KR810000853B1 - Process for the preparation of substituted phenylguanidines - Google Patents

Abstract

Title compds. (I; R,R1 = -COR4, -C=N-COOR5(NHCOR6); R4 = H, alkyl, cycloalkyl, amino and alkoxy; R5 = alkyl, alkenyl, alkinyl; R6 = H, alkyl, cycloalkyl, alkenyloxy, aralkyl and alkenyl; R2, R3 = H, C1-4 alkoxy, halogen, trifluoromethyl, and C1-4 alkyl; X = -O-SO2, -SO2-O; R7 = C1-4 alkyl), useful as parasiticides, were manufd. by reaction of II and III. Thus, 2-amino-4-phenoxysulfonyl-acetanilide refluxed with N,N'-bis-methoxy-carbonylisothio-urea-S-methylether and mixed with ethylacetate to give N-(2-acetamino-5-phenoxy-sulfonylphenyl)-N',N"-bis-methoxycarbony1-guanidine.

Description

Method for preparing substituted phenylguanidines

The present invention relates to a method for producing substituted phenylguanidines having strong antiparasitic power against parasites and liver dystomies.

The fact that phenylguanidines have antiparasitic powers is described in German Publication Nos. 2117293, 2304764, 2423679 and the like.

Substituted-phenylguanidine compounds of the present invention have the following structural formula.

However, in the above structural formula

이며, 이때의 R⁴는 수소, 임의로 치환시킨 알킬, 임의로 치환시킨 사이클로알킬, 임의로 치환시킨 아릴, 임의로 치환시킨 아미노, 임의로 치환시킨 알콕시, 임의로 치환시킨 아르알킬이며 이때의 R⁵는 임의로 치환시킨 알킬, 임의로 치환시킨 알케닐, 임의로 치환시킨 킬키닐이며, 이때의 R⁶는 수소, 임의로 치환시킨 알킬, 임의로 치환시킨 사일클로알킬, 임의로 치환시킨 알콕시, 임의로 치환시킨 알케닐옥시, 임의로 치환시킨 알키닐옥시, 임의로 치환시킨 아릴, 임의로 치환시킨 아르킬킬, 임의로 치환시킨 알케닐, 임의로 치환시킨 킬키닐이며. R²와 R³는 각각 독립적으로 수소, C_1-4알콕시, 할로겐, 트리플루오로메틸, C_1-4킬알이며, X는 -O-SO₂-나 -SO₂-O와 같은 기이다. (단 윗구조식 설명에서 ＂임의로 치환시킨＂의 의미는 치환시키거나 또는 비치환된 형태를 의미하며 또한 ＂C_1-4＂는 ＂1 내지 4개의 탄소를 갖는＂ 의미를 말한다)R is different from R ¹ and each is -COR ⁴ or

Wherein R ⁴ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted amino, optionally substituted alkoxy, optionally substituted aralkyl, wherein R ⁵ is optionally substituted alkyl , Optionally substituted alkenyl, optionally substituted kilkynyl, wherein R ⁶ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyl Oxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted kilkynyl. R ² and R ³ are each independently hydrogen, C _1-4 alkoxy, halogen, trifluoromethyl, C _1-4 keal, and X is a group such as —O—SO ₂ — or —SO ₂ —O. (In the formula just described above means "optionally having substitution" is either substituted or unsubstituted, or refers to a ring shape, and also, "C _1-4" refers to the meaning "having from 1 to 4 carbon")

The compound of formula (1) of the present invention is made by reacting a substituted-aniline derivative of formula (2) with isothiourea of formula (3) in the presence of a diluent (and optionally also in the presence of acid).

With the proviso that R ² -R ⁶ are as defined above and X is also as defined above and is bonded at position 4 or 5 of the 1-amino-phenyl group and R ⁷ is alkyl of C _1-4 .

In the case of R ² -R ⁶ optionally substituted eggs in the structural formulas (2) and (3), _1-6 (particularly C _1-4 ) linear or side-chained killing may be preferable. , Ethyl, n-, i-propyl, n-, i-, t-butyl and the like.

When R ⁵ and R ⁶ in the formula (3) are alkenyl optionally substituted, C _2-6 (especially C _2-4 ) linear or branched alkyl is preferable. For example, ethenyl, propenyl- (1)-, propenyl- (2)-, and budenyl- (3)-which are each optionally substituted are preferable.

When R ⁵ and R ⁶ in the formula (3) are optionally substituted alkynyl, C _2-6 (especially C _2-4 ) linear or branched kilkynyl is preferable. For example, ethynyl, propynyl- (1)-, propenyl- (2)-, butenyl- (3)-, and the like, each optionally substituted.

In addition, R ² -R ^4, R ⁶ is optionally substituted, if kilkok admitted that there may be a straight or branched C _1-4 alkoxy group. For example, methoxy, ethoxy, n-, i-propoxy, n-, i-, t-butoxy and the like optionally substituted.

In the case where R ² and R ³ are halogen, fluorine, chlorine, bromine and iodine (particularly fluorine, chlorine and bromine) are preferable.

In addition, C _6-10 aryl is preferable when R ⁴ and R ⁶ are optionally substituted aryl. One example is optionally substituted phenyl or naphthyl.

In addition, when R ⁴ and R ⁶ are optionally substituted aralkyl, aralkyl may be C _6-10 of the aryl moiety and / or the aryl moiety. Particularly, the aryl moiety is C ₆ and the real moiety is C _1-4 (more C _{1 -2} ) is good and the egg part can be linear or branched. One example is optionally substituted benzyl or phenylethyl.

In addition, when R ⁴ and R ⁶ are optionally substituted cycloalkyl, C _3-10 (especially C _3, C ₅ , C ₆ ) monocyclic-, dicyclic-, tricyclic-cycloalkyl is preferable. For example, optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo- [2,2,1] -heptyl, bicyclo- [2,2,2] -octyl, adamantyl and the like good.

