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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• R 1 H is a pharmaceutically acceptable acid, selected from the group consisting of R S0 3 H, R 4 P0 3 H and YH wherein
• R 4 is selected from (C 1 -C ⁇ )alkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C,-C e )alkyl;
• Y is selected from Cl, S0 4 , HS0 4> N0 3 , HP0 3 H, and P0 4 , of the naphthyridone antibiotic 7-(1 ⁇ ,5 ⁇ ,6 ⁇ )-(6-amino-3-azabicyclo [3.1.0] hex-3-yl)- 1-(2,4-difluorophenyl)-6-fluoro-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid.
• R 1 !-! is a pharmaceutically acceptable acid selected from the group consisting of R S0 3 H, R 4 P0 3 H and YH wherein
• R 4 is selected from (C T -CgJalkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C,-C ⁇ )alkyl;
• Y is selected from Cl, S0 4 , HS0 4 , N0 3 , HP0 3 H, and P0 4 , which comprises treating a compound of the formula
• the invention also relates to a process for preparing a compound of the formula II wherein R 3 is NH 2 and R 2 is as defined above by treating a compound of the formula II wherein R 3 is N0 2 with a reducing agent in the presence of a compound of the formula R 1 H wherein R' H is as defined above.
• the present invention relates to a process for preparing a compound of the formula II wherein R 3 is N0 2 comprising reacting the compound of the formula
• R 2 is as defined above and J is a suitable leaving group.
• the compound of the formula IV is prepared by treating a compound of the formula
• R is selected from (C,-C 6 ) alkyl or (C 6 -C 10 )aryl wherein said aryl group may be substituted, optionally, with one or more substituents independently selected from halo, nitro, (C,-C 6 ) alkyl, (C,-C 6 ) alkoxy, amino and trifluoromethyl, with an N-dealkylating agent.
• R is phenyl or hydrogen.
• the compound of formula V may be prepared by treating the compound of formula
• R is as defined above, with a compound of the formula X-CH 2 -N0 2 , wherein X is a suitable leaving group, in the presence of a base.
• a preferred base is 1 ,2-dimethyl- 1 ,4,5,6-tetrahydropyrimidine.
• Yet another embodiment of the invention relates to a process for the preparation of a compound of formula I which comprises the steps of a) treating a compound of the formula VII with a compound of the formula X-CH 2 -N0 2 , wherein X is a leaving group, in the presence of a base to form a compound of the formula VI which is then treated with a reducing agent to form the compound of the formula V; b) treating the compound of the formula V with a dealkylating agent to form the compound of formula IV; c) treating the compound of formula IV with a compound of the formula
• R 2 is as defined above and J is a suitable leaving group, to form a compound of the formula II wherein R 3 is N0 2 ; and d) treating the compound of formula II, wherein R 3 is N0 2 , with a reducing agent comprising hydrogen in the presence of a catalyst or a metal and an acid of the formula R 1 !-!, as defined above, to form i) when the hydrogenation is effected in the presence of an acid
• R 1 H as defined above, or R'H is a compound of the formula YH or R S0 3 H, wherein Y and R 4 are as defined above, the compound of the formula I; or ii) the compound of the formula II, wherein R 3 is NH 2 , and then treating said compound with a compound of the formula R 1 H, which may be the same as or different from the R 1 !-! of the reducing step, or a compound of the formula R C0 2 H, wherein R 4 is defined as above, to form the compound of the formula I.
• R 2 is as defined above.
• R 2 is defined above.
• halo refers to fluoro, chloro, bromo or iodo. as applicable. -7-
• alkyl includes straight, and when comprised of more than two carbon atoms, branched hydrocarbon chains and hydrocarbon rings and combinations of the straight or branched hydrocarbon chains with the hydrocarbon rings.
• reaction of a compound 1 with a a compound of the formula X-CH 2 -N0 2 , wherein X is a suitable leaving group such as chloro and bromo. in the presence of a base yields the corresponding compound 2.
• This reaction is generally conducted in an inert, polar, aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAC), an ethereal solvent such as ethyl ether, glyme, diglyme, dioxane or tetrahydrofuran (THF) or an aromatic solvent such as optionally chlorinated benzene or toluene. Toluene is preferred.
• Suitable reaction temperatures range from about -78 °C to about 80 °C, with about 0°C to about -20 °C being preferred. It is preferable to add the base last.
• appropriate bases include carbonate bases such as potassium or sodium carbonate, phosphorine amide bases such as 2-tert-butylimino-2-diethylamino-1 ,3- dimethylperhydro-1 ,3,2-diaza-phosphorine, and amine bases such as triethylamine, guanidine, diisopropylethylamine.tetramethyl guanidine, 1 ,8-diazabicyclo-[5.4.0]undec- 7-ene (DBU), 1 ,5-diazaicyclo-[4.3.0]non-5-ene (DBN) and 1 ,2-dimethyl-l ,4,5,6- tetrahydropyrimidine.
