5,6-DIHYDRO-11-H-pyrimido{8 4,5-b{9 {8 1,4{9 benzodiazepines
United States Patent 1191 Juby et a1.  
 [ Apr. 29, 1975 1 5,6-DlllYDRO-l l-l-l-PYRIMlDO 4,5-  
 B][ 1,4]BENZODIAZEPINES [75] Inventors: Peter Frederick Juby, .lamesville;  
 Thomas William l-ludyma, Manlius. both of NY.  
 [73] Assignee: Bristol-Myers Company, New York,  
 [22] Filed: Feb. 25, 1974 [21] Appl. No.: 445,382  
  Related US. Application Data [63] Continuation-impart of Ser. No. 351.217. April 16.  
  52 us. Cl. 260/256.4 F; 250/2564 C; 260/2564 N: 424/251 51 1 Int. Cl i. C07d 57/02 [58] Field of Search 260/2564 F [56] References Cited OTHER PUBLICATIONS Yoneda et 211., Chem. Paarm. Bull. (1972) 20(8) 1815-1818.  
 Primary Examiner-James A. Patten Attorney, Agent, or Firm-Robert E. Havranek 14 Claims, No Drawings 1 5 ,6-DHYDRO-l l-H-PYRIMIDO[4,5- B] [1,41BENZODIAZEPINES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of copending application Ser. No. 351, 217, filed Apr. 16, 1973.  
 BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a series of 1 1H- pyrimido[4,5-b][1,4]benzodiazepines which show anti-hypoxic, hypothermic, anti-pyretic and antiinflammatory activity.  
 2. Description of the Prior Art A. E. C. Taylor and F. Yoneda, Angew. Chem. (International Ed. English) 6, 878 (1967) reported the preparation of the compound having the formula No biological data was reported.  
  B. K. .I. M. Andrews and B. P. Tong, J. Chem. 506., 1753 (1968) reported the preparation of the compound having the formula C N NVAT/ 1 k N No biological data was reported.  
  C. G. Schmidt. German Pat. No. 1,205,106 (1965) reports the compounds having the formula Schmidt et al., S. African Pat. No. 68/05,942 (1969) all report the compound having the general formula I ll NC l i I R in which R is H, alkyl or alkylaminomethyl; R is H or methyl; R is H or C1; and R is H or alkyl as possessing antipyretic, anti-inflammatory, analgetic and sedative activity.  
  E. R. E. Strube, U.S. Pat. No. 3,291,790 (1966) describes the preparation of the compound having the formula N C (I n N F. W. E. Coyne and .I. W. Cusic, J. Med. Chem., 10,  
 541 1967) describe the preparation of the compound of having the formula G. A. Wander, British Pat. No. 961,106 (1964) describes the antidepressant having the formula SUMMARY Compounds having the formula N R; R4  
 and  
  1 N-CHZ 2 q R K in which Y is di(lower)alkylamino, cyclo (lower)- alkylamine, benzylamino, phenethylamino, or di(- lower)-alkylamino (lower)alkylamino; R and R are alike or different and are H, (lower)alkyl or a radical of the formula (CH g in which n is an integer of l to 4 and R is chloro, H, CF fluoro, bromo, (lower)alkoxy or (lower)alkyl, R and R are alike or different and each is H, chloro, bromo, fluoro, CF (lower)alkyl, (lower)alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt thereof are useful compounds having biological activity.  
 FULL DISCLOSURE The new and novel compounds of the instant invention are compounds possessing useful activities as antihypoxic, hypothermic, antipyretic or anti-inflammatory agents. These compounds are represented by the compounds having the structures in which Y is di(lower)alkylamino, cyclo (lower) alkylamino, benzylamino, phenethylamino, or di (lower)alkylamino (lower)alkylamino; R and R are alike or different and are H, (lower)alkyl or a radical of the formula in which n is an integer of l to 4 and R is H, CF chloro, fluoro, bromo, (lower)alkoxy or (lower) alkyl, R and R are alike or different and each is H, chloro, bromo, CF fluoro, (lower)alkyl, (lower)-alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt thereof.  
  For the purpose of this disclosure, the term (lower), as in (lower)alkyl, shall mean a straight or branched chain hydrocarbon of 1 to 6 carbons. The term pharmaceutically acceptable -ntoxic salt&#34; shall mean an acid salt prepared by the rea-.tion of one mole of a compound of formula la or IL with one or more moles of a pharmaceutically acceptable nontoxic acid such as sulfuric, hydrochloric, hydrobromic, malic, maleic, citric, ascorbic, nitric, phosphoric or acetic acid, or some other functionally equivalent acid, to form a monoor poly acid salt.  
  Anti-hypoxic activity is defined here as the property of a compound to prolong the survival time of mammals in a low oxygen atmosphere. Hypothermic acitivty is the property of a compound to lower the normal body temperature of a mammal. Antipyretic activity is the property ofa compound to lower the elevated body temperature of a diseased mammal. Anti-inflammatory activity is the property of a compound to reduce the inflammation associated with physical trauma, arthritis, etc. Some of the compounds of the instant invention possess marginal anti-inflammatory activity. All of the compounds possess some activity as anti-hypoxic, antipyretic or hypothermic agents.  
  The compounds of the instant invention are prepared by one of three synthetic routes, the general scheme of which are diagrammed below:  
 Scheme I G1 on o c 2 N 2 HZN R4 NH R 2 R4 l. Nari ca 0 c 4 2 3 2 U 2. RI  
  9 N/ NH-C N l R 24 POCl g3 R, R R R and Y are as defined above Where R H in 23, the conversion to 24 fails be- CO CH cause a tautomeric form (23a) of 23 cyclizes instead to the pyrimido [4,3-b][ l ,4]quinazol-l0-one (50).  
  Scheme II CO C H c c n j 2 2 5 N N C1 --9 CH HN l 1. OH  
 3 2. CICO C A 3. NaN  
 N/ NCO A i IV I C0213 CHCl CHC 1 km l v CH CH CHCI CHCI 0 ll NH-- C Scheme three is illustrated by examples 26 thru 31. A preferred embodiment of the present invention is the compound having the formula (CH n Y N 2 in which n is an integer of l to 4 and R is chloro, CF H, fluoro, bromo, (lower)alkoxy or (lower)alkyl; R L l and R* are alike or different and each is H, chloro, N 4 bromo, fluoro, (lower)alkyl, CF (lower)-alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt R thereof.  
  Another preferred embodiment is the compound having the formula tlq Ia R in which Y is di(lower)alkylamino, cyclo(lower)- alkylamino, benzylamino, phenethylamino, or di(- in which Y is (lowe lkyl m n0. y (l lower)-alkylamino (lower)alkylamino; R and R are alkylamino. benzylamino, phenethylamino, or di(- alike or different and are H, (lower)alkyl or a radical l0wer)-alkyl min (l weflalkylamino; R is H, (lower of the formula )alkyl or a radical of the formula in which II is an integer of l to 4 and R is chloro, CF H, fluoro, bromo, (lower)alkoxy or (lower)alkyl. R is H, chloro, bromo, fluoro. (lower)alkyl, CF (lower)alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt thereof.  
  A more preferred embodiment is the compound of formula la wherein R is H. (lower)alkyl. benzyl or phenethyl. R is H. and Y is dimethylamino, cyclopropylamino, benzylamino or dimethylaminoethylamino; or a pharmaceutically acceptable, nontoxic salt thereof.  
  Another more preferred embodiment is the compound of formula Ia wherein R is methyl. R is H and Y is dimethylamino, cyclopropylamino, benzylamino or dimethylaminoethylamino; or a pharmacuetically acceptable, nontoxic salt thereof.  
 A preferred embodiment of the present invention is the compound having the formula --CH2 R2 N l Ib in which R and R are alike or different and are H, (lower)alkyl or a radical of the formula in which n is an integer of l to 4 and R is chloro, CF H, fluoro, bromo, (lower)alkoxy or (lower)alkyl. R is H, chloro, bromo, fluoro, (lower)alkyl, CF (lower)alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt thereof.  
