CS212773B2 - Method of preparing 2,6-anthraquinonylene amidines - Google Patents

Abstract

TITLE: 2,6 ANTHRAQUINONYLENE AMIDINES AS ANTI-AMEBIC AGENTS Novel 2,6 anthraquinonylene amidines that are effective against cecal and hepatic amebic infestations in warm-blooded animals.

Description

The present invention relates to novel 2,6-anthraquinonyleneamines of formula (I)

(I) where

H 1 is hydrogen, C 1 -C 3 straight chain alkyl, isopropyl, cyclopropyl, cyclobutyl or halogenated phenyl,

R 2 represents a substituted amino group of formula

R3 /

—N \

Ri where each of the symbols

R 3 and R 4 are hydrogen, C 1 -C 3 straight chain alkyl or isopropyl; or

R 3 and R 1 together with the adjacent nitrogen atom form a five- or six-membered heterocyclic ring selected from the group consisting of piperidino, morpholino or pyrrolidino, and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment of cecal infections (appendicitis) and hepatic amoebic infections in warm-blooded animals. The present invention provides a process for their preparation.

According to the invention, 2,6-anthrachinonylehamidines of the formula I are prepared by reacting 2,6-diaminoanthraquinone with a complex formed by mixing phosphorus oxychloride and N, N-dimethyl, N, N-diethyl or N, N-dipropylamine. or N-methyl-, N-ethyl- or N-propylamide in an inert solvent at 25 to 70 ° C for 1 to 24 hours.

The compounds of the present invention are normally crystalline solids that are soluble in dimethylformamide dimethyl sulfoxide and less soluble in chloroform, alcohol, and acetone. Salts (with one or two equivalents of acid) are well soluble in water and less soluble in alcohol.

Thus, the compounds of formula (I) can be prepared by reacting 2, (R, R, R, R) quinone (1 mol) with a complex formed with phosphorus oxychloride (1). 5 to 3 moles) and the above N, N-dialkylamide or N-alkylamide (2 to 6 or more moles) in a solvent such as acetonitrile (at a ratio of about 1 to 3 liters of solvent per mole of amine) at 25 to 70 ° C for 1 to 24 hours.

Specifically, phosphorus oxychloride is added to a solution of the above-mentioned Ν, dial-dialkylamide or N-alkylamide in a solvent at -5 to 20 ° C. . The resulting mixture was stirred at 0 ° C to room temperature for 30 minutes to 6 hours. 2,6-Diaminoanthraquinone was added and the reaction mixture was stirred at 25-70 ° C for 1-24 hours. The reaction mixture was poured into ice water and basified. The resulting crystals are filtered and recrystallized from a suitable solvent or solvent mixture such as chloroform / hexane.

The compounds of the present invention are effective in the treatment of caecal and hepatic amoebic infections in warm-blooded animals. This effect can be demonstrated by the following two tests:

Organism

In both tests, 200% of Entamoeba grains were used as organism. histolytica from the National Institute of Health (USA). This strain and unidentified faecal flora are cultured at 37 ° C in Cleveland-Collier medium. This medium consists of agar produced from the liver infusion as a base, which is covered with a mixture of horse serum: a mixture of salts (1: 6). which is added a few milligrams of sterile rice powder. . Amoeba are transferred twice a week to fresh medium. ·

C-aecal infection in white Wistar rats: <

During laparotomy, 0.25 ml of the upper culture layer containing a large amount of amoeb was injected into the caecum of anesthetized rats. Treatment is started one day after inoculation. Compounds are dissolved and suspended in 0.2% aqueous agar and administered by gavage once daily for 5 consecutive days. Six days after inoculation with amoebae, rats are sacrificed and the caecal wall scraps of each rat are mixed with a drop of 0.85% saline solution and microscopically detected for amoebae. A rat is considered cured when no amoeba is seen. The ratio of number of cured rats / number of rats treated for each treatment regimen is calculated, and this ratio is corrected for the non-specific cure observed in the untreated infected control subjects. The effective dose is considered to be the lowest dose (mg / kg / day) to dial 50 ·% or more of the rats so rotated. The results obtained with typical compounds are shown in the following table, together with comparative results obtained with known active drugs.

Hepatic infection in golden hamster females

In laparolemia of anesthetized hamsters, a piece of absorbable sponge impregnated with amoebae of about 25 mm ² is inserted between the middle lobes of the liver. Unwoven hamsters usually die as a result of the infection 7 days after inoculation. Treatment is initiated on the day of inoculation as soon as the hamsters recover from surgical anesthesia. Test compounds are dissolved or suspended in 0.2% aqueous agar and administered once daily by gavage for 5 consecutive days. Effective mode prevents death. Survival rate is corrected for the non-specific survival observed in the untreated groups. An effective dose is considered to be the lowest dose, expressed in mg / kg / day, that protects 50% or more of the hamsters treated (who survive 14 days after inoculation). The results obtained using the typical compounds of the present invention are shown for comparison along with the effective dose of known active drugs in the following table.

Table

Caecal infection lowest effective dose mg / kg / day

Hepatic infection lowest effective dose mg / kg / day

N - (- (2 ₎ 6-anthraquinenylene) bis-N, N-dimethylformamidine

N ‘, N‘ “- (2,6-anthraquinonylene) bis-Ν, Ν-diethylacetamidine (2,6-anthraquinonylene) bis-N-ethyl-N-methylformamide

N ', N ^UI - (2,6-anthraquinonylene) bis-NN-diisepropylformamidine

2,6-bis- (piperidinomethyleneamino) anthraquinone

2,6-bis- [(l-piperidinopropyllden) amino] anthraquinone

20 May 10 10 21 50 - 20 May 100 ALIGN! 20 May 100 ALIGN! 50 -

Caecal infection lowest effective dose mg / kg / day I-Iepatic infection lowest effective dose mg / kg / day 2,6-Bis - [(1-piperidinoethylidene) - amino) anthraquinone 50 - 2,6-bis - [[1- (4-methylpiperidino)] - ethylidene] amino / anthraquinone 10 - 6-n-Propyloxy-3-nitroimidazo [1,2- -bjpyridazine 20 May 25 2-methyl-5-nitroimidazole-1-ethanol 10 10 nitrimidazine 20 May 100 ALIGN! tinedazole 5 25

The novel 2,6-anthraquinonylenamidines of the present invention are useful in the treatment of caecal and hepatic amoebic infections in warm-blooded animals at a dose ranging from about 0.5 to about 40 mg / kg / day (mg substance per kg body weight per day). The preferred dosage for optimal results is about 2 to about 29 mg / kg / day. Thus, the daily dose for a patient of about 70 kg body weight is about 35 mg to about 2.8 g, preferably about 150 mg to about 2.0 g.