In addition, if R ⁶ is optionally substituted, the alkenyloxy which kill good alkenyloxy al straight or branched C _2-6 (particularly C _2-4). For example, ethenyloxy, protenyl- (1) -oxy, propenyl- (2) -oxy, butenyl- (3) -oxy and the like optionally substituted.

In addition, when the R ⁶ in which an optionally substituted oxy skill kinil has good straight-chain or branched alkynyl of a C _2-6 (particularly C _2-4). For example, ethynyloxy, propynyl- (1) -oxy, propynyl- (2)-, butynyl- (3) -oxy and the like optionally substituted.

In the case where R ⁷ is alkyl, methyl and ethyl are preferred.

Preferred groups for each group in the compound of formula (1) include the following ones.

R ² and R ³ include hydrogen, methyl, ethyl, n-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, cyano and trifluorotomethyl. When R ² is hydrogen, R ³ is the 3-position of the phenyl group. It is good to substitute in.

-메톡시에틸아미노가 있다.R ⁴ is methyl, ethyl, propyl, n-butyl, i-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl, phenyl, benzyl, methoxymethyl, methoxy, ethoxy, phenoxymethyl , Methylamino, ethylamino, n-butylamino, W-cyanopentylamino,

Methoxyethylamino.

R ⁵ is methyl, ethyl, i-propyl, sec-butyl, propenyl- (2), propynyl.

R ⁶ is methyl, ethyl, propyl, isopropyl, n-amyl, isoamyl, n-butyl, cyclohexyl, phenyl, benzyl, methoxymethyl, phenoxymethyl, allyl, crotyl, metalyl, methoxy, Ethoxy-, i-propoxy, sec-butyloxy, propenyl- (2) -oxy, propynyl- (2) -oxy, 2-methyl-propenyl- (2) -oxy and the like.

In addition, R ⁴ , R ⁵ , and R ^{6 in the} above-described structural formula (1) are suitable as substituents, respectively, as follows.

R ⁴ : Kilkill: C _1-2 -alkoxy, halogen, cyano, C _6-8 aryloxy (especially methoxy, chlorine, phenoxy)

For cyclokillkill: methyl, ethyl,

In the case of aryl; C _1-4 alkyl, halogen, C _1-4 kilkoxy (particularly methyl, chlorine, methoxy)

For amino: 1 or 2 C _1-4 eggs (especially dimethyl, diethyl)

In the case of alkoxy; C _1-2 alkyl, halogen

For aralkyl: C _1-2 alkyl, halogen, C _1-4 kilkoxy (particularly methyl, chlorine, methoxy)

R ⁵ : in the case of eggs; C _1-2 alkoxy, halogen, cyano (especially methoxy, chlorine)

Alkenyl or alkynyl: ethyl or methyl

R ⁶ : Kilkill: C _1-2 alkoxy, halogen, cyano, C _6-8 aryloxy, (especially methoxy, chlorine, phenoxy)

In case of cyclokillal: methyl, ethyl

Alkoxy: methoxy, chlorine

Alkenyloxy or alkynyloxy: methyl or ethyl

For aryl or aralkyl: C _1-4 alkyl, halogen, C _1-4 alkoxy, (especially methyl, chlorine, methoxy)

Alkenyl or alkynyl: methyl or ethyl

The compound of formula (3) used as starting material is described in US Pat. No. 2,93,502,502 and can be prepared by analogous extraordinary methods. This starting material is treated with an N-acylthio-urea with an alkylating agent (e.g., alkyl halides, sulfates, sulfonates) to form S-alkyl-N-acyl-iso-thiourea, which is then reacted with halogeno-formic acid esters. Or by reacting with pyrocarboxylic acid-dialkyl ester to form S-alkyl-N-acyl-N ¹ -alkoxycarbonyl-isothiourea. This final reaction is very similar to the theory of reacting S-alkyl-isothiourea with alkyl chloroformate esters.

Isogio-ureas that may be used in the reaction of the present invention include the following compounds.

N, N'-bis-methoxycarbonyl-S-methyl-isochio-urea (melting point 99-100 ° C)

N, N'-bis-ethoxycarbonyl-S-methyl-isochio-urea (melting point 50-51 degreeC)

N-ethoxycarbonyl-N'-propionyl-S-methyl-isothia-urea (melting point 92-94 ° C)

N-methoxycarbonyl-N'-propionyl-S-methyl-isochio-urea (melting point 97-99 ° C)

N-methoxycarbonyl-N'-ethoxyacetyl-S-methyl-isothia-urea (melting point 69-70 ° C.)

N-methoxycarbonyl-N'-cyclohexylcarbonyl-S-methyl-isothia-urea (melting point 67-68 ° C)

N-methoxycarbonyl-N'-phenylacetyl-S-methyl-isochio-urea (melting point 55-56 ° C.)

N-ethoxycarbonyl-N'-benzoyl-S-methyl-isothia-urea (melting point 79-80 ° C.)

N-ethoxycarbonyl-N'-methoxycarbonyl-S-methylisothia-urea (melting point 69 ° C)

N-aryloxycarbonyl-N'-methoxycarbonyl-S-methyl-isochio-urea,

N-propionyloxycarbonyl-N'-methoxycarbonyl-S-methyl-isothio-urea,

N, N'-bis-aryloxycarbonyl-S-methyl-isochio-urea,

N, N'-bis-propionyloxycarbonyl-S-methyl-isothia-urea.

2-amino-anilides used as starting materials can be prepared in a conventional manner. For example, 2-amino-4-phenoxasulfonyl-butyranilide is reacted with phenol by 3-nitro-4-chloro-benzene-sulfonic acid-chloride. 2-nitro-4-phenolsulfonyfonyl-chlorobenzene was made and reacted with ammonia again to form 2-nitro-4-phenoxy-sulfonyl-aniline and then reacted with butyryl chloride to form 2-nitro-4-phenoxa Ponynil-butyr anilide is made by catalytic hydrogenation.

Meanwhile, 2-amino-4-phenylsulfonyl-cypropionanilide reacts benzene-sulfonic acid-chloride with 2-nitro-4-hydroxyaniline to form 2-nitro-4-phenyl-sulfonyloxy-aniline Treatment with propionylchloride produces 2-nitro-4-phenyl-sulfonyloxy-propionanilide, which is catalytically hydrogenated.

