Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• ABSTRACT Benzimidazo [2,l-b]quinazolin- 12(6H)ones, immunosuppressives and agents for treatment of auto-immune diseases are prepared via (1) reacting a 2-chlorobenzimidazole with an anthranilic acid or ester; (2) reacting a Z-aminobenzimidazole with an anthranilic acid or ester in the presence of trifluoroacetic acid or (3) reacting a 2-methylmercaptobenzimidazole with an anthraniloyl halide hydrohalide.
• autoimmune diseases Many disease conditions have been characterized as autoimmune diseases. For example, such diseases as the hemolytic anemias, Myasthenia gravis and rheumatoid arthritis have been described as auto-immune diseases in that such conditions are ascribed in part to the immune response mechanism.
• auto-immune diseases There exists a need for additional and more effective agents to inhibit or control the immune response mechanism and thereby provide a means for the treatment of auto-immune diseases.
• more effective immunosuppressive agents can play a major role in the success of surgical transplant operations.
• Another object of the present invention is to provide compositions for suppressing the immune response in mammals employing benzimidazo-[2,l-b]quinazolin-l2(6H)-ones.
• illi m represents an integer of from to 2, with the limitation that R and R being a moiety other than methyl or chloro m is 0;
• R is hydrogen, C, to C,, alkyl, C,, to C,, alkenyl, C
• n is an integer of from 0 to 4 and Y is carboxy lower alkyl, carbalkoxy lower alkyl, phenyl, naphthyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, nitro, amino, trifluoromethyl, carboxy or carbalkoxy, or naphthyl substituted by lower alkoxy, halogen, nitro, amino, carboxy or carbalkoxy, with the limitation that when Y is carboxy lower alkyl or
• the compounds described herein are prepared generally by the reaction of a 2chlorobenzimidazole with an anthranilic acid or ester thereof. Where the desired substituted 2- chlorobenzimidazole is difficult to obtain, a 2- aminobenzimidazole, desirably substituted, is reacted with an anthranilic acid or ester in the presence of an acidic catalyst.
• Certain polyalkylated benzimidazo[ 2, l -b ]quinazolinl2(6l-I)ones, such as the trior tetra-methylated compounds are best synthesized by the novel reaction of a desirably alkylated 2-methylmercaptobenzimidazole with an anthraniloyl halide hydrohalide.
• benzimidazo[2,l-b]quinazolin-l2(6H)ones prepared by the above described methods undergo N-alkylation and N- acylation predominantly at the nitrogen in the 6-position.
• the compounds of the present invention are useful as immunosuppressant agents.
• R, R R and R when taken separately are hydrogen, C, to C,, lower alkyl, C, to C,, lower alkoxy, halogen, amino, nitro, carbalkoxy, or trifluoromethyl; and R and R or R and R when taken together with the adjacent benzene ring carbon atoms to which they are attached form a six-membered aromatic carbocyclic ring; R represents methyl or chloro and m represents an integer of from 0 to 2, with the limitation that R and R being a moiety other than methyl or chloro m is 0; and wherein R is hydrogen, C, to C, alkyl, C, to C alkenyl, C to C,, epoxyalkyl, C to C,,, alkanoyl, benzyl, C, to C,, cycloalkanoyl, C,, to C,,, bicycloalkanoyl, C,, to C,,, bicycloalkenoyl
• lower alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.
• Lower alkoxy refers to methoxy, ethoxy, npropoxy, isopropoxy, and sec-butoxy.
• Halogen refers to fluoro, chloro, bromo and iodo.
• carbalkoxy refers to the esters of the carboxylic acid function formed with the lower alcohols such as methanol, ethanol, isopropanol, n-butune] and the like.
• R can be a straight or branched carbon chain such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isooctyl, n-nonyl, n-decyl, 3-methylnonyl, n-undecyl, n-dodecyl and the like.
• R When R is C to C alkenyl R can be allyl, 2-butenyl, 3-butenyl, Z-pentenyl, 4-pentenyl an like unsaturated radicals.
• R When R is C to C epoxyalkyl, R can be 2,3-epoxypropyl, 2,3-epoxybutyl, 3,4-epoxybutyl, 2,3- epoxypentyl, 3,4-epoxypentyl and the like.
• R When R is C -C alkanoyl R can be acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, caproyl, heptanoyl, caprylyl, pelargonoyl, decanoyl (capryl), hendecanoyl, lauroyl, myristoyl, palmitoyl, and the like.
• R can be cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, 4-methylcyclohexanoyl, 4-isopropylhexanoyl, cycloheptanoyl, 3-methylcycloheptanoyl, cyclooctanoyl, 3- ethylcyclooctanoyl and the like.
• R When R is C -C bicycloalkanoyl R can be bicyclo [2,2,1]heptan-2-oyl, bicyclol 2,2,21octan-2-oyl, l,7,7-trimethylbicyclo[2,2,l ]heptan-3-oyl, dimethyladamantoyl, bicyclo[5,3,0 ⁇ dodecanoyl and the like, and when R is C -C bicycloalkenoyl, R can be bicyclo[2,2,l lheptenoyl, bicyclo[3,3,0]octenoyl, bicyclo[2,2,2]octenoyl, 5-methylbicyclo[ 5,3,0]decenoyl and the like.
