CA1105038A - 2-amino-substituted isothioureidobenzene - Google Patents
2-amino-substituted isothioureidobenzeneInfo
- Publication number
- CA1105038A CA1105038A CA277,661A CA277661A CA1105038A CA 1105038 A CA1105038 A CA 1105038A CA 277661 A CA277661 A CA 277661A CA 1105038 A CA1105038 A CA 1105038A
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- Prior art keywords
- lower alkyl
- carbomethoxy
- aminobenzophenone
- mole
- solution
- 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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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/38—Isothioureas containing any of the groups, X being a hetero atom, Y being any atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Indole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
2-Amino-substituted-isothioureidobenzene products useful as anthelmintics and fungicides are dis-closed. The products are prepared by treating 2-amino-thioureidobenzene with a base and an organic halide or sulfonate.
2-Amino-substituted-isothioureidobenzene products useful as anthelmintics and fungicides are dis-closed. The products are prepared by treating 2-amino-thioureidobenzene with a base and an organic halide or sulfonate.
Description
~ J A ~
"~ ' 3~
, .
This invention relates to 2-amin3-substituted-isothioureidobenzenes~ to processes fo making such compounds, to methods of t~eating helminth infections and fungus and to anthelmintic and antifungal compositions containing them.
Description of ~he Prior Art British Pat. No. 1,307,250; U~ S. Pat. No~
o 3 ,950 ,oo8 and Netherlands Pat~ No. 7,401,797 disclose numerous thioureas, though none ha~e a substi~uent on the sulfur, use-~ul as anthelminticsO German Pat. No. 2,303,0~8 discloses
"~ ' 3~
, .
This invention relates to 2-amin3-substituted-isothioureidobenzenes~ to processes fo making such compounds, to methods of t~eating helminth infections and fungus and to anthelmintic and antifungal compositions containing them.
Description of ~he Prior Art British Pat. No. 1,307,250; U~ S. Pat. No~
o 3 ,950 ,oo8 and Netherlands Pat~ No. 7,401,797 disclose numerous thioureas, though none ha~e a substi~uent on the sulfur, use-~ul as anthelminticsO German Pat. No. 2,303,0~8 discloses
2-acylated-am~no-S-substituted-isothioureidobenzenes as anthelmintics. ~owever, there is no prior art disclosing .
compoun~s having both a ~ree ortho amino substituent on the b~nzene ring and a substituted sulfur atom in the thioureido group. Other patents disclosing anthelmintic compounds in- ~ -clude U~ S. Pat. Nos. 3,865,9~8 and ~,005,217 and British Pat. NoO 1,350,277~
object of this invention is to provide a new class o~ 2-amino-substituted-isothioureidobenzenes infraj,~methods for preparing these compounds 7 comp~si-tions containlng said compounds and to their use as anthelmintic and anti~ungal agents.
The novel 2-am m o-substituted-isothioureido-benzenes (I, infra) 3f this invention have the followi~g structural formula~
H-C=N-~-OR
~ SR
:: . . ~ .
? -wherein R is alkyl, for example, alkyl of from 1 to 19 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, _so-butyl~ sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyll octadecyl, nonadecyl and the like;
alkenyl, for example, lower alkenyl of from 3 to 8 carbon atoms such as allyl, propenyl, l~methylpropenyl 9 butenyl, pentenyl, hexellyl,-heptenyl7 octenyl and the like; alkynyl, for example, lower alkynyl of from 3 to 8 carbon atoms such as propynyl, butynyl, pent~yl, hexynyl, heptynyl, octynyl and the like; polynuclear axalkyl such as napthylmethyl, napthylethyl, phenanthracenylmethyl and the like; mono-nuclear aralkyl such as ben~yl, phenethyl, phen~lpropyl and the like which may be substltuted with from 1 to 3 groups such as halo, alkyl, alkox~, nitro and the like; mononuclear aryloxy lower alkyl, for example~ phenoxy lower alkyl of from 3 to 6 carbon atoms in the alkyl group including phenoxypropyl, phenoxybutyl, phenoxypentyl, phenoxyhexyl and the like; cycloalkylalkyl, for example, cycloalkyl lower alkyl o~ ~rom 5 to ~ nuclear carbon atoms such as cyclo-pentylmethyl, cyclopsntylethyl, cyclohexylmethyl, cyclo-- hexylethyl and the like; cyano lower alkyl-of ~rom 3 to 6 carbon atoms such as cyan~propyl, cyanobutyl, cyanopentyl, cyanohexyl and the like; hydroxy lower alkyl of from 3 to 8 carbon atoms such as hydroxypropyl, hyd.roxybutyl, hydroxy-pentyl, hydroxyoctyl and the like; aralkenyl, lor example, poly- and mono~uclear aralkenyl, such as phenylpropenyl an~
the like; alkoxyalkyl, for example, lower alkoxy lower alkyl, such as msthoxypropyl, ethoxypropyl, methoxybutyl, propoxy-butyl and the like; alkoxycarbonylalkyl, ~or example, loweralkoxycarb~nyl lower alkyl wherein the lower alkyl has 3 to 6 : : .
~ 3 -'~5~ 33~
carbon atoms, such as methoxycarb~nylpropyl, et}loxycarbonyl-butyl, ethoxycarbonylpentyl, propox~carbonylhexyl and the like; N-monomlclear arylcarbamoyl lower alkyl such as N-~(4-4-acetam]dophenylthio)phenyl~carbamoylethyl and the like phthalim:ido lower alkyl such as phthali~idobutyl andthe like; phenoxycarbonylalkyl, for example, ph.enoxycarbonyl lower alkyl of from 3 to 6 carbon atoms such as phenoxy-carbonylp:ropyl, phenoxycarbonylbutyl, phenoxycarbonylpentylr, phenoxycarbonylhexyl and the like; R~ is lower alXyl of 10 from 1 ~o 6 carbon atoms such as methyl, ethyl, n-propyl~
iso-propyl, n-bl~tyl, ~so-butyl, tert-butyl, pentyl, hexyl and t.he like; lower alkoxy lower alkyl such as methoxyethyl and the like; and X is hydrogen, nitro, halo, such as chloro, bromo, fluoro and the like; lower alkanoyl o~ from 2 to 5 15 carbon atoms such as acetyl, propionyl, butyryl, pentanoyl and the like; lower alkyl of from 1 to 4 carbon atoms such as met~yl, ethyl~ propyl, n--butyl and the like; thiocyanato;
a radical of the formula: Y-S(O)n wherein ~ is lower alkyl of from 1 to 5 carbon atoms; lower alkeny.L (C3-C6), lower 20 alkynyl (C3-C6), cyclo lower al~yl (C3-C7), a 5- or 6-membered heterocycle, such as p~Jridyl, thienyl, furyl, pyr-imidinyl~ thiazoloyl and the like or mononuclea:r aryl such - as phenyl and n is 0 to 3, X is also lower alkoxycarbonyl-amino (Cl-C4) such as methoxycarbonylam:ino, isopropo~y-25 carbonylamino ancl the like; a radical o~ the fo:rmula:
O ~ .
Y'C- wherein Y' is mononuclear aryl such as phenyl and the like; cyclo lower alkyl (C3-C7), a 5- or 6-membered heter3-cycle, such as pyrldyl, 2-thienyl., furyl and the like or X
is also a radical of thQ formula: Y"0-, wherein yll i.s lower ~ : 3o alkyl ~Cl-C5~, mononuclear aryl, such as phenyl and the like;
.~, .
'~5-133~
lower alkenyl~ mononuclear aralkyl or a 5- or 6-me~mbered heterocyclic and, when substituted,the substituents on the Y, Y' and Y" are selected from halo, cyano, lower alkyl, lower alkoxy, lower alkanoyl lower alkylthio, lower alkyl-sulfinyl, lower alkylsulfonyl, phenylthio~ phenylsulfinyl ,phenylsulfonyl~ phenoxy~ halophenoxy, benzyloxy, trifluoro-,~ ~ methyl or carbo lower alkoxy~ and the nontoxic, pharmaceut-ically acceptable acid addîtion salts such as those formed with acids such as hydrochloric, sulfuric, nitric, phosphoric, acetic, citric, benzoic, lactic and the like~ and amides of th~ester such as amino, mono- and di-lower alkylamino and the like.
When compounds of General Formula 1 can exist in various isomer and stereoisomer forms all such isomers and t.heir mix.tures and racemates are includes within the sco7e of this present inventi.onO
' .
~ . .
.~ .
~f'r`~.`3~
Preferred E~bodiment A preferred embodiment of this in~Jention relates to the 2-amino-substituted-isothioureidobenzen~s (Iag supra) of the following structl1ral formula: :-~HNH-C=NC-oR3 xl SR2 wherein R3 is lower alkyl of from 1 to 4 carbon atoms, R2 is lower alkyl, lower alkenyl, lower alkynyl, benzyl, 2~6-dichlorobenzyl, phenethyl, cycloalkyl lower alkyl of from 5 to 6 nuclear atoms, phenoxy lower alkyl of from 3 to 6 carbon atoms, cyano lower alkyl of fro~ 3 to 6 carbon atoms; `
lower alkoxy carbonyl lower alkyl wherein lower means from 5 to 6 carbon atoms; phthalimido lower alkyl; phenyl lower alkenyl of from 3 to 6 carbon atoms or hydroxy lower alkyl : :
and Xl is hydrogen, lower alkyl, alkoxycarboIlylamlno, lower .
alkoxy, propylthio, propylsul~inyl, propylsul~onyl, phenyl-thio, phenylsulfinyl, phenylsulfonyl, lower alkanoyl or .
benzoyl. These compounds exhibit particularly good anthel- ~
'' ' : ': .
I mintic and antl~ungal actlvity.
` The 2-amino-substituted-isothioureidob~nzenes j 20 (I,supra) of this invention are prepared by treating the : corresponding 2-amino-substituted~hioureidobenzene (II, infra) with a base, for example, an alkali metal or alkaline earth metal base such as sodium hydro~ide, potassium hy~roxide .
or calclum hydroxide, followed by treatment with an organic halid~ or sul~onate (RX2). The reaction may be conducted at a tempernture~in the range of from 0C. to 40C. for a .
';1~ "l? . ~
f`- 1 ~
period ~f tirne from a few minutes to ab~ut on~ hour and the reaction with RX2 be mg conducted in the same tempera-tllre range for from a few minutes to abou' thL~ee days. Any solven+ in which the reactants are reasonably soluble and substantially inert may be employed. Suitablè solven-ts in-clude dim~thyl forma~ide (D~iF), acetone and the like. The following equation illustrates this process:
~.
X Y
O ~ ~ NH2o II I
wherein R, R1 and X are as de~ined above and x2 is halo such as chloro, br~mo or iodo and the like or sul~onate.
- Tne com~unds of ~ormulaII are either known compounds or may be prepared by kn~wn procedures as dis-closed in British Pat. Nos~ 1,307,250 a~ 1,3~0,~28 and also dlsclosed in Netherlands Pat. No~ 7,~01,~97, , One procedure for préparing the comp~unds of Formula II comprises treating an appropriat~ly ~bstituted l-amino (or l-nitro) 2-aminobenzene with a carboalkoxyiso-thiocyanate (IV, infra~, and when l-nitro, treating said ~3 nitro compound with a reducing agent, to afford the desired compounds of Formula II~ The following equation illustrates this process:
.
.
.
'~ '' ~,1 `$~
X
1 Reduction ~ ~ NH
2 ~ S=C=NC-OR if \ / 20 \ ~ / re~uired \ ~=~
'--~`NH2 or (N02) `N~CNHCOR
III IV . II
wherein Rl ana X are as defined above. - .
The diamlnes and nitroamines ol For~nul~ IIT.
(supra) are either known (see, for example, U. S. Pat.
Nos~ 3,657,267; 3,929,823; 3,929,82~; 3,935~209; 3,993,768;
compoun~s having both a ~ree ortho amino substituent on the b~nzene ring and a substituted sulfur atom in the thioureido group. Other patents disclosing anthelmintic compounds in- ~ -clude U~ S. Pat. Nos. 3,865,9~8 and ~,005,217 and British Pat. NoO 1,350,277~
object of this invention is to provide a new class o~ 2-amino-substituted-isothioureidobenzenes infraj,~methods for preparing these compounds 7 comp~si-tions containlng said compounds and to their use as anthelmintic and anti~ungal agents.
The novel 2-am m o-substituted-isothioureido-benzenes (I, infra) 3f this invention have the followi~g structural formula~
H-C=N-~-OR
~ SR
:: . . ~ .
? -wherein R is alkyl, for example, alkyl of from 1 to 19 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, _so-butyl~ sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyll octadecyl, nonadecyl and the like;
alkenyl, for example, lower alkenyl of from 3 to 8 carbon atoms such as allyl, propenyl, l~methylpropenyl 9 butenyl, pentenyl, hexellyl,-heptenyl7 octenyl and the like; alkynyl, for example, lower alkynyl of from 3 to 8 carbon atoms such as propynyl, butynyl, pent~yl, hexynyl, heptynyl, octynyl and the like; polynuclear axalkyl such as napthylmethyl, napthylethyl, phenanthracenylmethyl and the like; mono-nuclear aralkyl such as ben~yl, phenethyl, phen~lpropyl and the like which may be substltuted with from 1 to 3 groups such as halo, alkyl, alkox~, nitro and the like; mononuclear aryloxy lower alkyl, for example~ phenoxy lower alkyl of from 3 to 6 carbon atoms in the alkyl group including phenoxypropyl, phenoxybutyl, phenoxypentyl, phenoxyhexyl and the like; cycloalkylalkyl, for example, cycloalkyl lower alkyl o~ ~rom 5 to ~ nuclear carbon atoms such as cyclo-pentylmethyl, cyclopsntylethyl, cyclohexylmethyl, cyclo-- hexylethyl and the like; cyano lower alkyl-of ~rom 3 to 6 carbon atoms such as cyan~propyl, cyanobutyl, cyanopentyl, cyanohexyl and the like; hydroxy lower alkyl of from 3 to 8 carbon atoms such as hydroxypropyl, hyd.roxybutyl, hydroxy-pentyl, hydroxyoctyl and the like; aralkenyl, lor example, poly- and mono~uclear aralkenyl, such as phenylpropenyl an~
the like; alkoxyalkyl, for example, lower alkoxy lower alkyl, such as msthoxypropyl, ethoxypropyl, methoxybutyl, propoxy-butyl and the like; alkoxycarbonylalkyl, ~or example, loweralkoxycarb~nyl lower alkyl wherein the lower alkyl has 3 to 6 : : .
~ 3 -'~5~ 33~
carbon atoms, such as methoxycarb~nylpropyl, et}loxycarbonyl-butyl, ethoxycarbonylpentyl, propox~carbonylhexyl and the like; N-monomlclear arylcarbamoyl lower alkyl such as N-~(4-4-acetam]dophenylthio)phenyl~carbamoylethyl and the like phthalim:ido lower alkyl such as phthali~idobutyl andthe like; phenoxycarbonylalkyl, for example, ph.enoxycarbonyl lower alkyl of from 3 to 6 carbon atoms such as phenoxy-carbonylp:ropyl, phenoxycarbonylbutyl, phenoxycarbonylpentylr, phenoxycarbonylhexyl and the like; R~ is lower alXyl of 10 from 1 ~o 6 carbon atoms such as methyl, ethyl, n-propyl~
iso-propyl, n-bl~tyl, ~so-butyl, tert-butyl, pentyl, hexyl and t.he like; lower alkoxy lower alkyl such as methoxyethyl and the like; and X is hydrogen, nitro, halo, such as chloro, bromo, fluoro and the like; lower alkanoyl o~ from 2 to 5 15 carbon atoms such as acetyl, propionyl, butyryl, pentanoyl and the like; lower alkyl of from 1 to 4 carbon atoms such as met~yl, ethyl~ propyl, n--butyl and the like; thiocyanato;
a radical of the formula: Y-S(O)n wherein ~ is lower alkyl of from 1 to 5 carbon atoms; lower alkeny.L (C3-C6), lower 20 alkynyl (C3-C6), cyclo lower al~yl (C3-C7), a 5- or 6-membered heterocycle, such as p~Jridyl, thienyl, furyl, pyr-imidinyl~ thiazoloyl and the like or mononuclea:r aryl such - as phenyl and n is 0 to 3, X is also lower alkoxycarbonyl-amino (Cl-C4) such as methoxycarbonylam:ino, isopropo~y-25 carbonylamino ancl the like; a radical o~ the fo:rmula:
O ~ .
Y'C- wherein Y' is mononuclear aryl such as phenyl and the like; cyclo lower alkyl (C3-C7), a 5- or 6-membered heter3-cycle, such as pyrldyl, 2-thienyl., furyl and the like or X
is also a radical of thQ formula: Y"0-, wherein yll i.s lower ~ : 3o alkyl ~Cl-C5~, mononuclear aryl, such as phenyl and the like;
.~, .
'~5-133~
lower alkenyl~ mononuclear aralkyl or a 5- or 6-me~mbered heterocyclic and, when substituted,the substituents on the Y, Y' and Y" are selected from halo, cyano, lower alkyl, lower alkoxy, lower alkanoyl lower alkylthio, lower alkyl-sulfinyl, lower alkylsulfonyl, phenylthio~ phenylsulfinyl ,phenylsulfonyl~ phenoxy~ halophenoxy, benzyloxy, trifluoro-,~ ~ methyl or carbo lower alkoxy~ and the nontoxic, pharmaceut-ically acceptable acid addîtion salts such as those formed with acids such as hydrochloric, sulfuric, nitric, phosphoric, acetic, citric, benzoic, lactic and the like~ and amides of th~ester such as amino, mono- and di-lower alkylamino and the like.
When compounds of General Formula 1 can exist in various isomer and stereoisomer forms all such isomers and t.heir mix.tures and racemates are includes within the sco7e of this present inventi.onO
' .
~ . .
.~ .
~f'r`~.`3~
Preferred E~bodiment A preferred embodiment of this in~Jention relates to the 2-amino-substituted-isothioureidobenzen~s (Iag supra) of the following structl1ral formula: :-~HNH-C=NC-oR3 xl SR2 wherein R3 is lower alkyl of from 1 to 4 carbon atoms, R2 is lower alkyl, lower alkenyl, lower alkynyl, benzyl, 2~6-dichlorobenzyl, phenethyl, cycloalkyl lower alkyl of from 5 to 6 nuclear atoms, phenoxy lower alkyl of from 3 to 6 carbon atoms, cyano lower alkyl of fro~ 3 to 6 carbon atoms; `
lower alkoxy carbonyl lower alkyl wherein lower means from 5 to 6 carbon atoms; phthalimido lower alkyl; phenyl lower alkenyl of from 3 to 6 carbon atoms or hydroxy lower alkyl : :
and Xl is hydrogen, lower alkyl, alkoxycarboIlylamlno, lower .
alkoxy, propylthio, propylsul~inyl, propylsul~onyl, phenyl-thio, phenylsulfinyl, phenylsulfonyl, lower alkanoyl or .
benzoyl. These compounds exhibit particularly good anthel- ~
'' ' : ': .
I mintic and antl~ungal actlvity.
` The 2-amino-substituted-isothioureidob~nzenes j 20 (I,supra) of this invention are prepared by treating the : corresponding 2-amino-substituted~hioureidobenzene (II, infra) with a base, for example, an alkali metal or alkaline earth metal base such as sodium hydro~ide, potassium hy~roxide .
or calclum hydroxide, followed by treatment with an organic halid~ or sul~onate (RX2). The reaction may be conducted at a tempernture~in the range of from 0C. to 40C. for a .
';1~ "l? . ~
f`- 1 ~
period ~f tirne from a few minutes to ab~ut on~ hour and the reaction with RX2 be mg conducted in the same tempera-tllre range for from a few minutes to abou' thL~ee days. Any solven+ in which the reactants are reasonably soluble and substantially inert may be employed. Suitablè solven-ts in-clude dim~thyl forma~ide (D~iF), acetone and the like. The following equation illustrates this process:
~.
X Y
O ~ ~ NH2o II I
wherein R, R1 and X are as de~ined above and x2 is halo such as chloro, br~mo or iodo and the like or sul~onate.
- Tne com~unds of ~ormulaII are either known compounds or may be prepared by kn~wn procedures as dis-closed in British Pat. Nos~ 1,307,250 a~ 1,3~0,~28 and also dlsclosed in Netherlands Pat. No~ 7,~01,~97, , One procedure for préparing the comp~unds of Formula II comprises treating an appropriat~ly ~bstituted l-amino (or l-nitro) 2-aminobenzene with a carboalkoxyiso-thiocyanate (IV, infra~, and when l-nitro, treating said ~3 nitro compound with a reducing agent, to afford the desired compounds of Formula II~ The following equation illustrates this process:
.
.
.
'~ '' ~,1 `$~
X
1 Reduction ~ ~ NH
2 ~ S=C=NC-OR if \ / 20 \ ~ / re~uired \ ~=~
'--~`NH2 or (N02) `N~CNHCOR
III IV . II
wherein Rl ana X are as defined above. - .
The diamlnes and nitroamines ol For~nul~ IIT.
(supra) are either known (see, for example, U. S. Pat.
Nos~ 3,657,267; 3,929,823; 3,929,82~; 3,935~209; 3,993,768;
3,996,368; 3,996,369; 3,984S561 and 4,002,640; an~ also,French Pat~ No. 2,2~8,037 and Germ~n Pat~ No. 2,129,960) ,or may be prepared by the deacetylation of products disclosed in French Pat. No.
. 10 2,270,861 by hydrolysis.
Representative of the tvpe of product which can be prepa.red in the manner described above and which would have anthelmintic actlvit~ include: ' .
~.
~ .
, ~ ~ :
: :
.' . ~ .
~ . 8 75~ 3-~
2-(3-carbomethoY.y~S-rnethylisothiouxeido)-5-(1+-cyan~phen~rl-thio)aniline;
2-(3-carbomethoxy-S-butylisothioureido)-5-(4--methylthio-phenylthio)aniline;
5.~ 2-(3-carbomethoxy-S-butylisothioureido)-5~(3-cyanophenyl-thio)aIlilirle, 2-(3-carbomethoxy-S-methylisothioureido)-5-~3-rnethylthio-phenyl.thio)aniline;
2-(3-carbomethoxy-S-methylisothiourei.do)-5-(4~acetylpheny.L-~7 10 thio)aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-(4-methoxycarbonyl-phenylt.hio)aniline;
2-(3-carbomethoxy-S-metllylisothioureido)-4-(~-cyanophenyl-sulfinyl)aniline;
L5 2-(3-carb~methoxy S-butylisothioureido)-4-(~-acetylphenyl-sulfi.nyl)aniline;
2-(3~carbomethoxy-S-allylisothioureido)-L~ -methylth.io-phenylsulfinyl)aniline;
2-(3-carbom~thoxy-S-methylisothioureid~-LI-~4-methoxycarbonyl-20 phenylsl1lfinyl)aniline;
2-(3--carbomethoxy-S-methylisothioureido)-L~ +-cyanophenyl-sulfonyl)aniline;
2 (3-carbomethoxy-S-methylisothioureido)~L~ +-acetylphenyl-sulfonyl)aniline;
25 2-(~-carbomethoxy-S-methyliso~hioureido)-L~ -proplollylphenyl-sulfonyl)aniline;
2-(3-carbomethoxy-S-methyLisothioure:ido)-L~- (4 -methoxycarbonyl- ..
phenylsulfonyl)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-~ -acetylphenyl-30 sulfinyl)a.niline;
2-(3-ca:rbomethoxy-S-methylisothioureido)-5-(1+-methoxycarbonyl- ',' phenylsul~inyl)ani:Line;
2~(3-carbomethoxy-S-methylisothioureido)-5-(propargylthio)-; anili.ne;
35 2-(3-carbomethoxy-S-met]lylisothioureido)-5-(but 3-en-1-ylkhio)-an~line;
2-(3-carbometho}:y-S-methylisothioureido)-5-(but-3-en-1-yl-sul~ nyl)ani'Line, 2-~3-carbomethoxy-s~et~yliso-thioureido)-5-~but-3-en l~o sulfonyl)aniline;
, _9_ 2-(3-carbomethoxy-S-methylisothloure:ido)-5-(benzylthio)-aniLine;
2-(3-carbomethoxy-S-methylLsothioureido)-5- ~benzylsulfinyl)-anlline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(thiazol-2-ylthio)-aniline;
2-(3-carbomethoxy-S-methylisothioureido~-5-(thiazol-2-yl-sulfinyl)aniline;
2-(3-carbomethoxy-S-butylisothioureido)-5- (pyrid-2-ylthio)-10 anlline;
2-(3-carbomethoxy-S-butylisothioureido)-5-(pyrid-2--ylsulfinyl)- ~ .
an.iline;
2-~3-carbomethoxy-S-methylisothioureido)-5-(pyrimidin-2-yl- I.
thio)aniline; I .
