US3856801A - Certain 6,7-dihydro-pyrido{8 1,2-d{9 {8 1,4,6{9 -benzodiazocines and 6 h-pyrido{8 1,2-c{9 {8 1,3,5{9 -benzoxadiazepines - Google Patents

Abstract

EXHIBIT CENTRAL NERVOUS SYSTEM STIMULATING PROPERTIES AND ACT AS MUSCLE RELAXANTS.

Compounds of the formula

Description

Emile [1 1 1111 3,856,8M Yale et el. Dec. 24, 1974 [54] CERTAIN 3,565,914 2/1971 Yalc et al. 260/296 H 6,7-DllllYDRO-IPYRTDO[11,2-D] 1,4,6]- lBIENZODlIAZOCINES AND 6 llll-PYIRIDO[ 1,2-C 1,3,5]- BENZOXADHAZEPINES Inventors: Harry Louis Yale, New Brunswick;

Ramesh B. Petigara, Somerset, both of N.J.

E. R. Squibb & Sons, llnc., Princeton, NJ.

Filed: Apr. 4, 1973 Appl. No.: 347,939

Assignee:

References Cited UNITED STATES PATENTS 3/1964 Yale et al. 260/296 H Primary ExaminerAlan L. Rotman Attorney, Agent, or Firm L. S. Levinson [57] ABSTRACT Compounds of the formula exhibit central nervous system stimulating properties and act as muscle relaxants.

2 Claims, N0 Drawings CERTAIN 6,7-lDllll-llYDRO-PYRIDO[1,2-D][1,4,6]- BIENZODIAZOCINES AND 6 ll-l-PYRllDOl 1,2-C][l,3,5]-BENZOXADIAZEFINES OBJECTS OF THE INVENTION object is to provide a method for the preparation ofboth 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 R may be hydrogen, halogen (F, Cl, Br, or 1), alkyl of from one to four carbons, alkoxy of from 1 to 4 carbons, alkylmercapto of from one to four carbons, alkylsulfonyl wherein the alkyl radical has from one to four carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical may have from one to four carbons, trifluoromethyl, monosubstituted phenyl or mono-substituted phenyloxy wherein the substituent may be halogen F, Cl, Br or I), alkyl of from one to four carbons, alkoxy of from one to four carbons or trifluoromethyl; provided that R occupies the position para to the carbon atom joined to oxygen when R is alkylsulfonyl, sulfamoyl, dialkylamidosulfonyl, phenyl, phenoxy, mono-substituted phenyl or mono-substituted phenoxy;

n may be 0 or 1;

and R" may be alkyl of from one to four carbons. or hydrogen and pharmaceutically acceptable acid-addition salts thereof.

The foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.

