GB1576633A - 2-(3-carboxy - s - substituted - isothioureido)-anilines - Google Patents

2-(3-carboxy - s - substituted - isothioureido)-anilines Download PDF

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GB1576633A
GB1576633A GB18212/77A GB1821277A GB1576633A GB 1576633 A GB1576633 A GB 1576633A GB 18212/77 A GB18212/77 A GB 18212/77A GB 1821277 A GB1821277 A GB 1821277A GB 1576633 A GB1576633 A GB 1576633A
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carbomethoxy
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methylisothioureido
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Rohm and Haas Co
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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

Abstract

The compound of formula <IMAGE> in which R, R1, and X have the meanings shown in Claim 1, is obtained by treatment of a compound of formula <IMAGE> with a base, and then by carrying out a treatment with a compound having the formula RX<2> in which X<2> is a halo or sulfonate radical, or else, in the case where the desired product is an addition salt with an acid, by reacting a compound having the formula (I) with an acid. This compound has fungicidal properties which make it useful in agriculture.

Description

(54) 2-(3-CARBOXY-S-SUBSTITUTED ISOTHIOUREIDO)-ANILINES (71) We, ROHM AND HAAS COMPANY, a corporation organized under the laws of the State of Delaware, United States of America, of Independence Mall West, Philadelphia, Pennsylvania 19105, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention concerns novel 2 - (3 - carboxyl- S - substituted isothioureido).
British Pat. Specification No. 1,307,250; U.S. Pat. No. 3,958,008 and Netherlands Pat. Specification No. 7,401,797 disclose numerous thioureas, though none have a substituent on the sulfur, useful as anthelmintics. German Pat.
Specification No. 2,303,048 discloses 2 - acylated - amino - S - substituted isothioureidobenzenes as anthelmintics. However, there is no prior art disclosing compounds having both a free ortho amino substituent on the benzene ring and a substituted sulfur atom in the thioureido group. Other patents disclosing anthelmintic compounds include U.S. Pat. Nos. 3,865,948 and 4,005,217 and British Pat. Specification No. 1,350,277.
The novel 2 - amino - substituted - isothioureido - benzenes (1, infra) of this invention have the following formula:
wherein R is alkyl, for example. alkyl of from 1 to 19 carbon atoms (e.g. from 1 to 4, 6 or 8 carbon atoms) such as methyl, ethyl, n-propyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and nonadecyl; alkenyl, for example, alkenyl of up to 8 carbon atoms, e.g. C3-C8 alkenyl such as allyl, propenyl, 1methylpropenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl; alkynyl, for example, lower alkynyl of up to 8 carbon atoms such as propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl; polynuclear aralkyl such as naphthylmethyl, naphthylethyl and phenanthrylmethyl; mononuclear aralkyl, such as benzyl, phenethyl and phenylpropyl, optionally substituted in the aryl ring with from 1 to 3 substituents which may, for example, be selected from halo, nitro, alkyl and alkoxy, the latter two groups preferably having up to 4, 6 or 8 carbon atoms; mononuclear aryloxy(C,-C,)alkyl, for example, aryloxy(C3-C6)alkyl including phenoxypropyl, phenoxybutyl, phenoxypentyl and phenoxyhexyl; cycloalkylalkyl, for example, (C5-C6)cycloalkyl (C1-C8) (or C1-C4 or C6)alkyl such as cyclopentylmethyl, cyclopentylethyl, cyclophexylmethyl and cyclohexylethyl; cyano(C1-C3)alkyl, e.g. cyano(C3-C6)alkyl such as cyanopropyl, cyanobutyl, cyanopentyl and cyanohexyl; hydroxy(C,-C,)alkyl, e.g. hydroxy(C3-C8)alkyl such as hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyoctyl; aralkenyl, for example, poly- and mononuclear aralkenyl having up to 8 carbon atoms in the alkenyl portion, such as phenylpropenyl; alkoxyalkyl, for example (C,- C,)alkoxy(C,-C,)alky1, such as methoxypropyl, ethoxypropyl, methoxybutyl and propoxybutyl; alkoxycarbonylalkyl, for example alkoxycarbonyl alkyl preferably having up to 8 carbon atoms in each of the two alkoxy and alkyl moieties and more preferably having 3 to 6 carbon atoms in the alkyl moiety, such as methoxycarbonylpropyl, ethoxycarbonylbutyl, ethoxycarbonylpentyl and propoxycarbonylhexyl; carbamoyl(C1-C8)alkyl in which the N atom contains as a substituent a mononuclear aryl group itself optionally containing an alkanoylaminoarylthio substituent so as to form an R group such as N - [4 - (4 acetamidophenylthio)phenyl]carbamoylethyl; phthalimido(C,-C,)alkyl, preferably phthalimido(C3-C6)alkyl such as phthalimidobutyl; phenoxycarbonylalkyl, for example, phenoxycarbonyl(C,-C,)alkyl, preferably phenoxycarbonyl(C3-C6)alkyl such as phenoxycarbonylpropyl, phenoxycarbonylbutyl, phenoxycarbonylpentyl and phenoxycarbonylhexyl; R' is (C1-C6)alkyl such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tertbutyl, pentyl and hexyl or (C1-C6)alkoxy(C1-C6)alkyl such as methoxyethyl and X is (1) hydrogen; (2) nitro; (3) halo, such as chloro, bromo or fluoro; (4) (C2- C5)alkanoyl such as acetyl, propionyl butyryl and pentanoyl; (5) C1-C4 alkyl such as methyl, ethyl, propyl and n-butyl; (6) thiocyanato; (7) a radical of the formula: Y--S(O), wherein Y is (C1-C5)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, (C3- C7)cycloalkyl, a 5- or 6-membered heterocycle (e.g. pyridyl, thienyl, furyl, pyrimidinyl or thiazolyl) or substituted or unsubstitued mononuclear aryl or aralkyl such as phenyl or benzyl each optionally substituted with halo and n is 0 or an integer of 1 to 3; (8) alkoxycarbonylamino preferably having up to 4 carbon atoms in the alkoxy group, such as methoxycarbonylamino or isopropoxycarbonylamino; (9) a radical of the formula:
wherein Y' is mononuclear aryl such as phenyl, (C3-C7)cycloalkyl, a 5- or 6membered heterocycle (e.g. pyridyl, 2-thienyl or furyl) or (10) is a radical of the formula: Y"O-, wherein Y" is (C1-C5)alkyl, mononuclear aryl such as phenyl, (C3-C6)alkenyl, mononuclear aralkyl or a 5- or 6-membered heterocycle, with the proviso that the Y, Y' and Y" groups defined above can be substituted with one or more substituents which may be the same or different and which are selected from (a) halo. (b) cyano, (c) alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl and carboalkoxy, each of these groups listed under (c) containing no more than 8 carbon atoms, preferably not more that 6 carbon atoms and more preferably not more than 4 carbon atoms, (d) phenylthio, (e) phenylsulfinyl, (f) phenylsulfonyl, (g) phenoxy, (h) halophenoxy, (i) benzyloxy and (i) trifluoromethyl.
Also included within the invention are (I) pharmaceutically and/or agronomically acceptable acid addition salts of compounds of Formula I, e.g. acid addition salts such as those formed by reaction with acids such as hydrochloric, sulfuric, nitric, phosphoric, acetic, citric, benzoic or lactic and (II) amides wherein the -OR' group in Formula I is replaced with an amino or substituted amino group such as amino, mono- and di-(C,-C,)alkylamino.
The amides may be formed by the reaction of ammonia, amine or substituted amine with a compound of Formula I.
When compounds of Formula I can exist in various isomer and stereoisomer forms all such isomers and their mixtures and racemates are included within the scope of this present invention.
Preferred compounds concerned in this invention are of the formula:
wherein R3 is (C1-C4)alkyl, or R2 is (C1-C4)alkyl, (C3-C8)alkenyl, (C3- C8)alkynyl, benzyl, 2,6-dichlorobenzyl, phenethyl, (C5-C6)cycloalkyl(C1- C4)alkyl, phenoxy(C3-C6)alkyl, cyano(C3-C6)alkyl; alkoxycarbonylalkyl wherein the alkoxy moiety has from 1--5 carbon atoms and the alkyl moiety has from 3-6 carbon atoms; phthalimido(C3-C8)alkyl; phenyl(C3-C6)alkenyl or hydroxy(C3- C8)alkyl and Xis hydrogen, (C1-C4)alkyl, alkoxycarbonylamino having up to 4 carbon atoms in the alkoxy group, (C1-C5)alkoxy, (C1-C4)alkylthio (e.g. propylthio), (C,-C,)alkylsulfinyl (e.g. propylsulfinyl), (C,-C,)alkylsulfonyl (e.g. propylsulfonyl), phenylthio, phenylsulfinyl, phenylsulfonyl, (C2-C5)alkanoyl or benzoyl. These compounds exhibit particularly good anthelmintic and antifungal activity.