Suitable oral preparations are, for example, capsules, tablets, pills, suspensions, syrups, etc. In the case of tablets, the main active ingredient is mixed with conventional ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, medium calcium phosphate. , resins, or the like, such as non-toxic pharmaceutically acceptable diluents or carriers.

Delayed dosage forms may also be used.

Suitable liquid dosage forms for the active compounds according to the invention are suitable flavored emulsions with edible oils, such as cottonseed oil, sesame oil, coconut oil, peanut oil, elixirs and the like. parenteral use. Isotonic preparations containing suitable preservatives are also suitable for injectable use.

Example 1

N, N‘- (2,6-anthraquinonylene) diformimidic acid diethyl ester

35.7 g of 2,6-diaminoanthraquinone are mixed with 100 ml of triethyl orthoformate containing 5 drops of concentrated sulfuric acid. The mixture was refluxed and the alcohol formed was removed within 2 hours. The reaction mixture was cooled to 1010 ° C, the solid which formed was filtered off, washed with 2 V alcohol and air dried. Recrystallization from dimethylformamide gave brown crystals, m.p. 235-250 ° C.

Example 2

2,6-bis- (4-methyl-1-

(piperazinylmethylene) amino] anthraquinone

5.25 g of N, N &apos;-( 2,6-anthraquinonylene) di-formimide acid diethyl ester, 4.0 ml of N-methylpiperazine and 100 ml of dimethylformamide were heated together on a steam bath overnight. The mixture was cooled, filtered and the solid washed with dimethylformamide and 2B alcohol and dried under vacuum over phosphorus pentoxide at 78 ° C. An orange solid is obtained, m.p. 278-281 ° C.

Example 3

N ', N ^' - (2,6-anthraquinonylene) bis-NN-dimethylformamide

A suspension of 7.15 g of 2,6-diaminoanthraquinone in 17.68 g of N, N -dimethylformamide diethyl acetal is stirred and heated in an oil bath at 150 ° C for 17 hours. The by-product ethanol is distilled off. Dimethylformamide (30 ml) was added and the hot mixture was filtered. The solid was washed with acetone and the resulting red-brown sticks were recrystallized from 30 mL of dimethylformamide and then dried at 80 for 4 hours to give a pale yellow solid.

Example 4

N ‘, N‘ ‘- (2,6-anthraquinonylene) -bis-N, N.

-diethylformamidine

5.95 g of 2,6-diaminoanthraquinone and 14.7 g of diethylformamide dimethyl acetal [prepared according to H, Bredereck et al., Chem. Ber. 101, 41-50 (1968)] and the mixture was refluxed for 66 hours at 153 ° C in an oil bath. Remove the reflux condenser and allow the distillate to boil. The remaining volatiles were removed under vacuum. The residue was suspended in 50 ml of hexane, filtered, the solid was washed with hexane and air dried. Extract the solid with 2 X X 100 mL of boiling methanol, filter while hot, and cool the filtrate to -10 ° C. The resulting solid was filtered off and dried in vacuo over phosphorus pentoxide. The solid is recrystallized from 200 ml of boiling ethylene glycol monomethyl ether (hereinafter methylcellosolv), the solution is cooled to -10 ° C and the red solid is filtered off and dried in vacuo over phosphorus pentoxide. Its melting point is 182-184 ° C.

Example 5

N ‘, N‘ ‘- (2,6-anthraquinonylene) -bis-N, N-dibutylformamidine

50 ml of Ν, Ν-dibutylformamide and 5.95 g of 2,6-diaminoannhraquinone are mixed and 16.9 g of p-toluenesulfonyl chloride are added. The mixture was heated on a steam bath for 2 1/2 hours. Add 150 mL of 2B alcohol mixture. Heat to boiling and filter while hot. The filtrate was cooled to 1010 ° C and the brown solid obtained was collected and dried at 78 ° C under vacuum over phosphorus pentoxide. This solid was dissolved in 300 ml of hot water and added with 20 ¹ ml of 1 N sodium hydroxide. The resulting solid was recrystallized from 150 ml of methanol (cooled to -10 ° C). The product is dried at 78 ° C under vacuum over phosphorus pentoxide. An orange solid is obtained with a melting point of 98-100 ° C.

Example 6

N ‘, N‘ ‘- (Z ^-í n ^ ^ ^ ^ 1 -quinazinonylene) bis-N, N-diethylacetamide

To a solution of 276.0 g of dried N, N-diethyl acetamide in 800 ml of acetonitrile, cooled in an ice-water bath to 5-10 ° C, was added dropwise 87.4 ml of phosphorus oxychloride over 10-15 minutes. The ice bath was removed and the resulting mixture was stirred at room temperature for 1 hour. To the resulting mixture was added 95.2 g of 2,6-diammoanthraquinone and the mixture was stirred without heating for 1 hour and then for 7 hours at 60 ° C. The mixture was cooled to room temperature and poured into 100 ml of ice / water. The aqueous solution was diluted to 3000 mL and basified with 5 N sodium hydroxide. The resulting orange-yellow crystals were filtered off, washed with water and air dried. The product is dissolved in 450 ml of chloroform, the solution is filtered and the product is precipitated with about 400 ml of hexane. The resulting product consists of orange crystals, m.p. 173-175 ° C.

Example 7

N ‘, N‘ ‘- (2,6-anthraquinonylene) -bis-N, N-dipropylformamide

95.3 g of 2,6-diaminoanthraquinone, 260 ml of triethyl orthoformate and 6 drops of concentrated sulfuric acid are added and the mixture is heated in an oil bath for 2 hours to distill off the ethanol. 140 ml of triethyl ortho formate was added and heating at 140 ° C in an oil bath was continued for 6 hours. The mixture was cooled in an ice bath and filtered. The solid was washed twice with ether, dried at 64 ° C overnight and then at 78 ° C under vacuum over phosphorus pentoxide. A brown solid is obtained. 10 g of this solid are mixed with 50 ml of di-n-propylamine and the mixture is heated in an oil bath at 140 ° C for 90 minutes with stirring. The mixture was allowed to cool overnight and the volatiles were removed in vacuo. The brown solid was recrystallized from 400 mL of 2B alcohol. The orange solid obtained was recrystallized from 200 ml of methylcellosolv (the solution was cooled to 1010 ° C). 182 DEG-185 DEG.

