Certain 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 benzothiadiaza compounds
United States Patent 1191 Yale et al. Apr. 1, 1975 [5 CERTAIN 3,704,303 11 1972 Wei 260/256.5 R 3,740,394 6/1973 Baetz 260/256.5 R  
 6H-PYRIMIDO[1,2- C][1,3,5]BENZOTHIADIAZA COMPOUNDS [75] Inventors: Harry Louis Yale, New Brunswick,  
 N.J.; Ramesh B. Petigara, Lansdale, Pa.  
 [73] Assignee: E. R. Squibb &amp; Sons, Inc.,  
 Princeton, NJ.  
 [22] Filed: July 26, 1973 [21] Appl. No.: 382,802  
 [52] U.S. Cl. 260/256.5 R, 260/253, 260/505, 260/556 AR, 260/607 A, 260/609 R, 424/200, 424/232, 424/251, 424/253 [51] Int. Cl C07d 57/12 [58] Field of Search 260/256.5 R, 253  
 [56] References Cited UNITED STATES PATENTS 3,634,427 1/1972 Schweizer et al. 260/256.5 R  
 Primary Examiner-Richard J. Gallagher Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith; Burton Rodney [57] ABSTRACT Compounds of the formula exhibit central nervous system stimulating properties and act as muscle relaxants.  
 5 Claims, N0 Drawings CERTAIN 6H-PYRIMIDO[1,2-C] [1,3,5]BENZOTHIADIAZA COMPOUNDS OBJECTS OF THE INVENTION It is an object of the present invention to provide new compounds having central nervous system (CNS) stimulating activity. Another object is to provide new compounds having muscle relaxant properties. A further object is to provide intermediates for the preparation of the final compounds of the invention. Yet another object is to provide a method for the preparation of both the intermediate and the final compounds of the present invention. Still another object is to provide a method for the administration of the final compounds of the invention. A still further object is to provide pharmaceutical compositions containing as active ingredients the final compounds of the present invention.  
  These and other objects of the present invention will be apparent from the following description.  
 SUMMARY OF THE INVENTION The compounds of the present invention have the following formula wherein m may be 1 or 2; when m is l, R occupies either position-4 or -5 of the original Z-aminopyrimidine but when R is halogen it occupies only position-5; when m is 2, the two Rs occupy the 4- and 5- positions of the original 2-aminopyrimidine, but only one of the two R-substitutents can be halogen and it must occupy the 5position.  
 R may be the same or different and may be hydrogen, halogen (F, Cl, or Br), alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein the substituent may be halogen (F, Cl, Br or 1), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;  
 DETAILED DESCRIPTION The final compound I of the present invention may be prepared by reacting a 2-aminopyrimidine I! wherein R is as previously defined with an o-bromophenyl-Z-alkylene halide III wherein R&#34; is as previously defined and X is chlorine or bromine. This reaction takes place in any solvent or solvent mixture in which the reactants can be dissolved and which has a boiling point of at least about C. Typical solvents are aromatic hydrocarbons, ethers, aliphatic alcohols or arylsubstituted aliphatic alcohols. Toluene and xylene are examples of suitable aromatic hydrocarbons. Monomethyl ether of diethylene glycol, dimethyl ether of diethylene glycol (diglyme), monomethyl ether of ethylene glycol or dimethyl ether of ethylene glycol (glyme) are examples of suitable ethers. n-Amyl alcohol is an example of a suitable aliphatic alcohol, while benzyl alcohol is an example of a suitable aryl-substituted aliphatic alcohol. Heating compounds II and III in a solvent as described above, or a mixture thereof, at temperatures from about 50 to about 140C for a period of several hours, typically from about 3 to about 24 hours produces a pyrimidinium compound IV. The latter is converted to an imino compound V by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbon atoms, or with an alkali metal carbonate, e.g., K CO Na CO RbCO etc. The reaction takes place at room temperature over a period of from about 1 to about 4 hours, or at from about 50 to about 80C in about 1 hour. Compound V may be converted to the final compound I by treating with a water miscible alcohol and an alkali alkoxide of up to 3 carbons in the presence of copper at a temperature of from about 60 to about C for a period, typically from about 4 to about 10 days. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60 to about 120C for a period, typically from about 4 to about 10 days, in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene. Alternatively, IV may be converted directly to l by heating at a temperature of from about 60 to about 120C for about 4 to 10 days, typically from about 6 to about 8 days in the presence of an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate in an anhydrous alcohol solvent, e.g., ethanol, propanol, butanol, pentanol in the presence of copper. Specific examples of suitable compounds include LiOH, NaOl-l, KOl-l, RbOl-l, CsOl-I, Nagcog, K2C03, Rb CO CS CO Na PO K3P04, Rb3PO4, CS3PO4, NazBzoq, Na B O K2B204, and K B O,.  