The 2 - amino - substituted - isothioureidobenzenes (1, supra) concerned in this invention and their salts and amides can be prepared by methods known per se for analogous compounds. However, it is preferred that the compounds of Formula I are prepared by treating the corresponding 2 - amino - substituted thioureidobenzene (II, infra) with a base, for example, an alkali metal or alkaline earth metal base such as sodium hydroxide, potassium hydroxide or calcium hydroxide, followed by treatment with an organic halide or sulfonate (RX2). The reaction may be conducted at a temperature in the range of from 0 C to 400C, (e.g. from 10 C. to 400C.) for a period of time from a few minutes to about one hour and the reaction with RX2 being conducted in the same temperature range for from a few minutes to about three days. Any solvent in which the reactants are reasonably soluble and substantially inert may be employed. Suitable solvents include dimethyl formamide (DMF) and acetone. The following equation illustrates this process:
wherein R, R' and X are as defined above and X2 is halo such as chloro, bromo or iodo or sulfonate.
The compounds of Formula II are either known compounds or may be prepared by known procedures as disclosed in British Pat. Specification Nos.
1,307,250 and 1,340,428 and in Netherlands Pat. Specification No. 7,401,497.
One procedure for preparing the compounds of Formula II comprises treating an aDDroDriately substituted 1 - amino (or 1 - nitro) - 2 - aminobenzene with a carboalkoxyisothiocyanate (IV, infra), and in the case of a l-nitro compound, treating said nitro compound with a reducing agent, to afford the desired compounds of Formula II. The following reaction scheme illustrates this process:
x 0 NH2 NH2 + S=C=NC-OR1 requir m9e NH2 0 NH2 or (N02) NHCNHCOR1 III IV II II S wherein R' and X are as defined above.
The diamines and nitroamines of Formula III (supra) are either known (see, for example, U.S. Pat. Nos. 3,657,267; 3,929,823* 3,929,824; 3,935,209; 3,993,768; 3,996,368; 3,996,369; 3,984,561 and 4,002,6403; French Pat. Specification No.
2,248,037 and German Pat. Specification No. 2,129,960) or may be prepared by the deacetylation by hydrolysis of compounds disclosed in French Pat. No.
Specification 2,270,861.
Compounds of Formula I wherein X=YS(O)n, n being other than zero, can be prepared by oxidizing the sulfur atom in the group YS- as is illustrated in Example 48 and 49 presented later.
Illustrative compounds of Formula I are: 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - cyanophenylthio)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (4 - methylthiophenylthio)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (3 - cyanophenylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3 - methylthiophenylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - acetylphenylthio)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (4 - methoxycarbonylphenylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (4 - cyanophenylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 4 - (4 - acetylphenyl- sulfinyl)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 4 - (4 - methylthiophenylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (4 - methoxycarbonylphenylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (4 - cyanophenylsulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (4 - acetylphenylsulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (4 - propionylphenylsulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (4 - methoxycarbonylphenylsulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - acetylphenylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - methoxycarbonylphenylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (propargylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (but - 3 - en - I ylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (but - 3 - en - I - yl sulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (but - 3 - en - I - yl sulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (benzylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (benzylsulfinyl)aniline 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (thiazol - 2ylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (thiazol - 2 - yl sulfinyl)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (pyrid - 2 ylthio)aniline; 2 - (3 - carbomethoxy S - butylisothioureido) - 5 - (pyrid - 2 ylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (pyrimidin - 2ylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (pyrimidin - 2ylsulfinyl)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 - chloropropylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3 - chloropopylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (3 - chloroprop - 2 en - ylthio)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (3 - chloroprop - 2 en - ylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (2 - cyanoethylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (2 - cyanoethyl- sulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (2 - benzyloxyethoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - [2 - (2' methoxyethoxy)ethoxy] aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (p - chlorophenoxyethoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (t - butoxyethylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (t butoxyethylsulfinyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (benzyloxyethylthio)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 (phenoxybutylthio)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (phenoxybutylsulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (2 phenylthioethylthio)aniline; 2 - (3 - carbomethoxy - S - benzylisothioureido) - 5 - [2 - (phenylsulfinyl)ethylthio] aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - [2 - (ethylsulfinyl) ethylthiojaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - [2 - (phenylthio)ethoxy] aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (cyclopropylcarbonyl)aniline; 2 - (3 - carbom thoxy - S - butylisothioureido) - 4 - (cyclopentylcarbonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (2 - thenoyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (phenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - chlorophenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (3 - chlorophenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3,5 - dichlorophenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (4 - methylphenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - benzylisothioureido) - 5 - (3 trifluoromethylphenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - methoxyphenylsulfonyloxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (phenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - chlorophenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (3 - chlorophenoxy- sulfonyl)aniline; 2 - (3 - carbomethoxy - S - benzylisothioureido) - 5 - (2 - chlorophenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (3,5 - dichlorophenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - methylphenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - isothioureido) - 5 - (4 - methoxyphenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (3 - cyanophenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3 trifluoromethylphenoxysulfonyl)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3 - chloropropoxy) aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (2 - phenylethoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3 - phenylprop - 2 en - I - yloxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (pyrid - 2 - yloxy) aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (thiazol - 2 yloxy)- aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (phenoxy)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (4 - methylphenoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (3 - methylphenoxy)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - (2 - methylphenoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 - chlorophenoxy) aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (3 - methylthiophenoxy)- aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - (3 - trifluoromethylphenoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (4 methoxyphenoxy)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - (2,3 - dichloro prop - 2 - en - I - ylthio)aniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - propionylaniline; 4 - (3 - carbomethoxy - S - propionylisothioureido)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 4 - butyrylaniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 4 - valerylaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - propoxyaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - ethoxyaniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 5 - n - butoxyaniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - isopropoxyaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - thiocyanatoaniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 5 - thiocyanatoaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - S - isopropoxycarbonylaminoaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - isopropoxycarbonylaminoaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - methoxycarbonylaminoaniline; 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (p - chlorobenzoyl)aniline; 2 - (3 - carbomethoxy - S - allylisothioureido) - 4 - (p - fluorobenzoyl)aniline; 2 - (3 - carbomethoxy - S - butylisothioureido) - 4 - p - toloyl)aniline; 2 - (3 - carbomethoxy - S - benzylisothioureido) - 4 - p - methoxybenzoyl)aniline; and 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - (3 - trifluoromethylbenzoyl)aniline.
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 exhibit high activity against various helmintic infections of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
For example, the compounds are generally effective in clearing mice of worm infections for laboratory purposes, among others: Syphada obvelata and Aspilcularis tetraptera (mouse pinworm), the migratory stages of Ascaris suum, Hymenolepsis nana and Hematospiroides dubius.
Compounds of Formula I have been demonstrated as efficacious against parasitic gastroenteritis in sheep such as Monieza spp, Haemonchus contortus, Ostertagia spp, Trichostrongylus spp, Nematodirus spp, Trichuris ovis, Cooperia spp, Capillaria spp and Strongyloides papillosus. Bunostomum trigonocephalum and Oesophagostomum spp, are other important parasites of sheep. The compounds are active against lung worms in ruminants especially Dictyocaulus filaria, in sheep and Dictyocaulus viviparas, in cattle. In addition, the compounds are effective against liver flukes (Fasciola hepatica) in sheep.
Animals of low weight are treated with unit doses ranging not higher than a few milligrams; whereas, animals of high body weight, such as ruminants, require proportionately larger unit doses ranging up to several grams. Preferably, a single dose is administered for each animal species based on the weight of that species.
The amount of ingredient administered will depend on the weight of the host, but will usually be a unit dosage between 1 or 5 mg./kg and 125 mg./kg. of body weight. It is contemplated that dosage units containing the compounds of Formula I as the essentially active ingredient will be administered, orally or by injection, in the treatment and control of helmintic infections in domestic animals such as sheep, cattle, horses, dogs, cats, fish, swine and goats.
The compounds of Formula I are of particular utility for controlling a helminth infection in a non-human host animal reared or tendered by humans usually on an industrial scale for commerical gain; for example, (a) animals for slaughter to provide food for humans (or their pets) or to provide other products for human use such as skins, fur and wool or (b) animals for commerical breeding purposes to provide animals for human use, e.g. for food production, sporting, showing or experimental use on behalf of humans or on behalf of animals raised or tended by humans for commercial gain.
Further, it has been found that the compounds of Formula I display broad spectrum antifungal activity. Therefore, such compounds of antifungal compositions containing them as an essential active ingredient will be employed on controlling the growth of fungi in or on animals and plants as well as in the paint, wood, textile, cosmetic, leather, tobacco, fur, rope, paper, pulp, plastic, fuel, rubber and food industries.
