US3120521A - 2-methyl-7-trifluoromethyl-4h-3, 1 benzoxazine-4-one - Google Patents

Description

United States Patent 3,120,521 Z-METHYL-7-TRIFLUOROMETHYL-4H-3,1 BENZGXAZINE-l-ONE Leo Henryk ternbach, Upper Montclair, N..l., and

Gabriel Saucy, Riehen, Switzerland, assignors to Hotlmann-La Roche Inc, Nutley, N1, a corporation of New Jersey No Drawing. Filed Mar. 23, 1962, Ser. No. 182,131 Claims priority, application Switzerland Dec. 2, 1960 1 Claim. (Cl. 260-244) This invention relates to Z-amino-trifiuoromethylbenzophenones as Well as precursors and derivatives therewherein R is chosen from the group consisting of hydrogen and lower :alkyl, R; is chosen from the group consisting of hydrogen, halogen, nitro, amino and trilluoromethyl.

The invention relates also to the compounds which are intermediates for these amino-benzoplienones and to the compounds which can be produced from them.

fl-amino-triiluoromethylbenzophenones are especially valuable 'for the synthesis of benzodiazepine compounds, e.g. compounds represented by one of the following forwherein A represents a carbon nitrogen grouping which completes the seven-membered diazepine ring and which is selected from the group consisting of and R R R and R each represent a member of the group [consisting of hydrogen and lower alkyl, R, is chosen from the group consisting oat hydrogen, halogen, nitro, amino and trifluoromethyl.

These compounds (i.e. those of Formulas II and 111 above) are valuable therapeutic agents. In addition to the compounds within the scope of Formulas I1 and III above there are also encompassed in the invention the pharmaceutically acceptable salts of said compounds. Certain compounds of the above formulas form pharmaceutically acceptable acid addition salts and/ or pharmaceutically acceptable quaternary ammonium salts. Thus, the basic benzodiazepine compounds (i.e. those of Formulas l1 and III above except those illustrated by Formula VI below) of the invention form acid addition salts by reaction with inorganic and organic acids such as mineral acids, e.g. hydrohalic acids, for example by hydrochloric acid, hydrobro-mic acid and the like, nitric acid, sulfuric acid, phosphoric acid, etc. and acetic acid, methanesullfiOItlC acid, succinic acid and the like. Also the compounds containing a tertiary amino nitrogen atom in the 4-position, ie the compounds of Formulas II and III wherein R, is lower alkyl, form phanmaceutically acceptable quaternary salts with conventional quaternlzing agents such as lower alkyl halides and the like.

The compounds formed during the synthesis of the trifluoromethyl benzophenone and those formed during the prepanation of the benzodiazepines are novel compounds which, except as pointed out below, are within the scope of this invention.

The Z-amino-triliuoromethylbenzophenone compounds of the invention can be produced by a variety of methods, which are illustrated in detail in the examples to follow. One method involves the reaction of an anthra-nilic acid derivative with acetic anhydride to produce a Z-methyl- 3,1-benzoxazin-4cne. By reacting this latter compound with a phenyl Grignard agent and hydrolyzing the resulting crude product, the desired Z-amino-triflnoromethylbenzophenone can be obtained. When an :anthnanilic acid starting material bearing a trifluoromethyl substituent is used, the ring bearing the Z-amino substituent in the benzophenone is substituted by a trifluorornethyl group. However, the phenyl Grignard agent is substituted by a tniiiuoromethyl group, then the benzophenone benzene ring which does not contain the Z-aminogroup will be triilworo-methyl substituted. Also a 3,1-benzoxazin 4-one, derived from a trifluoromethyl-substituted .anthranilic acid, can be reacted with a trifiuoromethyl-substituted plienyl Grignar d agent to yield a 2-amino bis(tniiiuonomethyl)- benzophenone.

