Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • 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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom

Definitions

• 260/256.4 C, 260/256.4 N, Int Cl 260/2563 exhibit central nervous system stimulating properties 581 Field of Search 260/2564 F, 256.5 R and act as muscle relaxants 3 Claims, No Drawings THERAPEUTIC COMPOUNDS AND INTERMEDIATES THEREFOR OBJECTS OF THE INVENTION.
• CNS central nervous system
• 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.
• the compounds of the present invention have the following formula I (CH wherein m may be I or 2; when m is l, R occupies either the 4 or 5- positions of the original 2- aminopyrimidine, but when R is halogen, it occupies only position-5', when m is 2, the two R-substituents occupy the 4- and 5-positions of the original 2- aminopyrimidine, but only one of the two R- substituents can be halogen and it must occupy the 5- position;
• 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 I), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;
• R may be hydrogen, halogen (F, Cl, Br or I), alkyl of from I to 4 carbons, alkoxy of from 1 to 4 carbons, alkylthio of from I to 4 carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4 carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical may have from 1 to 4 carbons, trifluoromethyl, mono-substituted phenyl or monosubstituted 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; n is 2 or 3. and pharmaceutically acceptable acid addition salts thereof.
• halogen F, Cl, Br or I
• alkyl of from I to 4 carbons alkoxy of from 1 to 4 carbons
• 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 a 2aminopyrimidine II with an o-bromophenalkylene bromide III. This reaction takes place in any solvent or solvent mixture in which the reactants can be dissolved and wh ichhas 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
• 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 l40C 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.
• the reaction takes place at room temperature over a period of from about I 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 days, typically from about 4 to about 10 days.
• IV may be converted directly to I by heating at a temperature of from about 60C to about 120C for about 4 to 10 days, typically from about 6 to about 8 days in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene.
• 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 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 a solvent comprising a mixture of water and a water miscible alcohol in the presence of copper.
• 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 a solvent comprising a mixture of water and a water miscible alcohol in the presence of copper.
• suitable compounds include LiOH, NaOH, KOl-l, RbOl-I, CsOH, Na CO K CO Rb CO CS2CO3, Na PO K3PO4, Rb PO4, CS3PO4, Na2B O Na B O K B O 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 intermediates of formula III wherein n is 2 may be prepared by treating an o-bromobenzyl alcohol VI with PBr at temperatures of from about 0 to about 100C for a period of from about I 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 obromophenylacetonitrile 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 obromophenethanol.
• the intermediates of formula Ill wherein n is 3 may be prepared by treating a compound of formula XI with sodium cyanide in the presence of water 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 obromophenpropanol. Treatment of the latter with PBr at temperatures within the range of from about 0 to about 100C for a period of from about I to about 6 hours yields the corresponding o-bromophenpropyl bromide XV.
• the foregoing reaction sequence is illustrated by the following equations CH CH Br N XII CH CH CN R @cn ca cn oa XIV' PBr
• the compounds of formula XI or XV may be prepared by nitrating an o-bromobenzyl alcohol XVI at 0C using a mixture of nitric and sulfuric acids. The resulting isomeric mixture of nitrated 2- bromobenzyl alcohols is separated by conventional techniques. Each separated isomer XVII may then be reduced to the corresponding amine XVIII by means of zinc and hydrochloric acid. Treatment of the amino derivative XVIII with nitrous acid and then with sodium alkylmercaptide yields the corresponding alkylthio-2- bromobe n zyl alcohol XIX.
• the intermediate of formula VII may be prepared by reacting a trifluoromethylphenyl magnesium bromide XX with methyl iodide to obtain a trifluoromethyl toluene XXI. Treatment of the latter with bromine in the presence of iron powder at C yields a bromo-substituted trifluoromethyl toluene XXII. Treatment of the latter with bromine in the presence of light and a peroxide catalyst yields the'corresponding bromo-trifluoromethylbenzyl bromide XXIII.
• koxy-substituted phenyl, or trifluoromethyl-substituted phenyl may be prepared by treating an aminosubstituted o-bromobenzoic acid XXVIII with acetic anhydride and then with nitrous acid.
• the resulting N- acetamido-N-nitroso-o-bromobenzoic 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 o-bromobenzoic acid is then treated with LiAlH or AlH according to known tcch- 65 about four divided doses for both activities.
• the compounds of the present invention may be administered to mammalian species as central nervous system stimulants and as muscle rclaxants.
• 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, 1.e., within about 15 minutes;
• the activity persists for about 2 hours or longer.
• the dosage range varies from about 6.25 to about mg/kg for both activities, while in humans the dosage range varies from about 40 to about 2000 mg. daily in
• 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. .1. 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 pyrogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli, 7, Pasturella multocida, 8, and Mycobacterium tuberculosis, 9.
• 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 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.
• 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 course, be varied and may conveniently be between about 5% to about 75% 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 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.
• 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, 2-acetoxybenzoic, salicyclic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, or methanesulfonic.
• inorganic acids such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid
• organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicyclic, succinic acid, theophylline, 8
• 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- dihydropyrimido[2,1-b][1,3]benzodiazepine, mp about 4546.
• the 2-bromo-5-aminobenzoic acid is diazotized with sodium nitrite in aqueous sulfuric acid, and the diazonium compound treated with sodium methylmercaptide to give 2-bromo-5- methylthiobenzoic acid.
• the 2-bromo-5- methylthiobenzoic acid is converted to its methyl ester by heating under reflux with methanol-concentrated sulfuric acid, the methylester is isolated by ether extraction from the esterification mixture, recovered from the ether solution, distilled for purification, and reduced with lithium aluminum hydride to yield 2-bromo-5-methylthiobenzyl alcohol.
• 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 magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.
• EXAMPLE 54 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 solutioii. The volume is adjusted to milliliters with distilled water,
• a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used.
• Phosphates, citrates 0r tartrates may be added as buffers.
• Preserva tives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.
• R is the same or different and is hydrogen, F, Cl, Br, alkyl of from i to 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein the substituent is F, Cl, Br, I, alkyl of from l to 4 carbons, alkoxy of from l to 4 carbons, or trifluoromethyl; provided that when R is halogen, and m is l, R occupies only the 5-position in the starting Z-aminopyrimidine with the proviso that R may not be adjacent tertiary alkyl;
• R is hydrogen, F, Cl, Br, I, alkyl of from I to 4 car bons, alkoxy of from I to 4 carbons, alkylthio of from I to 4 carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4 carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical has from l to 4 carbons, trifluoromethyl, mono-substituted phenyl or mono-substituted phenyloxy wherein the substituent is F, Cl, Br, 1,
• a compound of claim 1 having the name li ig UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3 868 374 DATED 1 February 25, 1975 INVENTOR(S) Harry Louis Yale et al.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

Priority Applications (7)

Applications Claiming Priority (1)

Related Child Applications (1)

Publications (1)

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Family Applications (1)

Country Status (6)

Cited By (3)

• 1973
  • 1973-07-26 US US382804A patent/US3868374A/en not_active Expired - Lifetime
• 1974
  • 1974-06-28 CA CA203,632A patent/CA1051885A/fr not_active Expired
  • 1974-07-03 GB GB2953474A patent/GB1474252A/en not_active Expired
  • 1974-07-23 DE DE2435384A patent/DE2435384A1/de not_active Withdrawn
  • 1974-07-26 JP JP49086509A patent/JPS5041894A/ja active Pending
  • 1974-07-26 FR FR7426129A patent/FR2238490B1/fr not_active Expired

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