As an antifungal application, there may be singled out for mention a method of controlling fungi (i.e. preventing, arresting or reducing fungal attack) on seeds or plants capable of yielding or yielding a vendible agronomic crop which comprises applying to the seeds, plants or plant loci a fungicidally effective amount of one or more compounds of Formula I.
When used as an anthelmintic agent for the treatment and/or prevention of helminthiasis, the novel compounds of Formula I may be administered orally in a unit dosage form such as a paste, powder, gel, capsule, bolus, tablet or as a liquid Anthelmintic medicaments in unit dosage form contain a pharmaceutically acceptable carrier and are medicaments in the form of discrete portions each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active ingredients. Such portions may for example, be in monolithic coherent form, such as tablets, pills or dragees, or may be in wrapped or concealed form suitable for oral administration, e.g. soluble capsules.
The anthelmintic compounds may be administered orally by intimately dispersing them in an animal feedstuff or by using them as a top dressing in a feedstuff or in the form of pellets which are added to a finished feed. Alternatively, they may be administered to animals in a liquid carrier vehicle by intraruminal, intramuscular and intratracheal injection. The quantity of active material required to give best anthelmintic response will depend upon the particular compound employed, the species of animal to be treated and the type and severity of helminth infection. Good results are usually obtained when there is administered a total dose of from about I to about 125 mg. of active ingredient per kg. of animal body weight.
Such total dose may be given at one time or in divided doses over a short period of time such as I to 2 days.
When used as antifungal agents, the 2- amino - S - substituted isothioureidobenzenes (I supra) may be incorporated into diverse formulations such as solids, including finely divided powders (e.g. dusts or wettable powders) and granular materials, as well as liquids, such as solutions, emulsions, suspensions, concentrates, emulsifiable concentrates and slurries, depending upon the application intended and the formulation media desired. Formulations which are wettable powders, emulsions, emulsifiable concentrates or suspensions will usually contain a surface active agent. Thus it will be appreciated that the compounds of this invention may be employed to form fungicidally active compositions containing a fungicidally active quantity of such compounds as an essential active ingredient. Such compositions may also contain finely divided dry or liquid diluents, extenders, fillers, conditions and excipients including various clays, diatomaceous earth or talc, or water and various organic liquids, for example, lower alkanols such as ethanol and isopropanol, or kerosene, benzene, toluene and other petroleum distillate fractions or mixtures thereof. Ready-for-use formulations will usually contain from about 50 to 800 parts per million of active ingredient and preferably from about 200 to 500 parts per million. It will be understood of course that any ingredient in formulations such as a carrier or diluent will be acceptable pharmaceutically or, as the case may be, agronomically acceptable particularly to plants yielding a vendible agronomic crop.
The following Examples illustrate the compounds concerned in this invention and the methods by which they are prepared. However, the Examples are illustrative only and it will be apparent to those having ordinary skill in the art that all of the products embraced by Formula I, supra, may also be prepared in an analogous manner by substituting the appropriate starting materials for those set forth in the Examples.
Example 1 3 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - aminobenzophenone 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 solution (500/n aqueous; 0.8 g.; 0.01 mole) is added and the solution 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. (82.80/n yield) of 3 - (3 - carbomethoxy - S - methyl isothioureido) - 4 - aminobenzophenone, m.p. mole) and the resulting solution stirred at room temperature for 1.5 hours. Allyl bromide (2.42 g.; 0.02 mole) is then added. The reaction mixture is stirred at room temperature for 18 hours and then poured into water (500 ml.). The precipitate is collected by vacuum filtration and the filter cake is washed with ether and then dried to afford 5 g. (690/n yield) of 3 - (3 - carbomethoxy - S - allylisothioureido) 4 - aminobenzophenone, m.p. 1280--1310C. 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 100C., is added 5 ml. of water (exotherm to 200 C.). The solution is cooled to 100C. and potassium hydroxide pellets (0.65 g.; 0.01 mole) added. After 15 minutes of stirring at 100C. a solution forms and to it is added benzyl bromide (3.42 g.; 0.02 mole). The solution is allowed to warm to room temperature and after 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. 1750C. 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 Example 4 3 - (3 - Carboethoxy - S - methylisothioureido) - 4 - aminobenzophenone To a turbid solution of 3 - (3 - carboethoxythioureido) - 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 (15 ml.) is added and the reaction mixture 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 - carboethoxy - S - methylisothioureido) - 4 aminobenzophenone, m.p. 1440--1460C. dec.
Elemental Analysis for C1sH 19N3O3S 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 (500/, aqueous; 0.8 g.; 0.01 mole). The solution is stirred at room temperature for 1.5 hours. Butyl iodide (1.84 g.; 0.01 mole) is added and the reaction mixture is stirred at room temperature for 18 hours. The solution is poured into water (300 ml.) and the precipitate is collected by vacuum filtration. The filter cake is washed with ether and dried to afford 2.5 g. (65% yield) of 3 - (3 carbomethoxy - S - n - butylisothioureido) - 4 - aminobenzophenone, m.p.
132"C. dec.
Elemental Analysis for C30H23N3O3S Calc.: C, 62.31; H, 6.01; N, 10.90 Found: C, 61.81; H, 5.97; N, 10.90 Example 6 3 - (3 - Carbomethoxy - S - ethylisothioureido) - 4 - aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 4 - aminobenzophenone (3.29 g.; 0.01 mole) in DMF (25 ml.) is added water (10 ml.) (exothermic reaction).
The solution is cooled to room temperature and a sodium hydroxide solution (50% aqueous; O.S 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 filtration. 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--1560C. dec.
Elemental Analysis for C1sH1sN3O3S (M.W. 357, 416) Calc.: C, 60.48; H, 5.36; N, 11.76 Found: C, 60.38; H, 5.44; N, 11.75 Example 7 3 - (3 - Carbomethoxy - S - cyclohexylmethylisothioureido) - 4 aminobenzophenone 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.
Cyclohexylmethyl 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 carbomethoxy - S - cyclohexylmethylisothioureido) - 4 - aminobenzophenone, m.p. 155--1580C. dec.
Elemental Analysis for C23H27N3O3S Calc.: C, 64.91; H, 6.40; N, 9.87 Found: C, 65.27; H, 6.80; N, 9.96 Example 8 3 - (3 - Carbomethoxy - S - cyanobutylisothioureido) - 4 - aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 4 - aminobenzophenone (6.5 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 g., 0.02 mole) is added. The solution is stirred at room temperature for 1.5 hours and then 5-bromovaleronitrile (3.24 g.; 0.02 mole) is added. The solution is stirred at room temperature 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, 155 160"C. dec.
Example 9 3 - (3 - Carbomethoxy - S - ethoxycarbonylpropylisothioureido) - 4 aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 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 for four days then poured into an excess of water. The semi-solid tarry precipitate is collected and triturated with 5 milliliters of ether. The solid is collected, washed with ether and dried to afford 2.7 g. (62 /" yield) of 3 - (3 - carbomethoxy - S ethoxycarbonylpropylisothioureido) - 4 - aminobenzophenone, m.p. 1l9-l200C. dec.
Example 10 3 - (3 - Carbomethoxy - S - phthalimidobutylisothioureido) - 4 aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 4 - aminobenzophenone (3.29 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 /n yield) of 3 - (3 carbomethoxy - S - phthalimidobutylisothioureido) - 4 - aminobenzophenone, m.p. 1540--1570C. dec.
Example 11 3 - (3 - Carbomethoxy - S - propargylisothioureido) - 4 - aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 4 - aminobenzophenone (6.58 g.; 0.02 ml.) in DMF (50 ml.) is added water (IS ml.). The solution is 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 afford 5.1 g. (69% yield) of 3 - (3 - carbomethoxy - S propargylisothioureido) - 4 - aminobenzophenone, m.p. 1700C. dec.
Example 12 3 - (3 - Carbomethoxy - S - hydroxypropylisothioureido - 4 aminobenzophenone 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 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 water. After stirring at room temperature for five days, the precipitate is collected by filtration, washed with water and dried to afford 4.65 gms. (60 /n yield) of 3 - (3 - carbomethoxy - S hydroxypropylisothioureido) - 4 - aminobenzophenone, m.p. 1240C. dec.
Example 13 3 - (3 - Carbomethoxy - S - but - 3 - enylisothioureido) - 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 - 1 - 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 of water. The resulting mixture is stirred at room temperature for three days and the white precipitate collected by filtration, washed with water and then dried to afford 6.3 gms, (82% yield) of 3 - (3 - carbomethoxy - S - but - 3 - enylisothioureido) - 4 aminobenzophenone, m.p. 1220C. dec.
