US3853864A - 1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid alkyl esters - Google Patents

1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid alkyl esters Download PDF

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Publication number
US3853864A
US3853864A US00313048A US31304872A US3853864A US 3853864 A US3853864 A US 3853864A US 00313048 A US00313048 A US 00313048A US 31304872 A US31304872 A US 31304872A US 3853864 A US3853864 A US 3853864A
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United States
Prior art keywords
dihydro
hydroxy
naphthyridine
carboxylic acid
compound
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Expired - Lifetime
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US00313048A
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English (en)
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A Santilli
A Scotese
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Wyeth LLC
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American Home Products Corp
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Priority to US00313048A priority Critical patent/US3853864A/en
Priority to CA186,799A priority patent/CA1017341A/en
Priority to GB5612873A priority patent/GB1426200A/en
Priority to DE2360329A priority patent/DE2360329A1/de
Priority to FR7343444A priority patent/FR2209568B1/fr
Priority to JP13855973A priority patent/JPS5653554B2/ja
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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 invention sought to be patented in its broadest aspect comprises chemical compounds of the structural formula I COR1 ⁇ N N wherein R is a straight-chain lower alkyl group, R and- R are each a straight-chain or branched lower alkyl group, and M is hydrogen or an alkali metal, and, when M is hydrogen, the non-toxic, pharmaceutically acceptable acid addition salts thereof.
  • Preferred embodiments of the compounds of Formula I are those wherein R is ethyl, R is methyl, R is a straight-chain or branched lower alkyl group, and M is hydrogen.
  • the compounds of Formula I exhibit in vivo antibacterial effects as demonstrated by evaluation in standard in vivo anti-bacterial test procedures.
  • a nicotinic acid ester (II), having a displaceable substituent in the 2-position is reacted with a 3-[N-alkylamino1propionic acid ester (III) to produce a nicotinic acid ester compound (IV) having an (alkoxycarbonylethyl)alkylamino substituent in the 2-position.
  • the reaction is carried out in the presence of an acid acceptor, such as sodium carbonate, in'a reaction-inert solvent, such as dimethylformamide (DMF) or dimethyl-acetamide (DMA), at a temperature ranging from 150C to 175C. With DMF or DMA as solvents, it is convenient to perform the reaction at the reflux temperature.
  • the Z-nicotinic acid ester compound (IV) is cyclized under Dieckmann reaction conditions to afford an alkyl 1,7-dialkyl-l,2-dihydro-4- hydroxy-l ,8-naphthyridine-3-carboxylate.
  • the cyclization reaction is preferably effected by heating the intermediate (IV) at a temperature ranging from 50C to 100C, (preferably 60C to 80C) in the presence of an alkali metal lower alkoxide in a nonreactive organic solvent, preferably a lower alkanol.
  • the product is obtained as the alkali metal enolate salt (V).
  • V alkali metal enolate salt
  • the alkali metal alkoxide can conveniently be prepared in situ by dissolving the alkali metal in the desired alkanol solvent, and thereafter adding the intermediate to be cyclized.
  • the enol salt (V) can be converted to the enol (VI) by acidification with an acid whereby the alkali metal (M) is replaced by hydrogen.
  • an acid i.e., one which will not protonate the amine function
  • the product is obtained in the form of the free amine.
  • the free amine can be converted to an acid addition salt by treatment with a strong acid.
  • the acid employed for formation of the acid addition salt must be non-toxic and acceptable for pharmaceutical use.
  • suitable acids are hydrochloric, hydrobromic, sulfuric, nitric, sulfonic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, or phosphoric.
  • lower alkyl means an alkyl group having from one to six carbon atoms.
  • lower alkoxide means an alkoxy group having from one to six carbon atoms.
  • Alkali metal means sodium or potassium.
  • the starting compounds for the processes described herein are either known compounds or can be prepared from known compounds by procedures well known in the art. 4
  • Infrared and nuclear magnetic resonance spectrographic data indicate that the enol form (I) is the predominate form.
