Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
  • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
  • C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• m may be 1 or 2;
• R may be the same or different and may be hydrogen
• halogen F, Cl, or Br
• falkyl of from 1 to carbons
• R may be hydrogen, halogen F, Cl, Br or I), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4 carbons, alkylsulfonyl wherein the alkyl radical has from'l to 4 carbons, phenyl, phenloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical may have from 1 to 4 carbons, trifiuoromethyl, mono-substituted phenyl or mono-substituted phenyloxy wherein the substituent may be halogen (F, Cl, Br or I), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons or trifluoromethyl; and
• n 2 or 3.
• the foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.
• the final compound I of the present invention may be prepared by reacting an 2-aminopyridine II with an obromophenalkylene bromide III. 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 or 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
• 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 100 to about 140 C. for a period of several hours, typically from about 3 to about 24 hours produces a pyridinium compound IV.
• the latter is converted to an imino compound V by treating with a water miscible alcohol and an alkali metal alkoxidc of up to 3 carbon atoms. 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 3 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.
• IV may be converted directly to I by heating at a temperature of from about 60 to about 120 C. 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.
• IV may be converted directly to I by heating at a temperature of from about 60 to about 120 C.
• alkali metal bonate for Several hours, typically from about 1 to about 4 hours in the a 3 presence of an alkali metal bonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate in a solvent comprising a mixture of water and a water miscible alcohol in the presence of copper.
• suitable compounds include LiOH, NaOH, KOH, RbOH, CsOH, Na2CO3, K CO Rb CO CSgCOg, Na PO K3PO4, Rb3PO4, CS3PO4, Na B2O4, NH2B407, K2B204, and K B O
• the ratios of water and alcohol in the mixture of water and a Water miscible alcohol are such that a homogeneous single phase system results.
• the foregoing reaction sequence is illustrated bythe following equations.
• the intermediates of formula III wherein n is 2 may be prepared by treating an o-brornobenzyl alcohol VI with PBr at temperatures of from about to about 100 C. for a period of from about 1 to about 6 hours.
• the resulting o-bromobenzyl bromide VII is then treated with sodium cyanide in the presence of water and a water miscible alcohol to yield an o-bromophenylacetonitrile VIII.
• Treatment of the latter with an alcohol in the presence of concentrated sulfuric acid yields the corresponding ester IX.
• Treatment of the latter with lithium aluminum hydride yields an o-bromophenethanol.
• lNaCN hydroxide alkali metal car x XI
• the intermediates of formula III wherein n is 3 may be prepared by treating a compound. (Bf-formula XI .with sodium cyanide in the presence ofwater and a water miscible alcohol to yield an o-bromophenylpropionitrile XII. Treatment of the latter with an alcohol in the presence of concentrated sulfuric acid yields the corresponding ester XIII. Treatment of the latter with lithium aluminum hydride yields an o-bromophenpropanol. Treatment of the latter with PBr at temperatures within the range of from about 0 to about C.
• the intermediate of formula VII may be prepared by reacting a trifluoromethylphenyl magnesium bromide XX with methyl iodide to obtain a trifluoromethyl toluene XXI.
• a trifluoromethylphenyl magnesium bromide XX with methyl iodide
• Treatment of the latter with bromine in the presence of iron powder at 20 C. yields a bromo-substituted trifiuoromethyl toluene XXII.
• Treatment of the latter with bromine in the presence of light and a peroxide catalyst yields the corresponding bromotrifiuoromethylbenzyl bromide XXIII.
• the product XXV is a 3-substituted pyridine wherein the N-acetamido-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, 1216 (1914), Chem. Zentr. H, 1064 (1915), to give the aminopyridines XXXII and XXXIII.
• XXVI XXVII Z F Z H, or alkoxy C
• R phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxysubstituted phenyl, or trifiuorornethyl-substituted phenyl
• R phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxysubstituted phenyl, or trifiuorornethyl-substituted phenyl
• N-acetamido-N-nitroso-obromobenzoic acid XXIX is then treated with benzene or an R-substituted benzene wherein R is halogen, alkyl, alkoxy or trifluoromethyl according to the procedure of Haworth et al., supra.