Example 8

N ‘, N‘ - (2,6-anthraquinonylene) -bis-N-octyl-N-methylformamidine 10.0 g of N, N ‘- (2,6-anthraquinonylamino) -dimimidic acid diethyl ester are mixed and

13.3 g of N-methyloctylamine and the mixture was heated in an oil bath at 150 ° C for 90 minutes. The mixture was cooled and the volatile component was removed in vacuo. The residue was suspended in two 50 ml portions of hexane and filtered off each time. The orange solid obtained was air dried. The product is recrystallized. from a hot mixture of 100 ml benzene and 200 ml hexane. Cooling the mixture to 4 ° C gives the product, which is dried at 78 ° C. vacuum over phosphorus pentoxide. 81 DEG-83 DEG.

Example 9

N ‘, N‘ ‘- (2,6-anthraquinonylene) -bis-N, N-diisopropylformamidine

5.95 g of 2,6-diaimnoannhrachmon and 10.0 g of diisopropylformamide are mixed to form a suspension. To this suspension was added 14.3 g of p-toluenesulfonyl chloride. The mixture was heated on a steam bath for 2 x / 2 hours. 100 ml of 2B alcohol are added and the mixture is refluxed for 5 minutes. The mixture was heated to boiling and the solid was filtered, washed with 2'B alcohol and air dried. The solid is suspended in 150 ml of hot water, filtered while hot, and the insoluble solid is washed twice with water. The filtrate and washings were basified with an excess of 10N sodium hydroxide to pH 10. The orange precipitate was washed twice with water and air dried. This. the solid is recrystallized from 150 ml of 2B alcohol (cooled to -10 ° C) and dried under vacuum at 78 ° C over phosphorus pentoxide to give an orange solid, m.p. 206-208 ° C.

Example 10

N ‘, N‘ ‘- (2,6-anthraquinonylene) bis- (N- (p-chlorophenyl) iformamidine)

10.0 g of N, N &apos;-( 2,6-anthraquinonylene) diformimidic acid -diethyl ester and 7.66 g of p-chloroaniline are combined and the mixture is heated in an oil bath at 160 DEG C. for 7 hours and then allowed to stand at room temperature. room temperature. The solid residue is recrystallized from -350 ml of dimethylforinamide (the solution is cooled to 1010 ° C) and dried at 78 ° C under vacuum over phosphorus pentoxide. A red solid is obtained.

Example 11

N ‘, N‘ ‘- (2,6-anthraquinonyl) bis- (N-methyl-N-phenyl) -formamidine

10.0 g of N, N '- (2,6 * anthraquinonylene) -dimide diethyl ester and 25 ml of N-methylaniline were heated at 140 ° C in an oil bath for 2 hours and then allowed to stand overnight at room temperature. with two 50 ml portions of hexane and air-dried to give an orange-brown solid which was recrystallized from 200 ml of dimethylformamide by cooling to -4 DEG C. The solid was filtered off, washed with dimethylformamide and twice with 2B alcohol. After drying at 78 ° C under vacuum over phosphorus pentoxide, a dark orange solid is obtained with a melting point of 308-312 ° C.

Example 12

2,6-bis- (piperidinomethyleneamino) anthraquinone

A mixture of N, N &apos; * 7.0 diethyl ester (2,6-anthraquinonylenediimidimic acid) and 7.48 g of piperidine was heated at 130-140 degrees Celsius in an oil bath for 2 hours and then allowed to stand overnight at room temperature. The reaction mixture was triturated with two 50 mL portions of hexane and the brown solid was air dried, the solid was recrystallized from 275 mL boiling methylcellosive, filtered hot and then cooled to 4 ° C. The solid was washed with methylcellosolvenl and 2B alcohol. and dried in vacuo at 78 ° C over phosphorus pentoxide to give an orange solid at a melting point of 229-233 ° C.

Example 13

N., N'-2,6-anthraquinonylene-di-acetimidic acid diethyl ester A mixture of 35.7 g of 2,6-diaminoanthraquinone, 100 ml of triethylcetyl acetate and 6 drops of concentrated sulfuric acid was heated in an oil bath at 130 ° C for 6 hours. A 10 cm Vigreux column and a separator cooler are connected to the flask. 5 ml of ethyl alcohol are collected and the mixture is left stirring at room temperature overnight. An additional 60 ml triethyl ^and thylorl: hcacetátu mixture was refluxed for 6 hours and then stirred overnight at room temperature. The brownish solid was filtered off, washed with ether and dried under vacuum. A 10 g sample of this product is recrystallized from 400 ml of methyl cellulose, the solid is filtered off, washed twice with ether and dried under vacuum at 50 ° C. Orange-brown crystals are obtained.

a sample of the brownish solid described above is recrystallized to 100 ml of dimethylformamide. Orange crystals were obtained (after drying under vacuum at 50 ° C). The recrystallized materials are combined to form the final product, m.p. 195-197 ° C.

Example 14

N ‘, N‘ ‘- 2,6-anthrachlnonylene-bis- (N-1,1,3,3-etramethylbutylformamide)

Mix 95.3 g of -2,6-diamino-anthhrachione, 260 ml of triethyl orthoformate and 6 drops of concentrated sulfuric acid in a 1 liter round bottom flask equipped with a short Vigreux column fused to a collecting condenser. The flask contents are boiled in an oil bath to distill off the ethanol. After 2 hours, it is collected with a total of 35 ml of ethanol, then 140 ml of triethyl orthoformate is added to the concentrated reaction mixture and heating is continued in an oil bath at 140 ° C. About -100 ml of distillate were collected at about 80 ° C over 6 hours. Remove the column and replace it with a collection condenser and heat the oil bath to 165 ° C. A further 15 ml of distillate was collected at 140 ° C. The flask is removed from the oil bath, cooled in an ice bath, and the residue is filtered off. The solid was washed twice with ether, squeezed to dryness and dried overnight at 64 ° C in an air-circulating oven. The product is then dried under vacuum at 78 ° C over phosphorus pentoxide. 233 DEG-280 DEG C., identified as N, N‘- (2,6-anthraquinonylene) di-formimide-odiethyl ester.

