AU603352B2 - Benzoheterocyclic compounds - Google Patents

Description

Applicati Complete Priority: CON MON WE ALT H OFA STRAL3:, PATEN4T AC7.M 1952 COMPLETE SPECIII ICATION (original) FOR OFFICE USE Class Int. Class on Number: 9 Lodged: Specification Lodged: Accepted: Published: T71,P-7 067.

52 Relatfed Art: Y-GSH-I-NAR--H-I-GUeHiE 4 On 0 4 44 4 4 Name of Applicant: 040 Address of Applicant: Q*4 Actual Inventor(s) tC r Address for Service: apaf-pi HIRAKI UEDA SHINJI AKI dtTcS~ 4 2&\.efV e.) HISASHI MIYAMOTO TATSUYA OTSUKA DAVIES COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

4

C

Complete Specification for the invention entitled: "BENZ OHETEROCYCLIC COMPOUNDS" The fol~lowing statemeant is a full description of this invention, including the best method of performing it knowi; to me Insert place and date of signature.

Signature of Declarant(s) (no attestation required).

Note: Initial all alterations.

4. 1 .Ir the first application ad in a"Convention country in respect of the invention the subject of the -application.

Declared at this y of Nara-ken, JAPAN 25th Fe ua y 19C7 DAVIES COLLISONk MELBOURNE and CANBERRA.

t" -la- BENZOHETEROCYCUIC

COMPOUNDS

The present invention relates to novel antimicrobial benzoheterocyclic compounds of the formula EXI-i.

0 ~eq f ft tIff ft

I

r ff1 ''If t I ft t 01

COOH

wherein when R 3 is methyl or ethyl group, R2is a I-

IA

I

RI

pyrrolidinyl group of the formula:

R

NJR

wherein R, is an amino C 1

-C

6 alkyl group, said amino group being optionally substituted by one C 1

-C

6 alkyl group; or an amino group which is optionally substituted by one -C alkyl group and RJ is hydrogen atom; a C 1

C

6 alkyl group; or a piperazinyl group which has optionally one substitu~rit selected from the group consisting of oxo, hydroxy and a halogen; or a heterocyclic group selected from the group consisting of the following groups: NNRD, RG R N -N N R 1 and-N u 1; I lb in which RB is a 2-oxo-l,3--dioxolenemethyl substituted by a Cl-C 6 alkyl or a C 3

-C

8 cycloalkyl; RC is hydrogen, a Cl-C 6 alkyl, 8 Cl 7

C

6 alkoxycarbonyl, or a phenyl (Cl-

C

6 )alkyl; RD is hydrogen or a Cl-C 6 alkyl; RG is a lC alkyl; and RH is a Cl-C 6 alkanoyl; -N 0 or a group of the formula: wherein RK is Ii 4 00 o 48* ~I 0* 0404 4 8 *440 4., 4. 0* 0048 *400 *00' 0*00 08 *0 0 *0 8 8080 it :tct t 4, 4~ S 4 4. 8 44 hydrogen or a Cl-C 6 alkyl group or a morpholino group which is subsituted by one to three Cl 7

C

6 alkyl groups where each of the alkyl group is substituted by 1 to 3 substituents selected from the 'group consisting of -NH 2 and a halogen; or when R 3 is methyl having 1 to 3 halogens, -CH 2

OH,

-CH

2

-NJ

1 a (Cl-C 6 )alkylthiomethyl, or a (Cl-C 6 )alkoxy- 0 RD methyl, R 2 is a group of the formula: -N \/N-RC (wherein RC and RD are as defined above) or -N /-N0, or a pharmaceutically acceptable salt thereof.

The benzoheter'ocyclic compounds of the formula C1IJ and salts thereof have excellent antibacterial activities against various gram positive and gram negative bacteria, I I 2 and are useful for the treatment of various infectious diseases induced by various bacteria in human, other animals and fish and are also useful as an external antimicrobial or disinfectant agent for medical instruments or the like.

Prior art There are many literatures which disclose 4oxoquinoline-3-carboxylic acid derivaties useful as antibacterial agents. Among these literatures, European Patent So". Publication Nos. 113092 and 113093 and U.S. Patent 4559342 a" disclose 1-cyclopropyl-7-piperazino-dihydroquinoline carboxylic acid derivatives of the formula: 0

R

1 -N N R 4 _4 R German Patent 3248507 discloses 1-cyclopropyldihydroquinoline carboxylic acid derivatives of the formula: 0 .i R I

COOH

R

wherein R I is H, F, Cl, Br or NO 2

R

2 is H, Cl, F or NR 3

R

4 wherein R 3 and R 4 together may form 5- or 6-membered saturated or partly unsaturated heterocycles.

South African Patent 8504087 discloses 1cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylio acid T 0,

'U~

i 3 derivatives of the formula: 0 F COOH

N

R

1 -N N I R2 wherein 1 is H, CH 3

C

2

H

5 or -CH 2

CH

2 0H, R 2 is H, Cl or F.