DETAILED DESCRIPTION The final compound I of the present invention may be prepared by reacting a 2-aminopyridine 11 wherein R is as previously defined with an obromophenoxyalkylene halide Ill wherein R 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 aryl-substituted 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 alco hol is an example of a suitable aliphatic alcohol, while benzyl alcohol is an example of a suitable arylsubstituted aliphatic alcohol. Heating compounds [I and III in a solvent as described above, or a mixture thereof, at temperatures from about 100 to about 140C for a period of several hours, typically from about 3 to about 24 hours produces a p yridinium compound IV. The latteris 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 an alkali metal carbonate. The reaction takes place at room temperature over a period of from about 1 to about 4 hours. Compound V may be converted to the final compound I by treating with a water miscible alcohol and an alkali metal alkoxide of up to three carbons in the presence of copper at a temperature of from about 60 to about for several hours, typically from about 2 to about 4 hours. Alternatively, 1V may be converted directly to I by heating at a temperature of from about 60 to about 120C for several hours, typically from about 1 to about 4 hours in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene. Alternatively, however, 1V may be converted directly to l by heating at a temperature of from about 60 to about 120C for several hours, typically from about 1 to about 4 hours in the presence of an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetra-borate in a solvent comprising a mixture of water and a water III The intermediates of formula lll wherein n is may be prepared by refluxing about equimolar amounts of a l,l-dibromoalkane or a l-bromo-l-chloralkane of one to four carbons Vl with a saturated solution of Na S0,, for a period of from about 40 to about 120 hours. The resulting l-bromoalkane-l-sodium sulfonate Vll is then reacted by heating with about equimolar amounts of an o-bromophenol Vlll in the presence of aqueous alkali to yield a sodium o-bromophenoxyalkylenesulfonate lX. Treatment of the latter with PCl or PBr 5 at ambient temperature yields the corresponding 0- bromophenoxy-alkyl chloride or bromide X. The foregoing reaction sequence is illustrated by the following equations IX X The intermediates of formula lll wherein n is 1 may be prepared by reacting a l-bromo-Z-chloroalkane of formula Xl with about equimolar amounts of a compound of formula Vlll in the presence of aqueous alkali. Alternatively, a compound of formula XII may be prepared by reacting an o-bromophenoxyalkanol Xlll with PCI or PBr The foregoing reaction sequence is illustrated by the following equations XIII Compounds of formula Vlll wherein R is fluorine, CF or alkylthio wherein the alkyl radical is from one to four carbons may be prepared by brominating a fluorophenol, a trifluoromethylphenol or an alkylthiophenol in the presence of Fe catalyst at from about 30 to about 40C. From about 1 part by weight of iron to about 10 parts by weight of the substituted phenol are generally used. A halogenated solvent, e.g., chloroform or carbon tetrachloride, may be used in those cases where the substituted phenol is a solid at reaction temperatures. The foregoing reaction sequence is illustrated by the following equations HO- HO- Fe catalyst Compounds of formula VIII wherein R in the position para to the hydroxyl group is alkylsulfone, sulfamyl or dialkylsulfamyl may be prepared by the following sequence of reactions The chlorine atom in the compound of formula XIV, XV or XVI is replaced by a hydroxyl group by following the procedure of Pettit et al., J. Chem. Soc., 3852, 1954. Treatment ofthe resulting hydroxy derivative according to the procedure of Yale et al., J. Med. Chem., 13, 713, 1970, converts the nitro group to an amino group. Subjecting the resulting amino derivative to the Sandmeyer reaction serves to replace the amino group by a hydroxyl group to give the compound Br R wherein R is sulfamoyl, alkylsulfonyl or dialkylamidosulfonyl wherein the alkyl groups have from one to four carbon atoms.

Compounds of formula Vlll wherein R is phenyl or phenoxy are prepared by bromination of a hydroxybiphenyl or of a hydroxydiphenyl ether according to the procedure of Bradsher et al., J. Org. Chem, 22, 500 (1957) and Janssen et al., J. Org. Chem, 20, 1326-9 (1955). The foregoing reaction sequence is illustrated by the following equations Br: Br

Compounds of formula Vlll wherein R is halophenyl, alkylphenyl, alkoxyphenyl, or trifluoromethylphenyl may be prepared by reacting an R- substituted aniline with phenol according to the procedure of Hirsch, Ber. 23, 3710 (1890). Bromination of the resulting p-(substituted phenyl)Phenol by the pro cedure of Bradsher et al., supra, gives the o-bromo-p- (substituted phenyl)phenol. The foregoing reaction sequence is illustrated by the following equations:

1) HONO O NH2 2 OH R Br I{'=hlalogen. 3) Br: lkoxy or CF; X/

Compounds of formula VIII wherein R is halophenoxy, alkylphenoxy, or trifluoromethylphenoxy may be prepared by the methods of Organic Syntheses Coll. Vol. III, p. 566 and Coll. Vol. II, p. 455; followed by the methods of Janssen et al. and Bradsher et al., supra. The reaction sequence is as follows:

Compounds of formula Vlll wherein R is alkoxysubstituted phenyl may be prepared by reacting pchloronitrobenzene with an alkoxy-substituted phenol in the presence of KOH, reducing the resulting p- (alkoxyphenoxy)-nitrobenzene to the corresponding amine and treating the latter with nitrous acid and water to convert the amino group to the hydroxyl group, and brominating the resulting p-(alkoxyphenoxy)phenol. The reaction sequence is as follows:

oiN Ko 11 Starting materials of formula 11 wherein R is phenyl, halo-substituted phenyl, alkyl-substituted phenyl, alkoxy-substituted phenyl or trifluoromethyl-substituted phenyl may be prepared by heating 3-(N-acetamido-N- nitroso)pyridine XXIV with benzene, halo-substituted benzene, alkyl-substituted benzene, alkoxy-substituted benzene or trifluoromethyl-substituted benzene according to the procedure of Haworth et al., J. Chem. Soc., 1940, 372, and J. Chem. Soc., 1954, 4516.The product XXV is a 3-substituted pyridine wherein the N-aeetamido-N-nitroso radical is replaced by a phenyl or substituted phenyl radical derived from the compound with which the 3-(N-acetamido-N- nitroso)pyridine is heated. The product of formula XXV is treated with sodamide according to the procedure of Chichibabin et al., J. Russ, Phys. Chem. Soc. 46, I216 (1914),Chem. Zentr. II, 1064 (l9l5),t0 give the aminopyridines XXXll and XXXllI.

lilo... 4 B e e a R=lmlo,n,lkyl, alkoxst i. CF] or 1y rogon N ENII:

XXXIII XXXH X=llalogen z -1" llzN- 0 Compounds of formula [I wherein R is halophenyl may be prepared by reacting a halo-substituted N- nitrosoacetanilide with pyridine according to the procedure of Bachmann et al., Organic Reactions, Vol. 11, pp. 224-261. The resulting halo-substituted phenylpyridine is treated with sodamide according to the procedure of Chichibabin et al., supra. to give the desired halophenylsubstituted 2-aminopyridine. The reaction sequence is as follows:

XXVI XXVIl' 2:11, or alkoxy Compounds of formula 11 wherein R is phenylmercapto, alkylmercapto, benzyl, phenethyl or phenoxy may be prepared by treating a substituted pyridine of the formula Didi N 9 wherein R is a phenylmercapto, alkylmercapto, benzyl, phenethyl or phenoxy substituent occupying the 3-, 4-, 5- or 6-position, with sodamide according to the procedure of Chichibabin et al., supra.

The compounds of the present invention may be administered to mammalian species as central nervous system stimulants and as muscle relaxants. In the rat, responses to the stimulant activity of the compounds of the present invention include increased .activity and body tremors. The muscle relaxant properties manifest themselves by responses that include decreased limb 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 2,000 mg. daily in about four divided doses for both activities.

In addition to serving as intermediatesfor the preparation of compounds of formula I, the pyridinium 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., Emglewood Cliffs, N. J., 3rd Ed., p. 858, are employed to determine the bactericidal properties of the pyridinium compounds IV of this invention. The bacteria employed include Staphyloc0ccus aureus, 1, Streptococcus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli,

of active compound in such therapeutically useful com- 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 enpositions 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 maybe 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 acid-addition 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, Z-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, pacetamidobenzoic, or methanesulfonic.

The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures in the following examples as well as the preceding description are expressed in degreesCentigrade.

EXAMPLE I 6H-Pyrido[1,2-c][1,3,5]benzoxadiazepine, hydrochloride A. Sodium bromomethane sulfonate B. (o-Bromophenoxy)methane sulfonic acid, sodium salt To a solution of 61.3 g of o-bromophenol in aqueous NaOH solution [15.5 g of sodium hydroxide in 61 m1 of water], is added 68.0 g of sodium bromomethanesul fonate. While stirring, the reaction mixture is slowly heated to 150, in an oil bath, with simultaneous removal of water. In about 3 hours of heating, 61 ml of water is distilled, and the residue solidifies; this is further heated at 200 for about 2.5 hours. The solid is dissolved in 800 ml of warm water, the solution filtered and the filtrate adjusted to pH 5 and washed with 2 X 200 ml of ether. The aqueous phase is concentrated to 600 ml and cooled. The crystalline solid is filtered and dried in vacuo to give 63.3 g of the product, which is recrystallized from 600 ml of 90% aqueous ethanol to furnish about 57.5 g of the title product, mp about 282284.

C. o-Bromo-a-chloroanisole A mixture of 29.0 g of o-bromo-a-chloroanisole and 50.0 g of PCl are thoroughly blended in a mortar. After about minutes of continuous mixing, the mixture partly melts, a vigorous reaction occurs, and the whole turns to a liquid. The mixture is kept minutes with occasional stirring, 700 ml of ether is added (a white solid separates) and the mixture is poured into 750 g of crushed ice. The ether solution is separated, washed, dried, and concentrated in vacuo to give about 21.0 g of a liquid residue. This distilled under reduced pressure to give about 19.5 g of the colorless liquid product, b 7475, n 1.5799.