A suspension of 10 g of this compound in 20 ml of tertiary octylamine was heated in an oil bath at 170 ° C in an open flask. The spaghetti thickens in about 10 minutes and periodically mix with a spatula. Within 2 hours, the liquid having a boiling point of about 80 ° C distills off. The heat was removed and the mixture was allowed to stand in an oil bath overnight. for example, the reaction mixture is suspended in hexane and filtered off, this process repeated once more and the dark orange solid dried in air. The product is extracted three times with 100 ml of boiling benzene and, after drying, recrystallized from 100 ml of methylcellosive. An orange-yellow solid is obtained, m.p. 195-198 ° C.

Example 15

2,6-bis- [1- (4-methyl-1-plpierazinyl) ethylidene] amino / anthraquinone

A mixture of 7.5 g of N, N-.alpha.-anthraquinoneendi-212773 acetimidodiethyl ester and 40 ml of N-methylpiperazine is heated in an oil bath at 145 DEG C. under reflux for 24 hours. The condenser was removed and the mixture was heated for an additional 30 minutes. After cooling to room temperature, a solid formed which was diluted with 100 mL of diethyl ether and filtered. A brownish solid is obtained, which is washed with diethyl ether and dried under vacuum. The dried material was recrystallized from 85. ml of dimethylformamide. Yellowish crystals are obtained. The product is dried under vacuum at 80 ° C.

Example 16

N ‘, N‘ ‘- (2,6-anthraquinonylene) -bis- [Ν, Ν-dimethyl] acetamidine

To a mixture of 5.96 g of 2,6-diaminoanthraquinone and 20 ml of Ν, Ν-dimethylacetamide is added

14.3 g of p-toluenesulfonyl chloride. The mixture was then heated on a steam bath for 2 hours, changing from red to brown. 100 ml of 2B ethanol are added, the solution is heated to boiling and filtered. The filtrate was cooled to -10 ° C. The solid was collected and washed with 2B alcohol. It is then suspended in hot water, the suspension is filtered while hot and the insoluble solid is washed twice with hot water. The filtrate and washings were made basic with sodium hydroxide. The orange solid was dried, recrystallized from 2B alcohol and dried at 78 ° C under vacuum over phosphorus pentoxide. Its melting point is 295-330 ° C.

Example 17

N, N‘-2 (N, N-N, N-N) -quinazinonylenedipropionimidodiethyl ester

Mixture. 7.2 g of 2,6-diaminoanthraquinone, 30 ml of triethylorthopropionate and 25 ml of acetic anhydride are refluxed for 2 hours. Mixture. The mixture was cooled to room temperature and the solid collected by filtration, washed with diethyl ether and dried in vacuo. The product was recrystallized from dimethylformamide. Orange crystals of m.p. 195 DEG-198 DEG C. are obtained.

Example 18

2,6-bis - [1- (4-methyl-1-piperazinyl) propylidene] amino / anthraquinone

A mixture of 8.12 g of N, N‘-2,6-anthraquinonylenedipropionimidodiethyl ester and 40 ml of N-methylpiperazine is heated in an oil bath at about 140 ° C under reflux for 20 hours. The condenser was removed and the mixture was heated for an additional hour and then concentrated in vacuo to a thick brown syrup. The syrup is stirred in 125 ml of diethyl ether and the orange-brown solid is filtered off, washed with ether and dried in vacuo. The dried material was recrystallized from 70 ml of dimethylformamide.

Dark yellow crystals of m.p. 208 DEG-210 DEG C. are obtained.

Example 19

2,6-bis [(1-piperidinylpropenene) amino] anthraquinone

A mixture of 8.12 g of N, N‘-2,6-anthraquinonylenedipropionimidodiethyl ester and 40 ml of piperidine was heated in an oil bath at 115 ° C for 18 hours under reflux. Remove the condenser, heat the mixture for an additional hour and then. Concentrate in vacuo to a brown syrup. The syrup is stirred in 100 ml of diethyl ether, the brown solid is filtered off, washed with ether and dried in vacuo. The dried product was recrystallized from 40 ml of dimethylformamide. Dark yellow crystals of m.p. 183-185 ° C are obtained.

Example 20

2,6-bis [(1-piperidinylmethyl) amino] anthraquinone

A mixture of 7.56 g of N, N‘-2,6-anthraquinonylenediacetimidodiethyl ester and 40 ml of piperidine was refluxed in an oil bath at 120 ° C for 20 hours. Remove the condenser, heat the mixture for an additional hour and then concentrate in vacuo to a dark syrup. The syrup was triturated with 100 ml of diethyl ether, the resulting orange solid was filtered off, washed with ether and dried in vacuo. The dried material was recrystallized from 40 ml of dimethylformamide. Yellow crystals of m.p. 233 DEG-235 DEG C. are obtained.

Example 21

2.6- bis] /. [4- (3-dimethylaminopropyl) piperidinoylmethyleneaminoanthraquinone

Suspension 7.0. g of N, N '- (2,6-anthraquinonylene-imidimidodiethyl ester) and 15.0 g of 4- (3-dimethylaminopropyl) piperidine dihydrochloride are heated for 3 hours in a flask equipped with a short Vigreux column fused to an oil cooler at 160 ° C During this time, the distillate is boiled at 78 DEG C. The reaction mixture is allowed to cool in an oil bath, then suspended in hexane and filtered, the solid dissolved in boiling dimethylformamide (100 ml) and the solution filtered hot. The filtrate was cooled to 1010 ° C and filtered to give an orange solid, which was recrystallized from 25 mL of methylcellosolv, the solution was filtered hot to clarify, and the filtrate was cooled to 1010 ° C and orange. The solid was collected and dried at 78 ° C over phosphorus pentoxide to give an orange solid, mp 171-174 ° C.

Example 22

2,6-bis [(1-morpholinoethylidene) amino] anthraquinone g of 2,6-tetrahydroquinone, 300 ml of triethyl orthoacetate and 250 ml of acetic anhydride are refluxed for 3 hours, cooled in an ice bath and the resulting brownish crystals filtered off, The organic layer was washed with ether and dried to give N, N'-2,6-anthraquinonylene diacetamidodiethyl ester.

