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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
  • C07D213/80—Acids; Esters in position 3
• • 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

• the anti-ulcer agents of this invention function in their anti-secretory capacity to reduce (1) total gastric volume, (2) hydrogen ion secretion, or (3) hydrogen ion concentration.
• the reduction of any one of these parameters aids in attenuating the general debilitating influence of a peptic ulcer.
• the use of compounds exhibiting anti-secretory activity in the curative and/or prophylactic treatment of peptic ulcer disease is an established, beheficial procedure.
• anti-secretory agents of this invention are compounds of the formula:
• R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, alken-(3, 4, 5 or 6)-yl of 3 to 6 carbon atoms or alkyn(3, 4, 5 or 6)-yl of 3 to 6 carbon atoms;
• R 2 is -CN, -CO 2 H, -CO 2 R 7 where R 7 is alkyl of 1 to 6 carbon atoms, -CONHNH 2 or
• R 8 and R 9 are independently hydrogen or alkyl of 1 to 6 carbon atoms
• R 3 and R 4 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, dialkylaminoalkyl of 4 to 8 carbon atoms, alkanoyl of 2 to 4 carbon atoms, haloalkanoyl of 2 to 4 carbon atoms, or.
• R 3 and R 4 when taken together with the nitrogen atom to which they are attached, R 3 and R 4 complete a heterocyclic group selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkylpiperazinyl, 4-phenylpiperazinyl, 4-[1-ethyl-1,2-dihydro-7-methyl- 2-oxo-1,8-naphthyridine-4-yl-3-carboxylic acid ethyl ester]-piperazinyl, 4-carb(lower) alkoxypiperazinyl, morpholinyl, thiomorpholinyl or a ring substituted lower alkyl analogue thereof; R 5 and R 6 are independently hydrogen, alkyl of 1 to 4 carbon atoms, halo, alkylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable
• R 1 is hydrogen, methyl, ethyl, propyl, allyl, propargyl, cyclohexyl, or isobutyl;
• R 3 is hydrogen, alkyl of 1 to 6 carbon atoms or trifluoroacetyl
• R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, or when taken with R 3 and the nitrogen atom to which they are attached forms a heterocyclic group selected from pyrrolidinyl, morpholinyl, piperazinyl, or 4-methyl-piperazinyl;
• R 6 is hydrogen or methyl; and R 10 is hydroxy, alkoxy of 1 to 6 carbon atoms or hydrazinyl; or a pharmaceutically acceptable salt thereof.
• Those compounds containing a basic amino group in the 4-position are capable of forming acid addition salts. It is intended throughout this specification and claims to embrace the pharmaceutically acceptable salts of such compounds, which salts are conveniently dederived from such acids as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, ptoluene sulfonic, acetic, citric, maleic, succinic acid and the like.
• the compounds in their free carboxylic acid form are converted by standard techniques well-known to the chemist into alkali metal (sodium or potassium), alkaline earth metal (calcium or magnesium), ammonium or primary, secondary and tertiary alkylamine salts, the latter containing from 1 to 6 carbon atoms in their alkyl moieties.
• alkali metal sodium or potassium
• alkaline earth metal calcium or magnesium
• ammonium or primary, secondary and tertiary alkylamine salts the latter containing from 1 to 6 carbon atoms in their alkyl moieties.
• lower alkyl and lower alkoxy are intended to embrace groups containing from 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms.
• halo means chloro, bromo, iodo, or fluoro, preferably chloro or bromo.
• diuretic agents are those compounds in which the substituent in 4 position is primary amino.
• the compounds possessing diuretic activity may be depicted by the structural formula
• each of the R groups is defined in conjunction with the structural formula generically depicting compounds with anti-secretory activity.
• the 4-amino-1,8-naphthyridine derivatives demonstrated effectiveness generally comparable to hydrochlorothiazide in the standard, scientifically recognized test procedure of Lipschitz et al., J. Pharmacol. Exp. Therap., 79, 97 (1945) wherein male Sprague-Dawley rats 14 to 17 weeks old (175-200 grams), after fasting for one day are given an oral physiological saline prime dose of 25 ml/kg. of the compound being tested. Each compound is given to 8 rats, urea at a dose of 960 mg/kg.
• the dosage regimen for therapeutic use of the antisecretory agents disclosed herein will vary with the mode of administration, size and age of the person under treatment as well as the severity of the dysfunction. Therefore, treatment of peptic ulcer disease must be individualized for the patient under the guidance of the attending physician.
• the use of the 4-amino-1,8-naphthyridines as diuretics must similarly be controlled in the human.
• the 4-amino-1,8-naphthyridines afford the decided advantage of single compound treatment for both problems. Where the conditions occur separately, the second activity of the 4-amino-1,8-naphthyridines is not deleterious and not contraindieative of applicability of the treatment.
• the compounds of this invention may be administered by conventional oral or parenteral routes as solids, liquids or isotonic solutions. Conventional adjuvants known to the art may be combined with the compounds disclosed herein to provide compositions and solutions for administration purposes although it is considered desirable and feasible to use the compounds neat or pure without additives other than for the purpose of providing suitable pharmaceutically acceptable solid or liquid dosage units.
• the intermediate 4-halo-naphthyridine precursors for production of the anti-secretory agents of this invention are compounds of the formula:
• R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, alken-(3, 4, 5 or 6)-yl of 3 to 6 carbon atoms, or alkyn(3, 4, 5 or 6)-yl of 3 to 6 carbon atoms;
• R 2 is -CCl 3 , -CN, -CO 2 H, or -CO 2 R 7 where R 7 is alkyl of 1 to 6 carbon atoms;
• X is chloro, bromo, or iodo; and R 5 and R 6 are, independently, hydrogen, halo, alkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 4 carbon atoms, or alkyl of 1 to 4 carbon atoms.
