Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the compounds of this invention may be isolated and used as the free base or as a pharmaceutically acceptable acid addition salt.
• Such salts are formed by reaction of the free base with the desired inorganic or organic acide
• the salts are prepared using methods known to those skilled in this art. Exemplary inorganic acids
• loweralkoxy is intended to include those alkoxy groups of either straight or branched configuration which contain from 1 to 6 carbon atoms.
• alkyl groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, sec butoxy, pentoxy and the like.
• haloloweralkyl is defined as a loweralkyl group with 1, 2 or 3 halo substituents.
• halo or halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
• N-loweralkylcarbamoyl and “N-loweralkyl thiocarbamoyl” groups are respectively visualized as follows: X' being oxygen or sulfur
• the compounds of the present invention wherein X is oxygen are prepared by reacting a substituted 2,6-diamino pyridine with a substituted 1, 3-alkanedione; converting the 2-amino naphthyridine thus prepared to the 1-unsubstituted naphthyridin-2-one by a diazotizatin- hydrolysis, and then alkylating at the 1-position with the substituted amino alkyl group.
• the reaction is outlined in the following reaction scheme: wherein R 1 , R 2 , R 3' R 4' R 5 , R 6 , R 7 and n are as previously defined, and Hal is a halogen.
• an appropriately substituted 2,6-diamino pyridine (I) is combined with a 1, 3-alkanedione (II) in phosphoric acid.
• R 3 is hydrogen the 1, 3 alkanedione is a 3-oxo- aldehyde and generally the reagent is employed in the form of a dialkylacetal.
• the mixture is heated at temperatures of from 75 to 110°C for from 3 to 16 hours.
• the reaction mixture is then cooled and the product isolated using techniques known to those skilled in this art.
• the 2-amino-1, 8-naphthyridine (III) thus produced is converted to the diazonium salt with sodium nitrite in an acid, preferably trifluoroacetic acid or sulfuric acid.
• the diazonium salt is prepared at -5°C or less during the addition, over a period of about 2 hours, of the sodium nitrite.
• the reaction mixture then is generally maintained at 'this temperature for an additional hour, and combined with a mixture of ice and water.
• the aqueous mixture is then made alkaline preferably with ammonium hydroxide; and.the product 1,8-naphthyridine-2-(1H) -one (IV) isolated using known techniques.
• the alkali metal salt of the 1- unsubstituted compound is first prepared, using an alkali metal hycride, preferably sodium hydride in an aprotic solvent.
• the preferred solvents are polar aprotic solvent such as limethyl formamide or dioxane.
• the alkali metal salt is generally prepared at room temperature.
• the alkali metal salt may be prepared from an alkali moral alkoxide such as an alkali metal methoxide or ethoxie.
• the reaction is generally carried out with the alka.. metal in an alcohol. The reaction is carried oul at from rom temperature to the reflux temperature of the reaction ixture.
• the alkali metal salt is generally not isolated but rather used in situ.
• a substituted amino akyl halide is then added to the reaction mixture and it . 3 heated at from 50 to 125°C for from 3 to 24 hour:
• the product 1-substituted naphthyridine-2(lH)one (V) is isolatet ising known techniques.
• reaction conditions for the preparation of the phthalimido intermediate (VI) utilize the alkali metal salt as in the preparation of compound (V).
• the same reaction conditions are employed except that a phthalimido alkyl halide is used as the reagent.
• T ahthalimido intermediate (VI) is combined in a polar solvene, such as a loweralkanol, with hydrazine and heated at reflux for from 10 minutes to 2 hours, preferably fcr from 1/2 to 1 hour.
• a polar solvene such as a loweralkanol
• the reaction mixture is cooled and coidified and the product (VII) isolated usually as the addition salt with the acidifying acid.
• Hydrochloric acid is preferred, however, other mineral acids are acceptable.
• the compounds wherein X is sulfur are prepared from those wherein X is oxygen by treatment with phosphorus pentasulfide or from hydrogen sulfide and hydrogen chloride.
• the phosphorus pentasulfide reaction takes place in methylene chloride or pyridine at from room temperature to the reflux temperature for a period of about 4 hours.
• the reaction is conducted at from about room temperature to 50°C.
• the product is isolated using known techniques.
• reaction with hydrogen sulfide and hydrogen chloride is carried out generally in an alcohol solvent it temperatures of from 0°C to room temperature and is complete in from 1/2 hour to 2 days.
• the starting material (V) is dissolved in a solvent such as a lower alkanoic acid preferably acetic acid and a catalyst such as platinum oxide is added.
• a solvent such as a lower alkanoic acid preferably acetic acid
• a catalyst such as platinum oxide
• the mixture is then agitated under an atmosphere of hydrogen, either at atmospheric pressure or pressurized. Pressures of up to 50 pounds per square inch are utilized in the normal laboratory hydrogenation apparatus.