  A more preferred embodiment is the compound of formula lb wherein R is H, (lower)alkyl, benzyl or phenethyl, R is H or chloro, and R is H, (lower)-alkyl. benzyl or phenethyl; or a pharmaceutically acceptable, nontoxic salt thereof.  
  Another more preferred embodiment is the compound of formula lb wherein R is methyl or benzyl, R is H or chloro and R is H or methyl: or a pharmaceutically acceptable, nontoxic salt thereof.  
  Most preferred embodiments are the compounds of formula lb wherein A. R is H, R is benzyl and R is H; B. R is chloro, R and R are methyl;  
 C. R and R are H and R is methyl; D. R is chloro, R is H and R is methyl; and E. R and R are methyl and R is H: F. R, G. R  
  R and R are H. 2 is methyl, R is H and R is methyl.  
 in which Y is di(l0wer)alkylamino, cyclo(lower)- alkylamino, benzylamino, phenethylamino, or ditlower)-alkylamino (lower)alkylamino; R is H, (lower )alkyl or a radical of the formula 5 (CH2) mg in which n is an integer of l to 4 and R is chloro, CF H, fluoro, bromo, (lower)alkoxy 0r (lower)alkyl. R is H, chloro, bromo, fluoro,-(lower)alkyl, CF (lower)alkoxy or nitro&#39;, or a pharmaceutically acceptable nontoxic salt thereof.  
  A more preferred embodiment is the compound of formula 10 wherein R is&#39;H, (lower)alkyl, benzyl or phenethyl, R is H, and Y is dimethylamino, cyclopropylamino, benzylamino or dimethylaminoethylamino; or a pharmaceutically acceptable, nontoxic salt thereof.  
  Another more preferred embodiment is the compound of formula lc wherein R is methyl, R is H and Y is dimethylamino, eyclopropylamino, benzylamino or dimethylaminoethylamino; or a pharmaceutically acceptable, nontoxic salt thereof.  
  A preferred embodiment of the present invention is the compound having the formula in which R and R&#34; are alike or different and are H, (lower)alkyl or a radical of the formula in which n is an integer of l to 4 and R is chloro, CF H, fluoro, bromo, (lower)alkoxy or (lower)alkyl. R is H. chloro, bromo, fluoro, (lower)alkyl, CF (lower)alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt thereof.  
  A more preferred embodiment is the compound of formula Id wherein R is H, (lower)alkyl. benzyl or phenethyl, R is H or chloro, and R is H, (lower)-alkyl. benzyl or phenethyl; or a pharmaceutically acceptable, nontoxic salt thereof.  
  Another more preferred embodiment is the compound of formula Id wherein R is methyl or benzyl, R is H or chloro and R is H or methyl; or a pharmaceutically acceptable, nontoxic salt thereof.  
  Most preferred embodiments are the compounds of formula Id wherein A. R is H, R is benzyl and R is H;  
 B. R is chloro, R and R are methyl;  
 C. R and R are H and R is methyl;  
 D. R is chloro, R is H and R is methyl; and E. R and R are methyl and R is H;  
 F. R, R and R are H.  
 G. R is methyl, R is H and R is methyl.  
  Another most preferred embodiment is the compound of formula [C wherein Y is cyclopropylamino, R is methyl and R is CH The compounds are screened for the pharmacological properties by the following standard procedures:  
  Mouse Hypoxia Survival Time An incubator was adapted for use as a hypoxia cham- 5 her allowing continuous visualization of 12 mice housed individually&#39;within the chamber. Six mice are treatd intraperitoneally with the test drug and six control mice are treated with the drug vehicle. Approximately 20-30 minutes later a commercially prepared 3% oxygen in nitrogen mixture is flushed through the chamber for 15 min at a flow rate of 55 cubic feet/min. At the end of 15 min the flow rate is reduced to 5 cubic feet/min.  
  The precise time to death in minutes for each mouse 5 is obtained and the mean survival time i 1 Standard error calculated for each group. A greater than 50% increase in survival time is the level of significance During the above procedure the partial pressure of oxygen within the chamber is continuously monitored.  
  Hypothermic Activity In conjunction with hypoxia testing, observations are made on the effect of the test agents on body temperature. Rectal temperatures are measured by means of a thermistor temperature probe (Yellow Springs Instrument Co.) in both the vehicle and drug treated groups of mice. Approximately -30 minutes later rectal temperatures are retaken. Changes in the normal body temperature of 2C or above are considered the level of significance in this test.  
 Antipyretic Activity This test refers to the ability of a drug to reduce an elevated body temperature rather than reducing a nordotoxin.  
 Table I 1&#39;13 N/ N-CH 2 N l R Anti-Hypoxic Hypothermic Activity* Activity-&#39;- Change Antipyretic in Activity CQmPOund 4 2 Dose Survival Dose R R R R ing/kg Time mg/kg &#34;6 MED, rug/kg 42 H ll C ll Cll ll 10 81 10 -2. 4 30 24 30 3. 2 44 H Cl CH CH 10 81 1O 3. 5 30 84 30 -3. l  
 28 H H CH ll 10 178 10 -3.9 8  
  30 138 30 -3. 5 3 10 v 3 -O.6 29 H C1 CH ll 10 87 i 10 3.8 30 30 30 3.2 10 5s 10 6 53 21 ll CH ll 30 2 18 30 l0 l..9 54 li CH CH H 30 82 30 Anti-Hypoxic Hypothermic Activity* Activity+ 7r Change Antipyretic in Activity Com- Dose Survival Dose pound No. R R R mg/kg Time mg/kg &#34;C MED, s/  
 42 H H C H CH H I 81 10 2.4 30 24 30 3.2 44 H Cl CH CH l0 8] l0 3.5 30 84 30 3.1 28 H H CH H 10 178 10 3.9 8  
  30 l38 30 3.5 3 l0 3 -().6 29 H Cl CH H 10 87 10 3.8 30 30 30 3.2 10 55 i0 53 Cl H CH H 30 248 30 2.6 4.4 10 0 l0 -1 .9 54 H CH CH H 30 82 30 3.8 34 CH;, CH lo 31 10 -09 H 30 84 30 .0 52 H H l0 H H lOS Dosed i.p. in mice. A change in survival time of 507 is considered significant. +Dosed i.p. in mice. A drup in temperature of 2 is considered significant. &#34;Doscd pro. in rats.  
 i Y l N N s N a Anti-Hypoxic 3 Activity* Hypothermic Compound Dose Change in Activity+ No. Y mg/kg Survival Time C 30 (CH N 2d O 2.7  
 31 -ini 3o 41 -3.2 32 PhCH NH 3o 0 2.7 33 (CH N(CH NH 30 0 2.6  
 *Dosed i.p. in mice. A change in survival time of 502; is considered significant. +Dosed i.p. in mice. A drop in temperature of 2 is considered significant.  
  The compounds of the instant invention are useful The dosage range of the compounds is about 1 to 30 for their anti-hypoxic, hypothermic and antipyretic acmg./kg., one to six times a day. tivity in mammals, including man. They are potentially An alternative process for the preparation of comuseful to lower tissue oxygen requirements during sur- 50 pounds lb in which R is CH; has been found as illustrated below:  
  3 2 R 1) Nail, DMF N \N N R4 2) CH 3 3 CH gery, in cardiac disorder situations and, perhaps, in R R and R are as disclosed within. Example 40 is ilspncc travel where oxygen consumption can be critical. lustrative of the procedure.  
 EXAMPLES OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Preparation of Methyl N-(6-Chloro-5-nitro-4-pyrimidinyl)anthranilate (20).  
  A solution of 4,6-dichloro--nitropyrimidine (1.0 g. 0.000515 mole), methyl anthranilate (0.78 g. 0.00515 mole) and triethylamine (0.52 g, 0.00515 mole) in benzene (8 ml) was heated under reflux for 0.5 hour. The reaction mixture was cooled to 23 and filtered. The filtrate was concentrated to give a brown, gummy solid which was extracted with boiling cyclohexane. From the cooled extract was obtained a yellow crystalline solid (0.53 g, 33%), mp 140-143. The solid was recrystallized twice from cyclohexane to give methyl N- (6-chloro-5-nitro-4-pyrimidinyl)anthranilate, mp 144145.  