15 2-(3-carbometho~y-S-methylisothioureido)-5-(pyrimidin-2-yl-sulfinyl)aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-~thien-2-ylthio)- :
aniline; .
2-(3-carbomethoxy-S-allylisothioureido)-5-(thien-2-yl-sulfinyl)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(fur-2-ylthio)-aniline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(3-chloropropyl-thio)anilins;
2-(3 carbomethox~-S-mathyl.isothioureido)-5-(3-chloropropyl-sulfinyl)anil.ine;
2-(3-carbomethox~-S-allylisothioure:ldo)-5-(3-chloroprop-2-en-~ylthi.o)aniline;
2-(3-carbomethoxy-S-al:l.ylisothioureido~-5-(3-chloroprop-2-3 en-~ylsulfinyl)aniLine;
2-(3-carbom~hox.y-S-methylisothi.oureido~-5-(2-cyanoethylthio)-aniline;
2-(3-carbomethoxy-$-msthylisothioureido)-5-(2-cyanoethylsulf-inyl)aniline;
2-(3-carbomethoxy-S methylisothioureido~5-(2-b~nzyloxyethoxy~-aniline;
2-(3-ca:rbomethoxy-S-methylisothioureido)-5-[2-(2'-rnethoxy~
ethoxy)ethoxy)anl.l.ine;
2-(3-ca~bomethox~-S-methylisothioureido)-5-(p-chlorophenoxy-40 ethoxy)anili.ne;
' ~:
L () 75~~3~
2-(3~carbom~thoxy-S-methylisothi.oureldo~5-(t-butoxyetllyl-thio)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(~-butoxyethyl-sulfinyl)aniline;
2-(3--carbomethoxy-S~methylisothioureido)-5--(benzyloxyethyl-thio)aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-(phenoxybutylthio)-aniline;
2-(3-carbomethoxy-S-allylisothioureldo)-5-(phenoxybutyl-10 sulfonyl)aniline; ,, 2-(3-carbomethoxy-S-methylisothioureido)-5-(2-phenylthio-ethylthio)aniline;
2-(3-carbomsthoxy-S-benzylisothiourei.do)-5-[2-(phenylslllf:Lnyl)-ethylthio]aniline;
15 2-(3-carbomethoxy-S-methyl:isothioureido)-5-[2-(ethylsulfinyl)-ethylthio~aniline;
2-(3-carbomethoxy-S-methylisothiou.reido)-5-[2-(phenylthlo~-ethoxy]aniline;
2-(3-carbomr~thoxy-S-me-thylisothioureido)-~-(cyclopropyl-20 carbony~aniline;
2-(3-carbomethoxy-S-butylisothioureido)-4-(cyclopelltyl-carbonyl)aniline;
2-(3-carbomethoxy-S-me~hylisothiourei.do)-L~(2-thenoy:L)an-l:line;
2-(3-carbomethoxy-S-methylisothi.oureido)-5~heny:Lsulfonyloxy)-25 aniline;
2-(3-carbomethox~-S-methylisothloureido)-5-(L~-chlo.rophenyl-sulfollyloxy)ani.line;
2-(3-carbomethoxy-S-butylisothioureido)-5-(3-chlorophenyl-sulfonyloxy~aniline;
3 2-(3-carbomethoxy-S-methylisothioureiclo)-5-(3~5-dichloro-ph~nylsul~onyloxy)aniline;
2-(3-carbomethoY.y-S-allylisothioureido)-5-(~-methylphenyl-sulfonyloxy)aniline;
2-(3-carbomethoxy-S-benzyl.i.sol;hioureido~-5-(3-trifluorol;lethyl-35 phenylsulfonyloxy)anilin3;
; 2~(3-carb~methoxy-S-methylisothioureido)-5-(4-msthoxyphenyl-sulfonyloxy)aniLine;
2-(3-carbomethoxy-S-methyl:isoth-i.oureido)-5-(pllenoxysulfonyl)-aniline;
llO 2-(3-carbomethoxy-S-methylisothioureido)-~-l-chloropherloxy-sulfonyl)aniline;
.:
'~5-1.:':3~
2-(3-carbornethoxy-S-butylisothiouleido)-5-t3-ch~Lorophenoxy-sulfonyl)anlline;
2-(3-carbomethoxy-S-benzylisothioureido)-5-(2-chlorophenoxy- .:
sulf'onyl)aniline;
5 2-(3-carbomethoxy-S-allyllsothioureido)-5-(3,5-dichlorophenoxy-sulfonyl)anillne;
2~(3~carbomethoxy-S-methylisothioureido)-5-(4-methylpherloxy-sulfonyl)aniline;
2-(3-carbomethoxy-S-isothlourei.do)-5-(L~-mcthoxyphenoxysulfonyl)-aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-(3-cyanophenoxy sulfonyl)aniline;
2-(3-carbom-3khoxy-S-methyli.sothlou:reido)-5-(3-trifluoromethyl-phenoxysulfonyl)anillne;
2-(3-carbomethoxy-S-methylisothioureido)-5-(3-chloropropoxy)_ àniline;
2-(3-carbometho.xy-S-methylisothioureido)-5-(2-phenylethox~)-aniline;
2-(3-carbomethoxy-S-methylisothlollreido)-5-(3-phellylprop-2-en-l-yloxy)an:lli.ne;
2-t3-carbomethoxy-S-rnethylisothiou.reîdo)-5-(pyrid-2-yloxy)-aniline;
2-(3-carbom3thoxy-S-butylisothioureido)-5-(th-iazo]-2-yloxy)-aniline;
2-(3-carbomethoxy-S-methylisothioureldo) 5~(phen~xy)ani'1ine;
2-(3-carbomethoxy-S-butylisothioureido)-5-~4-methylphenoxy)-ani:Lins;
2-(3-carbomethoxy-S-methyl.isothioureido)-5-(3-methylphenoxy)-aniline;
2-(3-carbomethoxy-S-butylisothioureido)-5-(2-mothylphenoxy)-aniline;
2-(3-carbomethoxy-S-rnethyllsotllioureido)-5- (~-ch'lorophenoxy)-aniline;
2-(3-ca:rbom~tho:xy-S-alLyli.sothioureido)-5-(3-methylthiophenoxy)-35' aniline;
; 2-(3-carbomethoxy-S-ally'l.isothioureido) -5- t3-txi~luoromethy~L~
phenoxy)ani:Line;
2-(3-carbomethoxy-S-rll~thylisothiou..eido)-5-(~-methoxyphenoxy)-an-,Lline;
- 1,:' '7 ~ A
3~
2-(3-carbomethoxy-S-methylisothioureido)-5-~2,3-dichloro-prop-2-erl-1-yl-thio)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-4-propion.ylaniline;
. 10 2,270,861 by hydrolysis.
Representative of the tvpe of product which can be prepa.red in the manner described above and which would have anthelmintic actlvit~ include: ' .
~.
~ .
, ~ ~ :
: :
.' . ~ .
~ . 8 75~ 3-~
2-(3-carbomethoY.y~S-rnethylisothiouxeido)-5-(1+-cyan~phen~rl-thio)aniline;
2-(3-carbomethoxy-S-butylisothioureido)-5-(4--methylthio-phenylthio)aniline;
5.~ 2-(3-carbomethoxy-S-butylisothioureido)-5~(3-cyanophenyl-thio)aIlilirle, 2-(3-carbomethoxy-S-methylisothioureido)-5-~3-rnethylthio-phenyl.thio)aniline;
2-(3-carbomethoxy-S-methylisothiourei.do)-5-(4~acetylpheny.L-~7 10 thio)aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-(4-methoxycarbonyl-phenylt.hio)aniline;
2-(3-carbomethoxy-S-metllylisothioureido)-4-(~-cyanophenyl-sulfinyl)aniline;
L5 2-(3-carb~methoxy S-butylisothioureido)-4-(~-acetylphenyl-sulfi.nyl)aniline;
2-(3~carbomethoxy-S-allylisothioureido)-L~ -methylth.io-phenylsulfinyl)aniline;
2-(3-carbom~thoxy-S-methylisothioureid~-LI-~4-methoxycarbonyl-20 phenylsl1lfinyl)aniline;
2-(3--carbomethoxy-S-methylisothioureido)-L~ +-cyanophenyl-sulfonyl)aniline;
2 (3-carbomethoxy-S-methylisothioureido)~L~ +-acetylphenyl-sulfonyl)aniline;
25 2-(~-carbomethoxy-S-methyliso~hioureido)-L~ -proplollylphenyl-sulfonyl)aniline;
2-(3-carbomethoxy-S-methyLisothioure:ido)-L~- (4 -methoxycarbonyl- ..
phenylsulfonyl)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-~ -acetylphenyl-30 sulfinyl)a.niline;
2-(3-ca:rbomethoxy-S-methylisothioureido)-5-(1+-methoxycarbonyl- ',' phenylsul~inyl)ani:Line;
2~(3-carbomethoxy-S-methylisothioureido)-5-(propargylthio)-; anili.ne;
35 2-(3-carbomethoxy-S-met]lylisothioureido)-5-(but 3-en-1-ylkhio)-an~line;
2-(3-carbometho}:y-S-methylisothioureido)-5-(but-3-en-1-yl-sul~ nyl)ani'Line, 2-~3-carbomethoxy-s~et~yliso-thioureido)-5-~but-3-en l~o sulfonyl)aniline;
, _9_ 2-(3-carbomethoxy-S-methylisothloure:ido)-5-(benzylthio)-aniLine;
2-(3-carbomethoxy-S-methylLsothioureido)-5- ~benzylsulfinyl)-anlline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(thiazol-2-ylthio)-aniline;
2-(3-carbomethoxy-S-methylisothioureido~-5-(thiazol-2-yl-sulfinyl)aniline;
2-(3-carbomethoxy-S-butylisothioureido)-5- (pyrid-2-ylthio)-10 anlline;
2-(3-carbomethoxy-S-butylisothioureido)-5-(pyrid-2--ylsulfinyl)- ~ .
an.iline;
2-~3-carbomethoxy-S-methylisothioureido)-5-(pyrimidin-2-yl- I.
thio)aniline; I .
15 2-(3-carbometho~y-S-methylisothioureido)-5-(pyrimidin-2-yl-sulfinyl)aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-~thien-2-ylthio)- :
aniline; .
2-(3-carbomethoxy-S-allylisothioureido)-5-(thien-2-yl-sulfinyl)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(fur-2-ylthio)-aniline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(3-chloropropyl-thio)anilins;
2-(3 carbomethox~-S-mathyl.isothioureido)-5-(3-chloropropyl-sulfinyl)anil.ine;
2-(3-carbomethox~-S-allylisothioure:ldo)-5-(3-chloroprop-2-en-~ylthi.o)aniline;
2-(3-carbomethoxy-S-al:l.ylisothioureido~-5-(3-chloroprop-2-3 en-~ylsulfinyl)aniLine;
2-(3-carbom~hox.y-S-methylisothi.oureido~-5-(2-cyanoethylthio)-aniline;
2-(3-carbomethoxy-$-msthylisothioureido)-5-(2-cyanoethylsulf-inyl)aniline;
2-(3-carbomethoxy-S methylisothioureido~5-(2-b~nzyloxyethoxy~-aniline;
2-(3-ca:rbomethoxy-S-methylisothioureido)-5-[2-(2'-rnethoxy~
ethoxy)ethoxy)anl.l.ine;
2-(3-ca~bomethox~-S-methylisothioureido)-5-(p-chlorophenoxy-40 ethoxy)anili.ne;
' ~:
L () 75~~3~
2-(3~carbom~thoxy-S-methylisothi.oureldo~5-(t-butoxyetllyl-thio)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-5-(~-butoxyethyl-sulfinyl)aniline;
2-(3--carbomethoxy-S~methylisothioureido)-5--(benzyloxyethyl-thio)aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-(phenoxybutylthio)-aniline;
2-(3-carbomethoxy-S-allylisothioureldo)-5-(phenoxybutyl-10 sulfonyl)aniline; ,, 2-(3-carbomethoxy-S-methylisothioureido)-5-(2-phenylthio-ethylthio)aniline;
2-(3-carbomsthoxy-S-benzylisothiourei.do)-5-[2-(phenylslllf:Lnyl)-ethylthio]aniline;
15 2-(3-carbomethoxy-S-methyl:isothioureido)-5-[2-(ethylsulfinyl)-ethylthio~aniline;
2-(3-carbomethoxy-S-methylisothiou.reido)-5-[2-(phenylthlo~-ethoxy]aniline;
2-(3-carbomr~thoxy-S-me-thylisothioureido)-~-(cyclopropyl-20 carbony~aniline;
2-(3-carbomethoxy-S-butylisothioureido)-4-(cyclopelltyl-carbonyl)aniline;
2-(3-carbomethoxy-S-me~hylisothiourei.do)-L~(2-thenoy:L)an-l:line;
2-(3-carbomethoxy-S-methylisothi.oureido)-5~heny:Lsulfonyloxy)-25 aniline;
2-(3-carbomethox~-S-methylisothloureido)-5-(L~-chlo.rophenyl-sulfollyloxy)ani.line;
2-(3-carbomethoxy-S-butylisothioureido)-5-(3-chlorophenyl-sulfonyloxy~aniline;
3 2-(3-carbomethoxy-S-methylisothioureiclo)-5-(3~5-dichloro-ph~nylsul~onyloxy)aniline;
2-(3-carbomethoY.y-S-allylisothioureido)-5-(~-methylphenyl-sulfonyloxy)aniline;
2-(3-carbomethoxy-S-benzyl.i.sol;hioureido~-5-(3-trifluorol;lethyl-35 phenylsulfonyloxy)anilin3;
; 2~(3-carb~methoxy-S-methylisothioureido)-5-(4-msthoxyphenyl-sulfonyloxy)aniLine;
2-(3-carbomethoxy-S-methyl:isoth-i.oureido)-5-(pllenoxysulfonyl)-aniline;
llO 2-(3-carbomethoxy-S-methylisothioureido)-~-l-chloropherloxy-sulfonyl)aniline;
.:
'~5-1.:':3~
2-(3-carbornethoxy-S-butylisothiouleido)-5-t3-ch~Lorophenoxy-sulfonyl)anlline;
2-(3-carbomethoxy-S-benzylisothioureido)-5-(2-chlorophenoxy- .:
sulf'onyl)aniline;
5 2-(3-carbomethoxy-S-allyllsothioureido)-5-(3,5-dichlorophenoxy-sulfonyl)anillne;
2~(3~carbomethoxy-S-methylisothioureido)-5-(4-methylpherloxy-sulfonyl)aniline;
2-(3-carbomethoxy-S-isothlourei.do)-5-(L~-mcthoxyphenoxysulfonyl)-aniline;
2-(3-carbomethoxy-S-allylisothioureido)-5-(3-cyanophenoxy sulfonyl)aniline;
2-(3-carbom-3khoxy-S-methyli.sothlou:reido)-5-(3-trifluoromethyl-phenoxysulfonyl)anillne;
2-(3-carbomethoxy-S-methylisothioureido)-5-(3-chloropropoxy)_ àniline;
2-(3-carbometho.xy-S-methylisothioureido)-5-(2-phenylethox~)-aniline;
2-(3-carbomethoxy-S-methylisothlollreido)-5-(3-phellylprop-2-en-l-yloxy)an:lli.ne;
2-t3-carbomethoxy-S-rnethylisothiou.reîdo)-5-(pyrid-2-yloxy)-aniline;
2-(3-carbom3thoxy-S-butylisothioureido)-5-(th-iazo]-2-yloxy)-aniline;
2-(3-carbomethoxy-S-methylisothioureldo) 5~(phen~xy)ani'1ine;
2-(3-carbomethoxy-S-butylisothioureido)-5-~4-methylphenoxy)-ani:Lins;
2-(3-carbomethoxy-S-methyl.isothioureido)-5-(3-methylphenoxy)-aniline;
2-(3-carbomethoxy-S-butylisothioureido)-5-(2-mothylphenoxy)-aniline;
2-(3-carbomethoxy-S-rnethyllsotllioureido)-5- (~-ch'lorophenoxy)-aniline;
2-(3-ca:rbom~tho:xy-S-alLyli.sothioureido)-5-(3-methylthiophenoxy)-35' aniline;
; 2-(3-carbomethoxy-S-ally'l.isothioureido) -5- t3-txi~luoromethy~L~
phenoxy)ani:Line;
2-(3-carbomethoxy-S-rll~thylisothiou..eido)-5-(~-methoxyphenoxy)-an-,Lline;
- 1,:' '7 ~ A
3~
2-(3-carbomethoxy-S-methylisothioureido)-5-~2,3-dichloro-prop-2-erl-1-yl-thio)aniline;
2-(3-carbomethoxy-S-methylisothioureido)-4-propion.ylaniline;
4-~3-carbomethoxy-S-proplonylisothioureido~aniline;
~2-(3-carbomethoxy-S-allylisothioureido)-L~-butyrylanilin2;
2-(3-carbomethoxy-S-butylisothiou:reido)-4-valerylaniline;
2-(3-carbomethoxy-S~methylisothioureido)-5-p.ropoxyaniline;
2~(3-carbomethoxy-S-methylisothioureido)-5-ethoxyaniline;
2-(3-carbomethoxy-S~allylisothioureido)-5-n-b~toxyani.line;
2-(3-carbomethoxy-S-butylisothioureido)-5-isopropoxyaniline;
2-(3 carbomethoxy-~-methylisothioureido)-4-thiocyanatoaniline;
2-(3-carb~methoxy-S-butylisothiourQido)-5-thiocyanatoaniline;
2-(3-carbometho~y-S-methylisothioureido)-5-isopropoxycarbonyl-am:inoaniline;
2-(3-carbomethoxy-S-methylisothio1lr~ido)-L~-i.sopropo.{ycarbonyl-aminoaniline;
2-(3-carbomethoxy S-methylisothiou.reido)-4-methoxycarbonyl-aminoaniline~
2-(3-carbomethoxy-S-methylisothioureido)-4-(,~,-chlorobanzoyl)-aniline;
2-(3-carbomethoxy-S-allylisothîoureido)-L~ -fluorobenzoyl) aniline;
2-(3-carbomethoxy-S-but~lisothiollreido)-4-p-toloyl)~niline;
2-(3-carbomethoxy-S-benzylisothioureldo)-L~-p-m2thoxyb~nzoyl)-aniline;and 2-(3-carbomethoxy-S-methylisothioureido)-4-(3-trifluoromethyl-benzoyl)anll.ine~
.
. ..
2-Amino-substituted-isothioureidobenzenes of Formula I are anthelmintics and have broad spectrum activity against parasites of animals especially warm blooded animals, including both mature and immature parasitic forms. In particular, these compounds e~hibit high activit~ against various helmi~tic infections of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
For example~ the disclosed compounds are generally effective in clearing mice of wcrm infections for laboratory purposes, among others: ~Phacia obvelata and e~ larii tetraptera (mouse pinworm), the migratory stages of Ascaris ~ ymenole~sls nana and Nematospiroides dubius.`
Compounds of Formula I have been demonstrated as efficacious against parasitic gastroenteritis in sheep, such as Mo_ieza ~ a~EB~ contortus, Oster~ SPr~, ~l _ o~ a~ , E~ ---ru~ , Trichuris ovis, _o~ , Capil]aria ~ and Stron~loides J i~
unostomum triconocePhalum and Oeso~ha~ostomllm sp!~, are other important parasites of sheep. The compounds are active again~st lung worms in ruminants especially Dict~ocaulus f~larla, in sheep and Dict~ocaulus v_viparu~i, in cattle.
~-- In addition, the compounds are ef~ectiveagainst li~er flukas ~Fasciola heP~atica) in sheep~
~ Animals of low weight are treated with unit doses ranging no higher than a few milligrams; whereas, animals of high body weig~t, such as ruminants 9 require ; proportionately larger Ullit doses ran~ing up to se~eral grams. Preferably, a single dose is administered for each anirnal species b~sed on the weight of that species.
:
,A
~ he amount of ingredient administered will depend on the weight Or the host, but will usually be a unit dosage bet~een about 1 mgO/kg~ and 125 m~O/kg. of body weight. It ~ contemplated that dosage units con-tainin~ the compounds of Formula I of this inven~ion asthe essentially active ingredient will be administered, orally or by inje^tion, in~he treatment and control o~
helmintlc infections in domestic animals such as sheep, '~
cattle, horses, dogs, ca~s, fish~ swine and goats.
Further, applicants have found that the compounds of Formula I of this invention display broad spectrum antifun~al activity. It is contemplated 9 there-fore, that anti~ungal compositions containirLg these compounds as an essential active ingredient will be employed in con-trolling the growth of fungi in or on animals and plants as well as in '~he paint, wood, textile, cosmetic~ leather, tobacco, fur, rope, paper, pulp, plastic, fkel, rubber and ; - food industries~
en used as an anthelmintic agent for the treatment an~/or prevention of helminthiasis, the novel compounds of Formula I of this invention may be administered .
orall~ in a unit dosage form such as a paste, gel 7 capsule, bolus, tablet or as a liquid drench. They may also be administered orally by intimately dispersing them in an animal ~eedstuf~` or by using them as a top dressing or in the ~orm of p~llets which are added to a finished feed. Alternatively, they may be administexed to animals in a liquid carrier vehicle by intraruminal, in~ramuscular anl intratracheal injection.
The quantity Or active material required to give best anthel-mintic response will depend upon the particular compound em-~' ployed 9 the speci~s of animal ko be treated and the t~rpe and ..
.. . . .
severity of helminth infection. Good results are usually obtained when there is administered a total dose of from about l to about 125 mg. of active ingredient per kg. of animal body weight. Such to~al dose may be given at one time or in divided doses over a short period of time such as 1 to 2 days.