D. 2-Amino-l-[(o-bromophenoxy)methyl]pyridinium chloride To a solution of 7.1 g of 2-aminopyridine in 35 ml of xylene is added, dropwise, a solution of 11.1 g of obromo-achloroanisole in 45 ml of xylene. The mixture is warmed at 50 for 5 minutes and allowed to stir for 40 hours at room temperature. The solid is filtered and dried to give about 16.0 g of the product. This is recrystallized from 2-propanol to give about 14.0 g ofthe title product, mp 17l173.

E. 6H-Pyrido[1,2-c][1,3,5]benzoxadiazepine A mixture of 9.5 g of 2-amino-1-[(o-bromophenoxy)-methyl]pyridinium chloride, 8.3 g of potassium carbonate, 0.4 g of copper-bronze in 150 ml of n-propanol and 25 ml of water under N is heated under reflux for 12 hours while stirring. The mixture is filtered hot and the deep yellow filtrate is concentrated to dryness. The residue is dissolved in 400 ml of ether, the ether solution is washed, dried and the solvent removed to give about 6.4 g of the crude yellow product. This is recrystallized from cyclohexane to give about 3.6 g of the title product, mp about 125-127.

F. 6H-Pyrido[1,2-c][1,3,51benzoxadiazepine, hydrochloride To a solution of 1.0 g of 6H-pyrido[l,2-c][1,3,5]- benzoxadiazepine in 20 ml of 2-propanol is added 5.0 ml of 4.2N 2-propanolic hydrogen chloride. To the clear solution is added anhydrous ether until a turbidity forms. The pale yellow crystalline solid is filtered and recrystallized from acetonitrile to give about 1.0 g of the title compound, mp about 232234.

EXAMPLE 2 6H-Pyridol l ,2,-c][ 1,3,5 l-benzoxadiazcpine A B. 6H-Pyrido[1,2-c][1,3,5]-benzoxadiazepine To a solution of 4.65 g of the product from A in ml of n-propanol is added 0.20 g of copper bronze and 5.6 g of micronized, anhydrous, potassium carbonate, and the stirred suspension is heated under reflux for about ten hours. Workup as in Example 1E gives about 2.78 g of the title compound, m.p. about l25-l27.

EXAMPLES 31 3 Following the procedure of example 1 but substituting for Z-aminopyridine in part D the substituted pyridine listed below, there is obtained the correspondingly substituted compound of formula [V wherein R and R" are hydrogen and n=O which compound is then converted to the correspondingly substituted compound of formula 1:

CIIKCIIg-I C H1) 3 C Hz EXAMPLES 14-23 N o113 oim.. l-rvu- 1 20. (Born 1 1i... z 22. S D\N NHz 23. |C(CH3)3 EXAMPLE 24 2-Chloro-6 -H-pyrido[ l,2-c][1,3,5]benzoxadiazepine hydrochloride A. 2-Bromo-4-chlorophenoxymethanesulfonic acid, sodium salt To a solution of 75.0 g of 2-bromo-4-chlorophenol in 65 ml of water is added 16.0 g of sodium hydroxide and 100 g of bromomethanesulfonic acid, sodium salt. The procedure of Example 1, part B, is followed to give about 74.5 g of 2-bromo-4-chlorophenoxymethanesulfonic acid, sodium salt, m.p. above 315.

B. 2-Bromo-4-chlorophenyl chloromethyl ether A mixture of 71.0 g of the product from A and 1 10.0 g of phosphorus pentachloride is reacted as in Example 1, part C, to give about 55.7 g of 2-bromo-4- chlorophenyl chloromethyl ether, m.p. about 56.057.5.

C. 2-Amino-1-[2-bromo-4-chlorophenoxy)methyl]- pyridinium chloride To a solution of 14.1 g of 2-aminopyridine in 180 ml of warm, anhydrous xylene is added 25.6 g of the product from B in ml of anhydrous xylene and the mixture is stirred for about 4 hours at room temperature and then at for about 2 hours to give about 33.0 g of 2-amino-1-[(2-bromo-4-chlorophenoxy)methyl]- pyridinium chloride, m.p. about 237-239.

