NO166176B - Anthranilic acid. - Google Patents

Description

This invention relates to new anthranilic acid derivatives with the general formula:

where:

R' is hydrogen, lower alkyl, lower alkenyl or halo-lower alkyl,

R'' is lower alkyl, lower alkoxy, lower alkenyl, halogen-lower-alkyl, lower alkylthio, nitro, di-(lower)-alkylamino, lower alkoxycarbonylamino, lower alkanoylamido or di-(lower)-alkylureido,

R'<1>' is hydrogen, lower alkyl or benzyl,

X is lower alkyl which may optionally be substituted

with phenyl, and

a is 0, 1 or 2,

with the term "lower" referring to radicals with up to 4 carbon atoms.

The new anthranilic acid derivatives are useful as intermediates for the production of new, therapeutically effective 2-oxy-4H-3,1-benzoxazin-4-one derivatives and, in a pharmaceutical sense, acceptable acid addition salts thereof. These end-products are biologically active as inhibitors of enzymes and especially as inhibitors of serine proteases in humans and animals.

The production of the aforementioned, new, therapeutically active

me 2-oxy-4H-3,1-benzoxazin-4-one derivatives are the subject of Norwegian patent no. 163486. These derivatives are compounds with the general formula:

where

R' is hydrogen, lower alkyl, lower alkenyl or halo-lower alkyl,

R'<1> is lower alkoxy, lower alkyl, lower alkenyl, halogen-lower-alkyl, lower alkylthio, nitro, amino, di-(lower)-alkylamino, lower alkoxycarbonylamino, lower acylamido or di-(lower)- alkyl ureido,

X is lower alkyl optionally substituted with phenyl, and

a is 0. 1 or 2,

where the term "lower" refers to radicals with up to 4 carbon atoms,

with the proviso that when X is ethyl, the benzoxazine ring has at least one substituent R' or R'',

and pharmaceutically acceptable acid addition salts thereof.

For a more detailed description of these therapeutically active compounds, reference is made to Norwegian patent document no. 163486.

Some terms used in this document are defined below.

By "alkylene" is meant a branched or unbranched, saturated, bridge-forming hydrocarbon group having 1-4 carbon atoms and which includes methylene, ethylene, propylene, isopropylene, n-propylene, butylene, sec-butylene, isobutylene, etc.

By "lower alkyl" is meant a branched or unbranched, saturated hydrocarbon chain which, unless otherwise indicated, has 1-4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-propyl, butyl, sec-butyl, isobutyl, beer. Lower alkyl groups may be limited to fewer carbon atoms than 4 when specifically indicated.

By "lower alkenyl" is meant a branched or unbranched, unsaturated hydrocarbon chain having 2-4 carbon atoms, and which includes vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, 1,3-butadienyl, cis -2-butenyl, trans-2-butenyl, etc.

By "lower alkoxy" is meant the group -OR, where R is lower alkyl as defined above.

By "lower alkylthio" is meant the group -SR, where R is

lower alkyl as defined above.

By "halogen" is meant fluorine, chlorine, bromine and. iodine.

By "halogen-lower-alkyl" is meant the group -R-halogen, where R is lower alkyl and both lower alkyl and halogen are as defined above. The alkyl group can have 1-3 halogen substituents. Examples of such substituted alkyl groups are bromomethyl, dibromomethyl, chloroethyl, dichloroethyl, trifluoromethyl, etc.

The new anthranilic acid derivatives according to the invention can be prepared as shown in the following reaction scheme:

The suitably substituted lower alkyl anthranilate (preferably ethylanthranilate) of formula V is converted to the carbamoyl chloride derivative by treatment with 0.5-1 equivalent, preferably approx. 0.75 equivalent, trichloromethyl chloroformate or phosgene in ethyl acetate at room temperature for two to three hours, preferably two hours. The resulting carbamoyl chloride derivative is then treated with about five times the equivalent amount of a suitable alcohol of the formula HOX (where X is as above) and a base, such as pyridine or triethylamine. The product with formula (A;R'''=alkyl) is isolated in a conventional manner. When necessary, the compound of formula (A; R'''=alkyl) can be hydrolyzed with a base in a mixture of aqueous sodium hydroxide and 1,2-dimethoxyethane in the mixing ratio 1:1, whereby after acidification the carboxylic acid of formula

(A; R'''=H).

The compounds of formula V which are used as starting materials in Reaction Scheme I can be prepared as illustrated in Reaction Scheme II.