~ len used as antifungal agents, the 2-amino-S- -substituted isothioureidobenzenes (I, supra) of this invention may be incorporated into diverse formulations such as solids,including finely divided powdars and granular materials, as well as liquids, such as solutions, emulsions, suspensions, concentrates, emulsifiable concentrates, slurries, and the liks~ clepending upon the application intended and the forrnulation media desired. Thus it will be appreciated that the compounds of th:is invention may be emplo~ed to form ~ungicidally active compositions containing a fungicidally active quantity of such compounds as an essential active ingredient. Such composltions may also con~ain finely divided dry or liquid diluents, extenders, fillers, conditioners and excipients including various clays, dia~omaceous ear~h, talc, and the like, or water and various organlc liquids, for example, lower alkanols such as ethanol and isopropanol, or kerosene, benzene 9 toluene and other petroleum distillate fractions or mixtures t~llereof~ ~he formulations contain 25 ~rom about 50 to 800 parks per million of active lngrsdient and preferably from about 200 to 500 parts per million.
The ~ollowing examples illustrate the compounds of ihis invention and the methods by which they are prepared.
However, the examples are illustrative only and it ~ill be apparent to those having ordinary skill in the art that all :
.~ " .
_ 16 _ .. . . :
-: . . .
of the products embraced by Formula I, supra, may also be prepared in an analogous manner b~J substitut ing the appropriate starting materials for those set forth in the examples.
, ':
':
: :: :: :
:
:
r~3 Example 1 - 3-(3-Carbomethoxy-S-methylisothioureido)-4-amino-_enzophenone To a solution of 3 (3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in dimethylformamide (DMF) (20 ml.) is added water (5 ml.). The solution is cooled to room temperature after the exothermic reaction subsides. A sodium hydroxide solu-tion (50% aqueous; 0.8 g.; 0.01 mole~ is added and the solu-tion is stirred at ; -room temperature for one hour. Methyl iodide ~1.42 g.;
0.01 mole) is added and within two minutes the solution is poured into water (200 ml.~. A suspension which forms is stirred at room temperature for one hour and collected by filtration. The filter cake is washed with ether, water and ether and then dried to afford 2.84 g. (82.8%
yield) of 3-(3-carbomethoxy-S-me-thylisothioureido)-4-aminoben~ophenone, m.p. 154C. dec.
Elemental Analysis for C17H17N3O3S
Calc.O C, 59.46; H, 4.99; N, 12.24 E`ound: C, 59.18; H/ 4.99; N, 12.28 Exam~ 2 - 3-(3-Carbomethoxy-5-allylisothioureido)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido-4-aminobenzophenone (6.58 g.; 0.02 mole) in DMF (75 ml.) is added water (20 ml.). A fine suspension Eorms to which is added a sodium hydroxide solution (50~ aqueous;
1.6 g.; 0.02 mole) and`the resulting solution stirred at room temperature for~l.5 hours. Allyl bromide (2.42 g.;
0.02 mole) is then added. The xeaction mixture is stirred at room temperature fGr 18 hours and then poured into ~ -.
water (500 ml.)~ The precipitate is collected by vacu~un filtration and the filter cake is washed with ether and ,, then dried to afford 5 g. (69% yield) of 3-(3-carbo~
methoxy-S-a]lylisothioureido)-4-aminobenzophenone, m.p.
128-131~C. dec.
Example 3 - 3-(3-Carbomethoxy-S-benzylisothioureido)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4 aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.), cooled to 10C., is added 5 ml. of water (exotherm to 20C.).
The solution is cooled to 10C. and potassium hydroxide pellets 10.65 g.; 0.01 mole) added. After 15 minutes of stirring at 10C. a solution forms and to it is added benæyl bromide (3.42 g.; 0.02 mole). The solution is allowed to warm to room temperature and aEter 10 minutes the suspension formed is collected. The filter cake is washed successively with ether, water and ether and then dried to afford 2.3 g. (50% yield) of 3-(3-carbomethoxy-S-benzylisothioureido)-4~aminobenzophenone, m.p. 175C.
dec.
Elemental Analysis for C23H21N3O3S
Calc.: C, 65.85; H, 5.05; N, 10.02 Found: C, 65.11, H, 5.18; N, 10.11 Examp].e 4 - 3-t3-carboethoxy-s-methylisothioureido)-4 aminobenzophenone To a tur~id solution of 3-(3-carboe-thoxythio-.
ureido)-4-aminobenzophenone (1.75 g.; 0.005 mole) in DMF
(25 ml.) and water (5 ml.) is added potassium hydroxide pellets (0.33 g.; 0.005 mole). The reaction mixture is stirred at room temperature for 15 minutes. Methyl iodide (0.71 g.; 0.005 mole) is then added and the reaction mixture is stirred at room temperature for one hour. More DMF t15 ml.) is added and the reaction mixture ,t~
' :
.. . . . . . . .. . ..
is stirred at room temperature for 30 minutes and poured into water (300 ml.~. The precipitate is collected by vacuum filtration and the filter cake washed with hexane and dried to afford 1.15 g (64.4% yield) of 3-(3-carbo-ethoxy-S-methylisothioureido)-4-aminobenzophenone, m.p.
144-146C. dec.
Elemental Analysis for C18HlgN3O3S
Calc.: C, 60.48; H, 5.36; N, 11.76 Found: C, 60.20; H, 5.24; N, 11.85 Example 5 - 3-(3-Carbomethoxy-S-n-butylisothioureido)-4-aminobenzophenone _ _ To a solution of 3-~3-carbomethoxythioureido)-4 aminobenzophenone in DMF (30 ml.) is added water (10 ml.). To the fine suspension is added a sodium hydroxide solution (50~ aqueous; 0.8 g.; 0.01 mole). The solution is stirred at room temperature or 1.5 hours. Butyl iodide (1.84 g.; 0.01 mole) is added and the reaction mix-ture is stirred at room temperature for 18 hours. The solution is poured into water (300 ml.) and the precipi-tate is collected by vacuum filtration. The filter cake is washed with ether and dried to aford 2.5 y. (65%
yield) cf 3-(3 carbomethoxy-S-n-butylisothioureido)~4-aminobenzophenone, m.p. 132C. dec.
i Elemental Analysis for C20H23N3O3S
Calc.: C,~62.31; H, 6.01; N, 10.90 Eound: C, 61.81; Hl 5.97; N, 10.90 ~ .
Example 6 - 3-(3-Carbomethoxy-S-ethylisothioureido)-4-aminobenzoph _ _ rro a soluti.on o 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3~29 g.; 0.01 mole) in DMF (25 ml.) is added water~(10 ml~.) (exothermic reaction). ~he : . .
:~: ~ : : . .
~ - , , .
solution is cooled to room temperature and a sodium hydroxide solution (50~ aqueous; 0.8 g~; 0.01 mole) is added. The mixture is stirred at room temperature for one hour and ethyl iodide (1.56 g.; 0.01 mole) is added.
The reaction mixture is stirred at room temperature for one hour and the precipitate collected by vacuum filtra-tion. The filter cake is washed successively with ether, water and ether and then dried to afford 1.45 g. (40.6 yield) of 3-(3-carbomethoxy-S-ethylisothioureido)-4-aminobenzophenone, m.p. 155-156C. dec.
Elemental Analysis for C18HlgN3O3S (M.W. 357~416) Calc.: C, 60.48; Hr 5.36; N, 11.76 Found. Cr 60.38; H, 5.44; N, 11.75 Example 7 - 3-(3-Carbomethoxy-S-cyclohexylmethylisothio-ureido)-4-aminohen~phenone _ To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.2 g.; 0.01 mole) in DMF (25 ml.) is added water ~7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50~ aqueous;
0.8 g.; 0.01 mole) is added and the resulting solution stirred at room temperature for one hour. Cyclohexyl-methyl bromide (1.77 g.; 0.01 mole) is then added and the solution stirred at room temperature for 19.5 hours. The precipitate is collected and washed successively with ether, water and ether and then dried to afford 1.7 g.
of 3-(3-carbometho~y-S-cyclohexylmethylisothioureido)-4 aminobenzophenone, m.p. 155-158C. dec.
Elemental Analysis for C23E27N3O3S
Calc.: C, 64.91; H, 6.40; N, ~.87 ~ound: C, 65.27, H, 6.80; N, 9.96 ~ .
:.
~ - 21 -Example 8 - 3-(3-Carbomethoxy-5-cyanobutylisothioureido)-4-_minoben~o~enone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.5 g.; 0.02 mole) in DMF (50 ml~) i5 added water (15 ml.). The solution is cooled ~o room temperature and a sodium hydroxide solution (50% aqueous, 1.6 g.; 0.02 mole) is added. The solution is stirred at room temperature for lo 5 hours and then 5-bromovalero-nitrile ~3.24 g.; 0.02 mole) is added. The solution is stirred at room tempera-ture for 18 hours then poured into 500 milliliters of water. The suspension formed is stirred for an additional 18 hours at room temperature, collected by filtration, washed with ether and dried to afford 7.35 g. (89.5~ yield) of 3-(3-carbomethoxy-S-cyanobutylisothioureido)-4-aminobenzophenone, 155-160C.
dec.
Example 9 - 3-(3-~Carbomethoxy-S-Ethoxycarbonylpropyliso thioureido~)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)- ;
ZO 4-aminobenzophenone (3.29 g.; 0.01 ml.~ in DMF (25 ml.) is added water (7.0 ml.). The solution is cooled and a sodium hydroxide solution (50% aqueous; 0.8 g.; 0.01 ml.) is added. This solution is stirred at room temperature for one hour. Ethyl-4-bromobutyrate (1.95 g.; 0.01 mole) is then added. The solution is stirred at room temperature ~or four days then poured into an excess of water. The semi-solid tarry precipitate is collected and tri--turated with 5 milliliters of ether. The solid is ; collected, washed with ether and dried to afford 2.7 g.
(62~ yield) o~ 3-(3-carbomethoxy-S-ethoxycarbonylpropyl-isothioureido)-4-aminobenzophenone, m.p. 119-120C. dec.
~ .
~ - 22 -,~
;3~
Example 10 - 3-(3-Carbomethoxy-S-phthalimidohutylisothio-ureldo)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.2g g.; 0.01 ml.) in DMF (25 ml.) is added water (7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
0.8 g.; 0.01 ml.) is added. The solution is stirred at room temperature for one hour and N (4~bromobutyl)-phthalimide (2.82 g.; 0.01 ml.) is added. The solution is stirred for 30 minutes at which time a precipitate begins to form. The precipitate is stirred at room temperature for an additional 30 minutes, collected by filtration, washed with water and ether and then dried to afford 2.9 g. (54.7% yield) of 3-(3-carbomethoxy-S-phthalimidobutylisothioureido)-4-aminobenzophenone, m.p.
154-157C. dec.
E~ e 11 - 3-(3-Carbomethoxy-S-propargylisothioureido~-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.58 g.; 0.02 ml.) in ~MF (50 ml.) is added water (15 ml.~. The solution i8 cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.6 g.; 0.02 ml.) is added and the solution stirred at room temperature for one hour. Propargyl bromide (2.38 ; g.; 0.02 ml.) is added and the solution is stirred at room temperature for three hours then poured into 500 milliliters of water. The precipitate is collected by filtration and dried to a~ford 5.1 g. (69% yield) of 3-(3-carbomethoxy-S-propargylisothioureido)-4-aminobenzophenone, m.p. 170C.
., .
~ 30 dec.
.
~ ~ ~3 ~
...
- . ,
~2-(3-carbomethoxy-S-allylisothioureido)-L~-butyrylanilin2;
2-(3-carbomethoxy-S-butylisothiou:reido)-4-valerylaniline;
2-(3-carbomethoxy-S~methylisothioureido)-5-p.ropoxyaniline;
2~(3-carbomethoxy-S-methylisothioureido)-5-ethoxyaniline;
2-(3-carbomethoxy-S~allylisothioureido)-5-n-b~toxyani.line;
2-(3-carbomethoxy-S-butylisothioureido)-5-isopropoxyaniline;
2-(3 carbomethoxy-~-methylisothioureido)-4-thiocyanatoaniline;
2-(3-carb~methoxy-S-butylisothiourQido)-5-thiocyanatoaniline;
2-(3-carbometho~y-S-methylisothioureido)-5-isopropoxycarbonyl-am:inoaniline;
2-(3-carbomethoxy-S-methylisothio1lr~ido)-L~-i.sopropo.{ycarbonyl-aminoaniline;
2-(3-carbomethoxy S-methylisothiou.reido)-4-methoxycarbonyl-aminoaniline~
2-(3-carbomethoxy-S-methylisothioureido)-4-(,~,-chlorobanzoyl)-aniline;
2-(3-carbomethoxy-S-allylisothîoureido)-L~ -fluorobenzoyl) aniline;
2-(3-carbomethoxy-S-but~lisothiollreido)-4-p-toloyl)~niline;
2-(3-carbomethoxy-S-benzylisothioureldo)-L~-p-m2thoxyb~nzoyl)-aniline;and 2-(3-carbomethoxy-S-methylisothioureido)-4-(3-trifluoromethyl-benzoyl)anll.ine~
.
. ..
2-Amino-substituted-isothioureidobenzenes of Formula I are anthelmintics and have broad spectrum activity against parasites of animals especially warm blooded animals, including both mature and immature parasitic forms. In particular, these compounds e~hibit high activit~ against various helmi~tic infections of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
For example~ the disclosed compounds are generally effective in clearing mice of wcrm infections for laboratory purposes, among others: ~Phacia obvelata and e~ larii tetraptera (mouse pinworm), the migratory stages of Ascaris ~ ymenole~sls nana and Nematospiroides dubius.`
Compounds of Formula I have been demonstrated as efficacious against parasitic gastroenteritis in sheep, such as Mo_ieza ~ a~EB~ contortus, Oster~ SPr~, ~l _ o~ a~ , E~ ---ru~ , Trichuris ovis, _o~ , Capil]aria ~ and Stron~loides J i~
unostomum triconocePhalum and Oeso~ha~ostomllm sp!~, are other important parasites of sheep. The compounds are active again~st lung worms in ruminants especially Dict~ocaulus f~larla, in sheep and Dict~ocaulus v_viparu~i, in cattle.
~-- In addition, the compounds are ef~ectiveagainst li~er flukas ~Fasciola heP~atica) in sheep~
~ Animals of low weight are treated with unit doses ranging no higher than a few milligrams; whereas, animals of high body weig~t, such as ruminants 9 require ; proportionately larger Ullit doses ran~ing up to se~eral grams. Preferably, a single dose is administered for each anirnal species b~sed on the weight of that species.
:
,A
~ he amount of ingredient administered will depend on the weight Or the host, but will usually be a unit dosage bet~een about 1 mgO/kg~ and 125 m~O/kg. of body weight. It ~ contemplated that dosage units con-tainin~ the compounds of Formula I of this inven~ion asthe essentially active ingredient will be administered, orally or by inje^tion, in~he treatment and control o~
helmintlc infections in domestic animals such as sheep, '~
cattle, horses, dogs, ca~s, fish~ swine and goats.
Further, applicants have found that the compounds of Formula I of this invention display broad spectrum antifun~al activity. It is contemplated 9 there-fore, that anti~ungal compositions containirLg these compounds as an essential active ingredient will be employed in con-trolling the growth of fungi in or on animals and plants as well as in '~he paint, wood, textile, cosmetic~ leather, tobacco, fur, rope, paper, pulp, plastic, fkel, rubber and ; - food industries~
en used as an anthelmintic agent for the treatment an~/or prevention of helminthiasis, the novel compounds of Formula I of this invention may be administered .
orall~ in a unit dosage form such as a paste, gel 7 capsule, bolus, tablet or as a liquid drench. They may also be administered orally by intimately dispersing them in an animal ~eedstuf~` or by using them as a top dressing or in the ~orm of p~llets which are added to a finished feed. Alternatively, they may be administexed to animals in a liquid carrier vehicle by intraruminal, in~ramuscular anl intratracheal injection.
The quantity Or active material required to give best anthel-mintic response will depend upon the particular compound em-~' ployed 9 the speci~s of animal ko be treated and the t~rpe and ..
.. . . .
severity of helminth infection. Good results are usually obtained when there is administered a total dose of from about l to about 125 mg. of active ingredient per kg. of animal body weight. Such to~al dose may be given at one time or in divided doses over a short period of time such as 1 to 2 days.
~ len used as antifungal agents, the 2-amino-S- -substituted isothioureidobenzenes (I, supra) of this invention may be incorporated into diverse formulations such as solids,including finely divided powdars and granular materials, as well as liquids, such as solutions, emulsions, suspensions, concentrates, emulsifiable concentrates, slurries, and the liks~ clepending upon the application intended and the forrnulation media desired. Thus it will be appreciated that the compounds of th:is invention may be emplo~ed to form ~ungicidally active compositions containing a fungicidally active quantity of such compounds as an essential active ingredient. Such composltions may also con~ain finely divided dry or liquid diluents, extenders, fillers, conditioners and excipients including various clays, dia~omaceous ear~h, talc, and the like, or water and various organlc liquids, for example, lower alkanols such as ethanol and isopropanol, or kerosene, benzene 9 toluene and other petroleum distillate fractions or mixtures t~llereof~ ~he formulations contain 25 ~rom about 50 to 800 parks per million of active lngrsdient and preferably from about 200 to 500 parts per million.
The ~ollowing examples illustrate the compounds of ihis invention and the methods by which they are prepared.
However, the examples are illustrative only and it ~ill be apparent to those having ordinary skill in the art that all :
.~ " .
_ 16 _ .. . . :
-: . . .
of the products embraced by Formula I, supra, may also be prepared in an analogous manner b~J substitut ing the appropriate starting materials for those set forth in the examples.
, ':
':
: :: :: :
:
:
r~3 Example 1 - 3-(3-Carbomethoxy-S-methylisothioureido)-4-amino-_enzophenone To a solution of 3 (3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in dimethylformamide (DMF) (20 ml.) is added water (5 ml.). The solution is cooled to room temperature after the exothermic reaction subsides. A sodium hydroxide solu-tion (50% aqueous; 0.8 g.; 0.01 mole~ is added and the solu-tion is stirred at ; -room temperature for one hour. Methyl iodide ~1.42 g.;
0.01 mole) is added and within two minutes the solution is poured into water (200 ml.~. A suspension which forms is stirred at room temperature for one hour and collected by filtration. The filter cake is washed with ether, water and ether and then dried to afford 2.84 g. (82.8%
yield) of 3-(3-carbomethoxy-S-me-thylisothioureido)-4-aminoben~ophenone, m.p. 154C. dec.
Elemental Analysis for C17H17N3O3S
Calc.O C, 59.46; H, 4.99; N, 12.24 E`ound: C, 59.18; H/ 4.99; N, 12.28 Exam~ 2 - 3-(3-Carbomethoxy-5-allylisothioureido)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido-4-aminobenzophenone (6.58 g.; 0.02 mole) in DMF (75 ml.) is added water (20 ml.). A fine suspension Eorms to which is added a sodium hydroxide solution (50~ aqueous;
1.6 g.; 0.02 mole) and`the resulting solution stirred at room temperature for~l.5 hours. Allyl bromide (2.42 g.;
0.02 mole) is then added. The xeaction mixture is stirred at room temperature fGr 18 hours and then poured into ~ -.
water (500 ml.)~ The precipitate is collected by vacu~un filtration and the filter cake is washed with ether and ,, then dried to afford 5 g. (69% yield) of 3-(3-carbo~
methoxy-S-a]lylisothioureido)-4-aminobenzophenone, m.p.
128-131~C. dec.
Example 3 - 3-(3-Carbomethoxy-S-benzylisothioureido)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4 aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.), cooled to 10C., is added 5 ml. of water (exotherm to 20C.).
The solution is cooled to 10C. and potassium hydroxide pellets 10.65 g.; 0.01 mole) added. After 15 minutes of stirring at 10C. a solution forms and to it is added benæyl bromide (3.42 g.; 0.02 mole). The solution is allowed to warm to room temperature and aEter 10 minutes the suspension formed is collected. The filter cake is washed successively with ether, water and ether and then dried to afford 2.3 g. (50% yield) of 3-(3-carbomethoxy-S-benzylisothioureido)-4~aminobenzophenone, m.p. 175C.
dec.
Elemental Analysis for C23H21N3O3S
Calc.: C, 65.85; H, 5.05; N, 10.02 Found: C, 65.11, H, 5.18; N, 10.11 Examp].e 4 - 3-t3-carboethoxy-s-methylisothioureido)-4 aminobenzophenone To a tur~id solution of 3-(3-carboe-thoxythio-.
ureido)-4-aminobenzophenone (1.75 g.; 0.005 mole) in DMF
(25 ml.) and water (5 ml.) is added potassium hydroxide pellets (0.33 g.; 0.005 mole). The reaction mixture is stirred at room temperature for 15 minutes. Methyl iodide (0.71 g.; 0.005 mole) is then added and the reaction mixture is stirred at room temperature for one hour. More DMF t15 ml.) is added and the reaction mixture ,t~
' :
.. . . . . . . .. . ..
is stirred at room temperature for 30 minutes and poured into water (300 ml.~. The precipitate is collected by vacuum filtration and the filter cake washed with hexane and dried to afford 1.15 g (64.4% yield) of 3-(3-carbo-ethoxy-S-methylisothioureido)-4-aminobenzophenone, m.p.
144-146C. dec.
Elemental Analysis for C18HlgN3O3S
Calc.: C, 60.48; H, 5.36; N, 11.76 Found: C, 60.20; H, 5.24; N, 11.85 Example 5 - 3-(3-Carbomethoxy-S-n-butylisothioureido)-4-aminobenzophenone _ _ To a solution of 3-~3-carbomethoxythioureido)-4 aminobenzophenone in DMF (30 ml.) is added water (10 ml.). To the fine suspension is added a sodium hydroxide solution (50~ aqueous; 0.8 g.; 0.01 mole). The solution is stirred at room temperature or 1.5 hours. Butyl iodide (1.84 g.; 0.01 mole) is added and the reaction mix-ture is stirred at room temperature for 18 hours. The solution is poured into water (300 ml.) and the precipi-tate is collected by vacuum filtration. The filter cake is washed with ether and dried to aford 2.5 y. (65%
yield) cf 3-(3 carbomethoxy-S-n-butylisothioureido)~4-aminobenzophenone, m.p. 132C. dec.
i Elemental Analysis for C20H23N3O3S
Calc.: C,~62.31; H, 6.01; N, 10.90 Eound: C, 61.81; Hl 5.97; N, 10.90 ~ .
Example 6 - 3-(3-Carbomethoxy-S-ethylisothioureido)-4-aminobenzoph _ _ rro a soluti.on o 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3~29 g.; 0.01 mole) in DMF (25 ml.) is added water~(10 ml~.) (exothermic reaction). ~he : . .
:~: ~ : : . .
~ - , , .
solution is cooled to room temperature and a sodium hydroxide solution (50~ aqueous; 0.8 g~; 0.01 mole) is added. The mixture is stirred at room temperature for one hour and ethyl iodide (1.56 g.; 0.01 mole) is added.
The reaction mixture is stirred at room temperature for one hour and the precipitate collected by vacuum filtra-tion. The filter cake is washed successively with ether, water and ether and then dried to afford 1.45 g. (40.6 yield) of 3-(3-carbomethoxy-S-ethylisothioureido)-4-aminobenzophenone, m.p. 155-156C. dec.
Elemental Analysis for C18HlgN3O3S (M.W. 357~416) Calc.: C, 60.48; Hr 5.36; N, 11.76 Found. Cr 60.38; H, 5.44; N, 11.75 Example 7 - 3-(3-Carbomethoxy-S-cyclohexylmethylisothio-ureido)-4-aminohen~phenone _ To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.2 g.; 0.01 mole) in DMF (25 ml.) is added water ~7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50~ aqueous;
0.8 g.; 0.01 mole) is added and the resulting solution stirred at room temperature for one hour. Cyclohexyl-methyl bromide (1.77 g.; 0.01 mole) is then added and the solution stirred at room temperature for 19.5 hours. The precipitate is collected and washed successively with ether, water and ether and then dried to afford 1.7 g.
of 3-(3-carbometho~y-S-cyclohexylmethylisothioureido)-4 aminobenzophenone, m.p. 155-158C. dec.