  When m is 1, and when R occupies only the 5- position of I], only one isomer, I, is formed. When m is l, and when R occupies only the 4-position of IIa, two isomers, la and lb are formed via the intermediates lVa or Va and lVb and Vb, respectively. When m is 2, and since the two Rs occupy only the 4-, 5-positions, two isomeric products, lo and Id are formed. The isomers in all instances, can be separated by conventional procedure, e.g., fractional recrystallization or column chromatography.  
  The foregoing reaction sequence is illustrated by the following equations:  
  The intermediates of formula III wherein n is 0 and Z is S may be prepared by refluxing about equimolar amounts of a l,l-dibromoalkane or a l-bromo-lchloroalkane of l to 4 carbons VI with a saturated solution of Na SO for a period of from about 40 to about 5 120 hours. The resulting l-bromoalkane-l-sodium sulfonate VII is then reacted by heating with about equimolar amounts of an o-bromothiophenol VIII in the presence of aqueous alkali to yield a sodium 0- bromophenylthioalkylene-sulfonate IX. Treatment of the latter with PC], or PBr, at ambient temperature yields the corresponding o-bromophenylthioalkyl chloride or bromide X. The foregoing reaction sequence is 40 bromosuccinimide in CCl, according to the procedure illustrated by the following equations Compounds of formula VIII wherein R is H, halogen, alkyl of from 1 to 4 carbons, phenyl, dialkylamidosulfonyl or trifluoromethyl may be prepared by reacting an R&#39;-substituted aniline XXIV with N- of Arcoria et al., Ann. Chim. (Rome), 54 139-155 (1964) to yield an o-bromo-R-substituted aniline XXV. The latter is treated with NaNO in HCl and then with S0 according to the procedure of Meerwein et al., J. prakt. Chem. 152, 237 (1939) to yield the corresponding sulfonyl chloride XXVI. The latter is treated with Zn in H 80 according to the procedure of Organic Syntheses, Collective Volume I, pp. 504-506 to yield the desired o-bromo-R&#39;-substituted thiophenol VIII. The reaction sequence is as follows:  
 Syntheses, Coll. Vol. I, pp. 492 (1941). Reacting the sodium sulfinate XXX with a 1,1-dihaloalkane following the procedure of Michael et al., J.A.C.S., 6, p. 253 (1884) gives the compound of formula III wherein Z is SO, and n is 0. Reacting the sodium sulfinate XXX with a l-bromo2-chloroalkane following the procedure of Michael et al., supra, gives the compound of formula III wherein Z is SO: and n is l. The foregoing reaction sequence is illustrated by the following equations:  
 t. R cits ClSO I 2 HObTO 2 so 2 HC]. 0 Z Br Br Br xxv XKVIII xxrx IR&#34; x-cH-so Br I X=Cl,3r  
 &#39; zoo:  
  n O i cl-cacn so,  
 Ell  
 HZN N-bromon u R liuaao c150 succinio made M502 7 B: B3: ccl 5 xxv XXIV  
 VIi:  
 Compounds of the formula III wherein Z is SO, may 60 The compounds of the present invention may be ad= ministered to mammalian species as central nervous system stimulants and as muscle relaxants: In the rat; responses to the stimulant activity of the compounds of 65 the present invention include increased activity and body tremors. The muscle relaxant properties manifest themselves by responses that include decreasedlimb tone, decreased grip strength, and limb paralysis= In both the stimulant and muscle relaxant activities, the onset of activity is rapid, i.e., within about minutes; the activity persists for about 2 hours or longer. In the rat the dosage range varies from about 6.25 to about 50 mg/kg for both activities, while in humans the dosage range varies from about 40 to about 2000 mg. daily in about four divided doses for both activities.  