• DBU diazabicyclo-[5.4.0]undec- 7-ene
• DBN
• reducing agents include borane, sodium borohydride and boron trifluoride»etherate complexes.
• Inert ethereal solvents useful in the reduction include glyme, diglyme, diisopropyl ether, dimethyl sulfide, DMSO, diethyl ether and THF.
• the preferred reducing agent is borane and the preferred solvents are THF or diethyl ether.
• the reduction is typically carried out at temperatures ranging from about 25 °C to about 90° C.
• R is (C 6 -C 10 )aryl hydrogenolytic removal of the RCH 2 group from compound 3 is generally accomplished by reacting said compound with hydrogen gas at a pressure from about 10 psi to about 2000 psi, preferably from about 14 to about 60 psi, in the presence of a noble metal catalyst, such as palladium, platinum or rhodium, or salts thereof. Palladium, or palladium hydroxide, on carbon is preferred.
• the temperature may range from about 20°C to about 80°C, and is preferably about 25°C.
• the solvent is usually a (C ⁇ C g Jalkyl alcohol and is preferably methanol.
• R 2 is as defined above and J is a suitable leaving group such as chloro and bromo.
• a preferred leaving group is chloro or bromo and a most preferred leaving group is chloro.
• the reaction may be conducted with or without a solvent.
• the solvent when used, must be inert under the reaction conditions. Suitable solvents are acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, water, or mixtures thereof.
• the reaction temperature usually ranges from about 20 °C to about 150°C.
• the reaction may advantageously be carried out in the presence of an acid acceptor such as an inorganic or organic base, e.g. an alkali metal or alkaline earth metal carbonate or bicarbonate, or a tertiary amine, e.g. triethylamine, pyridine or picoline.
• an acid acceptor such as an inorganic or organic base, e.g. an alkali metal or alkaline earth metal carbonate or bicarbonate, or a tertiary amine, e.g. triethylamine, pyridine or picoline.
• Compound 5 is converted to compound 6 by treatment with a metal and acid, of the formula R 1 ⁇ wherein R ] H is defined as above, in the presence of an aqueous aprotic solvent such as acetonitrile or DMF.
• a metal and acid of the formula R 1 ⁇ wherein R ] H is defined as above, in the presence of an aqueous aprotic solvent such as acetonitrile or DMF.
• the preferred metal is zinc.
• Suitable acids include inorganic acids, such as hydrochloric and sulfuric acids, and organic acids, such as sulfonic acids, e. g., methane-, trifluoromethane- and p-toluenesulfonic acids. Methanesulfonic acid or hydrochloric acid is preferred.
• This reaction is generally conducted in an aqueous (C,-C 6 )alkyl alcohol solvent, such as ethanol, methanol, 1- propanol and 2-propanol, preferably ethanol, at a temperature from about 0°C to about 80°C, preferably at about 25°C.
• an aqueous (C,-C 6 )alkyl alcohol solvent such as ethanol, methanol, 1- propanol and 2-propanol, preferably ethanol
• compound 5 can be converted to 6 by treatment with hydrogen in the presence of Raney nickel or a noble metal catalyst.
• Raney nickel is the preferred catalyst.
• the hydrogenation reaction is generally conducted in an aqueous solvent mixture.
• Suitable solvents include (C 1 -C 6 )alkyl alcohols such a ethanol, methanol 1- propanol and 2-propanol; and water miscible aprotic solvents such as DMF, THF, dimethylacetamide, dioxane, and (C ⁇ C ⁇ Jalkyl ethers.
• Hydrogen pressures used are in the range from about 14 to about 100 psi, preferably in the range about 40 to about 60 psi and temperatures are in the range of about 15°C to about 80°C, preferably the from about 20 to about 30 °C.
• Compound 6 is converted to compound 7 by treatment with a compound of the formula R'H, as defined as above, in an aqueous medium.
• compound 5 may be converted directly into compound 7 by treatment with a metal and an acid of the formula R 1 H, such as those described above, in an aqueous medium.
• a preferred metal is zinc and a preferred acid is methanesulfonic acid.
• the pharmaceutically acceptable acid addition salts wherein the acid is a compound of the formula R 4 C0 2 H or R 1 ⁇ wherein R 4 and R are defined as above, are prepared in a conventional manner by treating a solution or suspension of the free base form of compound I with about one chemical equivalent of the pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts.
• Suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, methanesulfonic, p-toluenesulfonic, cinnamic, fumaric, phosphonic, hydrochloric, hydrobromic, hydroidic, sulfamic, and sulfonic acid.
• the antibacte ⁇ al compounds of formula I and the related azabicyclo naphthyridone carboxylic acid antibiotics that can be synthesized using the methods and intermediates of this invention are useful in the treatment of animals, and humans having bacterial infections. They are useful in treating bacterial infections of broad spectrum, particularly in treating gram-positive bacterial strains.