2-amino-anilides used as starting materials of the present invention include the following.

a) 2-amino-4-phenoxasulfonyl-methoxyacetanilide

2-amino-4-phenoxasulfonyl-acetanilide

2-amino-4-phenoxasulfonyl-propionanilide

2-amino-4-phenoxysulfonyl-butyleneanilide

2-amino-4-phenoxysulfonyl-iso-butyleneanilide

2-amino-4-phenoxysulfonyl-barylanilide

2-amino-4-phenoxysulfonyl-iso-barylanilide

2-amino-4-phenoxysulfonyl-capron-anilide

2-amino-4-phenoxysulfonyl-iso-capron-anilide

2-Amino-4-phenoxysulfonyl-cyclopentane-carbonylanilide

2-amino-4-phenoxysulfonyl-cyclohexene-carbonylanilide

2-amino-4-phenoxysulfonyl-phenylacetanilide

2-amino-4-phenoxysulfonyl-phenoxyacetanilide

2-amino-4-phenoxysulfonyl-benzanilide;

b) 2-amino-4- (4-chloro-phenoxysulfonyl) -acetanilide

2-Amino-4- (3-chloro-phenoxysulfonyl) -acetanilide

2-Amino-4- (2-chloro-phenoxysulfonyl) -acetanilide

And homologues according to item a).

c) 2-amino-4- (4-bromo-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-tert-butyl-phenoxysulfonyl) -acetanilide

2-amino-4- (4-methoxy-phenoxysulfonyl) -acetanilide

2-amino-4- (4-ethoxy-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-propoxy-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-isopropoxy-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-butoxy-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-isobutoxy-phenoxysulfonyl) -acetanilide

2-amino-4- (4-cyano-phenoxysulfonyl) -acetanilide

And their regioisomers and homologues corresponding to b)

d) 2-amino-4- (3-trifluoromethyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (3, 5-bis-trifluoromethyl-phenoxysulfonyl) -acetanilide

And homologues according to item a).

e) 2-amino-4- (2-chloro-3-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (2-chloro-4-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (2-chloro-5-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (2-chloro-6-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (3-chloro-2-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (3-chloro-4-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (3-chloro-5-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (3-chloro-6-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-chloro-2-methyl-phenoxysulfonyl) -acetanilide

2-Amino-4- (4-chloro-3-methyl-phenoxysulfonyl) -acetanilide

And homologues according to item a).

f) 2-amino-4- (2,3-dichloro-phenoxysulfonyl) -acetanilide

2-amino-4- (2,4-dichloro-phenoxysulfonyl) -acetanilide

2-amino-4- (2,5-dichloro-phenoxysulfonyl) -acetanilide

2-amino-4- (2,6-dichloro-phenoxysulfonyl) -acetanilide

2-amino-4- (3,4-dichloro-phenoxysulfonyl) -acetanilide

2-amino-4- (3,5-dichloro-phenoxysulfonyl) -acetanilide

And homologues according to item a).

g) 2-amino-4- (2,3-dimethyl-phenoxysulfonyl) -acetanilide

And their regioisomers and homologues corresponding to f)

h) 2-amino-5-phenoxysulfonyl-acetanilide

And homologues corresponding to items a) -g)

i) 2-amino-4-phenylsulfonyloxy-acetanilide

And homologues corresponding to items a) -b)

k) 2-amino-5-phenylsulfonyloxy-acetanilide

And homologues corresponding to items a) -h)

l) N- (2-amino-4-phenoxysulfonyl-phenyl) -N'-methyl-urea

N- (2-Amino-4-phenoxysulfonyl-phenyl) -N'-ethyl-urea

N- (2-amino-4-phenoxysulfonyl-phenyl) -N'-butyl-urea

N- (2-amino-4-phenoxysulfonyl-phenyl) -N'-W-cyanopentyl-urea

N- (2-Amino-4-phenoxysulfonyl-phenyl) -N'-β-methoxyethyl-urea

N- (2-amino-4-phenoxysulfonyl-phenyl) -N'-benzyl-urea

N- (2-amino-4-phenoxysulfonyl-phenyl) -N'-phenyl-urea

m) N- (2-amino-4- (4-chloro-phenoxysulfonyl-phenyl) -N'-methyl-urea

And regioisomers corresponding to b) and homologues corresponding to l).

n) N-2) -amino-4- (4-bromo-phenoxysulfonyl-phenyl) -N'-methyl-urea

And regioisomers corresponding to item c) and homologues corresponding to item e).

p) N- (2-amino-4- (3-trifluoromethyl-phenoxysulfonyl-phenyl) -N'- methyl-urea,

N- (2-amino-4- (3,5-bis-trifluoromethyl-phenoxysulfonyl-phenyl) -N'-methyl-urea and the corresponding analogue to l)

q) N- (2-amino-4-2-chloro-3-methyl-phenoxysulfonyl-phenyl) -N'-methyl-urea and isomers corresponding to item e) and homologues corresponding to item 1)

r) N- (2-amino-4-2,3-dichloro-phenoxysulfonyl-phenyl) -N'-methyl-urea and a positional body corresponding to f) and a homologue corresponding to l)

s) N- (2-amino-4-2,3-dimethyl-phenoxysulfonyl-phenyl) -N'-methyl-urea and a positional body corresponding to item g) and a homologue corresponding to item 1)

t) homologues corresponding to N- (2-amino-5-phenoxysulfonyl-phenoxy) -N'-methyl-urea and l) -s)

u) homologues corresponding to terms N- (2-amino-4-phenoxulfonyloxy-phenyl) -N'-methyl-urea and l) -t)

v) homologues corresponding to N- (2-amino-5-phenylsulfonyloxy-phenyl) -N'-methyl-urea and l) -t)

In the reaction method of the present invention, the isothio-urea-ether is used in an amount of 1 mole based on 1 mole of substituted 2-amino-anilide.