7.56 g of this imino ether and 40 ml of pickling were heated in an oil bath at 135 ° C for 18 hours under reflux. The mixture was cooled in an ice bath. The brownish crystals are filtered off, washed with ether and dried under vacuum. The crystals are suspended in 100 ml of dimethylformamide, the suspension is heated to boiling and filtered. The filtrate is stirred in the refrigerator for 3 hours and the resulting yellow-orange crystals are filtered off and dried in vacuo. Their melting point is 285-288 ° C.

Example 23 is placed in a freezer for 2 hours. The product was filtered off and washed with a small amount of methylcellosolv and then with diethyl ether. The product is then dried under vacuum at 80 ° C. Yellow crystals of m.p. 150-153 ° C are obtained.

Example 26

N ‘, N‘ ‘- 2,6-anthraquinonylene-bis- (N, N-dipropyl) pr opionamidine

A mixture of 8.12 g of N, N ^{'<-2,6-anthrachinonylendipropionimidodiethylesteru,} 45 ml of di-n-propylamine and 2.35 ml of glacial acetic acid was heated at 110 ° C oil bath for 18 hours under reflux. The reaction mixture was cooled to room temperature, filtered and the precipitate was washed with diethyl ether. The filtrate and washings were concentrated in vacuo to a dark brown syrup. The syrup is taken up in 50 ml of methanol and the solution is stored in a freezer overnight.

The product was filtered off and dried in vacuo. Orange crystals of m.p. 125-128 ° C are obtained.

2,6c bis [(1-morpholinyl oil crude) amino] anthraquinone

A mixture of 8.12 g of N, N ,, ^t c2 ^ - C ^ i ^ 1 ^ 1 ^]? Achinonylendipropionimidodiethylesteru (Example - 17) and 40 ml morpholine was heated in an oil - bath to reflux at 130 ° C for 18 hours . The mixture was cooled in an ice bath, the dark yellow solid was filtered off, washed with ether and dried at 80 ° C under vacuum. Its melting point is 220-223 ° C. _:

Example -k 1 and -d 24

2.6c bis / [1c (4c-methoxy);

ethylidene] amino / anthraquinone _;

7.56 g of N, N-anthraquinonyleneclacetimic dodiethyl ester and 40 ml of 4-methylpiperidine were heated in an oil bath at 130 ° C for 18 hours under reflux. The mixture was cooled in an ice bath, the orange solid was filtered off, washed with ether and dried under vacuum at 80 ° C. The solid is recrystallized from 100 ml of methylcellosolv and the yellow crystals are dried under vacuum at 80 ° C. Mp 206-202 ° C.

Example 25

2.6c bis / [1c (4-methylpiperidine) propylidene] amino / anthraquinone

A mixture of 8.12 g of N, N‘‘2íccccn^^^in (quinonylendic propionimidodiethyl ester) and 40 ml of 4-methylpiperidine was heated under reflux for 18 hours at 130 ° C. The reaction mixture was cooled in an ice bath and filtered.

The filtrate was concentrated in vacuo to a dark brown resin which was taken up in 50 ml of methylcellosolv with heating. Solution

Example 27

N ^^^^ - anthraquinonylene-bisc [N, Ndibutyl] propionamidine

A mixture of 8.12 g of NN'-2 _: 6α-quinazinonylenedione propionimidodiethyl ester, 50 ml of di-butylamine and 2.35 ml of glacial acetic acid was heated in an oil bath at 150 ° C for 18 hours. The reaction mixture was cooled in an ice bath and diluted with an equal volume of diethyl ether. The remaining reddish brown solid was filtered off, washed with ether and dried in vacuo. The dried substance is taken up in about 40 ml of methanol and the solution is allowed to stand overnight in the refrigerator. The solution was filtered and the orange crystals were dried under vacuum at 80 ° C. The product was recrystallized from 30 ml of 2B ethyl alcohol. Orange crystals having a melting point of 115-117 ° C are obtained.

^ Example 28 fi

,6 N ‘, N‘ ‘2,6-anthraquinonylene-bisc m - (N-butyl-N-methyl) propionamidine: A mixture of 8.1-4 g of N, ΓN-26 a aalhraahiadonylenedipropionamidodiethyl ester, 45 butylamine and 2.35 ml of acid. it is heated under reflux condenser at a temperature of 130 ° C.

The reaction mixture was cooled to room temperature and filtered. Yippee. The filtrate is concentrated in vacuo to a dark brown syrup which is taken up in 30 ml of methanol. The resulting solution was placed in a freezer. After 2 hours, the orange crystals are filtered off, washed with a little methanol and dried in vacuo. The product is then recrystallized from 30 ml of methanol. Yellow crystals of m.p. 80-82 ° C are obtained.

Example 29

2,6-bis [[(4-methylpiperldino) methylene] amino] anthroquinone

A mixture of 6.8 g of N, N '- (2,6-anthraquinonylene-iodoimidodiethyl ester) and 8.93 g of 4-methylpiperidine was heated in an oil bath at 140 ° C for 2 hours while being placed in a flask equipped with a short Vigreux column. During this time, the distillate having a boiling point of 78 DEG C. was distilled off, the reaction mixture was allowed to cool overnight in an oil bath and then triturated with two 50 ml portions of hexane. The solution was cooled to 4 ° C and the solid was filtered and washed with methylcellosolv and 2B ethyl alcohol. The product was dried under vacuum at 78 ° C. over phosphorus pentoxide to give an orange solid, mp 229-233 ° C.

Example 30

2,6-bis (4,5,6,7-tetrahydro-3H-azepine-2-

-ylamino) anthraquinone

A mixture of 11.9 g of 2,6-diaminoanthraquinone, 28.0 g of 1-aza-2-methoxy-1-cycloheptene and 6.0 g of glacial acetic acid in 50 ml of N, N-dimethylacetamide was heated under reflux in oily for 2 hours. bath. The mixture was cooled to room temperature and 100 mL of diethyl ether was added. The resulting product is filtered off and washed extensively with dimethylsulfoxide, ethyl alcohol and finally ether. Greenish yellow crystals are obtained. The obtained material was dissolved in chloroform, filtered and the filtrate was evaporated to about 30 ml. The final product was precipitated with ether. After filtration, the product was washed with ether. Orange-yellow crystals of m.p. 295-298 ° C are obtained.