• the compounds of formula I may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
• a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
• they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
• they are advantageously contained in an animal feed or drinking water in a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm.
• the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to about 50 mg/kg/day, advantageously about 0.2 to about 10 mg/kg/day given in a single daily dose or up to 3 divided doses.
• the invention also provides pharmaceutical compositions comprising an antibacterially effective amount of a compound of the formula I together with a pharmaceutically acceptable diluent or carrier.
• the compounds of the invention can be administered to humans for the treatment of bacterial diseases by either oral or parenteral routes, and may be administered orally at dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dosage or up to 3 divided dosages.
• dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day.
• intramuscular administration may be a single dose or up to 3 divided doses
• intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.
• the antibacterial activity of the compounds of the invention is shown by testing according to the Steer's replicator technique which is a standard in vitro bacterial testing method described by E. Steers et al., Antibiotics and Chemotherapy, 9, 307 (1959).
• a 22 L vessel equipped with overhead stirrer, thermometer, dropping funnel, cooling bath, condenser, exit bubbler and nitrogen inlet was purged with nitrogen.
• the nitrogen purged vessel was charged with N-benzylmaleimide (500 gm, 2.67 moles), toluene (12 L), bromonitromethane (751 gm, 90%, 4.83 moles) and powdered molecular sieves (2020 gm) and stirred at about 10 to about 15°C.
• the slurry was treated dropwise with 1 ,2-dimethyl-1 ,4,5,6-tetrahydropyrimidine (DMTHP) (616 gm, 5.49 moles) over 3 hours.
• DTHP 1 ,2-dimethyl-1 ,4,5,6-tetrahydropyrimidine
• the mixture was then cooled to about 25 °C, filtered through a Celite (Trademark) precoated Buchner funnel, and the residue washed two times with 500 mLtoluene.
• the carbon treated filtrate was stripped under vacuum in a 12 L round bottom flask equipped with overhead stirrer, thermometer, vacuum addition port, distillation head, condenser and 22 L receiver. Vacuum stripping was complete with about 2 to about 3 L concentrate remaining.
• the concentrated solution was slowly treated with 4 liters of 2-propanol. Azeotropic vacuum distillation (25°C) was continued until toluene was no longer present ( as evidenced by a 10°C temp. rise).
• reaction completion determined by TLC.
• the solvent and excess ACE-CI were removed by rotary evaporation.
• the resulting black residue was dissolved in methanol (100 mL) and heated to about 55 to about 60° C for 3 hours.
• the resultant slurry was cooled to room temperature and granulated for 18 hours.
• the slurry was then treated with cone, hydrochloric acid (10 mL, 115 mmol) and stirred for 1.5 hours.
• the product was isolated by suction filtration.
• the cake was washed with chloroform (25 mL) and dried under vacuum. Yield: 9.99 g, 60 mmol (53%), m.p. 170-180° C (Dec).
• 'H NMR (d 6 -DMSO) ⁇ 9.8 (br s, 2H), 4.9 (s, 1 H), 3.5 (m, 4H), 2.9 (s, 2H).
• a 500 mL 3 neck round bottom vessel equipped with an overhead stirrer, condenser and thermometer was charged with acetonitrile (190 mL), 7-chloro-6-fluoro-1 - (2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid ethyl ester (19.07g, 50 mmol), the title component of example 2 (9.88 g, 60 mmol), and triethylamine (15.3 g, 151 mmol).
• the reaction mixture was cooled to room temperature, purged with nitrogen and tested for completion by TLC (89 CHCI 3 : 10 methanol: 1 NH 4 OH).
• the catalyst was collected through a Celite precoated funnel and was washed with water (25 mL). The filtrate to which water (40 mL) was added, extracted three times with 100 mL ethyl acetate . The ethyl acetate layer was then concentrated to 100 mL and extracted with water (100 mL) to remove residual DMF. The ethyl acetate layer was evaporated to dryness by rotary evaporation. Crude Wt. Yield: 1.36g (71.1 %). HPLC purity assay (76.5%). Purity Yield (54%). The product was characterized by HPLC (versus an authentic sample). The 1 NMR data were the same as for the product of section A above.
• the grey slurry was warmed to about 50 °C and treated with a 5 mL of a solution of 70%aq methanesulfonic acid (3.3 g, 24 mmol). The reaction was monitored periodically, by HPLC, for completion (23 hours). The reaction was heated to about 80 to about 85°C, then treated with additional 70%aq methanesulfonic acid (2.6 g, 19 mmol) to completely hydrolyse the ester (HPLC). The reaction mixture was cooled to room temperature and treated with water (250 mL) to yield a tan slurry. The slurry was filtered and 500 mL water was added to the filtrate. The resultant solution was concentrated by rotary evaporation to remove acetonitrile.

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• 1994
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