The Z-aminotrifluoromethylbenzophenones can be converted with glycine or an ester thereof to form tr-iiluoromethyl-S-phenyl-SH-1,4-benzodiazepin-2( 1 H) -.ones which have the structunal formula q J or its ester, then a substituent can be introduced into the 3-position, e.g. (V) R1 I F30 N---C CH-R2 \C=N wherein R R and R have the same meaning as above. Alternatively, Z-amino tnifluoromethylbenzophenones can be treated with hydroxylamine hydrochloride to form corresponding 2-amino-trifluoromethylbenzophenone oximes. Reaction of the oxime with chloroacetyl chloride in acetic acid produces the chloroacetaminoderivative which cyolizes to rform a 2-chlorometh-yl-4-phenylquinazoline 3-oxide bearing a tnifluoromethyl s-ubstituent. The last named compound can then be reacted with an alkali metal hydroxide or alkaline earth metal hydroxide, preferably in an inert organic solvent such as alcohol, acetone, dioxane, and the like, to enlarge the ring and produce a -phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide bearing a trifluoromethyl substituent and having the structural formula (VI) R1 0 wherein R and R have the same meaning as above, or it can be reacted with ammonia or lower alkylarnine to yield a 2-amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide or a Z-lower alkylamino-5-phenyl-3Hl,4-benzodiazepine 4-ox-ide, respectively. The latter two products can be represented by the structural formula (VII) NH-R3 wherein R and R have the same meaning as above.

The compounds of Formula VI can be converted to compounds of Formula IV by treatment with phosphorus triohlonide or by catalytic hydrogenation, for example in the presence of Raney nickel. By the same procedures, compounds of Formula VII can be converted into compounds represented by the formula (VIII) N H-- R3 wherein R and R have the same meaning as above.

When S-phenyl-SH-1,4-benzodiazepine compounds, ie. compounds of Formulas IV, V and VIII above, are reduced with hydrogen in the presence of a platinum catalyst, the corresponding 5-phenyl-4,5-dihydro3H-l,4-benzodiazepines are obtained, i.e. those compounds of Formulas II and III wherein A represents are produced.

The compounds corresponding to Formula -II (i.e. Formulas IV, V and VI) wherein R is hydrogen and those corresponding to Formulas II and H1, wherein R is hydrogen can be modified so that R, and/or R are lower alkyl by a variety of methods. Compounds of Formula II wherein R is lower alkyl can be obtained by reacting corresponding compounds wherein R is hydrogen with a diazo-alkane, alkyl sulfate or alkyl halide, in a medium such as ether, benzene, alcohol or dioxane. Further, the compounds of formula II wherein R is lower alkyl can be obtained directly from 2-(N-lower alkyl)- aminobenzophenones. Compounds of Formula II wherein R is lower alkyl and R is hydrogen can be converted into corresponding compounds wherein R is lower alkyl by reaction with a lower alkyl halide. By alkylation of compounds of Formula II wherein R and R are both hydrogen and by altering the conditions of the reaction, any one of four reaction pnoducts can be obtained. More explicitly, the four reaction products which can be obtained are those wherein the 1-position hydrogen alone is replaced, those where the 4-position hydrogen alone is replaced, those where both the 1- and 4-position hydrogens are simultaneously replaced and those where the 4- position nitrogen is quaternized. Thus, treatment of a solution of a compound of Formula 11, wherein A is and both R and R are hydrogen, with an excess of lower alkyl halide gives the corresponding derivative wherein R is converted to lower alkyl, while prolonged heating results in the quaternization of the 4position nitrogen atom. On the other hand, by using sodium methoxide, sodium hydride or the like, to form the sodio derivative of the 1-position nitrogen atom, and reacting this with an equivalent amount of lower alkyl halide, the corresponding compound of formula II wherein only the 1-position nitrogen atom is substituted is obtained. Using an excess of lower alkyl halide and prolonged heating with a sodio derivative of a compound of Formula II wherein either both R and R are hydrogen, or wherein R alone is hydrogen, results in the 1,4-di-lower alkyl compound wherein both R and R are lower alkyl. Further, as discussed above, this 1,4-disubstituted compound can also be obtained by heating a compound wherein R is lower alkyl and R is hydrogen with an excess of lower alkyl halide.

The direct synthesis of the benzodiazepinones by reaction of the Z-amino-trifluoromethylbenzophenones with an a-amino acid or ester thereof forms an important feature of the invention. According to this method the ketone is heated with an a-amino acid or ester thereof such as glycine or a glycine ester; for example a glycine lower alkyl ester such as glycine ethyl ester, a-alanine or an tat-alanine lower alkyl ester, and the like. The reaction is preferably eifected in a solvent such as pyridine, dimethylformamide, and the like. It is also preferable to have an ion of a strong acid present in the reaction mixture and therefore it is convenient to use reagents in the form of the salt of a strong organic or inorganic acid, eg glycine hydrochloride, glycine ethyl ester hydrochloride, melamine hydrochloride, lat-alanine methyl ester hydrochloride or part of the pyridine as pyridine hydrochloride.

