WO1992012155A1 - Novel quinolone compounds and processes for preparation thereof - Google Patents

Novel quinolone compounds and processes for preparation thereof Download PDF

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Publication number
WO1992012155A1
WO1992012155A1 PCT/KR1992/000003 KR9200003W WO9212155A1 WO 1992012155 A1 WO1992012155 A1 WO 1992012155A1 KR 9200003 W KR9200003 W KR 9200003W WO 9212155 A1 WO9212155 A1 WO 9212155A1
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Prior art keywords
diazabicyclo
carbon atoms
dihydro
oxo
cyclopropyl
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PCT/KR1992/000003
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French (fr)
Inventor
Soon Ku Moon
Gwan Sun Lee
Eui Sang Ryoo
Young Kil Chang
Young Ho Moon
Sang Tae Kim
Jong Pil Chun
Joon Hyung Koh
Young Hwan Gil
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Hanmi Pharmaceutical Co., Ltd.
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Priority claimed from KR1019910017787A external-priority patent/KR940008419B1/en
Priority claimed from KR1019910025396A external-priority patent/KR940008420B1/en
Application filed by Hanmi Pharmaceutical Co., Ltd. filed Critical Hanmi Pharmaceutical Co., Ltd.
Priority to JP4502607A priority Critical patent/JPH06509792A/en
Publication of WO1992012155A1 publication Critical patent/WO1992012155A1/en

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    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel quinolone compounds having more improved antimicrobial activity and their pharmaceutically acceptable salts, and processes for preparation thereof.
  • quinolone antimicrobial agents such as norfloxacin, pefloxacin, ofloxacin, ciprofloxacin, and sparfloxacin show excellent antimicrobial activities against gram negative bacteria, but show comparatively low activities against gram positive bacteria.
  • diazabicyclic compounds are reported as a substituent at 7-position of quinolone antimicrobial agents, and some examples are described in the following.
  • R 2 is a diazabicycloalkyl group selected from the following structural formula.
  • n 1, 2, or 3, m is 1 or 2, P is 0 or 1, Q is hydrogen or (C 1 ⁇ C 3 ) alkyl
  • R 1 is substituted or unsubstituted tert-alkyl group
  • Z is a N-heterocyclic group selected from the following structural formula.
  • n is an integer from 0 to 3).
  • the object of present invention is to provide more potent and improved quinolone antimicrobial agents than previously developed ones both against gram positive and negative bacteria by introducing novel amine substituents at C 7 -position of quinolone nucleus.
  • This invention relates to novel quinolone compounds of Formula(I) and thier pharmaceutically acceptable salts.
  • R 1 is hydrogen or protective group
  • R 2 is hydrogen, amino, alkylamino from one to four carbon atoms, hydroxy, alkoxy from one to four carbon atoms, mercapto, alkylthio from one to four carbon atome, or halogen,
  • R 3 is alkyl from one to four carbon atoms, alkenyl from two to four carbon atoms, cycloalkyl from three to six carbon atoms, haloalkyl, hydroxyalkyl from two to four carbon atoms, methoxy, amino, alkylamino from one to two carbon atoms, dimethylamino, or optionally substituted phenyl with more than one of halogen atoms or alkyl from one to three carbon atoms,
  • R 4 is hydrogen or alkyl from one to four carbon atoms
  • R 5 and R 7 are, same or different, hydrogen or alkyl from one to two carbon atoms
  • X is N or C-R 6 (wherein, R 6 is hydrogen, hydroxy, methyl, cyano, nitro, methoxy, halogen, or can form a bridge of the following Formula with R 3 ;
  • This invention includes a process for preparing a compound of the above Formula(I) by reacting a compound of Formula(II) with a compound of Formula (III) in the presence of a solvent and a base.
  • R 1 , R 2 , R 3 , X and Z are as defined above, and Y is halogen.
  • novel quinolone compound of the above Formula(I) in accordance with this invention has excellent antimicrobial activity both against gram positive and negative bacteria.
  • the compound of Formula(I) in this invention is characterized by introducing Z group, a novel 3,6-diazabicyclo[3.1.0] hexane derivative of the following Formula.
  • R 4 , R 5 and R 7 are as defined above, at C 7 -position of quinolone nucleus.
  • This invention also relates to the process for preparing a compound of Formula( ⁇ ) by reacting 3-quinolinecarboxylic acid derivative of Formula(II) with
  • the compound of Formula(I) is easily prepared by reacting a compound of Formula(II) with an amine of Formula(III) according to the following scheme,
  • R 1 , R 2 , R 3 , Z, X, and Y are as defined above.
  • a compound of Formula(II) can be prepared according to the reported methods or applying them, for example, Chem. Pharm. Bull., 34(10), 4098- 4102(1986), J. Med. Chem., 30(3), 504-509(1987), U.S .Patent No. 4,885,386, E.P.
  • a novel amine compound of Formula(III) is prepared in three ways according to the following reaction schemes.
  • R 5 and R 7 are as defined above,
  • R is amino protective group which can be removed by acid or base hydrolysis, or catalytic hydrogenation, and
  • R' is alkyl from one to four carbon atoms or amino protective group.
  • the maleimide compound of Formula(III-3) is obtained by reacting maleic anhydride compound of Formula(III- 1) with benzylamine derivatives (R-NH 2 ) and cyclizing the mixture of maleamic acid(III-2a + III-2b) with acetic anhydride-sodium acetate system, or by in situ reaction of maleic anhydride compound of Formula(III-1) with benzylamine devivatives(R-NH 2 ) and bisbenzylammonium sulfate. 1,3-Dipolar cycloaddition of (III-3) with alkyl azide(R'-N 3 ) affords a mixture of triazoline compounds(III-4a + III-4b). Subsequent thermolysis or photolysis reaction of the above mixture affords a compound of Formula(III-5) which the pyrrolidine ring and aziridine ring are fused together.
  • X' is halogen such as chloro or bromo
  • R, R 4 , and R 5 are as defined above.
  • 3-Pyrroline derivative (III-9) is reacted with chlorine gas, and the resulting chlorohydrine intermmediate is cyclized with base to obtain an epoxide compound of Formula(III-10).
  • Reaction of (III- 10) with an amine (R 4 -NH 2 ) affords a mixture of amino alcohols (III-11a+III-11b), which is subsequently cyclized to aziridine compound of Formula(III-6) with diethylazodicarboxylate(DEAD) and triphenylphosphine(Ph 3 P).
  • R' is an amino protective group
  • X" is a leaving group such as halogen, methanesulfonyl oxy, p-toluene-sulfonyloxy, diethylphosphoryl oxy, diethylthiophosphoryloxy, acetoxy, or alkoxy, R, R 4 , and R 5 are as defined above.
  • a compound of Formula(III-10) is reacted with sodium azide(NaN 3 ) to obtain a mixture of azido alcohols (III-12a+III- 12b), which is subsequently derivatized to a mixture of compounds (III-13a+III- 13b) having good leaving group. Reduction of the above mixture affords an aziridine compound of Formula(III-6a).
  • a compound of Formula(III-6a) is directly deprotected or another protective group is introduced at aziridine ring followed by selective deprotection to afford a novel amine compound of Formula(III).
  • a compound of Formula(I) is prepared by reacting a compound of Formula(II) with an amine of Formula(III).
  • proper reaction solvents include tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpymolidone, acetonitrile, water, alcohol(for example, methanol, ethanol, n-propanol, or iso-propanol), glycol monomethyl ether, pyridine, or a mixture of them.
  • This reaction can be carried out in the absence of solvent, but it is desirable to add some base in the reaction mixture if the solvent is not a basic solvent(ex. pyridine).
  • the base promotes the completion of reaction by reacting with hydrohalide formed from the reaction mixture.
  • Typical inorganic or organic base such as alkali metal hydroxide, alkali metal carbonate, organic amine and amidine, especially, triethylamine, 1,4-diazabicyclo[2.2.2] octane(DABCO), 1,8-diazabicyclo[5.4.0]unde-7-cene(DBU), 1,5-diazabicyclo[4.3.0] non-5-ene(DBN), or excess amount of amine(III) can be desirably used.
  • alkali metal hydroxide alkali metal carbonate
  • organic amine and amidine especially, triethylamine, 1,4-diazabicyclo[2.2.2] octane(DABCO), 1,8-diazabicyclo[5.4.0]unde-7-cene(DBU), 1,5-diazabicyclo[4.3.0] non-5-ene(DBN), or excess amount of amine(III) can be desirably used.
  • This reaction can be carried out at a temperature of 15 ⁇ 300oC , desirably at
  • This reaction can be carried out for several days, desirably for 1 ⁇ 24 hr. Typically, the higher reaction temperature reduces the reaction time.
  • the amine compound of Formula(III) can be used in the reaction in the form of an inorganic or organic salt.
  • inorganic or organic salt include hydrochloride, hydrobromide, sulfate, formate, acetate and oxalate.
  • one to six equivalent of amine compound of Formula(III) against quinoline carboxylic acid of Formula(II) is desirably used.
  • the compounds of the invention are therefore useful in the antibiotic treatment of susceptible bacterial infections in both humans and animals.
  • the compounds may be used in scrub solutions, for surface inhibition of bacterial growth, e.g., on counter surfaces, and the like.
  • Susceptible organisms generally include those gram positive and gram negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,
  • Salmonella Schigella, Serratia, Haemophilus, Brucella, and other organisms.
  • the in vitro activity spectrum of the compounds according to this invention was measured by two fold agar-dilution method using Mueller-Hinton agar. According to the standard procedure recommended by Japanese Society of
  • the MIC was defined as the lowest drug concentration which prevented visible bacterial growth.
  • the MIC of compounds according to the invention is listed in Table 1 compared with ciprofloxacin, and the test compounds are denoted as the number of
  • Test compound was administered orally and subcutaneously to ICR mouse weighed about 18g as 40mg/kg of dose, collected serum after 10, 20, 30, 45, 60, 90, 120, 150, 180, 240 min and urine for 24 hr after administration.
  • the pharmacokinetic parameters were determined by bioassay using E. coli 055 as a standard organism, and the results are denoted in Table 2.
  • the compounds of Formula(I) according to this invention are capable of forming pharmaceutically acceptable salts, herein the term
  • “pharmaceutically acceptable salts” means nontoxic acid addition and base salts formed by alkali metal, alkaline earth metal, or organic amines.
  • salts can be prepared in situ during the final isolation and purification of the compounds of Formula(I), or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively.
  • Representative acid addition salts in this case include hydrochloride, hydrobromide, sulfate, bisulfate, formate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tartarate, and ascorbate, and representative alkali metal and alkali earth metal salts include sodium, potassium, calcium, and magnesium salts.
  • Suitable organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
  • carboxyl protective group is intended to include all the reported protective groups such as alkyl of from one to four carbon atoms, cycloalkyl of from three to seven carbon atoms and benzyl group, and amino protective group include acyl, alkoxycarbonyl,
  • alkyl is intended to include both straight and branched carbon chains such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, and so on, alkenyl also include both straight and branched carbon chains such as ethenyl, propenyl, iso-propenyl, and so on.
  • haloalkyl is intended to include alkyl group substituted with more than one halogen atom which is same or different, and the term, halogen, include fluorine, chlorine, bromine and iodine.
  • halogen include fluorine, chlorine, bromine and iodine.
  • Asymmetric caibon atoms may be present in a substituent such as an alkyl group or fused caibon atoms, but all such isomers as well as mixtures thereof are intended to be included in the invention.
  • the compounds of this invention may also be formulated into compositions together with pharmaceutically acceptable carriers for parental injection, for oral administration in solid or liquid form, for rectal administration, for ointment, and the like.
  • compositions according to the invention for parental injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions or emulsions.
  • suitable nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil or sesame oil, and injectable organic esters such as ethyl oleate.
  • compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert carrier such as sucrose, lactose, dicalcium phosphate, cellulose, pectin, dextrin, gelatin or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert solid carriers, e.g., lubricating agents such as magnesium stearate.
  • the dosage form may also comprise buffering agents.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • compositions for rectal administration are preferably suppositories which may contain, in addition to active substance, excipients such as cocoa butter or a suppositiony wax.
  • Ointment preparations contain metal salts of a compound of
  • the carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water-soluble, oil-in-water emulsion which may be applied to an affected burn surface or infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • compositions of the invention may be varied so as to obtain an amount of active ingredient effective to achieve antibacterial activity in accordance with the desired method of administration.
  • the selected dosage level therfore depends upon the nature of the active compound administered, the route of administration, the desired duration of treatment and other factors. Generally, daily dosage levels of the compounds of Formula(I) of about 0.5 to about 500mg of active ingredient per kg of body weight are effective when administered orally to a mammalian patient suffering from an infection caused by a susceptable organism. If desired, the daily dose may be divided into multiple doses for administration, e.g., two or four times per day.
  • reaction mixture was heated to reflux for 3hr, cooled in an ice bath, and added 0.85ml of water, 0.85 ml of 15%-KOH solution, and 2.5ml of water, successively. Tetrahydrofuran was evaporated in vacuo, and the residue was extracted with 100ml of chloroform. The chloroform extract was washed with saturated sodium chloride solution, dried, filtered, and evaporated in vacuo to afford
  • the two vessels were connected by glass tube in order for the methyl azide gas evolved to be transferred into the maleimide solution, and NaOH trap was connected between them.
  • reaction solution was irradiated with 254nm UV lamp for 6hr.
  • reaction mixture was heated to reflux for 3hr, cooled in an ice bath, and added 0.85ml of water, 0.85ml of 15%-KOH solution, and 2.5ml of water, successively, at about 10oC .
  • Tetrahydrofuran was evaporated in vacuo, and the residue was extracted with 100 ml of chloroform.
  • the chloroform extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo.
  • the pH of the solution was adjusted to 9 ⁇ 10 by adding 20%-NaOH solution, extracted with 50ml of methylene chloride, and evaporated in vacuo. To the residue was added 5ml of 20%-NaOH solution and stirred overnight at room temperature.
  • reaction mixture was stirred for 8hr at room temperature, added 0.5 ml of water as dropwise, transferred the solution to separatoiy funnel, and washed with water. Benzene layer was separated, dried over magnesium sulfate and evaporated in vacuo.
  • reaction mixture was evaporated in vacuo, and the residue was used in the next step without further purification.
  • Example 12 9-Fluoro-2,3-dihydro-3-methyl- 10-( 1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[l,2,3,-de]- 1,4-benzoxazine-6-carboxylic acid
  • reaction mixture was cooled to room temperature, filtered the crystals formed, and washed successively with small amount of acetonitrile, water, and acetonitrile. It was recrystallized from N,N-dimethylformamide, and afforded 44mg(yield : 36%) of titled compound as a white solid.