• R When R is a group represented by the formula and Y is naphthy] or substituted naphthyl, and n is O, R can be l-naphthoyl, Z-naphthoyl, 2-amino-3-naphthoyl, 4-bromolnaphthoyl, 5-chloro-2-naphthoyl 3- nitro-l-naphthoyl, 4-carboxynaphthoyl, l-methoxy-Z-naphthoyl, 2-ethoxy6- naphthoyl, 4-carbomethoxy-l-naphthoyl, and the like; and when Y is carboxy lower alkyl n is or 1, R can be carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyvaleryl, 2- oxo-3-carboxyacetyl, 2-oxo-4-carboxybuty
• R is -[CH ],,-Z and p is an integer from 1 to 4 and Z is lower alkoxy R can be methoxyrnethyl, ethoxymethyl, Z-methoxyethyl, 3-methoxypropyl, 2- methoxypropyl; 4-isopropoxybutyl, 3-ethoxybutyl, n-butoxymethyl, and the like.
• Z is carboxy R can be carboxymethyl, 2-carboxy ethyl, 4-carboxybutyl, 3-carboxybutyl, 2- carboxypropyl and the like.
• R can be carbomethoxymethyl, carboethoxymethyl, 2-carbomethoxyethyl, 3-carbomethoxypropyl, 4-carboethoxybutyl, carbopropoxymethyl and the like.
• R, R, R R" and R have the same meaning as previously defined.
• the compounds described herein are formally named as benzimidazo[2,l-bjquinazolin-12(6H)ones but for the purposes of this description they are informally designated as azaquinazolinones.
• the compounds of this invention are prepared by employing a variety of experimental methods. Generally, the azaquinazolinone or the substituted azaquinazolinone wherein R is hydrogen is prepared by the reaction of 2- chlorobenzimidazole or a substituted Z-chlorobenzimidazole with anthranilic acid or its ester or with substituted derivatives thereof.
• the desired azaquinazolinone can be prepared by the novel reaction of a substituted 2-aminobenzimidazole with the appropriate anthranilic acid or ester.
• azaquinazolinones containing a nitro substituent in the l, 2, 3 or 4 positions are preferably prepared by the reaction of 2-chlorobenzimidazole with a nitroanthraniloyl halide in the form of its hydrochloride salt.
• the polyalkylated azaquinazolinones for example 2, 8, 9- trimethylbenzimidazol 2, l -b]quinazolinl 2(6H )one, are generally unobtainable by the above described general procedures.
• the polyalkylated azaquinazolinones described 5 herein are synthesized by the novel reaction of an appropriately substituted 2-methylmercaptobenzimidazole with a substituted anthraniloyl chloride in the form of its hydrochloride salt.
• the compounds wherein R is other than hydrogen are prepared by employing commonly known acylation and alkylation procedures on the previously prepared azaquinazolinone nucleus wherein R is hydrogen.
• the sodium salt of the azaquinazolinone is formed in a suitable inert solvent by reaction with sodium hydride.
• the hydrogen atom attached to the nitrogen in the 6-position of the azaquinazolinone nucleus is acidic in character and reacts with sodiumhydride to form the anionic form of the azaquinazolinone.
• the sodium salt is then alkylated with an alkyl or substituted alkyl halide or acylated with an alkanoyl or aroyl halide to form the desired -substituted azaquinazolinone.
• azaquinazolinones of this invention are obtained by employing a variety of methods.
• a Z-chlorobenzimidazole is reacted with 70 an anthranilic acid or an ester thereof in a suitable unreactive solvent at a temperature sufficient to provide a convenient reaction rate.
• the 2-chlorobenzimidazole can be substituted at any of the available positions of the benzene ring.
• substituted benzimidazoles which can be employed in the present reaction are 2-chloro-4-nitrobenzimidazole, 2-chloro- S-methylbenzimidazole, Z-chloro-6-methylbenzimidazole,
• anthranilic acid methyl anthranilate, methyl 4-methyl anthranilate, methyl 4-chloroanthranilate, methyl 5-iodoanthranilate, ethyl 4-nitroanthranilate and the like can be employed in preparing the compounds of the present invention.
• the corresponding substituted azaquinazolinone is obtained.
• the benzimidazole moiety is mono substituted the possibility of obtaining mixtures of position isomers arises.
• the reaction can be carried out without the aid of a solvent by heating a mixture of the anthranilic acid ester with a 2- chlorobenzimidazole. It is desirable, however, to carry out the reaction in the presence of a suitable unreactive solvent, preferably diglyme.
• a suitable unreactive solvent preferably diglyme.
• the 2-chlorobenzimidazcle is dissolved or suspended in diglyme and a solution or suspension of the anthranilic acid ester in diglyme is added with stirring.
• the reaction mixture is then refluxed for periods of from 12 to 24 hours.