Example 14 3 - (3 - Carbomethoxy - S - phenethylisothioureido) - 4 - aminobenzophenone 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 is collected by filtration and dried to afford 3.7 gms. of 3 - (3 - carbomethoxy - S phenethylisothioureido) - 4 - aminobenzophenone, m.p. 1 190C. dec.
Example 15 3 - (3 - Carbomethoxy - S - cinnamylisothioureido) - 4 - aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 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 hours, poured into 250 milliliters of water and stirred for an additional 18 hours at room temperature. The precipitate is collected by filtration, washed with water and dried to afford 4.0 gms. of 3 - (3 carbomethoxy - S - cinnamylisothioureido) - 4- aminobenzophenone, m.p.
110 C. dec.
Example 16 3 - [Carbomethoxy - S - (3 - methylbutyl)isothioureido] - 4 aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 4 - aminobenzophenone (6.58 gms.; 0.02 mole) in DMF (50 ml.) is added water (15 ml.). The solution is cooled to room temperature and sodium hydroxide (50% aqueous; 1.6 gms.; 0.02 mole) is added and the solution stirred for one hour. I-Bromo-3-methylbutane (3.02 gms.; 0.02 mole) is added and the solution stirred for one hour at room temperature. 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 - methylbutyl)isothioureido] - 4 - aminobenzophenone, m.p. 1420--1440C.
Example 17 3 - [3 - Carbomethoxy - S - (2,6 - dichlorobenzyl) - isothioureido] - 4 aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 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, ct - Bromo - 2,6 - dichlorotoluene (2.4 gms.; 0.01 mole) is added and the solution stirred at room temperature for 48 hours and then poured into 200 milliliters of water. The precipitate is collected and dried to afford 4.5 gms. of 3 [3 - carbomethoxy - S - (2,6 - dichlorobenzyl)isothioureido] - 4 aminobenzophenone, m.p. 800--1000C. dec.
Example 18 3 - (3 - Carbobutoxy - S - methylisothioureido) - 4 - aminobenzophenone To a solution 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 (1.42 g.; 0.01 mole) is then added and the reaction mixture stirred at room temperature for 18 hours and then poured into water (300 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. 1020C. dec.
Example 19 3 - (3 - Carbomethoxy - S - phenoxypropylisothioureido) - 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 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 precipitate 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. 620--80"C.
Example 20 Improved Preparation of 3 - (3 - Carbomethoxy - S - methylisothioureido) - 4 aminobenzophenone To a suspension fo 3 - (3 - carbomethoxythioureido) - 4 aminobenzophenone (6.58 g.; 0.02 mole) in acetone (30 ml.) and water (10 ml.) is added sodium hydroxide (50in 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. 1630-1640C.
Example 21 3 - (3 - Carbopropoxy - S - methylisothioureido) - 4 - aminobenzophenone To a suspension of 3 - (3 - carbopropoxythioureido) - 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 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 /" yield) of 3 - (3 - carbopropoxy - S - methylisothioureido) - 4 aminobenzophenone, m.p. 1280--1300C, dec.
Example 22 3 - (3 - Carboisopropoxy - S - methylisothioureido) - 4 - aminobenzophenone To a suspension of 3 - (3 - carboisopropoxythioureido) - 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 temperature 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 by filtration, washed with water and dried to afford 1.1 g. (59 /" yield) of 3 - (3 carboisopropoxy - S - methylisothioureido) - 4 - aminobenzophenone, m.p.
1390-l420C 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 for 18 hours and is vacuum filtered through Celite (Celite is a Registered Trade Mark). The filtrate is concentrated in vacuo to afford crude carbophenethoxy isothiocyanate.
Step 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.; 0.01 mole). 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 - methylisothioureido) - 4 aminobenzophenone To a mixture of 3 - (3 - carbophenethoxythioureido) - 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 afford 3 - (3 - carbophenethoxy - S - methylisothioureido) - 4aminobenzophenone.
Example 24 3 - (3 - Carbomethoxy - S - (2 - naphthyl)methylisothioureido) - 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 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 - (bromomethyl)naphthalene (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 filtered and the filter cake is dried to afford 3 - (3 - carbomethoxy - S - methyl - naphthylisothioureido) - 4 aminobenzophenone.
Example 25 3 - (3 - Carbomethoxy - S - 4 - methoxybutylisothioureido) - 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 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 4-methoxybutyl bromide (1.67 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 filtered and the filter cake dried to afford 3 - (3 - carbomethoxy - S - methoxybutylisothioureido) - 4 aminobenzophenone.
Example 26 3 - (3 - Carbomethoxy - S - 3 - carbophenoxypropylisothioureido) - 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 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 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 I-Amino- - Amino - 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - propylsulfonylbenzene Step A-l - Amino - 2 - (3 - carbomethoxythioureido) - 4 propylsulfonylbenzene To a mixture of l,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 for four hours and is vacuum filtered.
The filter cake is dried to afford I - amino - 2 - (3 - carbomethoxythiouredio) 4 - propyl - sulfonylbenzene.
Step B-I - Amino - 2 - (3 - carbomethoxy - S - methyl - isothioureido - 4 propylsulfonylbenzene To a mixture of 1 - amino - 2 - (3 - carbomethoxythioureido) - 4 propylsulfonylbenzene (3.33 g.; 0.01 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 (0.8 g.; 0.01 mole; 50% aqueous). The mixture is stirred at room temperature for one hour and to it is added methyl iodide (1.42 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 filtered and the filter cake dried to afford I - amino - 2 - (3 - carbomethoxy - S - methylisothioureido - 4propylsulfonylbenzene.
Example 28 3 - (3 - Carbohexoxy - S - methylisothioureido) - 4 - aminobenzophenone Step A-Carbohexoxy isothiocyanate 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 18 hours and is vacuum filtered through Celite. The filtrate is concentrated in vacuo to afford carbohexoxy isothiocyanate.
Step B-3 - (3 - Carbohexoxythioureido) - 4 - aminobenzophenone To a solution of 3,4-diaminobenzophenone (2.12 g.; 0.01 mole) in ether (200 ml.) is added carbohexoxy isothiocyanate (1.87 g.; 0.01 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 - methylisothioureido) - 4 aminobenzophenone 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 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 one hour and methyl iodide (0.71 g.; 0.005 mole) is added. The mixture is 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 ethyl 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. 2290C. dec.
Step B-2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - nitroaniline To a solution of 2 - (3 - carbomethyoxythioureido) - 4 - nitroaniline (2.0 g.; 0.0074 mole) in DMF (20 ml.) is added water (4 ml.). The solution becomes warm and is cooled to room temperature. A sodium hydroxide solution (0.59 g.; 0.0074 mole; 50% aqueous) is added and the solution stirred at room temperature for 45 minutes. Methyl iodide (1.05 g.; 0.0074 mole) is added and 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. 1690--1710C., 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 carbomethoxy isothiocyanate (2.93 g.; 0.025 mole). A suspension forms immediately. The reaction mixture is stirred at OOC. for five minutes and the precipitate is collected by filtration. The product is washed with ether and dried to afford 2 - (3 - carbomethoxythioureido) - aniline (4.25 g.), m.p. 1900--191oC., dec.
Step B-2 - (3 - Carbomethoxy - S - methylisothioureido)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 reaction occurs and the solution is then cooled to room temperature. A sodium hydroxide solution (0.8 g.; 0.01 mole; 50% aqueous) is added and the reaction mixture is stirred at room temperature for one hour. Methyl 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 collected by filtration and then dried to afford 2 - (3 carbomethoxy - S - methylisothioureido)aniline (1.6 g.).
Example 31 2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - phenylsulfonylaniline Step A-2 - (3 - Carbomethoxythioureido) - 4 - phenylsulfonylaniline To a solution of 2 - amino - 4 - phenylsulfonylaniline (4.96 g.; 0.02 mole) in ether (200 ml.) and chloroform (150 ml.) is added carbomethoxy isothiocyanate (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 - carbomethoxy thioureido) - 4 - phenylsulfonylaniline (2.65 g.), m.p. 1970C, dec.
Elemental Analysis for C,5H,5N304S3 Calc.: C, 49.30; H, 4.14; N, 11.50 Found: C, 49.03; H, 4.21; N, 11.05 Step B-2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 phenylsulfon by filtration, washed with ether and dried to afford 0.35 g. of 3 - (2 carbomethoxythioureido) - 4 - aminoacetophenone, m.p. 2000C. dec.
Step B-3 - (3 - Carbomethoxy - S - methylisothioureido) - 4 aminoacetophenone 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) is added and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture is poured into 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. 1650--1670C., dec.