  • reaction mixture was cooled to room temperature, solid was filtered and washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 55mg(yield : 39%) of titled compound as a yellow solid.
  • Example 21 7-(3,6-Diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro-1- ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
  • the reaction mixture was cooled, and obtained the crystal by filtration.
  • the crystal was dispersed in 10ml of methanol, filtered, and dried to afford
  • Example 36 1-Ethyl-7-(1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
  • the precipitate was obtained by filtration, the filtrate evaporated in vacuo, and added 3ml of methanol to the residue for crystallization.
  • the two crops of precipitate were combined, dispersed in 5ml of methanol, filtered, and dried to afford 79mg(yield : 59%) of titled compound as a pale green solid.
  • Example 45 to 47 illustrate pharmaceutical compositions containing the compounds of the invention as active ingredients.
  • Talc 1.5g The above components were blended with ethanol, granulated and filled into 100 capsules in accordance with conventional methods.
  • the above components were blended with ethanol, granulated and made into 100 tablets in a known manner.

Abstract

This invention relates to the novel quinolone compound of formula (I) having excellent antimicrobial activity both against gram positive and negative bacteria, its pharmaceutically acceptable salt, and the process for preparation thereof; wherein R1 is hydrogen or protective group, R2 is hydrogen, amino, alkylamino from one to four carbon atoms, hydroxy, alkoxy from one to four carbon atoms, mercapto, alkylthio from one to four carbon atoms, or halogen, R3 is alkyl from one to four carbon atoms, alkenyl from two to four carbon atoms, cycloalkyl from three to six carbon atoms, haloalkyl, hydroxyalkyl from two to four carbon atoms, methoxy, amino, alkylamino from one to two carbon atoms, dimethylamino, or optionally substituted phenyl with more than one of halogen atoms or alkyl from one to three carbon atoms, Z is an amine of formula (II), (wherein R4 is hydrogen or alkyl from one to four carbon atoms, R?5 and R7¿ are, same or different, hydrogen or alkyl from one to two carbon atoms), X is N or C-R6 (wherein R6 is hydrogen, hydroxy, methyl, cyano, nitro, methoxy, halogen, or can form a bridge of formula (a), (b), (c) or (d) with R3.

Description

NOVEL QUINOLONE COMPOUNDS AND PROCESSES FOR PREPARATION THEREOF BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to novel quinolone compounds having more improved antimicrobial activity and their pharmaceutically acceptable salts, and processes for preparation thereof.
Description of the Prior Art
Previously developed quinolone antimicrobial agents such as norfloxacin, pefloxacin, ofloxacin, ciprofloxacin, and sparfloxacin show excellent antimicrobial activities against gram negative bacteria, but show comparatively low activities against gram positive bacteria.
Moreover, a lot of resistant bacterial strains to these agents are also found clinically, demanding more potent and improved antimicrobial agents.
Recently, considerable effort for overcoming these problems and providing more improved quinolone antimicrobial agents has been made.
Various kinds of diazabicyclic compounds are reported as a substituent at 7-position of quinolone antimicrobial agents, and some examples are described in the following.
European Patent Application No. 215,650-A2 discloses compounds having the following structural formula,
Figure imgf000003_0001
wherein R2 is a diazabicycloalkyl group selected from the following structural formula.
Figure imgf000004_0001
(wherein n is 1, 2, or 3, m is 1 or 2, P is 0 or 1, Q is hydrogen or (C1 ~ C3) alkyl)
European Patent Application No. 266,576-A2 discloses compounds having the following structural formula,
Figure imgf000004_0002
wherein,
R1 is substituted or unsubstituted tert-alkyl group,
Z is a N-heterocyclic group selected from the following structural formula.
Figure imgf000005_0001
and
Figure imgf000005_0002
(wherein R2 is hydrogen or alkyl group, n is an integer from 0 to 3).
But the above mentioned diazabicycloamine derivatives didn't exhibit much improved properties in antimicrobial aspects compared to the previously developed ones.
SUMMARY OF THE INVENTION
The object of present invention is to provide more potent and improved quinolone antimicrobial agents than previously developed ones both against gram positive and negative bacteria by introducing novel amine substituents at C7-position of quinolone nucleus.
This invention relates to novel quinolone compounds of Formula(I) and thier pharmaceutically acceptable salts.
Figure imgf000005_0003
wherein,
R1 is hydrogen or protective group,
R2 is hydrogen, amino, alkylamino from one to four carbon atoms, hydroxy, alkoxy from one to four carbon atoms, mercapto, alkylthio from one to four carbon atome, or halogen,
R3 is alkyl from one to four carbon atoms, alkenyl from two to four carbon atoms, cycloalkyl from three to six carbon atoms, haloalkyl, hydroxyalkyl from two to four carbon atoms, methoxy, amino, alkylamino from one to two carbon atoms, dimethylamino, or optionally substituted phenyl with more than one of halogen atoms or alkyl from one to three carbon atoms,
Z is an amine of the following Formula,
Figure imgf000006_0002
(wherein, R4 is hydrogen or alkyl from one to four carbon atoms, R5 and R7 are, same or different, hydrogen or alkyl from one to two carbon atoms) X is N or C-R6 (wherein, R6 is hydrogen, hydroxy, methyl, cyano, nitro, methoxy, halogen, or can form a bridge of the following Formula with R3 ;
Figure imgf000006_0001
This invention includes a process for preparing a compound of the above Formula(I) by reacting a compound of Formula(II) with a compound of Formula (III) in the presence of a solvent and a base.
Figure imgf000007_0002
wherein, R1, R2, R3, X and Z are as defined above, and Y is halogen.
DETAILED DESCRIPTION OF THE INVENTION
The novel quinolone compound of the above Formula(I) in accordance with this invention has excellent antimicrobial activity both against gram positive and negative bacteria.
The compound of Formula(I) in this invention is characterized by introducing Z group, a novel 3,6-diazabicyclo[3.1.0] hexane derivative of the following Formula.
Figure imgf000007_0001
wherein R4, R5 and R7 are as defined above, at C7-position of quinolone nucleus.
This invention also relates to the process for preparing a compound of Formula(ι) by reacting 3-quinolinecarboxylic acid derivative of Formula(II) with
3,6-diazabicyclo[3.1.0] hexane derivative of Formula(III) in the presence or absence of solvent at a temperature of 15 to 300ºC,
Figure imgf000008_0001
wherein R1, R2, R3, Z, and X are as defined above, Y is halogen, and to the pharmaceutical composition containing one or more of the compound of Formula(I) or its pharmaceutically acceptable salt as an active ingredient
More particularly, the compound of Formula(I) is easily prepared by reacting a compound of Formula(II) with an amine of Formula(III) according to the following scheme,
Figure imgf000008_0002
wherein, R1, R2, R3, Z, X, and Y are as defined above. A compound of Formula(II) can be prepared according to the reported methods or applying them, for example, Chem. Pharm. Bull., 34(10), 4098- 4102(1986), J. Med. Chem., 30(3), 504-509(1987), U.S .Patent No. 4,885,386, E.P.
Publication No. 235,762, J.RPublication No. 7203085, G.B. Patent No. 2,057,440, and so on.
A novel amine compound of Formula(III) is prepared in three ways according to the following reaction schemes.
Figure imgf000009_0001
wherein,
R5 and R7 are as defined above,
R is amino protective group which can be removed by acid or base hydrolysis, or catalytic hydrogenation, and
R' is alkyl from one to four carbon atoms or amino protective group.
In the reaction sequence of Scheme A, the maleimide compound of Formula(III-3) is obtained by reacting maleic anhydride compound of Formula(III- 1) with benzylamine derivatives (R-NH2) and cyclizing the mixture of maleamic acid(III-2a + III-2b) with acetic anhydride-sodium acetate system, or by in situ reaction of maleic anhydride compound of Formula(III-1) with benzylamine devivatives(R-NH2) and bisbenzylammonium sulfate. 1,3-Dipolar cycloaddition of (III-3) with alkyl azide(R'-N3) affords a mixture of triazoline compounds(III-4a + III-4b). Subsequent thermolysis or photolysis reaction of the above mixture affords a compound of Formula(III-5) which the pyrrolidine ring and aziridine ring are fused together.
Reduction of (III-5) using lithium aluminium hydride affords a compound of Formula(III-6) which is deprotected by hydrolysis or hydrogenolysis to give a novel amine compound of Formula(III).
Figure imgf000011_0001
wherein,
X' is halogen such as chloro or bromo,
R, R4, and R5 are as defined above.
In the reaction sequence of Scheme B, a compound of Formula(III-8) (in the case of R5=H, it is commercially available, but in the case of R5=alkyl, it is prepared from (III- 1) through reduction and halogenation) is cyclized using an amine(R4-NH2) to afford a compound of Formula(III-9).
3-Pyrroline derivative (III-9) is reacted with chlorine gas, and the resulting chlorohydrine intermmediate is cyclized with base to obtain an epoxide compound of Formula(III-10). Reaction of (III- 10) with an amine (R4-NH2) affords a mixture of amino alcohols (III-11a+III-11b), which is subsequently cyclized to aziridine compound of Formula(III-6) with diethylazodicarboxylate(DEAD) and triphenylphosphine(Ph3P).
Deprotection of (III-6) finally affords a novel amine compound of
Formula(m).
Figure imgf000012_0001
wherein,
R' is an amino protective group,
X" is a leaving group such as halogen, methanesulfonyl oxy, p-toluene-sulfonyloxy, diethylphosphoryl oxy, diethylthiophosphoryloxy, acetoxy, or alkoxy, R, R4, and R5 are as defined above. In the reaction sequence of Scheme C, a compound of Formula(III-10) is reacted with sodium azide(NaN3) to obtain a mixture of azido alcohols (III-12a+III- 12b), which is subsequently derivatized to a mixture of compounds (III-13a+III- 13b) having good leaving group. Reduction of the above mixture affords an aziridine compound of Formula(III-6a).
A compound of Formula(III-6a) is directly deprotected or another protective group is introduced at aziridine ring followed by selective deprotection to afford a novel amine compound of Formula(III).
Thereafter, a compound of Formula(I) is prepared by reacting a compound of Formula(II) with an amine of Formula(III). Examples of proper reaction solvents include tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpymolidone, acetonitrile, water, alcohol(for example, methanol, ethanol, n-propanol, or iso-propanol), glycol monomethyl ether, pyridine, or a mixture of them.
This reaction can be carried out in the absence of solvent, but it is desirable to add some base in the reaction mixture if the solvent is not a basic solvent(ex. pyridine).
The base promotes the completion of reaction by reacting with hydrohalide formed from the reaction mixture.
Typical inorganic or organic base such as alkali metal hydroxide, alkali metal carbonate, organic amine and amidine, especially, triethylamine, 1,4-diazabicyclo[2.2.2] octane(DABCO), 1,8-diazabicyclo[5.4.0]unde-7-cene(DBU), 1,5-diazabicyclo[4.3.0] non-5-ene(DBN), or excess amount of amine(III) can be desirably used.
This reaction can be carried out at a temperature of 15 ~ 300ºC , desirably at
60 ~ 120ºC or reflux temperature of the solvent.
This reaction can be carried out for several days, desirably for 1 ~ 24 hr. Typically, the higher reaction temperature reduces the reaction time.
The amine compound of Formula(III) can be used in the reaction in the form of an inorganic or organic salt. Some examples of inorganic or organic salt include hydrochloride, hydrobromide, sulfate, formate, acetate and oxalate. In addition, one to six equivalent of amine compound of Formula(III) against quinoline carboxylic acid of Formula(II) is desirably used.
It has been proved form the following in vitro tests that the compounds of general Formula(I) in this invention possess potent antibacterial activity against a wide spectrum of gram positive and gram negative bacteria.
The compounds of the invention are therefore useful in the antibiotic treatment of susceptible bacterial infections in both humans and animals. In addition, the compounds may be used in scrub solutions, for surface inhibition of bacterial growth, e.g., on counter surfaces, and the like.
Susceptible organisms generally include those gram positive and gram negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,
Proteus, Citrobacter, Nisseria, Baccullus, Bacteroides, Peptococcus, Clostridium,
Salmonella, Schigella, Serratia, Haemophilus, Brucella, and other organisms.
The in vitro activity spectrum of the compounds according to this invention was measured by two fold agar-dilution method using Mueller-Hinton agar. According to the standard procedure recommended by Japanese Society of
Chemotheraphy[Chemotheraphy, 29(1), 76-79(1981)], an overnight culture of test organisms which was diluted for each bacterial inoculum to be contained about 104 colony forming unit (106 cells/ml) was inoculated onto drug-containing agar, and incubated for 18hr at 37ºC .
The MIC was defined as the lowest drug concentration which prevented visible bacterial growth.
The MIC of compounds according to the invention is listed in Table 1 compared with ciprofloxacin, and the test compounds are denoted as the number of
Examples. Test organisms
1. Streptococcus pyogenes 308A
2. Streptococcus pyogenes 77A
3. Streptococcus faecium MD 86 4. Staphylococcus aureus SG511
5. Staphylococcus aureus 285
6. Staphylococcus aureus 503
7. Escherichia coli 055
8. Escherichia coli DCO
9. Escherichia coli DC2
10. Escherichia coli TEM
11. Escherichia coli 1507E
12. Pseudomonas aeruginosa 9027
13. Pseudomonas aeruginosa 1592E 14. Pseudomonas aeruginosa 1771
15. Pseudomonas aeruginosa 1771M
16. Salmonella typhimurium
17. Klebsiella oxytoca 1082E
18. Klebsiella aerogenes 1522E 19. Enterobacter cloacae P99
20. Enterobacter cloacae 1321E
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Some pharmacokinetic parameters of the compound according to this invention was measured in mouse.
Test compound was administered orally and subcutaneously to ICR mouse weighed about 18g as 40mg/kg of dose, collected serum after 10, 20, 30, 45, 60, 90, 120, 150, 180, 240 min and urine for 24 hr after administration.
The pharmacokinetic parameters were determined by bioassay using E. coli 055 as a standard organism, and the results are denoted in Table 2.
Figure imgf000024_0001
PO : per os
SC : Subcutaneous
Cmax : maximum concentration in serum
Tmax : time for maximum concentration in serum
T1/2 : serum half life
AUC : area under curve
UR : urinary recovery In the one hand, the compounds of Formula(I) according to this invention are capable of forming pharmaceutically acceptable salts, herein the term
"pharmaceutically acceptable salts" means nontoxic acid addition and base salts formed by alkali metal, alkaline earth metal, or organic amines.
These salts can be prepared in situ during the final isolation and purification of the compounds of Formula(I), or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively.