• the azaquinazolinone is precipitated from the reaction mixture by cooling and diluting with a large volume of cold water and is purified by recrystallization.
• a second procedure employed in this invention for the preparation of the azaquinazolinone nucleus involves the reaction of a 2-aminobenzimidazole with an anthranilic acid or ester thereof. This procedure is designated herein as Method II. As with the procedure of Method I, ring substituted Z-aminobenzimidazoles and substituted antliranilic acids and esters can be employed. According to this method, the 2- aminobenzimidazole and the anthranilic acid or ester are reacted in the presence of an acid catalyst, preferably trifluoroacetic acid, at a temperature between about 175 and 275 C. The preferred temperature range is between about 200 and 250 C.
• an acid catalyst preferably trifluoroacetic acid
• the acid catalyst is employed in an amount equal to at least one molar equivalent of the 2- aminobenzimidazole reactant. Generally, a slight excess of acid catalyst is preferred.
• the anthranilic acid reactant is used in amounts of about 0.1 to 0.2 moles in excess of the 2- aminobenzimidazole reactant.
• the 2-aminobenzimidazole, anthranilic acid ester and trifluoroacetic acid mixture when heated from about 4 to about 8 hours affords the desired azaquinazolinone.
• the reaction mixture In the presence of an inert solvent the reaction mixture is refluxed over a somewhat longer period of from about 12 to 24 hours to obtain the desired product.
• the preferred manner of preparing a 2- or nitrobenzimidazo[ 2,1 ]quinazolinl 2( 6H )one comprises reacting the required 2- chlorobenzimidazole with the nitroanthraniloyl chloride or bromide, as the hydrochloride or hydrobromide salt respec tively, in an inert solvent such as benzene, toluene, Xylene, or decalin at reflux temperature.
• an inert solvent such as benzene, toluene, Xylene, or decalin at reflux temperature.
• the anthraniloyl halide salts formed with inorganic acids, such as hydrochloric or sulfuric acid are suitable for use in this method, though generally the hydrochloride formed in making the acid chloride is used.
• reaction mixture is usually refluxed for about 5 hours, although shorter periods of reflux can provide significant yields of the desired product.
• Method III can also be employed for the synthesis of azaquinazolinones wherein R, R R, R and R, represent other substituent groups, as previously defined, but it is particularly useful for preparing the nitroazaquinazolinones.
• N i I l 1 In the above formula X is C1 or Br and R, R R", R and R have the same meaning as previously assigned.
• the reaction is carried out by adding the anthraniloyl halide hydrohalide, preferably the anthraniloyl chloride hydrochloride, in dry toluene to a solution of the appropriately substituted 2- methylmercaptobenzimidazole in dry pyridine.
• the reaction mixture is initially stirred at ambient temperature for about 2 hours and then diluted with dry dimethylformamide and stirred under reflux for about 5 hours.
• the azaquinazolinone reaction product is generally recovered from the reaction mixture by evaporating the mixture and fractionally crystallizeing the solid residue from an appropriate solvent.
• the reaction is carried out in two stages. lnitially, the reaction is carried out at room temperature under mild acylation conditions in a basic solvent combination, preferably toluene and pyridine. Following the initial reaction, during which a preponderance of a single intermediate is formed as indicated by thin layer chromatography, the reaction mixture is heated to a temperature between about 150 and 250 C. to complete the reaction. The increase in temperature is accomplished by adding to the initial reaction mixture a dry high boiling solvent such as dimethylformamide and heating the mixture to the reflux temperature.
• a dry high boiling solvent such as dimethylformamide
• the reaction is particularly useful for the preparation of the polymethylated azaquinazolinones, some of which are not conveniently synthesized by the previously described Methods I and Ill.
• the required substituted 2-methylmercaptobenzimidazole is prepared by the reaction of the appropriately substituted o-phenylenediamine with carbon disulfide in the presence of sodium hydroxide to yield the 2-n1ercaptobenzimidazole which is methylated with methyl iodide in the presence of sodium hydroxide.
• the anthraniloyl halide hydrohalide employed in Method Ill for the preparation of nitroazaquinazolinones and in Method IV for the preparation of the polysubstituted azaquinazolinones, is preferably the anthraniloyl chloride hydrochloride, conveniently formed by the reaction of the anthranilic acid with thionyl chloride.
• the anthraniloyl chloride hydrochloride can be isolated and purified prior to use as a reactant, it is conveniently employed in less pure form as obtained directly from the reaction mixture in which it is formed. After evaporation of excess thionyl chloride and hydrogen chloride from the reaction mixture, the product residue is used directly as a reactant for the preparation of the desired azaquinazolinone.
• the Z-chlorobenzimidazoles are prepared by the chlorination of 2-hydroxybenzimidazoles with phosphorous oxychloride.
• 2- Aminobenzimidazoles are prepared by the reaction of an ophenylenediamine with cyanogen bromide.
• an alternative procedure was employed. In this procedure, a desirably substituted Z-mercaptobenzimidazole suspended in a solution of methanol and concentrated hydrochloric acid is reacted with chlorine by bubbling the gas through the solution. The temperature of the reaction mixture is maintained at about to C.
