KR820000178B1 - Process for the preparation substituted o-phenylenediamine derivatives - Google Patents

Abstract

Title compds. I[R = substituted alkyl, alkenyl, alkynyl; R1,R2 are different and may be C(NHCO2R4:NCO2R3 or COR5, resp (R3,R4 = alkyl; R5 = H, substituted alkyl or alkoxy); X = SO, SO2 and their physiol. tolerable salts, useful as anthelmintics, were prepd. by oxidizing compds IV. Thus, 19.8 g N-(2-propionylamino-5-propylthiophenyl)-N',N"-bis-methoxycarbonyl-guanidine was dissolved in 650ml acetic anhydride, 42 g H2O2 added and stirred for overnight, the mixt. was distilled in vacuum and recrystallized to give 22.2 g compds. V(m.p. 165-6≰C).

Description

Process for preparing substituted O-phenylenediamine derivatives

The present invention relates to novel substituted o-phenylenediamine derivatives of the general formula (I) and salts thereof which are effective as antiparasitic agents.

Wherein R is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, X is SO or SO ₂ , R ¹ and R ² are different from each other and

-CO-R⁵이고,

-CO-R ⁵ ,

R ³ and R ⁴ are the same or different and are alkyl and R ⁵ is hydrogen, optionally substituted alkyl or optionally substituted alkoxy.

In the prior art it is described that phenylguanidine of the following general formula exhibits antiparasitic action.

[Reference: German Public Statement No. 2,117,293]

In the above general formula, R is lower alkyl and R 'is alkyl or hydrogen.

Compounds of the invention (eg, general formula (I) and salts thereof) exhibit very good antiparasitic action. Moreover, the antiparasitic action of the compounds of the present invention is far superior to that of known substituted phenylguanidines.

Salts of the compounds of the present invention are most importantly and preferably pharmaceutically nontoxic.

The compounds of formula (I) and salts thereof of the present invention are prepared by treating the compounds of formula (IV) with the corresponding amounts of oxidizing agent and converting the obtained compounds into salts by separating or optionally reacting with organic or inorganic acids. .

In the above formula, R, R ¹ and R ² are as described above.

이고, R³과 R⁴가 같지 않은 두 개의 알킬그룹인 경우, 본 발명의 일반식(Ⅰ)화합물은 다음과 같이 토오토머 형태로 존재할 수 있다.R ¹ is

When R ³ and R ⁴ are not the same two alkyl groups, the general formula (I) compound of the present invention may exist in a tautomeric form as follows.

For the sake of uniformity, the specific structural formulas herein are shown as one in all cases in the same manner.

However, these general formulas contain all the tautomers of the compound.

In the above reaction, for the reaction of the compound of the general formula (IV) with the oxidizing agent, N- (2-phospholiaminoamino-4-propylthio-phenyl) -N, N'-bis-methoxycarbonyl-guanidine and hydrogen peroxide When using as a starting material, the reaction can be expressed as follows.

Alkyl groups optionally substituted in R and R ⁵ are methyl, ethyl, n- and i-propyl and n, i- and tert-butyl optionally substituted with straight or branched chain alkyl groups having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. This is preferred.

The optionally substituted alkenyl group in R is preferably a straight or branched chain alkenyl group having 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, and optionally substituted ethenyl, propen-1-yl, propen-2-yl and buten-3 -There is work.

Alkynyl groups optionally substituted in R are ethynyl, propyn-1-yl, propyn-3-yl and butyn-3- optionally substituted with straight chain or branched alkynyl groups of 2 to 6 carbohydrates, especially 2 to 4 carbohydrates. Work is preferred.

The alkyl group in R ³ and R ⁴ is preferably a straight or branched chain alkyl group having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, for example, optionally substituted methyl, ethyl, n- and i-propyl and n, i- and 3 There is a tert-butyl.

The alkoxy group in R ⁵ is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, for example, optionally substituted methoxy, ethoxy, n- and i-propoxy and n-, i- and 3 Rapid-butoxy.

Substituents for the optionally substituted alkyl alkenyl and alkenyl group R are halogen, in particular fluorine, chlorine and bromine, cyano, (C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₄ ) -alkylthio .

Substituents for an optionally substituted alkyl group R ⁵ are (C ₁ -C ₆ ) -alkoxy, halogen, (C ₁ -C ₄ ) -alkylmer cloto, cyano and the group of the following general formula.