Elemental Analysis for C23E27N3O3S
Calc.: C, 64.91; H, 6.40; N, ~.87 ~ound: C, 65.27, H, 6.80; N, 9.96 ~ .
:.
~ - 21 -Example 8 - 3-(3-Carbomethoxy-5-cyanobutylisothioureido)-4-_minoben~o~enone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.5 g.; 0.02 mole) in DMF (50 ml~) i5 added water (15 ml.). The solution is cooled ~o room temperature and a sodium hydroxide solution (50% aqueous, 1.6 g.; 0.02 mole) is added. The solution is stirred at room temperature for lo 5 hours and then 5-bromovalero-nitrile ~3.24 g.; 0.02 mole) is added. The solution is stirred at room tempera-ture for 18 hours then poured into 500 milliliters of water. The suspension formed is stirred for an additional 18 hours at room temperature, collected by filtration, washed with ether and dried to afford 7.35 g. (89.5~ yield) of 3-(3-carbomethoxy-S-cyanobutylisothioureido)-4-aminobenzophenone, 155-160C.
dec.
Example 9 - 3-(3-~Carbomethoxy-S-Ethoxycarbonylpropyliso thioureido~)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)- ;
ZO 4-aminobenzophenone (3.29 g.; 0.01 ml.~ in DMF (25 ml.) is added water (7.0 ml.). The solution is cooled and a sodium hydroxide solution (50% aqueous; 0.8 g.; 0.01 ml.) is added. This solution is stirred at room temperature for one hour. Ethyl-4-bromobutyrate (1.95 g.; 0.01 mole) is then added. The solution is stirred at room temperature ~or four days then poured into an excess of water. The semi-solid tarry precipitate is collected and tri--turated with 5 milliliters of ether. The solid is ; collected, washed with ether and dried to afford 2.7 g.
(62~ yield) o~ 3-(3-carbomethoxy-S-ethoxycarbonylpropyl-isothioureido)-4-aminobenzophenone, m.p. 119-120C. dec.
~ .
~ - 22 -,~
;3~
Example 10 - 3-(3-Carbomethoxy-S-phthalimidohutylisothio-ureldo)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.2g g.; 0.01 ml.) in DMF (25 ml.) is added water (7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
0.8 g.; 0.01 ml.) is added. The solution is stirred at room temperature for one hour and N (4~bromobutyl)-phthalimide (2.82 g.; 0.01 ml.) is added. The solution is stirred for 30 minutes at which time a precipitate begins to form. The precipitate is stirred at room temperature for an additional 30 minutes, collected by filtration, washed with water and ether and then dried to afford 2.9 g. (54.7% yield) of 3-(3-carbomethoxy-S-phthalimidobutylisothioureido)-4-aminobenzophenone, m.p.
154-157C. dec.
E~ e 11 - 3-(3-Carbomethoxy-S-propargylisothioureido~-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.58 g.; 0.02 ml.) in ~MF (50 ml.) is added water (15 ml.~. The solution i8 cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.6 g.; 0.02 ml.) is added and the solution stirred at room temperature for one hour. Propargyl bromide (2.38 ; g.; 0.02 ml.) is added and the solution is stirred at room temperature for three hours then poured into 500 milliliters of water. The precipitate is collected by filtration and dried to a~ford 5.1 g. (69% yield) of 3-(3-carbomethoxy-S-propargylisothioureido)-4-aminobenzophenone, m.p. 170C.
., .
~ 30 dec.
.
~ ~ ~3 ~
...
- . ,
5`~3~
Example 12 - 3-(3-Carbomethoxy-S-hydroxypropylisothio-_reido)-4-aminobenzophenone To a solutlon of 3-(3-carbomethoxythioureido) 4-aminobenzophenone ~6.58 g.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.6 gms.; 0~02 mole) is added and the solution stirred for one hour at room temperature. 3-Bromopropanol (2.79 gms.;
0.02 mole) is added and the reaction mixture is stirred for 48 hours and then poured into 300 milliliters of wa-ter.
~fter stirring at room temperature or five days, the precipitate is collected by filtration, washed with water and dried -to afford 4.65 gms. (60% yield) of 3-(3-carbo~
methoxy-S-hydroxypropylisothioureido)-4-aminobenzophenone, m.p. 124C. dec.
Example 13 - 3-(3-Carbomethoxy-S-butenylisothioureido)-4-aminobenzophenone _ _ _ _ To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.59 g.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.16 gms.; 0.02 mole) is added and the solution stirred at room temperature for one~hour. 4-Bromo-l-butene (2.7 gms.; 0.02 mole) is added and the solution stirred at room temperature for 48 hours and then poured into 250 milliliters o water. The resulting mixture is stirred at room temperature or three days and the white pre~
cipitate collected by filtrat~on, washed with water and then dried to aord 6.3 gms. (82% yield) of 3~~3-carbo-methoxy~S-butenylisothioureido)-4-aminobenzophenone, m.p. 122C. dec.
- 2~ -Example 14 - 3-(3-Carbomethoxy-S-phenethylisothioureido)-4-aminobenzophe}lone To a solution of 3-(3-carbomethoxythioureido) 4-aminobenzophenone (6.58 g.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.)~ The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.6 gms.; 0.02 mole) is added. The solution is stirred at room temperature for one hour and then phenethyl bromide (3.9 gms; 0.02 mole) is added and the solution stirred at room temperature for 48 hours. The solution is then poured into 250 milliliters of water and stirred at room temperature for three days. The fine white precipitate i5 collected by filtration and dried to afford 3.7 gms.
o 3-(3-carbomethoxy-S-phenethylisothioureido)-4-amino-benzophenone, m.p. 119C. dec.
Example 15 - 3-(3-Carbomethoxy-S-cinnamylisothioureido)-4-amin benzophenone_ _ To a solution of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (3.29 gms.; 0.01 mole) in DMF
(25 ml.) is added water (7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution ~50%
aqueous; 0.8 gms.; 0.01 mole) is added and the solution stirred for one hour at room temperature. Cinnamyl bromide (1.97 gms.; 0.01 mole) is added and the solution stirred at room temperature for two hou~s, poured into 250 milliliters of water and stirred for an additional 18 hours at room temperature. The precipitate is collected by filtration, washed wikh water and dried to afford 4.0 gms. of~3-(3-carbomethoxy-S-cinnamylisothio-ureido)-4-aminobenzophenone, m.p. 110C. dec.
. .
, , , :. . ' ' : ., . ': ' ', , .`3~
Example 16 - 3-[Carbomethoxy-S-(3-methylbutyl)iso-thioureido]-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.58 gms.; 0.02 mole) in DMF (50 ml.) is added wa-ter (15 ml.). The solution is cooled to room temperature and sodium hydroxide (50% aqueous; 1.5 gms.;
0.02 mole) is added and the solution stirred for one hour.
l-Bromo-3-methylbutane (3.02 gms.; 0.02 mole) i5 added and the solution ~tirred for one hour at room temperatureO
The precipitate which forms is collected by filtration, washed with ether, water and ether to afford 2.3 gms.
(29% yield) of 3 ~carbomethoxy-S-(3-methy].butyl)isothio-ureido]-4-aminobenzophenone, m.p. 142-144C.
Example 17 - 3-[3-Carbomethoxy-S-(2,6-dichlorobenzyl)-sothioureido]~4-aminobenzophenone ~o a solution of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (3.29 gms.; 0.01 mole) in DMF (25 ml.~ is added water (7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous; 0.8 gms.; 0.01 mole) is added and the solution stirred at room temperature for one hour a-Bromo-2,6-dichlorotoluene (2.4 gms.; 0.01 mole) is added and the solution stirred at xoom temperature for 48 hours and then poured into 200 milliliters of water. The pre-; cipitate is collected and dried to afEord 4.5 gms. of 3-[3-carbomethoxy-S-(2,6 dichIorobenzyl)isothioureido]-4-aminobenzophenone, n.~. 80-100C. dec.
.
~ - 26 -Example 18 - 3-(3-Carbobutoxy-S-methylisothioureido)-4-aminobenzophenone To a solutlon of 3-(3-carbobutoxythioureido)-4-aminobenzophenone (3.71 g.; 0.01 mole) in DMF (50 ml.) is added water (10 ml.). To this is added a sodium hydroxide solution (50% aqueous; 0.8 g.; 0.01 mole) and the resulting solution is stirred at room temperature for 1.25 hours. Methyl iodide (lo 42 g.; 0.01 mole) is then added and the reaction mixture stirred at room temperature for 18 hours and then poured into water t300 ml.). The precipitate is collected by vacuum filtration, washed ~-with ether and dried to afford 1.95 g. (51% yield) of 3-(3-carbobutoxy-S-methylisothioureido)-4-aminobenzophenone, m.p. 102C. dec.
Example 19 - 3-(3-Carbomethoxy-S-phenoxypropylisothio-ureido~-4-amlnobenzophenone To a solution of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF
(25 ml.) is added wa~er (7 ml.). The solution is cooled ~to room temperature and sodium hydroxide (50% aqueous;
0.8 g.; 0.01 mole) is added and the solution is stirred at room temperature for one hour. 3-Phenoxypropyl bromide (0.01 mole) is added to the solution and the solution is allowed to stand at room temperature over the weekend.
The solution is poured into water and the precipi ate collected and washed with water and hexane and then dried to afford 4.3 g. (93% yield) of 3~(3-carbomethoxy-S-phenoxypropylisothioureido)-4-aminobenzophenone, m.p.
62-80C.
.-: ... , : .... . -. ... - . . . .
Examp]e 20 - Improved Preparation of 3~(3-Carbomethoxy-S-me~lisothioureido)-4-aminobenzophenone .
To a suspension of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (6.58 g.; 0.02 mole) in acetone (30 ml.) and water (lO ml.~ is added sodium hydroxide (50% aqueous; 1.76 g.; 0.022 mole). This mixture is stirred at room temperature for one hour. The solution is decanted from a small amount of oil. To the solution is then added methyl iodide (3.124 g.; 0.022 mole)~ A thick suspension which forms is stirred at room temperature for 15 minutes and the solid collected by filtration is washed successively with ether, water and ether and then dried to afford 4.66 grams of 3-(3-carbomethoxy-S-methylisothioureido)-4-aminobenzophenone, m.p. 163-164C.
Example 21 - 3-(3-Carbopropoxy-S-methylisothioureido)-4-To a suspension of 3-(3-carbopropoxythio-ureido)-4~aminobenzophenone (1.79 g.; 0.005 mole) in acetone (lO ml.) and water (5 ml.) is added an aqueous solution of sodium hydroxide (50~ aqueous; 0.4 g.; 0.005 mole). The mixture is stirred at room temperakure for one hour and then methyl~iodide (0.71 g.; 0.005 mole) is added. The resulting suspension is stirred at room temperature for 15 minutes. The precipitate is collected by filtration and washed successively with acetone, water and ether and then dried to afford 0.7 g. (38~ yleld) of 3-(3-carbopropo-xy-S-methylisothioureido)-4-aminobenzo-phenone, m.p. 128-130C. dec.
- ~8 -~..
Example 22 - 3-(3-Carboisopropoxy-S-methylisothioureido)-4-aminobenzophenone To a suspension of 3-(3-carboisopropoxy-thioureido)-4-aminobenzophenone (1.79 g.; 0.005 mole) in acetone ~10 ml.) and water (5 ml.) is added an aqueous -~
solution of sodium hydroxide ~50% aqueous; 0.4 g.; 0.005 mole). The mixture is stirred at room temperature for one hour and then methyl iodide ~0.71 g.; 0.005 mole) is added. The reaction mixture is stirred at room tempera-ture for four hours and then poured into water (200 ml.).
The resulting mixture is stirred at room temperature for 18 hours. The yellow precipitate is collected hy ~iltra-tion, washed with water and dried to afford 1.1 g. (59%
yield) of 3-(3-carboisopropoxy-S-methylisothioureido)-4-aminobenzophenone, m.p. 139-142C. dec.
Example 23 ~ 3-(3-Carbophenethoxy-S-methylisothioureido)-4-aminobenzophenone Step A - Carbophenethoxy isothiocyanate To a suspension of potassium thiocyanate (9.7 g.; 0.1 mole) in ethyl acetate (200 ml.) is added ::
' - ~, . -, :, . - ~
phenethyl chloroformate (18.5 g.; 0.1 mole)~ The mixture is stirred at room temperature :Eor 18 hours and is vacuum filtered through "Celite"*. The filtrate is concentrated n vacuo to afford crude carbophenethoxy isothiocyanate.
B - 3-(3-Carbophenethoxythioureido-4-aminobenzophenone _ To a solution of 3,4-diaminobenzophenone (2.12 g.; 0.01 mole) in ether (200 ml.) is added carbophenethoxy isothiocyanate (2.07 g.j 0.01 mole).
1~ The mixture is stirred at room temperature for 2 hours and is vacuum filtered. The filter cake is dried to afford 3-(3-carbophenethoxythioureido)-4-aminobenzophenone.
Step C - 3-(3-Carbophenethoxy-S-methylisothio-ureido)-4-aminobenzophenone .
To a mixture of 3-(3-carbophenethoxy-thioureido)-4-aminobenzophenone (2.08 g.; 0.005 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The mixture is cooled to room temperature and to it is added sodium hydroxide (0.4 g.; 0.005 mole; 50~ aqueous). The mixture is stirred at room temperature for 1 hour and to it is added methyl iodide (0.71 g.; 0.005 mole). The mixture is stirred at room temperature for 4 hours and is poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afEord 3-(3-carbophenethoxy-S-methylisothioureido)-4-ami.nobenzophenone.
':
*Trademark of the Johns~Manville Corp., for a finely divided, amorphous diatomaceous earth, used as a clar-ifying agent.
:: ' 5(~ a~
~ .~
Example 24 - 3-(3-Carbomethoxy-S-2-methylnapthyliso-thioureido)-A-aminobenzophenone To a solution of 3-t3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The solu-tion is cooled ~o room ~emperature and to it is added sodium hydroxide (0.8 g.; 0.01 mole; 50% aqueous). The solution is stirred at room temperature for one hour and to it is added 2-bromomethylnapthalene (2.21 g.; 0.01 mole). The mixture is stirred at room temperature for four hours and is poured into water (200 ml.). The suspension formed is vacuum Eiltered and the filter cake is dried to afford 3-(3-carbomethoxy-S-methyl-napthylisothioureido)-4~aminobenzophenone.
Example 25 - 3-(3-Carbomethoxy-S-4-methoxybutylisothio-ureido)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.? (exothermic reaction). The solution is cooled to room temperature and to it is added sodiwm hydroxide (0.8 g., 0.01 mole; 50~ aqueous). The solution is stirred at room temperature Eor one hour and to it is added 4-methoxybutyl bromide (1.67 g.; 0.01 mole). The mixture is stirred at room temperature for Eour hours and i.s poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afford 3-(3~carbomethoxy-S-methoxybutylisothiourei.do)-4-; aminobenzophenone.
~' ~
' ExamE_e 26 - 3-(3-Carbomethoxy-S-3-carbophenoxypropyl-isothioureido)-4-aminobenzo~henone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The solution is cooled to room temperature and to it is added sodium hydroxide (0.8 g.; Q.01 mole; 50% aqueous). The solution is stirred at room tempera~ure for one hour and to it is added phenyl-3-bromobutyrate (2.43 g.; 0.01 mole). The mixture is stirred for four hours and is poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afford 3-(3-carbomethoxy-S-3-carbophenoxypropylisothioureido)-4-aminobenzophenone.
Example 27 l-Amino-2-(3-carbomethoxy-S-methylisothio-ureido)-4-propylsulfonylbenzene Step A - l-Amino-2-(3-carbomethoxythio-ureido) 4 ro~ylsulfonYlbènaene P
To a mixture of 1,2-diamino-4-propylsulfonyl-benzene (2.14 g.; 0.01 mole) in chloroform (200 ml.) is added carbomethoxy isothiocyanate (1.17 g.; 0.01 mole).
The mixture is stirred at room temperature Eor our hours and is vacuum filtered. The filter cake is dried to a~ford 1-amino-2-(3-carbomethoxythiourei.do)-4-propyl-sulfonylbenzene.
Step B - l-Amino-2-~3-carbomethoxy-S-methyl _othioureido-4-pr~y_sule ~
To a mixture of l amino-2-(3 carbomethoxythioureido)-4-propylsulfonylbenzene (3.33 g.; o.nl mole) in DMF ~25 ml.) is -~
added water (7 ml.) (exothermic reaction). The mixture is cooled to xoom temperature and to it is added sodium hydroxide (0.8 g.; O.Ol mole; 50% aqueous). The mixture is stirred at room temperature for one hour and to it is added methyl iodide (l.42 q.; 0.01 mole). The mixture is stirred at room temperature ~ 32 -- .: - - :: ., , . , ., . - . :. --. . .
., ~, - , ~ . . . .
for four hours and is poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afford l-amino-2-(3-carbomethoxy-S-methylisothio-ureido-4-propylsulfonylbenzene.
Example 28 - 3-(3-Carbohexoxy-S methylisothioureido)-4-aminobenzophenone _ . . . ..
Step A - Carbohexoxy isocyanate To a suspension of potassium thiocyanate (9.7 g.; 0.1 mole) in ethyl acetate (200 ml.) is added n-hexyl chloroformate (16.5 g.; 0.1 mole). The mixture is stirred at room temperature for ].8 hours and is vacuum filtered through "Celite". The filtrate is con-centrated in vacuo to afford carbohexoxy isothiocyanate.
Step B - 3-(3-Carbohexoxythioureido)-4-aminobenzophenone To a solution of 3,4-diaminoben~ophenone (2.12 g.; 0.01 mole) in ether (200 ml.) is added carbo-hexoxy isothiocyanate (1.87 g.; O.Ol mole). The mixture :
is stirred at room temperature for two hours and is vacuum filtered. The filter cake is dried to afford 3-(3-carbohexoxythioureido)-4-aminobenzophenone.
Step C - 3-(3-Carbohexoxy-S-Methylisothio-ureido)~4-aminobenzopherlone To a mixture of 3-(3-carbohexoxythioureido)-4-aminobenzophenone (2.0 g.; 0.005 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The mix-ture is cooled to room temperature and to it is added sodium hydroxide (0.4 g.; 0.005 mole; 50% aqueous). The ~ mixture is stirred at room temperature for one hour and methyl iodide (0.7L g.r O.005 mole) is added. The mix-ture i9 stirred at room temperature for four hours and -is poured into water (200 ml.). The suspension which ;
- - ., -forms is vacuum filtered and the filter cake dried to afford 3-(3-carbohexoxy-S-methylisothioureido)-4-amino-benzophenone.
Example 29 - 2-(3-Carbomethoxy-S-methylisothioureido)-4-nitroaniline .
Step A - 2-(3-Carbomethoxythioureido)-4-nitroaniline To a solution of 4-nitro-o-phenylenediamine (3.83 g.; 0.0025 mole) in e-thyl acetate (800 ml.~ is added carbomethoxy isothiocyanate (2.8 g.; 0.0025 mole).
The solution is stirred at room temperature for two hours and the precipitate is collected and dried to afford 2-(3-carbomethoxythioureido)-4-nitroaniline (2.5 g.), m.p. 229C., dec.
Step B - 2-(3-Carbomethoxy-S-methylisothio-ureido) 4-nitro- ~l~A~ _ To a solution of 2-(3-carbomethoxykhio-ureido)~4-nitroaniline (2~0 g.; 0.0074 mole in D~F
(20 ml.) is added water (4 ml.). The solution becomes warm and is cooled to room temperature. A sodium hydroxide solut.ion (0.59 g.; 0.0074 mole; 50~ aqueous) is added and the solution stirred at room temperature for 45 minutes. Methyl iodide (I..05 g.; 0.0074 mole) is added an~ the solution stirred at room temperature for 30 minutes and then poured into water (300 ml.). The precipitate is collected, washed with ether and dried to afford 2-(3-carbomethoxy-S-methylisothioureido)-4- .
nitroaniline, m.p. 169-171~C., dec.
.
, ..
: . .
Example_ 30 - 2-(3-Carbomethoxy-S-methylisothioureido)-aniline Step A - 2-~3-Carbomethoxythioureido)-aniline To an ice cold solution of o-phenylene-diamine (2.75 g.; 0.025 mole) in ether (400 ml.~ is added carbomethxoy isothiocyanate (2.93 g.; 0.025 mole). A
suspension forms immediately. The reaction mixture is stirred at 0C. for five minutes and the precipitate is collected by filtration. The product is washed with ether and dried to afford 2-(3-carbomethoxy-thioureido)-aniline (4.25 g.), m.p. 190-191C., dec.
Step B - 2-(3-Carbomethoxy-S-methylisothio-_reido)aniline To a solution of 2-(3-carbomethoxythioureido)-aniline ~2.25 g.; 0.01 mole) in DMF (25 ml.~ is added water (5 ml.). An exothermic reackion occurs and the -solution is then cooled to room temperature. A sodium ~ hydroxide solutlon (0.8 g.; 0~01 mole; 50% aqueous) is added and the reaction mixture is stirred at room temperature for one hour. Methy:L iodide (1.42 g.; 0.01 mole) is added and the reaction mixture stirred at room temperature for three minutes and then poured into water (200 ml.). The solution is stirred at room temperature for five minutes and the precipitate is collectecl by filtration and then dried to afford 2-(3-carbomethoxy~S-methylisothioureido)aniline (1.6 g.).
, ~
,~ .
., .
~.5~3~
Example 31 - 2-(3~Carbomethoxy-S-methylisothioureido)-4-p ylsu~lfonylaniline S-tep A - 2~(3-Carbome-thoxythioureido)-4-~enylsulfonylaniline To a solution of 2 amino-4-phenylsulfonyl- -aniline (4.96 g.; 0.02 mole) in ether (200 ml~) and chloroform (150 ml.) is added carbomethoxy isocyanate (2.34 g.; 0.02 mole). The reaction mixture is stirred at room temperature for two hours and the precipitate collected by filtration to afford 2-(3-carbome-thoxy-thioureido)-4-phenylsulfonylan~iline (2.65 g.), m.p.
197C., dec.
Elemental Analysis for C15~I15N3O4S3 Calc.; C, 49.30; H, 4.14; N, 11.50 Found: C, 49.03; H, 4.21; N, 11.05 ~:
f~
S ep B - 2 (3-Carbomethoxy-S-methyliso-thioureido)-4-phenylsulfonylaniline To a solution of 2-(3-carbomethoxythioureido)-4-phenylsulfonylaniline (1.0 g.; 0.0025 mole) in DMF (15 ml.) is added water (3 ml.). The solution is cooled to room temperature and a 50% aqueous sodium hydroxide solution (0.22 g.; 0.0027 mole) is added. The solution is stirred at room temperature for one hour and methyl iodide (0.39 g.;
0.0027 mole) is added and the solution stirred at room temperature for 18 hours. The solution is poured into an excess of water and the precipitate is collected by filtration to afford 0.75 g. of 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylsulfonylaniline, m.p. 126-130C., dec.