German Patent 3420743 disclose 7-amino-1-cyclopropyl-3-quinoline carboxylic acid derivatives of the formula: 0 e4

COOH

S1

N

4 0 2 N R2/N X2 ao 4 wherein X1 and X are each Cl or F, R1 and R2 may combine *o together with N atom to form a 5- or 6-membered heterocyclic ring.

German Patents 3420770 and 3420798 disclose 1cyclopropyl-7-piperazinyl-dihydroquinoline carboxylic acid derivatives of the formula: 0 F COOH

N

R

1 -N N R R2 wherein R is oxo or phenyl, etc. and R2 is H or F.

_c

F.~

4 Similar 1-cyclopropyl-7-heterocyclic group-substituted dihydroquinoline carboxylic acid derivatives are also disclosed in other many literatures such as Japanese Patent First Publication (Kokai) Nos. 214777/1985, 36265/1986, 91183/1986, 122272/1986, 143363/1986, 143364/1986, 186379/1986, 205240/1986, 205259/1986, 218574/1986, 218575/1986, 218585/1986, 225181/1986, and 229877/1986, European Patent Publication Nos. 178388, 183129, 187085, 191185, and 195316, South African Patent 8504792, Spanish Patent 8602674 and 8601968, and Portugal Patent 80546.

However, the compounds disclosed in these literatures are different from the compounds of this invention in view of having no alkyl substituent at 8position.

There are disclosed 1-cyclopropyl-7-heterocyclic vgroup-8-alkyl-dihydroquinoline carboxylic acid derivatives in some literatures. For instance, Japanese Patent First Publication (Kokai) No. 126271/1985 Portugal Patent 79616) discloses quinolone carboxylic acid derivatives of the formula: 0 F COOH R-N N s--a w Y Ar wherein R is H, CH3, p-nitobenzyl or p-aminobenzyl, Y is Cl, 5 F, or CH 3 but this literature does not disclose any specific example of 8-CH 3 derivative (all examples are concerned with 8-Cl or 8-F derivatives).

Besides, German Patent 3441788 Japanese Patent First Publication (Kokai) No. 122272/1986) discloses 1cyclopropyl-4-oxoquinoline-3-carboxylic acid derivatives of the formula: 0 I C OOH .I 2 T

N

3 4X3 wherein X 1

X

2 and X3 are each H or C 1 -3 alkyl, but these compounds have no heterocyclic group as X 2 Brief Description of the Invention The object of the present invention is to provide novel benzoheterocyclic compounds of the formula and I salts thereof which have excellent antimicrobial activity and excellent absorbability. Another object of the invention is to provide a pharmaceutical composition S containing as an active ingredient a compound of the formula or a pharmaceutically acceptable salt thereof, which is useful for the treatment of various infectious diseases.

These and other objects of the invention will be apparent to persons skilled in the art from the following description.

-IIII-- LYI ~^_I~_WY)~UYFPUI.~-~WIUD-PU~M6-_I-I~-X-U 6 Detailed Description of the Invention The novel benzoheterocyclic compounds of the present invention have the formula as mentioned above and include pharmaceutically acceptable salts thereof.

In the specification, the term "halogen atom" inoludes fluorine, chlorine, bromine or iodine atom.

The term "C 1

-C

6 alkyl" includes straight chain or branched chain C 1

-C

6 alkyl groups, such as methyl, ethyl, o "propyl, isopropyl, butyl, tert-butyl, pantyl and hexyl.

The piperzinyl group which has optionally one substituent selected from the group consisting of OXO, S hydroxy and a halogen includes 4-hydroxy-l-piperazinyl, 3-hydroxy-l-piperazinyl, 2-hydroxy-l-piperazinyl, 2-oxo- 1-piperazinyl, 3-oxo-l-piperazinyl.

The term "C 3

-C

8 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "C 1

-C

6 alkanoyl includes straight chain or branched chain C 1

-C

6 alkanoyl groups, such as, formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl.

The term "C 1

-C

6 alkoxycarbonyl" includes straight chain or branched chain C 1

-C

6 alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentloxycarbonyl and hexyloxycarbonyl.

The term "amino which may be substituted by a C1-C6 alkyl includes amino groups which may be substituted by 1 or 2 of a straight chain or branched chain C 1

-C

6 alkyl group such as amino, methyl-amino, ethylamino, propylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, dihexylamino, N-methyl-N-n-butylamino,

N-

methyl-N-pentylamino or N-ethyl-N-hexylamino.

-7 The term "Cl-C 6 alkaxy" includes straight chain or branched chain C 1

-C

6 alkoxy groups, such as methoxy, ethoxy, propoxy, isoprcpoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy.