  • the compounds of the invention are depicted and named herein in the enol form as 1,2- dihydro-4-hydroxyl ,8-naphthyridine-3-carboxylic acids rather than as l,2,3,4-tetrahydro-4-oxo-l ,8- naphthyridine-3-carboxylic acids. It is understood that both the enol and keto forms are equivalent for the purposes of the invention.
  • the compounds of the invention When employed as in vivo anti-bacterial agents, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, lactose, magnesium stearate, and so forth. They may be administered orally in the form of solution or they may be injected parenterally, e.g. intramuscularly. For parenteral administration, they may be used in the form of a sterile solution or suspensions containing other solutes, for example, enough saline or glucose to make the solution isotonic.
  • pharmaceutically acceptable carriers the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • they may be administered orally in the form of tablets or capsules containing such excipients as starch, lactose, magnesium stearate,
  • the dosage of the present pharmacologically active agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. T hereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a dosage that will generally afford effective results without causing any harmful or deleterious side effects.
  • EXAMPLE V1 2-[(Z-Ethoxycarbonylethyl )n-Butylaminol-(u-Methylnicotinic Acid Methyl Ester
  • a mixture of 3.7 g. of 2-chloro-6-methylnicotinic acid methyl ester, 3.4 g. of ethyl 3- butylaminopropionate and 2.12 g. of sodium carbonate in 40 ml. of dimethylformamide (DMF) is heated under reflux for 6 hours.
  • the mixture is filtered and the filtrate is partitioned between 500 ml. of water and 100 ml. of chloroform.
  • the chloroform layer is dried over magnesium sulfate, filtered, and evaporated to give an oil which is used directly in Example Vll.
  • mice Forty male mice, weighing 18 g. i l g., are divided into four separate groups containing ten mice in each group. Each animal is injected intraperitoneally with 0.5 ml. of a standardized suspension of the infective agent in 5% gastric mucin. Six hours post infection, each mouse is given a single oral dose of the test compound.
  • the amount of compound given varies in each of the four groups; i.e., 4 graded doses are administered.
  • l-ethyl-l ,2- dihydro-4- hydroxy-7-methyl-1 ,8-naphthyridine-3-carboxylic acid ethyl ester hydrochloride showed therapeutic activity, as measured by CD values, against infections caused by the following gram-negative organisms at a dosage level in the range of 2 to 6 mg/mouse: Escherichia coli 920, Salmonella typhimurium SaB-l, Salmonella typhosa SaD-l 2, Proteus vulgaris 347, and Proteus mirabilis 3.
  • R is a straight-chain lower alkyl group
  • R and R are each a straight-chain or branched lower alkyl group
  • M is hydrogen or an alkali metal, and, when M is hydrogen, the non-toxic, pharmaceutically acceptable acid addition salts thereof.
  • a compound as defined in claim 2 which is l-ethyl- 1 ,2-dihydro-4-hydroxy-7-methyl-1,8-naphthyridine-3- carboxylic acid ethyl ester.
  • a compound as defined in claim 2 which is l-ethyll ,2-dihydro-4-hydroxy-7-methyl-l ,8-naphthyridine-3- carboxylic acid ethyl ester, hydrochloride.
  • a compound as defined in claim 2 which is l-ethyl- 1 ,2-dihydro-4-hydroxy-7-methyl-l ,8-naphthyridine-3- carboxylic acid butyl ester.
  • a compound as defined in claim 2 which is l-ethyll ,2-dihydro-4-hydroxy-7-methyl-1,8-naphthyridine-3- carboxylic acid butyl ester, hydrochloride.
  • a compound as defined in claim 1 which is lbutyl-l ,2-dihydro-4-hydroxy-7-methyll ,8-naphthyridine-3-carboxylic acid ethyl ester.
  • a compound as defined in claim 1 which is lbutyl-l ,2-dihydro-4-hydroxy-7-methyl-1 ,8-naphthyridine-3-carb0xylic acid ethyl ester, hydrochloride.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
US00313048A 1972-12-07 1972-12-07 1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid alkyl esters Expired - Lifetime US3853864A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US00313048A US3853864A (en) 1972-12-07 1972-12-07 1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid alkyl esters
CA186,799A CA1017341A (en) 1972-12-07 1973-11-27 1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid alkyl esters
GB5612873A GB1426200A (en) 1972-12-07 1973-12-04 Nahpthyridine derivatives
DE2360329A DE2360329A1 (de) 1972-12-07 1973-12-04 1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8naphthyridin-3-carbonsaeurealkylester
FR7343444A FR2209568B1 (ja) 1972-12-07 1973-12-05
JP13855973A JPS5653554B2 (ja) 1972-12-07 1973-12-06