The reaction proceeds in the presence of an alkyl mercaptan produced as a by-product in a boiling solvent. Cooling the reaction mixture yields a crystalline final product which is filtered off with suction and optionally re-dissolved or recrystallized.

The solvent used in the reaction of the present invention includes a polar organic solvent. Examples include alcohols (e.g. methanol, ethanol, iso-propanol, aqueous solutions thereof), ketones (e.g. acetone, aqueous solutions thereof), acetic acid and its aqueous solutions, ethers (e.g. dioxane, tetrahydrofuran) Etc.

In order to accelerate the reaction of the present invention, any acid can be added as a catalyst, and the acid can be either an organic acid or an inorganic acid. Examples of such acids include hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetinic acid, P-toluene-sulfonic acid, and the like.

The reaction temperature range varies considerably and maintains 0 ° -120 ℃ in general, especially 30 ° -100 ℃ and the reaction pressure is atmospheric pressure.

Substituted-phenylguanidines of formula (1), which is a novel compound of the present invention, include the following compounds.

a) N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-ethoxycarbonyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-propoxycarbonyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-isopropoxycarbonyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-butoxycarbonyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-isobutoxy-carbonyl-guanidine

b) N- (2-propiamido-5-phenoxysulfonyl) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-iso-butyramido-5-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-valylamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-iso-valylamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-capronamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-iso-capronamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-methoxyacetamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-cyclopentane-carbonylamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-cyclohexene-carbonylamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-phenylacetamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-phenoxyacetamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-benzamido-5-phenoxysulfonyl) -N ', N' '-bis-methoxy-carbonyl-guanidine

And homologues according to item a).

c) N- (2-acetamido-5- (4-chloro-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (3-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (2-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-Butyramido-5- (3-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxy-carbonyl-guanidine

N- [2-methoxyacetamido-5- (3-chloro-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-propionamido-5- (3-chloro-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-Butyramido-5- (2-chloro-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

And homologs corresponding to items a) and b).

d) N- (2-acetamido-5- (4-bromo-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-methyl-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-tert-butyl-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-methoxy-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-ethoxy-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-propoxy-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-isopropoxy-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-butoxy-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-isobutoxy-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (4-cyano-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-acetamido-5- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxy-carbonyl-guanidine

N- (2-methoxyacetamido-5- (3-methyl-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-Butyramido-5- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxy-carbonyl-guanidine

And regioisomers corresponding to c) and homologues corresponding to a) and b).

N- [2-methoxyacetamido-5- (3-methyl-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-methoxyacetamido-5- (3-cyano-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-propionamido-5- (3-methyl-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-propionamido-5- (3-cyano-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-Butyramido-5- (3-methyl-phenoxysulfonyl)]-N ', N "-bismethoxy-carbonyl-guanidine

N- [2-Butyramido-5- (3-cyano-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

And c) isomers corresponding to

e) N- (2-acetamido-5- (3-trifluoromethyl-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonylguanidine

N- (2-acetamido-5- (3,5-bis-trifluoromethyl-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-methoxyacetamido-5- (3-trifluoromethyl-phenoxysulfonyl))-N ', N "-bis-methoxy-carbonyl-guanidine

N- (2-Butyramido-5- (3-trifluoromethyl-phenoxysulfonyl))-N ', N' '-bis-methoxy-carbonyl-guanidine

N- [2-methoxyacetamido-5- (3-trifluoromethyl-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-propionamido-5- (3-trifluoromethyl-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

N- [2-Butyramido-5- (3-trifluoromethyl-phenoxysulfonyl)]-N ', N "-bis-methoxycarbonyl-guanidine

And homologs corresponding to items a) and b).

f) N- (2-acetamido-5- (2-chloro-3-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (2-chloro-4-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (2-chloro-5-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (2-chloro-6-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-chloro-2-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-chloro-4-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-chloro-5-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-chloro-6-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (4-chloro-2-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (4-chloro-3-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

And homologs corresponding to items a) and b).

g) N- (2-acetamido-5- (2,3-dichloro-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (2,4-dichloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (2,5-dichloro-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (2,6-dichloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2--acetamido-5- (3,4-dichloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3,5-dichloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

And homologs corresponding to items a) and b).

h) N- (2-acetamido-5- (2,3-dimethyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

And regioisomers corresponding to g) and homologues corresponding to a), b)

i) N- (2-acetamido-4- (4-methyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-trifluoromethyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-cyano-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (4-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-trifluoromethyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-cyano-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4-phenoxysulfonyl) -N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (4-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-dotrifluoromethyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-cyano-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (4-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-chloro-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-trifluoromethyl-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-cyano-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4-phenoxysulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

And homologues corresponding to items a) -h)

k) N- (2-acetamido-5- (4-methyl-phenoxysulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-methyl-phenoxysulfonyl))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-chloro-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5- (3-cyano-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-5-phenylsulfonyloxy) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-5- (4-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-5- (3-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-5- (3-chloro-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-5- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-5- (3-cyano-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-5-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-5- (4-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-5- (3-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-5- (3-chloro-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-5- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-propionamido-5- (3-cyano-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5-phenylsulfonyloxy) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5- (4-methylphenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5- (3-methyl-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5- (3-chloro-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-5- (3-cyano-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-5-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

And homologues corresponding to items a) -i)

l) N- (2-acetamido-4- (4-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-chloro-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4- (3-cyano-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4-phenylsulfonyloxy) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (4-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-chloro-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-methoxyacetamido-4- (3-cyano-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4-phenylsulfonyloxy) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (4-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-chloro-phenylsulfonyloxy))-N ', N' '-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-propionamido-4- (3-cyano-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4-phenylsulfonyloxy) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (4-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-methyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-chloro-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-trifluoromethyl-phenylsulfonyloxy))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2-Butyramido-4- (3-cyano-phenylsulfonyloxy))-N ', N' '-bis-methoxycarbonyl-guanidine

N- (2-acetamido-4-phenylsulfonyloxy) -N ', N "-bis-methoxycarbonyl-guanidine

And homologues corresponding to items a) -i)

m) N- (2-N ² -methylureido) -5-phenoxysulfonyl) -N ', N "-bis-methoxycarbonyl-guanidine