 Anal. Calcd for C, H ClN O,: C, 46.69;  
 H, 2.94; Cl, 11.49; N, 18.15 18.15.  
 Found: C. 46.76; H, 2.97; C], 11.38; N, 18.10.  
 EXAMPLE 2 Preparation of Methyl N-(6-Chloro-5-nitro-4-pyrimidinyl)-N- methylanthranilate (21) Method A. Sodium hydride (0.311 g ofa 50% sodium hydride dispersion in mineral oil, 0.00648 mole sodium hydride) was added to a cooled (ice-water), stirred suspension of methyl N-(6-chloro -5-nitro-4- pyrimidinyl)anthranilate (2.0 g, 0.00648 mole) in DMF [dimethylformamide ml)].  
  Stirring was continued for 1 hour. Methyl iodide (3 ml) was then added and stirring was continued for 16 hours while the temperature of the reaction mixuture was allowed to slowly rise to room temperature. The reaction mixture was concentrated to leave a viscous residue which was washed with Skellysolve B (petroleum ether, essentially n-hexane) and then extracted with boiling cyclohexane. The extract was reduced in volume. From the cooled extract was obtained a yellow crystalline solid (1.18 g, 56.5%), mp l34.5l35.5. The solid was recyrstallized from cyclohexane to give methyl N-(O-chloro-S-nitro-4-pyrimidinyl)-N- methylanthranilate as yellow needles, mp 136137.5.  
 Anal. Calcd for C, H,,C1N O C, 48.38; H,  
 Found: C, 48.15; H, 3.74; Cl, 10.72.  
  Method B. A mixture of 4,6-dichloro-5- nitropyrimidine (5.0 g, 0.0258 mole) and methyl N- methylanthranilate (8.53 g, 0.0516 mole) in benzene (100 ml) was heated under reflux for 5 hours. The cooled solution was washed with water and concentrated. The semi-solid residue was recrystallized from cyclohexane to give methyl N-(6-chloro-5-nitro-4- pyrimidinyl)-N-methylanthranilate (5.36 g, 64.4%), mp 133.5135.5.  
 EXAMPLE 3 Preparation of Methyl 5-Chloro-N-(6-chloro-5-nitro-4-pyrimidinyl)-N- methylanthraniliate (22) A solution of4,6-dichloro-5-nitropyrimidine 1.99 g, 0.01025 mole) and methyl 5-chloro-N- methylanthranilate (4.08 g, 0.0205 mole) in toluene (50 ml) was heated under reflux for 7 hours and then allowed to stand at 25 for 19 hours. The mixture was filtered and the filtrate concentrated. The residue was crystallized from Skellysolve B to give methyl 5-chloro- N-(6-chloro-5-nitro-4-pyrimidinyl)-N- methylanthranilate (1.65 g, 45%), mp 104-107. Recrystallization from Skellysolve B gave orange-yellow crystals, mp l07l08.  
 Anal. Calcd for C, H, ,Cl N O C, 43.72;  
 H, 2.821C1, 19.85; N, 15.69.  
 Found: C, 44.04; H, 2.97; C1, 19.55; N, 15.73.  
 EXAMPLE 4 Preparation of Methyl N-( 5-Amino-4-pyrimidinyl )-N-methylanthranilate A solution of methyl N-(6-chloro-5-nitro-4- pyrimidinyl)-N-methylanthranilate (12.2 g, 0.0378 mole) and triethylamine (4.21 g, 0.0416 mole) in ethyl acetate (300 ml) containing 10% pd-C (3.0 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until the uptake of hydrogen ceased. The reaction mixture was filtered. The collected solid was well washed with hot ethyl acetate. The combined filtrate and washings was reduced to dryness to give methyl N- (5-amino-4-pyrimidinyl)-N-methylanthranilate (9.0 g, 92%), mp 1l8122. A portion of the product was recyrstallized from ethyl acetate to give pale yellow crystals, mp 12l.5123.5.  
 Anal. Calcd for G l-1 N 0 C, 60.45; H,  
 Found: C, 60.41; H, 5.60; N, 21.99.  
 EXAMPLE 5 Preparation of l l-Methyl-l lH-pyrimido[4,5-b][1,4]benzodiazepin- 6(5H)-one (24) A flask containing methyl N-(5-amino-4- pyrimidinyl)-N-methylanthranilate (7.8 g) was placed in an oil bath maintained at for 10 minutes. The solid product was extracted and recrystallized from ethanol to give ll-rnethyl-l lfl -pyrimido [4,5-b][1,4]- benzodiazepin-6(5fl)-one (5.6 g, 82%), mp 282284. A portion of the product was sublimed at 138 (0.7 mm Hg) to give pale yellow crystals, mp 282284.  
 Anal. Calcd for C H N O: C, 63.70; H,  
 Found: C, 63.96; H, 4.64; N, 24.94.  
 EXAMPLE 6 Preparation of 8-Ch1oro-11-methyl-l lH-pyrimido[4,5- b][1,4]benzodiazepin-6(5fl)&#39;-one (25) A mixture of methyl 5-chloro-N-(6-chloro-5-nitro-4- pyrimidinyl)-N-methylanthranilate 10.7 g, 0.03 mole), triethylamine (4.2 ml. 0.03 mole), and 10% Pd-C (3.0 g) in ethyl acetate (200 ml) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until four equivalents of hydrogen had been consumed. The mixture was filtered and the filtrate concentrated. The residual oil was heated on a steam bath for 0.5 hours and then heated. at a pressure of 0.05 mm, by means of an oil bath maintained at 220 for 1 hour. Part of the product was purified by sublimation at 250 (0.05 mm) to give yellow crystals. mp 303310, and part was purified by recrystallization from n-butyl alcohol to give light brown crystals, mp 3l43l8. The two fractions (4.7 g, 60%) were recrystallized from n-butyl alcohol EXAMPLE 7 Preparation of 5,11-Dimethyl-1lH-pyrimido[4,5- b][1,4]benzodiazepin-6(5fl)-one Hydrochloride (26) Sodium hydride (0.716 g of a 57% sodium hydride dispersion in mineral oil. 0.017 mole of sodium hydride) was added to a stirred, cooled (ice-water) mixture of ll-methyl-l1H-pyrimido-[4,5-b][1,4]- benzodiazepin-6(5 H)-one (3.51 g, 0.0155 mole) in DMF (40 m1) under nitrogen. The mixture was stirred for 0.75 hour at 25. The resulting solution was cooled (ice-water) and a solution of methyl p-toluenesulfonate (3.17 g, 0.017 mole) in DMF (8 ml) was added over a period of minutes. The mixture was heated by means of an oil bath maintained at 105 for 2.5 hours. The re-.  
 action mixture was concentrated andthe residue partitioned between ether and water. The ether layer was dried (Na- 50 and concentrated to give a yellow oil. The aqueous layer was concentrated and the residue extracted with benzene. The benzene extract was concentrated to give a red oil. The yellow and red oils were chromatographed on silicic acid with toluene-acetone (8:1) to give an oil (2.85 g) which was treated with hydrogen chloride in ether. The resulting solid (3.1 g, 72%) was recrystallized from ethanol-ether to give 5.1- l-dimethyl-l lH-pyrimido[4,5-  
 b][ l ,4]benzodiazepin-6( 5H )-one hydrochloride pale yellow crystals, mp 214-223 (&#39;decomp).  
 Anal. Calcd for&#39;C H N OHCl: C, 56.42; I  
 Found: C, 56.16; H, 4.92; C], 13.01.  