Example 32 - 3-(3-Carbomethoxy~S-methylisothioureido) -4-aminoaceto~henone A - 3-(3-Carbomethoxythioureido)-4-~ aminoacetophenone To a solution of 3,4-diaminoacetophenone .
(0.85 g.; 0.0057 mole) in chloroform (150 ml.) is added carbomethoxy isothiocyanate (0.66 g.; 0.0057 mole) and the solution is stirred at room temperature for two hours.
The precipitate is collected by filtration, washed with ether and dried to afford 0.35 g. o~ 3-(2-carbomethoxy~
thioureido)-4-aminoacetophenone, m.p. 200C., dec.
3-(3-Carbomethoxy-S-methylisothio-ureido)-4-aminoacet~ none .
To a solution of 3-(2-carbomethoxythioureido)-; ~ .
4-aminoacetophenone (0.5 g.; 0.00187 mole) in DMF (15 ml.) is added water ~4 ml. ? and then a 50~ aqueous solution of sodium hydroxide (0.15 g.; 0.00187 mole) is added. The solution is stirred at room temperature for one hour and methyl iodide (0.127 g~; 0.00187 mole) i9 added and ~ 37 ~ 3~
the reaction mix-ture stirred at room temperature for 18 hours. The reaction mixture i5 poured in-to water (100 ml) and stirred at room temperature for 1-1/2 hours. The precipitate is collected, washed with ether and dried to afford 0.25 g. of 3-(3-carbomethoxy-S-methylisothioureido)~4-aminoacetophenone, m.p. 165Q-167C., dec.
Example 33 - 3-(3~Carbomethoxy-S-nonadecylisothioureido)-4-aminobenzophenone To a suspension of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (1.65 g.; 0.005 mole) in acetone (15 ml.) and water (5 ml.) is added a 50% aqueous solution of sodium hydroxide (0.4 g.; 0.005 mole). The solution is stirred at room temperature for 30 minutes and l-iodononadecanane (1.97 g.; 0.005 mole) in acetone ~50 ml.) is added. The suspension is stirred at room temperature for 42 hours and the precipitate collected by filtration and is washed with acetone and is dried to afford lo 05 g. of 3-(3-carbomethoxy-S-nonadecyliso-thioureido)-4-aminobenzophenone, m.p. 76-80C., dec.
- 38 - ;
~.~ v~
~ 3~, EY~MPL~ ~)+ ~ 3-t3-Carbo- (2-methoxyethoxy~-S-methyli~thi o-ureidol-4-aminobenzophenone Ste~ A - 2-Methoxyeth~l chloroforma~,e ~o an ice cooled solution of phosgen~
- (87 g.; 0.11 mole; 12,5% in benzene~ in benzene (25 ml.) is added methyl 'Cellosolve"* (7.6 g~ 0.1 mo1e) in benzene ~50 ml.). ~he solution is stirred at 5C~ for 2 h~urs and at room temperature for 18 hours. ~he solution is con-centrated under vacuu~ to afford 15.1 g. of 2-methoxy-ethylchloroformate as a colorless oil.Step B - Carbo-(2-methox~)ethox,~isothioc~anate, ~ o a suspension of potassium thioc~anate (9O7 g~; 0vl mole) in ethyl acetate (150 m ) is ad~ed 2-methoxyethyl chloroformate in ethyl acetate (25 ml.). The 15 mixture is stirred at room temperature for one hour, refluxed ;- for 1-1/2 hour~ and ~tirred at room tempsrature overnight.
The mixture is filtered through "Celite" and the filtrate con-centrated under vacuum at room temperature to afford 15 g.
of carbo-(2-methoxy)e~hoxyisothiocyanate as an orange liquido _tep C - 3-[3-Carbo-(2-methoxy)ethoxythioure do~-r L~-aminobenzophen~ne ~o a solution of 3,~-diamin~benzopllenone .
(~24 gO; 0.02 mole) in ether (500 ml.) ~ added carbo-(2-methoxy)ethoxy isothioc~anate (3.22 g.; 0.02 mole~. The solution is stirred for one hour and the p~ecipitate formed is collec~ed by f.iltration and dried to afford 2~85 g. of -,, ' 3-~3-carbo-(2-methoxy)ethoxythioureido~-4-aminobenzophenone, , .
~I~p~ 147-151Co (decO )~
.
Elemental an~alysis for C18H19N3Q~
Calc.:~ C~ 57J86; H, 5013; N,'11O29 Found: C, 57O89; H, 5.82; N, 10~77 *~rademark. Methyl "Ge1losolve" ~is ethylene glycol monomethyl ether.
~ 3~3~~
. . ., . . . . . .
St~p D - 3-[3-Carbo-(2-methoxy)ethoxy-S-methyl-isothioureido~-~-aminohenzo~henone To a solution of 3-[3-carbo-(2-methoxy)-ethoxythioureido)-~-aminobenzophenone (1.87 g.; 0.005 mole) in dimethyl formamide (15 ml.) is added water (3 ml.). To this solution is added a~ueous sodium hydroxide (50~;
0.4 g.) and the solution stirred at room tempexature for 1 hour. Methyl iodide (0.71 g~; 0.005 mole) is added and the solution is stirred at room temperature for 18 hours~ The solution is poured into water (200 ml.) and the pracipitate collected by filtration, washed with water and dried to afford 1.1 gO of 3-[3-carbo-(2-methoxy)ethoxy-S-methyliso-thioureido]-4-aminobenzophenone.
Eleme~tal analysis Por C19~21N301~S
Calc.: C, 58.90; H, 5.1~6; N, 10.85 Found: C, 58~31; H, 5.34; N, 11~05 - 3-Amino-4-(3-carbomethoxy-S-methylisothioureido~-Step A - 3-Nitro-~-(3-carbomethoxythioureido)-benzophenone _ _ A mixture of 3-nitro-1~-aminobenzophenone (9~9 g; 0.041 mole), carbomethoxyisothiocyanate (4.8 g.; 0~041 mole)in acetonitrile (25 ml~) is stirred and re~lu~ed ~or 17 hours. The reaction mixture is cooled and the precipitate collected by filtration, washed with acetonitrile an~ dried to a~ford 8.7 g. of 3-nitro-4-(3-carbometho~thioureido)-benzopherlone, m.p~ 17~-183C. (dec.).
Step B - 3-Amino-~-(3-carbomethoxythioureido~- ;
b~ophenone ~ A mixture of 3-nitro-l~-(3-carbomethoxy-thioureido)benzophellone ~3.6 ~.; 0.01 mole),sta~nous ~hloride (11.3 g.; 0~05 mole)1 concentrated h-ydrochloric acid (20 nl.~, methanol ~40 m~O) and acetic acid ~40 mlO ) is he~ted with ; ~
~ '3~
stirring -to reflux. After 10 minutes, most of the solid is dissolved~ The reaction mixture is refluxed for a total o~
35 minutes and then filtered to remove a small amount of colored material. The filtrate is added to water (600 ml.) with stirring and the precipitate is collected by filtration to afford 3.5 g. of 3-amino-4-(3-carbomethoxythioureido)-benzophenone, m,p. 187C~ (dec.).
~ - 3-Amino-~-(3-carbomethoxy-S-methyl-To a stirred slurry of 3-amino-4-~-carbometho~ythioureido)benzophenone (2.5 g.; 0.0076 mole) in dimeth~Jl formamide (20 ml.) is added a 50~ sodium hydro~-ide solution ~0.61 g.; 0.0076 mole) in deionized wa~er (10 ml.). The clear red-orange solution which forms is 15 cooled to 4C. an~ then methyl iodide tl.l g.; 0~0076 mole) is added. '~he temperature rises to 7C. (p~I 7.8), After 3 minutes, the reaction mixture is added to deionized water (200 ml.) with stirring~ The precipitate is collected to af~ord 1-8 gO of 3-ami~o-~-(3-carbomethoxy-S-methyl-20 isothioureido~benzophenone.
Elemental anal~sis ~or C17H17N202S
Calc.: C, 59.45; ~, 5.00; N, 12.24; S, 9.34 Found: C, 590~8; H, 5~11; N, 12.59; S, 8~90 EXAM~ ~F. ~6 - 3-[3-Carbomethoxy-S~(2-nitro)benzylisothioureido]-4-aminobenzophenone _ To a solution of 3-(3-carbomethoxythio-ureido)-~-aminobenzophenone (3.29 g; 0~01 mole) in dlmet~yl ~ormamide (25 ml.) is added water (7 ml.). Tile solutio~ is cooled to room temperatllre and then an aqueous solution of sodium 30 hydroxlde (50~; 0.8 g.) is added. The solution is stirred at room temperature for one hour . o-Nitrobenzyl bromide (2.1 g.~ 0.01 mole) in dimethyl formamide (20 ml.) is added.
~ - 41 -.
.
The solution is s-tirred at room temperature for 24 hours and poured into water (300 ml.). A suspension forms and is stirred at room temperature for 18 hours and then collect-ed by filtration and dried to afford 4.25 g. of 3-[3-carbo-methoxy-S-(2-nltro)benzylisothioureido]-4-aminobenzopheneone, m.p. 75-85C. (dec.) Elemental analysis for C23H20N4O5S
Calc.: C, 59.47; ~1, 4.34; N, 12.06 Found: C, 57.91; H, 4.20; N, 12.98 Example 37 - 3-[3-Carbomethoxy-S-(p-nitro)benzylisothio-ureido]-4-aminobenzophenone -To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.). The solution is cooled to room temperature and an aqueous solution of sodium hydroxide (50~;
0.8 g.) is added. The solution is stirred at room temperature for l hour and p~-nitrobenzyl bromide (2.11 g.; 0.01 mole) in DME' (20 ml.) is added. The solu~ion is stirred at room temperature for 24 hours and then poured into water (300 ml.).
The suspension Formediis stirred at room temperature for 18 hours and the precipitate collected by filtration and dried to afford 4~25 g. o~ 3-~3 carbomethoxy-S-tp nitro)benzyliso~
thioureido~-4-aminobenzophenone, 100-105C. (dec.).
Elemental analysis for C23H20N~O5S
Calc~: C, 59~47; H, 4~34; N, 12.06 Found: C~, 57.91; H, 4.29; El, 11.89 In a manner similar to that described in Example 37 and by substituting for the p-nitrobenzyl bromide ~ ~ an equimolar quantity of p-methylbenzyl bromide, m~methylbenzyl ; 30 bromide, p-chlorobenzyl chloride, crotyl chloride and 3-~ chloro-2-methylpropene and by following substantially the :
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procedure described therein, there is obtained, respectively, the following compounds:
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EY~PL~ 4~ - 3-(3-Carbometho~y-S-2-[4-(4-acetam.idophenyl-thio)phenylcarbamy.]el;hylisothioureido-4-amin~be:n%op'lenone _ _ S~,e~ A - 4-(~-Bromoproplonamido)-4'-nitro.~i-~ Y~ de _ _ _ To a suspension of 4-amino-4~-nitro-diphenylsu'fi~e (7.4 g.; 0O03 ~ole) in toluene ~200 ml~) is ad~ed 3-bromop~opionyl chloridet5.14 g.; 0.03 mole)~ The mixture is refluxed and stirred for 3 hours and then stirred o~7ernig.ht at room temperature~ Tne precipi~a~ is collected by filtra~ion, washed with hexane and dried to afford 10.1 g.
of 4-~3-bromopropionamido)-4~-nitrodiphenylsulfide~ m.p. .
136-138~C. (dec.).
Step B - ~ Bromopropionamido)-4'-aminodi-~hen~lsulfide To a suspension of 4-(3-bromopropion- 1:
amido)-4'-nitro~iphenylsulfid~(~ g.; 0.0105 mole) in ethanol ~250 ml.~ is added palladium on carbon (5%; 0.2 g.). ~he ; . .
mixture is shaken on a Parr hydrogenator for 5 hours and 20 lefi stan~ng at room temperature overnight~ No hydrogen uptakeO ~he mixtu.re is flushed with nitro~en and Ran~y nick~
(1 g.) ~s adde~ The m.ixtl1re is shaken on a Parr hydrogenator (initial pressure 50 psi) for 5 hours. A~ter 5 hours, there is 1 pound of hydrogen uptake. The reaction mixture is kept 25 under pressure for 18 hours at which tims there is a to~al hydrogen uptake of 2 pounds. The mixture is filtered and the filtr~te concelltrated under vacuum to afford 2.7 g. of ~-t3-bromopropiorlamido)~ aminodiphenylsulfide, mvp. 1~1- .. .
'~ 148~C. tdec~).
~ 3-Bromopropionamido)-4'-acet,ami.do~
d iphenyl S!ll fid e , _ _ _ .
To a suspension of 4~t~-bromopropion-amido3~4l-aminoaiphenylsulfide ~2 gO; 0.0057 mole) in toluene , ~
(150 ml.) is added acetic anhJdride (o~58 g.; 0,0057 mole)O
Example 12 - 3-(3-Carbomethoxy-S-hydroxypropylisothio-_reido)-4-aminobenzophenone To a solutlon of 3-(3-carbomethoxythioureido) 4-aminobenzophenone ~6.58 g.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.6 gms.; 0~02 mole) is added and the solution stirred for one hour at room temperature. 3-Bromopropanol (2.79 gms.;
0.02 mole) is added and the reaction mixture is stirred for 48 hours and then poured into 300 milliliters of wa-ter.
~fter stirring at room temperature or five days, the precipitate is collected by filtration, washed with water and dried -to afford 4.65 gms. (60% yield) of 3-(3-carbo~
methoxy-S-hydroxypropylisothioureido)-4-aminobenzophenone, m.p. 124C. dec.
Example 13 - 3-(3-Carbomethoxy-S-butenylisothioureido)-4-aminobenzophenone _ _ _ _ To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.59 g.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.16 gms.; 0.02 mole) is added and the solution stirred at room temperature for one~hour. 4-Bromo-l-butene (2.7 gms.; 0.02 mole) is added and the solution stirred at room temperature for 48 hours and then poured into 250 milliliters o water. The resulting mixture is stirred at room temperature or three days and the white pre~
cipitate collected by filtrat~on, washed with water and then dried to aord 6.3 gms. (82% yield) of 3~~3-carbo-methoxy~S-butenylisothioureido)-4-aminobenzophenone, m.p. 122C. dec.
- 2~ -Example 14 - 3-(3-Carbomethoxy-S-phenethylisothioureido)-4-aminobenzophe}lone To a solution of 3-(3-carbomethoxythioureido) 4-aminobenzophenone (6.58 g.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.)~ The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous;
1.6 gms.; 0.02 mole) is added. The solution is stirred at room temperature for one hour and then phenethyl bromide (3.9 gms; 0.02 mole) is added and the solution stirred at room temperature for 48 hours. The solution is then poured into 250 milliliters of water and stirred at room temperature for three days. The fine white precipitate i5 collected by filtration and dried to afford 3.7 gms.
o 3-(3-carbomethoxy-S-phenethylisothioureido)-4-amino-benzophenone, m.p. 119C. dec.
Example 15 - 3-(3-Carbomethoxy-S-cinnamylisothioureido)-4-amin benzophenone_ _ To a solution of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (3.29 gms.; 0.01 mole) in DMF
(25 ml.) is added water (7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution ~50%
aqueous; 0.8 gms.; 0.01 mole) is added and the solution stirred for one hour at room temperature. Cinnamyl bromide (1.97 gms.; 0.01 mole) is added and the solution stirred at room temperature for two hou~s, poured into 250 milliliters of water and stirred for an additional 18 hours at room temperature. The precipitate is collected by filtration, washed wikh water and dried to afford 4.0 gms. of~3-(3-carbomethoxy-S-cinnamylisothio-ureido)-4-aminobenzophenone, m.p. 110C. dec.
. .
, , , :. . ' ' : ., . ': ' ', , .`3~
Example 16 - 3-[Carbomethoxy-S-(3-methylbutyl)iso-thioureido]-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (6.58 gms.; 0.02 mole) in DMF (50 ml.) is added wa-ter (15 ml.). The solution is cooled to room temperature and sodium hydroxide (50% aqueous; 1.5 gms.;
0.02 mole) is added and the solution stirred for one hour.
l-Bromo-3-methylbutane (3.02 gms.; 0.02 mole) i5 added and the solution ~tirred for one hour at room temperatureO
The precipitate which forms is collected by filtration, washed with ether, water and ether to afford 2.3 gms.
(29% yield) of 3 ~carbomethoxy-S-(3-methy].butyl)isothio-ureido]-4-aminobenzophenone, m.p. 142-144C.
Example 17 - 3-[3-Carbomethoxy-S-(2,6-dichlorobenzyl)-sothioureido]~4-aminobenzophenone ~o a solution of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (3.29 gms.; 0.01 mole) in DMF (25 ml.~ is added water (7 ml.). The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous; 0.8 gms.; 0.01 mole) is added and the solution stirred at room temperature for one hour a-Bromo-2,6-dichlorotoluene (2.4 gms.; 0.01 mole) is added and the solution stirred at xoom temperature for 48 hours and then poured into 200 milliliters of water. The pre-; cipitate is collected and dried to afEord 4.5 gms. of 3-[3-carbomethoxy-S-(2,6 dichIorobenzyl)isothioureido]-4-aminobenzophenone, n.~. 80-100C. dec.
.
~ - 26 -Example 18 - 3-(3-Carbobutoxy-S-methylisothioureido)-4-aminobenzophenone To a solutlon of 3-(3-carbobutoxythioureido)-4-aminobenzophenone (3.71 g.; 0.01 mole) in DMF (50 ml.) is added water (10 ml.). To this is added a sodium hydroxide solution (50% aqueous; 0.8 g.; 0.01 mole) and the resulting solution is stirred at room temperature for 1.25 hours. Methyl iodide (lo 42 g.; 0.01 mole) is then added and the reaction mixture stirred at room temperature for 18 hours and then poured into water t300 ml.). The precipitate is collected by vacuum filtration, washed ~-with ether and dried to afford 1.95 g. (51% yield) of 3-(3-carbobutoxy-S-methylisothioureido)-4-aminobenzophenone, m.p. 102C. dec.
Example 19 - 3-(3-Carbomethoxy-S-phenoxypropylisothio-ureido~-4-amlnobenzophenone To a solution of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF
(25 ml.) is added wa~er (7 ml.). The solution is cooled ~to room temperature and sodium hydroxide (50% aqueous;
0.8 g.; 0.01 mole) is added and the solution is stirred at room temperature for one hour. 3-Phenoxypropyl bromide (0.01 mole) is added to the solution and the solution is allowed to stand at room temperature over the weekend.
The solution is poured into water and the precipi ate collected and washed with water and hexane and then dried to afford 4.3 g. (93% yield) of 3~(3-carbomethoxy-S-phenoxypropylisothioureido)-4-aminobenzophenone, m.p.
62-80C.
.-: ... , : .... . -. ... - . . . .
Examp]e 20 - Improved Preparation of 3~(3-Carbomethoxy-S-me~lisothioureido)-4-aminobenzophenone .
To a suspension of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (6.58 g.; 0.02 mole) in acetone (30 ml.) and water (lO ml.~ is added sodium hydroxide (50% aqueous; 1.76 g.; 0.022 mole). This mixture is stirred at room temperature for one hour. The solution is decanted from a small amount of oil. To the solution is then added methyl iodide (3.124 g.; 0.022 mole)~ A thick suspension which forms is stirred at room temperature for 15 minutes and the solid collected by filtration is washed successively with ether, water and ether and then dried to afford 4.66 grams of 3-(3-carbomethoxy-S-methylisothioureido)-4-aminobenzophenone, m.p. 163-164C.
Example 21 - 3-(3-Carbopropoxy-S-methylisothioureido)-4-To a suspension of 3-(3-carbopropoxythio-ureido)-4~aminobenzophenone (1.79 g.; 0.005 mole) in acetone (lO ml.) and water (5 ml.) is added an aqueous solution of sodium hydroxide (50~ aqueous; 0.4 g.; 0.005 mole). The mixture is stirred at room temperakure for one hour and then methyl~iodide (0.71 g.; 0.005 mole) is added. The resulting suspension is stirred at room temperature for 15 minutes. The precipitate is collected by filtration and washed successively with acetone, water and ether and then dried to afford 0.7 g. (38~ yleld) of 3-(3-carbopropo-xy-S-methylisothioureido)-4-aminobenzo-phenone, m.p. 128-130C. dec.
- ~8 -~..
Example 22 - 3-(3-Carboisopropoxy-S-methylisothioureido)-4-aminobenzophenone To a suspension of 3-(3-carboisopropoxy-thioureido)-4-aminobenzophenone (1.79 g.; 0.005 mole) in acetone ~10 ml.) and water (5 ml.) is added an aqueous -~
solution of sodium hydroxide ~50% aqueous; 0.4 g.; 0.005 mole). The mixture is stirred at room temperature for one hour and then methyl iodide ~0.71 g.; 0.005 mole) is added. The reaction mixture is stirred at room tempera-ture for four hours and then poured into water (200 ml.).
The resulting mixture is stirred at room temperature for 18 hours. The yellow precipitate is collected hy ~iltra-tion, washed with water and dried to afford 1.1 g. (59%
yield) of 3-(3-carboisopropoxy-S-methylisothioureido)-4-aminobenzophenone, m.p. 139-142C. dec.
Example 23 ~ 3-(3-Carbophenethoxy-S-methylisothioureido)-4-aminobenzophenone Step A - Carbophenethoxy isothiocyanate To a suspension of potassium thiocyanate (9.7 g.; 0.1 mole) in ethyl acetate (200 ml.) is added ::
' - ~, . -, :, . - ~
phenethyl chloroformate (18.5 g.; 0.1 mole)~ The mixture is stirred at room temperature :Eor 18 hours and is vacuum filtered through "Celite"*. The filtrate is concentrated n vacuo to afford crude carbophenethoxy isothiocyanate.
B - 3-(3-Carbophenethoxythioureido-4-aminobenzophenone _ To a solution of 3,4-diaminobenzophenone (2.12 g.; 0.01 mole) in ether (200 ml.) is added carbophenethoxy isothiocyanate (2.07 g.j 0.01 mole).
1~ The mixture is stirred at room temperature for 2 hours and is vacuum filtered. The filter cake is dried to afford 3-(3-carbophenethoxythioureido)-4-aminobenzophenone.
Step C - 3-(3-Carbophenethoxy-S-methylisothio-ureido)-4-aminobenzophenone .
To a mixture of 3-(3-carbophenethoxy-thioureido)-4-aminobenzophenone (2.08 g.; 0.005 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The mixture is cooled to room temperature and to it is added sodium hydroxide (0.4 g.; 0.005 mole; 50~ aqueous). The mixture is stirred at room temperature for 1 hour and to it is added methyl iodide (0.71 g.; 0.005 mole). The mixture is stirred at room temperature for 4 hours and is poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afEord 3-(3-carbophenethoxy-S-methylisothioureido)-4-ami.nobenzophenone.
':
*Trademark of the Johns~Manville Corp., for a finely divided, amorphous diatomaceous earth, used as a clar-ifying agent.
:: ' 5(~ a~
~ .~
Example 24 - 3-(3-Carbomethoxy-S-2-methylnapthyliso-thioureido)-A-aminobenzophenone To a solution of 3-t3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The solu-tion is cooled ~o room ~emperature and to it is added sodium hydroxide (0.8 g.; 0.01 mole; 50% aqueous). The solution is stirred at room temperature for one hour and to it is added 2-bromomethylnapthalene (2.21 g.; 0.01 mole). The mixture is stirred at room temperature for four hours and is poured into water (200 ml.). The suspension formed is vacuum Eiltered and the filter cake is dried to afford 3-(3-carbomethoxy-S-methyl-napthylisothioureido)-4~aminobenzophenone.