Example 33 3 - (3 - Carbomethoxy - S - nonadecylisothioureido) - 4 - aminobenzophenone To a suspension of 3 - (3 - carbomethoxythioureido) - 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-iodononadecane (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 1.05 g. of 3 - (3 - carbomethoxy - S nonadecylisothioureido) - 4 - aminobenzophenone, m.p. 760--800C., dec.
Example 34 3 - [3 - Carbo - (2 - methoxyethoxy)- S - methylisothioureido] - 4 aminobenzophenone Step A-2-Methoxyethyl chloroformate To an ice cooled solution of phosgene (87 g.; 0.11 mole; 12.5% in benzene) in benzene (25 ml.) is added methyl Cellosolve (7.6 g.; 0.1 mole) in benzene (50 ml.).
(Note: Cellosolve is a Registered Trade Mark). The solution is stirred at 5"C. for 2 hours and at room temperature for 18 hours. The solution is concentrated under vacuum to afford 15.1 g. of 2-methoxyethylchloroformate as a colorless oil.
Step B-Carbo - (2 - methoxy)ethoxyisothiocyanate To a suspension of potassium thiocyanate (9.7 g.; 0.1 mole) in ethyl acetate (150 ml.) is added 2-methoxyethyl chloroformate in ethyl acetate (25 ml.). The mixture is stirred at room temperature for one hour, refluxed for 1-1/2 hours and stirred at room temperature overnight. The mixture is filtered through Celite and the filtrate concentrated under vacuum at room temperature to afford 15 g. of carbo - (2 - methoxy)ethoxyisothiocyanate as an orange liquid.
Step C-3 - [3 - Carbo - (2 - methoxy)ethoxythioureido) - 4 aminobenzophenone To a solution of 3,4-diaminobenzophenone (4.24 g.; 0.02 mole) in ether (500 ml.) is added carbo - (2 - methoxy)ethoxy isothiocyanate (3.22 g.; 0.02 mole). The solution is stirred for one hour and the precipitate formed is collected by filtration and dried to afford 2.85 g. of 3 - [3 - carbo - (2 - methoxy)ethoxythioureido] - 4 aminobenzophenone, m.p. 1470--1510C. (dec.).
Elemental Analysis for C18Ht9N3O4S Calc.: C, 57.86; H, 5.13; N, 11.29 Found: C, 57.89; H, 5.82; N, 10.77 Step D-3 - [3 - Carbo - (2 - methoxy)ethoxy - S - methyl - isothioureido] - 4 aminobenzophenone To a solution of 3 - [3 - carbo - (2 - methoxy) - ethoxythioureido] - 4 aminobenzophenone (1.87 g.; 0.005 mole) in dimethyl formamide(l5 ml.) is added water (3 ml.). To this solution is added aqueous sodium hydroxide (50 /n 0.4 g.) and the solution stirred at room temperature for I 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 precipitate collected by filtration, washed with water and dried to afford 1.1 g. of 3 - [3 - carbo - (2 methoxy)ethoxy - S - methylisothioureidol - 4 - aminobenzophenone.
Elemental analysis for C19H2,N304S Calc.: C, 58.90; H, 5.46; N, 10.85 Found: C, 58.31; H, 5.34; N, 11.05 Example 35 3 - Amino - 4 - (3 - carbomethoxy - S - methylisothioureido) - benzophenone Step A-3 - Nitro - 4 -(3 - carbomethoxythioureido) - benzophenone A mixture of 3 - nitro - 4 - aminobenzophenone (9.9 g; 0.041 mole), carbomethoxyisothiocyanate (4.8 g.; 0.041 mole) in acetonitrile (25 ml.) is stirred and refluxed for 17 hours. The reaction mixture is cooled and the precipitate collected by filtration, washed with acetonitrile and dried to afford 8.7 g. of 3 nitro - 4 - (3 - carbomethoxythioureido) - benzophenone, m.p. 1780--1830C.
(dec.).
Step B-3 - Amino - 4 - (3 - carbomethoxythioureido) - benzophenone A mixture of 3 - nitro - 4 - (3 - carbomethoxy - thioureido)benzophenone (3.6 g.; 0.01 mole), stannous chloride (11.3 g.; 0.05 mole), concentrated hydrochloric acid (20 ml.), methanol (40 ml.) and acetic acid (40 ml.) is heated with stirring to reflux. After 10 minutes, most of the solid is dissolved. The reaction mixture is refluxed for a total of 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. 1870C. (dec.).
Step C-3 - Amino - 4 - (3 - carbomethoxy - S - methyl isothioureido)benzophenone To a stirred slurry of 3 - amino - 4 - (3 carbomethoxythioureido)benzophenone (2.5 g.; 0.0076 mole) in dimethyl formamide (20 ml.) is added a 50% sodium hydroxide solution (0.61 g.; 0.0076 mole) in deionized water (10 ml.). The clear red-orange solution which forms is cooled to 4"C. and then methyl iodide (1.1 g.; 0.0076 mole) is added. The temperature rises to 7"C. (pH 7.8). After 3 minutes, the reaction mixture is added to deionized water (200 ml.) with stirring. The precipitate is collected to afford 1.8 g. of 3 - amino - 4 (3 - carbomethoxy - S - methyl - isothioureido)benzophenone.
Elemental analysis for C,7H,7N303S Calc.: C, 59.45; H, 5.00; N, 12.24; S, 9.34 Found: C, 59.48; H, 5.11; N, 12.59; S, 8.90 Example 36 3 - [3 - Carbomethoxy - S - (2 - nitro)benzylisothioureido] - 4 aminobenzophenone To a solution of 3 - (3 - carbomethoxythioureido) - 4 - aminobenzophenone (3.29 g; 0.01 mole) in dimethyl formamide (25 ml) is added water (7 ml.). The solution is cooled to room temperature and then an aqueous solution of sodium hydroxide (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. The solution is stirred 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 collected by filtration and dried to afford 4.25 g. of 3 - [3 carbomethoxy - S - (2 - nitro)benzylisothioureido] - 4 - aminobenzophenone, m.p. 750-850C. (dec.).
Elemental analysis for C23H20N4O5S Calc.: C, 59.47; H, 4.34; N, 12.06 Found: C, 57.91; H, 4.20; N, 12.98 Example 37 3 - [3 - Carbomethoxy - S - (p - nitro)benzylisothioureido] - 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 1 hour and p-nitrobenzyl bromide (2.11 g; 0.01 mole) in DMF (20 ml.) is added. The solution is stirred at room temperature for 24 hours and then poured into water (300 ml.). The suspension formed is stirred at room temperature for 18 hours and the precipitate collected by filtration and dried to afford 4.25 g. of 3 - [3 - carbomethoxy - S (p - nitro)benzylisothioureido] - 4 - aminobenzophenone, l000-l050C. (dec.).
Elemental analysis for C23H20N4OsS Calc.: C, 59.47; H, 4.34; N, 12.06 Found: C, 57.91; H, 4.29; N, 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, In- methylbenzyl bromide, p-chlorobenzyl chloride, crotyl chloride and 3-chloro-2methylpropene and by following substantially the procedure described therein, there is obtained, respectively, the following compounds: m.p. Elemental analysis Ex.No. Title 38 3-[@-Carbomethoxy-S-(4-methyl) C24H23N3O3S benzylisothioureido]-4-amino- 157 -159 C.
Calc.: C, 66.49; H, 5.35; N, 9.69 benzophenone Found: C, 65.93; H, 5.42; N, 10.09 39 3-[3-Carbomethoxy-S-(3-methyl) C24H23N3O3S benzylisothioureido]-4-amino- 143 -145 C.
Calc.: C, 66.49; H, 5.35; N, 9.69 benzophenone Found: C, 65,85; H, 5.33; N, 9.89 40 3-[3-Carbomethoxy-S-(p-chloro) C23H20ClN3O3S benzylisothioureido]-4-amino- 153 -155 C.
Calc.: C, 60.85; H, 4.44; N, 9.26 benzophenone Found: C, 61.04; H, 4.43; N, 9.40 41 3-[3-Carbomethoxy-S-(buten-2-yl) C20H21N3O3S 156 -157 C. isothioureido]-4-aminobenzophenone Calc.: C, 62.64; H, 5.52; N, 10.96 Found: C, 63.24; H, 5.49; N, 12.11 42 3-[3-Carbomethoxy-S-(2-methyl) C20H21N3O3s propen-2-yl)isothioureido]-4110 -112 C. aminobenzophenone Calc.: C, 62.64; H, 5.52; N, 10.96 Found: C, 61.78; H, 5.35; N, 11.65 Example 43 3 - (3 - Carbomethoxy - S - 2 - [4 - (4 - acetamidophenylthio) phenylcarbamyllethylisothioureido - 4 - aminobenzophenone Step A4 - (3 - Bromopropionamido) - 4' - nitrodiphenylsulfide To a suspension of 4 - amino - 4' - nitrodiphenylsulfide (7.4 g.; 0.03 mole) in toluene (200 ml.) is added 3-bromopropionyl chloride (5.14 g.; 0.03 mole). The mixture is refluxed and stirred for 3 hours and then stirred overnight at room temperature. The precipitate is collected by filtration, washed with hexane and dried to afford 10.1 g. of 4 - (3 - bromopropionamido) - 4' - nitrodiphenylsulfide, m.p. 1360--1380C. (dec.).