 &#34;EXAMPLE 8 Preparation of 6-Chloro-1 l methyl-l1 l:l -pyrimido[4,5- b][ 1,4]benzodiazepine (27) A mixture of ll-methyl-l lfl-pyrimido[4,5-b]- l1,4]benzodiazepin-6(5fl)-one (g) and P(.)C1;, (20 ml) was heated under reflux for 2.5 hours. The reaction mixture was concentrated and a CH solution of the residue poured onto ice. The mixture was neutralized with K CO;,. The CH Cl vlaycr was washed with cold aqueous K CO followed by cold water. dried 55 (Na SO and reduced to dryness. The residue (1.5g) was chromatographed on alumina g) with benzeneacetone 1:1 to give 6-chloro-1 l-methyl-l lflpyrimido[4,5-b][1,4]-benzodiazepine (0.93 g, 43%), mp 12512&#39;6-.&#39; The product was-&#34;recrystallized from Skellysolve B and then sublimed at 80 -1 10 (0.02 mm Hg) to give yellow crystals. mp 126128.&#39;=  
 Anal. Calcd for C H ClN C, 58.90; H,  
 3.71; CI, 14.49;.N, 22.90  
 Found: C, 58.93; H.387; Cl, 14.58; N,  
  EXAMPLE 9 Preparation of 5,6-Dihydro-1 l-methyl-l 1 lj-pyrimido[4,5- b][ 1,4]benzodiazepine (28) Method A. A solution of 6-ch1oro-11-methyl-11H- pyrimido[4,5-b][1,4]benzodiazepine (1.71 g, 0.007 mole) and triethylamine (0.709 g, 0.007 mole) in ethyl acetate ml) containing 10% Pd-C (0.8 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until the uptake of hydrogen ceased. The reaction mixture was filtered and the filtrate reduced to dryness to leave 5,6-dihydro-1 l-methyl-l 1H- pyrimido[4,5-b][1,4]benzodiazepine (1.35 g, 92.5%) as a colorless solid, mp 1 45151. The solid was recrystallized twice from cyclohexane to give colorless crystals, mp 155157.  
 Anal. Calcd for C, H N C, 67.90; H,  
 Found: C, 67.87; H, 5.77; N, 26.54.  
  Method B. Diborane in THF [tetrahydrofuran] (4.12 ml of 0.5 M, 0.00206 mole of diborane) was added to a cooled (ice-water), stirred mixture of ll-methyl- U H-pyrimido[4,5-b][1,4]benzodiazepin-6-(5fl)-one (0.466 g, 0.00206 mole) in THF (25 ml) under nitrogen. The mixture was stirred at 25,for 15 minutes. The yellow solution was heated under reflux for one hour and then allowed to stand at 25 for 18 hours. To the cooled (ice-water) stirred mixture was added 6N HCl (10 ml). Stirring with cooling was continued for 15 minutes, then the mixture was heated under reflux for 10 minutes. The THF was removed. The residual aqueous solution was diluted with water. treated with activated charcoal, and filtered. The filtrate was made basic with 5N NaOH and extracted with methylene chloride. The extract was washed successively with water and saturated aqueous sodium chloride, dried (Na SOQ and concentrated. The residue was recrystallized from cyclohexane to give 5,6-dihydro-1 l-methyll lH-pyrimido[4.5-b][1,4]benzodiazepine (0.129 g. 30%), mp 152.  
 EXAMPLE l0 Preparation of 8-Chloro-5 ,6-dihydro-l l-methyl-l l-fl-pyrimidol[4.5-  
  b][1,4]benzodiazepine (29) Diborane in THF (7.7 ml of 0.5M, 0.00385 mole of diborane) was added to&#39; a stirred, cooled (ice-water) mixture of 8-chloro-1 1&#39;-methyl-1 lfl-pyrimido-[4,5- b][1,4]-benzodiazepine-6(5H)-one (1.0 g. 0.00384 mole) in THF (50 ml). The mixture was stirred at 25 for 0.5 hour and-then heated under reflux for 1.25 hours. The cooled (ice-water) mixture was treated with 6N HCl (15 m1) and then stirred at 25 for 15 minutes. The solution was heated under reflux for 10 minutes. TheTHF was removed, the solution was filtered, and the filtrate made &#39;basi&#39;c&#39;with 5N NaOH. The precipitated&#39;solid was crystallized from benzene to give 8- b][1&#34;,4]-benzodiazepine (0.34 g, 36%), mp 196&#39;.5 -198.5. Recrystallization from methanol gave product with mp 200-202.  
 , Anal. Calcd for C H ClN C. 58.42; H,  
 Fourid: C, 58.68; H-, 4.68; Cl. 13.95; N,  
 EXAMPLE 11 Preparation of 6-Dimethylamino-l l-methyl-l lfl-pyrimido[4.5- b][ 1,4]benzodiazepine (30) Dimethylamine (2.36 g, 0.0524 mole) was added to a cold (ice-water) mixture of 6-chloro-l l-methyl-l 1H- pyrimido[4,5-b][1,4]benzodiazepine (3.2 g, 0.0131 mole) in benzene contained in a pressure bottle. The bottle was heated on a steam bath for 1 hour and was then allowed to stand at 25 for 17 hours. The reaction mixture was filtered and the filtrate reduced to dryness. The residual yellow solid was recrystallized from Skellysolve B to give 6-dimethylamino-l l-methyl-l 1H- pyrimido[4,--b][1,4]benzodiazepine (3.3 g, 100%), mp 119.5-122. The product was recrystallized from Skellysolve B to give yellow needles, mp ll9l2l.  
 Anal. Calcd for C H, N C, 66.38; H,  
 Found: C, 66.49; H, 6.05; N, 27.99.  
 EXAMPLE 12 Preparation of 6-Cyclopropylamino-1 l-methyl-l lfl-pyrimido[4,5- b][ 1,4]benzodiazepine (31) A mixture of 6-chloro-1 l-methyl-l lli-pryimido[4,5- b][l,4benzodiazepine (1.5 g) and cyclopropylamine (3ml) was heated under reflux for 1.25 hours. The reaction mixture was reduced to dryness. The residue was treated with water and the mixture filtered. The collected 6-cyclopropylamino-l l-methyl-l lflpyrimido[4,5-b][1,4]benzodiazepine (1.54 g, 94.5%), mp 268270, was recrystallized twice from methyl isobutyl ketone to give yellow crystals, mp 266257.5.  
 Anal. Calcd for C, =,H N C, 67.90; H, 5.70; N, 26.40. Found: C, 68.31; H, 5.90; N, 26.44  
 EXAMPLE 13 Preparation of 6-Benzylamino-1l-methyl-l lfl-pyrimido[4,5- b][1,4]benzodiazepine (32) A mixture of 6-chloro-l l-methyl-l lfl-Py imido[4,5- b][ 1,4]benzodiazepine 1.5 g, 0.00612 mole) and benzylamine (2.3 g, 0.0215 mole) in benzene (40 ml) was heated under reflux for 5 hours and was then allowed to stand at 25 for 5 days. The reaction mixture was filtered to give solid A and filtrate B. Solid A (2.0 g) was washed with water to leave yellow crystals (1.47 g), mp 247-249. Filtrate B was washed with water and reduced to dryness. The residual solid (0.7 g) was recrystallized from toluene to give yellow crystals (0.32 g), mp 245.5-247.5. The combined product (1.79 g, 93%) was recrystallized from toluene to give 6- benzylamino-l l-methyl-l lfl-pyrimido[4,5-b][ 1,4]- benzodiazepine as pale yellow crystals, mp 245247.  
 Anal. Calcd for C H N z C, 72.36; H, 5.43;  
 Found: C, 72.16; H, 5.44; N, 22.37.  
 EXAMPLE 14 Preparation of 6-(2-Dimethylaminoethylamino)-1 l-methyl-l 1L1- pyrimido[4,5-b][1,4]benzodiazepine (33).  
 A solution of 6-chloro-11-methyl-1lfl-pyrimido- [4,5-b][1,4lbenzodiazepine (2.0 g, 0.00818 mole) and Z-dimethylaminoethylamine (1.44 g, 0.0164 mole) in benzene ml) was heated under reflux for 4 hours. The mixture was filtered and the filtrate reduced to dryness. The residual solid was recrystallized from cyclohexane to give 6-(Z-dimethylaminoethylamino)-l lmethyl-l 1fl-pyrimido[4,5-b][ 1,4]benzodiazepine (2.23 g, 92%), mp 16ll64. The product was recrystallized from cyclohexane to give plate yellow crystals, mp l62l63.5.  