D. 2-Chloro-6H-pyrido[1,2-c][1,3,5]benzoxadiazepine hydrochloride A mixture of 14.0 g of 2-amino-l-[(2-bromo-4- chlorophenoxy)methyl]pyridinium chloride, 11.1 g of micronized, anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml of anhydrous n-propanol is EXAMLPES 2564 Following the procedure of example 24 but substituting for 2-bromo-4-chlorophenol the substituted 2- bromophenol listed in column I, there is obtained the correspondingly substituted compound from parts B and C, and finally the compound of the following formula wherein R and the position it occupies are indicated in column ll.

It H

wherein R is as indicated in column ll.

Example I II (11") 65 1,1-dibromoethanc CI I;

66 1,l-dibromoisohutmte-... OH;

EXAMPLES 71-97 Following the procedure of example 1 but substituting for 2-aminopyrid ine in part D an equivalent amount 25 of the substituted pyridine listed in column I, there is obtained the correspondingly substituted pyridinium Example I ll 25. 2.4-dibromophenol 2-bromo 26. 2,6-dibromophenol 4-bromo 27. 2-bromo-4-iodophenol 2-iodo 28. 2-bromo-4-methylphenol Z-methyl 29. 2-bromo-6methylphenol 4-methyl 30. 2-bromo-3-chlorophenol l-chloro 3 l. Z-bromo-S-chlorophenol 3-chloro 32. 2-bromo-4-n-butylphenol Z-n-butyl 33. 2-bromo-4-i-butylphenol Z-i-butyl 34. 2-bromo4-n-butoxyphenol 2-n-butoxy 35. 2-bromo-6-fluorophenol 4-fluoro 36. 2-bromo-5-fluorophenol 3-fluoro 37. 2-bro'mo-4-fluorophenol Z-fluoro 38. 2-bromo-4-(methylmercapto)phenol Z-(methylmereapto) 39. 6-bromo-a,a,a-trifluoro-m-cresol 3-trifluoromethyl 42. 2-bromo-3-(ethylmercapto)phenol l-(ethylmercaplo) 43. 2-bromo-4-phenylphenol Z-phenyl 44. Z-bromo-3-trifluoromethylphenol l-trifluoromethyl 46. 2-hromo-4-phenoxyphenol 2-phenoxy 48. 2-bromo-4-(o chlorophenyl)phenol Z-(o-chlorophenyl) 49. 2-bromo-4-(m-bromophcnyUphenol Z-(m-bromophenyl) 50. 2-bromo-4-(p-iodophenyl)phenol 2-(p-iodophcnyl) 5l. 2-bromo-4-(m-fluorophenyloxylphenoI 2-(m-fluorophenyloxy) S2. 2-bromo-4-(p-chlorophenyloxy)phenol 2-(p'chlorophenyloxy) 53. 2-bromo-4-(m-iodiphenyloxy)phenol 2-(m-iodophenyloxy) 54. 2-bromo-4-(o-bromophenyloxy)phenol 2-(o-bromophenyloxy) 55. 2-bromo-4-(o-methylphenyl)phenol Z-(o-methylphenyl) 56. 2-bromo-4-(m-ethylphenyl)phenol 2 (m ethylphenyl) 57. 2-bromo-4-(p-methoxyphenyl)phenol Z-(p-methoxyphenyl) 58. 2-hromo-4-(o-propoxyphenyl)phenol 2-(o-propoxyphenyl) 59. 2-hromo-4-(p-trifluoromethylphenyU- Z-(ntrifluoromethylphenol phenyl 60. 2-hromo-4-sulfumoylpheno] Z-sulfamoyl 6|. 2-hromo-4dimelhylamidosulfonyl- Z-dimethylamidophenol sulfonyl 62. 2gbronlio-4-dihutylamidosulfonyl 2-dibutylamidosu|fonyl p eno 63. 2-bromo-4-ethylsulfonylphenol 2-cthylsulfonyl 64. 2-bromo-4-propylsulfonyIphenol Z-propylsulfonyl EXAMPLES 65-68 Following the procedure of example l but substitutchloride (from part D), the correspondingly substituted base (from part E), and the correspondingly substiing for dibromomethane the compound listed in col- 65 tuted hydrochloride salt (from part F). The substituent umn I, there is obtained the compound of the following formula and the position it occupies in the final product of the formula KAI ll? U lll U W and 50.0 g of o-bromophenyl 2-chloropropyl ether and 200 ml of anhydrous toluene is heated under reflux for about 6 hours, cooled, and the crystalline product filtered to give about 73.2 g of 2-amino-1-[2-(obromophenoxy-l -methylethyl)]-5- phenethylpyridmium chloride as a colorless, crystalline are indicated in column ll. solid.