  In addition to serving as intermediates for the preparation of compounds of formula, I, the pyrimidinium compounds of formula IV are themselves effective bactericides.  
  Microbial bioassays, as described in The Microbial World, by R. Y. Stanier, M. Doudoroff and E. A. Adelberg, Prentice-Hall, Inc., Englewood Cliffs, N.J., 3rd Ed., p. 858, are employed to determine the bactericidal properties of the pyrimidinium compounds IV of this invention. The bacteria employed include Staphylococcus aureus, 1, Streptococcus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli, 7, Pasturella multocida, 8, and Mycobacterium tuberculosis, 9.  
  In the procedure, a sterile agar plate is seeded with the test organism, and then a number of glass cylinders are placed on its surface, forming a series of little cups. A known dilution of the compounds of this invention is added to each cup and the entire plate is then incubated until significant bacterial growth has occurred. The compounds of this invention diffuse out of the cup into the surrounding agar and produce a zone of inhibition. In this fashion it is possible to find the minimum inhibiting concentration (mic), of the compound that produces a recognizable zone of inhibition. The following summarizes the data.  
  The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.  
  The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.  
  The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.  
  As to the pharmaceutically acceptable salts, those coming within the purview of this invention include the pharmaceutically acceptable acid-addition salts. Acids useful for preparing these acidaddition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, pacetamidobenzoic, or methanesulfonic.  
  The following examples illustrate the invention without, however, limiting the same thereto. All temperatures given are in degrees Centigrade.  
 EXAMPLE 1 [(o-Bromophenyl)thio]methanesulfonic acid, sodium salt To a solution of 40.0 g of o-bromobenzenethiol in aqueous sodium hydroxide (10.0 g of sodium hydroxide in 40 ml of water) is added 60.0 g of bromomethanesulfonic acid, sodium salt and the mixture is heated so that the water distills. To the dry residue is added a second portion of 40 ml of water and the distillation to dryness is repeated. The dry residue is heated for 3 hours, cooled, and dissolved in 600 ml of hot water. The pH is adjusted to 5.0 and cooled to give about 63.3 g of the named compound, mp 310.  
 EXAMPLE 2 o-Bromophenyl chloromethyl sulfide A mixture of 60.4 g of [(o-bromophenyl)thio]methane-sulfonic acid, sodium salt and 98.0 g of phosphorus pentachloride is blended until liquified, diluted with 600 ml of ether, and then poured on 1.2 kg of crushed ice. The ether layer is separated, washed, dried, and concentrated to give about 43.7 g of the named compound, bp about 86 (0.6 mm), mp about 28-30.  
 EXAMPLE 3 2-Amino- 1 o-bromophenyl )thio methyl pyrimidinium chloride To a solution of 14.1 g of 2-aminopyrimidine in 180 ml of xylene is added a solution of 24.0 g of obromophenyl chloromethyl sulfide in 40 ml of xylene. The mixture is heated at 90-95 for about 15 hours to give about 27.3 g of the named compound.  
 EXAMPLE 4 [(2-Bromo-5 -chlorophenyl )thio ]methanesulfonic acid, sodium salt EXAMPLE 5 [(2-Bromo-5-tolyl)thio]methanesulfonic acid, sodium salt When 44.7 g of 2-bromo-5-toluenethiol replaces the 2-bromobenzenethiol in Example 1, there is obtained about 65.7 g of the named product, mp 300.  
  The 2-bromo-5-toluenethiol is prepared from 2-bromo-5-methyl-aniline by the procedure reported in Organic Syntheses (vide supra).  
 EXAMPLE 6 [(2-Bromo-5-( a,a,a-trifluorotolyl )thio ]methanesulfonic acid, sodium salt A. To 161.0 g of m-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at -40, 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional 2 hours and then distilled in vacuo to give 4-bromo-3- aminobenzotrifluoride.  
  B. The product from (A) is subjected to the procedure of Organic Syntheses (vide supra) to give 2- bromo-S-a,a,a-trifluorotoluenethiol.  