Step B-4 - (3 - Bromopropionamido) - 4' - aminodiphenylsulfide To a suspension of 4 - (3 - bromopropionamido) - 4' - nitrodiphenylsulfide (4 g.; 0.0105 mole) in ethanol (250 ml.) is added palladium on carbon (5%; 0.2 g.). The mixture is shaken on a Parr hydrogenator for 5 hours and left standing at room temperature overnight. No hydrogen uptake. The mixture is flushed with nitrogen and Raney nickel (I g.) is added. The mixture is shaken on a Parr hydrogenator (initial pressure 50 psi) for 5 hours. After 5 hours, there is 1 pound of hydrogen uptake. The reaction mixture is kept under pressure for 18 hours at which time there is a total hydrogen uptake of 2 pounds. The mixture is filtered and the filtrate concentrated under vacuum to afford 2.7 g. of 4 - (3 - bromopropionamido) - 4' aminodiphenylsulfide, m.p. 1410--1480C. (dec.).
Step C - (3 - Bromopropionamido) - 4' - acetamido - diphenylsulfide To a suspension of 4 - (3 - bromopropionamido) - 4' - aminodiphenylsulfide (2 g.; 0.0057 mole) in toluene (150 ml.) is added acetic anhydride (0.58 g.; 0.0057 mole). The suspension is refluxed and stirred for 3 hours and allowed to stand at room temperature overnight. The precipitate formed was collected by filtration, washed with hexane and dried to afford 1.4 g. of 4 - (3 - bromopropionamido) 4' - acetamidodiphenyl sulfide, 1890-1930C. (dec.).
Elemental analysis for C17H17BrN2O2S Calc.: C, 51.97; H, 4.36; N, 7.12 Found: C, 52.70; H, 4.50; N, 7.43 Step D-3 - (3 - Carbomethoxy)- S - 2- [4 - (4 - acetamidophenylthio) phenylcarbamyl]ethylisothioureido - 4 - aminobenzophenone To a solution of 3 - (3 - carbomethoxy - thioureido) - 4 aminobenzophenone (0.84 g.; 0.00254 mole) in DMF (10 ml.) and water (2 ml.) there is added an aqueous solution of sodium hydroxide (0.2 g.). The solution is stirred at room temperature for one hour and 4 - (3 - bromo - propionamido) 4' - acetamidodiphenylsulfide (I g.) and DMF (5 ml.) is added. The solution is stirred at room temperature for 18 hours and the solution poured into water (300 ml.). This was stirred for 30 minutes and the precipitate collected by filtration and dried to afford 1.45 g. of 3 - [3 - carbomethoxy - S - 2 - [4- (4 acetoamidophenylthio)phenylcarbamyliethyl - isothioureido - 4 aminobenzophenone, m.p. 120 C. with dec. at 1620---1660C.
Elemental analysis for C33H31NsO5S2 Calc.: C, 61.76; H, 4.87; N, 10.91 Found: C, 61.14; H, 4.91; N, 11.57 Example 44 2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - phenoxysulfonylaniline Step A-2 - (3 - Carbomethoxythioureido) - 4 - phenoxysulfonylaniline To a solution of 2 - amino - 5 - phenoxy - sulfonylaniline (5.28 g.; 0.02 mole) in ether (350 ml.) is added carbomethoxyisothiocyanate (2.34 g.; 0.02 mole). The solution is stirred at room temperature for I hour and the precipitate which forms is collected by filtration, washed with ether and dried to afford 5.65 g. of 2 - (3 carbomethoxy - thioureido) - 4 - phenoxysulfonylaniline, m.p. 1850--1860C.
(dec.).
Elemental analysis for C15H15N3O5S3 Calc.: C, 47.23; H, 3.96; N, 11.02 Found: C, 47.83; H, 4.13; N, 10.66 Step B-2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 phenoxysulfonylaniline To a solution of 2 - (3 carbomethoxythioureido) - 4 phenoxysulfonylaniline (4.0 g; 0.0105 mole) in DMF (25 ml.) and water (5 ml.) there is added an aqueous solution of sodium hydroxide (50%, 0.84 g.). The solution is stirred at room temperature for 1 hour and then methyl iodide (1.49 g.) is added.
The solution is stirred at room temperature for + hour, poured into water (500 ml.) and the precipitate which forms is collected by filtration and dried to afford 3.4 g. of 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 - phenoxysulfonylaniline, m.p. 1080--113"C.
Elemental analysis for C16H17N3OsS2 Calc.: C, 48.59; H, 4.33; N, 10.63; N, 16.22 Found: C, 48.20; H, 4.41; N, 10.74; N, 15.89 Example 45 2 - (3 - Carbomethoxy - S - methylisothioureido) - 5 - butylaniline Step A-2 - (3 - Carbomethoxythioureido) - 5 - n - butylaniline To a solution of 4 - n - butyl - o - phenylenediamine (5.0 g.; 0.0305 mole) in ether (250 ml.) is added carbomethoxy isothiocyanate (3.57 g.; 0.0305 mole). The solution is stirred at room temperature for 2 hours (a very fine precipitate begins to form). The mixture is stirred at 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. 1620--1650C. (dec.).
Step B-2 - (3 - Carbomethoxy - S - methylisothioureido) - 5 - butylaniline To a solution of 2 - (3 - carbomethoxythioureido) - 5 - n - butylaniline (1 g.; 0.00355 mole) in DMF (15 ml.) is added water (5 ml.). The solution is cooled to room temperature and aqueous sodium hydroxide (50%; 0.284 mole) is added. The solution is stirred at room temperature for 1 hour and then methyl iodide (0.505 g.) is added. The solution is stirred at room temperature-for 10 minutes and then poured into water (200 ml.). The suspension is stirred at room temperature for 10 minutes and the precipitate is collected by filtration and dried to afford 0.8 g. of 2 (3 - carbomethoxy - S - methylisothioureido) - 5 - butylaniline.
Elemental analysis for C,4H2,N302S Calc.: C, 56.92; H, 7.17; N, 14.22; S, 10.86 Found: C, 57.15; H, 7.11; N, 14.47; S, 10.48 By substituting for the 4 - n - butyl - o - phenylenediamine of Step A of Example 45, 3,4-diaminopropylthiobenzene and by following substantially the procedure described therein, there is obtained 2 - (3 - carbomethoxythioureido) 5 - propyl - thioaniline, m.p. 1670--1680C. (dec.), which product when treated with methyl iodide in the manner of Step B of Example 45, affords 2 - (3 carbomethoxy - S - methylisothioureido) - 5 - propylthioaniline.
Elemental analysis for C13H19N3O2S2 Calc.: C, 49.81; H, 6.12; N, 13.41; S, 20.45 Found: C, 49.17; H, 6.02; N, 13.53; S, 20.58 Example 46 2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - propylthioaniline Step A-2 - (3 - Carbomethoxythioureido) - 4 - propyl - thionitrobenzene A mixture of 2 - nitro - 5 - propylthioaniline (5.4 g.; 0.026 mole), carbomethoxy isothiocyanate (3.1 g.; 0.026 mole) and acetonitrile (10 ml.) is stirred and refluxed for 1 hour. The reaction mixture is cooled, ether is added and the mixture filtered to afford 6.3 g. of 2 - (3 - carbomethoxy - thioureido) - 4 propylthionitrobenzene, m.p. 1230--1250C.
Step B-2 - (3 - Carbomethoxythioureido) - 4 - propyl - thioaniline A mixture of 2 - (3 - carbomethoxythioureido) - 4 - propylthionitrobenzene (8.8 g.; 0.027 mole), stannous chloride (30.2 g.; 0.135 mole), concentrated hydrochloric acid (30 ml.), acetic acid (60 ml.) and methanol (60 ml.) is stirred and refluxed for ? hour and then poured into water. The precipitate is collected by filtration, stirred with aqueous sodium bicarbonate and filtered to afford 6.7 g. of 2 - (3 - carbomethoxythioureido) - 4 - propylthioaniline, m.p. 1270-l350C.
(dec.).
Step C-2 - (3 - Carbomethoxy - S - methylthioureido) - 4 - propylthioaniline By following substantially the procedure of Step B of Example 45, the 2 - (3 carbomethoxythioureido) - 4 - propylthioaniline is reacted with methyl iodide to afford 2 - (3 - carbomethoxy - S - methylthioureido) - 4 - propylthioaniline.