Representative acid addition salts in this case include hydrochloride, hydrobromide, sulfate, bisulfate, formate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tartarate, and ascorbate, and representative alkali metal and alkali earth metal salts include sodium, potassium, calcium, and magnesium salts.
In addition, examples of suitable organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
Among the term, protective group, in this invention, carboxyl protective group is intended to include all the reported protective groups such as alkyl of from one to four carbon atoms, cycloalkyl of from three to seven carbon atoms and benzyl group, and amino protective group include acyl, alkoxycarbonyl,
(substituted)sulfonyl, (substituted) benzyloxycarbonyl, (substituted)benzyl, and so on.
The term, alkyl, is intended to include both straight and branched carbon chains such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, and so on, alkenyl also include both straight and branched carbon chains such as ethenyl, propenyl, iso-propenyl, and so on.
The term, haloalkyl, is intended to include alkyl group substituted with more than one halogen atom which is same or different, and the term, halogen, include fluorine, chlorine, bromine and iodine. Certain compounds of the invention exist in optically active form, especially pure D isomer, pure L isomer as well as mixtures thereof ;
including racemic mixtures, meso-isomer, dl-isomer, diastereomeric mixtures, are contemplated by the invention. Asymmetric caibon atoms may be present in a substituent such as an alkyl group or fused caibon atoms, but all such isomers as well as mixtures thereof are intended to be included in the invention.
The representative compounds of Formula(I) according to this invention are illustrated in the following.
(1) 1-Cyclopropyl-6-fluoro-7-(6-methyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(2) 1-Cyclopropyl-6,8-difluoro-7-(6-methyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salt.
(3) 5-Amino-1-cyclopropyl-6,8-difIuoro-7-(6-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxyIic acid and its salts.
(4) 1-Cyclopropyl-6-fluoro-7-(6-methyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its salts.
(5) 6,8-Difluoro-1 -(2,4-difluorophenyl)-7-(6-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(6) 1-Cyclopropyl-8-chloro-6-fluoro-7-(6-methyl-3,6-diazabicyclo[3.1.0]hexan- 3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(7) 9-Fluoro-2,3-dihydro-3-methyl-10-(6-methyl-3,6-diazabicyclo[3.1.0]hexan- 3-yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and its salts.
(8) 1-Cyclopropyl-6-fluoro-8-methoxy-7-(6-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yI)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(9) 1-Cyclopropyl-6-fluoro-7-(1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its salts.
(10) 1-Cyclopropyl-6-fluoro-7-(1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(11) 5-Amino-1-cyclopropyl-6,8-difluoro-7-(1,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(12) 9-Fluoro-2,3-dihydro-3-methyl-10-(1 ,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[1 ,2,3-de]-1 ,4-benzoxazine-6- carboxylic acid and its salts.
(13) 1-Cyclopropyl-6-fluoro-8-methoxy-7-( 1,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(14) 1-Cyclopropyl-6,8-difluoro-7-(1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexan- 3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(15) 1-Cyclopropyl-8-chloro-6-fluoro-7-(1 ,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(16) 1-Cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid and its salts.
(17) 1-Cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6-fluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and its salts.
(18) 1-Cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(19) 1-Cyclopropyl-8-chloro-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(20) 5-Amino-1-cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(21) 7-(3,6-Diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro-1-ethyl-1,4-dihydro-3- quinolinecarboxylic acid and its salts. (22) 9-Fluoro-2,3-dihydro-3-methyl-10-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-7- oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and its salts.
(23) 1-Cyclopropyl-6,8-difluoro-7-(1-methyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(24) 1-Cyclopropyl-8-chloιo-6-fluoro-7-(1-methyl-3,6-diazabicyclo[3.1.0]hexan- 3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(25) 5-Amino-1-cyclopropyl-6,8-difluoro-7-(1-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts,
(26) 1-Cyclopropyl-6-fluoro-7-(1-methyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its salts.
(27) 1-Cyclopropyl-6-fluoro-7-(1-methyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(28) 9-Fluoro-2,3-dihydro-3-methyl-10-(1-methyl-3,6-diazabicyclo[3.1.0]hexan- 3-yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and its salts.
(29) 6,8-Difluoro-1-(2,4-difluorophenyl)-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(30) 6,8-Difluoro-1 -(2,4-difluorophenyl)-7-(1-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(31) 6,8-Difluoro-1-(2,4-difluorophenyl)-7-(1,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(32) 1-Cyclopropyl-6,8-difluoro-7-(1,5-dimethyl-3,6-diazabicyclo[3.1.0jhexan- 3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(33) 1-Cyclopropyl-8-chloro-6-fluoro-7-(1,5-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts. (34) 5-Amino-1-cyclopropyl-6,8-difluoro-7-(1,5-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(35) 1-Cyclopropyl-7-(1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its salts.
(36) 1-Cyclopropyl-7-( 1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(37) 1-Ethyl-7-(1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(38) 9-Fluoro-2,3-dihydro-3-methyl-10-(1 ,5-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[1 ,2,3-de]-1 ,4-benzoxazine-6- carboxylic acid and its salts.
(39) 6,8-Difluoro-1-(2,4-difluorophenyl)-7-(1,5-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(40) 1-Cyclopropyl-6,8-difluoro-7-(1,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(41) 8-Chloro-1-cyclopropyl-6-fluoro-7-( 1,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(42) 5-Amino-1-cyclopropyl-6,8-difluoro-7-(1,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(43) 1-Cyclopropyl-6-flouro-7-(1,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its salts.
(44) 1-Cyclopropyl-6-fluoro-7-(1,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
(45) 1-Enthyl-6,8-difluoro-7-(1 ,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexan-3- yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.
The compounds of this invention may also be formulated into compositions together with pharmaceutically acceptable carriers for parental injection, for oral administration in solid or liquid form, for rectal administration, for ointment, and the like.
Compositions according to the invention for parental injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of suitable nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil or sesame oil, and injectable organic esters such as ethyl oleate.
Such compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert carrier such as sucrose, lactose, dicalcium phosphate, cellulose, pectin, dextrin, gelatin or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert solid carriers, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Compositions for rectal administration are preferably suppositories which may contain, in addition to active substance, excipients such as cocoa butter or a suppositiony wax. Ointment preparations contain metal salts of a compound of
Formula(I) with a pharmaceutically acceptable carrier. The carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water-soluble, oil-in-water emulsion which may be applied to an affected burn surface or infected surface with a minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient effective to achieve antibacterial activity in accordance with the desired method of administration.
The selected dosage level therfore depends upon the nature of the active compound administered, the route of administration, the desired duration of treatment and other factors. Generally, daily dosage levels of the compounds of Formula(I) of about 0.5 to about 500mg of active ingredient per kg of body weight are effective when administered orally to a mammalian patient suffering from an infection caused by a susceptable organism. If desired, the daily dose may be divided into multiple doses for administration, e.g., two or four times per day.
The following examples illustrate this invention in more detail, but are not to be construed as limiting its scope.
Preparation 1 N-Benzylmaleamic Acid
To a stirred solution of 9.8g(0.10 M) of maleic anhydride in 150ml of methylene chloride was added 10.7g(0.10 mole) of benzylamine as dropwise for 30 min at room temperature. The reaction mixture was stirred for 3hr at room temperature, filtered, washed with methylene chloride, and dried to afford 17.8g(yield : 87%) of titled compound as a white crystalline solid,
m. p. : 135 ~ 136ºC 1H-NMR(CDCl3) : δ 4.2(s, 2H), 6.0 ~ 7.9,(m, 7H), 9.7(s, 1H),
13.0 ~ 16.0(broad s, 1H).
Preparation 2 N-Benzylmaleimide
A mixture of 5g(24 mM) of N-benzylmaleamic acid and 1.2g of sodium acetate in 12ml of acetic anhydride was stirred for 1.5 hr at 95 ~ 100ºC . The reaction mixutre was poured into 50g of crushed ice and stirred mechanically for 2hr.
Aqueous layer was decanted, 500ml of ether was added to the dark- brownish residue, and stirred for 20 min. The insoluble dark-brownish solid was removed by filtration, and the filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated in vacuo.
The residue was recrystallized from methanol, and afforded 2g(yield : 44%) of titled compound as a light yellow crystalline solid.
m. p. : 67 ~ 68ºC
1H-NMR(CDCl3) : δ 4.6(s, 2H), 6.6(s, 2H), 7.3(s, 5H).
Preparation 3 2-Methyl-2,3,4,7-tetraazabicyclo[3.3.0]-oct-3-en-6,8-dione
To a 1 l 3-neck flask equipped with thermometer, dropping funnel and condenser were added 8.46g(0.13M) of sodium azide and 21g of NaHCO3- NA2CO3(1 : 1 mole ratio) in 480 ml of H2O, and heated in an oil bath. In another vessel was dissolved 4g(21.4mM) of maleimide in 100ml of toluene and cooled to -
50 ~ -78ºC in a dry ice-acetone bath. The two vessels were connected by glass tube in order for the methyl azide gas evolved to be transferred into the N-benzylmaleimide solution, and NaOH trap was connected between them.
To the basic solution was dropped 37.2 ml(0.4M) of dimethyl sulfate for 40min at 75 ~ 85ºC and removed the dry ice-acetone bath from the reaction solution.
The reaction mixture was stood overnight at room temperature, and evaporated in vacuo. The residue was filtered, washed with ether, and dried in vacuo to afford 4.8g (yield : 93%) of titled compound as a white crystalline solid. m. p. : 139ºC
1H-NMR(CDCl3) : δ 3.4(s, 3H), 4.1(d, 1H, J=12.0Hz), 4.6(s, 2H),
5.4(d, 1H, J=12.0Hz), 7.2(s, 5H).
Preparation 4 3-Benzyl-6-methyl-3,6-diazabicyclo[3.1.0]hexan-2,4-dione
[ Method 1 : Photolysis reaction ]
To a 500ml of quartz reactor was added 4.0g(12.3mM) of 2-methyl-2,3,4,7-tetraazabicyclo[3.3.0]-oct-3-en-6,8-dione in 300ml of 1,4-dioxane and N2 gas was bubbled for 15 min. The reaction solution was irradiated with 254nm UV lamp for 4hr. The solvent was evaporated in vacuo, and the residue was recrystallized from isopropyl ether to afford 2.2g(yield : 62%) of titled compound as a light yellow solid.
m. p. : 78 ~ 85ºC
1H-NMR(CDCl3) : δ 2.4(s, 3H), 2.8(s, 2H), 4.5(s, 2H), 7.3(s, 5H).
[ Method 2 : Thermolysis reaction ]
A mixture of 13.7g (56.1 mM) of 2-methyl-2,3,4,7-tetraazabicyclo[3.3.0] oct-3-en-6,8-dione in 300ml xylene(mixture of ortho-, meta- and para-isomer) was heated to reflux for 7hr.
Xylene was evaporated in vacuo, the residue was partly purified by column chromatography (Eluent ; ethyl acetate : n-hexane = 1 : 3), and further purified by 3 to 4 times of recrystallization from isopropyl ether to afford 3.6g (yield : 30%) of titled compound as a light yellow solid.
m.p. and 1H-NMR data are same as in method 1.
Preparation 5 3-Benzyl-6-methyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred solution of 1.76g (46.3mM) of lithium aluminium hydride in 50 ml of dry tetrahydrofuran was added as dropwise 5g(23.1mM) of 3-benzyl-6- methyl-3,6-diazabicyclo[3.1.0] hexane-2,4-dione in 15ml of dry tetrahydrofuran at room temperature.
The reaction mixture was heated to reflux for 3hr, cooled in an ice bath, and added 0.85ml of water, 0.85 ml of 15%-KOH solution, and 2.5ml of water, successively. Tetrahydrofuran was evaporated in vacuo, and the residue was extracted with 100ml of chloroform. The chloroform extract was washed with saturated sodium chloride solution, dried, filtered, and evaporated in vacuo to afford
4.0g of brownish residue.
The residue was purified by column chromatopraphy(Eluent ; ethanol : ethyl acetate = 1 : 4), and afforded 1.44g(yield : 33%) of titled compound as a yellow oil. 1H-NMR(CDCl3) : δ 2.0(s, 2H), 2.2(s, 3H), 2.3(dd, 2H), 3.1(d, 2H, J=12.0Hz),
3.6(s, 2H), 7.3(s, 5H).
Preparation 6 6-Methyl-3,6-diazabicyclo[3.1.0]hexane · acetate
A mixture of 1.0g (5.3 mM) of 3-benzyl-6-methyl-3,6-diazabicyclo[3.1.0] hexane, 0.32g (5.3mM) of acetic acid and 1.0g of 10% Pd-C catalyst in 100ml of methanol was hydrogenated for Ihr at room temperature under 60 psi of H2 pressure.
The reaction mixutre was filtered through celite pad, and evaporated in vacuo to afford 0.78g(yield : 93%) of titled compound as a pale brown semi-solid. 1H-NMR(CDCl3) : δ 2.0(s, 3H), 2.1(s, 2H), 2.3(s, 3H), 2.8(d, 2H, J=12.0Hz),
3.2(d, 2H, J=12.0Hz), 7.4(s, 1H), 8.2(broad s, 2H).
Preparation 7 Mixture of 2-methyl-5-benzylmaleamic acid and 3-methyl- 5-benzylmaleamic acid (1 : 1 mixture)
To a stirred solution of 11.2g (0.1M) of citraconic anhydride in 150ml of methylene chloride was added 10.7g(0.10M) of benzylamine as dropwise for 30min at room temperature. The reaction mixture was stirred for 3hr at room temperature, filtered, washed with 50ml of methylene chloride, and dried to afford 17.6g (yield : 80%) of titled compound as a white crystalline solid.
m. p. : 103 ~ 105ºC
1H-NMR(DMSO-d6) : δ 1.9(s, 3H), 4.3(d, 2H), 5.7(s, 1/2H), 6.1(s, 1/2H),
7.3(s, 5H), 8.5(broad s, 1/2H), 8.9(broad s, 1/2H).
Preparation 8 1-Benzyl-3-methylmaleimide
A mixture of 8g(36.5 mM) of 2- and 3-methyl-5-benzylmaleamic acid(l : 1 mixture, compound of preparation 7) and 1.6g of sodium acetate in 16ml of acetic anhydride was stirred for 1hr at 100 ~ 110ºC . The reaction mixture was poured into 60g of crushed ice, and stirred mechanically for 1hr.
Aqueous layer was decanted, 500ml of ether was added to the dark-brownish residue, and stirred for 10 min. The insoluble dark-brownish solid was removed by filtration, and the filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated in vacuo.
The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 2.9g (yield : 40%) of titled compound as a yellow oil.