• the azaquinazolinones prepared by any of the above described methods undergo alkylation and acylation substitution reactions in which the hydrogen attached to the nitrogen in the six position is replaced.
• Conventional methods of alkylation and acylation can be employed.
• Alkylation or acylation can occur at either the 5- or 6-position, though generally the 6-substituted product proved to be the preponderant isomer.
• the isomers can be separated by careful fractional recrystallization from appropriate solvents. It is possible to differentiate between the 5- and 6-substituted products on the basis of their spectral characteristics.
• the alkylation of the azaquinazolinones described herein, where R is hydrogen, is carried out by the reaction with sodium, or preferably sodium hydride, in anhydrous dimethylformamide to form the sodio derivative which is then reacted with the appropriate alkyl, alkenyl or epoxyalkyl halide.
• the sodio derivative imparts a characteristic yellow color to the dimethylformamide solution. On reaction with the alkylating agent, the yellow color gradually fades and disappears.
• R is and n is an integer of from 1 to 4 or R is -[CH -Z the corresponding halides and X-[CH ,,-Z wherein X is chloro, bromo or iodo, comprise the alkylating agent.
• An alternative method of alkylation comprises reacting the azaquinazolinone with a dialkyl ester of sulfuric acid such as dimethyl sulfate and diethyl sulfate. This method can be employed to advantage for the synthesis of compounds wherein R is lower alkyl, for example, methyl, ethyl or propyl.
• Acylation of the azaquinazolinones is generally carried out by employing conventional procedures.
• the sodio derivative of azaquinazolinone can be reacted with an alkanoyl halide to obtain the desired 6-acylated product.
• R is and n is O
• the corresponding halides wherein X is chloro or bromo comprise the acylating agent.
• the acylating agent is benzoyl chloride or a substituted benzoyl chloride.
• the preferred solvent and the one most generally applicable for the acylation of the sodium salt of the azaquinazolinones, is dimethylformamide.
• certain acylated azaquinazolinones are best prepared by employing other solvents such as tetrahydrofuran.
• tetrahydrofuran For example, in the case of acylation with 2,4,6-trimethylbenzoyl chloride it is necessary to make and react the sodium salt of the azaquinazolinone in tetrahydrofuran rather than dimethylformamide. When the latter solvent is employed a quantitative recovery of unacylated starting material is obtained.
• the compounds of this invention are useful in suppressing the immune reaction in mammals.
• compounds can be classed as immunosuppressant agents, by which is meant agents which suppress the formation of antibodies to foreign substances.
• the activity of the compounds of this invention can also be characterized as anti-allergic activity in that the allergic reaction is part of the immune reaction against foreign antigens. Such anti-allergic activity differs from the well-known anti-histamine activity.
• mice Groups of five 20 g. male Swiss mice are injected intraperitoneally with 0.2 ml. of a 1-80 suspension of washed sheep red blood cells (approximately X cells/mouse). Forty-eight hours before and 48 hours after the red blood cell injections, the test compounds are administered intraperitoneally in various dosages to various animal groups. Seven days after the red blood cell antigen injections, the mice are bled by cardiac puncture and the sera from each group of five mice is pooled.
• Antibody determinations are made on the serum pools by a hemagglutination pattern procedure, in which 2-fold serum dilutions are mixed with equal volumes of one percent suspensions of sheep red blood cells in plastic depression trays, which are then incubated for four hours at 37 C., and assessed for hemagglutinin content. Comparisons between serum pools from treated and control groups are made, and 75 percent (4-fold) or greater suppression of hemagglutinin in treated groups is considered significant and is the basis for the stated activities of the test compounds.
• Table l includes azaquinazolinones unsubstituted at the 6-position.
• Table II includes 6-alkyl, 6-alkenyl, 6alkanoyl, 6-epoxyalkyl, and 6bicycloalkenoyl-substituted azaquinazolinones.
• Table III lists exemplary compounds of the invention wherein the -substituent is represented by the formula and Y is phenyl.
• Table IV lists exemplary 6-substituted azaquinazolinones wherein the substituent group R is represented by the formula n [CHz]nO-Y and Y is carbalkoxy lower alkyl.
• Table V includes 6-substituted azaquinazolinones wherein the substituent group R is represented by the formula [CH ],,-Z and Z is lower alkoxy, di-lower alkylamino, carboxy or carbalkoxy.
• the compounds of the present invention are effective in inhibiting the immune response mechanism.
• the compounds can also be administered and are effective by the subcutaneous or intramuscular routes. Commonly employed pharmaceutical formulations for such parenteral routes can be used with the instant compounds. For example, when subcutaneous administration is the desired route, the compounds are suspended in their highly divided crystalline state in an inert diluent such as water. For intramuscular administration the compounds can be formulated with commonly employed excipients such as ethyl oleate, peanut oil, sesame oil or the like.
