~, DESCRIPTION
BICYCLIC AMINO GROUP-SUBSTITUTED PYRIDONE-CARBOXYLIC ACID DERIVATIVES, ESTERS THEREOF
AND SALTS THEREOF, AND BICYCLIC AMINES USEFUL
AS INTERMEDIATES THEREOF
Technical Field This invention relates to novel compounds useful as antibacterial agents, and bicyclic amines useful as intermediates for the synthesis thereof.
Back~round Art A variety of antibacterial pyridonecarboxylic acid derivatives are known. For example, Japanese Patent Application Laid-Open No. 56673/'89 describes pyridonecarboxylic aGids of the general formuia O ., ~ ~ C O O H
wherein R repre.sents a lower alkyl group, a halogenated lower alkyl group, a lower alkenyl group, a cycloalkyl group" or a phemyl group which may have one or more substituents; X represents a nitrogen atom or C-A in which A represents a hydrogen atom or a halogen atom; Y
repre:;ents a hydrogen atom or a halogen atom; and Z
repre:;ents a group of the formula R1, (R,3CH)n ~ /
CA 022l2226 l997-08-Ol in which R~ represents a hydrogen atom, a lower alkyl-oxycarbonyl group, or an acyl group that may be substi-tuted by one or more halogen atoms; two of R 2~ R 3, R 4 and R5 are connected directly or through a lower alky3 chain to form a ring, and the others represent hydrogen atoms; and n is 0 or 1, provided that R 2 and R 3 are directly connected. However, no specific example o~ a compound of the above ~ormula (A) in which R 4 and R5 are connected through an ethylene chain to form a ring is 10 disclosed therein.
Moreover, European Patent Application Laid-~pen No. 0343524 discloses pyridonecarboxylic acid derivatives of the general formula / (~ H2)P
(C H2 ~ N-A (B) R1/ (CH2)m-R2 wherein R1 is hydrogen, hydroxy, C,-C4 alkyl, C1-C4 alkoxy,l oxo, halogen, or amino which may optionally be substi-tul;ed by C1-C4 alkyl and/or Ct-G4 alkanoyl; R2 is azido, hydroxy, I,l-C4 alkoxy, C1-C4 alkoxycarbonyl.
25 C1 -C4 alkanoyl, or amino which may optionally be substi-tuted by C1 -C4 aIkyl and/or C1-C4 alkanoyl; A is R~ O R5 O
RG~3,COOR3 R6~3,COOR3 R4 0~_,X
R3 is hydrogen or a carboxyl-protecting group; R4 is 35 Ct-G4 alkyl, G2-C,5 alkenyl, C3-C5 CyC loalkyl, mono- or difluorophenyl, or a five-membered or six-membered heterocyclic gr OUp which may optionally be substituted by halogen and/or Cl-C4 alkyl; R5 is hydrogen, amino, hydroxy or C1-C4 alkoxy; R6 is halogen; X is CH-(C1-G4 alkyl:), C=CH2, W-H or N-(Cl-C4 alkyl); Z is CQ or N; Q
is hydrogen, C1-C4 alkoxy, halogen, ~1 -C4 alkyl or cyano; m is an integer of O or 1; and n and p are each an in-teger of 1 to 3. However, they do not include any compound in which n is 0.
Furthermore, Chemical Abstract, 66, 37500b (1967,~ and Japanese Patent Application Laid-Open No.
11729,/'81 disclose compounds of the formula ¦ ~ ,NH
where;n R represents a hy,drogen atom or a carboxyl group.
Conventional pyridonecarboxylic acid deriva-20 tives substituted by a bicyclic amino group, such as those represented by the above general formulae (A) and (B), are useful as antibacterial agents. However, their antibacterial ac:tivities and, in particular, in vivo antibacterial ac:tivities are not always satisfactory.
The present invention has been completed as a result: of extensive investigations conductedL with a view to developing a pyridonecarboxylic acid derivative showing a furthe:r enhancement in antibacterial activity and, in particular, in vivo antibacterial activity.
D;sclosure of thle Invention Accordling to the present invention, there are provided novel blicyclic amino group-substituted pyr;-doneca!rboxylic acid derivatives of the general formula (I) =
A-Pri (I).
esters thereof ,and salts thereof, wherein:
Pri i~s a pyridonecarboxylic acid residue, and A is a bicyclic amino group represented by the following formula (C) and joined to the 7-position o~
the pyridonecarboxylic acid or a position equivalent to the 7--position ithereof.
F~1\
(ClJ2)n R3 L/ N ( C ) wher~in R1 and R2 may be,the same or different and each represents a hyd.rogen atom, a lower alkyl group or an amino-protecting group; R3~and R4 may be the same or 20 different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an oxo group, a lower alkoxy group or a lower alkyl group; and n is an integer of 0 or 1.
According to the.present invention, there are 25 also provided bicy.clic amine compounds of the following general formula (Ill) and salts thereof which are useful as int,ermediates for the synthesis of pyridonecarboxylic acid derivatives of the general formula (I).
R.~ -(I~ t 2)n R3 L/ - ~NH ( m CA 022l2226 l997-08-Ol wherein Rl, R2, R3, R4 and n have the same meanings as described previously~
The pyridonecarboxylic acid residue repre-sented herein by "Pri" is a group having a skeletal struct:ure of the following formula (D) in the mol~cule.
CO~
wherein x, y ancl z may be the same or different and each repres;ents a carbon atom or a nitrogen atom, and w represients a carbon atom.
"The 7-position of the pyridonecarboxylic acid or a p,osition equivaIent to the 7-position thereof"
means the position of w in the above formula (D). For . example, this me:ans the 7-position in pyridonecarboxyIic 20 acids having the: quinoline or 1,8-naphthyridine struc-ture, the 2-position in pyridonecarboxylic acids having the pyrido~2,3-cl]pyrimidine structure, and the 10-posi-tion in pyridone~carboxylic acids having the ofloxacin structure.
Accordingly, the present invention preferably provides bicycIic amino group-substituted pyridonecar-boxylic acid derivatives of the following general for-mula (I-A), esters thereof and saIts thereof.