Example 31

-2,6-anthraquinonylene-bis- (Ν, Ν-diethyl) propionamidine 2,6-diaminoanthraquinone, 300 ml of triethylorthopropionate and 250 ml of acetic anhydride are refluxed for 2 hours and then cooled in an ice bath. The reddish brown solid was filtered off, washed with ether and dried. This material was suspended in 1 L of chloroform and filtered. The filtrate was treated with charcoal, filtered and concentrated in vacuo. An orange solid is obtained, which is N, N‘-2,6-anthraquinonylendipropionimidodiethyl ester.

8.12 g of this imino ether, 65 ml of diethylamine and 2.35 ml of glacial acetic acid were heated in an autoclave at 125 ° C for 16 hours. The Au stream is cooled in an ice bath and then opened. The reaction mixture was filtered and the filtrate was concentrated in vacuo. A sticky solid is obtained. The solid is taken up in 30 ml of methanol with heat and the solution is stored in a freezer for 2 hours. The orange-yellow crystals formed are filtered off, washed with a small amount of methanol and dried under vacuum. The resulting material was suspended in 50 ml of methanol, the mixture was heated to boiling and the insoluble yellow solid was filtered off. This solid was suspended in 50 mL of water and filtered. A yellow solid is obtained which, after drying under vacuum at 80 ° C, has a melting point of 147-150 ° C.

Example 32

N ', N' - 2,6-anthraquinonylene-bis- (N, N-butyl-N-methyl) acetamidine A mixture of 72 g of 2,6-diaminoanthraquinone, 300 ml of triethyl orthoacetate and 250 ml of acetic anhydride is refluxed for 3 hours, then cool in an ice bath. The brown crystals were filtered off, washed with ether and dried. The material is suspended in 800 ml of chloroform, filtered, and the filtrate is concentrated in vacuo. An orange solid is obtained, which is N, N‘-2,6-anthraquinonylendiacetimidodiethyl ester.

7.56 g of this imino ether, 45 ml of N-methylbutylamine and 2.35 ml of glacial acetic acid were heated in an oil bath for 17 hours and then the mixture was filtered. The filtrate was evaporated in vacuo. A brown resin is obtained. This resin was dissolved in 30 ml of methanol with heat and stored in a freezer for 2 hours. The orange crystals are filtered off, washed with methanol, dried and recrystallized from 30 ml of methanol. The product is obtained in the form of orange crystals, m.p. 114-116 ° C.

Example 33

N ‘, N‘ ‘- 2,6-anthraquinonylene-bis- (N, N‘ -dimethyl) propionamidine

To a solution of 24.2 g of N, N-dimethylpropionamide in 200 ml of acetonitrile which is cooled in an ice-water bath to 5 to 15 ° C is added dropwise 21.6 ml of phosphorus oxychloride. The resulting mixture was stirred at room temperature for 30 minutes, then 23.8 g of 2,6-diaminoanthraquinone were added and stirring was continued at room temperature for 16 hours. The mixture was then stirred at 60 ° C for 5 hours. The reaction mixture was poured into 1 liter of ice water, stirred and then filtered through a sinter funnel. The filter substance was extracted several times with water and the combined filtrate and extract solution was made basic with 5 N sodium hydroxide. The orange crystals that are formed are filtered off. The crystalline material is washed with water and air-dried. Then the product is recrystallized from me212773 η

thylcellosolv. Orange crystals of m.p. 206 DEG-209 DEG C. are obtained.

Example 34

N ‘, N‘ ‘- (2,6-anthraquinonylene-) bis-N, N-diethylncetamidine dihydrochloride

N ‘, N‘ - (2,6-anthraquinonylene) -bis-N, N-diethylacetamidine was suspended in methanol and methanolic hydrogen chloride was added with stirring until a solution was formed. Ether was then added until turbidity occurred. The solution is kept overnight at 0 ° C and then filtered. The precipitate which is N, N, N- (2,6-anthraquinonylene) -bls-N, N-diethylacetamidine dihydrochloride is separated.

Example 35

2,6-bis (piperidinomethylenamipo) anthraquinone dihydrochloride trihydrate

6.1 g of 2,6-bis- (piperidinomethyleneamino) -trinocinone prepared according to Example 12 are suspended in 300 ml of chloroform C. The suspension is filtered, and 10 ml of 4.5 N hydrochloric acid in isopropylalcohol is added to the filtrate. The mixture was kept at -10 ° C and then filtered, and the separated product was washed with chloroform on the filter and then dried at 78 ° C under vacuum over phosphorus pentoxide to give a light orange solid, which is dihydrochloride trihydrate.

Example 36

N ‘, N‘ ‘- 2,6-anthrothidyl-bis- [Ν, Ν-diethyl) bedzcmidld

To a solution of 75.2 g of diethyl amine in 600 ml of diethylene was added a solution of 56.3 g of bedzoyl chloride in 100 ml of ether. The mixture is stirred at room temperature for 2 hours, 50 ml of water are added to dissolve any excess of amine n amine hydrochloride. Wash the ether layer with 3 additional portions of water and dry the pck with anhydrous sodium sulfate. The ether is removed after all. There was obtained Ν, Ν-diethylbenzamide as a colorless oil.

To a solution of 23.8 g of this product in 200 ml of acetone-Uu maintained at 5-10 ° C with an ice-water bath was added 36.8 g of phosphorus oxychloride while stirring. The ice-water bath was removed and the resulting mixture was stirred at room temperature for 1 hour. Pnk is added 23.8 g of 2,6-diaminothiazonone and the mixture is stirred at 60 ° C for 10 hours. The reaction mixture was then poured into 600 ml of ice water and made basic with 5N sodium hydroxide solution. The product precipitated as orange crystals. The crystals are filtered off and washed with water. The product was recrystallized from chloroform / hexane. The orange-red crystals were reddish, m.p. 243 DEG-246 DEG.

Example 37

2,6-bis (a-piperidinylbenzylidenamno) anthrahhidone

To a solution of 28.6 g of Bedzrylpiperidine in 150 ml of cetonitrile, maintained in an ice-water bath at 5 ° C to 10 ° C, was added 18.4 g of phosphorus oxychloride with stirring. The ice-water bath was removed and the resulting mixture was stirred at room temperature for 1 hour. 11.9 g of 2,6-diamino-O -hrahhidone are added and the mixture is stirred at 60 ° C for 10 hours. The reaction mixture was poured into 500 ml of ice water and basified with 5N sodium hydroxide solution. The product is formed as orange crystals. These crystals are filtered off and washed with water. The product was recrystallized from chloroform / acetone. Orange crystals of m.p. 264 DEG-266 DEG C. are obtained.