• the compounds can be administered on a daily single dose basis; however, it may be desirable to administer two or three smaller doses on a daily basis. In suitable cases, after the desired drug effect is observed following the initial daily dose regimen, less frequent administration, such as weekly or bi-weekly doses, may be found to be adequate.
• immunosuppressant agents are also useful in various diseases which have been in part ascribed to the immune response.
• diseases have been categorized as auto-immune diseases and include among others, hemolytic anemia, lupus erythematosus, lupus nephritis, lupoid hepatitis and rheumatoid arthritis.
• the present invention provides certain novel compounds which are especially useful in suppressing the immune response.
• Such compounds are represented by the following general formula:
• n is an integer of from 0 to 4 and Y is carboxy lower alkyl, carbalkoxy lower alkyl, phenyl, naphthyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, nitro, amino, trifluoromethyl, carboxy or carbalkoxy, or naphthyl substituted by lower alkoxy, halogen, nitro, amino, carboxy or carbalkoxy, with the limitations that when Y is carboxy lower alkyl or carbalkoxy lower alkyl, n is 0 or 1, and when Y is naphthyl or substituted naphthyl n is 0; provided that when R is hydrogen at least one of R R, R", R, R, R", R and R is a group other than hydrogen; and in addition, R or R is methyl, R and R are both methyl, R is methyl when both R and R are methyl
• Certain of the above defined novel compounds are highly effective in suppressing the immune response and are preferred compounds in the practice of the present invention.
• preferred compounds are the following: 3-methylbenzimidazo[2, 1 -b]quinazo1in-1 2(6l-l )one, 6-methy1benzimidazo[2,l-b]quinazolin-12(6H)one, 8,9-dimethylbenzimidazoI 2, l -b]quinazolin-l 2(6H)one, 6,8,9-trimethylbenzimidazo[2, l-b]quinazolin-12(6H)one, 2,8,9-trimethylbenzimidazo[2,1-b]quinazolin-l 2(6H)one,
• EXAMPLE 4 The reaction of 2-chloro-5-methylbenzimidazole with anthranilic acid according to the procedure described in Example 1 yielded a solid mixture comprising B-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one and 9-methylbenzimidazo[ 2, l-b]quinazolinl 2( 6H )one.
• the pH of the mixture was adjusted to a pH of about 8 by the addition of ammonium hydroxide.
• the precipitate was filtered, washed with water and crystallized from ethanol-water to yield 2,4,7- trichloro-S,6-dimethylbenzimidazole melting at about 280285 C.
• 3-Chlorobenzimidazo[2, 1 -b ]quinazolinl 2( 6H )one is prepared with 2-chlorobenzimidazole and 4-chloroanthranilic acid.
• 2-Chlorobenzimidazo[2, l -b ]quinazolinl 2( 6H)one is prepared with 2-chlorobenzimidazole and 5chloroanthranilic acid.
• 2-Methylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 5-methylanthranilic acid.
• 4,8,9-Trimethylbenzimidazo[2,1-b]quinazolin-l2(6H)one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 3- methylanthranilic acid.
• 3-Chloro-8 ,9-dimethylbenzimidazo[ 2 l-b ]quinazolin- 12(6H)-one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 4-chloroanthranilic acid.
• 2-Bromo-8 ,9-dimethylbenzimidazo[2,1-b]quinazolin- 12(6H)-one is prepared with 2-chloro-5,6-dimethylbenzimidazole and S-bromoanthranilic acid.
• 3-Ethoxybenzimidazo[2,1-b]quinazolin-l2(6H)one is prepared with 2-chlorobenzimidazole and 4-ethoxyanthranilic acid.
• a mixture of 8-methyl and 9-methylbenzimidazo[ 2,1-b]- quinazolin-l2( 6H )one is prepared from 2-amino-5-methylbenzimidazole and methylanthranilate.
• a mixture of 8-chloro and 9-chlrobenzimidazo[2,l-b]-quinazolin-12(6H)one is prepared from 2-amino-5- chlorobenzimidazole and methylanthranilate.
• 2-Nitrobenzimidazo[2, l -b]quinazolin- 1 2( 6H )one is prepared with 2-chlorobenzimidazole and S-nitroanthraniloyl chloride hydrochloride.
• 3-Nitro-8,9-dichlorobenzimidazo[2,l-b]quinazolin- 12(6H)-one is prepared with 2,5,6-trichlorobenzimidazole and 4-nitroanthraniloyl chloride hydrochloride.
• lir eparation of Benzimidazo[2,1-b]Quinazolinl 2(6H)Ones which Method IV EXAMPLE 1 Following the procedure described in Example 15, 3,8,9- trimethylbenzimidazo[2,1-b]quinazolin-l2(6l-1)one was prepared by the reaction of 2-methylmercapto-5,6 dimethylbenzimidazole with 4-methylanthraniloyl chloride hydrochloride.
• the product failed to crystallize from the reaction mixture on reflux. Instead, the product was obtained by evaporating the reaction mixture to dryness, triturating the solid residue with dichloromethane, filtering the insoluble material and recrystallizing the solid material from dimethylformamide.