~\ X ~
(C~2)11 D ~ C O O H (I - A) R ' ~Nl'T N,G
-;
wherein R5 represents a lower alkyl group, a lower alkeny~l group, al lower cycloalkyl group, a phenyl group or a heterocyclic group ~all of which may further be substituted); G represents ~-E or a nitrogen atom in which E represents a hydrogen atom or combines with Rs to form a bridge~ represented by the formula -S-CH(CH 3) -;
T represents C-Z: or a nitrogen atom in which Z repre-sents a hydrogen a~om, a halogen atom, a cyano group, a lower alkoxy group, a halogenated lower alkoxy group, a lower alkyl growp or a halogenated lower alkyl group, or combines with R5 to form a bridge represented by the formula -0-CH2-C'H(CH3)-; X represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or an amino group which may be protected; D represents C-Y
15 or a nitrogen atom in which Y represents a hydrogen atom or a halogen atom; and Rl, R 2~ R3, R 4 and n have the same ~leanings as; describe~ previously.
The compounds (I) of the present invention are structurally characterized by the fact that a speeific 20 b;cyclic amino g:roup is chosen as a substituent joined to the! 7-position of the pyridonecarboxylic acid or a position equivalent to the 7-position thereof.
The terms as used herein in connection with substituents andl the like are described below.
Although no particular limitation is placed on the scope of the term "halogen atom", fluorine, chlorine and bromine are preferred. The term "lower" means groups containing 1 to 7 carbon atoms, unless otherwise specified. The term "lower alkyl" comprehends, for 30 example, straight-chain and branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and pentyl, of which methyl is preferred. The term "lower alkenyl" comprehends, for example, vinyl, allyl, 1-pro-penyl and isopropenyl, of which vinyl is preferred. The 35 term "lower cycloalkyl" comprehends, for example, cyclo-propyl, cyclobutyl. cyclopentyl and cyclohexyl, of which cyclopropyl is preferred. The term "lower alkoxy"
comprehends, for exan-ple, methoxy and ethoxy.
In the ~definition of R 5, examples of the substituent(s) used in the "lower alkyl group which may further be substituted", the S'lower alkenyl group which may further be substituted", or the "lower cycloalkyl group which may further be substituted" include halogen atoms such as fluorine and chlorine. Examples of the substituent~s) used in the "phenyl group which may 10 further be substituted" include halogen, lower alkyl, lower alkoxy, hydroxy, nitro and amino. The term "heterocyclic group" as used in the definition of R5 comprehends, for example, five-membered and six-membered heterocyclic groups having N, 0 or S as a heteroatom, 15 such as pyrrole, furan, thiophene. thiazole, isothia-zole, oxazole, isoxazole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine an,d pyrazine. The heterocyclic groups may further be substituted. for example, by halogen, lower alkyl, IDwer alkoxy, hydroxy, nitro 20 and/or amino.
As the "protecting group" or "amino-protecting group" used in the "amino group which may be protected", there may be employed any of various groups which can readily be eliminated by a common deprotection reaction 25 such as hydrolysis or hydrogenolysis, without exerting no substantial influence on the other structural part.
Examples of easily hydrolyzable amino-protect-ing groups which can readily be eliminated by hydrolysis inclu,de oxycarbonyl groups such as ethoxycarbonyl, 30 t-butoxycarbonyl (abbreviated as Boc), benzyloxycar-bonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl and ~-(p-toluenesulfonyl)ethoxycarbonyl; acyl groups such as formyl, acetyl ;and trifluoroacetyl; and o-nitrophenyl-sulfenyl, trimethylsilyl, tetrahydropyranyl and di-35 phenylphosphinyl.
Examples of easily hydrogenolyzable amino-protec:ting groups which can readily be eliminated by hydrogenolysis include arytsulfonyl groups such as p-toluenesulfon~l; phenyl- or benzyloxy-substitut~d methyl groups such as benzyl, trityl and benzyloxy-methyl; arylmethoxycarbonyl groups such as benzyloxy-carbonyl and o-methoxybenzyloxycarbonyl; and halogeno-ethoxycarbonyl groups such as ~ -trichloroethoxy-carbonyl and ~-iodoethoxycarbonyl.
"Esters" should preferably be those which can 1~ be converted in~:o the corresponding free carboxylic acids (I) of th~: present invention by chemical or enzymological means. The esters which can be converted into the corresponding free carboxylic acids by c~emical means such as hydrolysis include, for example, lower aikyl esters such as methyl esters and ethyl esters.
The esters which can be converted into the corresponding free carboxylic acids not,only by chemical means but also by enzymological means include, for example, lower alkanoyloxy-lower alkyl esters such as acetoxymethyl 20 esters, 1-aceto,cyethyl esters and pivaloyloxymethyl esters; lower alkoxycarbonyloxy-lower alkyl esters such as 1-ethoxycarbonyloxyethyl esters; aminoethyl esters such as 2-dimethylaminoethyl esters and 2-(1-piperi-dinyl'~ethyl esters; and other esters such as 3-butyro-2~ lactonyl esters, choline esters, phthalidyl esters and(5-methyl-2-oxo--1,3-dioxol-4-yl)methyl esters.
As the salts of the compounds (I) of the present invention, pharmaceutically acceptable salts thereof are especially preferred. Examples thereof include salts formed with organic acids such as tri-fluoroacetic acid, aGetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid and amino acids (e.g., aspartic acid and glutamic acid); salts formed with inorganic acids such as hydrochloric acid and phosphoric acid; metallic salts such ;as sodium, potassium, zinc and s'iIver salts; ammo-.
nium salts; and salts formed with organic bases such as trimethylamine, triethylamine and N-methylmorpholine.
Salts of the compounds (111) of the present invent:ion which are useful as intermediates include salts formed wit:h inorganic acids such as hydrochloric acid alnd s~lfuric acid; and salts formed with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid.
The compounds (I) and ~111) of the present invention may sometimes exist in the form of hydrates and solvates. Moreover, they may exist in the form of optical isomers and stereoisomers ~cis- and trans-forms). These compounds are also within the scope of the present invention~
1~ Preferred examples of the compounds ~I) of the present invention are the compounds represented by the following general formula.(l-B).
X; O
zo H2N V~COOH
25 wherein ~5, G, T, X, Y and n have the same meanings as described previously.
More preferred examples of the compounds (I) of the present invention are the compounds represented by the following general formula (I-C).