 Anal. Calcd for C H N C, 65.84; H, 6.80, N, 28.36. Found: C, 65.65; H, 6.95; N, 28.64.  
 EXAMPLE 15 Preparation of 5,6-Dihydro-5,l l-dimethyl-l lfl-pyrimido[4,5- b][1,4]benzodiazepine Hydrochloride (34) Sodium hydride (1.1 g of a 57% sodium hydride dispersion in mineral oil, 0.0262 mole of sodium hydride) was added to a stirred solution of 5,6-dihydro-1 1- methyl-l 1H-pyrimido[4,5-b][1,4]benzodiazepine (5.07 g, 0.0242 mole) in DMF (50 ml) under nitrogen. The stirred mixture was then heated by means of an oil bath maintained at 75-80 for 1 hour. The solution was cooled to 5. A solution of methyl p-toluenesulfonate (4.88 g, 0.0262 mole) in DMF (5 ml) was added dropwise over a period of 5 minutes. The stirred mixture was heated by means of an oil bath maintained at 60 for 1 hour and was then kept at 25 for 18 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water followed by saturated aqueous sodium chloride, dried (Na- SO and concentrated. The residue was extracted with boiling Skellysolve B. The extract was concentrated and the residue chromatographed on alumina (200 g) with toluene-acetone-diethylamine 1.: 1 :0.02). The product was recrystallized from Skellysolve B to give yellow crystals (2.16 g), mp 9l93. This product was dissolved in an equivalent of 1N HCl. The solution was reduced to dryness. The residual solid was recrystallized from ethanol to give 5,6-dihydro-5,ll-dimethyl-l1H- pyrimido[4,5-b][ l,4]-benzodiazepine hydrochloride as yellow crystals (2.2 g, 34.5%), mp 253-257 (decomp).  
 Anal. Calcd for C H N .HCl: C, 59.42; H,  
 5.75; Cl, 13.49; N, 21.82.  
 Found: C, 59.28; H, 5.90; Cl, 13.65; N, 21.62.  
 EXAMPLE 16 Preparation of Ethyl 4-(N-Methylanilino)pyrimidine 5-carboxylate (35) A solution of N-methylaniline (6.9 g, 0.0645 mole) and ethyl 4-chloropyrimidine-5-carboxylate (6.0 g, 0.0323 mole) in benzene (35 ml) was heated under reflux for 2 hours. The mixture was allowed to stand at room temperature overnight. The mixture was filtered and the filtrate concentrated. The residue was chromatographed on alumina (250 g) with benzenechloroform to give a brown oil which was distilled at -l42 (0.1 mm) to give a pale yellow oil which crystallized on standing. The product was recrystallized from Skellysolve B to give ethyl 4-(N- methylanilino)pyrimidine-S-carboxylate (0.825 g) as colorless crystals, mp 72-73.  
 Anal. Calcd for C H N O C, 65.35; N, 5.88; N, 16.33. Found: C, 65.20; H, 5.82; N, 16.45.  
 EXAMPLE 17 Preparation of 4-(N-Methylanilino)pyrimidine-S-carboxylic Acid A solution of ethyl 4-(N-methylanilino)-pyrimidine- -carboxylate (2.0 g) and potassium hydroxide (2.5 g) in ethanol (20 ml) and water (5 ml) was heated under reflux for 3.5 hours. Removal of the ethanol and acidification with hydrochloric acid gave a solid which was recrystallized from acetone to give 4-(N- methylanilino)pyrimidine-S-carboxylic acid (0.80 g), mp 2l0-2l2. Recrystallization from acetone gave colorless crystals, mp 2l2-2l3.  
 Anal. Calcd for C, H N O C, 62,87; H,  
 Found: C, 62.80; H, 4.93; N, 18.45.  
 EXAMPLE 18 Preparation of l l-Methyl-l lfl-pyrimido[4,5-b][ l,4]-benzodiazepin- 6(5H )-one (24) Triethylamine (0.6 ml, 0.00422 mole) was added to a stirred mixture of 4-(N-methylanilino)pyrimidine-S- carboxylic acid (0.966 g, 0.00422 mole) in THF ml). The resulting solution was cooled in an ice-NaCl bath. Ethyl chloroformate (0.457 g, 0.00422 mole) was added and the mixture stirred with cooling for 0.5 hr. With continued stirring and cooling, a solution of sodium azide (0.550 g, 0.00844 mole) in water (50 ml) was added over a period of 1 hour. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried (Nat S0 and concentrated. A solution of the residue in 1,1,2,2-tetrachloroethane was heated on a steam bath until the evolution of nitrogen ceased. This solution was then added over a period of 0.5 hour to a stirred mixture of aluminum chloride (0.0025 mole) in 1,1,2,2-tetrachloroethane (3ml) at 9095. The mixture was stirred for an additional 1 hour at 90- 95. The cooled mixture was poured into a mixture of l N HCl (4 ml) and water (10 ml). The organic concentrated. was dried (Na SO and conventrated. The re sidual solid was sublimed at 200 (0.1 mm). The product was recrystallized from ethanol to give 1 l-methyl- 1 lH-pyrimido[4,5-b][ l ,4]benzodiazepin-6(5H)-one (30 mg) as colorless crystals, mp 281-283.  
 EXAMPLE 19 Preparation of Methyl N-Benzyl-N-(6-chloro-5-nitro-4- pyrimidinyl)anthranilate (38) Sodium hydride (0.405 g of a 59.4% sodium hydridedispsersion in mineral oil, 0.01 mole sodium hydride) was added to a cooled (ice-water), stirred suspension of methyl N-(6-chloro-5-nitro-4-pyrimidinyl) anthranilate (3.08 g, 0.01 mole) in diglyme (25 ml). The mixture was stirred for 20 minutes with cooling followed by 40 minutes at Benzyl iodide (2.18 g, 0.01 mole) was then added to the cooled (ice-water) mixture, and stirring was continued for 18 hours while the temperature of the reaction mixture was allowed to slowly rise to 25. The reaction mixture was filtered and concentrated. The residue was treated with methylene chloride (200 ml), water ml) and glacial acetic acid (1 ml). The methylene chloride layer was washed with water, dried (Na- SO and concentrated. The residue was extracted with boiling cyclohexane (2 X ml). The extracts were reduced in volume and allowed to cool. The crystalline product (2.54 g, 64%) was recrystallized twice from cyclohexane to give methyl N- benzyl-N-( 6-chloro-5-nitro-4-pyrimidinyl)anthranilate as yellow crystals, mp 1 l2-l 135.  
  Anal. Calcd for C H, ClN,O C, 57.22; H, 3.79; C 1 8.89; N, 14.05.  
 Found: C, 57.36; H, 3.80; Cl, 9.02; N, 14.14.  
 EXAMPLE 20 Preparation of Methyl N-(5-Amino-4-pyrimidinyl)-N-benzylanthranilate (39) A solution of methyl N-benzyl-N-(6-chloro-5-nitro- 4-pyrimidinyl)anthranilate (2.08 g, 0.00522 mole) and triethylamine (0.527 g, 0.00522 mole) in ethyl acetate 100 ml) containing 10% Pd-C (0.5 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until the uptake of hydrogen ceased. The reaction mixture was filtered. The filtrate was concentrated to leave methyl N-(5-amino-4-pyrimidinyl)-N-benzylanthranilate as a viscous oil. The product was characterized as a hydrobromide salt (1.8 g, 83%) which was recrystallized from acetonitrile followed by methanol-ether to give colorless crystals, mp l89-l90 (decomp).  
 Anal. CalCCl fOI C 9H H4O2.HBr: C,  
 H, 4.61; N, 13.49; Br. 19.24.  
 Found: C, 54.94; H, 4.76; N, 13.68; Br, 19.43.  
 EXAMPLE 21 Preparation of 1 l-Benzyl-l lli-pyrimido [4,5-b] [1, 4] -benzodiazepin-6(5H)-one (40) A flask containing methyl N-(5-amino-4- pyrimidinyl)-N-benzylanthranilate (8.85 g) was placed in an oil bath maintained at -l85 for 15 minutes. The solid product was cooled, triturated with cold methylene chloride, and the mixture filtered. The collected solid (5.9 g, 74% mp 242.5-244.5 was recrystallized from ethanol to give ll-benzyl-l ll-l pyrimido[4,5-b] [1,4] benzodiazepin-6(5H)-one as colorless plates, mp 242.5-244.  