• EXAMPLE 18 To a vigorously stirred suspension of 1.18 g. (0.005 mole) of benzimidazol2,1-b]quinazolin-12( 6l-l)one in 50 ml. of dry dimethylformamide was added 0.23 g. of a suspension of sodium hydride in mineral 011 (containing 58.8 percent sodium hydride). Stirring was continued for 1 hour to insure formation of the sodio derivative as indicated by dissolution of the azaquinazolinone with the formation of a yellow solution of the anion. To this solution, 1.24 ml. of n-amyl bromide were added and, after continuous agitation for 4 hours at ambient temperature, a precipitate formed. The reaction mixture was placed in the refrigerator overnight.
• 6-Ethylbenzimidazo[2,l-b]quinazo1in-1 2( 61-1 )one is prepared with benzimidazo[2,1-b]quinazolin-12(6l-l)one and ethyl bromide.
• 6-lsopropylbenzimidazo[ 2 ,1 -b]quinazolin-l2(6l-1)one is prepared with benzimidazo[2,l-b]quinazolin-l2(6l-l)one and isopropyl bromide.
• 6-( n-Octyl )benzimidazo[ 2, 1 -b ]quinazolin-l 2( 61-1 )one is prepared with benzimidazo[ 2 l -b]quinazo1inl 2( 61-1 )one and n-octyl bromide.
• 6-Methyl-8 ,9-dichlorobenizimidazoI2, l-b]quinazolinl 2(61-1)-one is prepared with 8,9-dichlorobenzimidazo[2, l bJquinazolin- 1 2-(61-l )one and methyl bromide.
• 6-( n-Butyl )benzimidazo[ 2, 1 -b]quinazolinl 2( 611 )one is prepared with benzimidazo[ 2 l-b lquinazolin 1 2( 61-1 )one and n-butyl bromide.
• 6-Methyl-3-trifluoromethylbenzimidazo[2, l -b]quinazolinl 2(61-1 )one is prepared with 3-trifluoromethylbenzimidazo[ 2, l -b]quinazolin -12(6l-1)one and methyl iodide.
• 6-(n-Dodecyl)benzimidazo[2, 1 -b ⁇ quinazolin- 1 2(61-l)one is prepared with benzimidazo[ 2, l-b lquinazolin- 1 2(61-1)one and n-dodecyl bromide.
• 6-( n-Propyl )-3-nitrobenzimidazo[ 2, l -b]quinazolin- 1 2( 6H )-one is prepared with 3-nitrobenzimidazo[ 2, 1 -b]quinazolin-12(6l-1)one and n-propyl bromide.
• 3,8,9-Trichloro-6-( n-propyl )benzimidazo[ 2, l-b]quinazolin-l 2( 6l-l)one is prepared with 3 ,8 ,9- trichlorobenzimidazo[2,1-b]-quinazolin-l2(6l-l)one and npropyl bromide.
• 3-Bromo-6-( n-hexyl)benzimidazo[2,1-b]quinazolin- 12(61-1)-one is prepared with 3-bromobenzimidazo[ 2, l blquinazolin- 1 2( 61-1 )one and n-hexyl bromide.
• 3-Ethoxy-6-isobutyl-8 ,9-dimethylbenzimidazo[ 2, 1 -b l-quinazolin- 1 2( 61-1)one is prepared with 3ethoxy-8 ,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6I-1)one and isobutyl bromide.
• 6-A1lylbenzimidazo[2, l-b lquinazolin -1 2( 6H )one is prepared with benzimidazo[ 2, 1 -b]quinazolin-1 2(61-1)one and allyl bromide.
• 3-Chloro-6-( 3-pentenyl)-8,9-dimethylbenzimidazo[2,1-b]- quinazolin-l 2( 6H )one is prepared with 3-chloro-8,9- dimethy1benzimidazo[2, 1 -b]quinazolinl 2(61-1)one and lbromopentene-3
• 6-Benzylbenzimidazo 2,1-b1quinazolin-12(6H)one is prepared with benzimidazo[2, 1 -b]quinazolin- 1 2(61-1 )one and benzyl chloride.
• 6-Ethoxymethylbenzimidazo[2,1-b]quinazolin-l2(6H)one is prepared with benzimidazo[2,l-b]quinazolin-l2(6l-l)one and chloromethylethyl ether.
• 3-Chloro-6-n-butoxymethyl-7-nitrobenzimidazo[ 2, l -b]- quinazolin-l2(6l-l)one is prepared with 3-chloro-7- nitrobenzimidazo-[ 2 l -b ]quinazolin- 1 2( 6H )one and chloromethyl-n-butyl ether.
• 6-(Carbomethoxyethyl)-3-methyl-8,9- dichlorobenzimidazo-[ 2, l -b]quinazolinl 2( 6H )one is prepared with 3-methyl-8,9-dichlorobenzimidazo[2.l-b]quinazolinl 2( 61-! )one and methyl 3-chloropropionate.