X' O
~ ~COOH ( I - C) wherein R5' is a, cyclopropyl group which may be substi-tuted by f I uorine, a 2,4-di f I uorophenyl group or a t-butyl group, X' is a hydrogen atom, a halogen atom or an amino group, and T' is C~, CF, CCI, C-OCH3, C-~C~F2 or a nitrogen atom.
More specific examples thereof are the Gom-pounds described in the Examples which will be given later.
The following compounds and physiologically 10 acceptable salts thereof are also preferred examples of the compounds (I) of the present invention.
7-(1-Amino-3-azabicyclo~3.2.0]hept-3-yl)-8-cyano-1-cyclopropyl-B-fluoro-1,4-dihydro-4-oxoquinoline-3-car-boxylic acid.
7-~1-Amino-3-azabicyclo[3.2.0~hept-3-yl)-8-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-car-boxylic acid. t 7-(1-Amino-3-azabicyclo[3.2~0]hept-3-yl)-1-cyclo-propyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-20 carboxylic acid.
7-~1-Amino-3-azabicyclo[3.2.0~hept-3-yl)-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-quinoline-~-carboxylic acid.
The compounds (I) of the present invention may 25 be prelpared, for example, by the following (a) amination reacti,on, (b) hy,drolysis reaction and (c) ring closure reacti,on.
(a) Amination reaction The compounds (I) of the present invention, 30 esters thereof and salts thereof may readily be prepared by reacting a compound of the general formula (Il) L-Pri ~II) 35 wherein Pri has ithe same meaning as described previ-ously, L is a leaving group joined to Pri at the 7-posi-tion c~f Pri Qr al position equivalent to the 7-position thereof, and the carboxyl and oxo groups present in the pyridonecarboxylic acid residue represented by Pri may form a boron chelate bond therebetween, an ester thereof or a s,alt thereof with a bicyclic amine compound of the generall formula (Ill) F~ N
(C~ 2)n ( III ) 15 wherein Rl, R2, R3, R4 and n have the same meanings as described previously; and if a boron chelate part is present in the product, hydrolyzing it.
Examples of the leaving group L in the gereral formula (Il) inc:lude halogein atoms, lower alkoxy groups, lower alkylthio groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups, lower alkylsulfonyloxy groups and arylsulfonyloxy groups. Among others, halo-gen atoms such clS fluorine and chlorine are preferred.
This reaction may be carried out by stirring a 25 mixture of the compound (Il) and the compound (Ill) in an inert solvenl: at a temperature of 10 to 130~C and preferably 20 to 130~~, for a period of time ranging from 10 minutes to 24 hours and preferably from 30 minute~s to 3 hours. Useful solvents include water, 30 methanol, ethanol, acetonitrile, chloroform, pyridine, dimethylformamide, dimethyl sulfoxide, 1-methyl-2--pyrrolidone and the like. These solvents may be used alone or in admixture.
This reaction is generally carried out in the 35 presence of an acid acceptor by using the compound (Ill) in an amount equivalent to or slightly in excess of that of the! compound (Il). The compound (lli) may be used in excess so as to function as an acid acceptor too~
Preferred examples of the acid acceptor include organic bases such as triethylamine, 1,8-diazabicyclo~5~4.0]-7-undecene (DBU), pyridine, quinoline and picoline; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
Compounds (Il) are well known or may be pre-10 pared according to well-known processes. Bicyclic amine compounds (Ill) are all novel and the processes for the preparation thereof will be described later.
(b) Hydrolysis reaction 0~ the compounds (I) of the present inventi on, 15 those in carboxylic acid form may also be prepared by hydrol~yzing a compound of the general formula (IV) r ~ X O
R2---N ~ (IV~
R3 L ~ N 1 T N
25 wherein U represents a group which can be converted into a carboxyl group by hydrolysis, and R1, R 2~ R 3, R 4~ R 5, n, G, 1, X and D have the same meanings as described previ OLIS I y.
In this, case, examples of the group U convert-ible into a carboxyl group include an ester group, acyano group, an amido group, an amidino group, and a group of the formula -C(=NH)-O-(lower alkyl).
The above hydrolysis reaction may be carried out by bringing the aforesaid compound (IV) into contact 35 with water in a suitable solvent. In order to acceler-ate this reaction, it is usuallY carried out in the presence of a catalyst such as an acid or a base.
Usable acid catalysts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and organic acids such as acetic ac f d, trifluoroacetic acid, formic acid and p-toluenesulfonic acid. Usable base catalysts include metal hydroxides such as sodium hydroxide and barium hydroxide; carbon-ates such as soclium carbonate and potassium carbonate;
and sodium acetalte.
Usually, water is used as the solvent. How-ever, according to the properties of the compound ~IV), a water-miscible organic solvent such as ethanol, ethyl-ene glycol dimethyl ether, benzene or dioxane may be used in combination with water. The reaction tempera-15 ture may usually range from 0 to 150~C and pre~erably from 30 to 100~C.
This reaction may also be carried out by , heating the compound (IV) directly in the presence of an acid as described above. an~ then adding water thereto.
(c) Ring closure reaction Furthermore, the compounds (I) of the present invention may also be prepared by subjecting a compound of the general formula (V) ~, X O
(Cl- 2)n Ds~COoR
R3 ~ ~Nl T" L' 'NHR5"
wherein L' repre'sents a leaving group, R5" represents a lower alkyl group, a lower alkenyl group, a lower cyclo-alkyl group, a phenyl group or a heterocyclic group (all of whi ch may fur-ther be substituted), G' represents CH
or a n;trogen atom, T" represents C-Z or a nitrogen atom ..
in which ~ has the same meaning as described previously, R6 represents a lower alkyl group, an alIyl group or a benzyl group, amd R1, R2, R3, R4, n, X and D have the same meanings as described previously, to a ring closure reaction.
In this case, examples of the leaving group L' inclulde the same groups as described previously for ~he leavimg group L Among others, halogen atoms such as fluorine and chlorine are preferred.
This ring closure reaction may be carried out by stirring a mixture of the compound (V) and a solvent at a temperature of 30 to 150~C and preferably 30 to 100~C for a period of time ranging from 1 to 6 hours in the presence of a base (e.g., potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide or potassium fluoride) which is used in an amount of 1 to 3 moles per mole of the compound (V). Preferred examples of -the solvent include ethanol, dioxane, tetrahydrofuran, dimethylformamide and dimethyl sul-20 foxide.