N- (2-N ² -ethylureido) -5-phenoxysulfonyl) -N ', N''-bis-methoxycarbonyl-guanidine

N- (2-N ² -butylureido) -5-phenylsulfonyl) -N ', N''-bis-methoxycarbonyl-guanidine

N- (2-N ² -W-cyanopentylureido) -5-phenylsulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2- (N ² -β-methoxyethylureido) -5-phenylsulfonyl))-N ', N "-bis-methoxycarbonyl-guanidine

N- (2- (N ² -benzylureido) -5-phenoxysulfonyl) -N ', N''-bis-methoxycarbonyl-guanidine

N- (2- (N ² -phenylureido) -5-phenoxysulfonyl) -N ', N''-bis-methoxycarbonyl-guanidine

And homologues corresponding to a) -l)

n) N- (2-acetamido-5-phenylsulfonyl) -N'-methoxycarbonyl-N ''-acetyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-propionyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-butyryl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-cyclohexene-carbonyl-guanidine

N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-benzoyl-guanidine

N- (2-acetamino-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-phenacetyl-guanidine

N- (2-acetamino-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-phenoxyacetyl-guanidine

And homologues corresponding to a) -m)

o) N- (2-acetamino-5-phenoxysulfonyl) -N'-ethoxycarbonyl-N ''-acetyl-guanidine

N- (2-acetamino-5-phenoxysulfonyl) -N'-propoxycarbonyl-N ''-acetyl-guanidine

N- (2-acetamino-5-phenoxysulfonyl) -N'-isopropoxycarbonyl-N ''-acetyl-guanidine

N- (2-acetamino-5-phenoxysulfonyl) -N'-butoxycarbonyl-N ''-acetyl-guanidine

Homologues corresponding to N- (2-acetamino-5-phenoxysulfonyl) -N'-isobutoxycarbonyl-N ''-acetyl-guanidine and a) -n)

Substituted-phenylguanidines, which are compounds of the present invention, are useful as chemotherapeutic agents for parasitic infections such as enteroparasites and liver dystomies. The range of application of such compounds is as examples of parasites: Haemon Chus, Trichostronglus, Ostertagia, Strongyloides, Cooperia, and Veso Phagostomum. ), Porcine red parasites (Hyostrongulus), Ankylostoma, Asaris, bird nematodes (Heterahis), Gandistoma (Facciola).

The compounds of the present invention have strong antiparasitic activity, particularly against gastrointestinal nematodes and liver dystomies of ruminants. Therefore, the compounds are more useful for livestock.

In the method of administration of the compound of formula (1), one dose is quantitatively administered at 0.5-50 mg / kg for 1-14 days in some cases. In the oral administration, the adjuvant and carrier are mixed with the active ingredient in the form of tablets, granules, capsules, powders, pasta, and the like. The carriers are starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, Calcium carbonate, purified silicic acid, carboxymethyl cellulose, and other similar materials are used.

In addition, the compound is excellent in parenteral administration, in which case liquids, that is, sesame oil or castor oil or synthetic triglycerides are mixed with the active ingredient to make an emulsion. In this case, tocopherol is also used as an antioxidant and a surfactant such as sorbitan-fatty acid-ester. Is optionally added and used. If necessary, a weighting agent such as polyethylene glycol or carboxymethyl cellulose may be added. The active ingredient concentration in the drug is maintained at 2-20% by weight in livestock and 20-80% in human.

The compounds of the present invention have particularly excellent activity against gandistoma. As can be seen in Examples 5-2, 5-3, and 6-30, oral administration of 10 mg / kg was found to have a salvage effect of 90% or more.

In addition, as shown in Example 4-1, the subcutaneous administration of 2.5 mg / kg was found to be more than 90% of the control effect on the gastro-intestinal nematode.

In the following, some examples are listed to further illustrate the present invention.

[Example of Manufacturing]

Example 1-1

37 g of 2-amino-4-phenoxasulfonyl-acetanilide was added to 250 ml of methanol, and 25 g of N, N'-bis-methoxy-carbonylisosio-urea-S-methylether and 0.01 g of P-toluene Reflux with sulfonic acid for 5 hours. The solvent is distilled off under reduced pressure, and the residue is stirred with ethyl acetate. Crystalline N- (2-acetamino-5-phenoxy-sulfonylphenyl) -N ', N' '-bis-methoxycarbonyl-guanidine was filtered and washed with ethyl acetate and methanol to obtain 13 g of pure N- (2-acetamino-5-phenoxy-sulfonylphenyl) -N ', N "-bis-methoxycarbonyl-guanidine produces. Melting Point 190 ° C (Decomposition)

When making 2-amino-4-phenoxasulfonyl-acetanilide, 40 g of 2-nitro-4-phenoxasulfonyl-acetanilide was added to 500 ml of methanol, hydrogenated using ranicel under atmospheric pressure, and concentrated under reduced pressure. . 32 g of the target compound (melting point: 130 ° C: methanolic crystals) is produced without other manipulations.

2-nitro-4-phenoxasulfonyl-acetanilide is mixed with 50 g of 2-nitro-4-phenoxasulfonyl-anilinol and 250 ml of acetanehydride, followed by heating to 1 ml of concentrated sulfuric acid. Stirring of this is continued for 2 hours and the mixture is concentrated under reduced pressure. Diisopropyl ether is added to the solid residue, and 2-nitro-4-phenoxasulfonyl-acetanilide is suction filtered when crystallized. Yield 40g, melting point 124 degreeC (methanol).