• 6-(Carboethoxypropyl)-3-methyl-9-ethoxybenzimidazo[2, l-b]quinazolin in l2(6l-l)one is prepared with 3-methyl-9- ethoxybenzimidazo[2,l-blquinazolin-l2(6H)one and ethyl 4-bromobutyrate.
• 6-( 3-Carboethoxy-2-oxopropyl )-4-nitro-8 ,9-dimethylbenzimidazo[2, l-b]quinazolin-12(6H)one is prepared with 4- nitro-8 ,9-dimethylbenzimidazo[ 2, l -b]quinazolinl 2( 6H )one and ethyl 3-oxo-4-chlorobutyrate.
• EXAMPLE 24 A dispersion of sodium hydride in mineral oil, 1.07 g. containing 57 percent sodium hydride, was added to a vigorously stirred mixture of 4.7 g. of benzimidazo[2,l-b]quinazolinl2(6H)-one in 130 ml. of dry dimethylformamide and stirring was continued until complete solution was attained. A solution of 3.16 g. of 3-chlorodimethylaminopropane in 10 ml. of dry dimethylformamide was added dropwise over 25 minutes with continued stirring. The reaction mixture was stirred for 1 hour at room temperature and then heated to a temperature of C. for 2 hours.
• 6-(Z-Dimethylaminoethyl)-4-chlorobenzimidazo[2, 1-b]- quinazolin-l2( 6H)one is prepared with chlorobenzimidazo[2,l-bl-quinazolin-l2(6H)one and chlorodimethylaminoetharief 6-(4-Diethylamino-n-butyl)-3,8,9-trimethylbenzimidazo- [2,l-b]quinazolin-l2(6l-l)one is prepared with 3,8,9- trimethylbenzimidazo[ 2, l -b]quinazolinl 2( 6H )one and 4- bromodiethylaminobutane.
• 6-( 2-di( n-Propyl )aminoethyl)-3-methoxybenzimidazo[ 2, l b]-quinazolin-l2(6l-l)one is prepared with 3-methoxybenzimidazo[ 2, l b]-quinazolinl 2( 6H )one and 2- chlorodi(n-propyl)aminoethane.
• EXAMPLE 2s Benzimidazo[2,l-b]quinazolin-l2( 6H)one, 4.7 g, was converted to the sodium salt with sodium hydride in 180 ml. of dry dimethylformamide and 5.18 g. of phenacyl bromide was added with vigorous agitation. The reaction mixture was stirred overnight and poured into ice water. The solid which separated was filtered, dried, and recrystallized from dimethylformamide to yield 4.2 g. of 6-phenacy1- benzimidazo[2,l-b]quinazolin-12(6H)one melting with decomposition at about 200 C.
• 6-( 4-Methylphenacyl )-8 ,9-dimethylbenzimidazo[ 2,1-b]- quinazolin-12(6H)one is prepared with 8,9-dimethylbenzirnidazo-[ 2, l -b]quinazolinl 2( 6H )one and 4- methylphenacyl bromide.
• 6-[B-(4-Methoxybenzoyl)ethyl ⁇ -2-chlorobenzimidazo[2,1- b ]-quinazolinl 2(6H )one is prepared with 2- chlorobenzimidazo[2, l -b]-quinazolin-l 2(6H)one and 2 (4- methoiiyberizo ymathylbromidef "TTUH PM "Mm-WT V 6- [4-( 4-Chlorobenzoyl )butyl l-2-methyl 8 ,9- dichlorobenzimidazo[2, l -b]qui.nazolinl 2( 6H )one is prepared with 2-methyl-8,9-dichlorobenzimidazo[2,l-b]quinazolinl 2(6H )one and 4-( 4-chlorobenzoyl)butyl bromide.
• 6-Acetyl-3-chlorobenzimidazo[ 2, l -b]quinazolinl2(6l-l)one is prepared with 3-chlorobenzimidazofi2, l-b]quinazolinl 2( 6H )one and acetyl chloride.
• 6-Propionyl-3-methylbenzimidazo[ 2, l -b quinazolinl2( 6H )-one is prepared with 3-methylbenzimidazo[ 2,1- b]quinazolinl 2( 6H )-one and propionyl chloride.
• 6-Palmitoyl-8 ,9-dimethylbenzimidazo[ 2, l-b ]quinazolinl 2( 6H )one is prepared with 8,9-benzimidazo[ 2,1-b1quinazolin-l 2( 6H )-one and palmitoyl chloride.
• 6-Cyclopentanoyl-2-chlorobenzimidazo[2, 1 -b ]quinazolinl2(6H)one is prepared with 2-chlorobenzimidazo[2,l-bjquinazolin-l 2( 6H )one and cyclopentanoy] chloride.
• 6-( 4-Methylcyclohexanoyl)benzirnidazo[ 2, i -b ]quinazolinl2( 6H )one is prepared with benzimidazo[ 2, l -b]quinazolinl2( 6H )one and 4-methylcyclohexanoyl chloride.
• 6-( 3-Methylcyclooctanoyl benzimidazol 2 l -b ]quinazolin- 12(6H )one is prepared with benzimidazo[2,l-b]quinazolinl2( 6H )one and B-methylcyclooctanoyl choride.