  C. By substituting 56.6 g of 2-bromo-5-a,oz,atrifluorotoluenethiol for the o-bromobenzenethiol in example 1, there is obtained about 70.2 g of 2-bromo- 5-(a,a,a-trifluorotolyl)thio]methanesulfonic acid, sodium salt, mp 300.  
  EXAMPLE 7 6fl-Pyrimido[ 1,2-c][ 1,3 ,5 ]benzothiadiazepine A mixture of 33.2 g of 2-amino-1-[[(obromophenyl)-thio[methyl]pyrimidinium chloride, 27.7 g of anhydrous potassium carbonate, 0.8 g of copper bronze, and 750 ml of n-propanol is heated and stirred, under reflux, for 6 days, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 600 ml of ether, and the ether solution is washed, dried, decolorized with Darco, and concentrated to give about 23.7 g of a yellow solid. Recrystallization from cyclohexane-benzene gives about 17.4 g of the named compound.  
 EXAMPLES 8-12 By employing the procedure described in Organic Syntheses, Collective Volume 3, pp. 809-811, the aniline derivatives in Column 1 are converted to the thiol derivatives in Column 2, and the latter derivatives, following the procedure of examples 1 and 2, give the chloromethyl sulfides in Column 3.  
 Example Aniline Thio Ch loromethyl No Derivative Derivative Sulfide CH NH CH CH SH 8 g 2 3 9. (CH3 c NR2 (CH3 c. SH (CH3 c SCH Cl Br Br Br Br Br Br fl cF NH2 c1? SH CF3 SCH CI 3 SCH Cl -Continued Example Ahiline Thiol chloromethyl No. Derivative Derivative Sulfide NH2 SH SCH2C1 r Br Br 2 5 z s z s (CH3 )ZN&#39;SO2 (CH3 2NSO2 (CH3 )2NSO2 I H cn cl EXAMPLES 13-21 25 an equivalent amount of the substituted aminopyrimidine in Column 2 for the aminopyrimidine in example By substituting an equivalent amount of the chloro- 3 and employing the procedure of that example, the methyl sulfides of Column 3, examples 8-12, for the opyrimidinium chlorides shown in Column 3 are obbromophenyl chloromethyl sulfide in example 3, and tained.  
 Example chloromethyl Substituted Pyrimidinium No. sulfide Aminopyrimidine Chlor l.de  
  H3C CH Cl c1 c1 9 13. I gi C1 N NJNHZ ea Br 2 ea s 14 (cH c @fc1i c1 BrY I Br N ci o Br O J NH2 o f z Br cn s 15. g f K Br cle CF3 SCI-l C1 N el NH CH2S y N ANH v Continued Example Chloromethyl Substituted Pyrimidinium No Sulfide Aminogzrimiding Chloride 9 (CH NSO Cl Br o HIH c H N NH 2 SCH c1 4 9 2 so men on s 3 2 SO N(CH 2 e 2 3 NCH 0* 2 9 C H N 2 Br Cl EXAMPLE 22 EXAMPLE 25 [(2-Bromo-5-chlorophenyl)thio]methanesulfonic acid, sodium salt By substituting 49.2 g of 2-bromo-5- chlorobenzenethiol for the 2-bromo-4- chlorobenzenethiol in example 4, there is obtained 68.7 g of the named product, mp 300.  
  EXAMPLE 23 2-Iminol (o-bromophenyl)thio]methyl]pyrimidine EXAMPLE 24 6l;I-Pyrimido[1,2-c][l,3,5]benzthiadiazepine Hydrochloride-H O A mixture of 14.8 g of 2-imino-1-[[(obromophenyl)-thio)methyl]pyrimidine, 13.8 g of anhydrous potassium carbonate, 0.5 g of copper bronze, and 400 ml of anhydrous n-propanol is stirred and heated under nitrogen for about 80 hours, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is distributed between 250 ml of water and ether, the other layer is separated, dried, and concentrated to give about 7.2 g of the base product. By the usual methods, the base gives a hydrochloride, monohydrate.  