The aforementioned 2-nitro-4-phenoxysulfonyl-aniline was added 54 g of 2-nitro-4-phenoxysulfonyl-chlorobenzene to 500 ml of dioxane and placed in an autoclave. Hold for 5 hours. The solvent is then evaporated under reduced pressure and a mixture of 200 ml of the same amount of methanol and water is added to the residue. After a while, the target compound is crystallized and then purified by methanol and benzene, respectively. Yield: 28g, Melting point: 104 ° C

The aforementioned 2-nitro-4-phenoxasulfonyl-chlorobenzene is made as follows. 51 g of 3-nitro-4-chlorobenzene-sulfonic acid chloride was added dropwise with 120 ml of acetone and 18.8 g of phenol, followed by dropwise addition of 28 ml of triethylamine with cooling to an internal temperature not exceeding 10 DEG C;

Thereafter, the mixture is stirred at room temperature, water is added, and then ether is added to give a target compound. Yield: 54 g, Melting point: 71 ° C. (metholol)

Using a method analogous to the one described above, the compounds of the present invention can be prepared using 2-amino-4-phenoxysulfonyl-acetanilide and starting materials of 1-10 in 1-2 below.

1.2 N, N'-bis-ethoxycarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-ethoxy Carbonyl-guanidine

1.3 N, N'-bis-propoxycarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-tenoxysulfonyl) -N ', N' '-bis-propoxy Carbonyl-guanidine

1.4 N, N'-bis-isopropoxycarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-iso Propoxycarbonyl-Guanidine

1.5 N, N'-bis-butoxycarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N ', N' '-bis-butoxy Carbonyl-guanidine

1.6 N, N'-bis-isobutoxycarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N ', N "-bis-isobutoxy Carbonyl-guanidine

1.7 N-methoxycarbonyl-N'-propionyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl-N ' '-Propionyl-guanidine

1.8 N-ethoxycarbonyl-N'-benzoyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N'-ethoxycarbonyl-N '' -Benzoyl-guanidine

1.9 N-methoxycarbonyl-N'-cyclohexylcarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl- N ''-cyclohexylcarbonyl-guanidine

1.10 N-methoxycarbonyl-N'-ethoxymethylcarbonyl-isochio-urea-S-methylether, N- (2-acetamido-5-phenoxysulfonyl) -N'-methoxycarbonyl -N ''-ethoxymethylcarbonyl-guanidine

Example 2-1

Similar to the method of Example 1, 27 g of 2-amino-4-phenoxasulfonyl-butyranilide was reacted with 20 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether 9 g of N- (2-butyramido-5-phenoxasulfonylphenyl) -N ', N' '-bis-methoxycarbonyl-guanidine are made.

The 2-amino-4-phenoxasulfonyl-butianilide was added 14 mL of butyryl chloride to 29.6 g of 2-nitro-4-phenoxasulfonyl-aniline (melting point: 104 ° C), and 100 ° C in 300 ml of toluene. It is kept stirring and refluxed for 2 hours. After that, the solution was concentrated under reduced pressure, and diisopropyl ether was added to the residue to produce 2-nitiro-4-phenoxasulfonyl-butyminillide, which was then filtered and hydrogenated to give the desired compound.

By the method similar to the above, the following products were prepared according to each starting material. The starting material at this time is slightly different, but the treatment method is the same as in Example 1.

Example 4-1

In 200 ml of methanol, 34 g of 2-amino-phenylsulfonyloxy-acetanilide was added to 40 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether and 0.01 g of P-toluene-sulfone Stir with acid for 5 hours. The solvent is then evaporated off under reduced pressure and the residue is stirred with ethyl acetate. When N- (2-acetamido-5-phenyl-sulfonyloxyphenyl) -N ', N "-bis-methoxycarbonyl-guanidine crystallizes, it is filtered and washed with ethyl acetate and methanol. Yield: 35 g, Melting point: 181 ° C. (decomposition)

The electrostarter 2-amino-4-phenylsulfonyloxy-acetanilide is hydrogenated with 50 g of 2-nitro-4-phenylsulfonyloxy-acetanilide using raninickel in 250 ml of methanol.

At this time, the temperature is room temperature and the pressure is normal pressure. The catalyst is then filtered off, washed with dimethylformamide and the filtrate is concentrated under reduced pressure. The material produced is pure enough without any further filtration. Yield: 44 g, Melting point: 154 ° C (methanol)

In addition, 2-nitro-4-phenylsulfonyloxy-acetanilide is mixed with 48 g of 2-nitro-4-phenylsulfonyloxy-aniline with 1 ml of concentrated sulfuric acid in 250 ml of anhydrous acetic acid and heated during the reaction. Stirring was continued for 2 hours, and the reaction mixture was concentrated under reduced pressure, and the oily residue was treated with ethyl acetate to give the title compound as a solid residue. The resulting compound was dissolved in 100 ml of hot methanol, diluted with 100 ml of water, and filtered to give 52 g of the target compound. . Melting Point: 98 ° C (Methanol)

2-nitro-4-phenylsulfonyloxy-aniline 15.4 g of 3-nitro-4-amino-phenyl was reacted with 14 ml of trienylamine in 100 ml acetic acid and then 17.6 g of benzene-sulfonic acid in 30 ml acetic acid The chloride dissolved solution is stirred and added dropwise to room temperature (up to 20 ° C). After stirring for 3 hours, the reaction solution is filtered through triethylamine hydrochloride and the filtrate is dried in vacuo. Thereafter, the filtrate is filtered with 50 ml of methanol and the target compound is produced. Yield: 18 g, Melting point: 140 ° C. (metholol)

By a similar method, the following compounds can be made from 2-amino-4-phenylsulfonyloxy-acet anilide.