Wherein R ⁶ and R ⁷ are the same or different and each represents hydrogen or a (C ₁ -C ₄ ) -alkoxy, trifluoromethyl or cyano optionally substituted (C ₁ -C ₄ ) -alkyl group R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring into which other heteroatoms (eg nitrogen, oxygen and sulfur) can be inserted. )

Examples of each substituted alkyl, alkenyl or alkynyl group R are chloropropyl, chlorobutyl, cyano ethyl, cyanopropyl, cyanobutyl, cyanohexyl, bromopropyl, bromobutyl, trifluorotoethyl, Fluoropropyl, fluorobutyl, 3-chloropropen-2-yl, 2,3-dichloropropene 2-yl, 3-chloro-3-methyl-propen-2-yl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-methylmergatoethyl, 2-ethylmergatoethyl and 2-mergatopropyl.

Optionally substituted alkyl groups R ⁵ include methoxyethyl, ethoxyethyl, methylmerfatoethyl, ethylmerctooltoethyl, methylmerboxtopropyl, chloromethyl, chloroethyl, cyanomethyl and cyanoethyl.

의 예로는 디메틸아미노, 디에틸아미노, 디프로필 아미노, 피롤리디닐, 피페리디닐과 헥사메틸렌이미닐이 있고 질소, 산소 및 황과 같은 복소원자가 삽입된 예로는 모르폴리닐, 티오모르폴리닐, 피페라지닐과 N－메틸피페라지닐이 있다.

Examples include dimethylamino, diethylamino, dipropyl amino, pyrrolidinyl, piperidinyl and hexamethyleneiminyl, and examples of inserting heteroatoms such as nitrogen, oxygen and sulfur include morpholinyl, thiomorpholinyl, There are piperazinyl and N-methylpiperazinyl.

Substituted alkyl groups R ⁵ include dimethylamino methyl, dimethylamino ethyl, diethylaminomethyl, diethylaminoethyl, pyrrolidinomethyl, pyrrolidinoethyl, pyrrolidinopropyl, piperidinomethyl, piperidinoethyl, Hexamethyleneiminomethyl, hexamethyleneiminoethyl, morpholinomethyl, morpholino ethyl, morpholinopropyl, diomorpholinoethyl, piperazinomethyl, piperazinoethyl, N-methylpiperazinoethyl Etc.

In addition to hydrogen peroxide, the following oxidants can be used to oxidize the o-phenylenediamine derivatives of general formula (IV). Organic peracids such as peracetic acid, performic acid, perbenzoic acid, m-chloroperbenzoic acid and monoperphthalic acid; Inorganic peroxides such as hydrogen peroxide dissolved in water or rare organic acids; Halogen oxyacids such as chromic acid, nitric acid, potassium permanganate, chlorine, bromine, hypochlorous acid, chlorous acid, hydrochloric acid or perchloric acid, tripole-butyl- hypochloride, methyl, hypochlorite or tripole-butyl chromate; N-halogeno compounds such as N-chlorosuccinimide, N-bromo succinimide, N-halogenosulfonic acid amide or N-halogenocarboxylic acid amide.

In general, the reaction of oxidizing the compound of general formula (IV) to the compound of general formula (I) is carried out at a temperature of 0 to 100 캜, preferably 20 to 60 캜 in the presence of a diluent inert to the reaction, for example acetic anhydride or acetic acid. Perform.

By selecting the oxidizing agent and the reaction conditions, the oxidation potential is adjusted in each case to control the oxidation reaction to control the sulfoxide (compound of formula (IV) in which Z is SO) or sulfone (formula (IV) in which Z is SO ₂ ). Compounds) can be prepared.

The compounds of the invention can be administered orally and have a surprising effect even parenterally and in the latter case hydrohalides, in particular chlorides, sulfates, phosphate nitrates, maleates, fumarates, acetates, methane sulfonates, naphthalenes It can be used in the form of pharmaceutically toxic salts such as sulfonates and the like.

The compounds prepared according to the invention are surprisingly excellent and exhibit a wide range of activities against the following nematodes and insects.

Insects (e.g., Uncinaria stemcephala, Acylostoma caninum and Bunostomium trigonocephalum)

2. Nematode nematodes (eg, Nipotstrongylus muris), Haemonchus contortus, Tricoslongitus coluqriformis, Osterragia sylcincinta (Ostertagia Circumc incta)

3. Advanced nematodes (eg Oesophagostomum columb ianum)

4. Reptiles (eg, Strongyloides ratti)

5. Roundworms (eg Ascaris suum, Toxocara canis and Toxascaris leonina)

6. Insects (eg Aspiculuris tetrapera)

7. Nematodes (eg Heterakis spumosa)

8. Insects (eg Trichiris muris)

9. Filaments (e.g. Litomosoides carinii) and Dipetalonema witei

10. Insects (such as Hymenolepis nona, Taenia pisiformis and Fchinococcus multilocu laris)

11.Reptiles (e.g. Fasciola hepatica)

Its activity is administered to animals severely infected with parasites by oral and parenteral administration.