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US00313048A US3853864A (en) 1972-12-07 1972-12-07 1,7-dialkyl-1,2-dihydro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid alkyl esters

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US (1) US3853864A (ja)
JP (1) JPS5653554B2 (ja)
CA (1) CA1017341A (ja)
DE (1) DE2360329A1 (ja)
FR (1) FR2209568B1 (ja)
GB (1) GB1426200A (ja)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128649A (en) * 1977-06-29 1978-12-05 Sandoz, Inc. 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters
US4273930A (en) * 1977-06-20 1981-06-16 Sandoz, Inc. 4-Hydroxy-2-quinolinone-3-carboxylic acid esters
US4281131A (en) * 1977-06-20 1981-07-28 Sandoz, Inc. 4-Hydroxy-2-quinolinone-3-carboxylic acids and salts thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2808070A1 (de) * 1978-02-24 1979-08-30 Bayer Ag Verfahren zur herstellung von 4-pyridon-3-carbonsaeuren und/oder deren derivaten

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3590036A (en) * 1968-11-18 1971-06-29 George Y Lesher Naphthyridine-3-carboxylic acids,their derivatives and preparation thereof
US3786043A (en) * 1972-06-19 1974-01-15 Sterling Drug Inc 7-methyl-4-chloro (or -4-lower-alkoxy)-1,8-naphthyridine-3-carboxylates
US3813406A (en) * 1970-02-20 1974-05-28 Koei Chemical Co Process for preparing 1-alkyl-1,8-naphthyridine compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3590036A (en) * 1968-11-18 1971-06-29 George Y Lesher Naphthyridine-3-carboxylic acids,their derivatives and preparation thereof
US3813406A (en) * 1970-02-20 1974-05-28 Koei Chemical Co Process for preparing 1-alkyl-1,8-naphthyridine compounds
US3786043A (en) * 1972-06-19 1974-01-15 Sterling Drug Inc 7-methyl-4-chloro (or -4-lower-alkoxy)-1,8-naphthyridine-3-carboxylates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Lesher et al., Journal of Medicinal And Pharmaceutical Chemistry, Vol. 5, No. 5, Pages 1063 1065, Sept. 1962 Rsl J5. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273930A (en) * 1977-06-20 1981-06-16 Sandoz, Inc. 4-Hydroxy-2-quinolinone-3-carboxylic acid esters
US4281131A (en) * 1977-06-20 1981-07-28 Sandoz, Inc. 4-Hydroxy-2-quinolinone-3-carboxylic acids and salts thereof
US4128649A (en) * 1977-06-29 1978-12-05 Sandoz, Inc. 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters

Also Published As

Publication number Publication date
FR2209568A1 (ja) 1974-07-05
GB1426200A (en) 1976-02-25
CA1017341A (en) 1977-09-13
FR2209568B1 (ja) 1978-07-28
DE2360329A1 (de) 1974-06-20
JPS4987699A (ja) 1974-08-22
JPS5653554B2 (ja) 1981-12-19

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