As shown in Reaction core II, a nitrophenol derivative of formula 2, which is either commercially available or can easily be prepared according to known standard methods, such as those described under Preparation of starting material, part A, below, is transferred to the corresponding chlorine compound of formula 3 according to the method described by B. Boothroyd and E.R. Clark, J. Chem. Soc., p. 1504, London (1953). Details regarding this reaction will be found under Preparation of starting material, part B, below. The compound with formula 3 is then reacted at room temperature with an excess of approx. ten times the equivalent amount of pentane-2,4-dione and an excess of three to four times the equivalent amount of sodium methoxide in the presence of HMPA as solvent, whereby (2-alkyl-6-nitrophenyl)-diacetyl-methane with formula 4. The compound with formula 4 is then cyclized in concentrated sulfuric acid at 100-120°C, preferably at approx. 110°C for one to five hours, preferably for approx. three hours, whereby 4-alkyl-anthranil with formula 5 is obtained. Details regarding this method are described by I.R. Gambir and S.S. Joshi in Indian Chem. Soc. Journal, V. 41, pages 43-46 (1964). The method is shown in Production of output food, part C, below. Upon subsequent ring opening by treating the anthranile of formula 5 with a base, such as e.g. potassium carbonate or sodium carbonate, and a lower alkanol, such as e.g. ethanol, at reflux temperature, the ethyl-4-nitro-6-alkyl-2-amino-benzoate of formula (V; alkyl = ethyl) is obtained.

The anthranilic acid derivatives of the general formula A

can be transferred to therapeutically effective 2-oxy-4H-3,1-benzoxa-zin-4-one derivatives according to Norwegian patent document no: 163486 by ring-closing a compound with the formula (A):

where R', R'', R''', a and X are as indicated above, to a compound of formula (I), and if necessary reacts the obtained compound of formula I with an acid to form an in pharma- zytologically acceptable non-toxic acid addition salt.

For example, 2-ethoxy-5-ethyl-7-nitro-4H-3,1-benzoxazin-4-one (formula I) can be prepared as follows: A solution of 2-carboethoxyamino-4-nitro-6 -ethyl-benzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 25 ml of anhydrous THF were stirred at room temperature for 2.5 hours. The solution was evaporated to dryness, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to a solid. The solid was recrystallized from methylene chloride:petroleum ether to give the desired compound, 2-ethoxy-5-ethyl-7-nitro-4H-3,1-benzoxazin-4-one. Melting point 106-107°C. IR: 1770, 1660, 1600, 1595, 1535, 1515 cm.

The following examples illustrate the preparation of the new anthranilic acid derivatives according to the invention. First, however, the production of some starting materials must be illustrated.

Production of starting materials.

Ethyl-2-amino-6-ethyl-4-nitrobenzoate and related compounds of formula V.

A. 2,4-dinitro-6-ethylphenol.

(i) 25 g of concentrated sulfuric acid was added to 25 g of 2-ethyl-phenol (Aldrich) under vortexing. The solution was heated on a steam bath for one hour, after which it was cooled and 25 ml of water was added. The solution was placed in a dropping funnel and was added dropwise to 40 g of 70% nitric acid while cooling with a bath of ice and salt which was cooled with glycol. The solution in the dropping funnel was added during 1.5-2 hours, while the temperature was kept lower than 0°C. The resulting mixture was stirred at 0°C for three hours, after which the ice bath was removed and the mixture was further stirred overnight at room temperature. The mixture was then heated on a steam bath for one hour, after which it was cooled and 50

ml of water. After extraction with diethyl ether, the ether layer was washed with brine, dried over MgSO 4 and evaporated to a dark oil, which was passed through a silica gel column

using 10% ethyl acetate-petroiether. The combined filtrates gave a yellow-orange oil, which solidified by dry pumping, whereby 34 g of 2,4-dinitro-6-ethylphenol was obtained.

(ii) By proceeding in a similar way, but instead starting with 2-propylphenol, 2,4-dinitro-6-propylphen-

nol in the form of an oil.

B. 1-chloro-2^4-dinitro^6-ethylbenzene.

(i) 10 g of 2,4-dinitro-6-ethylphenol was placed in a 250

ml round-bottomed flask, and 60 ml of phosphorus oxychloride (Fisher) was added.

15 ml of N,N-diethylaniline (Aldrich) was added portionwise,

and the mixture became hot. The flask was placed under a condenser equipped with a drying tube and was heated in a steam bath for two hours and then cooled. The mixture was then carefully poured onto ice, with stirring, and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO 4 , and evaporated to a dark oil, which was passed through a silica gel column using 10% ethyl acetate-petroeether. The evaporated filtrates gave a reddish oil which solidified when pumped dry. The solid was recrystallized from ethyl acetate-petroiether, whereby 8.1 g of pale yellow needles of 1-chloro-2,4-dinitro-6-ethylbenzene were obtained. Melting point 41-44°C.

IR: 3400 cm, 3090 cm, 2980 cm, 1800 cm (w), 1540 cm, 1345

cm.

(ii) In a similar manner, the following compound was prepared:

1-chloro-2,4-dinitro-6-propylbenzene (oil).

C. i^-ethvl^^-dinitroenyl)-diacetyl-methane .

(i) 8.16 g of sodium methoxyde was placed in a flask containing 50 ml of hexamethylphosphoramide (Aldrich). 50 ml of 2,4-pentanedione (Aldrich) was added and the mixture was stirred under gentle heating with a heating mantle (Variac 25/140) for 30 minutes. .10 g of 6-ethyl-2,4-dinitrochlorobenzene in slightly dry tetrahydrofuran was added, and the mixture was heated at the same setting of the heating power for a further two hours. The reaction mixture was cooled and partitioned between ethyl acetate and 5N hydrochloric acid.