The amount used is safe for the test animal.

The novel active compounds can be used as antiparasitic agents for both human and veterinary use.

The present invention also provides a pharmaceutical composition in which an active compound of the present invention is mixed with a solid or liquid gas diluent or a liquid diluent which is not a solvent having a molecular weight of 200 or less (preferably 350 or less) in the absence of a surfactant.

The present invention also provides a pharmaceutical composition containing the compound of the present invention as an active substance in the form of a sterile or isotonic aqueous solution, and also provides a medicament in unit dosage form containing the compound of the present invention. It may be formulated as a tablet (lozenges and granules), dragees, capsules, pills, ampoules or suppositories.

As used herein, "medicament" means having a physically clear condensation site suitable for pharmaceutical administration.

까지)을 담체와 혼합하거나 및/또는 용기내에 충진된 물리적으로 분명한 단위 응결부위를 갖는 의약 투여용에 적합한 것을 의미한다.As used herein, a "drug form of a medicament" refers to the daily or higher dose (up to four times) or smaller (

Means suitable for medicament administration by mixing the carrier with and / or having a physically apparent unit condensation site filled in the container.

또는

의 용량의 함유 여부는 약제를 각각 1회, 2회, 3회, 또는 4회로 투여하느냐에 달려있다.Half the daily use or half of the drug,

or

Dosage of depends on whether the drug is administered once, twice, three times, or four times, respectively.

The pharmaceutical composition according to the present invention is an ointment, a gel, a pasta, a cream, a spray (including an aerosol), a lotion, a suspending agent, and a liquid and an emulsion in which an active or water-insoluble diluent is dissolved in a syrup, granule or powder. It can be formulated.

Diluents used in pharmaceutical compositions (eg granules) for formulation into tablets, dragees, capsules and pills are as follows.

a) Fillers and weights, e.g. starch, sucrose, mannitol and silicic acid:

b) disintegrants, such as carboxymethyl cerose and other ceroses and derivatives, alginates, gelatin and polyvinyl pyrrolidone;

c) wetting agents: eg glycerol;

d) sealing agents: eg agar-agar, calcium carbonate and sodium bicarbonate;

e) dissolution retardant: eg paraffin;

f) dissolution accelerators: eg quaternary ammonium compounds;

g) surfactants: eg cetyl alcohol, glycerol monostearate;

h) adsorbents, eg kaolin and bentonite;

i) Sliding agents: eg talc, calcium and magnesium stearate and solid polyethylene glycols.

Tablets, dragee capsules and pills prepared from the pharmaceutical compositions of the present invention may contain coatings, sheaths and protective matrices in a conventional manner, including milk whites. They may be such that only the active substance is released slowly, preferably at a specific site of the intestine, preferably over a long time as possible. Coatings, sheaths and protective matrices may be made of polymeric materials or waxes.

The components can also be made in the form of microcapsules together with the diluents mentioned above.

Diluents used in suppository pharmaceutical compositions include polyethylene glycols and fats (e.g. cocoa butter and higher esters (e.g., C ₁₄ -alcohols and C ₁₆ -fatty acids)) or mixtures of these diluents. There are conventional water soluble or water insoluble diluents.

Pharmaceutical compositions such as ointments, pastas, creams and gels are for example animal and vegetable fats, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc And conventional diluents such as zinc oxide or mixtures thereof.

Pharmaceutical compositions such as powders and sprays may contain conventional diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof,

Aerosols may contain conventional jetting agents, such as chlorofluorohydrocarbons.

Pharmaceutical compositions that are liquids and emulsions may contain, for example, conventional diluents such as solvents, solubilizers and emulsifiers (except for solvents having a molecular weight of 200 or less in the absence of surfactants, as mentioned above, of course) and examples of such diluents include water, Ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. peanut oil), glycerol, tetrahydrofurfuryl alcohol , Fatty acid esters of polyethylene glycol, sorbitol, or mixtures thereof.

For parenteral administration, solutions and emulsions must be sterilized and, if necessary, plasma isoform.

Pharmaceutical compositions that are suspending agents include water, ethyl alcohol, propylene glycol, surfactants (e.g., ethoxylated isosteatyl alcohols, polyoxyethylene sorbitan and sorbitan esters), microcrystalline ceroses, aluminum metahydroxides, And common diluents such as bentonite, agar-agar, and tracant or mixtures thereof.

All pharmaceutical compositions according to the invention may contain colorants, preservatives, fragrances, flavoring agents (eg peppermint oil and yukari oil) and sweetening agents (eg saccharin).