 Example No. Pzrimidinium Chloride CH S 2-Bromo-5-chlorophenyl chloromethyl sulfide A mixture of 68.2 g of the product from example 4 and 98.0 g of phosphorus pentachloride is blended until liquefaction occurs, diluted with 600 ml of ether and then poured on 1.3 kg of crushed ice. Workup of the ether layer yields about 47.3 g of the named compound, bp about 98 (0.5 mm.).  
 EXAMPLE 26 2-Aminol 2-bromo-5-chlorophenyl )thio]methyl]- pyrimidinium chloride To a solution of 18.8 g of 2-aminopyrimidine in 180 ml of benzene is added 54.6 g of the product from example 25, and the mixture stirred and heated under reflux for about 12 hours. The cooled mixture is filtered to give about 62.8 g of the named compound, mp about 240242.  
 EXAMPLE 27 3-Chloro-6fl-pyrimido[ 1,2- c][1,3,5]benzothiadiazepine Hydrochloride H O A mixture of 7.4 g of the product from example 26, 2.8 g of anhydrous potassium carbonate, 0.1 g of copper bronze, and 100 ml of anhydrous n-butanol is heated at 1 10 for about 15 hours. Workup as in example 7 yields about 3.6 g of the named compound.  
 EXAMPLES 28-41 By substituting equivalent amounts of the pyrimidinium chlorides in column 2 for the 2-amino-l- [(o-bromophenyl)-thio]methyl]pyrimidinium chloride in example 7, the correspondingly substituted 61ipyrimido&#39;[1,2-c][l,3,5]benzothiadiazepines shown in column 3 are obtained.  
 Substd. 6pyrimido[l, 2-c] [1, 3 5]- benzothiacliazepines Continued Example No Pyrimidinium Chloride CH S EXAMPLE 37 6l;i-Pyrimido[ l,2-c][ l ,3,5 ]benzothiadiazepine, hydrochloride To a solution of 1.0 g of 6fl-pyrimido[l,2-c][l,3,5]- benzothiadiazepine in ml of anhydrous 2-propanol is added about 5.0 ml of 4.2 N 2-propanolic hydrogen chloride. The clear solution that is formed is diluted with anhydrous ether until a turbidity persists and is then cooled to give the pale yellow crystalline product. Recrystallization from acetonitrile gives about 1.0 of the named product.  
 EXAMPLE 38 6,7-Dihydro-7-n-propylpyrimido[ 1,2- d] 1 ,4,6]benzothiadiazocine, hydrochloride heated under reflux for 2 hours. The mixture is filtered and the filtrate concentrated in vacuo at 40 to give about 255.7 g of o-bromophenyl 2-chloro-l-pentyl sulfide as a pale yellow oil. B. 2-Amino-1 2 o-bromophenylthio- 1 -pentyl pyrimidinium chloride To a solution of 58.7 g of the product from (A) and 18.4 g of 2-aminopyrimidine in 200 ml of anhydrous toluene is heated under reflux for about 6 hours, cooled, and the crystalline product filtered to give about 67.2 g of the title compound as a pale yellow crystalline solid. C. l-[2-(o-Bromophenylthiol -pentyl )-1 ,2-dihydro-2- iminopyrimidine To a solution of 7.7 g of the product from (B) in 100 ml of 95 percent ethanol is added 2.8 g of potassium carbonate and the mixture is stirred at about 40 for 1 Substd. 6pyrimido[l,2c][1,3,5]-  
 benzothiadiazepines so rucn N 2 3 2 \|//N hour, filtered and the filtrate concentrated in vacuo. The residue is recrystallized from cyclohexane to give 6.3 g of l-[2-(o-bromophenylthio)-l-pentyl)-1,2-dihydro-2-iminopyrimidine as a pale yellow crystalline solid. D. 6,7-Dihydro-7-n-propylpyrimido[ l ,2-d][ 1,4,6]- benzothiadiazocine, hydrochloride The product from (C), 15.4 g, 13.8 g of anhydrous micronized potassium carbonate, 0.5 g of copper bronze and ml of anhydrous n-butanol are stirred and heated under reflux for about 6 days, filtered, and the filtrate concentrated, in vacuo, to give the product as a deep yellow-colored viscous oil. The oil, 12.7 g, in ml of anhydrous ether, is cooled to 0 and treated slowly, with stirring with 10 ml of 1.5 N ethereal hydrogen chloride. The solid that separates is filtered, and recrystallized from 2-propanol to give the title compound, as a pale yellow crystalline product.  