I ll

71. 2-amino-3-phenylpyridine ll-phenyl 72. 2-amino-3-(o-chlorophenyl)pyridine l l-(o-chlorophenyl) 73. 2-amino4-(m-brornophenyl)pyridine lO-(m-bromophenyl) 74. 2-amino-5-(p-fluorophenyl)pyridine 9-(p-fluorophenyl) 75. 2-amino-6-(m-iodophenyl)pyridine 8-(m'iodophenyl) 76. 2-amino-3-(o-tolyl)pyridine ll-(o-tolyl) 77. 2'amino-5-(p'ethylphenyUpyridine 9-(p-ethylphenyl) 78. 2-amino-3-lm-propoxyphenyl)pyridine l l-(m-propoxyphenyl) 79. 2amino-5-(p-butoxyphenyl)pyridine 9-(p-butoxyphenyl) 80. 2-amino-3-(p-trifluoromethy l l-(p-trifluorophenyl)pyridine methylphenyl) 81. 2-amino-3-(methylmercapto)pyridine ll-(methylmercapto) 82. 2-amino-6-(phenylmercapto)pyridine 8-(phenylmercapto) 83. -Z-amino-S-(phenylmercapl )Py idine 9-(phenylmercapto) 84. 2-amino-4-(phenylmercapto pyridine IO-(phenylmercapto) 85. 2-amino-3-(phenylmercapto)pyridine l l-(phenylmercapto) 86. 2-amino-6-(methylmercapto)pyridine B-(methylmercapto) 87. 2-amino-5-(butylmercapto)pyridine 9-(butylmercapto) 88. 2-amino-5-(propylmercapto)pyridine 9-(propylmercapto) 89. 2-amino-4-(methylmercapto)pyridine IO-(methylmercapto) 90, 2-amino-4-(ethylmercapto)pyridine lO-(ethylmercapto) 9 l. 2-amino-4-(ethylmercapto )6- lO-(ethylmercaptomethylpyrldine S-methyl 92. 2-amino-3-(phenethyl)pyridine l l-(phenethyl) 93. 2-amino-4-benzylpyridine IO-benzyl 94. 2-amino-5 (phenethyl)pyridine 9-(phcnethyl) 95. Z-amino--benzylpyridine 8-benzyl 96. 2-amino-6-phenoxypyridine 8phenoxy 97. 2-amino-4-phenoxypyridine l0phenoxy EXAMPLE 98 6,7-Dihydro-7-methyl-10-phenethylpyrido[1,2- d l ,4,6]benzox adiazocine A. o-Bromophenyl 2-chloropropyl ether To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0, and treated, dropwise, with 157.5 g of l-br0mo-2-chloropropane. Thelast addition requires about 1 hour. The mixture is stirred at 0 for about 2 hours and slowly warmed to reflux during about 2 hours, heated under reflux for about 2' hours, filtered from the precipitated sodium bromide, and the filtrate is connected in vacuo at to give about 240.2'

g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquid.

B. Z-Aminol -[2'-(o-bromophenoxy-l -methylethyl)]-5- phenethylpyridinium chloride A solution of 40.1 g of 2-amino-5-phenethylpyridine C. l-[2'-(o-Bromophenoxy-l -methylethyl)]-l ,2-dihydro- 2-imino-5-phenethylpyridine D. 6,7-Dihydro-7-methyl-lO-phenethylpyridol1,2- d H l ,4,6 lbenzoxadiazocine The product from C, 3.69 g, 50 ml of anhydrous npropanol, 2.8 g of anhydrous, micronized potassium carbonate, and 0.25 g of copper bronze are stirred and heated under reflux for about 6 hours, filtered hot, and the deep, yellow colored filtrate is concentrated to dryness in vacuo at 40. The deep yellow-colored solid is recrystallized from ligroin to give about 2.42 g of'6,7- dihydro-7-methyl-l0-phenethylpyrido[ l,2-d][ 1,4,6]- benzoxadiazocine.