1H-NMR(CDCl3) : δ 2.0(s, 3H), 4.6(s, 2H), 6.3(s, 1H), 7.3(s, 5H). Preparation 9 Mixture of 1,2-dimethyl-2,3,4,7-tetraazabicyclo[3.3.0] oct- 3-en-6,8-dione and 1,4-dimethyl-2,3,4,7-tetraazabicyclo [3.3.0] oct-3-en-6,8-dione
To a 3 l 3-neck flask equipped with thermometer, dropping funnel and condenser were added 56.2g(0.86M) of sodium azide and 86.4g of NaHCO3-Na2CO3(1 : 1 mole ratio) in 1.8 l of H2O, and heated in an oil bath.
In another vessel was dissolved 18g(89.6mM) of 1 -benzyl-3-methyl maleimide in 360ml of toluene and cooled to -50 ~ -78ºC in a dry ice- acetone bath.
The two vessels were connected by glass tube in order for the methyl azide gas evolved to be transferred into the maleimide solution, and NaOH trap was connected between them.
To the basic solution was dropped 203g(1.6M) of dimethyl sulfate for 1hr
20 min at 75 ~ 85ºC and removed the dry ice-acetone bath from the reaction solution.
The reaction mixture was stood overnight at 80 ~ 85ºC and evaporated in vacuo. The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 21g (yield : 91 %) of titled compound as a pale yellow solid.
m. p. : 86 ~ 88ºC
1H-NMR(CDCl3) : δ 1.5(s, 3/5 × 3H), 1.6(s, 2/5 × 3H), 3.3(s, 3/5 × 2H),
3.4(s, 2/5 × 2H), 3.8(s, 2/5 × 1H), 4.6(s, 2H),
5.1(s, 3/5 × 1H), 7.3(s, 5H).
Preparation 10 3-Benzyl-1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexan-2,4- dione
[ Method 1. Photolysis reaction ]
To a 500ml of Quartz reactor was added 4.0g(11.6mM) of triazoline compound(preparation 9) in 300ml of 1,4-dioxane and N2 gas was bubbled for 15 min.
The reaction solution was irradiated with 254nm UV lamp for 6hr. The solvent was evaporated in vacuo, and the residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3) to afford 2.3g(yield : 65%) of titled compound as a pale yellow crystalline solid,
m. p. : 79 ~ 81ºC
1H-NMR(CDCl3) : δ 1.5(s, 1/4 × 3H), 1.6(s, 3/4 × 3H), 2.3(s, 1H),
2.4(s, 3/4 × 3H), 2.5(s, 1/4 × 3H), 4.6(s, 2H),
7.3(s, 5H). [ Method 2. Thermolysis reaction ]
A mixture of 10.0g (29mM) of triazoline compound (preparation 9) in 300 ml of diphenyl ether was stirred for 6hr at 170 ~ 180ºC , and evaporated in vacuo to remove diphenyl ether. The residue was purified by column chromatogrphy(Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 6.7g(yield :
75%) of titled compound as a light yellow solid.
m. p. and 1H-NMR date are same as in method 1.
Preparation 11 3-Benzyl-1 ,6-dimethyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred solution of 2.0g (52.6mM) of lithium aluminium hydride in 100 ml dry tetrahydrofuran was added as dropwise 5.0g (21.7mM) of 3-benzyl-1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexan-2,4-dione in 25ml of dry tetrahydrofuran at room temperature.
The reaction mixture was heated to reflux for 3hr, cooled in an ice bath, and added 0.85ml of water, 0.85ml of 15%-KOH solution, and 2.5ml of water, successively, at about 10ºC .
Tetrahydrofuran was evaporated in vacuo, and the residue was extracted with 100 ml of chloroform. The chloroform extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo.
The yellow residue was purified by column chromatography(Eluent ; ethanol : ethyl acetate = 1 : 4), and afforded 2.2g (yield : 50%) of titled compound as a light yellow oil.
1H-NMR(CDCl3) : δ 1.3(s, 3H), 1.7(s, 1H), 2.1 ~ 2.6(m, 2H),
2.3(s, 3H), 2.8 ~ 3.2(m, 2H), 3.6(s, 2H), 7.3(s, 5H).
Preparation 12 1,6-Dimethyl-3,6-diazabicyclo[3.1.0]hexane · acetate
A mixture of 1.0g(5.0mM) of 3-benzyl- 1,6-dimethyl-3,6-diazabicyclo [3.1.0]hexane, 0.30g(5.0mM) of acetic acid and 1.0g of 10% Pd-C catalyst in 100 ml of methanol was hydrogenated for 1.5hr at room temperature under 60 psi of H2 pressure.
The reaction mixture was filtered through celite pad, and evaporated in vacuo to afford 0.80g(yield : 95%) of titled compound as a light yellow semi-solid. 1H-NMR(CDCl3) : δ 1.3(s, 3H), 1.9(s, 4H), 2.3(s, 3H),
2.9(dd, 4H, J=12Hz), 8.5(s, 1H).
Preparation 13 1-Benzyl-3-pyrroline
To a stirred solution of 12.5g(0.10M) of cis-1,4-dichloro-2-butene in 400ml of benzene was added 33.2g(0.31M) of benzyl amine as dropwise at room temperature. The reaction mixture was stirred for 1 hr and stood overnight. The solid was removed by filtration, and filtrate was washed with water, dried over magnesium sulfate, and evaporated in vacuo.
The residue was purified by column chromatography (Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 13.5g(yield : 85%) of titled compound as a light yellow oil.
1H-NMR(CDCl3) : δ 3.4(s, 4H), 3.7(s, 2H), 5.8(s, 2H), 7.2(s, 5H).
Preparation 14 1-Benzyl-3,4-epoxypyrrolidine
To a stirred solution of 16g(0.1M) of 1-benzyl-3-pyrroline in 100ml of water and 10ml of cone, hydrochloric acid was bubbled chlorine gas for 30min at room temperature. The pH of the solution was adjusted to 9 ~ 10 with 20%-NaOH solution, extracted with 500ml of methylene chloride, and evaporated in vacuo.
To the residue was added 100ml of 20%-NaOH solution, and the resulting solution was stirred for overnight. It was extracted with 500mZ of methylene chloride, dried, and evaporated in vacuo. The residue was purified by column chromatography (Eluent ; ethyl acetate : n-hexane = 2 : 1), and afforded 11.5g(yield : 66%) of titled compound as a light brownish oil. 1H-NMR(CDCl3) : δ 2.5(d, 2H, J=12Hz), 3.2(d, 2H, J=12Hz),
3.5(s, 2H), 3.7(s, 2H), 7.3(s, 5H).
Preparation 15 1-Benzyl-trans-4-azido-3-hydroxypyrrolidine
To a stirred solution of 6.0g (34 mM) of 1-benzyl-3,4-epoxypyrrolidine in
100ml of acetone and 100ml of distilled water was added 13.4g(0.21M) of sodium azide at room temperature. The reaction mixture was refluxed overnight, extracted with 2 × 200ml of chloroform, and dried over magnesium sulfate.
It was filtered, evaporated in vacuo, and purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 1) to afford 6.8g (yield :
92%) of titled compound as a dark brownish oil.
1H-NMR(CDCl3) : δ 2.1 ~ 3.3(m, 5H), 3.6(s, 2H), 3.5 ~ 3.9(m, 1H),
4.1 ~ 4.3(m, 1H), 7.3(s, 5H). Preparation 16 1-Benzyl-trans-4-azido-3-mesyloxy-pyrrolidine
To a stirred solution of 5.0g (23mM) of 1-benzyl-trans-4-azido-3-hydro xypyrrolidine in 150ml of dry benzene was added 3.0g(30mM) of triethylamine in an ice-bath, and added 3.2g(28mM) of methanesulfonyl chloride in 20ml of dry benzene as dropwise for 10min.
The reaction mixture was stirred for 2hr, and added 1 ml of water to it, transferred to separatoiy funnel, and washed with water. The benzene layer was collected, dried, and evaporated in vacuo. The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 6.4g(yield : 95%) of titled compound as a dark brownish oil.
1H-NMR(CDCl3) : δ 2.4 ~ 3.2(m, 4H), 3.0(s, 3H), 3.6(s, 2H),
3.9 ~ 4.2(m, 1H), 4.8 ~ 5.1(m, 1H), 7.3(s, 5H). Preparation 17 3-Benzyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred solution of 1.0g (3.4mM) of 1-benzyl-trans-4-azido-3- mesyloxypyrrolidine in 30ml of dry ether was added 0.25g(6.8mM) of lithium aluminium hydride as portionwise at room temperature.
The reaction mixture was stirred for 2hr at room temperature, and added
0.15ml of water, 0.5ml of 15%-KOH solution, 0.5ml of water, and 20ml of ether- acetone(1 : 1, v/v), successively. The resulting solution was filtered, dried over magnesium sulfate, and evaporated in vacuo.
The residue was purified by column chromatography(Eluent ; ethanol : ethyl acetate = 1 : 3), and afforded 0.5g (yield : 85%) of titled compound as a yellow oil. 1H-NMR(CDCl3) : δ 1.8(broad s, 1H), 2.3(d, 2H, J=10Hz), 2.4(s, 2H),
3.1(d, 2H, J=10Hz), 3.6(s, 2H), 7.2(s, 5H).
Preparation 18 3,6-Diazabicyclo[3.1.0]hexane
A mixture of 0.5g (2.9mM) of 3-benzyl-3,6-diazabicyclo[3.1.0]hexane, 170 μl(2.9mM) of acetic acid and 0.5g of 10% Pd-C catalyst in 60ml of methanol was hydrogenated for 1hr at room temperature under 50 psi of H2 pressure.
The reaction mixture was filtered through celite pad, evaporated in vacuo and afforded 0.39g of titled compound as a crude acetic acid salt. It was purified by column chromatography(Eluent ; methanol : 40%-methylamine = 24 : 1), and afforded 0.12g(yield : 45%) of titled compound as a colorless oil.
1H-NMR(CDCl3) : δ 1.4(s, 2H), 2.5(s, 2H), 2.9(q, 4H, J=12Hz).
Preparation 19 3-Benzyl-6-methoxycarbonyl-3,6-diazabicyclo[3.1.0]hexane To a stirred solution of 3.5g(20mM) of 3-benzyl-3,6-diazabicyclo
[3.1.0]hexane in 100ml of dry benzene were added 2.4g(24mM) of triethylamine and 2.1g(22mM) of methyl chloroformate in 20ml of dry benzene as dropwise for 15min at room temperature.
The reaction mixture was stirred for 2.5hr at room temperature and filtered. The filtrate was washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 4.3g(yield : 92%) of titled compound as a dark brownish oil.
1H-NMR(CDCl3) : δ 2.3(d, 2H, J=10Hz), 2.9(s, 2H), 3.3(d, 2H, J=10Hz),
3.6(s, 2H), 3.7(s, 3H), 7.3(s, 5H).
Preparation 20 6-Methoxycarbonyl-3,6-diazabicyclo[3.1.0]hexane
A mixture of 1.5g(6.5mM) of 3-benzyl-6-methoxycarbonyl-3,6-diazabicyclo[3.1.0]hexane and 0.75g of 10% Pd-C catalyst in 100ml of methanol was hydrogenated for 4.5hr at room temperature under 50 psi of H2 pressure.
The reaction mixture was filtered through celite pad, evaporated in vacuo, and purified by column chromatography (Eluent ; ethanol : ethyl acetate = 1 : 3) to afford 0.60g(yield ; 65%) of titled compound as a white solid.
m. p. : 85ºC
1H-NMR(CDCl3) : δ 1.3(broad s, 1H), 2.7(s, 2H), 3.3(d, 2H, J=12Hz),
3.6(s, 2H), 5.6(d, 2H, J=12Hz).
Preparation 21 3,6-Diazabicyclo[3.1.0]hexane · acetate
To a stirred solution of 1.5 g (11mM) of 6-methoxycarbonyl-3,6-diazabicyclo[3.1.0]hexane in 35ml of methanol was added 3g of sodium hydroxide, and stirred overnight at 70 ~ 80ºC . The reaction mixture was cooled in an ice bath, added 4.5g of acetic acid as dropwise and evaporated in vacuo. The residue was extracted with 100ml of chloroform, and evaporated in vacuo to afford 1.34g(yield : 88%) of titled compound as a semi-solid.
1H-NMR(CDCl3) : δ 1.9(s, 3H), 2.7(s, 2H), 3.0(q, 4H, J=12Hz),
3.4(s, 2H), 5.6(broad s, 1H). Preparation 22 cis-1,4-Dihydroxy-2-methyl-2-butene
To a stirred solution of 6.7g (0.18M) of lithium aluminium hydride in 300ml of dry tetrahydrofuran was added 10.0g(0.089M) of citraconic anhydride as dropwise at -20 ~ -10ºC . The reaction mixture was stirred for 1hr at -20 ~ -10ºC , adjusted pH of the solution as 7 ~ 8 with 30%-H2SO4 solution, filtered, and washed with 300ml of ether-acetone(1 : 1, v/v) mixture.
The combined filtrate was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography(Eluent
; ethyl acetate), and afforded 1.1g(yield : 12%) of titled compound as a yellow oil. 1H-NMR(CDCl3) : δ 1.7(s, 3H), 3.2 ~ 3.8(m, 2H), 3.9 ~ 4.2(m, 4H),
5.5(t, 1H, J=8Hz).
Preparation 23 cis-1,4-dibromo-2-methyl-2-butene
To a stirred solution of 1.0g (9.8mM) of cis-1,4-dihydroxy-2-methyl-2-butene and 2.3g(23mM) of triethylamine in 30ml of dry methylene chloride was added 5.9g(22mM) of phosphorous tribromide as dropwise in an ice bath.
The reaction mixture was stirred for 1.5hr, added 1ml of water, and transferred it to separatoiy funnel. Organic layer was washed with 10ml of water, separated, and dried. The solution was filtered, evaporated in vacuo, and the residue was purified by column chromatography(Eluent : ethyl acetate : n-hexane =
1 : 4) to afford 1.5g(yield : 67%) of titled compound as a pale yellow oil.
1H-NMR(CDCl3) : δ 1.9(s, 3H), 4.0 ~ 4.2(m, 4H), 5.6(t, 1H).
Preparation 24 1-Benzyl-3-methyl-3-pyrroline
To a stirred solution of 3.0g(13mM) of cis-1,4-dibromo-2-methyl-2-butene in 120ml of benzene was dropped 4.4g(41mM) of benzylamine at room temperature, and stirred for 30min. The resulting solution was stood overnight and the precipitate was removed by filtration.
The filtrate was washed with water, dried, and evaporated in vacuo. The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane =
1 : 3), and afforded 1.6g(yield : 70%) of titled compound as a yellow oil.