Example 25 - 3-(3-Carbomethoxy-S-4-methoxybutylisothio-ureido)-4-aminobenzophenone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.? (exothermic reaction). The solution is cooled to room temperature and to it is added sodiwm hydroxide (0.8 g., 0.01 mole; 50~ aqueous). The solution is stirred at room temperature Eor one hour and to it is added 4-methoxybutyl bromide (1.67 g.; 0.01 mole). The mixture is stirred at room temperature for Eour hours and i.s poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afford 3-(3~carbomethoxy-S-methoxybutylisothiourei.do)-4-; aminobenzophenone.
~' ~
' ExamE_e 26 - 3-(3-Carbomethoxy-S-3-carbophenoxypropyl-isothioureido)-4-aminobenzo~henone To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The solution is cooled to room temperature and to it is added sodium hydroxide (0.8 g.; Q.01 mole; 50% aqueous). The solution is stirred at room tempera~ure for one hour and to it is added phenyl-3-bromobutyrate (2.43 g.; 0.01 mole). The mixture is stirred for four hours and is poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afford 3-(3-carbomethoxy-S-3-carbophenoxypropylisothioureido)-4-aminobenzophenone.
Example 27 l-Amino-2-(3-carbomethoxy-S-methylisothio-ureido)-4-propylsulfonylbenzene Step A - l-Amino-2-(3-carbomethoxythio-ureido) 4 ro~ylsulfonYlbènaene P
To a mixture of 1,2-diamino-4-propylsulfonyl-benzene (2.14 g.; 0.01 mole) in chloroform (200 ml.) is added carbomethoxy isothiocyanate (1.17 g.; 0.01 mole).
The mixture is stirred at room temperature Eor our hours and is vacuum filtered. The filter cake is dried to a~ford 1-amino-2-(3-carbomethoxythiourei.do)-4-propyl-sulfonylbenzene.
Step B - l-Amino-2-~3-carbomethoxy-S-methyl _othioureido-4-pr~y_sule ~
To a mixture of l amino-2-(3 carbomethoxythioureido)-4-propylsulfonylbenzene (3.33 g.; o.nl mole) in DMF ~25 ml.) is -~
added water (7 ml.) (exothermic reaction). The mixture is cooled to xoom temperature and to it is added sodium hydroxide (0.8 g.; O.Ol mole; 50% aqueous). The mixture is stirred at room temperature for one hour and to it is added methyl iodide (l.42 q.; 0.01 mole). The mixture is stirred at room temperature ~ 32 -- .: - - :: ., , . , ., . - . :. --. . .
., ~, - , ~ . . . .
for four hours and is poured into water (200 ml.). The suspension formed is vacuum filtered and the filter cake dried to afford l-amino-2-(3-carbomethoxy-S-methylisothio-ureido-4-propylsulfonylbenzene.
Example 28 - 3-(3-Carbohexoxy-S methylisothioureido)-4-aminobenzophenone _ . . . ..
Step A - Carbohexoxy isocyanate To a suspension of potassium thiocyanate (9.7 g.; 0.1 mole) in ethyl acetate (200 ml.) is added n-hexyl chloroformate (16.5 g.; 0.1 mole). The mixture is stirred at room temperature for ].8 hours and is vacuum filtered through "Celite". The filtrate is con-centrated in vacuo to afford carbohexoxy isothiocyanate.
Step B - 3-(3-Carbohexoxythioureido)-4-aminobenzophenone To a solution of 3,4-diaminoben~ophenone (2.12 g.; 0.01 mole) in ether (200 ml.) is added carbo-hexoxy isothiocyanate (1.87 g.; O.Ol mole). The mixture :
is stirred at room temperature for two hours and is vacuum filtered. The filter cake is dried to afford 3-(3-carbohexoxythioureido)-4-aminobenzophenone.
Step C - 3-(3-Carbohexoxy-S-Methylisothio-ureido)~4-aminobenzopherlone To a mixture of 3-(3-carbohexoxythioureido)-4-aminobenzophenone (2.0 g.; 0.005 mole) in DMF (25 ml.) is added water (7 ml.) (exothermic reaction). The mix-ture is cooled to room temperature and to it is added sodium hydroxide (0.4 g.; 0.005 mole; 50% aqueous). The ~ mixture is stirred at room temperature for one hour and methyl iodide (0.7L g.r O.005 mole) is added. The mix-ture i9 stirred at room temperature for four hours and -is poured into water (200 ml.). The suspension which ;
- - ., -forms is vacuum filtered and the filter cake dried to afford 3-(3-carbohexoxy-S-methylisothioureido)-4-amino-benzophenone.
Example 29 - 2-(3-Carbomethoxy-S-methylisothioureido)-4-nitroaniline .
Step A - 2-(3-Carbomethoxythioureido)-4-nitroaniline To a solution of 4-nitro-o-phenylenediamine (3.83 g.; 0.0025 mole) in e-thyl acetate (800 ml.~ is added carbomethoxy isothiocyanate (2.8 g.; 0.0025 mole).
The solution is stirred at room temperature for two hours and the precipitate is collected and dried to afford 2-(3-carbomethoxythioureido)-4-nitroaniline (2.5 g.), m.p. 229C., dec.
Step B - 2-(3-Carbomethoxy-S-methylisothio-ureido) 4-nitro- ~l~A~ _ To a solution of 2-(3-carbomethoxykhio-ureido)~4-nitroaniline (2~0 g.; 0.0074 mole in D~F
(20 ml.) is added water (4 ml.). The solution becomes warm and is cooled to room temperature. A sodium hydroxide solut.ion (0.59 g.; 0.0074 mole; 50~ aqueous) is added and the solution stirred at room temperature for 45 minutes. Methyl iodide (I..05 g.; 0.0074 mole) is added an~ the solution stirred at room temperature for 30 minutes and then poured into water (300 ml.). The precipitate is collected, washed with ether and dried to afford 2-(3-carbomethoxy-S-methylisothioureido)-4- .
nitroaniline, m.p. 169-171~C., dec.
.
, ..
: . .
Example_ 30 - 2-(3-Carbomethoxy-S-methylisothioureido)-aniline Step A - 2-~3-Carbomethoxythioureido)-aniline To an ice cold solution of o-phenylene-diamine (2.75 g.; 0.025 mole) in ether (400 ml.~ is added carbomethxoy isothiocyanate (2.93 g.; 0.025 mole). A
suspension forms immediately. The reaction mixture is stirred at 0C. for five minutes and the precipitate is collected by filtration. The product is washed with ether and dried to afford 2-(3-carbomethoxy-thioureido)-aniline (4.25 g.), m.p. 190-191C., dec.
Step B - 2-(3-Carbomethoxy-S-methylisothio-_reido)aniline To a solution of 2-(3-carbomethoxythioureido)-aniline ~2.25 g.; 0.01 mole) in DMF (25 ml.~ is added water (5 ml.). An exothermic reackion occurs and the -solution is then cooled to room temperature. A sodium ~ hydroxide solutlon (0.8 g.; 0~01 mole; 50% aqueous) is added and the reaction mixture is stirred at room temperature for one hour. Methy:L iodide (1.42 g.; 0.01 mole) is added and the reaction mixture stirred at room temperature for three minutes and then poured into water (200 ml.). The solution is stirred at room temperature for five minutes and the precipitate is collectecl by filtration and then dried to afford 2-(3-carbomethoxy~S-methylisothioureido)aniline (1.6 g.).
, ~
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., .
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Example 31 - 2-(3~Carbomethoxy-S-methylisothioureido)-4-p ylsu~lfonylaniline S-tep A - 2~(3-Carbome-thoxythioureido)-4-~enylsulfonylaniline To a solution of 2 amino-4-phenylsulfonyl- -aniline (4.96 g.; 0.02 mole) in ether (200 ml~) and chloroform (150 ml.) is added carbomethoxy isocyanate (2.34 g.; 0.02 mole). The reaction mixture is stirred at room temperature for two hours and the precipitate collected by filtration to afford 2-(3-carbome-thoxy-thioureido)-4-phenylsulfonylan~iline (2.65 g.), m.p.
197C., dec.
Elemental Analysis for C15~I15N3O4S3 Calc.; C, 49.30; H, 4.14; N, 11.50 Found: C, 49.03; H, 4.21; N, 11.05 ~:
f~
S ep B - 2 (3-Carbomethoxy-S-methyliso-thioureido)-4-phenylsulfonylaniline To a solution of 2-(3-carbomethoxythioureido)-4-phenylsulfonylaniline (1.0 g.; 0.0025 mole) in DMF (15 ml.) is added water (3 ml.). The solution is cooled to room temperature and a 50% aqueous sodium hydroxide solution (0.22 g.; 0.0027 mole) is added. The solution is stirred at room temperature for one hour and methyl iodide (0.39 g.;
0.0027 mole) is added and the solution stirred at room temperature for 18 hours. The solution is poured into an excess of water and the precipitate is collected by filtration to afford 0.75 g. of 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylsulfonylaniline, m.p. 126-130C., dec.
Example 32 - 3-(3-Carbomethoxy~S-methylisothioureido) -4-aminoaceto~henone A - 3-(3-Carbomethoxythioureido)-4-~ aminoacetophenone To a solution of 3,4-diaminoacetophenone .
(0.85 g.; 0.0057 mole) in chloroform (150 ml.) is added carbomethoxy isothiocyanate (0.66 g.; 0.0057 mole) and the solution is stirred at room temperature for two hours.
The precipitate is collected by filtration, washed with ether and dried to afford 0.35 g. o~ 3-(2-carbomethoxy~
thioureido)-4-aminoacetophenone, m.p. 200C., dec.
3-(3-Carbomethoxy-S-methylisothio-ureido)-4-aminoacet~ none .
To a solution of 3-(2-carbomethoxythioureido)-; ~ .
4-aminoacetophenone (0.5 g.; 0.00187 mole) in DMF (15 ml.) is added water ~4 ml. ? and then a 50~ aqueous solution of sodium hydroxide (0.15 g.; 0.00187 mole) is added. The solution is stirred at room temperature for one hour and methyl iodide (0.127 g~; 0.00187 mole) i9 added and ~ 37 ~ 3~
the reaction mix-ture stirred at room temperature for 18 hours. The reaction mixture i5 poured in-to water (100 ml) and stirred at room temperature for 1-1/2 hours. The precipitate is collected, washed with ether and dried to afford 0.25 g. of 3-(3-carbomethoxy-S-methylisothioureido)~4-aminoacetophenone, m.p. 165Q-167C., dec.
Example 33 - 3-(3~Carbomethoxy-S-nonadecylisothioureido)-4-aminobenzophenone To a suspension of 3-(3-carbomethoxythio-ureido)-4-aminobenzophenone (1.65 g.; 0.005 mole) in acetone (15 ml.) and water (5 ml.) is added a 50% aqueous solution of sodium hydroxide (0.4 g.; 0.005 mole). The solution is stirred at room temperature for 30 minutes and l-iodononadecanane (1.97 g.; 0.005 mole) in acetone ~50 ml.) is added. The suspension is stirred at room temperature for 42 hours and the precipitate collected by filtration and is washed with acetone and is dried to afford lo 05 g. of 3-(3-carbomethoxy-S-nonadecyliso-thioureido)-4-aminobenzophenone, m.p. 76-80C., dec.
- 38 - ;
~.~ v~
~ 3~, EY~MPL~ ~)+ ~ 3-t3-Carbo- (2-methoxyethoxy~-S-methyli~thi o-ureidol-4-aminobenzophenone Ste~ A - 2-Methoxyeth~l chloroforma~,e ~o an ice cooled solution of phosgen~
- (87 g.; 0.11 mole; 12,5% in benzene~ in benzene (25 ml.) is added methyl 'Cellosolve"* (7.6 g~ 0.1 mo1e) in benzene ~50 ml.). ~he solution is stirred at 5C~ for 2 h~urs and at room temperature for 18 hours. ~he solution is con-centrated under vacuu~ to afford 15.1 g. of 2-methoxy-ethylchloroformate as a colorless oil.Step B - Carbo-(2-methox~)ethox,~isothioc~anate, ~ o a suspension of potassium thioc~anate (9O7 g~; 0vl mole) in ethyl acetate (150 m ) is ad~ed 2-methoxyethyl chloroformate in ethyl acetate (25 ml.). The 15 mixture is stirred at room temperature for one hour, refluxed ;- for 1-1/2 hour~ and ~tirred at room tempsrature overnight.
The mixture is filtered through "Celite" and the filtrate con-centrated under vacuum at room temperature to afford 15 g.
of carbo-(2-methoxy)e~hoxyisothiocyanate as an orange liquido _tep C - 3-[3-Carbo-(2-methoxy)ethoxythioure do~-r L~-aminobenzophen~ne ~o a solution of 3,~-diamin~benzopllenone .
(~24 gO; 0.02 mole) in ether (500 ml.) ~ added carbo-(2-methoxy)ethoxy isothioc~anate (3.22 g.; 0.02 mole~. The solution is stirred for one hour and the p~ecipitate formed is collec~ed by f.iltration and dried to afford 2~85 g. of -,, ' 3-~3-carbo-(2-methoxy)ethoxythioureido~-4-aminobenzophenone, , .
~I~p~ 147-151Co (decO )~
.
Elemental an~alysis for C18H19N3Q~
Calc.:~ C~ 57J86; H, 5013; N,'11O29 Found: C, 57O89; H, 5.82; N, 10~77 *~rademark. Methyl "Ge1losolve" ~is ethylene glycol monomethyl ether.
~ 3~3~~
. . ., . . . . . .
St~p D - 3-[3-Carbo-(2-methoxy)ethoxy-S-methyl-isothioureido~-~-aminohenzo~henone To a solution of 3-[3-carbo-(2-methoxy)-ethoxythioureido)-~-aminobenzophenone (1.87 g.; 0.005 mole) in dimethyl formamide (15 ml.) is added water (3 ml.). To this solution is added a~ueous sodium hydroxide (50~;
0.4 g.) and the solution stirred at room tempexature for 1 hour. Methyl iodide (0.71 g~; 0.005 mole) is added and the solution is stirred at room temperature for 18 hours~ The solution is poured into water (200 ml.) and the pracipitate collected by filtration, washed with water and dried to afford 1.1 gO of 3-[3-carbo-(2-methoxy)ethoxy-S-methyliso-thioureido]-4-aminobenzophenone.
Eleme~tal analysis Por C19~21N301~S
Calc.: C, 58.90; H, 5.1~6; N, 10.85 Found: C, 58~31; H, 5.34; N, 11~05 - 3-Amino-4-(3-carbomethoxy-S-methylisothioureido~-Step A - 3-Nitro-~-(3-carbomethoxythioureido)-benzophenone _ _ A mixture of 3-nitro-1~-aminobenzophenone (9~9 g; 0.041 mole), carbomethoxyisothiocyanate (4.8 g.; 0~041 mole)in acetonitrile (25 ml~) is stirred and re~lu~ed ~or 17 hours. The reaction mixture is cooled and the precipitate collected by filtration, washed with acetonitrile an~ dried to a~ford 8.7 g. of 3-nitro-4-(3-carbometho~thioureido)-benzopherlone, m.p~ 17~-183C. (dec.).
Step B - 3-Amino-~-(3-carbomethoxythioureido~- ;
b~ophenone ~ A mixture of 3-nitro-l~-(3-carbomethoxy-thioureido)benzophellone ~3.6 ~.; 0.01 mole),sta~nous ~hloride (11.3 g.; 0~05 mole)1 concentrated h-ydrochloric acid (20 nl.~, methanol ~40 m~O) and acetic acid ~40 mlO ) is he~ted with ; ~
~ '3~
stirring -to reflux. After 10 minutes, most of the solid is dissolved~ The reaction mixture is refluxed for a total o~
35 minutes and then filtered to remove a small amount of colored material. The filtrate is added to water (600 ml.) with stirring and the precipitate is collected by filtration to afford 3.5 g. of 3-amino-4-(3-carbomethoxythioureido)-benzophenone, m,p. 187C~ (dec.).
~ - 3-Amino-~-(3-carbomethoxy-S-methyl-To a stirred slurry of 3-amino-4-~-carbometho~ythioureido)benzophenone (2.5 g.; 0.0076 mole) in dimeth~Jl formamide (20 ml.) is added a 50~ sodium hydro~-ide solution ~0.61 g.; 0.0076 mole) in deionized wa~er (10 ml.). The clear red-orange solution which forms is 15 cooled to 4C. an~ then methyl iodide tl.l g.; 0~0076 mole) is added. '~he temperature rises to 7C. (p~I 7.8), After 3 minutes, the reaction mixture is added to deionized water (200 ml.) with stirring~ The precipitate is collected to af~ord 1-8 gO of 3-ami~o-~-(3-carbomethoxy-S-methyl-20 isothioureido~benzophenone.
Elemental anal~sis ~or C17H17N202S
Calc.: C, 59.45; ~, 5.00; N, 12.24; S, 9.34 Found: C, 590~8; H, 5~11; N, 12.59; S, 8~90 EXAM~ ~F. ~6 - 3-[3-Carbomethoxy-S~(2-nitro)benzylisothioureido]-4-aminobenzophenone _ To a solution of 3-(3-carbomethoxythio-ureido)-~-aminobenzophenone (3.29 g; 0~01 mole) in dlmet~yl ~ormamide (25 ml.) is added water (7 ml.). Tile solutio~ is cooled to room temperatllre and then an aqueous solution of sodium 30 hydroxlde (50~; 0.8 g.) is added. The solution is stirred at room temperature for one hour . o-Nitrobenzyl bromide (2.1 g.~ 0.01 mole) in dimethyl formamide (20 ml.) is added.
~ - 41 -.
.
The solution is s-tirred at room temperature for 24 hours and poured into water (300 ml.). A suspension forms and is stirred at room temperature for 18 hours and then collect-ed by filtration and dried to afford 4.25 g. of 3-[3-carbo-methoxy-S-(2-nltro)benzylisothioureido]-4-aminobenzopheneone, m.p. 75-85C. (dec.) Elemental analysis for C23H20N4O5S
Calc.: C, 59.47; ~1, 4.34; N, 12.06 Found: C, 57.91; H, 4.20; N, 12.98 Example 37 - 3-[3-Carbomethoxy-S-(p-nitro)benzylisothio-ureido]-4-aminobenzophenone -To a solution of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (7 ml.). The solution is cooled to room temperature and an aqueous solution of sodium hydroxide (50~;
0.8 g.) is added. The solution is stirred at room temperature for l hour and p~-nitrobenzyl bromide (2.11 g.; 0.01 mole) in DME' (20 ml.) is added. The solu~ion is stirred at room temperature for 24 hours and then poured into water (300 ml.).
The suspension Formediis stirred at room temperature for 18 hours and the precipitate collected by filtration and dried to afford 4~25 g. o~ 3-~3 carbomethoxy-S-tp nitro)benzyliso~
thioureido~-4-aminobenzophenone, 100-105C. (dec.).
Elemental analysis for C23H20N~O5S
Calc~: C, 59~47; H, 4~34; N, 12.06 Found: C~, 57.91; H, 4.29; El, 11.89 In a manner similar to that described in Example 37 and by substituting for the p-nitrobenzyl bromide ~ ~ an equimolar quantity of p-methylbenzyl bromide, m~methylbenzyl ; 30 bromide, p-chlorobenzyl chloride, crotyl chloride and 3-~ chloro-2-methylpropene and by following substantially the :
~ - 42 ~
~ ' . ', 3~ ~
procedure described therein, there is obtained, respectively, the following compounds:
, ~ .
.
~ 3 -7~-~L 33~;
C~O Cl~ ~ ~D O C~r I
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r-l O V V O V V '~ V O V ~
~ ~ - - O - - r-l - -r~ V Vrr ~ ) h V V ~ C~l Vf r~ ;
~ V V
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~11 C\l r~
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Fr~ C`'~) ~0 , cy 1:
r~l 1 oi 1: .
~ I r~ .
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r~ I
j~ r~
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El _~ ~ I S
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rl C) 0 ~0 rn I ~
S ~ C\l ~
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E-l .~ :~
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~ : : : :
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~ 3 ~
EY~PL~ 4~ - 3-(3-Carbometho~y-S-2-[4-(4-acetam.idophenyl-thio)phenylcarbamy.]el;hylisothioureido-4-amin~be:n%op'lenone _ _ S~,e~ A - 4-(~-Bromoproplonamido)-4'-nitro.~i-~ Y~ de _ _ _ To a suspension of 4-amino-4~-nitro-diphenylsu'fi~e (7.4 g.; 0O03 ~ole) in toluene ~200 ml~) is ad~ed 3-bromop~opionyl chloridet5.14 g.; 0.03 mole)~ The mixture is refluxed and stirred for 3 hours and then stirred o~7ernig.ht at room temperature~ Tne precipi~a~ is collected by filtra~ion, washed with hexane and dried to afford 10.1 g.
of 4-~3-bromopropionamido)-4~-nitrodiphenylsulfide~ m.p. .
136-138~C. (dec.).
Step B - ~ Bromopropionamido)-4'-aminodi-~hen~lsulfide To a suspension of 4-(3-bromopropion- 1:
amido)-4'-nitro~iphenylsulfid~(~ g.; 0.0105 mole) in ethanol ~250 ml.~ is added palladium on carbon (5%; 0.2 g.). ~he ; . .
mixture is shaken on a Parr hydrogenator for 5 hours and 20 lefi stan~ng at room temperature overnight~ No hydrogen uptakeO ~he mixtu.re is flushed with nitro~en and Ran~y nick~
(1 g.) ~s adde~ The m.ixtl1re is shaken on a Parr hydrogenator (initial pressure 50 psi) for 5 hours. A~ter 5 hours, there is 1 pound of hydrogen uptake. The reaction mixture is kept 25 under pressure for 18 hours at which tims there is a to~al hydrogen uptake of 2 pounds. The mixture is filtered and the filtr~te concelltrated under vacuum to afford 2.7 g. of ~-t3-bromopropiorlamido)~ aminodiphenylsulfide, mvp. 1~1- .. .
'~ 148~C. tdec~).
~ 3-Bromopropionamido)-4'-acet,ami.do~
d iphenyl S!ll fid e , _ _ _ .
To a suspension of 4~t~-bromopropion-amido3~4l-aminoaiphenylsulfide ~2 gO; 0.0057 mole) in toluene , ~
(150 ml.) is added acetic anhJdride (o~58 g.; 0,0057 mole)O
-6 -
7~--133 ~he su~pension is refluxed and stirred for 3 hours and allo~ed to stand ~t room temperatllre overnight. Th~ ;
precipl-tate :~ormed wa~ collected by filtration, washed with hexane and dried to afford 1~4 g~ of 4-(3-bromopropionamido)-4-'-acetamidodiphenyl.sulfide, 1851'-1`93~Ci, (dec.). '~:
Elemental analysis for C17H17BrN202S
Calc.: C, 51.97; H, I~.36; N, 7~12 Found: C, 52.70; H, 4.50; N, 7.43 ~ 3-(3-Carbomethoxy)-S-2-~ 4-acetamido~
lQ phenylthio)phenylcarbam~ ethylis~thio- ~:
ureido~L~-aminobenzo ~ none To a solution of 3-(3-caxbomethoxy-: thioureido)-l~-aminobenzophenone (008L~ g.; 0.0025l~ mole) in D~F (10 ml.) and water (2 ml.) there is added an aqueous 15 solution of sodiurn hydroxide (0.2 g.)~ The solution is stlrred at room temperature for one hour and L~-(3-bromo- !
propionamido)-L~'-acetamidodiphenylsulfide (1 g.) and DMF
(5 ml.) is added~ The solutio.n is stirred at room te.mperature for 18 hours and the solution poured into water (300 ml~
20 This was st:irred f`or 30 minukes and the precipitate collected b~ fi1.tration and dr:ied ko af:~ord l.L~5 g. oE 3-~3-car~ometh- 1 oxy-S-2-[L~ -acetoamidophenylth~)ph~nylca.rba~nyl~ethyl-isothiol1reido-L~-am.l.nobenzophenone, m.p. 120C. with dec. at 162-~.66~. 1 Elemental analysis ~or C33H31N505S2 '.