• the reaction is complete when a calculated molar quantity of hydrogen has been consumed.
• the reaction is generally carried out at room temperature, however, heating up to about 75°C is acceptable.
• N-loweralkylcarbamoyl and N,loweralkylthiocarbamoyl substituents for R 6 or R 7 are prepared from the compounds wherein R 6 and Ry are hydrogen according to the following reaction scheme: wierein R 8 is loweralkyl and X is oxygen or sulfur.
• the compounds are prepared by reacting the primary atino compound (VII) with a loweralkyl, isocyanate or ilothiocyanate.
• the reaction is carried out in aqueous milia generally at reflux temperature.
• the reaction is generally complete in about 10 minutes to 1 hour at reflux a 1 the product (XI) is isolated using known techniques.
• the primary amine compound (VII) is also an intermediate for an alternate preparation of the coupounds wherein R 6 and R 7 are methyl groups.
• the reaction is carried out in the presence of aqueous formaldehyde and formic acid.
• the reaction is preferably carried out in a polar solvent such as a lower alkanol.
• the choice of solvent is not critical so long as the solvent is stable under the reaction conditions employed.
• the palladium is plesent on the carbon substrate to the extent of about S 6 .
• the reaction is carried out generally at room temperature although heating to 50°C is possible.
• the reaction is complete when a calculated molar equivalent of hydrogen has been reacted as observed by a decrease in the pressure or volume of the hydrogenation apparatus. It is also preferred if the starting material is utilised in the form of the hydrohalic acid addition salt.
• the quaternary ammonium salts which form part of this invention are prepared from the compounds of structure V by treatment with a loweralkyl halide.
• R 8 is loweralkyl and Hal is a halide.
• the reaction is carried generally in a solvent such as a loweralkanol, preferably ethanol. '
• the reaction mixture is generally stirred at room temperature, higher temperatures are generally not needed, and is complete in about 5 minutes to 1 hour.
• the product XII is isolated using known techniques.
• the compounds of the present invention in the described dosages may be administered orally, however, other routes such as intraperitoneal, subcutaneous, intramuscular or intravenous 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, suppositories, 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.
• a liquid carrier such as a fatty oil.
• 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 4 The procedure of Example 4 is followed, using the compounds and reagents listed below to prepare the named naphthyridine-2(lH)-one compound.
• Example 6 The procedure of Example 6 is followed to prepare other 1-substituted naphthyridine-2(1H)-ones according to the following reaction scheme:
• the substituent groups and the quantities of each reagent and compound employed are set forth in Table I.
• Example 8 The procedure of Example 8 is followed to prepare the 1-substituted naphthyridin-2(lH)-ones according to the following reaction scheme:
• Example 8 The procedure of Example 8 is followed using the compounds and reagents listed below in ethanol to prepare the named naphthyridin-one compounds:
• Formic acid (10 ml., 0.265 mole) is added with stirring at 5°C in 1 ml. portions to 1-(4-aminobutyl)-5,7-dimethyl-1,8-naphthyridin-2-(1H) -one (13.7 g., 0.056 mole) (obtained as the free base from Example 12B).
• Formaldehyde (37%, 10 ml.) is added to the semi-solid mass and the mixture is refluxed for 18 hours.
• hydrochloric acid (12N, 13.7 ml.) is added and the mixture concentrated under vacuum. The residue is dissolved-in water and the solution is made alkaline with excess sodium hydroxide.
• the product is extracted into diethyl ether.
• Methyl iodide (1,7 g., 0.012 mole) is added to a solution of 1-(2-dimethylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(lH)-one (2.45 g., 0.01 mole) (obtained as the free base from Example 8B) in 10.ml. of absolute ethanol and the mixture is stirred for 20 minutes.
• Example 17 The procedure of Example 17 may be employed to-reduce other naphthyridin-2(lH)-ones to the corresponding 3,4-dihydronaphthyridin-2(lH)-ones.
• the products listed below are obtained:
• the confounds prepared by this procedure may be isolated as the free base, such as compound B or as the acid addition salt which are-prepared by the procedure described in Example 17.

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• 1977
  • 1977-07-18 US US05/816,617 patent/US4133885A/en not_active Expired - Lifetime
• 1978
  • 1978-07-10 EP EP78100341A patent/EP0000490A1/fr not_active Withdrawn
  • 1978-07-14 ES ES471767A patent/ES471767A1/es not_active Expired
  • 1978-07-14 PT PT68294A patent/PT68294A/pt unknown
  • 1978-07-17 IT IT7850335A patent/IT7850335A0/it unknown
  • 1978-07-18 JP JP8685778A patent/JPS5422394A/ja active Pending

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