 EXAMPLES 39-41 Following the procedure of examples l-7 but substituting for bromomethanesulfonic acid, sodium salt in example 1 the bromoalkylsulfonic acid, sodium salt listed in column 1, there is obtained the compound of wherein R&#34; is the radical indicated in column II.  
  CH-S I ll 39. l-bromoethane-l-sulfonic acid, --CH sodium salt 40. l-bromobutane-l-sulfonic acid, CH CH CH sodium salt 41 l-bromo-Z-methylpropanel CH(CH:)  
 sulfonic acid, sodium salt ously to about 50. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of 01,01,a-trifluoro-m-acetotoluidide. B. a,a,a-Trifluoro-m-N,N-diacetotoluidide The product from A, 102.0 g, and 500 ml of acetic anhydride are heated under reflux for about 18 hours. The mixture is then concentrated in vacuo to remove the excess of acetic anhydride. The residual solid crystallizes and is recrystallized from heptane to give 136.7 g of a,a,a-trifluoro-m-N,N-diacetotoluidide.  
 C. 2-Bromo-a,a,a-trifluoro-m-N,N-diacetotoluidide To a solution of 50.6 g of the product from B in 120 ml of carbon tetrachloride is added 35.6 g of N- bromosuccinimide and the mixture is stirred and heated under reflux for about 0.25 hours. Workup according to the procedure of Arcoria and Scarlata [Ann. Chim. (Rome), 54, 139 (1964)] yields about 58.7 g of 2-bromo-a,a,a-trifluoro-m-N,N-diacetotoluidide.  
 D. 2-Bromo-a,a,a-trifluoro-m-toluidine Hydrochloride The product from C, 58.0 g, 250 ml of 95 percent ethanol, and 10.0 ml of concentrated hydrochloric acid are heated under reflux for about 1 hour and then concentrated to dryneQs vacuo. The residue crystallizes on cooling t Y 3 g of 2-bromo-a,a,a-triluenesulfonyl chloride erwein, et al., J. prakt. of the product from D in 100 ml of 25 percent ydrochloric acid, at is treated dropwise, with a solution of 6.9 g of sodium nitrite in 14 ml of water. Subsequent to the addition, the mixture is stirred at 0 for 0.5 hour, 0.5 g of cupric chloride is added and while kept at 0, a rapid stream of sulfur dioxide is introduced into the reaction mixture for 0.5 hour. Subsequently, the mixture is slowly warmed to 50 while the introduction of sulfur dioxide continues. Workup of the reaction mixture gives 25.6 g of 2-bromo-a,a,a-trifluoro-m-toluenesulfonyl chloride.  
 F. Sodium 2-bromo-a,a,a-trifluoro-m-toluenesulfonate Into a suspension of 15.6 g of zinc dust in 115 ml of water is introduced dry steam until the internal temperature reaches 70. The steam is shut off, and 32.4 g of the product from E is added in small portions during about minutes. Stirring is maintained throughout the addition and for about 10 minutes afterwards. Steam is again introduced into the mixture, with stirring, until the internal temperature reaches 90 at which time the steam isshut off and 10 ml of l2N aqueous sodium hydroxide is added followed by 2.0 g portions of solid sodium carbonate until the mixture is strongly alkaline. Following this, the procedure of Org. Syntheses, Coll. Vol 1, 492 (1941) is followed to give about 24.7 g of sodium 2-bromo-a,a,a-trifluoro-m-toluenesulfonate.  
 G. 2-Bromo-a,a,a-trifluoro-m-tolyl Bromomethyl Sulfone  A mixture of 31.1 g of the product from F, 34.8 g of 1,1-dibromomethane, 500 ml of absolute ethanol, 13.8 g of anhydrous, micronized potassium carbonate, and 0.5 g of copper bronze is stirred and heated under reflux for about 9.5 hours. The hot solution is filtered and the filtrate concentrated to a volume of about 100 ml and cooled. The product that crystallizes is filtered to give about 30.6 g of 2-bromo-a,a,a-trifluoro-m tolyl bromomethyl sulfone.  