 Anal. Calcd for C H N O; C, 71.51; H,  
 Found: C, 71.27; H, 4.52; N, 18.63.  
 EXAMPLE 22 Preparation of 1 l-Benzyl--chloro-l lfl-pyrimido [4,5-b] [l,4]benzodiazepine (41) A mixture of ll-benzyl-l ll-l-pyrimido [4,5-b] [1, 4]benzodiazepin-6(5 l;l)-one (9.25 g) and POCl (90 ml) was heated under reflux for 0.75 hour. The reaction mixture was concentrated and a methylene chloride solution (200 ml) of the residue was poured onto a stirred mixture of concentrated NH,OH (25 ml), methylene chloride (100 ml), and ice (75 g). Stirring was continued for 10 minutes, the temperature of the mixture being maintained at l0l5. The methylene chloride layer was washed with cold water (3 X 100 ml) followed by saturated aqueous sodium chloride. The methylene chloride solution was then dried (Na SO and concentrated. The residual froth was chromatographed on basic alumina (200 g) with toluene-acetone (50: 1 to give a yellow solid. The solid was washed with a small volume of cold n-pentane to give 1 1-benzyl-6- chloro-l lH-pyrimido [4,5-6] [1,4]-benzodiazepine (6.6g, 67%), mp 1091 12. The product was recrystallized from Skellysolve B to give yellow crystals, mp 11 l.5-1l3.  
 Anal. Calcd for C ,H, ClN,: C, 67,39; H,  
 4.08; Cl, 11.05; N, 17.47.  
 Found: C, 67.03, H, 4.28; Cl, 11.12; N, 17.36.  
 EXAMPLE 23 Preparation of 1 l-Benzyl-5,6-dihydro-1lfl-pyrimido-[4,5-b] [1,4]benzodiazepine (42).  
  A solution of 1 1-benzyl-6-chloro-l lH-pyrimi&#39;do [4,5- b]-[1,4]benzodiazepine (5.7 g, 0.0178 mole) and triethylamine (2.0 g, 0.0198 mole) in ethyl acetate (200 ml) containing Pd-C (1.0 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until the uptake of hydrogen ceased. The reaction mixture was filtered and the filtrate concentrated to leave a yellow solid (5.0 g). The solid was recrystallized from Skellysolve C to give ll-benzyl-6,-dihydro-l1H- pyrimido[4,5-b] [l,4]benzodiazepine (4.2 g, 83.5%) as buff crystals, mp l18.5-119.5.  
  Anal. Calcd for C, H N C, 74.97; H, 5.59; N, 19.43.  
 Found: C, 74.94; H, 5.74; N, 19.14.  
 EXAMPLE 24 Preparation of 8-Chloro-5,l1-dimethyl-1 lfl-pyrimido-[4,5-b] [1,4]benzodiazepin-6(5H)-one (43) Sodium hydride (0.638 g of a 57% sodium hydride dispersion in mineral oil, 0.01516 mole of sodium hydride) was added to a stirred, cooled (ice-water) mixtrue of 8-chloro-l l-methyl-l ll;1 -pyrimido[4,5-b] [1,- 4]benzodiazepin-6(51;1)-one (3.59 g, 0.01378 mole in DMF (30 ml) under nitrogen. The mixture was then maintained at 50 until hydrogen evolution ceased (ca. 0.5 hour). Methyl p-toluenesulfonate (2.84 g, 0.0152 mole) in DMF (5 ml) was added to the cooled (icewater), stirred solution. The resulting solution was then heated by means of an oil bath maintained at 105 for 3 hours. The reaction mixture was concentrated and the residue treated with icewater. The solid was collected, washed with water, and dried. The product was recrystallized from cyclohexane to give 8-chloro-5,1 1- dimethyl-l 1H-pyrimido[4,5-b] [1,4]benzodiazepin- 6(5H)-one (2.5 g, 66%) as pale yellow crystals, mp 165-168. Recrystallization from cyclohexane gave pale yellow crystals, mp 166-168.  
 Anal. Calcd for C H CLN,O: C, 56.84; H,  
 4.04; Cl, 12.91; N, 20.39.  
 Found: C, 56.75; H, 4.14; Cl,&#39;l2.82; N, 20.72.  
 EXAMPLE 25 Preparation of 8-Chloro-5,6-dihydro-5,l l-dimethyl-l lflpyrimido[4,5-] [1,4]benzodiazepine (44) Sodium hydride (0.316 g of a 57% sodium hydride dispersion in mineral oil, 0.00749 mole sodium hydride) was added to a stirred solution of 8-chloro-5,6- dihydro-l l-methyl-l lfl-Pyrimido[4,5-b] [1,4]benzodiazepine (1.68 g, 0.00681 mole) in DMF ml) under nitrogen. The stirred mixture was heated by means of an oil bath maintained at -90 for 1 hour. The stirred solution was cooled (ice-water). A solution of methyl p-toluenesulfonate 1.39 g, 0.00749 mole) in DMF (3 ml) was then added. The resulting solution was stirred for 2 hours at 55 followed by 16 hours at room temperature. The reaction mixture was concentrated and the residue treated with ice-water. The collected solid (1.8 g), mp 120, was chromatographed on basic alumina (100 g) with toluene-acetone (10:1) containing 1% diethylamine to give 8-chl0ro-5,6- dihydro-5,l l-dimethyl-l IH-pyrimido [4,5-b] [1,4]benzodiazepine (1.31 g, 74%) as yellow crystals, mp 128l3l. Recrystallization from Skellysolve B gave product as pale yellow plates, mp 132-134.  
  Anal. Calcd for C H ClN C, 59.89; H, 5.03; Cl, 13.60; N, 21.49.  
 Found: C, 60.19; H, 5.17; Cl, 13.68; N, 21.87.  
 EXAMPLE 26 Preparation of Benzyl N-(4-Ethoxy-5-pyrimidinyl) carbamate (45) Diphenylphosphoryl azide (137.6 g, 0.50 mole) was added to a stirred solution of 4-ethoxypyrimidine-5- carboxylic acid (84.1 g, 0.50 mole), triethylamine (50.5 g, 0.50 mole) and benzyl alcohol (59.5 g, 0.55 mole) in 1,4-dioxane (1 litre) at 25. The stirred solution was heated until a moderate exothermic reaction set in, with gaseous evolution. External heating was stopped until the reaction had subsided. The solution was then heated under reflux for 1 hour. The solution was concentrated. A solution of the residue in toluene was washed successively with 1N HCl, water, aqueous NaHCO and saturated aqueous NaCl. The solution was dried (Na SO and concentrated. The residue was recrystallized from Skellysolve B to give benzyl N-(4- ethoxy-S-pyrimidinyl)carbamate (89.2 g, 65%) as pale yellow crystals, mp 97100. An analytical sample had mp 9799.  
  Anal. Calcd for C H N O z C, 61.53; H, 5.53; N, 15.38.  
 Found: C, 61.38; H, 5.77; N, 15.32  
 EXAMPLE 27 Preparation of 5- Amino-4-ethoxypyrimidine (46) A solution of benzyl N-(4-ethoxy-5-pyrimidinyl) carbamate (30.5 g, 0.1 12 mole) in ethanol (200 ml) containing 10% Pd-C (4.5 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm for 2 hours. The catalyst was removed by filtration and the filtrate concentrated to leave S-amino-4-ethoxypyrimidine 15.4 g, 99%) as a pale yellow oil.  
 EXAMPLE 28 Preparation of 4-Ethoxy-5-(o-nitrobenzalamino) pyrimidine (48) A solution of 5-amino-4-ethoxypyrimidine (15.1 g, 0.108 mole) and o-nitrobenzalehyde (16.4 g, 0.108 mole) in benzene ml) containing p-toluenesulfonic acid 1.0 g) was heated under reflux for one hour, with water being removed as it was formed. The reaction solution was reduced in volume. From the solution was obtained 4-ethoxy-5-(onitrobenzalamino)pyrimidine (25.5 g, 86.6%) by crystallization. Recrystallization of the product from cyclohexane gave yellow needles, mp 131-l33.5.&#34;.  