Example 38

2,6- bis (n-piperidino-4-

-chlrгbeItzyll · denam’no] aItthгaciгdon

To a solution of 33.55 g of p-chlorobenzylpiperidine in -100 ml of acetonitrile cooled to 5-15 ° C with an ice-n-water bath was added stirring over 30 minutes with 10.8 ml of phosphorus oxychloride. Remove the ice-water bath and continue stirring for 30 minutes at room temperature. Pnk is added 11.9 g

The 2,6-aminoanthraquinone -n mixture was stirred for one hour at room temperature for 20 hours at -60 ° C. The reaction mixture was carefully poured - into - mixtures - -500 ml of ice-water mixtures, and the resulting mixture was stirred for 1 hour, while a total of -75 ml of 10 N sodium hydroxide was gradually added. The formed reddish solid is filtered off, washed with water and dried under vacuum at 80 ° C. The dried substance - suspended in 300 ml - Chloroform - and then. the mixture is filtered. The filtrate is washed 4 times with water, dried over magnesium sulphate, filtered and vacuum filtered. The residue is suspended in 50 ml of methanol, and the orange crystals are filtered off and washed with diethyl ether. The product is dried under vacuum. The obtained orange crystals have a melting point of 275-277 ° C.

Example 39

2,6-bis (n-diethylamino-4-

(chlorobenzylideneamino) anthr quinod

To a solution of 31.75 g of N, N-diethyl-p-chlorobenzamide in 100 ml of acetoditrile was added 10.8 ml of phosphorus oxychloride over 30 minutes while stirring and cooling the ice-water bath to 5 ° -15 ° C. The ice-water bath is removed and stirring is continued at room temperature for 3 minutes for 30 minutes. Then 11.9 g is added

2.6-diaminoanthraquinone and the mixture was stirred at room temperature for 1 hour and then at 60 ° C for 20 hours. The reaction mixture was carefully poured into ice-water (500 mL) and the mixture was stirred for 1 hour while adding a total of 75 mL of 10 N sodium hydroxide. The red solid is filtered off, washed with water and dried under vacuum at 80 ° C. The dried substance is suspended in 300 ml of chloroform and the suspension is filtered. The filtrate was washed with water (2.times.), Dried (MgSO4), filtered and concentrated in vacuo to a syrup. The material was suspended in 25 ml of methanol and the resulting orange-red crystals were filtered off. The product was washed with diethyl ether and dried in vacuo. Melting point: 253-255 ° C.

Example 40

N ‘, N‘ - - 2,6-anthrachmonylene-bis- (N-isopropylation-tamidine)

To a solution of 99.2 g of isopropylamine in 600 mL of ether was added 60 g of acetyl chloride at -10 ° C while cooling the bath. from methanol and dry ice. The reaction mixture was kept at room temperature for 4 hours and then filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was distilled to give N-isopropylacetamide. in the form of a colorless oil.

23.8. 2,6-diaminoanthrachmone, 36.8 g of phosphorus oxychloride, 30.3 g of N-isopropylacetamide and 200 ml of acetonitrile were reacted as described in Example 1. The product was obtained as orange crystals, m.p. 264-267. Deň: 32 ° C.

Example 41

N ‘, N‘ ‘- 2,6-anthraquinonylene-bis (N-methylacetamidine)

A mixture of 31.8 g of N-methylacetamide, 23.8 g

2,6-diaminoanthraquinone, 36.8 g of phosphorus oxychloride and 200 ml of acetonitrile were reacted as described in Example 1. The crude product was brown. . Net. product. 266 DEG-269 DEG C. is obtained in the form of orange crystals. ’-,

Example 1 'd 42' '

N ', N''-2,6ganthrachirii> nyle ^: n-biSt'? . '' ... '

- (N, N-diethylacetamino) -4,4‘-methylene-bis- (3-hydroxy-2-naphthoate). '

4.326 g of 'N'; N '' - 2,6-anthraquinonylene-bis '(N ₎ -diethyl-acetamidine] and' 3.884 g. . pamo 'kyteliay-te will dissolve in '20. ml of dimethylformamide. and the 'solution-- is -. It is filtered and ether is added to precipitate the product as yellow crystals of pamoate, m.p. 253 DEG-255 DEG. : \ i ...

Example 43

N ‘, N‘ '- 2,6-anthraquinonylene-bis-

- (Ν, Ν-dimethylcyclopr opencarboxamidine)

To a solution of 300 mL of 40% aqueous dimethylamine in 500 mL of ether was added dropwise 52.0. g of cyclopropanecarbonyl chloride in 100 ml of ether at 10-25 ° C. The mixture was stirred at room temperature for 2 hours and then 50 ml of water was added. The ether layer was separated, washed with three 50 ml portions of water, dried over sodium sulfate and filtered. The ether was removed and the residue was distilled. There was obtained Ν, Ν-dimethylcyclopropanecarboxamide as a colorless oil.

4.0 g of the above product, 23.8 g of 2,6miamantanthrachmon, 36.8 g of phosphorus oxychloride and 200 ml of acetonitrile were reacted as described in Example 1. Recrystallization from 2-methoxyethaaol gave the product as orange crystals of m.p. mp 241-243 ° C.

Example 44

N ', N' '- 2,6-anthraquinonylene-bis-

- (N, N-Diethylcyclopropanecarboxamidine)

134 ml of diethylamine in 600 ml of ether and 52.0 g of cyclopropanecarbonyl chloride were reacted as described in Example 45. N-diethylcyclopropanecarboxamide was obtained as a colorless oil.

42.4 g of this product. 23.8 g of 2,6-diaminmanthrachiaone, 36.8 g of phosphorus oxychloride and 200 ml of acetonitrile were reacted as described in Example 1. Recrystallization from 2-methoxyethanol gave the product as orange crystals, m.p. 166-168 ° C. .