The compound ~V)'used as the starting materialis also novel, and this may be prepared, for example, according to the following reaction formula (1).
Reaction formula (1) X X O
5L~ L LJ~COOR6 Rl~ I IK R, ~I o R2--N D~.l~ COOR~' R2--N ~,,COOR6 ~CI- 2)n ll ~C~ 2~ D
10~ --~~Nl' r~L~ R3--~NlT"~L~
152 N ~ COOR6' R2--N ~ COOR6 R --~N ~' T" ~ L' G~ N ~ R7 R --~N 1' T" ~. G' NHR
4 ' R4 t 20 wherein R6' is a hydrogen atom or has the same meaning as described previously for R6, R7 and R8 may be the same or different and each represents a lower alkyl group, and R1, R2, R3, R4, R5", R6, n, G', T", D, X, L
and L' have the same meanings as described previously.
When the compound (l~ of the present invention prepare~d according to any of the above-described pro-cesses (a), (b) and (c) has an amino-protecting group, it may be subjected to a hydrolysis reaction or a hydro-genolys;is reaction as desired. Thus, there can be 30 obtaine!d a compound (I) of the present invention in which t:he amino-protecting group has been converted into a hydrogen atom.
The realction for eliminating the amino-pro-tecting group by hydrolysis may be carried out in the same manner as de~scribed in the above process (b).
Alternatively, the reaction for eliminating the amino-protecting group by hydrogenolysis may advan-tageously carried out by treating a compound (I) of the present invention having an easily hydrogenolyzable amino--protectingr group with hydrogen gas in a solvent in the presence of a catalyst. Thus, there can be obtained a compound of the present invention in which the amino-protec:ting group has been converted into a hydrogen atom. The catalysts which can be used in this re~ction inclucle, for example, platinum, palladium and Raney 10 nickél catalyst. Usable solvents include, for example, ethylene glycol, dioxane, dimethyl~ormamide, ethanol, acetic acid and water~ This reaction may be carried out at a t:emperature: of 60~C or below and is usually carried out at: room temperature.
When the easily hydrogenolyzabl e amino-pro-tecting group is; benzyl, trityl, benzyloxycarbonyl or p-toluenesulfonyl and the,like, the protecting group may be eliminated by metallic sodium treatment in liquid ammonia at a temperature of;-50 to -20~C.
The ccmpound (Ill) used as the starting mate-rial in the above-described process (a) may be prepared by tre!ating a ccmpound of the general formula (Vl) R
(C~ 2)n ~N R (VI) F~10 wherein R9 and R1o have the same meanings as described previously for R3 and R4, or represent groups convert-ible into R3 and R4, Rl1 represents an amino-protecting group, and R1, R2 and n have the same meanings as de-scribed previously, so as to eliminate the amino-pro-tecting group R1, and convert it into a hydrogen atom;
and w~en Rg and,~or R10 are groups convertible into R3 and/or R4, convlsrting Rg and/or Rlo into R3 and/or R4~
In this case, examples of the amino-protecting group Rt1 inclu~e the above-described easily hydrogeno-Iyzable amino-protecting groups and easily hydrolyzable amino--protecting groups. When Rl or R 2 i n the compound (Vl) ;s an amino-protecting group, it is desirable for subsequent reactions to employ, for R1l, an amino-pro-tecting group differing in character from the amino-10 protecting group represented by R1 or R 2 For exampie,when l:he amino-protecting group represented by Rl or ~2 is an easily hydrolyzable amino-protecting group such as t-butoxycarbonyl, an easily hydrogenolyzable amino-protecting group such as benzyl or trityl is pre~erably 15 chosen for Rll This elimination reaction may be carried out by subjecting the compound (Vl) to a hydrogenolysis or hydrolysis react:ion which has previously been explained.
With regard to Rg and R1o, examples of the "group,s convertible into R3 and R 4 i nclude methane-sulfonyloxy, p-toluenesulfonyloxy, benzyloxy, carboxyl, carbamloyl, hydroxyiminomethyl, benzylidene, cyclic acetal and dithioacetal.
Metha~esulfonyloxy and p-toluenesulfonyloxy 25 may be converted, by a nucleophilic substitution reac-tion, into a halogen atom, a cyano group or a lower alkoxy group as used for R3 or R4.
Benzyloxy may be converted into a hydroxyl group as used for R3 or R4, by a hydrogenolysis reaction 30 or a hydrolysis reaction. Carboxyl may be converted into a halogen atom as used for R3 or R4, by deriving an acid halide therefrom and then treating it with the Wilkinson catalyst {RhCl[P(C6H 5) 3]3}.
Furthermore, carbamoyl and hydroxyiminomethyl 35 may be converted into a cyano group as used for R3 or R4, by treatment with thionyl chloride or chlorosulfonyl isocyanate. Benzylidene, cyclic acetal and d;thioacetal may be convert~d into an oxo group as used for R 3 or R 4, by an oxidation reaction, a hydrolysis reaction using an acid catalyst cand a hydrolysi 5 reaction in the presence of me~rcuric chloride, respectively.
Compc~unds (Vl) are also novel and may be prepalred, for e:xample, according to the processes de-scribed in Examples I to lll which will be given later or processes equivalent thereto.
The compounds (I) of the present invention and the intermediate compounds ~III) thereof, which have been prepared in the above-described manner, may be isolalted an~ pulrified according to any conventional proce~dure. The!se compounds are obtained in the form of salts;, free acids or amines, or hydrates, depending on the c:onditions of isolation and purification. According to the intendeal purposes,r these forms may be converted into each other to obtain the compounds of the present invemtion in desired forms.
The stereoisomers of the compounds (I) and (Ill) of the present invention may be separated from each other by any conventional method such as fractional crystallization or chromatography. Their optical iso-mers may be i so lated by an optical resolution method 25 whichl is known per se.
The compounds (I) of the present invention and salts thereof, which have been obtained in the above-described manner, are all novel compounds and are valu-able as antibacterial agents because of their high 30 antibacterial activities. The compounds (I) of the present invention and salts thereof can be used not only as drugs for human beings and animals, but also as fish drugs, agricultural chemicals and food preservatives.
Esters of the compounds (I) of the present invention are valuable as raw materials for the synthe-sis of the compounds (I) of the present invention in carboxylic acid form. However, if these esters them-selves may readily be converted into the correspondin~
carboxylic acids in the body, they exhibit the same action and effect as the carboxylic acids and are hence useful as antibacterial agents.