4.2 N, N'-bis-ethoxycarbonyl-isochio-urea-S-methylether., Product:

N- (2-acetamido-5-phenylsulfonyloxy) -N ', N "-bis-ethoxycarbonyl-guanidine

4.3 N, N'-bis-propoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-5-phenylsulfonyloxy) -N ', N "-bis-propoxycarbonyl-guanidine

4.4 N, N'-bis-isopropoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-5-phenylsulfonyloxy) -N ', N "-bis-isopropoxycarbonyl-guanidine

4.5 N, N'-bis-butoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-5-phenylsulfonyloxy) -N ', N "-bis-butoxycarbonyl-guanidine

4.6 N, N'-bis-isobutoxycarbonyl-isothio-urea-S-methylether. Product:

N- (2-acetamido-5-phenylsulfonyloxy) -N ', N "-bis-isobutoxycarbonyl-guanidine

4.7 N-methoxycarbonyl-N'-propionyl-urea-S-methylether. Product:

N- (2-acetamido-5-phenylsulfonyloxy) -N'-methoxycarbonyl-N ''-propionyl-guanidine

4.8 N-ethoxycarbonyl-N'-benzoyl-isochio-urea-S-methylether. Product:

N- (2-acetamido-5-phenylsulfonyloxy) -N'-ethoxycarbonyl-N ''-benzoyl-guanidine

4.9 N-methoxycarbonyl-N'-cyclohexylcarbonyl-isothia-urea-S-methylether. Product:

N- (2-acetamido-5-phenylsulfonyloxy) -N'-methoxycarbonyl-N ''-cyclohexylcarbonyl-guanidine

4.10 N-methoxycarbonyl-N'-ethoxymethylcarbonyl-isochio-urea-S-methylether. Product:

N- (2-acetamido-5-phenylsulfonyloxy) -N'-methoxycarbonyl-N ''-ethoxymethylcarbonyl-guanidine

Example 5-1

Similar to the method of Example 4, 27 g of 2-amino-4-phenyl-sulfonyloxy-butyranilide was mixed with 20 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether The reaction yields 9 g of N- (2-butyramido-5-phenylsulfonyloxyphenyl) -N ', N' '-bis-methoxycarbonylguanidine (melting point: 158 ° C).

The above-mentioned 2-amino-4-phenylsulfonyloxy-butyranilide is prepared by adding 14 ml of butyryl chloride to 29.6 g of 2-nitro-4-phenylsulfonyloxy-aniline (melting point 148 DEG C) in 300 ml of toluene. After stirring with stirring at 2 DEG C, and then stirring for 2 hours, and then concentrated under reduced pressure, a target product having a melting point of 58 DEG C. was produced, filtered, washed with diisopropyl ether, and hydrogenated by the method of Example 4. Create

By a similar method, the following compounds can be prepared for each starting material.

Example 7-1

37 g of 2-amino-5-phenoxysulfonyl-acetanilide in 250 ml of methanol were charged with 25 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether and 0.01 g of P-toluene- It is heated with reflux for 5 hours and refluxed. The solvent is then evaporated under reduced pressure and the residue is stirred with ethyl acetate. The precipitated N- (2-acetamino-4-phenoxasulfonylphenyl) -N ', N' '-bis-methoxycarbonyl-guanidine is filtered to crystalline form and washed with ethyl acetate and methanol.

The former 2-amino-5-phenoxasulfonyl-acetanilide is made by hydrogenating 40 g of 2-nitro-5-phenoxasulfonyl-acetanilide in 500 ml of methanol with raninickel under atmospheric pressure. The catalyst is then removed and the filtrate is concentrated under reduced pressure to give the pure target.

The above 2-nitro-5-phenoxysulfonyl-acetanilide was added to 250 ml of anhydrous acetic acid, and then heated and stirred with 1 ml of concentrated sulfuric acid. After stirring for 2 hours, the mixture was concentrated under reduced pressure, and diisopropyl ether was added to the residue to precipitate the target substance.

The former 2-nitro-5-phenoxysulfonyl-aniline is used to maintain 54 g of 2-nitro-5-phenoxysulfonyl-chlorobenzene in 500 ml of dioxane together with ammonia gas at 6 atm and -50 ° C. Treatment removes the solvent under reduced pressure and adds a mixture of 200 ml of the same amount of water and methanol to the residue. As a result, a crystalline target is produced.

2-nitro-5-phenoxasulfonyl-chlorobenzene was prepared by reacting 51 g of 4-nitro-3-chloro-benzene-sulfonic acid chloride in 120 ml of acetone with 18.8 g of phenol, followed by 28 ml of triethylamyl. Cold add dropwise. The internal temperature at this time is 10 degrees C or less. The mixture is stirred for several hours at room temperature and water is added to separate the oil layer from the ether. As a result, a target is produced in the oil layer. Yield: 54g

7.2 In a similar manner, the following products are prepared from 2-amino-5-phenoxysulfonyl-acetanilide and the following compounds.

7.3 N- (2-acetamido-4-phenoxysulfonyl) -N ', N' '-bis-ethoxy in N, N'-bis-ethoxycarbonyl-isochio-urea-S-methylether Carbonyl-guanidine

7.4 N- (2-acetamido-4-phenoxysulfonyl) -N ', N' '-bis-propoxy in N, N'-bis-propoxycarbonyl-isochio-urea-S-methylether Carbonyl-guanidine

At 7.5 N, N'-bis-isopropoxycarbonyl-isochio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N ', N' '-bis-isopropoxycarbonyl-guanidine

7.6 in N, N′-bis-butoxycarbonyl-isochio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N ', N' '-bis-butoxycarbonyl-guanidine

7.7 in N, N'-bis-isobutoxycarbonyl-isochio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N ', N' '-bis-isobutoxycarbonyl-guanidine

7.8 N-methoxycarbonyl-N'-propionyl-isochio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-propionyl-guanidine

7.9 in N-ethoxycarbonyl-N'-benzoyl-isochio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N'-ethoxycarbonyl-N ''-guanidine

7.10 in N-methoxycarbonyl-N'-cyclohexylcarbonyl-isochio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-cyclohexylcarbonyl-guanidine

7.11 in N-methoxycarbonyl-N'-ethoxycarbonyl-isothio-urea-S-methylether,

N- (2-acetamido-4-phenoxysulfonyl) -N'-methoxycarbonyl-N ''-ethoxy-methylcarbonyl-guanidine

Example 8-1

According to the method of Example 7, 27 g of 2-amino-5-phenoxysulfonyl-butyranilide was reacted with 20 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether and 9 g N- (2-butyramido-4-phenoxasulfonylphenyl) -N ', N' '-bis-methoxycarbonyl-guanidine is produced.