Elemental analysis for C13H1,N3S2O2 Calc.: C, 49.81; H, 6.12; N, 13.41; S, 20.45 Found: C, 49.89; H, 6.16; N, 13.39; S, 20.26 By substituting for the 2 - nitro - 5 - propylthioaniline of Step A of Example 46 an equimolar quantity of 2 - nitro - 5 - phenylthioaniline and by following substantially the procedures of Steps A-C of Example 46, there is obtained 2 (3 - carbomethoxy - S - methylisothioureido) - 4 - phenylthioaniline, m.p. 1260-- 128"C. (dec.).
Example 47 2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - (p chloro)benzylthioaniline Step A-2 - Nitro - 5 - (p - chloro)benzylthioaniline 5 - Chloro - 2 - nitroaniline (3.1 g.; 0.018 mole) is dissolved in dimethylformamide (30 ml.). 4-Chlorobenzyl mercaptan (2.85 g.; 0.018 mole) and potassium carbonate (4 g.; 0.03 mole) are added followed by 10 ml. of dimethylformamide. The suspension is stirred and heated at 760C. for 8 hours. It is poured into 200 ml. of cold water. A yellow solid forms which is isolated by vacuum filtration, washed with water and dried to afford 4.9 g. (93%) of 2 - nitro - 5 - (p chloro)benzylthioaniline, m.p. 1600--1630C. (dec.).
Step B-I - (p - Chloro)benzylthio - 3 - (3 - carbomethoxy - thioureido) - 4 nitrobenzene To a solution of 2 - nitro - 5 - (p-chloro) - benzylthioaniline (3.6 g.; 0.013 mole) in acetone (75 ml.) is added carbomethoxy isothiocyanate (1.5 g.; 0.013 mole) in acetone (10 ml.). The reaction mixture is heated to boiling for 1 hour. Five drops of triethylamine is added and stirring continued at room temperature over the week-end. A precipitate forms which is collected by filtration, washed with acetonitrile and dried to afford 2.3 g. of 1 - (p - chloro) - benzylthio - 3 - (3 carbomethoxythioureido) - 4 - nitrobenzene, m.p. 1800--1900C. (dec.).
Elemental analysis for C,6H,4CIN3S202 Calc.: C, 46.65; H, 3.43; N, 10.20; S, 15.57; Cl, 8.61 Found: C, 46.48; H, 3.38; N, 11.27; S, 14.73; Cl, 8.36 Step C-2 - (3 - Carbomethoxythioureido) - 4 - (p - chloro) - benzylthioaniline A mixture of I - (p - chloro)benzylthio - 3 - (3 - carbomethoxythioureido) 4 - nitrobenzene (1.8 g.), concentrated hydrochloric acid (10 ml.), methanol (20 ml.), acetic acid (20 ml.) and stannous chloride (5.1 g.; 0.0226 mole) is stirred and heated to reflux for 30 minutes. The mixture is filtered to remove a small amount of insoluble material. The filtrate is poured into water (500 ml.) with stirring. The precipitate is collected by filtration, washed with water and dried to afford 1.4 g. of 2- (3 - carbomethoxythioureido) - 4 - (p - chloro) - benzylthioaniline, m.p.
161 0-l620C.
Step D-2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - (pchloro)benzylthioaniline A mixture of 2 - (3 - carbomethoxythioureido) - 4 - (p chloro)benzylthioaniline (0.9 g.) and an aqueous solution of sodium hydroxide (.0976 g.) in DMF (10 ml.) is cooled to 50C. A solution of methyl iodide (0.4 g.) in DMF (I ml.) is added with stirring. The temperature rises to 100C. The reaction mixture is stirred in an ice bath for 5 minutes, poured into ice water (400 ml.) with stirring. The aqueous material is extracted with ether and the ether removed to afford 3.0 g. of product. Additional precipitate forms in the aqueous layer which is collected by filtration and dried to afford 0.2 g. of product. The material is combined and sent for analysis.
Elemental analysis for C"H,6CIN3S202 Calc.: C, 51.56; H, 4.61; N, 10.78; S, 15.27; Cl, 9.00 Found: C, 51.01; H, 4.59; N, 10.61; S, 16.10; Cl, 8.95 Example 48 2 - (3 - Carbomethoxy - S - methylisothioureido) - 5 - propylsulfinylaniline To a stirred slurry of 2 - (3 - carbomethoxy - S - methyl - isothioureido) - 5 propylthioaniline (1.7 g.; 0.0542 mol) in 50 ml. ether is added 85% mchloroperoxybenzoic acid (1.1 g.; 0.0053 mol) in 20 ml. of ether. The mixture is stirred at room temperature for 20 minutes, then 50 ml. of 5% aqueous sodium bicarbonate is added. The layers are separated. The organic layer is washed with two more portions of 5% aqueous sodium bicarbonate, dried (MgSO4) and concentrated to yield 0.5 g. of crude product which is purified by chromatography (silica gel column developed with ethyl acetate) and crystallized from ether to give pure 2 - (3 - carbomethoxy - S - methylisothioureido) - 5 - propylsultinylaniline; m.p. 131--1320C. dec.
Elemental analysis for C,3H,9N303S2 Calc.: %C, 47.39; %H, 5.82; %N, 12.76; /nSl 19.81 Found: %C, 47.48; %H, 5.98; %N, 12.75; %S, 19.46 Example 49 2 - (3 - Carbomethoxy - S - methylisothioureido) - 4 - phenylsulfinylaniline A mixture of 2 - (3 - carbomethoxy - S - methylisothioureido) - 4 phenylthioaniline (6.0 g.; 0.0173 mol) and 200 ml. methylene chloride is cooled to -15"C. and filtered through Celite. To the filtrate (zero degrees C.) is added 85 /" m-chloroperoxybenzoic acid (3.6 g.; 0.0177 mol). The mixture is stirred at 0 + 10 C. for 20 minutes, then washed with four 75 ml. portions of 5% aqueous sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated. Ethyl acetate is added and the insoluble impurities removed by filtration. The filtrate is again concentrated and the residue crystallized from ether to give 3.5 g. (56% yield) of 2 (3 - carbomethoxy - S - methylisothioureido) - 4 - phenylsulfinylaniline; m.p.
126--128"C. dec.
Elemental analysis for C,6H,7N303S2 Calc. Theory: C, 52.89; H, 4.72; N, 11.56; S, 17.66 Found: C, 52.46; H, 4.73; N, 11.64; S, 18.16 The following are illustrative preparations of starting materials for use in making compounds of Formula I.
Preparation A-3 - (3 - Carbomethoxythioureido) - 4 - aminobenzophenone To a solution of 3,4-diaminobenzophenone (63.6 g.; 0.3 mole) in chloroform (1.5 1.) is added dropwise carbomethoxy isothiocyanate (52.6 g.; 0.45 mole) over a five minute period. The temperature of the reaction mixture went from 25"C. to 30"C. A suspension forms and the reaction mixture is stirred at room temperature for 30 minutes and the precipitate collected by filtration. The collected product is washed with chloroform, triturated in ether (500 ml.), collected and dried to afford 79.8 g. (80.9% yield) of 3 - (3 - carbomethoxythioureido) - 4 aminobenzophenone, m.p. 192"C., dec.
Preparation B-3 - (Carboethoxythioureido) - 4 - aminobenzophenone To a solution of 3,4-diaminobenzophenone (4.24 g.; 0.02 mol) in ether (600 ml.) is added carboethoxy isothiocyanate (2.62 g.; 0.02 mole). The suspension that forms is stirred at room temperature for 45 minutes and the precipitate collected by filtration to afford 3.1 g. (45% yield) of 3 - (carboethoxythioureido) - 4 aminobenzophenone as a yellow powder, m.p. 2000 C., dec.
By substituting for the carboethoxy isothiocyanate of Preparation B an eq uimolar quantity of carbo-n-propoxy isothiocyanate, carboisopropoxy isothiocyanate, carbo-n-butoxy isothiocyanate and by following substantially the procedure described therein, there is obtained 3-(carbo-n-propoxy)-4 aminobenzophenom, 3 - (carboisopropoxy) - 4 - aminobenzophenone and 3 (carbo - n - butoxy) - 4 - aminobenzophenone, respectively.