Example 45

N ', N' - 2,6-anthraquinonylene-bis-

- [N, N-dimethylcyclobutanecarboxamidine]

To a solution of N, N-dimethylcyclobutanecarboxamide (19.1 g) in acetonitrile (150 ml) was added phosphorus oxychloride (18.4 g) at 5-10 ° C. . The resulting mixture was stirred at room temperature for 1 hour, and then 11.9 g of 2,6'-diamia-anhrachihmau was added. The mixture was stirred at 60 ° C for 10 hours, poured into 600 ml of ice-water and then made alkaline. N - sodium hydroxide. The orange crystals are filtered off and washed with water. Crystals. ' is dissolved in chloroform. and filtering the solution; The chloroform was removed under reduced pressure. By recrystallizing the residue from methylcellosolves, 16.2 g of orange crystals are obtained having a melting point of 209-211 ° C.

21'27 7 3

Example 46

2,6-bis- (1-methyl-2-

-pyrrolidinylidene] amino] anthraquinone

To a solution of 34.5 g of 1-methyl-2-pyrrolidinone in 150 ml of acetonitrile is added 18.4 g of phosphorus oxychloride at 5-10 ° C. The mixture was stirred at room temperature for 1 hour. 11.9 g of 2,6-diaminoanthraquinone are added to the mixture. The resulting mixture was stirred at 60 ° C for 10 hours, poured into 1000 mL of ice-water and basified with 5 N sodium hydroxide. The reddish crystals formed are filtered off and washed with water. Recrystallization from methylcellosolv gave 14 g of reddish crystals, m.p. 267-269 ° C.

Example 47

N ‘, N‘ ‘- 2,6-anthraquinonylene-b: s- (Ν, Ν-2-trimethylpropionamidine)

To a solution of 23.3 g of N, N 2 -imethylpropionamide in 150 ml of acetonitrile is added 36.8 g of phosphorus oxychloride at 5 to 10 ° C. The resulting mixture was stirred at room temperature for 1 hour. 23.8 g of 2,6-diaminoanthraquinone are then added. The mixture was stirred at 60 ° C for 10 hours, poured into 600 mL of ice water and basified with 5 N sodium hydroxide. The orange crystals were filtered off and washed with water. The crystals were dissolved in chloroform and the solution was filtered. The chloroform was removed from the filtrate under reduced pressure. The residue was recrystallized from methylcellosolv. 166 g of orange crystals of melting point 166 DEG-168 DEG C. are obtained.

Example 48

N ‘, N‘ ‘- 2,6-anthraquinonylene-bis- (N-ethylacetamidine)

To a solution of 26.1 g of N-ethylacetamide in 200 ml of acetonitrile was added 36.8 g of phosphorus oxychloride at 5-10 ° C. The resulting mixture was stirred at room temperature for 1 hour and then 23.8 g of 2,6-diaminoanthraquinone were added. The mixture was stirred at 60 degrees Celsius for 10 hours, poured into 600 ml of ice-water and basified with 5 ml. N sodium hydroxide. The orange crystals were filtered off and washed with water. The crystals were dissolved in chloroform and the solution was filtered. From the filtrate, chloroform was removed under reduced pressure. The residue was recrystallized from chloroform / hexane. 10.5 g of orange crystals of melting point 271 DEG-273 DEG C. are obtained.

Example 49

4.33 g of N‘, N‘‘-2,6-anthraquinonylene-bis- (N, N-diethyl) acetamidine in 100 ml of chloroform and 1.18 g of succinic acid in 100 ml of methanol are mixed. The resulting solution was evaporated to dryness under reduced pressure. 5.5 g of orange crystals of melting point 165 DEG-166 DEG C. are obtained.

Example 50

N ‘, N‘ ‘- 2,6-anthraquinonylene-bis - N, N-dimethyl-3-dimethylpropionamidine]

To a solution of 19.4 g of N, N-dimethylpivalamide in 100 ml of acetonitrile is added 18.4 g of phosphorus oxychloride at 5 to 15 ° C over 30 minutes. The resulting mixture was stirred at room temperature for 30 minutes and then heated at 60 ° C in an oil bath for 1 hour. Then 11.9 g of 2,6- (1,2-diquinoline) were added. The mixture was poured into 500 ml of ice water, the mixture was separated into an oil and an aqueous phase, and the aqueous phase was decanted from the oil and filtered. The solid was collected, washed with water 3X and dried to give the product, m.p. 158-160 ° C.

Example 51

N ‘, N‘ ‘- 2,6-anthracyclinonylene-bis- (Ν, Ν-dimethyl-p-chlorobenzamidine)

To a solution of 27.6 g of Ν-dimetbyl-p-chlorobenzamide in 100 ml of acetonitrile was added 10.8 ml of phosphorus oxychloride over 30 minutes while stirring and cooling the ice-water bath to 5-15 ° C. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes. 11.9 g of 2,6-diaminoanthraquinone are then added and the mixture is further stirred for 1 hour at room temperature and 20 hours at 60 ° C. The reaction mixture was carefully poured into 500 ml of a water / ice mixture and stirring was continued for an hour while a total of 75 ml of 10 N sodium hydroxide was gradually added. The orange solid was filtered off, washed with water and dried in vacuo at 80 ° C. The dried substance is suspended in 300 ml of chloroform and the suspension is filtered. The filtrate is

The mixture was washed with water, dried (MgSO4), filtered and concentrated in vacuo to a syrup. This material was suspended in 25 ml of methanol and the ‘red crystals formed were filtered off. The product was washed with diethyl ether and dried in vacuo. Mp 296-298 ° C.

N ‘, N‘ ‘- 2,6-anthraquinonylene bis- (γ-N-diethyl) acetamidine succinate

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of 2,6-anthraquinonylenamidines of the general formula I (t) wherein R1 is hydrogen, straight chain alkyl having 1 to 3 carbon atoms, isopropyl, cyclopropyl, cyclobutyl or halogenated phenyl, 1 R 2 represents a substituted amino group of formula R3 / —N \ R4 where each of the symbols R 3 and R 4 are hydrogen, C 1 -C 3 straight chain alkyl or isopropyl; or R 3 and R 4 together with the adjacent nitrogen atom form a five- or six-membered heterocyclic ring selected from piperidino, morpholino or pyrrolidino, characterized in that 2,6-diaminoanthraquinone is reacted with a complex formed by mixing phosphorus oxychloride and N, N-dimethyl -, Ν, Ν-diethyl or N, N-dipropylamide or Ν-methyl-, N-ethyl- or N-propylamide in an inert solvent at 25 to 70 ° C for 1 to 24 hours.