Calc~: G, 61.76; H, L~o87; N, 10.91.
Fo~m d: C, 6.1; 1!l; H~ It. 91; N, 11~57 i~
' i I
~ 7 _ 7 ~
E~ lPI.13~ 2-(3-Carbomethoxy-S-mel;hylisothioureido)-ll-Eon~:]-n.i~in(~
- 2-(3-Carbornethoxythioureido)~
~h___x~rsul_on~la.rl line l'o a solution of 2-amino-5-phenoxy-sulfonylaniline (5.28 g.; 0.02 mole) i.n ether (350 ml.) is added carbomethoxyisothiOCyanate (2.34 g~; 0,02 mole). The solution is stirred at room I;emperature for 1 hour and the precipltate which forms is collec-ted by filtration, washed 10 with ether and dried to afford 5.65 g. of 2-(3-carbomethoxy-thioureido)-~phenoxysulfonylaniline, mp. 185-186C, (dec.).
Elemental analys.i.s for C15H 15N305S2 Calc.: C, 47.23; E, 3.96; N, 11.02 Found: C, L~7.83; H, L~.13; N~ 10.66 ~tep_B - 2-(3-Carbomekhoxy-S-methylisothioureido~-4-phenox~sulf~laniline _ To a solution of' 2-(3-carbomethoxy-thioureido~-L~-phenoxysulf~nylaniline (Lt.o ~; 0.0105 mole) in Dl,~F (25 ml.) and~water (5 ml.) there ls added an aqueous 20 solution of sodiwn hy~roxide ~50~, o.84 g~). Th~ solu-tion -1 skirred at room kemperatu:re for 1 hour and t.hellmethyl iodide (1.1~9 g.) is adcled. The solut:ion is stir.red at room temperature for 1/2 hour, poured into water (500 ml.) t and the precipi~te which forms is collected by filtration and dried to afford 3.4 g. of 2-(3-carbomethoxy-S-methyliso-; thloure~.ido)~l~-phenoxysulfDnylaniline,.m.p~ 108-113C.
Elemen-tal analysis for C H N O S
Calc~: C, L~8.59; H, 4.33; N~ 10.63; N, 16.22 Found: C, L~8.20; H, L~.41; N, 10.7L~; N, 15.89 ~, .
;
: .. .:
_ 11.~ ~
.
.. . . . .
,~5-:13~l EX~MPI,I~ 2-(3-Carbomet~loxy -S-methylisoth]ollre-ldo)-5 ut,~lanl]ine _ Ste~A ~ 2-(3-Carbomethoxyt~ioureido)-5-_-_u~n ] ine ~__~
~o a soLution o E 4-_-butyl-o-phenylene-diamine (5.0 gO; 0,0305 mole) in ether (250 ml~ ) is added carbomethoxy isothiocyanate (3.57 g,; 0.0305 mole)O The solution is sti rred at room temperature for 2 hours (a very fine precipitate beglns to Eorm). The mixture is stirred at 10 room temperature over the week-end and the precipitate collected by filtration and dried to afford 1,15 g. of 2- (3-carbomethoxythioureido)-5-n-butylaniline, m.p. 162-165 C. (dec.).
Step_B - 2-~3-Carbomethoxy-S-methylisothioureido)-15_u-t~lanil-ne _~_ To a solution OI 2-(3-carbomethoxy-thioureido)-5-n-butylaniline (1 g.; 0.00355 mole) in D~qF
(15 ml.) is added water (5 mlO). The solution is cooled to room temperature and aqueous sodium hydroxide (5070;
20 0.28L~ mole) is added. The solution is stirred at room temperature Eor 1 hour and then methyl iodide (0.505 g.) is added. The solutioll :is stirred at room ~vemperature E'or 10 minutes and then poured into water (200 m:l.). The suspension t is stirred ak room temperature for 10 minutes and the 25 precipitat3 is collected by :Eiltration and dried to afEord O.o g. oE 2~(3-carbomethoxy S-methylisothioureido)-5-bu tylarli line .
El~en~al analysis Eo r C1LI.F~21N32S
Calca: C, 56.92; H, 717; N~ o22; S, 10.o6 3Found: C~ 57015; II, 7.11; N, lL~ -7; S, lO.I~o '' .
_ ~l9 _ 7',,-'1, J,;A
By slibst:il;ut! n~- ror the 4~n-bu-tyl-o-ph3ny]erledi-amine of Step A o~ Examp~Le 45, 3,4-diaminopropyl-thioben7ene and by following substantially the procedure described t;here-in, there is obtained 2-(~-carbomethoxythioureido)-5-propyl-thio~niline, m.p. 167-168C (dec.), which product when trea-ted wi th methyl iodide in the manner of Step B oî Example 4 5, affords 2-(3-carbomethoxy-S-rnethylisothioureido)-5-propyl-thioaniLine.
Elemental analysis for CL3HlgN302S2 Calc.: C, 49.81; H, 6.12; N, 13.41; S, 20~45 Found: C, 1~9 ]7; H, 6.02; N, 13.53; S, 20.58 E~A~T,E L~6 - 2-(3-Carbomethoxy-S me-thylisothioureido)-4-propylthi oan31ine Step A - 2-(3-Carbomethoxythioureido)-4-propyl-~5 ~ ~ thio_~troben7ene _ __ A mixture Or 2-nitro-5-propylthioani-line (5.4 g.; 0.026 mole), carbomethoxy isothiocyanate (3.] g.;
0.026 mole) and acetonitrile (10 ml.) is s-tirred and refluxed f'or 1 hour. The reaction mixture is cooled; ether is added 20 and the mixture ~iltered to arford 6.3 g. Or 2~(3-carbomethoxy-th:i.oureiclo)-4-propylth:Lonltrobenzene, m.p. 123-125C.
Step B - 2-( 3-Carbomethoxyth:Loureido)-~l-prc)pyL-~--~~ th:loan~ L ne A mixture of 2-(~-carbornethoxythio-25 ureido)-L~-propylthionltrobenzene (8.8 g.; 0.027 mole), stannous-chLoride (30.2 g.; 0.135 mo1e), concenkrated hydrochlorlc acid (30 rnl.), acetic acid (60 ml,) and methanol (60 ml.) is stirred and re:Eluxed l:or 1/2 hour and -then poured into water.
The precipitate is collected by filtra-tion, stirred with 30 aqueous sodium bicarbonate and f'lltered to af:ford 6.7 g. of ~-2-(3-ca.rl)omethoxy-th:i.oureido)-4~propy'lthioanillne, m.p. '' 127~-135 C. (dec .).
'15--] ,~
Step C - 2-(3-Carbomel,hoxy-S-m~hy~-thioureid~)-4-p:ropyl thi o~ni 'I i n~ !
By following substantially the procedure of Step B of Example 45, the 2-(3-carbomethoxythioureido)-l~-propylthioaniline is reacted with methyL iodide to afford 2-(~-carbomethoxy-S-me-thylthioureido)-4-propylthioaniline.
Elemental analysis for Cl~El9N3$202 Calc.: C, 49.8l; H, 6.12; N, 13.41; S~ 20.45 Found: C, ~9.89; H, 6.16; N, 1~.39; S, 20.26 (r By substituting for the 2-nitro-5-propyl-thioaniline of Step A o~ Example 46 an equimolar quantity of I
2-nitro-5-phenylthioaniline and by ~ollowing substantially the procedures o~ Steps A-C of Example l~6, there is obtained 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylthioaniline, m.p.
1.26-128C. (dec.j.
EXAMP~E 47 - 2-(3-Carbometlloxy-S-methyLisothioureido)-4-(p-chloro)benzylthioaniline Step A - 2-Nitro~ p-chloro)benzylthioaniline 5-Chloro-2-nitroaniline (~.1 g.; 0.0l8 moLe) is dLssolved in dimethylformamide (30 ml.). 4-Chloro-.
benzyl mercaptan (2.85 g.;;0.018 mole) and potassium carbonate (4 g.; 0.03 mole) are added ~ollowed by lO ml. oL7 dimeth~lform amide. ~The suspens:Lon is sti.rred and heated at 76C. ~r 8 hours.~ It is poured into 200 ml. of col1 water. A yellow solid ~orms which :L~ l~olatecl by vacllum ~:iltration, washed wlth water and drLed to a~ford 4.9 e. ~93~) o:t 2-nitro-5-(~-chloro)benzyl- ~ -thioaniLine, m.p. 160-16~C. (dec.).
Ste~p B - l-(p-Ch10ro)benzy1thio~ carbomethoxy-thioureido)~ nitrobenzene 3o ~ To a solutlon of 2 nitro-5-(p-chloro)-benzy1thioaniline~ .6 ~., 0.0l3 mole) in acebone (75 ml.) is -~;
added carbomethoxy`isothtoc~ana~te (1.5 g., 0.01~ mole) in ~: - ''''L
~ . : . , . .- . -. .
acetone (10 ml .). The reacti on mixture ls hea-ted to boil:ing :[or 1 hour. F:ive drops Or trlethylam:Lne is added and stir-ring continued at room tempera-ture over the week-end. A
precipltate forms which is collected by filtration, washed 5 with acetonitrile and dried to afford 2.~ g. of 1-(p-chloro)-benzylthio-3-(3-carbomethoxythioureido)-4-nitrobenzene, m.p.
180-190C . (dec.).
Elemental analysis for C16H14ClN3S?02 ~.r Calc.: C, 46.65; H, 3.43; N, 10.20; S, 15.57;
] 0 Cl, 8.61 Found: C, 46.48; H, 3.38; N, 11.27; S, 14.73 Cl, 8.36 Step ~ - 2-(3-Carbomethoxythioureido)-4-(p-chloro)-benzylthioaniline A mixture of l-(p-chloro)benz~lthio-3-(3-carbome-thoxyl;hioureido)-l~-nitrobenzene (1.8 g.), concentrated hydrochloric acid (10 ml.), methanol (20 ml.), acetic acid (20 m~.) and stannous chloride (5.1 g.; 0.0226 mole) is stirred and heated to ref'lux for 30 minutes. The mixture is ~i Ltered to remove a smalL amount o:E insoluble material. The îiltrate is poured lnto water (500 ml.) with stirr:lng. The precipita-te is collected by :Eiltration, washed with water and dried to a~:~ord 1.4 g. o:E 2-(~-carbomethoxythioulleido)-lL-(p-chloro)-benzylthioaniline, m.p. 16L-162C.
.
Step D - 2-(~-Carbomethoxy-S-methylisothioureido)-l~-(p-chl.oro)benzylth:i.oan~ ire A mlxture o:~ 2-(~-carbomethoxythioureido)-4-~: (p-chloro)benzylthioaniline (0.9 g.) and an aqueous solution of sodium hydro~ide (o.og76 g.) in DM~ 10 ml.) is cooled to 5C.
.
A solution o:E me-thyl iodide (o.l~ g.) in ~ (1 ml.) is added with sti.rrlng. The temperature rises -to 10C. The reacti on m:i~cture ls stirred in an :ice bath f`or 5 minute~, poured into ~ . .
::
- 52 - ~ ~
:
. : , - . . ; -'~'j -l ')~ ; ' 3~
ice water (ll-00 rnl.) -w:i-th stirr:ing. The aqueous mater:ial is extrac-ted wit,h ether and. the ether removed to af:~ord ~.0 g. of product. Additional pre~cipitate forms in the aqueous layer which :is co]lect~d by ~iltration and dried to a~ford 0.2 g. of product. The material is combined and sen-t ~or analysis~ ' Elemental analysis f'or C H ClN S 0 ' CaLc.: C, 51.56; H, 4,61; N~ 10~78; S, 15.27 C1, 9,oo Found: C 58 01; H, 4.59, N, 10,61; S, 16.10 EXAMPLE 48 - 2~ Carbomethoxy-S-methylisokhioureldo)-5-propyl-' ~ ~ ~ul~inylaniline To a stirred slurry o~ 2-(3-carbomethoxy-S-methyl-isothioure~do)`5-propylthioaniline (1.7 g.; Q.0542 mol) in 5 ml. ether is added 85~ m-chloropsroxybenzoic acid (1.1 g.;
0,005~ rnol) in 20 ml. o~ ether. The mixture is stirred at room temperature fo 20 minutes, then 50,ml. o:~ 5~ aqueous sodium b'icarbonat,e is added. The layers are se~arated. The organic layer is~washed with two more portions o~ 5~ aqueous sodium bicarbonate, dried (MgSOL~) and concentrated to yield 0,5 g, o~
crude product which is puri~ied by chromatography (silica gel co'Lumn developed wi.th ethyl acetate) and crystallized :~rom ether to glve pure ~-(3-car'bomethoxy-S-met;h~l:Lsothioureldo)-5-propylsul~inylaniline;~m.p. 131-132C. dec. ;' ~ ~ Elemental analysLs .~or ~13Hl9N303S~
Calc.: a~cJ 47.39; ~M, 5.82; ~N, 12.76; a~s, 19.81 Found: ~C, ~7.48; ~H, 5.98; ~ , 12.75; a~s, 19.46 EXAMPLE 49 ~2-(3-Carbomethoxy-S-methylisothioureido)-l~-phen~
slllfinyl.aniline A~ml~ture~o~2~(~-ca~bomethoxy-S-tnethylis~-thio- ;~
ureido)-4-phen~li,hio~r~iLlne~(6.0~g.; 0.0173 moL) and 200 ml,~
meth~lene chlorlde i5 co~oled~to -15C, and fiLtered thru 5~
:: ~
~ , : ~ . . . :
7S~
~elite To the filtra-te (zero degree~ C.) is added 85% m-chloroperoY.ybenzoic acid (3.6 g.; 000177 mol). The mixture is stirred at 0~ ~ 10C. for 20 minutes, then washed with four 75 ml. portions of 5~ aqueous sodium bicarbonate. The organic layer is dried (MgS0~) and concentrated. Ethylacetate is adde~ and the insoluble impurities removed by filtration. The filtrate is ag~in concentrated and the residue crystallize~
from ether to give ~.5 g. (5 ~ yield) of 2~ carbomethoxy~
S-methylisothioureido)-4-phenylsulfinylaniline; m.p. 126-128C.
dec.
Elemental analysis for C16H17N~O~S2 ~alc. Theory: C, 52.89; H, 4.72; N, 11.56; S, 17.66 Found: C, 52.46; H~ 4.7~; N, 11.64, S, 18.16 Preparation of Starting Materials15 Example A ~ -Carbomethoxythioureido)-4-aminbbenæophenone To a solution of ~y4-diaminobenzophenone (6~.6 g.;
0.~ mole) in chloroform ~1.5 1.) is added dropwise carbomethoxy I -isothioc~anate (52.6 8.; -45 mole) over a ~ive ~inute period.
The temperature of the reaction mixture went ~rom 25C. to 30C. A suspension forms and the reaction mixture is stirred at room temperature for 70 minute~ and the preoip1tate collected by filtration. The collected product is washed w~th chloroform, triturated in ether (500 ~1.), collected and drie~
to afford 79.8 g. (80.9~ yield) of 3-(3-carbome-thoxythio-ureido)-4-amino~enzophenone, m.p. 192C., dec.
Example B - 3-(Carboethox~thioureido)-4-aminobenzophenone !:
~ ~ ~To a solution of 7,4-diaminobenzophenone (4.24 g.;
;~ 0.02 mole) in ether~(600 m~ added carboethoxy i~othio-cyanate ~2.62 g.; 0.02 mole?. The su~pen~ion that Iorms is ~tirred at room temperature for 45 minute~ and the precipitate . - - .
collec-ted by :riltrat:ion to ar:Lord 3.1 g. (45~ yield) of 3-(carboethoxyth:ioureido)-~ am:inobenzophenone as a yellow powder, m.p. 200C., dec.
By substituting for the carboethoxy :isothiocyanate ~of Example B an equimolar quantity of carbo-n-propoxy isothio-cyana-te~ carboisopropoxy isothiocyanate, carbo-n-butoxy iso-thiocyanate and by followin~ substantially the procedure described therein, there is obtainsd 3-(carbo-n-propoxy)-4 aminobenzopllenone, 3-(carboisopropoxy)-4-aminoben~,o-J?llenone and 3-(carbo--n-butoxy)-!t-arni.noben~.oph(J~.~on!, respsctLvely.
.::
- 5~-
precipl-tate :~ormed wa~ collected by filtration, washed with hexane and dried to afford 1~4 g~ of 4-(3-bromopropionamido)-4-'-acetamidodiphenyl.sulfide, 1851'-1`93~Ci, (dec.). '~:
Elemental analysis for C17H17BrN202S
Calc.: C, 51.97; H, I~.36; N, 7~12 Found: C, 52.70; H, 4.50; N, 7.43 ~ 3-(3-Carbomethoxy)-S-2-~ 4-acetamido~
lQ phenylthio)phenylcarbam~ ethylis~thio- ~:
ureido~L~-aminobenzo ~ none To a solution of 3-(3-caxbomethoxy-: thioureido)-l~-aminobenzophenone (008L~ g.; 0.0025l~ mole) in D~F (10 ml.) and water (2 ml.) there is added an aqueous 15 solution of sodiurn hydroxide (0.2 g.)~ The solution is stlrred at room temperature for one hour and L~-(3-bromo- !
propionamido)-L~'-acetamidodiphenylsulfide (1 g.) and DMF
(5 ml.) is added~ The solutio.n is stirred at room te.mperature for 18 hours and the solution poured into water (300 ml~
20 This was st:irred f`or 30 minukes and the precipitate collected b~ fi1.tration and dr:ied ko af:~ord l.L~5 g. oE 3-~3-car~ometh- 1 oxy-S-2-[L~ -acetoamidophenylth~)ph~nylca.rba~nyl~ethyl-isothiol1reido-L~-am.l.nobenzophenone, m.p. 120C. with dec. at 162-~.66~. 1 Elemental analysis ~or C33H31N505S2 '.
Calc~: G, 61.76; H, L~o87; N, 10.91.
Fo~m d: C, 6.1; 1!l; H~ It. 91; N, 11~57 i~
' i I
~ 7 _ 7 ~
E~ lPI.13~ 2-(3-Carbomethoxy-S-mel;hylisothioureido)-ll-Eon~:]-n.i~in(~
- 2-(3-Carbornethoxythioureido)~
~h___x~rsul_on~la.rl line l'o a solution of 2-amino-5-phenoxy-sulfonylaniline (5.28 g.; 0.02 mole) i.n ether (350 ml.) is added carbomethoxyisothiOCyanate (2.34 g~; 0,02 mole). The solution is stirred at room I;emperature for 1 hour and the precipltate which forms is collec-ted by filtration, washed 10 with ether and dried to afford 5.65 g. of 2-(3-carbomethoxy-thioureido)-~phenoxysulfonylaniline, mp. 185-186C, (dec.).
Elemental analys.i.s for C15H 15N305S2 Calc.: C, 47.23; E, 3.96; N, 11.02 Found: C, L~7.83; H, L~.13; N~ 10.66 ~tep_B - 2-(3-Carbomekhoxy-S-methylisothioureido~-4-phenox~sulf~laniline _ To a solution of' 2-(3-carbomethoxy-thioureido~-L~-phenoxysulf~nylaniline (Lt.o ~; 0.0105 mole) in Dl,~F (25 ml.) and~water (5 ml.) there ls added an aqueous 20 solution of sodiwn hy~roxide ~50~, o.84 g~). Th~ solu-tion -1 skirred at room kemperatu:re for 1 hour and t.hellmethyl iodide (1.1~9 g.) is adcled. The solut:ion is stir.red at room temperature for 1/2 hour, poured into water (500 ml.) t and the precipi~te which forms is collected by filtration and dried to afford 3.4 g. of 2-(3-carbomethoxy-S-methyliso-; thloure~.ido)~l~-phenoxysulfDnylaniline,.m.p~ 108-113C.
Elemen-tal analysis for C H N O S
Calc~: C, L~8.59; H, 4.33; N~ 10.63; N, 16.22 Found: C, L~8.20; H, L~.41; N, 10.7L~; N, 15.89 ~, .
;
: .. .:
_ 11.~ ~
.
.. . . . .
,~5-:13~l EX~MPI,I~ 2-(3-Carbomet~loxy -S-methylisoth]ollre-ldo)-5 ut,~lanl]ine _ Ste~A ~ 2-(3-Carbomethoxyt~ioureido)-5-_-_u~n ] ine ~__~
~o a soLution o E 4-_-butyl-o-phenylene-diamine (5.0 gO; 0,0305 mole) in ether (250 ml~ ) is added carbomethoxy isothiocyanate (3.57 g,; 0.0305 mole)O The solution is sti rred at room temperature for 2 hours (a very fine precipitate beglns to Eorm). The mixture is stirred at 10 room temperature over the week-end and the precipitate collected by filtration and dried to afford 1,15 g. of 2- (3-carbomethoxythioureido)-5-n-butylaniline, m.p. 162-165 C. (dec.).
Step_B - 2-~3-Carbomethoxy-S-methylisothioureido)-15_u-t~lanil-ne _~_ To a solution OI 2-(3-carbomethoxy-thioureido)-5-n-butylaniline (1 g.; 0.00355 mole) in D~qF
(15 ml.) is added water (5 mlO). The solution is cooled to room temperature and aqueous sodium hydroxide (5070;
20 0.28L~ mole) is added. The solution is stirred at room temperature Eor 1 hour and then methyl iodide (0.505 g.) is added. The solutioll :is stirred at room ~vemperature E'or 10 minutes and then poured into water (200 m:l.). The suspension t is stirred ak room temperature for 10 minutes and the 25 precipitat3 is collected by :Eiltration and dried to afEord O.o g. oE 2~(3-carbomethoxy S-methylisothioureido)-5-bu tylarli line .
El~en~al analysis Eo r C1LI.F~21N32S
Calca: C, 56.92; H, 717; N~ o22; S, 10.o6 3Found: C~ 57015; II, 7.11; N, lL~ -7; S, lO.I~o '' .
_ ~l9 _ 7',,-'1, J,;A
By slibst:il;ut! n~- ror the 4~n-bu-tyl-o-ph3ny]erledi-amine of Step A o~ Examp~Le 45, 3,4-diaminopropyl-thioben7ene and by following substantially the procedure described t;here-in, there is obtained 2-(~-carbomethoxythioureido)-5-propyl-thio~niline, m.p. 167-168C (dec.), which product when trea-ted wi th methyl iodide in the manner of Step B oî Example 4 5, affords 2-(3-carbomethoxy-S-rnethylisothioureido)-5-propyl-thioaniLine.
