulfonyloxy)-benzimidazole having a melting point of 243 C
29 (decomposition), - ~OG9908 ., .;~*
25. 3-Carbom0thoxyamino-7-(3-cyano-ph~nylsulfonyloxy)-1H-2,1,4-benzothiadiazine 2-carbo~ethoxyami~o-5(6)-(3-cyano-phenylsul~onyloxy)-bcnzimidazol having a m01ting point of 275 C ~de- :
compositio~.
.:: , - ':
": .
-- ~2
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 2-carbalkoxyamino-benzimidazol-derivative of the formula (1) (1) wherein R1 is alkyl having 1 to 4 carbon atoms, R2 and R3 represent, independently from each other hydrogen, alkoxy having 1 to 4 carbon atoms, halogen, trifluoromethyl, alkyl having 1 to 4 carbon atoms or CN, and X represents group -O-SO2- or -SO2-O-; in which a 2,1,4-benzothiadiazine derivative of the formula (2) (2) wherein R1 to R3 and X are as defined above and R4 represents hyd-rogen, an acetyl or benzoly radical and n is zero or 1, is treated with an acid or triphenylphosphine, or, when R4 represents the acetyl or benzoyl radical, the compound of the formula (2) is re-acted with a base.
2. A process as claimed in claim 1 in which the compound of the formula (2) is treated with an acid or triphenylphosphine.
3. A process as claimed in claim 1 in which a compound of the formula (2) wherein R4 represents the acetyl or benzoyl radical is treated with a base.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752541751 DE2541751A1 (en) | 1975-09-19 | 1975-09-19 | Benzimidazole carbamate derivs. - with anthelmintic activity (NL220377) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1069908A true CA1069908A (en) | 1980-01-15 |
Family
ID=5956861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA261,424A Expired CA1069908A (en) | 1975-09-19 | 1976-09-17 | Process for the preparation of anthelmintically active 2-carbalkoxyamino-benzimidazole derivatives |
Country Status (16)
| Country | Link |
|---|---|
| AT (1) | AT356651B (en) |
| CA (1) | CA1069908A (en) |
| CH (1) | CH605822A5 (en) |
| DE (1) | DE2541751A1 (en) |
| DK (1) | DK419976A (en) |
| EG (1) | EG12507A (en) |
| ES (1) | ES451512A1 (en) |
| FI (1) | FI762654A (en) |
| GR (1) | GR70297B (en) |
| HU (1) | HU172248B (en) |
| LU (1) | LU75816A1 (en) |
| MX (1) | MX3567E (en) |
| NL (1) | NL7610191A (en) |
| NO (1) | NO763197L (en) |
| PT (1) | PT65608B (en) |
| SE (1) | SE7610311L (en) |
-
1975
- 1975-09-19 DE DE19752541751 patent/DE2541751A1/en active Pending
-
1976
- 1976-09-11 EG EG76551A patent/EG12507A/en active
- 1976-09-14 MX MX764928U patent/MX3567E/en unknown
- 1976-09-14 ES ES451512A patent/ES451512A1/en not_active Expired
- 1976-09-14 NL NL7610191A patent/NL7610191A/en not_active Application Discontinuation
- 1976-09-16 LU LU75816A patent/LU75816A1/xx unknown
- 1976-09-16 SE SE7610311A patent/SE7610311L/en unknown
- 1976-09-16 HU HU76HO00001928A patent/HU172248B/en unknown
- 1976-09-16 FI FI762654A patent/FI762654A/fi not_active Application Discontinuation
- 1976-09-17 AT AT690976A patent/AT356651B/en not_active IP Right Cessation
- 1976-09-17 PT PT65608A patent/PT65608B/en unknown
- 1976-09-17 CA CA261,424A patent/CA1069908A/en not_active Expired
- 1976-09-17 DK DK419976A patent/DK419976A/en not_active Application Discontinuation
- 1976-09-17 NO NO763197A patent/NO763197L/en unknown
- 1976-09-17 CH CH1182276A patent/CH605822A5/xx not_active IP Right Cessation
- 1976-09-18 GR GR51722A patent/GR70297B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL7610191A (en) | 1977-03-22 |
| DK419976A (en) | 1977-03-20 |
| FI762654A (en) | 1977-03-20 |
| HU172248B (en) | 1978-07-28 |
| CH605822A5 (en) | 1978-10-13 |
| ATA690976A (en) | 1979-10-15 |
| PT65608A (en) | 1976-10-01 |
| MX3567E (en) | 1981-03-13 |
| NO763197L (en) | 1977-03-22 |
| AT356651B (en) | 1980-05-12 |
| PT65608B (en) | 1978-05-10 |
| LU75816A1 (en) | 1977-05-13 |
| ES451512A1 (en) | 1977-12-16 |
| GR70297B (en) | 1982-09-06 |
| SE7610311L (en) | 1977-03-20 |
| EG12507A (en) | 1978-12-31 |
| DE2541751A1 (en) | 1977-03-24 |
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