1H-NMR(CDCl3) : δ 1.7(s, 3H), 3.4(s, 4H), 3.7(s, 2H), 5.4(s, 1H), 7.3(s, 5H). Preparation 25 1-Benzyl-3,4-epoxy-3-methylpyrrolidine
To a stirred solution of 1.0g(5.7mM) of 1-benzyl-3-methyl-3-pyrroline in 10 mlf water and 1 ml of cone, hydrochloric acid was bubbled chlorine gas for 20min at room temperature.
The pH of the solution was adjusted to 9 ~ 10 by adding 20%-NaOH solution, extracted with 50ml of methylene chloride, and evaporated in vacuo. To the residue was added 5ml of 20%-NaOH solution and stirred overnight at room temperature.
The resulting solution was extracted with 2 × 50 ml of methylene chloride and the extract was dried and evaporated in vacuo. The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 2 : 1), and afforded
0.68g(yield : 62%) of titled compound as a yellow-brownish oil.
1H-NMR(CDCl3) : δ 1.5(s, 3H), 2.2 ~ 2.7(m, 2H), 3.9 ~ 3.3(m, 2H),
3.4(s, 1H), 3.7(s, 2H), 7.3(s, 5H). Preparation 26 Mixture of 1-benzyl-trans-4-azido-3-hydroxy-3 methylpyrrolidine and 1-benzyl-trans-4-azido-3-hydroxy-4-methylpyrrolidine
To a stirred solution of 1.0g(5.3mM) of l-benzyl-3,4-epoxy-3-methylpyrrolidine in 30ml of N,N-dimethylformamide were added 1.0g(15mM) of sodium azide and 0.03g(0.56mM) of ammonium chloride, and stirred overnight at 75 ~ 80ºC .
To the reaction mixture was added 30ml of chloroform, filtered, and the filtrate was evaporated in vacuo. To the residue was added 50ml of chloroform again, and filtered.
The filtrate was evaporated in vacuo, and the residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 1) to afford
0.92g(yield : 75%) of titled compound as a red-brownish oil.
1H-NMR(CDCl3) : δ 1.3(s, 3H), 2.1 ~ 3.4(m, 5H), 3.6(s, 2H),
3.8 ~ 4.1(m, 1H), 7.3(s, 5H).
Preparation 27 Mixture of 1-benzyl-trans-4-azido-3-mesyloxy-3-methylpyrrolidine and 1-benzyl-trans-4-azido-3-mesyloxy-4- methyl pyrrolidine
To a stiired solution of 2.0g(8.6mM) of azido alcohol(compound from preparation 26) in 60ml of dry benzene were added 1.1g(11mM) of triethylamine and 1.2g(10mM) of metiianesulfonyl chloride in 10ml of dry benzene for 5 min at 0
- 512.
The reaction mixture was stirred for 8hr at room temperature, added 0.5 ml of water as dropwise, transferred the solution to separatoiy funnel, and washed with water. Benzene layer was separated, dried over magnesium sulfate and evaporated in vacuo.
The residue was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 5), and afforded 1.7g(yield : 65%) of titled compound as a red-brownish oil.
1H-NMR(CDCl3) : δ 1.4(s, 3H), 2.5 ~ 3.5(m, 4H), 3.0(s, 3H),
3.6(s, 2H), 4.6 ~ 4.9(m, 1H), 7.3(s, 5H).
Preparation 28 3-Benzyl-1-methyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred solution of 1.0g(3.2mM) of azido mesylate(compound from preparation 27) in 30ml of dry ether was added 0.24g(6.5mM) of lithium aluminium hydride as portionwise at room temperature. The reaction mixture was stirred for
4hr at room temperature, and added 0.15mZ of water, 0.5ml of 15%-KOH solution,
0.5 ml of water, and 30ml of ether-acetone(1 : 1, v/v), successively.
The resulting solution was filtered, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography(Eluent ; ethanol : ethyl acetate = 1 : 5), and afforded 0.46g(yield : 76%) of titled compound as a yellow oil.
1H-NMR(CDCl3) : δ 1.2(s, 3H), 1.8(broad s, 1H), 2.2(t, 2H, J=10Hz),
2.9(t, 2H, J=10Hz), 3.6(s, 2H), 7.3(s, 5H).
Preparation 29 1-Methyl-3,6-diazabicyclo[3.1.0]hexane · acetate
A mixture of 0.5g(2.7mM) of 3-benzyl-1-methyl-3,6-diazabicyclo[3.1.0] hexane, 157/4(2.7mM) of acetic acid and 0.5g of 10% Pd-C catalyst in 60ml of methanol was hydrogenated for 1.5hr at room temperature under 50 psi of H2 pressure.
The reaction mixture was filtered through celite pad, and evaporated in vacuo to afford 0.38g (yield : 91%) of titled compound as an oil.
1H-NMR(D2O) : δ 1.3(s, 3H), 1.8(s, 3H), 2.7(s, 1H), 3.2 ~ 3.4(m, 4H).
Preparation 30 1-Benzyl-trans-3-hydroxy-4-methylaminopyrrolidine
To a stirred solution of 1.0g(5.7mM) of 1-benzyl-3,4-epoxypyιrolidine in 5 ml of 1,4-dioxane was added 25 ml of 40%-methylamine solution, and stirred overnight at 40 ~ 45ºC. The reaction mixture was evaporated in vacuo, added 30 ml of chloroform to it, dried over magnesium sulfate, and filtered.
The filtrate was evaporated in vacuo, and afforded 1.1g(yield : 94%) of titled compound as a yellow-brownish oil.
1H-NMR(CDCl3) : δ 2.2 ~ 3.2(m, 7H), 2.3(s, 3H), 3.6(s, 2H),
3.8 ~ 4.1(m, 1H), 7.3(s, 5H).
Preparation 31 3-Benzyl-6-methyl-3,6-diazabicyclo[3.1.0] hexane
To a stirred solution of 2.0g(9.7mM) of 1-benzyl-trans-3-hydroxy-4-methylaminopyirolidine in 25 ml of dry tetrahydrofuran was added 3.1g(12mM) of triphenylphosphine at 0 ~ 5ºC. To the above solution was added 1.85ml (12mM) of diethylazodicarboxylate(DEAD) and stirred for 1hr at 0 ~ 5ºC and 7hr at room temperature.
The resulting solution was evaporated in vacuo, added 30ml of ethyl acetate-pet. ether(1 : 1, v/v) to it, and the precipitate was removed by filtration.
The filtrate was evaporated in vacuo, and the residue was purified by column chromatography(Eluent ; ethanol : ethyl acetate = 1 : 3) to afford
1.25g(yield : 69%) of titled compound as a red-brownish oil.
1H-NMR(CDCl3) : δ 2.0(s, 2H), 2.2(s, 3H), 2.3(dd, 2H), 3.1(d, 2H, J=12Hz),
3.6(s, 2H), 7.3(s, 5H).
Preparation 32 Mixture of 1-Benzyl-trans-4-methylamino-3-hydroxy-3- methylpyrrolidine and 1-benzyl-trans-4-methylamino-3- hydroxy-4-methylpyrrolidine
To a stirred solution of 1.0g(5.3mM) of 1-benzyl-3,4-epoxy-3-methylpyrrolidine in 5ml of 1,4-dioxane was added 30ml of 40%-methylamine solution and stirred overnight at 50 ~ 60ºC . The reaction solution was evaporated in vacuo, added 30ml of chloroform to it, and dried over magensium sulfate.
It was filtered and the filtrate was evaporated in vacuo to afford 1.1g(yield :
92%) of titled compound as a yellow-brownish oil.
1H-NMR(CDCl3) : δ 1.3(s, 3H), 2.0 ~ 3.8(m, 7H), 2.4(s, 3H),
3.6(s, 2H), 7.3(s, 5H).
Preparation 33 3-Benzyl-1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred solution of 1.0g(4.5mM) of aminoalcohol(compound of preparation 33) in 15ml of dry tetrahydrofuran were added 1.4g(5.5mM) of triphenylphosphine and 0.9ml(5.7mM) of diethylazodicarboxylate successively at 0 ~ 5ºC. The reaction solution was stirred for 1hr at 0 ~ 5ºC and overnight at room temperature.
The resulting solution was evaporated in vacuo, added 20ml of ethyl acetate-pet. ether(1 : 1, v/v) to it, and the precipitate was removed by filtration.
The filtrate was evaporated in vacuo, and the residue was purified by column chromatography(Eluent ; ethanol : ethyl acetate = 1 : 3) to afford 0.61g(yield : 66%) of titled compound as a red-brownish oil.
1H-NMR data is same as in preparation 11.
Preparation 34 1-Benzyl-3,4-dimethylmaleimide
A suspension of 13.4g(0.14M) of sulfuric acid in 500ml of toluene was cooled in an ice-bath, added 14.6g(0.14M) of benzylamine as dropwise to it, and afforded bisbenzylammonium sulfate slurry.
In another vessel, 34g(0.32M) of benzylamine was added as dropwise to a solution of 30g(0.23M) of 2,3-dimethylmaleic anhydride in 500ml of toluene, stirred for 2hr at room temperature, and afforded N-benzylmaleamic acid as slurry.
To the N-benzylmaleamic acid slurry was added bisbenzylammonium sulfate slurry, equipped with Dean-Stark apparatus, and heated to reflux.
The extent of reaction was monitored by measuring the amount of water collected in Dean-Stark apparatus. After the reaction was finished, it was cooled and removed bisbenzylammonium sulfate by filtration. The filtrate was washed with 3 × 500ml of water, dried and evaporated in vacuo. The crude product was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3), and afforded 48.7g(yield : 95%) of titled compound as a white crystalline solid, m. p. : 39 ~ 40ºC
1H-NMR(CDCl3) : δ 1.9(s, 6H), 4.6(s, 2H), 7.3(s, 5H). Preparation 35 2.7-Dibenzyl- 1,5-dimethyl-2,3,4,7-tetraazabicyclo
[3.3.0]oct-3-en-6,8-dione
To a stirred solution of 32g(0.15M) of 1-benzyl-3,4-dimethylmaleimide in in 300ml of toluene was added 20g(0.15M) of benzyl azide as dropwise at room temperature, and heated to reflux for 4 days. The resulting solution was evaporated in vacuo, and purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3) to afford 14.2g(yield :
27%) of titled compound as a pale yellow solid.
m. p. : 108 ~ 109ºC
1H-NMR(CDCl3) : δ 1.2(s, 3H), 1.5(s, 3H), 4.6(s, 2H), 4.9(d, 2H, J=4Hz),
7.3(s, 10H).
Preparation 36 3,6-Dibenzyl-1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan- 2,4-dione
Method 1
A mixture of 6.9 g (20mM) of triazoline compound(compound of preparation 35) in 20ml of diphenyl ether was stirred for 2hr at 200 ~ 210ºC . The reaction mixture was cooled to room temperature, and purified by column chromatography(Eluent ; 1st ; n-hexane, 2nd; ethyl acetate : n-hexane = 1 : 3) to afford 5.8g(yield : 93%) of titled compound as a pale yellow syrup.
1H-NMR(CDCl3) : δ 1.4(s, 6H), 3.4(s, 2H), 4.6(s, 2H), 7.3(broads s, 10H).
Method 2
To a stirred solution of 19.5g (0.09M) of 1-benzyl-3,4-dimethylmaleimide in 300ml of toluene was added 24g(0.18M) of benzyl azide as dropwise at room temperature, and the reaction mixture was heated to reflux for a week.
Toluene was evaporated in vacuo, and the residue was purified by column chromatography (Eluent ; ethyl acetate : n-hexane = 1 : 6) to afford 17.9g (yield : 62%) of titled compound as a pale yellow syrup.
1H-NMR data is same as in Method 1.
Preparation 37 3,6-Dibenzyl-1,5-dimethyl-3,6-diazabicyclo[3.1.0] hexane
To a stirred mixture of 1.37g (36mM) of lithium aluminium hydride in 100 ml of dry tetrahydrofuran was added 5.8g (18mM) of 3,6-dibenzyl-1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexane-2,4-dione in 25ml of dry tetrahydrofuran as dropwise at room temperature, and the reaction mixture was heated to reflux for 2 days.
The resulting solution was cooled in an ice-bath and added successively 0.8 ml of water, 0.8ml of 15%-KOH solution, and 2.5ml of water. It was filtered, and filter cake was washed with tetrahydrofuran. The combined filtrate was dried over sodium sulfate, filtered and evaporated in vacuo to afford 4.8g(yield : 90%) of titled compound as a pale yellow syrup.
1H-NMR(CDCl3) : δ 1.2(s, 6H), 2.6(d, 2H, J=10Hz), 3.1(d, 2H, J=10Hz),
3.6(s, 3H), 4.2(s, 2H), 7.3(s, 10H). Preparation 38 1,5-Dimethyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred solution of 2.7g(9.2mM) of 3,6-dibenzyl-1,5-dimethyl-3,6-diazabicyclo[3.1.0] hexane and 4.3g(84mM) of ammonium formate in 80ml of methanol was added 2.7g of 10% Pd-C catalyst slowly, and stirred for 4.5hr at room temperature.
The reaction mixture was filtered through celite, and the filtrate was evaporated in vacuo. The residue was dissolved in 70ml of chloroform, stirred for 30min, filtered, and the filtrate was evaporated in vacuo to afford 1.5g of titled compound as formate.
It was dissolved in 40ml of methanol, added 0.4g(10mM) of sodium hydroxide, and stirred for 1hr at room temperature. Methanol was evaporated in vacuo, and added 70ml of chloroform for extraction. The chloroform extract was evaporated in vacuo, and afforded 0.96g(yield : 93%) of titled compound as a pale brown oil.
1H-NMR(CDCl3) : δ 1.2(s, 6H), 1.6(broad s, 2H), 2.8(q, 4H, J=12Hz).
Preparation 39 7-Benzyl-1,2,5-trimethyl-2,3,4,7-tetraazabicyclo[3.1.0]oct- 3-en-6,8-dione
A mixture of 31g(0.144M) of 1-benzyl-2,3-dimethylmaleimide and 51g (0.89M) of methyl azide in 300ml of toluene was stirred for 5 days at 100 ~ 105ºC. 30g(0.52M) of methyl azide was added again, and reacted for 5 days at the same temperature.
The reaction mixture was evaporated in vacuo, and the residue was used in the next step without further purification. Small amount of analytical sample was purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 3).
1H-NMR (CDCl3) : δ 1.4(s, 3H), 1.5(s, 3H), 3.4(s, 3H), 4.6(s, 2H), 7.3(s, 5H).