The former 2-amino-5-phenoxysulfonyl-butyranilide was added dropwise with stirring 14 ml of butynylchloride to 29.6 g 2-nitro-5-phenoxasulfonyl-anilide in 300 ml of toluene with stirring at 100 ° C. Stir for 2 hours. Thereafter, the solution was concentrated under reduced pressure, and the residue was mixed with diisopropane ether to give 2-nitro-5-phenoxysulfonyl-butyranilide, which was filtered and washed (diisopropyl ether) to obtain the method of Example 7. Hydrogenation together produces the desired compound.

By a similar method, the following compounds are produced from R-cocl.

Example 10-1

34 g of 2-amino-5-phenylsulfonyloxy-acetanilide in 200 ml methanol were charged with 40 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether and 0.01 g of P-toluene- Heat reflux for 5 hours with sulfonic acid. The solvent is then evaporated under reduced pressure and the residue is stirred with ethyl acetate. When N- (2-acetamido-4-phenylsulfonyloxy-acetanilide) -N ', N "-bis-methoxycarbonyl-guanidine precipitates in crystalline phase, it is filtered and washed with ethyl acetate and methanol.

The above-mentioned 2-amino-5-phenylsulfonyloxy-acetanilide is prepared by adding 50 g of 2-nitro-5-phenylsulfonyloxy-acetanilide to 250 ml of methanol and hydrogenating at room temperature and atmospheric pressure in the presence of raninickel. The catalyst is filtered off, washed with dimethyl-formamide and the filtrate is concentrated under reduced pressure. 2-amino-4-phenylsulfonyloxy acetanilide produced at this time does not need to be purified.

2-nitro-5-phenylsulfonyloxy-acetanilide is added 48 g of 2-nitro-5-phenylsulfonyloxy-aniline to 250 ml of acetic anhydride, whereupon 1 ml of concentrated sulfuric acid is added to heat the mixture. Stirring is continued for 2 hours and concentrated under reduced pressure. Extraction of the oily residue with ethyl acetate gives 2-nitro-5-phenylsulfonyloxy as a solid residue. It is dissolved in 100 ml of hot methanol, diluted with 100 ml of water and cooled, then 2-nitro-4-phenylsulfonyloxy-acetanilide is filtered off and washed with water.

2-nitro-5-phenylsulfonyloxy-aniline was mixed with 15.4 g of 4-nitro-3-amino-phenol in 100 ml of acetone and mixed with 14 ml of triethylamine, and 30 ml of 17.6 g of benzene-sulfoic acid chloride were added. Solution in acetone was added dropwise while stirring at room temperature (up to 20 ° C). After 3 hours triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. When the residue is stirred with 50 ml of methanol, the target compound precipitates, which is washed with methanol.

By a similar method, 2-amino-5-phenyl-sulfonyloxy-acetanilide and the following compounds are prepared.

10.2 N, N'-bis-ethoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N ', N "-bis-ethoxycarbonyl-guanidine

10.3 N, N'-bis-propoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N ', N "-bis-propoxycarbonyl-guanidine

10.4 N, N'-bis-isopropoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N ', N "-bis-isopropoxycarbonyl-guanidine

10.5 N, N'-bis-butoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N ', N "-bis-butoxycarbonyl-guanidine

10.6 N, N'-bis-isobutoxycarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N ', N "-bis-isobutoxycarbonyl-guanidine

10.7 N-methoxycarbonyl-N'-propionyl-isocio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N'-methoxycarbonyl-N ''-propionyl-guanidine

10.8 N-ethoxycarbonyl-N'-benzoyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N'-ethoxycarbonyl-N ''-benzoyl-guanidine

10.9 N-methoxycarbonyl-N'-cyclohexylcarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyl) -N'-methoxycarbonyl-N ''-cyclohexylcarbonyl-guanidine

10.10 N-methoxycarbonyl-N'-ethoxymethylcarbonyl-isochio-urea-S-methylether, product:

N- (2-acetamido-4-phenylsulfonyloxy) -N'-methoxycarbonyl-N ''-ethoxymethylcarbonyl-guanidine

Example 11-1

Reaction of 27 g of 2-amino-5-phenylsulfonyloxy-butyranilide with 20 g of N, N'-bis-methoxycarbonyl-isochio-urea-S-methylether according to a method analogous to Example 10 This yields 9 g of N- (2-butyramido-4-phenylsulfonyloxy) -N ', N' '-bis-methoxycarbonyl0guanidine.

The above-mentioned 2-amino-5-phenylsulfonyloxybutyranilide was added dropwise 14 ml of butyryl chloride to a solution containing 29.6 g of 2-nitro-5-phenoxysulfonyl-aniline in 300 ml of toluene while stirring at 100 ° C. And the mixture is refluxed for 2 hours. The solution was then concentrated under reduced pressure and the residue was treated with diisopropylether, then 2-nitro-4-phenylsulfonyloxy-butyanilide was filtered off and washed with diisopropylether according to the method of Example 10. Hydrogenation results in 2-amino-5-phenylsulfonyloxy-butyranilide.

In a similar manner, the products are each produced by the following starting materials.

Claims (1)

A method of preparing substituted-phenylguanidines of formula (1) is characterized in that the substituted-aniline derivatives of formula (2) are reacted with isothio-urea of formula (3) in the presence of a diluent (and optionally in the presence of acid). How to

In the above structural formula, R is different from R ¹ and each is -COR ⁴ or

Wherein R ⁴ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted amino, optionally substituted alkoxy, optionally substituted aralkyl, wherein R ⁵ is optionally substituted alkyl, Optionally substituted alkenyl, optionally substituted alkynyl wherein R ⁶ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally Substituted aryl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted alkynyl and R ² and R ³ are each independently hydrogen, C _1-4 alkoxy, halogen, trifluoromethyl, C _1-4 alkyl, X is a group such as -O-SO ₂ or -SO ₂ -O structural formula (2), 1-amino-coupled at the 4-or 5-position of the phenyl group R ⁷ is C _1-4 alkyl The. (In this case, "optionally substituted" means substituted or unsubstituted. In this case, "C1-4" has the meaning of "with _1-4 carbons.")