  Anal. Calcd for C H N O C, 57.35; H, 4.44; N, 20.58.  
 Found: C, 57.34; H, 4.39; N, 20.89  
 EXAMPLE 29 4-Ethoxy-S-(o-nitrobenzylamino)pyrimidine (50) Diborane in THF (57 ml of0.5 M, 0.0285 mole of diborane) was added over a period of 10 minutes to a cooled (ice-water), stirred mixture of 4-ethoxy-5-(onitro&#39;benzalamino)pyrimidine (15.5 g, 0.057 mole) in THF (200 ml) under nitrogen. The mixture was stirred at 25 for 30 minutes and then heated under reflux for 1 hour. The mixture was cooled and cautiously treated with 6N HCl 170 ml). When the vigorous gaseousevolution had ceased, the solution was heated under reflux for 15 minutes. Most of the THF was removed and the aqueous solution made strongly basic with NaOH. The precipitated material was extracted into ethyl acetate-diethyl ether (2:1 The organic layer was washed with water followed by saturated aqueous sodium chloride, dried (Na So,), and concentrated. The sticky crystalline product was recrystallized from cyclohexane followed by nitromethane to give 4- ethoxy-S- (o-nitrobenzylamino)pyrimidine (10.5 g, 67%) as yellow crystals, mp 124.5 126.5 Recrystallization from nitromethane gave bright yellow crystals, mp l25l26.5.  
  Anal. Calcd for C H N O C, 56.93; H, 5.15; N, 20.43.  
 Found: C, 57.00; H, 5.04; N, 20.81.  
 EXAMPLE 30 Preparation of S-(o-Aminobenzylamino)-4-ethoxypyrimidine (51 A mixture of 4-ethoxy-5-(o-nitrobenzylamino) p yrimidine (7.21 g) and Pd-C (1.5 g) in ethanol 100 ml) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until hydrogen uptake had ceased. The mixture was filtered and the filtrate concentrated. The residue was recrystallized from benzene-Skellysolve B to give 5-(o-aminobenzylamino) -4-ethoxypyrimidine (6.0 g, 93.5%) as pale yellow needles, mp 127-l29. Recrystallization from benzene-Skellysolve B gave pale yellow needles, mp 127l29.  
  Anal. Calcd for C, H,,,N,O: C, 63.91; H, 6.60; N, 22.94.  
 Found: C, 63.94; H, 6.82; N, 23.25.  
 EXAMPLE 31 Preparation of 5,6-Dihydro-l lH-pyrimido[4,5-b]  
 [ 1,4]benzodiazepine (52) Sodium hydride (0.745 g of 57% NaH dispersion in mineral oil, 0.0177 mole of NaH) was added to a stirred solution of 5-(o-aminobenzylamino)-4- ethoxypyrimidine (3.81 g, 0.0156 mole) in hexamethylphosphoramide (HMPA, 20 ml) at 25 under nitrogen. The mixture was heated, with stirring, by means of an oil bath maintained at l00-1 10 for one hour. The mixture was then stirred at 30 for 18 hours under nitrogen. About two-thirds of the HMPA was removed under vacuum. The gummy residue was treated with ice and water. The resulting solid was washed with cold water and dried. The solid (3.2 g) was recrystallized from toluene to give 5,6-dihydro-l lH-pyrimido [4,5-b] [l,4]benzodiazepine (2.2 g, 71%), mp 140-l42. Re-  
 crystallization from toluene gave the product as pale salmon crystals, mp l40l41.  
 Anal. Calcd. for C H N C, 66.65; H, 5.09; N,  
 Found: C, 66.94; H, 5,37; N, 28.56.  
 THF is tetrahydrofuran.  
 DMF is dimethylformamide.  
  Skellysolve B (Skelly B) is petroleum ether, B.P. 6068 C, consisting of essentially n-hexane.  
 EXAMPLE 32 Preparation of Methyl 4-Chloro-N-( 6-chloro-5-nitro-4-pyrimidinyl )-N- methylanthranilate A mixture of 4,6-dichloro-S-nitropyrimidine (27.1 g, 0.1394 mole), methyl 4-chloro-N-methylanthranilate (27.8 g, 0.1394 mole) and triethylamine (14.1 g, 0.1394 mole) in xylene (400 ml) was heated under reflux for 8 hours. The mixture was filtered and the filtrate concentrated. The residual oil was extracted with three 300 ml portions of boiling cyclohexane. The combined extracts were reduced in volume to about 175 ml by boiling and allowed to cool. Methyl 4-chloro-N-(6- chloro-5-nitro-4-pyrimidinyl )-N-methylanthranilate (22.0 g, 44.2%) was deposited as yellow crystals, mp l21l26. The product was recrystallized from cyclo hexane to give yellow crystals, mp l28-130.  
  Anal. calcd. for C H, Cl N,O,: C, 43.72; H, 2.82; Cl, 19.85; N, 15.69.  
 Found: C, 43.89; H, 3.02; Cl, 19.98; N, 15.50.  
 EXAMPLE 33 Preparation of 9-Chloro-5,6-dihydro-1 l-methyl-l lH-pyrimido[4,5- b][1,4]benzodiazepine A solution of methyl 4-chloro-N-(6-chloro-5-nitro-4- pyrimidinyl)-N-methylanthranilate (13.0 g, 0.0364 mole) and triethylamine (4.05 g, 0.040 mole) in ethyl acetate (200 ml) containing 10% Pd-C (4.0 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until there was an uptake of approximately 3.6 equivalents of hydrogen. The reaction mixture was filtered and the filtrate concentrated to leave crude methyl N-(5-amino-4-pyrimidinyl)-4-chloro-N- methylanthranilate (9.5 g). The crude oil was heated under nitrogen for 0.5 hour by means of an oil bath maintained at 160. The resulting solid was sublimed at 230 and 0.03 mm pressure to give 9-chloro-l l-methyll ll -l -pyrimido[4,5-b][ l ,4]benzodiazepin/-6(5H)-one (4.5 g) as yellow crystals, mp 280302. The product was recrystallized from n-butanol followed by 2- methoxyethanol to give pale yellow crystals (3.9 g), mp 298-315. To a cooled (ice-water), stirred suspension of this product (1.3 g, 0.0050 mole) in THF ml) under nitrogen was added diborane in THF 10.3 ml of 0.5M, 0.00515 mole of diborane). The mixture was stirred at room temperature for 15-20 minutes, heated under reflux for 1 hour, and finally stirred at room temperature for 18 hours. The reaction mixture was diluted with 6 N hydrochloric acid (25 ml) and then heated under reflux for 10 minutes. The THF was removed by evaporation. The aqueous residue was made basic with 30% sodium hydroxide and extracted with methylene chloride. The extract was dried over sodium sulfate and concentrated. The solid residue was triturated with ether and the mixture filtered. The collected solid (0.799 g) was recrystallized from ethanol to give 9- chloro-5,6-dihydro-1 l-methyl-l 1fl-pyrimido[4,5- b][1,4]benzodiazepine (310 mg), mp 2l7-218.  
  Anal. calcd. for C I-1 N 62 C, 58.42; H, 4.49; Cl, 14.37; N, 22.71.  
 Found: C, 58.54; H, 4.43; C1, 14.20; N, 23.03.  
 EXAMPLE 34 Preparation of N,5-Dimethylisatoic Anhydride A mixture of S-methylisatoic anhydride (50.1g, 0.30 mole), methyl iodide (85.2 g, 0.60 mole), sodium carbonate (31.8 g, 0.40 mole) in DMF was stirred overnight at room temperature. The DMF was removed under reduced pressure and the residue treated with ice-water. The granular solid was collected, washed with water and dried to give N,5-dimethy1isatoic anhydride (45.7 g, 85.7%); mp l59l6l. 1. F. P. Woener, H. Reimlinger, and R. Merenyi, Chem. Ber., 104, 2786 (1971 EXAMPLE 35 Preparation of Methyl N,5-Dimethylanthranilate A mixture of N,5-dimethylisatoic anhydride (44.5 g, 0.25 mole) and sodium hydroxide (0.4 g) in methanol (100 ml) was warmed gently until evolution of carbon dioxide ceased. The solution was poured into cold water. The mixture was extracted with methylene chloride. The extract was dried over sodium sulfate and concentrated. The residual oil was distilled at 184-185 (80-85 mm) to give methyl N,5- dimethylanthranilate (27.8 g, 62.1%).  