Benzodiazepin-one compounds corresponding to Formula IV above can also be produced by reacting a 2- aminotrifluoromethy-lbenziophenone corresponding to Formula I above, with an whalo-lower alkanoyl-halide, such as chloracetyl chloride, bromoacety-l bromide, a-bromopropionyl bromide and the like, to produce a Z-(ot-htilO- lower alkanoylamino) trifiuorome-thylbenzophenone corresponding to the formula (IX) R1 0 halogen wherein R and R have the same meaning as above, and R is selected from the group consisting of hydrogen and lower alkyl.

The compounds corresponding to Formula IX can then be directly cyclized by reaction with ammonia to yield compounds corresponding to Formula IV above or they can be reacted with ammonia so that the halogen atom is replaced by the amino group yielding a 2-(a-aminoh lower alkanoylamlino) triiluioromethylbenzophenone. which then can be cyclized to a compound corresponding to Formula IV above. The 2-(u-.a.-mino-lower alkanoylamino(-trifiuomcmemylbenzophenones and the method of cyclizing them to compounds of Formula IV above are not a part of this invention but are disclosed herein in order that the present disclosure may be complete.

Any of the compounds of Formulas I-IX above can be treated with an agent which introduces a nitro group into a position on one of the benzene rings thereof. Further, any nitro gmoup present in any of the compounds of Formulas 1-IX above can be reduced to an amino group.

The benzodiazepin compounds corresponding to Formulas II and III above, which are inclusive of the compounds corresponding to Formulas IV through VIII above, are valuable as therapeutic agents. They are useful as sedatives and anti-convulsants and can be used as tranquilizers and muscle relaxants. These compounds can be adminstered parenterally or orally in therapeutic dosage in solid or liquid dosage forms such as tablets, capsules, suspensions, elixirs and the like. The compounds which are basic in character can be administered in the form of the medicinally acceptable acid addition salts and those with a tertiary nitrogen atom in the 4-position can be administered in the form of their quaternary ammonium salt.

The following examples are illustrative of the invention but not limitative thereof. All temperatures are in degrees centigrade.

Example 1 75.9 g. of sodium nitrite were added slowly with stirring to 445 ml. of concentrated sulfuric acid at 010 C. After the addition was completed, the reaction mixture was allowed to stir without external cooling, whereupon the temperature rose to about 70 C. and the solution turned turbid. After cooling to 30 C., 206 g. of 2-nitro- 4-trifiuoromethyl-ani1line were added in portions over a period of about 2 hours, the temperature being kept at 30 to 35 C. Stirring was continued for an additional 1 /2 hours at room temperature. Then, the reaction mixture was poured over 1.35 kg. of ice. A small amount of insoluble material was filtered off and the filtrate treated with 270 g. of zinc-chloride, dissolved in a small amount of water. After cooling for several hours to 0 C., the precipitated diazonium zinc chloride double salt was filtered off and washed with a small amount of saturated sodium chloride solution. To a cold solution of 147 g. of sodium cyanide and 89.5 g. of cuprous cyanide in 750 ml. of water, the wet diazonium compound described above was added in small portions. During the addition, the temperature was kept below 20 C. After addition of 30 g. of sodium bicarbonate, the reaction mixture was stirred at room temperature for 2 hours. Then, it was heated for half an hour on a steam bath to 70 C. After cooling, water and ether was added to the reaction mixture; then, it was acidified, filtered and the filtrate extracted with ether the usual way to give an oil, which was purified by distillation. The fractions between 110/ 1-2 mm. Hg solidified and contain the Z-nitro- 4-trifluoromethylbenzonitrile.