• the preferred intermediates are those conforming in structure to the preferred group of anti-secretory agents.
• the 4-substituted amino-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives of this invention are prepared by Process 1 which involves reacting a primary or secondary amine with an appropriately substituted 4-halo-naphthyridine precursor.
• the 4-halo-naphthyridine precursors are prepared by conventional techniques involving displacement of a 4-hydroxyl group from the corresponding 4-hydroxy-naphthyridine with such halogenating reagents as thionyl chloride to obtain the 4-chloro-naphthyridines.
• the 4-iodo-naphthyridines are prepared by reaction of a 4-chloro-naphthyridine with sodium iodide in an appropriate inert solvent such as acetone.
• the 4-chloro, bromo or iodo-naphthyridines may also be prepared directly by nitrosation of the appropriately ring substituted 4-amino-naphthyridines in hydrochloric, hydrobromic or hydroiodic acid, respectively.
• the 4-amino-3-carboxy-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives of this invention are prepared directly from a 2-substituted amino nicotinonitrile reacting with a lower alkyl malonyl chloride followed by a Dieckman ring closure with sodium alkoxide, or an analogous strong base such as potassium alkoxide or NaH or NaNH 2 in an aprotic solvent, thusly;
• the 2-substituted aminonicotinonitrile may be reacted with the sodio salt of a di-lower alkyl malonate to give directly on acidification the 4- amino-3-carboxy-1,2-dihydro-2-oxo-1,8-naphthyridine derivative, thusly:
• the product may be treated with a lower alkali metal alkoxide and alkylated with a lower alkyl, alkenyl or alkynyl iodide, bromide or chloride (RX where R contains 1 to 6 carbon atoms) to afford alternatively the 1-alkyl-, alkenyl- or alkynyl-4-amino-3-carboxy-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives described above.
• RX where R contains 1 to 6 carbon atoms
• the amide substituent represent ing R 2 is readily produced at 3-position of the 4-amino and 4-substituted amino-3-alkoxycarbonyl-1,8-naphthyridine, derivatives by reaction of the ester -CO 2 R 7 with ammonia or a primary or secondary alkylamine by conventional techniques in which the alkyl group(s) independently contain from 1 to 6 carbon atoms.
• the 4-amino-3-carboxy or cyano-1,2-dihydro-2-oxo-1, 8-naphthyridine derivatives may also be prepared by reaction of ammonia with an appropriately substituted 3trichloromethyl-4-chloro-1,8-naphthyridine derivative, thusly: Process 4
• a third method of preparing 4-amino-1-ethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is as follows:
• the title compound was prepared from sodio di-n- butylmalonate and 2-ethylaminonicotinonitrile following the procedure of Example 9, m.p. 117-120° C.
• the title compound was prepared following the procedure of Example 9, employing 2-isobutylaminonicotinonitrile and ethyl malonyl chloride as the reactants, m.p. 157-159° C.
• the title compound was prepared following the procedure of Example 9, employing 2-cyclohexylaminonicotinonitrile and ethyl malonyl chloride as the reactants, m.p. 172-175° C.
• Example 18 The title compound is produced following the proceed ure of Example 18 with the exception that propargylamine is employed as an initial reactant rather than allylamine.
• the title compound is prepared by reaction of ethylamine with the product of Example 23.
• a hydrochloride was prepared by dissolving a few ml. of free base in ethyl acetate and adding dropwise a saturated solution of hydrogen chloride in diethyl ether. A few drops of ethanol was added. The solid which formed was removed by filtration and recrystallized from ethyl acetate-ethanol and dried in vacuo at 56° C. (m.p. 123-125° C).
• the title compound was prepared by reaction of 4-chloro-1-ethyl-1,2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carbonitrile, prepared by reacting 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 27) with ethanolic ammonia to form the 3-carboxamide, and that product with phosphorus oxychloride, with pyrrolidine following the procedure of Example 4, m.p. 211-213° C
• Example 4 The title compound was prepared following the procedure of Example 4, from pyrrolidine and 4-chloro-lethyl-1,2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, the latter compound being prepared from the corresponding 4-hydroxy compound and thionyl chloride as in Example 5 or by nitrosation of the corresponding 4-amino compound (described in Example 26) with NaNO 2 and HCl, m.p. 113-115° C.
• the product of the preceding paragraph was converted to its free base with excess sodium carbonate and then saponified with a stoichiometric amount of NaOH to yield the sodium salt of the carboxylic acid.
• the ethyl ester may be saponified with a stoichiometric amount of potassium hydroxide.
• Other salts may be produced directly from the free carboxylic acid by conventional means.
• the title compound was produced by the procedure of Example 50, substituting 2-methylaminoethanol for pyrrolidine, m.p. 111-113° C.
• Example 50 The procedure of Example 50 was repeated, substituting piperazine for pyrrolidine, to yield the title compound, m.p. 157-159° C. Analysis for: C 18 H 24 N 4 O 3 Calculated : C, 62.77; H, 7.02; N, 16.27 Found: C, 62.76; H, 6.85; N, 16.12. Percentage Inhibition : 98%
• Example 50 The procedure of Example 50 was repeated, employing 1-ethyl-1,2-dihydro-7-methyl-2-oxo-4-(1-piperazinyl)-1, 8-naphthyridine-5-carboxylic acid ethyl ester as the amine reactant in lieu of pyrrolidine, m.p. 264-267° C.

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

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• 1980
  • 1980-02-28 US US06/125,600 patent/US4324893A/en not_active Expired - Lifetime
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  • 1980-03-24 WO PCT/US1980/000319 patent/WO1980002287A1/en not_active Ceased
  • 1980-03-24 JP JP50102580A patent/JPS56500373A/ja active Pending
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• 1981
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