The pharmaceutical composition of the present invention contains from 0.1 to 99.5% of the total composition weight, preferably from 0.5 to 95% of the active ingredient.

In addition to the compounds of the present invention, the pharmaceutical compositions and medicaments of the present invention may contain other pharmaceutically active compounds and may also contain several compounds of the present invention.

Diluents used in the medicaments of the present invention are the same as those mentioned above in connection with the pharmaceutical compositions of the present invention. Such agents may contain a solvent having a molecular weight of 200 or less as a single diluent.

The clear condensation site constituting the medicament according to the present invention may generally be useful in a form or package suitable for medicament administration in general, for example:

Tablets (including lozenges and granules), pills, dragees, capsules, suppositories, and ampoules These forms may also be sustained release. Something like a gapsing agent can coat a protective film that encapsulates a physically obvious condensation site.

The daily dosage of the active substance is preferably 5 mg to 5 g.

The pharmaceutical composition and the method of preparing a medicament are known by mixing an active substance with a diluent to form a pharmaceutical composition (e.g. granules) and then formulating it into a medicament (e.g. tablets).

The present invention also provides a method for combating (including preventing, controlling and treating) the above-mentioned diseases in a human body or an animal by administering the compound of the present invention alone or in admixture with a diluent or as a medicament.

The compounds of the present invention may be administered orally, parenterally (eg, intramuscularly, intraperitoneally or intravenously), rectally or topically, preferably orally, and also parenterally, in particular subcutaneously and epidermally. . Preferred compositions and medicaments are suitably administered orally.

In general, the dosage of the novel compound is preferably about 0.1 to 50 mg / kg body weight per day for effective results.

However, sometimes the dosages mentioned may deviate and depend in particular on the weight of the test animal, the method of administration and the adaptability to the species of the animal and its medicament, the type of preparation, the time of administration or the interval of administration. In some cases, less than the above-mentioned minimum amount may be administered, and in larger cases, the maximum amount mentioned may be exceeded.

When administering a large amount it is preferable to administer divided into four times a day. The same dosage range may be administered to the medicament or veterinary medicine, and other described dosages may be applied.

The antiparasitic effect of the active compounds according to the invention is explained in detail in the following examples.

Example A

Parasite Test / Quantity of Stomach and Intestine

Infected sheep (Haemonchus contortus) or nematode (Trichostrongylus colubr iformis) are completely parasitic and treated.

The active compound is orally administered as the pure active compound contained in the gelatine capsule.

The activity level is determined by quantitatively counting the eggs excreted on the stool before and after treatment. Complete discontinuation of egg excretion after treatment means that the parasite has been eradicated or eradicated to the point where it can no longer spawn (effective amount).

The effective compound tested and the effective amount (minimum effective amount) are shown in the following table.

TABLE 1 (According to Example A)

Example 185

19.8 g of N- (2-propionylamino-5-propylthio-phenyl) -N 'and N "-bis-methoxycarbonyl-guanidine (Example 5) are dissolved in 650 ml of acetic anhydride. 42 g of hydrogen peroxide ( 30% strength) and the mixture was stirred overnight and then evaporated in vacuo.

The residue is crystallized (treated with a mixture of ethyl acetate and ether). The precipitate is filtered off and recrystallized from ethyl acetate. Yield: 22.2 g, Melting point: 165 to 166 ° C U, Z

Example 186-228

In each example, the sulfone of the following general formula is obtained by oxidizing the corresponding thioether in the same process as in Example 185.

Example 229-272

In each example, the sulfone of the following general formula is obtained by oxidizing the corresponding thioether in the same process as in Example 185.

Example 272

9.9 g of N- (2-propionyl amino-propylthio-phenyl) -N, N "-bis-methoxy carbonyl-guanidine (Example 101) are dissolved in 200 ml of acetic anhydride. 25.8 ml of hydrogen peroxide (30% Strength) and the mixture is stirred at 20 ° C. for 4 hours, then concentrated in vacuo and the residue is recrystallized from ethyl acetate.

Yield: 7.37 g, Melting point 152 DEG C u. z

Example 273-315

In each of these examples, the sulfoxide of the following general formula is obtained by oxidizing the corresponding thioether in the same process as in Example 272.

Example 316-358

In each of these examples, the compound of the following general formula is obtained by oxidizing the corresponding thioether in the same manner as in Example 272.

Claims (1)

A process for preparing a compound of formula (I) characterized by reacting a compound of formula (IV) with an oxidizing agent.

Wherein R is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, X is SO or SO ₂ , R ¹ and R ² are different from each other,

R ³ and R ⁴ are the same or different and are alkyl and R ⁵ is hydrogen, optionally substituted alkyl or optionally substituted alkoxy.