Moreover, the compounds (Ill) of the present invention are useful as direct intermediates for the synthesis of the compounds (I) of the present invention~
10 ~est l~ode for C,arrYin~ Out t~e Invention Now, the in vitro and in vivo antibacterial activities of the compounds (I) of the present invention are described with reference to the following experimen-tal data. The results are summarized in Table 1. The 15 figures given in th;s table indicate minimum inhibitory concentrations (MIC; ~g/ml) as measured according to the procel~ure described in ~hemotherapy, 2g(1), 76 (19&1), and tl~e figures given in brackets indicate effects (ED50; mg/kg~ on systemic infection in mice.
The eFfects (ED 5 o; mg~kg) on systemic infec-tion in mice were determined as follows: Male Std-ddy strain mice (weighing about 20 g) were infected with each of the pathogenic bacteria shown in Table 1 by administering 5 x 10 3 Vi able microorganisms intraper~-25 toneally to each mouse. Then, a suspension of each test compo~nd in o, 4a~ carboxymethylcellulose was orally adminiistered twiice, i.e., immediately after infection and 6 hours after infection. Seven days after infec-tion, the ED 5 0 value was calculated from the survival rate of each mouse group by probit analysis.
As re1:erence compounds, there were used pipe-midic acid that is an excellent antibacterial agent currently on the market, and 7-(1-amino-3-azabicyclo-[3.1.0]hex-3-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-35 4-oxoquinoline-3-carboxylic acid that has the following structure and is disclosed in Example 6 of the aforemen-tioned Japanese Patent Application Laid-Open No.
~673/'89.
H2N ~_COOH
Tab I e 1 Ant i bacter i a I act i v i t i es X O Bacterial s train F ~ StaphY- Pseudo-T ~ lococcus monas Rs aureus aeru nosa R s X T Salt 50774 No. 12 1 H C F - 0.025 0.39 ~ [0.928] [~.oo 2 H C-Cl CF3C02H 0.013 0.39 ~ [0.682] [~.28 3 H C-O~le CF3C02H 0.013 0.78 A [1.41 ] [8.62 4 H C H CF3C02H 0.1 0.78 ~ [~.42 ] [6.92 NH2 C F CF3C02H 0.025 0.39 ~ [1.16 ] [5.08 6 F C F - 0.05 1.56 ~ [~.81 ]
7 Ph-F2 H C H - 0.05 1.56 [2.25 ]
8 Ph-F2 H N CF3C02H 0.05 0.39 [0.799] [3.25 g H N - 0.05 0.78 ~ [1.18 ] [~.88 12 ~ H C-O~le H C 1 0.013 0.78 F [2.32 ]
Compound of Exa~r~le 6 of 0. 025 0.1 Japanese Patent Application[ 6.82 ] [12 5 Re:ference ];aid OPe~ No. 56673/'89 compound Pipemidic acid [215 ] [70 8 Ph-F2: 2,~-di~luorophenyl; Me: methyl As shown in Table 1 above, the compounds (1)-of the present invention exhibit an excellent antibacte-rial activity not only in vitro but also in animal experiments. E.specially in the in vivo experimer-ts, the compounds of the present invention exhibit a more excel-lent antibacterial activity than the reference com-poundls.
The compounds (I) of the present invention have low toxicity and can hence be used as antibacterial 10 ~gents for the prophylaxis and treatment of bacterial diseases in mam,mals including man.
When the compounds (I) of the present inven-tion àre used as antibacterial agents in human beings, ~heir dosage may vary according to the age and body 1~ weight of the patient, the severity o~ symptoms, the route of administration, and the like. However, it is recommended to administer them in a daily dose of 5 mg to 5 g which may be given once or in several divided ' doses. The route of administration may be either oral 20 or parenteral.
The compounds (I) of the present invention, may be administered alone to human beings and other mammals. However, they are usually combined with one or more Ipharmaceutically acceptable additives and adminis-25 tered in the form of pharmaceutical preparations. S~lchpharmaceutical preparations include tablets, solutions, capsules, granules, powders, syrups, injections, oint-ments artd the like. These pharmaceutical preparations may be made in the usual manner by using common addi-30 tives. For example, as additives for oral preparations,there may be used various carriers or diluents which are commonly used irt the field of pharmaceutics and do not react with the compounds (I) of the present invention, such as starch, mannitol, crystalline cellulose, car-35 boxymethylcellulose calcium, water and ethanol. More-over, as additives for injections, there may be used various additives which are commonly used in the field of injections, such as water, physiological saline, glucose solutions and trans~usions.
The aforesaid solutions and ointments may also be used for purposes of therapy and treatment in the fields of otorhinolaryngology and ophthalmology.
The present invention is further illustrated by thle following examples. Examples I to lll relate to the preparation of intermediates ~III), Examples 1 to 1 relate to the p;reparation of desired compounds (I~, and Example A relates to a pharmaceutical preparation.
ExamPle I
1-~t-Butoxvc;3rbonvlamino)-3-azabicYclo r3. 2.01hePtane (A~ :35.1 g of 1-cyclobutene-1-carboxylic acid 1~ (J. ~hem. Soc., p. 3002, 1953) was dissolved in 250 ml of melhylene chloride, and a solution of diphenyldiazo-methar~e in methylene chlorride was added dropwise thereto at room temperature until a red color did not disappear any longer. Afl:er this mixture was stirred at room 20 temperature for one hour, the dichloromethane was dis-tillecl off. To the resulting crude product were added 750 ml of tetrahydrofuran, 93.4 g of N-benzyl-N-(methoxymethyl)t:rimethylsilylmethylamine (Chem. Pharm.
B~ll., Vol. 33, p. 2762, 1985), 10.9 g of cesium fluo-2~ ride and 15.9 g of trimethylsilyl triflate, followed byheating at 60~C for 18 hours. The reaction mixture was cooled to ~~C, and 350 ml of a 15% aqueous solution of sodium hydroxide was added dropwise thereto, followed by stirring at that temperature for 30 minutes. After the 30 organic layer was separated and dried (over anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (using a 30:1 mixture o~ n-hexane and ethyl acetate as the eluent) and 3~ recrystallization (from diisopropyl ether) to obtain 52.1 g of 3-benzyl-1-diphenylmethoxycarbonyl-3-azabicyclo[3.2.0]heptane.