 H. 3-Trifluoromethyl-6lj-pyrimido[ l ,2- c] 1,3 ,5 ]benzothiadiazepine-S,5-dioxide Following the procedure of example 3 but substituting for o-bromophenyl chloromethyl sulfide an equivalent amount of the product from part G, there is obtained Z-aminol [(2-br0mo-5-a,a,a-triflu0r0-mtolyl)sulfonyl]methyl]pyrimidinium bromide. Following the procedure of example 7 but substituting the above pyrimidinium bromide for 2-amino-1-[[obromophenyl)-thio]methyl]pyiimidinium chloride, the title compound is obtained.  
 EXAMPLES 43-46 Following the procedure of example 42 but substituting for 1,1-dibromomethane in part G the dihaloalkane listed below in column I, there is obtained the compound of formula I of the formula 1 CH (ca s i i i k N wherein R&#34; and n are as indicated in columns II and III:  
 I II III 43. l-bromo-2-chloroethane H l 44. l, l -dibr0moethane -CH;, 0 45. l ,1-dibromo-2-methylpropane -CH(CH 0 46. l-bromo-Z-chloropentane -C H 1 EXAMPLE 47 Preparation of capsule formulation Ingredient Milligrams per Capsule thiadiazepine hydrochloride 400 Starch Magnesium stearate 5 The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 485 milligrams per capsule.  
 EXAMPLE 48 Preparation of tablet formulation Ingredient Milligrams per Tablet 6fl-Pyrimido[ l ,2-c][l,3,5 lbenzothiadiazepine-S ,5 -dioxide 300 Lactose 200 Corn starch (for mix) 50 Corn starch (for paste) S Magnesium stearate 6 The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.  
 EXAMPLE 49 Preparation of oral syrup formulation lngredient Amount 6,7-Dihydro-7-n-pr0pylpyrimido-[ l ,2-d]- [l,4,6]benzothiadiazocine, hydrochloride 500 mg. Sorbitol solution (70% N.F.) 40 ml. Sodium benzoate 150 mg. Sucaryl 90 mg. Saccharin 10 mg. Red Dye (F.D. &amp; Co. No. 2) 10 mg. Cherry flavor 50 mg. Distilled water qs to 100 ml.  
 citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.  
 What is claimed is:  
 1. A compound of the formula wherein m is l or 2; one of p and q is zero or one and the other is zero;  
 R is F, Cl, Br, alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein the substituent is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;  
 R&#39; is alkyl of from 1 to 4 carbons, benzyl, phenyl,  
 or mono-substituted phenyl wherein the substituent is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;  
 R is hydrogen, F, Cl, Br, CF alkyl of from 1 to 4 carbons, or dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons;  
 n is O or 1;  
 R&#34; is hydrogen or alkyl of from 1 to 4 carbons; and  
 Z is S or S0 and pharmaceutically acceptable acid-addition salts thereof.  
 2. A compound of claim 1 having the name 6&amp;-  
 pyrimido[ l ,2-c][ l ,3,5 ]benzothiadiazepine.  
 3. A compound of claim 1 having the name 3-chloro- 6fi-pyrimido[ 1,2-c 1,3 ,5 ]benzothiadiazepine.  
  4. A compound of claim 1 having the name 6,7- dihydro-8-n-propylpyrimido[ l ,2- d][ 1 ,4,6]benzothiadiazocine.  
  5. A compound of claim 1 having the name 3- trifluoromethyl-6lj-pyrimido[ l ,2-  
 c] 1,3 ,5 ]benzothiadiazepine-5 ,S-dioxide.  
  UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. I 3 ,875, 162 DATED 3 April 1, 1975 INVENTOR(S) 1 Harry Louis Yale and Ramesh B. Petigara It is certified that error appears in the ab0veidentified patent and that said Letters Patent are hereby corrected as shown below:  
 Column 12, line 19, &#34;thio[&#34; should read thio]-. Columu 2l line 34, &#34;1.0&#34; should read --l&#39;.0 g-.  
 Column 24, examples 43-46, the formula should read lRll Signed and Scaled this fourteenth Day Of October 1975 [SEAL] A ttes t:  
 RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj&#39;larents and Trademarks