Example 99 Preparation of capsule formulation Magnesium stearate 5 Example 160 and other flavors and dyes may be used in place of those listed above.

What is claimed is: 1. A compound of the formula Preparation of tablet formulation lngredient Milligrams per Tablet 2-Chloro-6H-pyrido l,2-c I l,3,5 1 benzoxadiazepine hydrochloride Lactose Corn starch (for mix) Corn starch (for paste) Magnesium stearate 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 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 lubri-. cated with magnesiumstearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.

The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.

Other ingredients may replace those listed in the above formulation. For example, a suspending agent S such as bentomte magma, tragacanth, carboxymethylcellulose, or methylcellulose'may be used. Phosphates, eitrates or tartrates may be added as buffers. Preservatlves may include the parabens, sorbic acid and the like V H 1|! 7 0 20 lI(CII:)nO

N (lo-"w @R/ wherein m is 1 or 2 R is the same or different and is hydrogen, halogen (F, Cl, or Br), alkyl of from one to four carbons, alkoxy of from I to 4 carbons, alkylthio of from one to four carbons, benzyl, phenethyl, phenyl, phenoxy, phenylmercapto or mono-substituted phenyl wherein the substituent may be halogen (F, Cl, Br or I), alkyl of from one to four carbons, alkoxy of from 1 to four carbons, or trifluoromethyl; provided that when R is halogen, R occupies only the 3- or S-position in the original 2-aminopyridine; R is hydrogen, halogen (F, Cl, Br or I), alkyl of from one to four carbons, alkoxy of from one to four carbons, alkylmercapto of from one to four carbons, alkylsulfonyl wherein the alkyl radical has from one to four carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical may have fromone to four carbons, trifluoromethyl, mono-substituted phenyl or monosubstituted phenyloxy wherein the substituent may be halogen (F, Cl, Br or I), alkyl of from one to four carbons, alkoxy of from one to four carbons of trifluoromethyl; provided that R occupies the position para to the carbon atom joined to oxygen when R is alkylsulfonyl sulfamoyl, dialkylamidosulfonyl, phenyl, phenoxy, monosubstituted phenyl or mono'substituted phenoxy; n isOor l;

and R" is hydrogen or alkyl of from one to four car- 4 5 bons, and pharmaceutically acceptable acidaddition salts thereof. 2. A compound according to claim 1 having the name 6l-l-pyrido[l ,2-c][1,3,S1benzoxadiazepine.

Page 1 of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,856,801

DATED December 24, 1974 INVENTOR(S) Harry Louis Yale and Ramesh B. Petigara Column 2, line 1, after "halogen" insert Column 3, line 23 "X should read -.X Column 4, line 66, "S=alkyl" should read -Salkyl. Column 7, formula XXV should read Column 9, line 26, "Emglewood" should read Englewood. Column 11, line 27, after "This" insert is. Column 13 example 14 should read NH Br 2 Column 14, line 32, "6-H" should read -6H-. Column 14, line 52, before "2-bromo" insert Column 15, example 53, "iodiphenyloxy" should read iodophenyloxy-. Column 16, example 68, "(CH CH should read (CH CH Column 17, the formula should read CH O 9 2 \N It is certified that error appears in the ab0ve-identified patent and that said Letters Patent are hereby corrected as shown below:

Page 2 of 2' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3 85 01 DATED December 24, 1974 vE 0 (5) 1 Harry Louis Yale and Ramesh B. Petigara It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 17, line 53, "connected" should read concentrated--. Column 20, line 48, "of" should read -or-. Column 20, line 50, after "alkylsulfonyl" insert a Signed and ,Zrcalcd this seventh Day of 0ct0'ber1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN' Arresting Officer Commissioner ofParenrs and Trademarks

Claims (2)

1. A COMPOUND OF THE FORMULA

2. A compound according to claim 1 having the name 6H-pyrido(1, 2-c)(1,3,5)benzoxadiazepine.