Preparation 40 3-Benzyl-1,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexane- 2,4-dione
A mixture of 0.144M of triazoline compound(compound of preparation 39) in 40ml of diphenyl ether was stirred for 2hr at 180 ~ 190ºC . The reaction mixture was cooled to room temperature, and purified by column chromatography(Eluent ; ethyl acetate : n-hexane = 1 : 10) to afford 34.7g(yield : 99%) of titled compound as a pale yellow oil.
1H-NMR(CDCl3) : δ 1.4(s, 6H), 2.3(s, 3H), 4.6(s, 2H), 7.3(s, 5H).
Preparation 41 3-Benzyl-1,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexane
To a stirred mixture of 1.51g(40mM) of lithium aluminium hydride in 200 ml of dry tetrahydrofuran was added 4.42g(18.1mM) of 3-benzyl-1,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexan-2,4-dione in 20ml of dry tetrahydrofuran as dropwise at room temperature, and the reaction mixture was heated to reflux for 20hr.
The resulting solution was cooled in an ice-bath, and added 30ml of water-tetrahydrofuran mixture(1 : 2, v/v) slowly. The solid was filtered, washed with 50 ml of tetrahydrofuran, and the combined filtrate was dried over magnesium sulfate. It was filtered, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (Eluent ; ethyl acetate : ethanol = 3 : 1), and afforded
3.34g(yield : 85%) of titled compound as a pale yellow oil.
1H-NMR(CDCl3) : δ 1.2(s, 6H), 2.5(s, 3H), 2.6(2d, 4H), 3.6(s, 2H), 7.3(s, 5H). Preparation 42 1 ,5,6-Trimethyl-3,6-diazabicyclo[3.1.0]hexane
A mixture of 4.67g(21.6mM) of 3-benzyl-1,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexane and 5g of 10% Pd-C catalyst in 230ml of methanol was hydrogenated for 5hr at room temperature under 62 psi of H2 pressure. The reaction mixture was filtered through celite pad, and the filtrate was evaporated in vacuo.
The residue was purified by column chromatography (Eluent ; methanol :
40%-methylamine solution = 24 : 1), and afforded a pale yellow oil. It was further purified by vacuum distillation, and afforded 1.3g(yield : 48%) of titled compound as a white solid.
m. p. : 39 ~ 40ºC
1H-NMR(CDCl3) : δ 1.1(s, 6H), 2.1(s, 1H), 2.2(s, 3H), 2.6(2d, 4H).
Example 1 1-Cyclopropyl-6-fluoro-7-(6-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)- 1 ,4-dihydro-4-oxo-3-quinoline carboxylic acid
A mixture of 100mg(0.377mM) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 129mg(1.34mM) of 6-methyl-3,6-diazabicyclo [3.1.0]hexane and 59mg(0.377mM) of 1,8-diazabicyclo[5.4.0]unde-7-cene in 2ml of acetonitrile and 1ml of N,N-dimethylformamide was heated to reflux for 4hr.
The resulting solution was refrigerated overnight, precipitate was filtered and washed with acetonitrile, water and acetonitrile, successively. The crude product was reciystallized from ethanol, and afforded 60mg (yield : 46%) of titled compound,
m. p. : 237 ~ 239ºC
1H-NMR(CDCl3) : δ 1.1 ~ 1.4(m, 4H), 2.4(s, 5H), 3.4 ~ 3.8(m, 3H),
4.0(dd, 2H, J=4Hz, 12Hz), 6.8(d, 1H, J=8Hz),
7.7(d, 1H, J=16Hz), 8.5(s, 1H).
IR(KBr) : 1723, 1630, 1544, 1507 cm-1 Example 2 1-Cyclopropyl-6,8-difluoro-7-(6-methy1-3,6-diazabicyclo
[3.1.0)hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinoline carboxylic acid
A mixture of 100mg(0.697mM) of 1-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecaιboxylic acid, 112mg(0.707mM) of 6-methyl-3,6- diazabicyclo [3.1.0]hexane · acetate and 106mg(0.389mM) of 1,8-diazabicyclo
[5.4.0]unde-7-cene in 2ml of acetonitrile and 1ml of N,N-dimethylformamide was heated to reflux for 4hr.
The resulting solution was refrigerated overnight, the crystals were filtered and washed with acetonitrile, water, acetonitrile, successively. The crude product was recrystallized from ethanol, and afforded 60mg(yield : 48%) of titled compound.
m. p. : 208 ~ 210ºC
1H-NMR(CDCl3) : δ 1.1 ~ 1.4(m, 4H), 2.3(s, 2H), 2.4(s, 3H), 3.5 ~ 4.2(m, 5H),
7.8(d, 1H, J=16Hz), 8.7(s, 1H).
IR(KBr) : 1725, 1624, 1541, 1514 cm-1
Example 3 5-Amino-1-cyclopropyl-6,8-difluoro-7-(6-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 2, 100mg(0.336mM) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 106mg(0.671 mM) of 6-methyl-3,6-diazabicyclo
[3.1.0]hexane · acetate for 8hr, and afforded 38mg(yield : 30%) of titled compound. m. p. : 236 ~ 238ºC
1H-NMR(CDCl3 + DMSO-d6) : δ 1.1 ~ 1.4(m, 4H), 2.3(s, 2H), 2.4(s, 3H),
3.5 ~ 4.2(m, 5H), 7.5(bs, 2H), 8.6(s, 1H).
IR(KBr) : 1725, 1626, 1513, 1425 cm-1 Example 4 1-Cyclopropyl-6-fluoro-7-(6-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid
In the same manner as described in Example 2, 100mg(0.354mM) of 1-cyclopropyl-7╌chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was allowed to react with 112mg(0.708 mM) of 6-methyl-3,6-diazabicyclo
[3.1.0]hexane · acetate for 30min, and recrystallized from n-butanol to afford
81mg(yield : 66%) of titled compound.
m. p. : 209 ~ 212ºC
1H-NMR(CDCl3 + DMSO-d6) : δ 1.1 ~ 1.4(m, 4H), 2.4(s, 5H), 3.5 ~ 4.0(m, 3H),
4.2(dd, 2H, J=4Hz, 12Hz),
7.9(d, 1H, J=12Hz), 8.7(s, 1H).
IR(KBr) : 1723, 1631, 1604, 1454 cm-1 Example 5 6,8-Difluoro-1-(2,4-difluorophenyl)-7-(6-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.28mM) of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 65mg(0.41mM) of 6-methyl-3,6-diazabicyclo[3.1.0]hexane · acetate and 79mg(0.56mM) of triehylamine in 5ml of acetonitrile was heated to reflux for 8hr.
The reaction mixture was refrigerated overnight, the crystals were filtered and washed with acetonitrile. The filtrate was evaporated in vacuo and the residue was crystallized from ethanol to afford 25mg(yield : 20%) of titled compound.
m. p. : 150 ~ 152ºC
1H-NMR(CDCl3) : δ 2.3(s, 2H), 2.4(s, 3H), 3.8(dd, 4H, J=12Hz, 20Hz),
6.8 ~ 8.0(m, 4H), 8.4(s, 1H).
IR(KBr) : 1728,1627,1538,1510 cm-1 Example 6 1-Cyclopropyl-8-chloro-6-fluoro-7-(6-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.334mM) of 1-cyclopropyl-8-chloro-6,7-difluoro-1,4* dihydro-4-oxo-3-quinolinecarboxylic acid, 158mg(1.0mM) of 6-methyl-3,6-diazabicyclo [3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 40 ~ 50 ºC . Pyridine was evaporated in vacuo, 2ml of acetonitrile and 1ml of N,N- dimethylformamide were added to the residue, and filtered the crystals formed.
The filtrate was refrigerated overnight and filtered again. The two crops of crystals were washed with small amount of acetonitrile, water, and ethanol, successively, and dried to afford 44mg(yield : 35%) of titled compound as a light- yellow solid,
m. p. : 190 ~ 191ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.4(m, 4H), 2.2(s, 2H), 2.3(s, 3H),
3.7(q, 4H, J=12Hz), 4.0 ~ 4.5(m, 1H),
7.9(d, 1H, J=14Hz), 8.8(s, 1H).
IR(KBr) : 1726, 1617, 1500, 1446 cm-1
Example 7 9-Fluoro-2,3-dihydro-3-methyl-10-(6-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[1,2,3-de]- 1,4-benzoxazine-6-carboxylic acid
A mixture of 100mg(0.356mM) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 169mg(1.07mM) of 6-methyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred for 2 days at 55 ~ 60ºC . Pyridine was evaporated in vacuo, and the crude product was purified by column chromatography(Eluent ; chloroform : methanol : water =
10 : 3 : 1) to afford 31mg(yield : 24%) of titled compound.
m. p. : 206 ~ 210ºC
1H-NMR(CDCl3) : δ 1.5(d, 3H, J=7Hz), 2.2(s, 2H), 2.3(s, 3H), 3.4 ~ 3.8(m, 2H), 3.9 ~ 4.7(m, 5H),
7.6(d, 1H, J=15Hz), 8.5(s, 1H).
IR(KBr) : 1721, 1621, 1524, 1452 cm-1 Example 8 1-Cyclopropyl-6-fluoro-8-methoxy-7-(6-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 7, 100mg(0.339mM) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 175mg of 6-methyl-3,6-diazabicyclo [3.1.0]hexane · acetate, and afforded 27mg(yield : 21%) of titled compound.
m. p. : 193 ~ 195ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.2(m, 4H), 2.2(s, 2H), 2.3(s, 3H),
3.3 ~ 4.2(m, 5H), 3.6(s, 3H),
7.7(d, 1H, J=15Hz), 8.7(s, 1H).
IR(KBr) : 1728, 1622, 1513, 1440 cm-1
Example 9 1-Cyclopropyl-6-fluoro-7-(1,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-1 ,8-naphthyridine-3- carboxylic acid
A mixture of 100mg(0.354mM) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 92mg(0.533mM) of 1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexane · acetate and 49mg(0.320mM) of 1 ,8-diazabicyclo[5.4.0]unde-7-cene in 2ml of acetonitrile was stirred overnight at room temperature.
The solid was filtered, washed successively with acetonitrile, water, and acetonitrile, and dried to afford 42mg(yield : 40%) of titled compound.
m. p. : 186 ~ 188ºC
1H-NMR(CDCl3) : δ 0.9 ~ 1.4(m, 4H), 1.5(s, 3H), 2.1(s, 1H), 2.4(s, 3H), 3.4 ~4.4(m, 5H), 7.9(d, 1H, J=14Hz), 8.6(s, 1H).
IR(KBr) : 1725, 1629, 1541, 1452 cm-1
Example 10 1-Cyclopropyl-6-fluoro-7-(1,6-dimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinoline carboxylic acid
A mixture of 100mg(0.337mM) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and 195mg(1.13mM) of 1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 40 ~ 50 ºC.
Pyridine was evaporated in vacuo, added 3ml of methanol to the residue, and stirred overnight at room temperature. Precipitate was filtered, washed successively with small amount of methanol, water, methanol, and recrystallized from acetonitrile to afford 42mg(yield : 31%) of titled compound.
m. p. : 214 ~ 215ºC
1H-NMR(CDCl3) : δ 1.0 ~ 1.4(m, 4H), 1.5(s, 3H), 2.1(s, 1H), 2.5(s, 3H),
3.2 ~ 4.2(m, 5H), 6.7(d, 1H, J=8Hz),
7.8(d, 1H, J=16Hz), 8.5(s, 1H).
IR(KBr) : 1725, 1630, 1511, 1466 cm-1
Example 11 5-Amino-1-cyclopropyl-6,8-difluoro-7-(1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.336mM) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and 173mg(1.01mM) of 1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 50 ~ 60ºC .
Pyridine was evaporated in vacuo, added 2ml of acetonitrile and 1ml of N,N-dimethylformamide to the residue, and the resulting solution was refrigerated overnight. The solid was filtered, washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 36mg(yield : 28%) of titled compound.
m. p. : 204 ~ 206ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.4(m, 4H), 1.5(s, 3H), 2.1(s, 1H), 2.5(s, 3H),
3.4 ~ 4.3(m, 5H), 6.3(broad s, 2H), 8.5(s, 1H).
IR(KBr) : 1725, 1633, 1516, 1436 cm-1
Example 12 9-Fluoro-2,3-dihydro-3-methyl- 10-( 1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[l,2,3,-de]- 1,4-benzoxazine-6-carboxylic acid
A mixture of 100mg(0.356mM) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 184mg(1.07mM) of 1,6-dimethyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred for 2 days at 50 ~ 60ºC.
Pyridine was evaporated in vacuo, and the residue was purified by column chromatography (Eluent ; chloroform : methanol : water = 10 : 3 : 1) to afford 28mg(yield : 22%) of titled compound,
m. p. : 162 ~ 164ºC
1H-NMR(CDCl3) : δ 1.5(d, 3H, J=7Hz), 1.9(s, 1H), 2.4(s, 3H),
3.2 ~4.5(m, 7H), 7.5(d, 1H, J=15Hz), 8.5(s, 1H).
IR(KBr) : 1722, 1621, 1525, 1466 cm-1
Example 13 1-Cyclopropyl-6-fluoro-8-methoxy-7-(1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 12, 100mg(0.339mM) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 175mg(1.02mM) of 1,6-dimethyl-3,6-diazabicyclo [3.1.0]hexane · acetate, and afforded 28mg(yield : 21%) of titled compound.
m. p. : 166 ~ 168ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.4(m, 4H), 1.5(s, 3H), 1.9(s, 1H), 2.5(s, 3H),
3.2 ~ 4.2(m, 5H), 3.6(s, 3H), 7.7(d, 1H, J=14Hz),
8.7(s, 1H).
IR(KBr) : 1728, 1621, 1512, 1456 cm-1
Example 14 1-Cyclopropyl-6,8-difluoro-7-(1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 12, 100mg(0.353mM) of 1- cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 182mg(1.06mM) of 1,6-dimethyl-3,6-diazabicyclo [3.1.0] hexane · acetate, and afforded 36mg(yield : 27%) of titled compound.
m. p. : 144 ~ 146ºC
1H-NMR(CDCl3) : δ 1.0 ~ 1.4(m, 4H), 1.5(s, 3H), 2.1(s, 1H), 2.5(s, 3H),
3.4 ~ 4.2(m, 5H), 7.7(d, 1H, J=14Hz), 8.7(s, 1H).