• 6-(Bicyclo[ 2,2,1 lheptanoyl )benzimidazo[2, l -b]quinazolin-l 2( 6H)one is prepared with benzimidazo[2,l-b]quinazolinl 2( 6H)one and bicyclo[ 2,2,1 Iheptanoyl bromide.
• 6-( 1 ,7,7-Trimethylbicyclo[ 2,2,1 ]heptanoyl)-2-methylbenzimidazo ⁇ 2,1-b ⁇ quinazolin-12(6H)one is prepared with 2- methenzimidazo[2,l-blquinazolin-1 2(6H)one and 1,7,7- trimethylbicyclo[2,2, l ]heptanoyl chloride.
• 6-(5-Methylbicyclo[ 3 .O]cyclodecenoyl )benzimidazo[2, l b]-quinazolin-l2( 6H)one is prepared with benzimidazo[2,lb lquinazolinl 2( 6H )one and 5-methylbicyclo[5,3 ,0 lcyclodecenoyl chloride.
• 6-Benzoyl-3-methyl-8 ,9-dichlorobenzirnidazo[ 2, 1 -b]-quinazolin-l 2( 61-! )one is prepared with 3-methyl-8,9- dichlorobenzimidazo[ 2 l -b )quinazolinl 2( 6H )one and benzoyl chloride.
• 6-( 3 ,S-Dim ethylbenzoyl )-3-methoxybenzimidazo[2, l -b]- quinazolin-l 2( 6H )one is prepared with 3-methoxybenzimidazo[ 2, l-b l-q uinazolinl 2( 6H )one and 3 ,5- dimethylbenzoyl chloride.
• 6-(2,4-Dichlorobenzoyl)-9-ethoxybenzimidazo[2,1-b]- quinazolin-l 2( 6H )one is prepared with 9-ethoxybenzimidazo[ 2, l -b]-quinazolin- I 2( 6H )one and 2,4- dichlorobenzoyl chloride.
• 6-( 2-Carbomethoxybenzoyl )-2-bromobenzimidazo[ 2, l-b]- quinazolinl 2( 6H )one is prepared with 2- bromobenzimidazo[ 2,1 ]-quin azolinl 2( 6H )one and 2-carbomethoxybenzoylchloride.
• 6-( 4-Isopropoxybenzoyl )-3 ,8 ,9-trimethylbenzimidazo[ 2 l b -quinazolin- 1 2( 6H )one is prepared with 3 ,8,9-trimeth ylbenzimidazo-[2, l -b]quinazolinl 2( 6H )one and 4isopropoxybenzoyl chloride.
• 6-( 3-Carbomethoxypropion yl )benzimidazo[ 2 l -b ]quinazolin-l2(6H)one is prepared with benzirnidazo[2,l-b]quinazolinl 2( 6H )one and methyl 3-( chloroformyl )propionate.
• 6-( 6-Carboethoxyhexanoyl )benzimidazo[ 2, l -b lquinazolin- 12(6H)one is prepared with benzimidazo[2,l-blquinazolin- EXAMPLE 28
• Benzimidaz0[2,l-blquinazolin-12(6H)one, 7.05 g. (30 mmole) was stirred in 200 ml. of dry tetrahydrofuran and 1.63 g. of a suspension of sodium hydride in mineral oil (containing 58 percent sodium hydride) was added. Stirring was continued until hydrogen evolution ceased.
• R", R", R R”, R, R R and R when taken separately are hydrogen, halogen, C, to C, lower alkyl, C, to C, alkoxy, nitro, amino, carbo C, to C, alkoxy or trifluoromethyl, and the adjacent R groups when taken together with the benzene ring carbon atoms to which they are attached form an unsubstituted six-membered aromatic carbocyclic ring; and wherein R is hydrogen, C, to C alkyl, C, to C, epoxyalkyl, -[CH ],,-Z wherein p is an integer of from 1 to 4 and Z is lower alkoxy, carboxy, carbo C, to C,, alkoxy or di-lower alkylamino, or a group of the formula:
• n is an integer of from to 4 and Y is carboxy lower alkyl, carbo C, to C alkoxy lower alkyl, phenyl, naphthyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, nitro, amino, trifluoromethyl, car-boxy or carbo C,t o C alkoxy, or naphthyl substituted by lower alkoxy, halogen, nitro, amino, carboxy or carbo C, to C alkoxy, with the limitations that when Y is carboxy lower alkyl or carbo C, to C, alkoxy lower alkyl, n is 0 or 1, and when Y is naphthyl or substituted naphthyl, n is 0; provided that when R is hydrogen at least one of R, R", R", R", R", R and R is a group other than hydrogen,

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  • BE BE759337D patent/BE759337A/xx unknown
• 1969
  • 1969-11-24 US US879579A patent/US3669969A/en not_active Expired - Lifetime
• 1970
  • 1970-11-02 IE IE1392/70A patent/IE34676B1/xx unknown
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  • 1970-11-17 CA CA098,317A patent/CA974992A/en not_active Expired
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