• the aryl-substituted 0-bromobenzoic acid is then treated with LiAlI-L; or AlH according to known techniques to yield the corresponding aryl-substituted o bromobenzyl alcohol XXXI.
• the reaction sequence is as follows: H
• the compounds of the present invention may be administered to mammalian species as central nervous system stimulants and as muscle relaxants.
• 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.
• the onset of activity is rapid, i.e., within about minutes; the activity persists for about 2 hours or longer.
• 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.
• the pyridinium compounds of formula IV are themselves effective bactericides.
• Microbial bioassays as described in The Microbial World, by R. Y. Stanier, M. Doudoroif and E. A. Adelberg, Prentice-Hall, Inc., Englewood 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 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 Mycobacteriumtuberculosis, 9.
• a sterile agar plate is seeded with the test organism, and then a number of glass cylindersare 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 (m.i.c.), of the compound that produces a recognizable zone of inhibition.
• 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 oral- 1y administered, for example,-with an inert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft gelatin capsules, or they may be compressed into tablets, orthey may be incorporated directly with the food of the diet.
• 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.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage in the compositions and preparations may, of ocurse, be varied and may conveniently be between about 5% to about or more of the weight of the unit.
• the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
• Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 10 and 200 milligrams of active compound
• 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.
• 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
• a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermin
• any material 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.
• any material used in preparing any dosage unit form should be 'pharmaceutically pure and substantially non-toxic in the amounts employed.
• EXAMPLE 1 A. o-Bromobenzyl Bromide To 187.0 g. of o-bromobenzyl alcohol at room temperature, with stirring, is added dropwise, 271.0 g. of phosphorus tribromide. After the addition is complete, stirring is continued for three hours at room temperature. The mixture is then heated at -100" for three hours and poured into 6 kg. of crushed ice. The hydrolysis mixture is extracted with three 600 ml. portions of ether, the ether extracts are washed, dried, and concentrated to give 0- bromobenzyl bromide, b.p. about 132 (15 mm.).
• a solution of 212.0 of o-bromophenethyl bromide in 400ml. of dryxylene is added asolution of 120.0 g. of 2-aminopyridine in 400 ml. of dry xylene.
• the mix ture is heated under reflux for about three hours, cooled, and the xylene solution is decanted from the crystalline solid.
• the solid is triturated with 300 ml. of 2-propanol, filtered, and dried to give 138.0 g. of the product.
• the xylenesolution is again heated under reflux for 16 hours and by the same procedure, an additional 43.0 g. of product is recovered.
• the total of about 181.0 g. of product is "recrystallized from 2-propanol to give 170.0 g. of the title compound, m.p. about 195 -197.
• the diisopropyl ether solution is treated with Darco, filtered, and concentrated to about 40 ml. to give on cooling, about 7.2. g. of 11,12- dihydropyrido[2,1-b] [l,3]benzodiazepine, m.p. about l22l24.
• 2-Bromo-4methylthiobenzyl bromide 2-Bromo-4-methylthiobenzyl alcohol is prepared by the following sequence of reactions: 2-bromo-4-nitrobenzoic acid is reduced to 2Fbromo-4-aminobenzoic acid by means of iron and hydrochloric acid in aqueous ethanol. The 2-bromo-4aminobenzoic acid is diazotized with sodium nitrite in aqueous sulfuric. acid, and the diazonium compound treated with sodium methylmercaptide to give 2-bromo-4-methylthioben'zoic acid.
• the 2-bromo-4-methylthiobenzoic acid is converted to its methyl ester by heating under reflux with methanol-concentrated sulfuric acid, the methyl ester is isolated by ether extraction from the esterification mixture, recovered from the ether solution, distilled for purification, and reduced with lithium B.