IR(KBr) : 1730, 1626, 1517, 1459 cm-1 Example 15 1-Cyclopropyl-8-chloro-6-fluoro-7-(1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 12, 100mg(0.334mM) of 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecaιboxylic acid was allowed to react with 172mg(1.0mM) of 1,6-dimethyl-3,6-diazabicyclo [3.1.0] hexane · acetate, and afforded 33mg(yield : 24%) of titled compound,
m. p. : 198 ~ 202ºC
1H-NMR(CDCl3) : δ 0.7 ~ 1.4(m, 4H), 1.5(s, 3H), 1.9(broad s, 1H), 2.5(s, 5H),
3.4 ~ 4.0(m, 4H), 4.0 ~ 4.4(m, 1H), 7.9(d, 1H, J=14Hz), 8.8(s, 1H).
IR(KBr) : 1735, 1621, 1577, 1451 cm-1
Example 16 1-Cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
A mixture of 70mg(0.25mM) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid, 27mg(0.33mM) of 3,6-diazabicyclo[3.1.0]hexane and 34mg(0.25mM) of 1,8-diazabicyclo[5.4.0]unde-7-cene in 2ml of acetonitrile was stirred for 6hr at room temperature.
The solid was filtered, washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 55mg(yield : 67%) of titled compound.
m. p. : 248 ~ 252ºC
1H-NMR(CDCl3) : δ 0.9 ~ 1.4(m, 4H), 2.8(broad s, 2H), 3.4 ~ 4.3(m, 5H),
7.9(d, 1H, J=14Hz), 8.5(s, 1H).
IR(KBr) : 1717, 1635, 1563, 1469 cm-1
Example 17 1-Cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 100mg(0.38mM) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and 164mg(1.1mM) of 3,6-diazabicyclo [3.1.0] hexane · acetate in 3ml of pyridine was stirred overnight at 45 ~ 55ºC
Pyridine was evaporated in vacuo, added 4ml of methanol to the residue, and stirred for 6hr at room temperature. The solid was filtered, washed successively with methanol, water, and methanol, and dried to afford 70mg(yield :
56%) of titled compound.
m. p. : 244 ~ 248ºC
1H-NMR(DMSO-d6) : δ 1.0 ~ 1.4(m, 4H), 2.8(broad s, 2H), 3.4 ~ 4.0(m, 5H), 7.0(d, 1H, J=8Hz), 7.8(d,; 1H, J=16Hz), 8.5(s, 1H).
IR(KBr) : 1719, 1632, 1508, 1473 cm-1
Example 18 1-Cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3-yl)-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 100mg(0.35mM) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid, 87mg(0.42mM) of 3,6-diazabicyclo [3.1.0] hexane · acetate and 118mg(0.77mM) of 1,8-diazabicyclo[5.4.0]unde-7-cene in 1.5 ml of acetonitrile and 1.5ml of N,N-dimethylformamide was stirred overnight at 40 ~50ºC
The reaction mixture was cooled to room temperature, filtered the crystals formed, and washed successively with small amount of acetonitrile, water, and acetonitrile. It was recrystallized from N,N-dimethylformamide, and afforded 44mg(yield : 36%) of titled compound as a white solid.
m. p. : 230 ~ 232ºC
1H-NMR(CDCl3) : δ 0.9 ~ 1.4(m, 4H), 2.8(s, 2H), 3.5 ~ 4.3(m, 1H),
3.8(q, 4H, J=12Hz), 7.8(d, 1H, J=14Hz), 8.6(s, 1H).
IR(KBr) : 1727, 1628, 1517, 1464 cm-1 Example 19 1-Cyclopropyl-8-chloro-7-(3,6-diazabicyclo[3.1.0]hexan-3- yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid In the same manner as described in Example 17, 100mg(0.33mM) of 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 144mg(1.0mM) of 3,6-diazabicyclo[3.1.0] hexane · acetate, and afforded 50mg(yield : 41%) of titled compound.
m. p. : 214 ~ 216ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.6(m, 4H), 2.7(s, 2H), 3.7(s, 4H), 4.2 ~ 4.5(m, 1H),
8.0(d, 1H, J=14Hz), 8.8(s, 1H).
IR(KBr) : 1726, 1614, 1502, 1448 cm-1 Example 20 5-Amino-1-cyclopropyl-7-(3,6-diazabicyclo[3.1.0]hexan-3- yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 117mg(0.39mM) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecaιboxylic acid, 68mg(0.47mM) of 3,6-diazabicyclo
[3.1.0]hexane · acetate and 131mg(0.87mM) of 1,8-diazabicyclo[5.4.0]unde-7-cene in 1ml acetonitrile and 2ml of N,N-dimethylformamide was stirred overnight at 50
- 60 ºC
The reaction mixture was cooled to room temperature, solid was filtered and washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 55mg(yield : 39%) of titled compound as a yellow solid.
m. p. : 218 ~ 220ºC
1H-NMR(DMSO-d6) : δ 0.9 ~ 1.2(m, 4H), 2.6(s, 2H),
3.4 ~ 4.2(m with dd at 3.7, 5H, J=8Hz, 12Hz),
7.0(broad s, 2H), 8.4(s, 1H).
IR(KBr) : 1726, 1638, 1542, 1517 cm-1
Example 21 7-(3,6-Diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro-1- ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 100mg(0.37mM) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid and 158mg(1.1mM) of 3,6-diazabicyclo [3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 55 ~ 65ºC .
The reaction mixture was cooled and the solid was filtered. It was dispersed in 10ml of methanol, filtered, and recrystallized from chloroform to afford 76mg(yield : 61 %) of titled compound,
m. p. : 222 ~ 224ºC
1H-NMR(DMSO-d6) : δ 1.4(t, 3H, J=6Hz), 2.6(s, 2H),
3.7(dd, 4H, J=8Hz, 12Hz),
4.3 ~ 4.7(m, 3H), 7.7(d, 1H, J=14Hz), 8.8(s, 1H).
IR(KBr) : 1712,1628,1521,1468,1445cm-1
Example 22 9-Fluro-2,3-dihydro-3-methyl-10-(3,6-diazabicyclo
[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4- benzoxazine-6-carboxylic acid
A mixture of 100mg(0.36mM) of 9,10-difluoro-2,3-dihydro-3-methyl-7- oxo-7H-pyrido[1,2,3-de)-1,4-benzoxazine-6-carboxylic acid and 154mg(1.1mM) of 3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 60 ~ 70ºC.
After cooling the reaction solution, the solid was removed by filtration, the filtrate was evaporated in vacuo, added 5ml of methanol to the residue, and stirred for 3hr at room temperature. The solid was filtered, washed successively with small amount of methanol, water, and methanol, and dried to afford 38mg(yield : 31 %) of titled compound.
m. p. : 242 ~ 244ºC
1H-NMR(CDCl3) : δ 1.5(d, 3H, J=6Hz), 2.6(s, 2H),
3.4 ~ 4.0(m, 5H), 4.3 ~ 4.8(m, 3H),
7.7(d, 1H, J=14Hz), 8.6(s, 1H).
IR(KBr) : 1712, 1621, 1531, 1474 cm-1
Example 23 1-Cyclopropyl-6,8-difluoro-7-(1-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 100mg(0.35mM) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and 166mg(1.1mM) of 1-methyl-3,6-diazabicyclo [3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 45 ~ 50ºC .
The reaction mixture was cooled and the solid was filtered. It was dispersed in 10ml of methanol, filtered, and recrystallized from chloroform to afford 97mg(yield : 76%) of titled compound.
m. p. : 228 ~ 230ºC
1H-NMR(CDCl3) : δ 0.9 ~ 1.4(m, 4H), 1.5(s, 3H), 2.4(s, 1H),
3.4 ~ 4.2(m, 5H), 7.6(d, 1H, J=14Hz), 8.7(m, 1H).
IR(KBr) : 1721, 1627, 1547, 1518, 1449 cm-1
Example 24 1-Cyclopropyl-8-chloro-6-fluoro-7-(1-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.33mM) of 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 161mg(1.0mM) of 1-methyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 60 ~ 65ºC.
The reaction mixture was evaporated in vacuo, added 3ml of acetonitrile to the residue, and stirred for 4hr at room temperature. The solid was filtered and dried to afford 41mg(yield : 32%) of titled compound,
m. p. : 216 ~ 218ºC
1H-NMR(CDCl3) : δ 0.7 ~ 1.5(m, 4H), 1.4(s, 3H), 2.4(s, 1H),
3.6(q, 4H, J=10Hz), 4.0 ~ 4.4(m, 1H),
7.9(d, 1H, J=14Hz), 8.8(s, 1H).
IR(KBr) : 1726, 1617, 1500, 1452 cm-1
Example 25 5-Amino-1-cyclopropyl-6,8-difluoro-7-( 1-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.34mM) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 159mg(1.0mM) of 1-methyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 65 ~70ºC . Pyridine was removed in vacuo, added 3ml of methanol to the residue, and stirred for 5hr at room temperature. The solid was filtered, washed successively with small amount of methanol, water, and methanol, and dried to afford
29mg(yield : 23%) of titled compound.
m. p. : 224 ~ 226ºC
1H-NMR(CDCl3) : δ 0.7 ~ 1.5(m, 4H), 1.4(s, 3H), 2.4(s, 1H),
3.4 ~ 4.1(m, 5H), 6.4(broad s , 2H), 8.7(s, 1H).
IR(KBr) : 1718, 1632, 1516, 1430 cm-1 Example 26 1-Cyclopropyl-6-fluoro-7-(l-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro 4-oxo-1,8-naphthyridine-3- carboxylic acid
A mixture of 74mg(0.26mM) of 1-cyclopropyl-7-chloro-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 50mg(0.32mM) of 1-methyl- 3,6-diazabicyclo[3.1.0]hexane · acetate, and 86μl(0.57mM) of 1,8-diazabicyclo
[5.4.0]unde-7-cene in 3ml of acetonitrile was stirred for 6hr at room temperature.
The solid was filtered, washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 74mg(yield : 79%) of titled compound.
m. p. : 249 ~ 251ºC
1H-NMR(DMSO-d6) : δ 0.9 ~ 1.4(m, 4H), 1.4(broad s, 3H), 2.4(s, 1H),
3.4 ~ 4.3(m, 5H), 7.9(d, 1H, J=14Hz), 8.5(s, 1H).
IR(KBr) : 1718, 1635, 1502, 1467 cm-1 Example 27 1-Cyclopropyl-6-fluoro-7-(1-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 100mg(0.38mM) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 72mg(0.45mM) of 1-methyl-3,6-diazabicyclo [3.1.0]hexane · acetate, and 125 μl(0.83mM) of 1,8-diazabicyclo[5.4.0]unde-7-cene in 5 ml of acetonitrile was stirred for 8hr at 50 ~ 60ºC .
The solid was filtered, washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 100mg(yield : 78%) of titled compound.
m. p. : 267 ~ 269ºC
1H-NMR(DMSO-d6) : δ 1.0 ~ 1.4(m, 4H), 1.4(broad s, 3H), 2.4(s, 1H),
3.4 ~ 4.0(m, 5H), 7.0(d, 1H, J=8Hz),
7.8(d, 1H, J=16Hz), 8.5(s, 1H).
IR(KBr) : 1712, 1632, 1512, 1469 cm-1
Example 28 1-Cyclopropyl-6-fluoro-7-(1-methyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid · lactate
To a stirred solution of 0.15g(0.44mM) of 1-cyclopropyl-6-fluoro-7-(1-methyl-3, 6-diazabicyclo [3. 1.0] hexan-3- yl) -1 ,4-dihydro-4-oxo-3 -quinolinecarboxylic acid in 20ml of chloroform and 5ml of methanol was added
36mg(90%, 30μl) of lactic acid, and the resulting solution was stirred for 30 min at room temperature.
The solvent was evaporated in vacuo, and crystallized by adding 10ml of ether. The solid was filtered, and dried in vacuo to afford 154mg(yield : 82%) of titled compound as a white solid.
m. p. : 160 ~ 162ºC
1H-NMR(CDCl3) : δ 1.0 ~ 1.5(m, 4H), 1.4(s, 3H), 2.7(s, 1H),
3.0 ~ 4.2(m, 11H), 6.8(d, 1H, J=8Hz),
7.7(d, 1H, J=16Hz), 8.4(s, 1H). Example 29 9-Fluoro-2,3-dihydro-3-methyl-10-(1-methyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[1,2,3-de)- 1,4-benzoxazine-6-carboxylic acid
A mixture of 100mg(0.36mM) of 9,10-difluoro-2,3-dihydro-3-methyl-7- oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-caιboxylic acid and 169mg(1.1mM) of
1-methyl-3,6-diazabicyclo[3.1.0]hexane · acetate in 3ml of pyridine was stirred overnight at 60 ~ 70ºC .
The reaction solution was evaporated in vacuo, and the residue was purified by column chromatography (Eluent ; chloroform : methanol : water = 10 : 3 : 1) to afford 30mg(yield : 23%) of titled compound as a yellow solid.
m. p. : 220 ~ 222ºC
1H-NMR(CDCl3) : δ 1.4(d, 3H, J=6Hz), 1.5(s, 3H), 2.3(s, 1H),
3.2 ~ 4.0(m, 5H), 4.1 ~ 4.8(m, 3H),
7.6(d, 1H, J=14Hz), 8.6(s, 1H).
IR(KBr) : 1719, 1623, 1531, 1476 cm-1
Example 30 6,8-Difluoro-1-(2,4-difluorophenyl)-7-(3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 100mg(0.28mM) of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 121mg(0.84mM) of 3,6-diazabicyclo [3.1.0]hexane · acetate in Ami of pyridine was stirred overnight at 55 ~ 60ºC.
The solid was removed by filtration, and the filtrate was evaporated in vacuo. The residue was crystallized by adding ether, filtered, washed with water, and dried to afford 45mg(yield : 38%) of titled compound as a pale yellow solid. m. p. : 245 ~ 247ºC
1H-NMR(CDCl3) : δ 2.1(s, 1H), 2.7(s, 2H), 3.7(q, 4H, J=12Hz),
4.8(broad s, 1H), 6.9 ~ 7.7(m, 3H),
7.8(d, 1H, J=16Hz), 8.4(s, 1H). IR(KBr) : 1732, 1622, 1511, 1467 cm-1
Example 31 1-Cyclopropyl-6,8-difluoro-7-( 1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
A mixture of 100mg(0.35mM) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro4-oxo-3-quinolinecarboxylic acid and 93mg(0.83mM) of 1,5-dimehyl-3,6-diazabicyclo[3.1.0]hexane in 3ml of pyridine was stirred overnight at 40 ~ 65ºC.
The reaction mixture was cooled, and obtained the crystal by filtration. The crystal was dispersed in 10ml of methanol, filtered, and dried to afford
53mg(yield : 40%) of titled compound as a white solid.
m. p. : 240 ~ 242ºC
1H-NMR(CDCl3) : δ 0.9 ~ 1.5(m, 4H), 1.4(s, 6H), 3.4 ~ 4.2(m, 5H),
7.8(d, 1H, J=14Hz), 8.7(s, 1H).