The ethyl acetate layer was washed with 5H HCl, water and brine, dried over MgSO 4 and evaporated to a dark oil. 350 ml of 10% ethyl acetate-petroiether was added, whereupon a pale yellow solid precipitated. This was passed through a silica gel column using 20% ethyl acetate-petroiether, whereby 5.4 g of 2,4-dinitro-6-ethyl)-diacetylmethane was obtained. Melting point 126-128°C.

IR: 3100 cm, 2980 cm, 1525 cm, 1345 cm. (ii) In a similar manner, the following compounds were prepared:

(6-methyl-2,4-dinitrophenyl)-diacetylmethane,

sm.p. 145-147°C and

(6-propyl-2,4-dinitrophenyl)-diacetylmethane,

sm.p. 147-147.5°C.

D. 4-Ethyl-6-nitro-anthranil.

(i) 5 g of (6-ethyl-2,4-dinitrophenyl)-diacetylmethane was dissolved in concentrated sulfuric acid, and the solution was heated at 90-110°C in an oil bath for three hours. The mixture was poured onto ice, with stirring, and was extracted with methylene chloride. The resulting emulsion was filtered through Celite to separate the layers. The methylene chloride layer was dried over MgSO 4 and evaporated to a dark solid, which was dissolved in a little methylene chloride and passed through a silica column using 10% ethyl acetate-petroiether. Evaporation of the filtrate gave 2.57 g of 4-ethyl-6-nitro-anthranil as an orange-coloured solid. Melting point 69-72°C.

IR: 3140 cm, 3100 cm, 2970 cm, 1550 cm, 740 cm. (i) In a similar manner, starting with other suitable compounds, the following compounds were prepared: 4-methyl-6-nitro-anthranil, m.p. 158-160°C and 4-propyl-6-nitro-anthranil, m.p. 82-84°C.

E. ethyl-2-amino-6-ethyl-4-nitrobenzoate {_ f forme 1_V|.

(i) 2 g of 4-ethyl-6-nitro-anthranil was refluxed for three hours in ethanol with potassium carbonate. The reaction mixture was cooled, filtered and evaporated to a dark, oily solid, which was dissolved in ethyl acetate and dried. The residue was dissolved in methylene chloride and passed through a silica gel column using 15% ethyl acetate-petroiether. The residue from the filtrate was recrystallized from methylene chloride-petroleum ether, whereby 1.9 g of ethyl-2-amino-6-ethyl-4-nitrobenzoate with melting point 68-70°C was obtained. IR: 3490 cm, 3380 cm, 3080 cm, 2980 cm, 1690 cm, 1620 cm, 1515 cm, 1350 cm. (ii) In a similar manner, starting instead with other suitable 4-alkyl-6-nitro-anthraniles, the following compounds of formula VII were prepared: ethyl-2-amino-6-methyl-4-nitrobenzoate, sm. p. 67-68°C and

ethyl 2-amino-6-propyl-4-nitrobenzoate, m.p. 78-79°C.

Example 1

Preparation of ethyl-2-carbethoxyamino-6-ethyl-nitro-benzoate.

A solution of 400 ml of ethyl-2-amino-6-ethyl-4-nitrobenzoate in 10 ml of ethyl acetate was added dropwise to 10 ml of a solution of trichloromethylchloroformate in ethyl acetate. A precipitate immediately formed, which was dissolved by stirring for 2.5 hours. A solution of 5 ml of ethanol and 5 ml of triethylamine was added. They formed a yellowish precipitate. After one hour, the solution was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to a reddish oil. The material was further purified by column chromatography on silica gel (10% ethyl acetate-petroiether), whereby a solid with a melting point of 47-48°C was obtained.

IR: 1530, 1710, 1740, 1610 cm,

Example 2

Preparation of 2-carboethoxyamino-4-nitro-6-ethyl-benzoic acid.

A solution of 10 ml of ethyl-2-carboethoxyamino-4-nitro-6-ethyl-benzoate in 20 ml of 10% sodium hydroxide was stirred at room temperature for 20 hours. The solution was extracted

with ethyl acetate. The aqueous layer was acidified to pH=1 with 6M HCl and then immediately extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over magnesium sulfate. Evaporating the solvent gave a solid which was recrystallized from methylene chloride-petroleum ether, whereby 2-carboethoxyamino-4-nitro-6-ethyl-benzoic acid was obtained in the form of orange-coloured crystals with a melting point of 121-123°C. IR: 1665, 1720, 1620, 1510, 1500-3200(br), 3500 cm.

Claims (1)

Anthranilic acid derivatives, characterized in that they have the general formula (A): where: R' is hydrogen, lower alkyl, lower alkenyl or halo-lower-alkyl, R'' is lower alkyl, lower alkoxy, lower alkenyl, halo-lower-alkyl, lower alkylthio, nitro, di-(lower)-al -alkylamino, lower alkoxycarbonylamino, lower alkanoylamido or di-(lower)alkylureido, R'<1>' is hydrogen, lower alkyl or benzyl, X is lower alkyl which may optionally be substituted with phenyl, and a is 0, 1 or 2, the term "lower" referring to radicals with up to 4 carbon atoms.