 EXAMPLE 36 Preparation of Methyl N-( 6-Chloro-5-nitro-4-pyrimidinyl)-N ,5- dimethylanthranilate A mixture of 4.6-dichloro--nitropyrimidine (30.1g, 0.156 mole), methyl N,5-dimethylanthranilate (27.8 g, 0.156 mole), and triethylamine (15.0 g, 0.156 mole) in xylene (200 ml) under nitrogen was heated under reflux for 8 hours. The mixture was then stirred at room temperature for 10 hours. The mixture was filtered and the filtrate concentrated. The residue was extracted with three 250 ml portions of hot cyclohexane. The combined extracts were concentrated. The semi-solid residue was recrystallized from 2-pr0panol to give methyl N-(6-chloro-5-nitro-4-pyrimidinyl)-N,5- dimethylanthranilate (25.24 g), mp 88-89.  
  Anal. calcd. for C H ClN O C, 49.93; H, 3.89; Cl, 10.53; N, 16.64.  
 Found: C, 50.05; H, 4,07; C], 10.39; N, 16.84.  
 EXAMPLE 37 Preparation of Methyl N-( 5-Amino-4-pyrimidinyl)-N,S-dimethylanthranilate A solution of methyl N-(6-chloro-5-nitro-4- pyrimidinyl)-N,S-dimethylanthranilate (6.72 g, 0.020 mole) and triethylamine (2.5 g, 0.025 mole) in ethyl acetate (100 ml) containing 10% Pd-C (2.0 g) was shaken with hydrogen at an initial pressure of 3.5 kg/cm until there was an uptake of four equivalents of hydrogen. The mixture was filtered and the filtrate concentrated. The residue was recrystallized from aqueous ethanol to give methyl N-(5-a iino-4-pyrimidinyl)-N,5- dimethylanthranilate (5.1 g),\,np 98-99.  
  28 Anal. calcd. for C H, N O C, 61.75; H, 5.92; N, 20.58.  
 Found: C, 61.56; H, 6.12; N, 20.25.  
 EXAMPLE 38 Preparation of 8,1 l-Dimethyl-l 1H-pyrimido[4,5-b]- 1,4]benzodiazepin-6(5H)-one Methyl N-(5-amino-4-pyrimidinyl)-N,5- dimethylanthranilate (13.6 g, 0.050 mole) was heated under nitrogen at 160 for 10 minutes. The produce was recrystallized from ethanol to give 8,1 l-dimethyl- 1 1H-pyrimido[4,5-b][1,4]benzodiazepin-6(Shh-one (5.9 g, 49.2%), mp 285286.  
  Anal. calcd. for C H N O: C, 64.98; H, 5.03; N, 23.32  
 Found: C, 64.80; H, 5.08; N, 23.10.  
 EXAMPLE 39 Preparation of 5 ,6-Dihydro-8,1 l-dimethyl-l 1H-pyrimido-[ 4,5- b][1,4]benzodiazepine (54) Diborane in THF (20.6 ml of 0.5 M, 0.0103 mole of diborane) was added to a cooled (ice-water), stirred suspension of 8,11-dimethyl-1lH-pyrimido [4,5-b]- [1,4]benzodiazepin-6(5H)-one (2.40 g, 0.010 mole) in THF ml). The mixture was stirred while being allowed to warm to room temperature (about 15 minutes), and then was heated under reflux for 1 hour. The mixture was then stirred at room temperature for 17 hours. The mixture was diluted with 6 N hydrochloric acid (50 ml) and heated under reflux for 10 minutes. The THF was removed under reduced pressure. The aqueous residue was made basic with 30% NaOH and extracted with methylene chloride. The extract was dried over sodium sulfate and concentrated. The residual oil (2.08 g) was chromatographed on basic alumina with ether and ether-methanol (49:1) to give 5,6- dihydro-8,l l-dimethyl-l ll:l-pyrimido[4,5- b][l,4]benzodiazepine (0.9 g). Recrystallization from ether gave product with mp 131.  
  Anal. calcd. for c H N C, 69.00; H, 6.24; N, 24.76.  
 Found: C, 69.07; H, 6.23; N, 24.92.  
 EXAMPLE 40 Preparation of 5,6-Dihydro-1 l-methyl-l lH-pyrimido-[4,5- b][ 1,4]benzodiazepine (28) To a stirred solution of 5,6-dihydro-1IH-pyrimido- [4,5-b][1,4]benzodiazepine (198 mg, 1.0 mmole) in DMF (3 ml) at 25 under nitrogen was added 57% sodium hydride dispersion in mineral oil (50 mg, 1.19 mmoles of sodium hydride). The solution was then heated by means of an oil bath maintained at 50 for one hour. The solution was cooled to 5. A solution of methyl P-toluenesulfonate (186 mg, 1.0 mmole) in DMF (0.5 ml) was added and the resulting solution heated by means of an oil bath maintained at 50 for one hour. The solution was concentrated and the residue partitioned between diethyl ether and water. The ethereal layer was washed twice with saturated aqueous sodium chloride and then concentrated. The residual gum was crystallized from ethyl acetate to give 5,6- dihydro-l l-methyl-l 1H-pyrimido[4,5-  
 b][ 1,4]benzodiazepine (30 mg); mp 152-155.  
 We claim: 1. The compound having the formula in which R and R are alike or different and are H, (lower)alkyl or a radical of the formula in which n is an integer of l to 4 and R is CF chloro, H, fluoro, bromo, (lower)alkoxy or (lower)alkyl; R is H, chloro, bromo, fluoro, CF (lower)alkyl, (lower)alkoxy or nitro; or a pharmaceutically acceptable, nontoxic salt thereof.  
  2. The compound of claim 1 wherein R is H, (lower- )alkyl, benzyl or phenethyl, R is H or chloro, and R is H, (lower)alkyl, benzyl or phenethyl; or a pharmaceutically acceptable, nontoxic salt thereof.  
  3. The compound of claim 1 wherein R is methyl or benzyl, R is H or chloro and R is H or methyl; or a pharmaceutically acceptable, nontoxic salt thereof.  
  4. The compound of claim 1 wherein R is H, R is benzyl and R is H.  
  5. The compound of claim 1 wherein R is chloro,-R is methyl and R is methyl.  
  6. The compound of claim 1 wherein R is methyl, R is H and R is H.  
  7. The compound of claim 1 wherein R is methyl, R is chloro and R is H.  
  30 8. The compound of claim 1 wherein R is methyl, R is H and R is methyl.  
  9. The compound of claim 1 wherein R, R and R are H.  
 10. The compound having the formula R l ICH I I R Id in which R and R are alike or different and are H, (lower)alkyl or a radical of the formula in which n is an integer of l to 4 and R is CF chloro, H, fluoro, bromo, (lower)alkoxy or (lower)-alkyl; R is H, chloro, bromo, fluoro, CF (lower)-alkyl, (lower- )alkoxy or nitro; or a pharmaceutically acceptable nontoxic salt thereof.  
  ll. The compound of claim 10 wherein R is H, (lower)alkyl, benzyl or phenethyl, R is H or chloro and R is H, (lower)alkyl, benzyl or phenethyl; or a pharmaceutically acceptable nontoxic salt thereof.  
  12. The compound of claim 10 wherein R is methyl or benzyl, R is H or chloro and R is H or methyl; or a pharmaceutically acceptable nontoxic salt thereof.  
  13. The compound of claim 10 wherein R is chloro, R is methyl and R is methyl.  
  14. The compound of claim 10 wherein R is methyl, R is chloro and R is H.