Elemental analysis for CL3HlgN302S2 Calc.: C, 49.81; H, 6.12; N, 13.41; S, 20~45 Found: C, 1~9 ]7; H, 6.02; N, 13.53; S, 20.58 E~A~T,E L~6 - 2-(3-Carbomethoxy-S me-thylisothioureido)-4-propylthi oan31ine Step A - 2-(3-Carbomethoxythioureido)-4-propyl-~5 ~ ~ thio_~troben7ene _ __ A mixture Or 2-nitro-5-propylthioani-line (5.4 g.; 0.026 mole), carbomethoxy isothiocyanate (3.] g.;
0.026 mole) and acetonitrile (10 ml.) is s-tirred and refluxed f'or 1 hour. The reaction mixture is cooled; ether is added 20 and the mixture ~iltered to arford 6.3 g. Or 2~(3-carbomethoxy-th:i.oureiclo)-4-propylth:Lonltrobenzene, m.p. 123-125C.
Step B - 2-( 3-Carbomethoxyth:Loureido)-~l-prc)pyL-~--~~ th:loan~ L ne A mixture of 2-(~-carbornethoxythio-25 ureido)-L~-propylthionltrobenzene (8.8 g.; 0.027 mole), stannous-chLoride (30.2 g.; 0.135 mo1e), concenkrated hydrochlorlc acid (30 rnl.), acetic acid (60 ml,) and methanol (60 ml.) is stirred and re:Eluxed l:or 1/2 hour and -then poured into water.
The precipitate is collected by filtra-tion, stirred with 30 aqueous sodium bicarbonate and f'lltered to af:ford 6.7 g. of ~-2-(3-ca.rl)omethoxy-th:i.oureido)-4~propy'lthioanillne, m.p. '' 127~-135 C. (dec .).
'15--] ,~
Step C - 2-(3-Carbomel,hoxy-S-m~hy~-thioureid~)-4-p:ropyl thi o~ni 'I i n~ !
By following substantially the procedure of Step B of Example 45, the 2-(3-carbomethoxythioureido)-l~-propylthioaniline is reacted with methyL iodide to afford 2-(~-carbomethoxy-S-me-thylthioureido)-4-propylthioaniline.
Elemental analysis for Cl~El9N3$202 Calc.: C, 49.8l; H, 6.12; N, 13.41; S~ 20.45 Found: C, ~9.89; H, 6.16; N, 1~.39; S, 20.26 (r By substituting for the 2-nitro-5-propyl-thioaniline of Step A o~ Example 46 an equimolar quantity of I
2-nitro-5-phenylthioaniline and by ~ollowing substantially the procedures o~ Steps A-C of Example l~6, there is obtained 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylthioaniline, m.p.
1.26-128C. (dec.j.
EXAMP~E 47 - 2-(3-Carbometlloxy-S-methyLisothioureido)-4-(p-chloro)benzylthioaniline Step A - 2-Nitro~ p-chloro)benzylthioaniline 5-Chloro-2-nitroaniline (~.1 g.; 0.0l8 moLe) is dLssolved in dimethylformamide (30 ml.). 4-Chloro-.
benzyl mercaptan (2.85 g.;;0.018 mole) and potassium carbonate (4 g.; 0.03 mole) are added ~ollowed by lO ml. oL7 dimeth~lform amide. ~The suspens:Lon is sti.rred and heated at 76C. ~r 8 hours.~ It is poured into 200 ml. of col1 water. A yellow solid ~orms which :L~ l~olatecl by vacllum ~:iltration, washed wlth water and drLed to a~ford 4.9 e. ~93~) o:t 2-nitro-5-(~-chloro)benzyl- ~ -thioaniLine, m.p. 160-16~C. (dec.).
Ste~p B - l-(p-Ch10ro)benzy1thio~ carbomethoxy-thioureido)~ nitrobenzene 3o ~ To a solutlon of 2 nitro-5-(p-chloro)-benzy1thioaniline~ .6 ~., 0.0l3 mole) in acebone (75 ml.) is -~;
added carbomethoxy`isothtoc~ana~te (1.5 g., 0.01~ mole) in ~: - ''''L
~ . : . , . .- . -. .
acetone (10 ml .). The reacti on mixture ls hea-ted to boil:ing :[or 1 hour. F:ive drops Or trlethylam:Lne is added and stir-ring continued at room tempera-ture over the week-end. A
precipltate forms which is collected by filtration, washed 5 with acetonitrile and dried to afford 2.~ g. of 1-(p-chloro)-benzylthio-3-(3-carbomethoxythioureido)-4-nitrobenzene, m.p.
180-190C . (dec.).
Elemental analysis for C16H14ClN3S?02 ~.r Calc.: C, 46.65; H, 3.43; N, 10.20; S, 15.57;
] 0 Cl, 8.61 Found: C, 46.48; H, 3.38; N, 11.27; S, 14.73 Cl, 8.36 Step ~ - 2-(3-Carbomethoxythioureido)-4-(p-chloro)-benzylthioaniline A mixture of l-(p-chloro)benz~lthio-3-(3-carbome-thoxyl;hioureido)-l~-nitrobenzene (1.8 g.), concentrated hydrochloric acid (10 ml.), methanol (20 ml.), acetic acid (20 m~.) and stannous chloride (5.1 g.; 0.0226 mole) is stirred and heated to ref'lux for 30 minutes. The mixture is ~i Ltered to remove a smalL amount o:E insoluble material. The îiltrate is poured lnto water (500 ml.) with stirr:lng. The precipita-te is collected by :Eiltration, washed with water and dried to a~:~ord 1.4 g. o:E 2-(~-carbomethoxythioulleido)-lL-(p-chloro)-benzylthioaniline, m.p. 16L-162C.
.
Step D - 2-(~-Carbomethoxy-S-methylisothioureido)-l~-(p-chl.oro)benzylth:i.oan~ ire A mlxture o:~ 2-(~-carbomethoxythioureido)-4-~: (p-chloro)benzylthioaniline (0.9 g.) and an aqueous solution of sodium hydro~ide (o.og76 g.) in DM~ 10 ml.) is cooled to 5C.
.
A solution o:E me-thyl iodide (o.l~ g.) in ~ (1 ml.) is added with sti.rrlng. The temperature rises -to 10C. The reacti on m:i~cture ls stirred in an :ice bath f`or 5 minute~, poured into ~ . .
::
- 52 - ~ ~
:
. : , - . . ; -'~'j -l ')~ ; ' 3~
ice water (ll-00 rnl.) -w:i-th stirr:ing. The aqueous mater:ial is extrac-ted wit,h ether and. the ether removed to af:~ord ~.0 g. of product. Additional pre~cipitate forms in the aqueous layer which :is co]lect~d by ~iltration and dried to a~ford 0.2 g. of product. The material is combined and sen-t ~or analysis~ ' Elemental analysis f'or C H ClN S 0 ' CaLc.: C, 51.56; H, 4,61; N~ 10~78; S, 15.27 C1, 9,oo Found: C 58 01; H, 4.59, N, 10,61; S, 16.10 EXAMPLE 48 - 2~ Carbomethoxy-S-methylisokhioureldo)-5-propyl-' ~ ~ ~ul~inylaniline To a stirred slurry o~ 2-(3-carbomethoxy-S-methyl-isothioure~do)`5-propylthioaniline (1.7 g.; Q.0542 mol) in 5 ml. ether is added 85~ m-chloropsroxybenzoic acid (1.1 g.;
0,005~ rnol) in 20 ml. o~ ether. The mixture is stirred at room temperature fo 20 minutes, then 50,ml. o:~ 5~ aqueous sodium b'icarbonat,e is added. The layers are se~arated. The organic layer is~washed with two more portions o~ 5~ aqueous sodium bicarbonate, dried (MgSOL~) and concentrated to yield 0,5 g, o~
crude product which is puri~ied by chromatography (silica gel co'Lumn developed wi.th ethyl acetate) and crystallized :~rom ether to glve pure ~-(3-car'bomethoxy-S-met;h~l:Lsothioureldo)-5-propylsul~inylaniline;~m.p. 131-132C. dec. ;' ~ ~ Elemental analysLs .~or ~13Hl9N303S~
Calc.: a~cJ 47.39; ~M, 5.82; ~N, 12.76; a~s, 19.81 Found: ~C, ~7.48; ~H, 5.98; ~ , 12.75; a~s, 19.46 EXAMPLE 49 ~2-(3-Carbomethoxy-S-methylisothioureido)-l~-phen~
slllfinyl.aniline A~ml~ture~o~2~(~-ca~bomethoxy-S-tnethylis~-thio- ;~
ureido)-4-phen~li,hio~r~iLlne~(6.0~g.; 0.0173 moL) and 200 ml,~
meth~lene chlorlde i5 co~oled~to -15C, and fiLtered thru 5~
:: ~
~ , : ~ . . . :
7S~
~elite To the filtra-te (zero degree~ C.) is added 85% m-chloroperoY.ybenzoic acid (3.6 g.; 000177 mol). The mixture is stirred at 0~ ~ 10C. for 20 minutes, then washed with four 75 ml. portions of 5~ aqueous sodium bicarbonate. The organic layer is dried (MgS0~) and concentrated. Ethylacetate is adde~ and the insoluble impurities removed by filtration. The filtrate is ag~in concentrated and the residue crystallize~
from ether to give ~.5 g. (5 ~ yield) of 2~ carbomethoxy~
S-methylisothioureido)-4-phenylsulfinylaniline; m.p. 126-128C.
dec.
Elemental analysis for C16H17N~O~S2 ~alc. Theory: C, 52.89; H, 4.72; N, 11.56; S, 17.66 Found: C, 52.46; H~ 4.7~; N, 11.64, S, 18.16 Preparation of Starting Materials15 Example A ~ -Carbomethoxythioureido)-4-aminbbenæophenone To a solution of ~y4-diaminobenzophenone (6~.6 g.;
0.~ mole) in chloroform ~1.5 1.) is added dropwise carbomethoxy I -isothioc~anate (52.6 8.; -45 mole) over a ~ive ~inute period.
The temperature of the reaction mixture went ~rom 25C. to 30C. A suspension forms and the reaction mixture is stirred at room temperature for 70 minute~ and the preoip1tate collected by filtration. The collected product is washed w~th chloroform, triturated in ether (500 ~1.), collected and drie~
to afford 79.8 g. (80.9~ yield) of 3-(3-carbome-thoxythio-ureido)-4-amino~enzophenone, m.p. 192C., dec.
Example B - 3-(Carboethox~thioureido)-4-aminobenzophenone !:
~ ~ ~To a solution of 7,4-diaminobenzophenone (4.24 g.;
;~ 0.02 mole) in ether~(600 m~ added carboethoxy i~othio-cyanate ~2.62 g.; 0.02 mole?. The su~pen~ion that Iorms is ~tirred at room temperature for 45 minute~ and the precipitate . - - .
collec-ted by :riltrat:ion to ar:Lord 3.1 g. (45~ yield) of 3-(carboethoxyth:ioureido)-~ am:inobenzophenone as a yellow powder, m.p. 200C., dec.
By substituting for the carboethoxy :isothiocyanate ~of Example B an equimolar quantity of carbo-n-propoxy isothio-cyana-te~ carboisopropoxy isothiocyanate, carbo-n-butoxy iso-thiocyanate and by followin~ substantially the procedure described therein, there is obtainsd 3-(carbo-n-propoxy)-4 aminobenzopllenone, 3-(carboisopropoxy)-4-aminoben~,o-J?llenone and 3-(carbo--n-butoxy)-!t-arni.noben~.oph(J~.~on!, respsctLvely.
.::
- 5~-
Claims (18)
1. A process for preparing the compound of the formula:
(I) wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cycloalkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, N-mononuclear aryl carbamoyl lower alkyl, phthalimido lower alkyl or phenoxycarbonylalkyl; R1 is lower alkyl; X is hydrogen, nitro, halo, lower alkanoyl, lower alkyl, thiocyanato, Y-S(O)?
wherein Y is lower alkyl, lower alkenyl, lower alkynyl, cyclo lower alkyl, , mononuclear aryl or carbo lower alkoxy and n is 0 to 3, X is also alkanoylamino, alkoxycarbonylamino; Y'C- wherein Y' is mononuclear aryl, or cyclo lower alkyl) or Y"O
wherein Y" is lower alkyl, mononuclear aryl, lower alkynyl, or mononuclear aralkyl, and when substituted the substituents on the Y, Y' and Y" are selected from halo, cyano, lower alkyl, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxy, halo-phenoxy, benzyloxy, trifluoromethyl or carbo lower alkoxy;
which comprises treating a compound of the formula:
wherein R1 and X are as defined above with a base followed by treatment with a compound of the formula: RX2 wherein is as defined above and X2 is halo or sulfonate;
and where desired, forming a nontoxic, pharmaceutically acceptable acid addition salt of said compound of formula I.
(I) wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cycloalkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, N-mononuclear aryl carbamoyl lower alkyl, phthalimido lower alkyl or phenoxycarbonylalkyl; R1 is lower alkyl; X is hydrogen, nitro, halo, lower alkanoyl, lower alkyl, thiocyanato, Y-S(O)?
wherein Y is lower alkyl, lower alkenyl, lower alkynyl, cyclo lower alkyl, , mononuclear aryl or carbo lower alkoxy and n is 0 to 3, X is also alkanoylamino, alkoxycarbonylamino; Y'C- wherein Y' is mononuclear aryl, or cyclo lower alkyl) or Y"O
wherein Y" is lower alkyl, mononuclear aryl, lower alkynyl, or mononuclear aralkyl, and when substituted the substituents on the Y, Y' and Y" are selected from halo, cyano, lower alkyl, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxy, halo-phenoxy, benzyloxy, trifluoromethyl or carbo lower alkoxy;
which comprises treating a compound of the formula:
wherein R1 and X are as defined above with a base followed by treatment with a compound of the formula: RX2 wherein is as defined above and X2 is halo or sulfonate;
and where desired, forming a nontoxic, pharmaceutically acceptable acid addition salt of said compound of formula I.
2. The process for preparing a compound of the formula, (Ia) wherein R3 is lower alkyl of from 1 to 4 carbon atoms; R2 is lower alkyl, lower alkenyl, lower alkynyl, 2,4-dichloro-benzyl, phenethyl, benzyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl, lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl and X1 is hydrogen, lower alkyl, alkoxycarbonylamino, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, phenylthio, phenyl-sulfinyl, phenylsulfonyl, lower alkanoyl or benzoyl which comprises treating the compound of the formula:
wherein X1 and R3 are as defined above, with a base, followed by treatment with a compound of the formula: R2X2 wherein R2 is as defined above and X2 is halo or sulfonate; and where desired, forming a nontoxic, pharmaceutically acceptable acid addition salt of said compound of formula Ia.
wherein X1 and R3 are as defined above, with a base, followed by treatment with a compound of the formula: R2X2 wherein R2 is as defined above and X2 is halo or sulfonate; and where desired, forming a nontoxic, pharmaceutically acceptable acid addition salt of said compound of formula Ia.
3. A process according to claim 2 wherein X1 is 5-benzoyl
4. The process for preparing 3-(3-carbomethoxy-S-methylisothioureido)-4-aminobenzophenone which comprises treating 3-(3-carbomethoxythioureido)-4-aminobenzophenone with a base and then with methyl iodide.
5. The process for preparing 2-(3-carbomethoxy-S-methylisothioureido)-5-propylthioaniline which comprises treating 2-(3-carbomethoxythioureido)-5-propylthioaniline with a base and then with methyl iodide.
6. The process for preparing 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylthianiline which comprises treating 2-(3-carbomethoxythioureido)-4-phenylthioaniline with a base and then with methyl iodide.
7. The process for preparing 2-(3-carbomethoxy-S-methyl-isothioureido)-4-phenylsulfinylaniline which comprises treating 2-(3-carbomethoxythioureido)-4-phenylsulfinylaniline with a base and then with methyl iodide.
8. The process for preparing 3-(3-carbomethoxy-S-hydroxypropylisothioureido)-4-aminobenzophenone which comprises treating 3-(3-carbomethoxythioureido)-4-aminobenzophenone with a base and then with 3-bromopropanol.
9. The process for preparing 3-(3-carbomethoxy-S-allylisothioureido)-4-aminobenzophenone which comprises treating 3-(3-carbomethoxythioureido)-4-aminobenzophenone with a base and then with allyl bromide.
10. A compound of the formula:
(I) wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cyclo-alkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, N-mononuclear aryl carba-moyl lower alkyl, phthalimido lower alkyl or phenoxycarbonyl-alkyl; R1 is lower alkyl or lower alkoxy lower alkyl; X is hydrogen, nitro, halo, lower alkanoyl, lower alkyl, thio-cyanato, Y-S(O)? wherein Y is lower alkyl, lower alkenyl, lower alkynyl, cyclo lower alkyl, or substituted or unsubstituted mononuclear aryl and n is 0 to 3, X is also alkoxycarbonylamino; Y'?- wherein Y' is mononuclear aryl, or cyclo lower alkyl or X is also Y"O wherein Y" is lower alkyl, mono-nuclear aryl, lower alkenyl, or mononuclear aralkyl . and, when substituted, the substituents on the Y, Y' or Y" are selected from halo, cyano, lower alkyl, sulfinyl, lower alkyl sulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxy, halophenoxy, benzyloxy, trifluoromethyl or carbo lower alkoxy; and the nontoxic, pharmaceutically acceptable acid addition salt and amides of said compound, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
(I) wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cyclo-alkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, N-mononuclear aryl carba-moyl lower alkyl, phthalimido lower alkyl or phenoxycarbonyl-alkyl; R1 is lower alkyl or lower alkoxy lower alkyl; X is hydrogen, nitro, halo, lower alkanoyl, lower alkyl, thio-cyanato, Y-S(O)? wherein Y is lower alkyl, lower alkenyl, lower alkynyl, cyclo lower alkyl, or substituted or unsubstituted mononuclear aryl and n is 0 to 3, X is also alkoxycarbonylamino; Y'?- wherein Y' is mononuclear aryl, or cyclo lower alkyl or X is also Y"O wherein Y" is lower alkyl, mono-nuclear aryl, lower alkenyl, or mononuclear aralkyl . and, when substituted, the substituents on the Y, Y' or Y" are selected from halo, cyano, lower alkyl, sulfinyl, lower alkyl sulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxy, halophenoxy, benzyloxy, trifluoromethyl or carbo lower alkoxy; and the nontoxic, pharmaceutically acceptable acid addition salt and amides of said compound, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
11. A compound of the formula:
(Ia) wherein R3 is lower alkyl of from 1 to 4 carbon atoms, R2 is lower alkyl, lower alkenyl, lower alkynyl, 2,6-dichloro-benzyl, phenethyl, benzyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl and X1 is hydrogen, lower alkyl, alkoxy-carbonylamino, lower alkoxy, lower alkylthio, lower alkyl-sulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, lower alkanoyl or benzoyl, and the nontoxic, pharmaceutically acceptable acid addition salts thereof, when prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
(Ia) wherein R3 is lower alkyl of from 1 to 4 carbon atoms, R2 is lower alkyl, lower alkenyl, lower alkynyl, 2,6-dichloro-benzyl, phenethyl, benzyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl and X1 is hydrogen, lower alkyl, alkoxy-carbonylamino, lower alkoxy, lower alkylthio, lower alkyl-sulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, lower alkanoyl or benzoyl, and the nontoxic, pharmaceutically acceptable acid addition salts thereof, when prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
12. The compound of claim 11 wherein X1 is 5-benzoyl, when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
13. The compound 3-(3-carbomethoxy-S-methylisothioureido) 4-aminobenzophenone, when prepared by the process of claim 4 or by an obvious chemical equivalent thereof.
14. The compound 2-(3-carbomethoxy-S-methylisothioureido)-5-propylthioaniline, when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
15. The compound 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylthioaniline, when prepared by the process of claim 6 or by an obvious chemical equivalent thereof.
16. The compound 2-(3-carbomethoxy-S-methylisothioureido)-4-phenylsulfinylaniline, when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
17. The compound 3-(3-carbomethoxy-S-hydroxypropyliso-thioureido)-4-aminobenzophenone, when prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
18. The compound 3-(3-carbomethoxy-S-allylisothioureido)-4-aminobenzophenone, when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68355476A | 1976-05-05 | 1976-05-05 | |
| US683,554 | 1976-05-05 | ||
| US78323477A | 1977-03-31 | 1977-03-31 | |
| US783,234 | 1977-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105038A true CA1105038A (en) | 1981-07-14 |
Family
ID=27103138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA277,661A Expired CA1105038A (en) | 1976-05-05 | 1977-05-04 | 2-amino-substituted isothioureidobenzene |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS537645A (en) |
| AR (1) | AR213309A1 (en) |
| AU (1) | AU2493077A (en) |
| BR (1) | BR7702864A (en) |
| CA (1) | CA1105038A (en) |
| CH (1) | CH621542A5 (en) |
| DE (1) | DE2720290A1 (en) |
| DK (1) | DK193177A (en) |
| FR (1) | FR2372154A1 (en) |
| GB (1) | GB1576633A (en) |
| IL (1) | IL52004A (en) |
| NL (1) | NL7704975A (en) |
| NZ (1) | NZ183993A (en) |
| SE (1) | SE7705156L (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4348406A (en) * | 1980-10-20 | 1982-09-07 | Schering Corporation | Novel guanidine derivatives |
| IT1177379B (en) * | 1984-12-11 | 1987-08-26 | Anic Spa | DERIVATIVES OF THE SUBSTANCE P AND ITS FRAGMENTS |
| JP5773975B2 (en) | 2012-12-26 | 2015-09-02 | 本田技研工業株式会社 | Exhaust pipe cover structure for saddle-ride type vehicles |
-
1977
- 1977-04-29 AR AR267417A patent/AR213309A1/en active
- 1977-05-02 GB GB18212/77A patent/GB1576633A/en not_active Expired
- 1977-05-03 NZ NZ183993A patent/NZ183993A/en unknown
- 1977-05-03 SE SE7705156A patent/SE7705156L/en unknown
- 1977-05-03 CH CH549577A patent/CH621542A5/en not_active IP Right Cessation
- 1977-05-03 DK DK193177A patent/DK193177A/en unknown
- 1977-05-04 CA CA277,661A patent/CA1105038A/en not_active Expired
- 1977-05-04 IL IL52004A patent/IL52004A/en unknown
- 1977-05-04 JP JP5166077A patent/JPS537645A/en active Pending
- 1977-05-04 BR BR7702864A patent/BR7702864A/en unknown
- 1977-05-05 AU AU24930/77A patent/AU2493077A/en not_active Expired
- 1977-05-05 FR FR7713728A patent/FR2372154A1/en active Granted
- 1977-05-05 DE DE19772720290 patent/DE2720290A1/en not_active Withdrawn
- 1977-05-05 NL NL7704975A patent/NL7704975A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NL7704975A (en) | 1977-11-08 |
| IL52004A (en) | 1981-05-20 |
| AR213309A1 (en) | 1979-01-15 |
| IL52004A0 (en) | 1977-07-31 |
| GB1576633A (en) | 1980-10-08 |
| CH621542A5 (en) | 1981-02-13 |
| NZ183993A (en) | 1979-11-01 |
| BR7702864A (en) | 1978-03-28 |
| DE2720290A1 (en) | 1977-11-17 |
| SE7705156L (en) | 1977-11-06 |
| JPS537645A (en) | 1978-01-24 |
| AU2493077A (en) | 1978-11-09 |
| FR2372154A1 (en) | 1978-06-23 |
| FR2372154B1 (en) | 1980-03-07 |
| DK193177A (en) | 1977-11-06 |
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