Melting point: 96-99~C
1H-NMIR (CDCI 3), (j: 1. 69-2.32 (m, 4H), 2.40-3.50 (m, 5H), 3.71 (s, 2H), 6.87 (s, 1H), 7.17-7.44 (m, 15H~
IR ~KI3r), cm~~: 1720 MS (m,~z): 398 (MH ) (B) 45.8 g of the compound obtained in the preceding step (A) and 92 ml of a 20% aqueous solution o~ sodium hydro,cide were added to 700 ml of methanol, 10 fol lowed by hea~ting under reflux for 5 hours. After cooling, this miixture was neutralized by the addition o~
20% hydrochloric: acid, and concentrated under reduced pressure. After the addition of water and diisopropyl ether, the resulting mixture was vigorously stirred and 1~ the aqueous phase was separated. After this aqueous layer was continuously extracted with chloroform, the extract was dried (over a~7hydrous magnesium sulfate) and the chloroform was distilled off. The resulting crude product was dissolved in 450 ml of t-butanol, and 88.2 g 20 o~ diphenylphosphoryl azide (DPPA) and 32.4 g of tri-ethylamine were added thereto. followed by heating under reflux ~or 15 hours. The reaction mixture was concen-trated under reduced pressure, mixed with ethyl acetate, and washed twice with a 10% aqueous solution of sodium 25 hydroxide. The organic layer was dried (over anhydrous magnesium sulfate) and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromiatography (using a 9:1 mixture of n-hexane and ethyl acetate as the eluent) and recrystal-lization (from n-hexane) to obtain 17.6 g of 3-benzyl-1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0~heptane.
Melting point: Ij9-70~C
1H-NMR (~DCI 3), ~j: 1. 42 (s, 9H), 1.50-1.77 (m, lH), 2.03-2~45 (m, 5H~, 2~60-2~80 (m, 1H), 2~73 (d, 1H, J=
3~ 9Hz), 3.01 (d. 1H, J=9Hz), 3.68 (s, 2H), 4.73 (br s, 1H), 7~19-7~41 (m, 5H) ..
~ 25 IR (K:Br), cm 1 3380, 1~85 MS (m/z): 303 (MH ) (C) 5 g o-F the compound obtained in the preceding step (B) was dissolved in 100 ml of ethanol, and 1 g of 10% palladium-carbon was added thereto.
Then, a stoichiometric amount of hydrogen was added there!to. After the catalyst was separated by fiItra-tion, the solve~nt was distilled off. The resulting crude! crystals were recrystallized from n-hexane diiso-10 propyl ether to obtain 3 g of 1-(t-butoxycarbonylamino)-3-azabicyclo~3.2.0]heptane.
Melting point~ 116~C
1H-NMIR (CDGI 3), ~: 1. 25-1.41 (m, 1H), 1.45 (s, 9H), 1.96-2.3~ (m, 4H~, 2.65-2.87 (m, 3H), 2.95-3.15 (m, 2H), 1~ 4.82 (br, 1H) IR (KBr), cm-1: 3294, 3185, 2982, 1692 MS (m/z): 213 (MH+) ~xample ll 1-Methvlamino-3-azabicYclor3.2.01he~tane (A) 6.8 g of 3-benzyl-1-(t-butoxycarbonyl-amino)-3-azabicyclo[3.2.0]heptane was dissolved in 20 ml of methylene chloride, and ~0 ml of trifluoroacetic acid was added thereto. followed by stirring for 3 hours.
The reaction mixture was concentrated, mixed with an Z5 aqueous solution of sodium hydroxide under cooling with ice, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate. the chloro-form was distilled off. The resulting crude product was dissolved in 47 ml of formic acid, and 17 g of acetic 30 anhydride was added dropwise thereto, under cooling with ice, over a period of 90 minutes. After the addition of ice water, the resulting mixture was neutralized by the addition of an aqueous solution of sodium hydroxide under cooling with ice, and extracted with ethyl ace-3~ tate. The organic layer was dried over anhydrous magne-sium sulfate and then concentrated under reduced pres-CA 022l2226 l997-08-Ol sure. The resulting residue was purified by silica gel column chromatography (using a 30:1 mixture of chloro-form and methanol as the eluent) to obtain 3.1 g of 3-benzyl-1-formylamino 3-azabicyclo[3.2.0]heptane.
1H-NMIR (CDCI 3), ~: 1. 61-1.82 (m, 1H), 2.08-2.50 ~m, 5H), .2.61-3.14 ~m, 3H), 3.69 (s, 2H), 5.90 (br, lH), 7.18-7.42 (m, 5iH), 8.~5 ~d, 1H, J=2Hz) IR ~neat), cm 1 3270, 3028, 2940, 2791, 1659, 1530 MS (m,/z): 231 ~MH ) (B) :3.1 g o~ the compound obtained in the preceding step (A) was dissolved in 30 ml of toluene, and 20 ml of a 10% solution of sodium bis(2-methoxy-ethoxy)aluminum hydride in toluene was added thereto, followêd by heal:ing under reflux for 2 hours. After 15 cooling, the reaction mixture was slowly added to 20%
sulfuric acid under cooling with ice, and the insoluble matter was separated by f,iItration. The fiItrate was adjust;ed to pH 11 by the addition of a 20% aqueous ' solution of sodium hydroxide, and then extracted with 20 chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (using a 100:1 mixture of n-hexane and ethyl aceta~e as the eluent) to obtain 1.97 g of 3-benzyl-1-methylamino-3-azabicyclo[3.2.0~hep-tane.
1H-NM~ (CDCI 3), ~: 1. 40-1.72 (m, 2H), 1.89-2.55 (m, 6H~, 2.33 (s, 3H), 2.79 (d, 1H, J=20Hz), 2.83 (d, 1H, J=20Hz), 3.66 (s, 2H), 7.18-7.43 (m, 5H) IR (neiat), cm I 3270, 2937, 2788 MS ~m/z): 217 (MH'), 187 (C) 1.95 g of the compound obtained in the preceding step ~13) was dissolved in 30 ml of ethanol, and 0.4 g of 10% palladium-carbon and 2 ml of concen-3~ trated hydrochloric acid were added thereto. Then, astoichiiometric arnount o~ hydrogen was added thereto at 50~C. The catalyst was separated by fiItration and washed with methanol. After the solvent was distilled off, the resulting residue was adjusted to pH 11 by the additlon of an aqueous solution of sodium hydroxide, and then extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled of~ under reduced pressure to obtain 0.96 g of 1-methylamino-3--azabicyclo~3~2.0~heptane.