• 3-(2-Bromo-4-methylthiophenyl)-1-propanol To a suspension of 25.0 g. of magnesium ribbon in a solution of 0.5 g. of iodine in 550 ml. of anhydrous ether is added 5 ml. of a solution of 296.0 g. of 4-methylthio-28-bromobenzyl bromide in 250 ml. of anhydrous ether.
• the reaction is initiated bygentle heating, and the remainder of the solution is then added dropwise so as to maintain a reflux. Subsequently, the mixture is heated and stirred under reflux for one hour, and then cooled to 10. A stream of nitrogen gas that has been cooled through a reservoir containing 48.0 g. of ethylene oxide is introduced into the reaction mixture. The addition of the ethylene oxide requires two hours. The mixture is subsequently stirred as it warms to room temperature, is stirred for four hours at room temperature, and then hydrolyzed by pouring on a mixture of 1 kg. of ice and 55.0 g. of ammonium chloride. Extraction with ether, followed by conventional workup of the ether solution, yields 210.0 g. of 3-(4-methylthio-2-bromophenyl)-1-propanol, b.p. about 125-127 (0.6 mm.).
• Example number for Z-aminopyridine an equivalent amount of Example number (CH2): H30 33/ lBr H2 Bt CH2): H50 69) NH: Br
• EXAMPLE 64 W The active ingredien tQIactOseand 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 waterland heated with StlI'I'iIlgvtO form a paste.
• This paste is thenfused to granulate the mixed powders.
• the wet granules are passed through a No. 8 screen and dried at 120 F.
• the dry granules are passed through a No. 16 screen.
• the mixture is lubricatedwith magnesium stearate and compressed into tablets. in aEsuitable tableting machine. Each tabletcontains 300 milligrams of active ingredient. s ,Y
• EXAMPLE 65 Preparation of oral syrup formulation Ingredient: Amount (mg) 1l,l2-Dihydropyrido[2,1-b][l,3]benzodiazepine 500 Cherry flavor Distilled water q.s. to mL t 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.
• a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes maybe used.in place of those listed above.
• R is the same or different and 'may be hydrogen, F,"Cl, or Br, alkyl of from 1 to 4 carbon atoms, al koxy of 29 30 from 1 to 4 carbon atoms, alkylthio of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms carbon atoms, benzyl, phenethyl, phenyl, phenylthio, or trilluoromethyl, and or mono-substituted phenyl wherein the substituent n is 2or 3. may be F, Cl, Br, I, alkyl of from 1 to 4 carbon 2.
• R is hydrogen, F, Cl, Br, 1, alkyl of from 1 to 9 carbon References Cited atoms, alkox-y of from 1 to 4 carbon atoms, alkyl- 10 UNITED STATES PATENTS thio of from 1 to 4 carbon atoms, alkylsulfonyl wherein the alkyl radical has from 1 to 4 carbon 3,565,914 2/1971 Yale et a1 260-4943 B atoms, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbon atoms, trifluoromethyl, mono-substituted 15 US Cl XR phenyl or mono-substituted phenyloxy wherein the substituent is F, Cl, Br or I, alkyl of from 1 to 4 260294.8 F, 294.8 G, 296 R, 296 H ALAN L.
• ROTMAN Primary Examiner Column 11,
• Example 7 delete “.Br from column 4 and insert in column 3
• Example 8 delete “.Br from column 4, and insert in column 3.

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• Oil, Petroleum & Natural Gas (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pyridine Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 1973
  • 1973-03-08 US US00339258A patent/US3825549A/en not_active Expired - Lifetime
  • 1973-10-09 CA CA182,816A patent/CA1016167A/en not_active Expired
  • 1973-10-17 GB GB4838973A patent/GB1449861A/en not_active Expired
  • 1973-10-22 DE DE19732352918 patent/DE2352918A1/de active Pending
  • 1973-10-22 DE DE2365309*A patent/DE2365309A1/de active Pending
  • 1973-10-24 JP JP48119816A patent/JPS4975595A/ja active Pending
  • 1973-10-24 FR FR7337914A patent/FR2203640B1/fr not_active Expired

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