IR(KBr) : 1722, 1625, 1517, 1450 cm-1
Example 32 1-Cyclopropyl-8-chloro-6-fluoro-7-( 1,5-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)- 1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.33mM) of 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 113mg(1.0mM) of 1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexane in 3ml of pyridine was stirred overnight at 50 ~ 60ºC .
Pyridine was evaporated in vacuo, and added 5ml of methanol to the residue. The precipitate was filtered, washed successively with methanol and acetonitrile, and dried to afford 78mg(yield : 59%) of titled compound as a white solid.
m. p. : 220 ~ 222ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.2(m, 2H), 1.2 ~ 1.5(m, 2H), 1.4(s, 6H),
3.6(s, 4H), 4.1 ~ 4.5(m, 1H), 8.0(d, 1H, J=14Hz), 8.8(s, 1H).
IR(KBr) : 1722, 1617, 1444 cm-1
Example 33 5-Amino-1-cyclopropyl-6,8-difluoro-7-(1,5-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 32, 100mg(0.34mM) of 5- amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 113mg(1.0mM) of 1,5-dimethyl-3,6-diazabicyclo[3.1.0] hexane, and afforded 68mg(yield : 52%) of titled compound as a yellow solid.
m. p. : 219 ~ 221ºC
1H-NMR(CDCl3) : δ 0.8 ~ 1.4(m, 4H), 1.3(s, 6H), 3.4 ~ 4.1(m, 5H),
6.4(broads,2H), 8.6(s, 1H).
IR(KBr) : 1723,1632,1516,1429 cm-1
Example 34 1-Cyclopropyl-7-( l,5-dimethyl-3 ,6-diazabicyclo
[3.1.0]hexan-3-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid
A mixture of 50mg(0.18mM) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 41mg(0.26mM) of
1,5-dimemyl-3,6-diazabicyclo[3.1.0]hexane · formate-3-carboxylic acid, and 27mg (0.18mM) of 1,8-diazabicyclo [5.4.0]unde-7-cene in 3ml of acetonitrile was stirred for 4hr at room temperature.
The precipitate was filtered, washed successively with acetonitrile, water, and acetonitrile, and dried to afford 46mg(yield : 73%) of titled compound as a white solid.
m. p. : 256 ~ 257ºC
1H-NMR(DMSO-d6) : δ 0.9 ~ 1.5(m, 4H), 1.4(s, 6H),
3.4 ~ 4.4(m, 5H), 7.9(d, 1H, J=14Hz), 8.6(s, 1H). Example 35 1-Cyclopropyl-7-( l,5-dim,ethyl-3,6-diazabicyclo[3.1.0] hexan-3-yl)-6-fluoro- 1 ,4-dihydro-4-oxo-3-quinoline carboxylic acid
A mixture of 60mg(0.23mM) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 107mg(0.68mM) of 1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan · formate in 3ml of pyridine was stirred overnight at 60 ~ 80ºC .
The reaction mixture was cooled to room temperature, and the precipitate was filtered. It was washed successively with methanol, water, and methanol, and dried to afford 43mg(yield : 53%) of titled compound as a white solid.
m. p. : 258 ~ 260ºC
1H-NMR(CF3CO2H) : δ 1.2 ~ 1.8(m, 4H), 1.9(s, 6H),
3.8 ~ 4.2(m, 1H), 4.1(d, 2H, J=14Hz),
4.8(d, 2H, J=14Hz), 7.5(d, 1H, J=8Hz),
8.2(d, 1H, J=14Hz), 9.2(s, 1H).
IR(KBr) : 1711, 1631, 1512, 1471 cm-1
Example 36 1-Ethyl-7-(1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 60mg(0.22mM) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid and 74mg(0.66mM) of 1,5-dimethyl-3,6-diazabicyclo [3.1.0]hexane in 3ml of pyridine was stirred overnight at 40 ~ 50ºC .
The reaction mixture was cooled, evaporated in vacuo, and added methanol to the residue. The precipitate was filtered, washed successively with methanol, water, and methanol, and dried to afford 54mg(yield : 68%) of titled compound as a white solid,
m. p. : 240 ~ 241ºC
1H-NMR(CDCl3) : δ 1.4(s, 6H), 1.5(t, 3H, J=6Hz),
3.7(q, 4H, J=14Hz), 4.2 ~ 4.7(m, 2H), 7.9(d, 1H, J=14Hz), 8.5(s, 1H).
IR(KBr) : 1722, 1627, 1521, 1447 cm-1
Example 37 9-Fluoro-2,3-dihydro-3-methyl-10-(1,5-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[1,2,3-de]- 1,4-benzoxazine-6-carboxylic acid
A mixture of 100mg(0.36mM) of 9,10-difluoro-2,3-dihydro-3-methyl-7- oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 120mg(1.1mM) of 1,5-dimethyl-3,6-diazabicycIo[3.1.0]hexane in 3ml of pyridine was stirred for 3 days at 60 ~ 75ºC.
The precipitate was obtained by filtration, the filtrate evaporated in vacuo, and added 3ml of methanol to the residue for crystallization. The two crops of precipitate were combined, dispersed in 5ml of methanol, filtered, and dried to afford 79mg(yield : 59%) of titled compound as a pale green solid.
m. p. : 286 ~ 288ºC
1H-NMR(CDCl3) : δ 1.3(s, 6H), 1.6(d, 3H, J=7Hz), 3.3 ~ 4.8(m, 7H),
7.6(d, 1H, J=14Hz), 8.6(s, 1H).
IR(KBr) : 1718, 1622, 1525, 1448 cm-1 Example 38 6,8-Difluoro-1-(2,4-difluorophenyl)-7-(1,5-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 100mg(0.28mM) of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 95mg(0.85mM) of 1,5-dimetfιyl-3,6-diazabicyclo[3.1.0jhexane in Ami of pyridine was stirred overnight at 45 ~ 55ºC .
The reaction mixture was evaporated in vacuo, and added methanol to the residue. The precipitate was filtered, washed with methanol, and dried to afford 85mg(yield : 68%) of titled compound as a pale yellow solid.
m. p. : 230 ~ 232ºC 1H-NMR(CDCl3) : δ 1.3(s, 6H), 3.6(q, 4H, J=12Hz),
6.8 ~ 7.6(m, 3H), 7.9(d, 1H, J=14Hz), 8.4(s, 1H).
IR(KBr) : 1725, 1622, 1508, 1441 cm-1 Example 39 1-Cyclopropyl-6,8-difluoro-7-(l,5,6-trimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)- 1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
A mixture of 0.22g(0.78mM) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 0.2g(1.58mM) of 1 ,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexane in 2ml of pyridine was stirred for 2hr at 50 ~ 60ºC .
To the reaction mixture was added 3ml of methanol and cooled gradually to room temperature. The precipitate was filtered, washed with methanol, and recrystallized several times from chloroform-methanol(1 : 3, v/v) to afford 0.2g(yield : 66%) of titled compound as a white solid.
m. p. : 212 ~ 213ºC
1H-NMR(CDCl3) : δ 1.1 ~ 1.5(m, 4H), 1.3(s, 6H), 2.4(s, 3H),
3.4 ~ 4.2(m, 5H), 7.7(d, 1H, J=14Hz), 8.7(s, 1H).
IR(KBr) : 1730, 1627, 1541, 1452 cm-1 Example 40 8-Chloro-1-cyclopropyl-6-fluoro-7-(1,5,6-trimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)- 1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 39, 0.22g(0.74mM) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 0.19g(1.48mM) of l,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexane, and afforded 0.21g(yield : 70%) of titled compound,
m. p. : 202 ~ 203ºC
1H-NMR(CDCl3) : δ 1.1(m, 4H), 1.3(s, 6H), 2.4(s, 3H), 3.8(m, 4H),
4.3(m, 1H), 7.8(d, 1H, J=14Hz), 8.8(s, 1H). IR(KBr) : 1731, 1616, 1550, 1497, 1438 cm-1
Example41 5-Amino-1-cyclopropyl-6,8-difluoro-7-(14,6-trimehyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid
In the same manner as described in Example 39, 0.22g(0.74mM) of 5- amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 0.91g(1.48mM) of 1,5,6-trimethyl-3,6-diazabicyclo [3.1.0]hexane, and afforded 0.2g(67%) of titled compound as a yellow solid.
m. p. : 203 ~ 204ºC
1H-NMR(CDCl3) : δ 1.1(m, 4H), 1.3(s, 6H), 2.4(s, 3H), 3.9(m, 5H),
6.4(broad s, 2H), 8.6(s, 1H).
IR(KBr) : 1726, 1633, 1515, 1434 cm-1 Example 42 1-Cyclopropyl-6-fluoro-7- (1 ,5,6-trimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid
In the same manner as described in Example 39, 0.2g(0.71mM) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was allowed to react with 0.18g(1.42mM) of 1,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexane, and afforded 0.1g(yield : 38%) of titled compound.
m. p. : 230 ~ 231 ºC
1H-NMR(CDCl3) : δ 1.0 ~ 1.3(m, 4H), 1.3(s, 6H), 2.3(s, 3H),
3.4~ 4.3(m, 5H), 8.0(d, 1H, J=14Hz), 8.7(s, 1H).
IR(KBr) : 1725, 1631, 1561, 1505, 1452 cm-1
Example 43 1-Cyclopropyl-6-fluoro-7-(1,5,7-trimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid In the same manner as described in Example 39, 0.18g(0.68mM) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 0.17g(1.36mM) of 1,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexane, and afforded 0.2g(yield : 79%) of titled compound.
m. p. : 238 ~ 239ºC
1H-NMR(CDCl3) : δ 1.1 ~ 1.7(m, 4H), 1.4(s, 6H), 2.3(s, 3H),
3.2 ~ 4.1(m, 5H), 6.8(d, 1H, J=6Hz),
7.9(d, 1H, J=16Hz), 8.7(s, 1H).
IR(KBr) : 1729, 1631, 1511, 1469, 1404 cm-1
Example 44 1-Ethyl-6,8-difluoro-7-(l,5,6-trimethyl-3,6-diazabicyclo
[3.1.0]hexan-3-yl)-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
In the same manner as described in Example 39, 0.17g(0.63mM) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was allowed to react with 0.16g(1.26mM) of l,5,6-trimethyl-3,6-diazabicyclo[3.1.0]hexane, and afforded 0.14g(yield : 62%) of titled compound.
m. p. : 204 ~ 205ºC
1H-NMR(CDCl3) : δ 1.3(s, 6H), 1.5(t, 3H, J=6Hz),
2.4(s, 3H), 3.4 ~ 4.6(m, 6H),
7.8(d, 1H, J=14Hz), 8.5(s, 1H).
Following Example 45 to 47 illustrate pharmaceutical compositions containing the compounds of the invention as active ingredients.
Example 45
Compound of Example 11 or 18 25g
Starch 5g
Lactose 3.5g
Talc 1.5g The above components were blended with ethanol, granulated and filled into 100 capsules in accordance with conventional methods.
Example 46
Compound of Example 11 or 18 25g
Starch 5.4g
Calcium carboxymethyl cellulose 4.0g
Microcrystalline cellulose 5.0g
Magnesium stearate 0.6g
The above components were blended with ethanol, granulated and made into 100 tablets in a known manner.
Example 47
Compound of Example 22 0.5g
Lactic acid 1.2g
The above components were dissolved in 100ml of distilled water, adjusted to pH 4 with an aqueous sodium hydroxide solution, and tiien filled in ampules(10 ml) to make an injectable solution.

Claims

CLAIMS What is claimed is :
1. A novel quinolone compound of the following Formula(I) and its pharmaceutically acceptable salts thereof
Figure imgf000075_0001
wherein,
R1 is hydrogen or protective group,
R2 is hydrogen, amino, alkylamino from one to four carbon atoms, hydroxy, alkoxy from one to four carbon atoms, mercapto, alkylthio from one to four carbon atoms, or halogen,
R3 is alkyl from one to four carbon atoms, alkenyl from two to four carbon atoms, cycloalkyl from three to six carbon atoms, haloalkyl, hydroxy alkyl from two to four carbon atoms, methoxy, amino, alkylamino from one to two carbon atoms, dimethylamino, or optionally substituted phenyl with more than one of halogen atoms or alkyl from one to three carbon atoms,
Z is an amine of the following Formula,
Figure imgf000075_0002
(wherein, R4 is hydrogen or alkyl from one to four carbon atoms, R5 and R7 are, same or different, hydrogen or alkyl from one to two carbon atoms)
X is N or C-R6 (wherein, R6 is hydrogen, hydroxy, methyl, cyano, nitro, methoxy, halogen, or can form a bridge of the following Formula with
R3 ;
Figure imgf000076_0001
2. A process for preparing a compound of Formula(I) which comprises reacting a compound of Formula(II) with an amine of Formula(III) or its acid addition salts in the presence of solvent and base.
Figure imgf000076_0002
Figure imgf000076_0003
ZH ( III )
wherein R1, R2, R3, X and Z are as defined in claim 1, and Y is halogen.
3. The process as defined in claim 2, wherein the solvent is more than one selected from the group of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, alcohol, water, pyridine and picoline.
4. The process as defined in claim 2, wherein the base is more than one selected from the group of sodium hydroxide, potassium hydroxide, triethylamine, pyridine, picoline, lutidine, 1,4-diazabicyclo [2.2.2] octane [DABCO], 1,8- diazabicyclo [5.4.0] unde-7-cene(DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene(DBN).
5. An antibacterial composition which comprises more than one of the
compound of Formula(I) or its pharmaceutically acceptable salts as active ingredients.
Figure imgf000077_0001
wherein R1, R2, R3, Z, and X are as defined in claim 1.
PCT/KR1992/000003 1991-01-14 1992-01-14 Novel quinolone compounds and processes for preparation thereof WO1992012155A1 (en)

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WO1996001262A1 (en) * 1994-07-02 1996-01-18 Hanmi Pharmaceutical Co., Ltd. Novel quinoline compound and process for preparation thereof
EP0924213A1 (en) * 1996-09-27 1999-06-23 Daiichi Pharmaceutical Co., Ltd. Pyridobenzoxazine derivatives
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles

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WO1996001262A1 (en) * 1994-07-02 1996-01-18 Hanmi Pharmaceutical Co., Ltd. Novel quinoline compound and process for preparation thereof
EP0924213A1 (en) * 1996-09-27 1999-06-23 Daiichi Pharmaceutical Co., Ltd. Pyridobenzoxazine derivatives
EP0924213A4 (en) * 1996-09-27 2002-10-23 Daiichi Seiyaku Co Pyridobenzoxazine derivatives
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles
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