'H-NMR (CDCI 3), ~: 1. 21-1.45 (m, 1H), 1.77-3.00 ~m, 10 10H), 2.38 (s, 3H) IR ~neat), cm 1 3270, 2942. 1692 Exam~le 111 1-~t-Butoxycarbonvlaminomethvl)-3-azabicvclor3.2.0l-he~tane (A) 13 g of 3-benzyl-1-diphenylmethoxycarbon-y3-3-azabicyclo[3.2.0]heptane was dissolved in 100 ml of tetrahydro~uran, and 2.8 g of lithium chloride was added thereto. After 2.5 g of sodium borohydride was added ' little by little, 30 ml of methanol was slowly added zO thereto and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, mixed with ice water, and extracted with ethyl acetate. After the extract was mixed with 10% hydrochloric acid and stirred 25 vigorously, the aqueous layer was separated. This aqueouC; layer was adjusted to pH 8 by the addition of a 10% aqueous solu1:ion of sodium hydroxide, and then extracted with el:hyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was 30 distilled off uncler reduced pressure. The resulting residue! was puri~ied by silica gel column chromatography (using a 4:1 mixture o-F n-hexane and acetone as the eluent) to obtain 5.4 g o~ 3-benzyi-1-hydroxymethyl-3-azabicyclo~3.2.0]heptane.
1H-NMR (CDCI 3), ~: 1. 64-2.19 (m. 6H), 2.28-2.80 (m, 4H), 3.52-3.77 (m, 4H), 7.18-7.43 (m, 5H) CA 022l2226 l997-08-Ol IR ~neat), cm 1: 3346, 2934, 2785 MS (m/z): 218 ~MH ) (B) 5.3 g of the compound obtained in the preceding step (A) was dissolved in 200 ml of tetra-hydrofuran, and 7.1 g of triphenyIphosphine, 5.~ g ofdiethyl azodicarboxylate and 7.4 g of diphenylphosphoryl azide were successively added thereto, followed by stirring at room temperature for 48 hours. After the reaction mixture was concentrated under reduced pres-10 sure, ethyl acetate and 10% hydrochloric acid were addedthereto. The resulting mixture was vigorously stirred and the aqueous phase was separated~ This aqueous layer was adjusted to pH 1~ by the addition of a 20% aqueous solution of sodium hydroxide, and then extracted with 15 chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (using a 30:1 mixture of n-hexane and ethyl acetate as the eluent) to obtain 20 5.4 g of 1-azidomethyl-3-benzyl-3-azabicyclo~3.2~0]-heptane.
1H-NMR (CDCI 3), ~: 1. 65-2.26 (m, 6H), 2.39-2~52 (m, 1H), 2.80 (d, 1H, J=9Hz), 2.81 (d, lH, J=9Hz), 3.37 (d, 1H, J=20Hz), 3.43 (d, 1H, J=20Hz), 3.64 (d, 1H, J=
16.5Hz), 3.71 (d, 1H, J=16.5Hz), 7.18-7.44 (m, 5H) IR (neat~, cm 1 2937. 2787, 2Q96 MS (m~z~: 243 ~MH ) (C) 3.4 g of the compound obtained in the preceding step (B) was dissolved in 70 rnl of tetrahydro-30 furan, and 5.9 g of triphenylphosphine was added there-to, followed by stirring at 50~C for 2 hours. Then, 55 ml of a 28% aqueous solution of ammonia was added there-to, f,ollowed by stirring at 50~C for 3 hours. The organic layer was separated and the aqueous layer was 35 extracted with ~diethyl ether. After 1N hydrochloric acid was added to the combined organic layers, the resulting mixture was vigorously stirred and the aqueous phase was separated~ This aqueous layer was adjusted to pH 11 by the addition of a 10% aqueous solution of sodiulm hydroxide, and then extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reducled pressurle. The resulting residue was dissolved in 100 ml of tetrahydrofuran~ Then, 7.7 g of di-t-butyl dicarlbonate was added thereto, followed by stirring at room temperature for 15 hours. After the reaction mixture was conoentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 9:1 mixture of n-hexane and ethyl acetate as the eluent~ and recrystallization (from n-hexane) to ob-tain 3.92 g of 3-benzyl-1-(t-butoxycar-bonylaminomethyl)-3-azabicyclo~3.2.0~heptane~
Melting point: 78-79~C
7H-NMR ~CDCI 3), ~: 1. 44 (s, 9H), 1~64-2.47 (m, 7H~, 2.72 (d, 1H, J=t3Hz), 2.74 (d, 1H, J=9Hz), 3.20 (dd, 1H, 20 J=23Hz, 6Hz), 3.28 (dd, 1H, J=23Hz, 6Hz) IR ~KE3r), cm~': 3372, 2972, 2932, 2797, 1688, 1530 MS (m,'z): 317 (Mh ), 259 (D) 2.9 g of the compound obtained in the preceding step l~C) was dissolved in 60 ml of ethanol, 25 and 0.6 g of 1O9D palladium-carbon was added thereto.
Then, a stoichiometric amount of hydrogen was added thereto at 50~C. After the catalyst was separated by filtration, the solvent was distilled off. The result-ing crude crystals were recrystallized from n-hexane-30 diisopropyl ether to obtain 1.58 g of 1-(t-butoxycar-bonylaminomethyl)-3-azabicyclo[3.2.0~heptane.