Example 2 1'00 g. of 2-nitro-4trifluoromethylbenzonitrile were dissolved in 2.5 liters of methanol and hydrogenated at atmospheric pressure in the presence of 20 g. of wet Raney nickel catalyst. The reaction was continued until 3 molar proportions of hydrogen were absorbed. The catalyst was filtered off and the methanol solution was evaporated to dryness. The residue was crystallized from a mixture of ether and petroleum ether. The 4-trifluoromethyl-anthranilic acid amide formed colorless needles metling'at 15 1-15 2 Example 3 68.5 g. of 4-trifiuoromethylanthranilic acid amide were refluxed with 700 ml. of a 50% sulfuric acid solution for one hour, then poured onto ice. The precipitated reaction product was filtered off and washed with water. The 4- trifluoromethylanthranil-ic acid was crystallized from a mixture of ethanol and water and then melted at 175.

Example 4 A solution of 23 g. of 4-trifiuoromethylanthranilic acid in 150 ml. of acetic anhydride was refluxed for one hour. Then the solvent was removed by distillation under reduced pressure and the residue was crystallized from benzene-hexane to obtain 2'methyl-7-trifluoromethyl-4H-3,1- benzoxazin-4-one, M.P. 68-70.

Example 5 A solution of phenylmagnesium bromide, prepared from 2.4 g. of magnesium, 15.2 g. of bromobenzene and 150 ml. of ether, was added to a solution of 18 g. of 2-methyl-6- trifluoromethyl-4H-3,l-benzoxazin-4-one in ml. of benzene while stirring and cooling with ice. The Grignard reagent was added slowly over a period of one hour. After stirring for one additional hour at 5, the reaction mixture was treated with ice and ammonium chloride. The crude reaction product was extracted with ether. The extract was concentrated in vacuo and the residue was refluxed for one hour with a mixture of 100 ml. of 3 N sodium hydroxide and 100 ml. of methanol. The reacion mixture was extracted with benzene. The benzene extract was concentrated in vacuo and the residual, crude 2-amino-4-trifiuorornethylenzophenone was dissolved in hexane and purified by chromatography using a 20 fold amount of neutral alumina (Brockmann activity state III). Elution with a mixture of hexane-ether (1:1) and evaporation yielded yellow 2-amino-4-trifiuoromethylbenzophenone which was recrystallized from hexane, M.P. 55-56 (corn).

Example 6 2 g. of 2-amino-4-tritluoromethyl'benzophenone Were reacted with 2.0 g. of glycine ethyl ester hydrochloride in pyridine precisely as described in Example 5. The crude reaction product was crystallized from ether-hexane to yield pure 8-trifluoromethyl-S-phenyl-3H-1,4-benzodiazopin-2(1H)-one, M.P. 186-1865".

By following the procedure described in Examples 6, 7, 8, 12 and 13 but using 2-amino-4-trifluoromethylbenzophenone as the original starting material, 8-trifiuoromethyl 5 phenyl-3H-1,4-benz0diazopin-2(1H)-one 4- oxide, 8 trifiuoromethyl-Z-amino-S-phenyl-3H-1,4-benzodiazopine 4-oxide and 8-tnifluoromethyl-Z-methylamino-5- phenyl-3H-1,4-benzodiazopine 4-oxide are obtained.

The present application is a continuation-in-part of application Serial No. 103,727, filed April 18, 1961 and now pending and application Serial No. 2,605, filed January 15, 1960, and now pending.

2,936,323 Eden May 10, 1961) 2,937,203 Fuller May 17, 1960 3,023,207 Rigterink Feb. 27, 1962 3,047,573 Takahashi et a1. July 31, 1962 OTHER REFERENCES Holt et al.: Proc. Ray Soc. (London), vol. 148 B, pp. 48194 (1958).

OSuldivan et 211.: J. Chem. Soc. (1957), pp. 2916-20.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3,120,521 February 41 1964 Leo Henryk Sternbach et all It is hereby certified that error appears in' the above numbered pat-- ent requiring correction and that the said Letters Patent should read as corrected below 1 Column 3, lines 29 to 39, formula (VI) upper left-hand portion, for "F C--" read F C- same column 3, line 43 I for "3H1,4" read 3H--l,4 column 6, line 64, for trifluo-romethylenzophenone" read trifluoromethylbenzophenonewcolumn 7, line 3, beginning with "By following the procedure strike out all to and including l-oxide are obtained.", in line 9 same column 7.

Signed and sealed this 21st day of July 1964. (SEAL) Attest:

ESTON G. JOHNSON EDWARD J. BRENNER Attesting Officer Commissioner of Patents