Claims (36)

  1. WHAT WE CLAIM IS:- 1. A compound of the formula:
    wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl optionally substituted in the aryl ring with from 1 to 3 substituents, mononuclear aryloxy(C1-C8)alkyl, cycloalkylalkyl, cyano(C,-C8)alkyl, hydroxy(C1-C8)alkyl, aralkenyl, alkoxvalkyl, alkoxycarbonylalkyl, phthalimido(C1-C8)alkyl, phenoxycarbonyl(C1-C,,)alkyl or carbamoyl(C1-C8)alkyl in which the N atom contains as a substituent a mononuclear aryl group itself optionally containing an alkanoylaminoarylthio substituent; R1 is (C1-C6)alkyl or (C1-C6)alkoxy(C1 C6)alkyl; X is (1) hydrogen, (2) nitro, (3) halo, (4) (C2-C5)alkanoyl, (5) (C1 C4)alkyl, (6) thiocyanato, (7) Y-S(O)n- wherein Y is (C1-C5)alkyl, (C3 C8)alkenyl, (C3-C6)alkynyl, (C3-C7)-cycloalkyl, a 5- or 6-membered heterocycle or substituted or unsubstituted mononuclear aryl or aralkyl and n is 0 or an integer of I to 3, (8) alkoxycarbonylamino, (9)
    wherein Y' is mononuclear aryl, (C3-C7)cycloalkyl or a 5- or 6-membered heterocycle or (10) Y"O wherein Y" is (C1-C5)alkyl, mononuclear aryl, (C3 C6)alkenyl, mononuclear aralkyl or a 5- or 6-membered heterocycle; with the proviso that the Y, Y' or Y" groups defined above can be substituted with one or more substituents selected from (a) halo, (b) cyano, (c) alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl and carboalkoxy, each of these groups listed under (c) containing no more than 8 carbon atoms, (d) phenylthio, (e) phenylsulfinyl, (f) phenylsulfonyl, (g) phenoxy, (h) halophenoxy, (i) benzyloxy and (j) trifluoromethyl; or a pharmaceutically or agronomically acceptable acid addition salt of a compound of Formula I; or an amide wherein the -OR' group of Formula I is replaced with an amino or substituted amino group.
  2. 2. A compound of the formula:
    wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy(C3-C6)alkyl, cycloalkylalkyl, cyano(C3-C6)alkyl, hydroxy(C3-C8)alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, phthalimido(C3-C6)alkyl or phenoxycarbonylalkyl; R1 is (C1-C6)alkyl; X is hydrogen, nitro, halo, (C2-C5)alkanoyl, (C1-C5)alkoxy, (C1-C4)alkyl, thiocyanato, (C1-C4)alkyl S(O)@ wherein n is 0, 1 or 2, alkoxycarbonylamino, benzoyl, phenylthio, phenylsulfinyl or phenylsulfonyl; a pharmaceutically or agronomically acceptable acid addition salt of a compound as defined above; or an amide wherein the --OR' group in a compound as defined above is replaced with an amino or substituted amino group.
  3. 3. A compound according to Claim 1 of the formula:
    wherein R3 is (C1-C4)alkyl, R2 is (C1-C4)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, benzyl, 2,6-dichlorobenzyl, phenethyl, (C5-C6)cycloalkyl(C1-C4)alkyl, phenoxy(C3-C6)alkyl, cyano(C5-C6)alkyl, alkoxycarbonylalkyl wherein the alkoxy moiety has from 1-5 carbon atoms and the alkyl moiety has from 3-6 carbon atoms, phthalimido(C3-C6)alkyl, phenyl(C3-C6)alkenyl or hydroxy(C3- C8)alkyl and X' is hydrogen, (C1-C4)alkyl, alkoxycarbonylamino having up to 4 carbon atoms in the alkoxy group, (C1-C5)alkoxy, (C1-C4)alkylthio, (C,- C4)alkylsulfinyl, (C,-C,)alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, (C3-C5)alkanoyl or benzoyl; a pharmaceutically or agronomically acceptable acid addition salt of a compound as defined above; or an amide wherein the -OR3 group in the Formula IA is replaced with an amino substituted amino group.
  4. 4. A compound according to Claim 3 wherein X' is 5-benzoyl.
  5. 5. A compound according to Claim 3 which is 3 - (3 - carbomethoxy - S methylisothioureido) - 4 - aminobenzophenone or a salt or amide thereof.
  6. 6. A compound according to Claim 3 which is 2 - (3 - carbomethoxy - S methylisothioureido) - 5 - propylthioaniline or a salt or amide thereof.
  7. 7. A compound according to Claim 3 which is 2 - (3 - carbomethoxy - S methylisothioureido) - 4 - phenylthioaniline or a salt or amide thereof.
  8. 8. A compound according to Claim 3 which is 2 -(3 - carbomethoxy - S methylisothioureido) - 4 - phenylsulfinyl - aniline or a salt or amide thereof.
  9. 9. A compound according to Claim 3 which is 3 -(3 - carbomethoxy - S hydroxypropylisothioureido) - 4 - amino - benzophenone or a salt or amide thereof.
  10. 10. A compound according to Claim 1 being any one of those compounds whose preparation is described in foregoing Example 1--33 with the exception of those compounds claimed in Claims 5-9.
  11. 11. A compound according to Claim 1, being any of those compounds whose preparation is described in foregoing Examples 34-49 with the exclusion of those compounds claimed in Claims 5--10.
  12. 12. A compound according to Claim 1, being any of those individual compounds disclosed in the foregoing description with the exception of those compounds claimed in Claims 5-11.
  13. 13. An anthelmintic or fungicidal composition which contains a compound according to any one of Claims 1--4 and a pharmaceutically or agronomically acceptable carrier or diluent as the case may be.
  14. 14. An anthelmintic composition according to Claim 13 in unit dosage form.
  15. 15. A composition according to Claim 13 or 14 containing a compound according to Claim 5 or 9.
  16. 16. A composition according to Claim 13 or 14 containing a compound according to any one Claims 6-8.
  17. 17. A composition according to Claim 13 containing a compound according to Claim 10.
  18. 18. A composition according to Claim 13 or 14 containing a compound according to Claim 11.
  19. 19. A composi.ion according to Claim 13 or 14 containing a compound according to Claim 12.
  20. 20. A fungicidal composition according to any one of Claims 13 or 15-19 in the form of (a) a dust, granules or slurry or (b) a wettable powder, emulsion, emulsifiable concentrate or suspension each containing a surfactant.
  21. 21. A method for controlling a helminth infection in a host animal other than a human which comprises administering to the animal an effective amount of a compound according to any one of Claim 1--12 or a composition according to any of Claim 13-19.
  22. 22. A method according to Claim 21, wherein the host animal is reared or tended by humans for commercial gain.
  23. 23. A method according to Claim 22, wherein the host animal is reared or tended for slaughter to provide food for humans.
  24. 24. A method according to any one of Claims 21-23 wherein the anthelmintic ingredient is administered in a dose from 1--125 mg per kg body weight of the host animal.
  25. 25. A method according to Claim 24, wherein the dose is from 5-125 mg per kg body weight.
  26. 26. A method of controlling fungi which comprises applying to the locus of the fungi a fungicidally effective amount of a compound according to any one of Claim 9-I 2.
  27. 27. A method according to Claim 26 as applied to the control of fungi on seeds or plants capable of yielding, or yielding, a vendible agronomic crop.
  28. 28. A process for preparing a compound of Formula I in Claim 1 which comprises treating a compound of the formula:
    with a base followed by treatment with a compound of the formula RX2 where, in the above formulae, R, R' and X are as defined in Claim I and X2 is halo or sulfonate.
  29. 29. A process according to Claim 28 carried out in solution at a temperature of 0 C to 40"C.
  30. 30. A process according to Claim 29 carried out at a temperature of 10"C to 40"C.
  31. 31. A process according to Claim 28 as applied to the preparation of a compound according to any one of Claim 25, 9 and 10.
  32. 32. A process according to Claim 31 carried out in accordance with Claim 30.
  33. 33. A process according to Claim 28 or 29 as applied to the preparation of a compound according to any one of Claims 6-8, 11 and 12.
  34. 34. A process according to Claim 28 carried out substantially as hereinbefore described with reference to any one of Examples 1--33.
  35. 35. A process according to Claim 28 carried out substantially as hereinbefore described with reference to any one of foregoing Examples 3447.
  36. 36. A compound according to Claim I when prepared by a process according to any one of Claims 28-35.
GB18212/77A 1976-05-05 1977-05-02 2-(3-carboxy - s - substituted - isothioureido)-anilines Expired GB1576633A (en)

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Publication number Priority date Publication date Assignee Title
US4406893A (en) * 1980-10-20 1983-09-27 Schering Corporation N-Alkoxycarbonyl-N'-[2-nitro-4 or 5-alkylthiophenyl]-N"-[substituted alkyl]-guanidines useful as anthelmintics

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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

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* Cited by examiner, † Cited by third party
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US4406893A (en) * 1980-10-20 1983-09-27 Schering Corporation N-Alkoxycarbonyl-N'-[2-nitro-4 or 5-alkylthiophenyl]-N"-[substituted alkyl]-guanidines useful as anthelmintics

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