Melting point: 83-86~C
IR (KEir), cm 7: 3311, 3192, 2960, 1720, 1556 Examplle 1 7-(1-Amino-3'-azabicvclor3.2~0]he~t-3-vl)-1-cvclo~ro-Pvl-6.8-difluoro-1,4-dihvdro-4-oxoauinoline-3 car-ba,xvlic acicl ~ A) 1.9 g of t-(t-butoxycarbonylamino)-3-azabicycl'o~3.2.0]heptane and 0.83 g of 1-cyclopropyl-6,7,8-trifluorc,-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were addecl to 1~ ml of pyridine, followed by heat-ing under reflulx for 4 hours. After the solvent was 10 distilled off ulnder reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 100:1 mixture of chloroform and methanol as the eluent) and recrystallization (from ethyl acetate-diiso-propyl ether) to obtain 0.99 g of 7-[1-(t-butoxycarbon-1~ ylamino)-8-azabicyclo[3.2.0]hept-3-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (m.p. 211-215~C~. , (B) 0.97 g of the compound obtained in the preceding step ~A) was dissolved in 20 ml of a 35%
20 solution of hydrogen chloride in ethanol, and this solution was heated at 80~C for 10 minutes. After the reaction solution was concentrated under reduced pres-sure, acetonitrile and diethyl ether were added thereto, a'n'd the formed crystals were collected by fiItration.
25 These crystals were purified by CHP-20P column chroma-tography (using a 7:3 mixture of water and acetonitrile as the eluent) to obtain 244 mg of the desired product [m.p. 242-247~C (dec.)].
ExamDle 2 7-(1-Amino-3-azabicvclor3.2.01hePt-3-vl~-8-chloro-1-cvcloProPvl-6-fluoro-1.4-dihvdro-4-oxoquinoline-3-carboxvlic acid trifluoroacetate (A) 1.22 g of 1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane, 0.96 g of 8-chloro-1-cyclo-35 propyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-car-boxylic acid and 0.58 g of 1,8-diazabicyclo[5.4~0]-7-undecene were added to 20 ml of acetonitrile, followed by heating under reflux for 3.5 hours~ After the sol-vent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography ~using a 100:1 mixture of chloroform and methanol as the elue~t) and recrystallization (from ethyl acetate-diisopropyl ether) to obtain 0.96 g of 7-rl - (t-butoxycarbonylamino)-3-azabicyclo~3.2~0]hept-3-yl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-10 oxoquinoline-3-carboxylic acid (m.p 200-202~C).
(B) ID.94 g of the compound obtained in the preceding step (A~ was dissolved in 10 ml of methylene chloride, and 2l0 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 15 15 hours. After the reaction mixture was concentrated under reduced pressure, acetonitrile and diethyl ether were added ther~eto and the formed crystals were col-lected by fiItration. These crystals were washed with acetonitrile to obtain 650 mg of the desired product [m.p. 236-240~C (dec.)~.
Exam~le 3 7-(1-Amino-3-azabicvclo[3.2.01hept-3-vl)-1-cYcloPro-Pvl-6-fluorQ-1.4-dihvdro-8-methoxv-4-oxoauinoline-3-carboxvlic acid trifluoroacetate ~A) 1.07 g of 1-~t-butoxycarbonylamino)-3-azabhcyclo[3.2.0]heptane, 1.15 g of 1-cyclopropyl-6,7-difluoro-1,4-dilhydro-8-methoxy-4-oxoquinoline-3-car-boxylic acid-BF 2 chelate and O.B8 g of triethylamine were ;added to 1,B ml of dimethyl sulfoxide, followed by 30 stirring at room temperature for 16 hours. After the addition of wat~er, the resulting mixture was extracted with chloroform and the solvent was distilled off. To the r,esulting r,es;due were added 300 ml of 80% ethanol-water and 50 ml of triethylamine, followed by heating under reflux for 3 hours. After the reaction mixture was concentrate,d under reduced pressure, the residue was mixed with water and extracted with chloroform. AFter the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (using a 10~:1 mixture of chloroForm and methanol as the eluent~ and recrystallization (from ethyl acetate-diiso-propyl ether) to obtain 1.17 g of 7-[1-~t-butoxycarbon-ylamino)-3-azabicyclo[3.2.0]hept-3-yl]-1-cyclopropyl-6-Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carbox-10 ylic acid (m.p. 211-213~C).
(B) The compound obtained in the preceding step (A) was treated in the same manner as described in step (B) oF Example 2 to obtain the desired product [m.p. 230-23~~C (dec.)].
15 ExamPles 4-11 The compounds shown in Table 2 below were obtained by carrying out .reaction and treatment in the same manner as described in Example 2.
t .
Table 2 Exam- R~--N ~ COOtl po nt R , R z n R s X T Salt A Boc H 1 234-236 4 0 ~ H CH
(dec.) A Boc H 229-231 0 ~ NH2 CF
(dec.) A Boc H ~ 230-235 6 0 ~ F CF
(dec.) A Boc H 147-150 7 0 Ph-F2 H CH
A Boc H 131-13 8 0 Ph-F2 H N
A Boc H 247-250 B H H ~ H CF3C02H261-267 - (dec.) A H H 0 t-Bu H N 245-253 (dec.) A Boc H 210-215 11 0 1 NH2 CH (dec.) (dec.) Boc: t-butoxycarbonYI; Ph-F2: 2,4-difluorophenyl Me: methyl; t-Bu: t-butyl Examcles 12-16 The compounds shown in Table 3 below were obtained by carrying out reaction and treatment in the same manner as described in Example 3.
Table 3 Rl Exam- R2 \N X O Melting ple (C~2)n ~ COOH po nt Rs R I R 2 n X R s T Salt A Boc H
Non-crys-12 0 H ~ ~C-OMe talline B H H F HCl 218-223 (dec.) 13 A Me H O H ~ C-OAle - 205-207 A Boc H - 188-190 1~ 1 k ~ C-OMe E, H H HCl 162-166 A Boc H . C 205-210 B, H H O ~ HCl 273-283 Me (S)(dec.) A Boc H - 1~6-152 16 0 H ~ C-OCHF2 B H H - 237-2~2 (dec.) Boc: t-butoxYcarbonyl; Me: methyl Exam~le A (Formation of tablets) Compound of Example 1 or 2 250 g Corn sitarch 54 g Carboxymethylcellulose calcium 40 g Microc:rystalline cellulose 50 g Magnes;ium stearate6 g The above ingredients were blended together with ethanol~ lhe resulting blend was granulated and tablet:ed in the usual manner. Thus, there were obtained 1,000 tablets each weighing 400 mg~
Ex~loitabilitv in Industrv As des,cribed above, the compounds (I) of the present invention are useful as drugs (antibacterial agents) for mammals including man. Moreover, the com-pounds (111) of the present invention are useful as direct: intermediates for ~the synthesis of the compounds (I) .