V The term "2-oxo-1,3-dioxolenmethyl substituted by (lower) alkyl" includes 2-oxo-1,3-dioxolenmethyl groups which may be substituted by a straight chain or branched I'chain Cl-C 6 alkyl group, such as (5-methyl-2-oxo-1,3dioxolen-4-yl)methyl, (5-tert-butyl-2-oxo-1,3-diLoxolen-4- V yl)methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-pentyl-2- V oxo-1,3-dioxolen--4--yl)methyl, (5-hexyl-2-oxo-1,3dioxolen-4-yl)methyl, (5-ethyl--2-oxo-1,3-dioxolen-4yl )methyl and (5-propyl-2-oxo-1,3-dioxolent-4-yl)methyl.

The term "(lower) alkyl which may be substituted by 1 to 3 of substituerits selected from am~no and a halogen atom" includes, in addition to the above-iiuentioned (lower) alkyl, straight chain or branched chainC- 6 alkyl groups which is substituted by 1 to 3 of substituents selected from the group consisting of fluoromethyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-f luoropentyl, difluoromethyl, 2,3dichlorohexyl, 2, 2,2-triflurorethyl, trifluoromethyl, chloromethyl, dibromomethyl, iodomethyl, dichloromethyl, aminomethyl, 2-aminoethy'l. 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and 3dimethyJlaminopropyl. The amino Cl-C 6 alkyl group said amino group being optionally substituted by one lC I alkyl group includes 2-ethylaminoe'thyl, 4-propylaminobutyl, 5-n-butyl-aminopentyl, 6-pentylamino- hexyl and methylaminomethyl.

The term "Cl-C 6 alkyithic" includes straight chain or branched chain C 1

-C

6 alkylthio groups, such as emthylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butyithia, pentylthio and hexylthio.

The compounds of the present invention of the above general formula can be prepared by various Ai 0 50 1 7 1 fT

I

Li'

A

I

I

'4

I

Ii a 8 processes and preferably prepared, for example, by the processes as shown in the following reaction schemes.

[Reaction scheme-I] F COHF

COX

3 Halogenation C 2] 3 0 'C CH C sR Ni *3 N VII hi I N C *4,Y* *0 4 V 09*

.INI

1 4 I I, 0

N

4.4.

R

4

CH

2

COOR

5 [41 [5]1 I, *4 4 40) N *44* *4 4 I .1

NA

N. t I 4 44 1) Removal of R 2) R6..cHX 7 11-1R 8 [6] NH2 [8] C 7] 0 11 C

COOR

5 19] Cyclization

I

I

I 'j

I

I

1 ii

I

I

Ii

I

I

-9

COOR

5 Hydrolysis F 4t 4 t t I I 4. t t I 1 1 t U t [la] wherein R 2 and R 3 are as defined above, R 2 is a halogen atom or a R 2 group (R 2 is as defined above), R 4 is a group of the formula: -COR 9 (wherein R 9 is a lower alkyl) or a group of the formula: -COOR 10 (wherein R 10 is a lower alkyl), R 5 is a lower alkyl, R 6 is a group of the formula: R11 -NR2 (wherein R 11 and R 12 are each a lower alkyl) or R 12 a lower alkoxy, X 2 and X 3 are each a halogen atom, R' and R are each a lower alkyl.

The halogenation of the compound is carried out by reacting with a halogenating agent in the presence or absence of a solvent. The solvent includes aromatic hydrocarbons benzene, toluene, xylene, etc.), halogenated hydrocarbons dichloromethane, chloroform, carbon tetrachloride, etc.), ethers dioxane, tetrahydrofuran, diethyl ether, etc.), dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The halogenating agent may be any conventional halogenating agents which can convert hydroxy in carboxy group into a halogen atom, and includes, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride and

~A,

Vz ci

~NTC-

phosphorus pentabromide. The amounts of the compound [2] and the halogenating agent are not specified, but, in case of using no solvent, the halogenating agent is usually used in a large excess amount, and in case of using a solvent, the halogenating agent is usually used in an amount of at least 1 mole, preferably 2 to 4 moles, per 1 mole of the compound The reaction temperature and the reaction period of time are not specified, either, but the reaction is usually carried out at a temperature of from room temperature to 100 0 C for 30 minutes to 6 hours.

I The reaction of the compound and the compound is carried out in a suitable solvent in the presence of a basic compound. The solvent may be any conventional solvents unless they give any undesirable effect on the f reaction, and includes, for example, water, ethers (e.g.

diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, W etc.), alcohols methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), aliphatic hydrocarbons n-hexane, heptane, cyclohexane, ligroin, etc.), amines pyridine, N,N-dimethylaniline, etc.), halogenated hydrocarbons chloroform, dichloromethane, carbon tetrachloride, etc.), aprotic polar solvents DMF, DMSO, hexamethylphosphoramide (HMPA), etc.), and a mixture of these solvents. The basic compound includes inorganic bases metallic sodium, metallic potassium, metallic magnesium, sodium hydride, sodium amide, sodium 11 hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.), metal alcoholates sodium methylate, sodium ethylate, etc.), and organic bases pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, etc.). The reaction is usually carried out at a temperature of from 00 to 150 0

C,

preferably from room temperature to 120 0 C, for 0.5 to hours. The compound is usually used in an amount of at S, least 1 mole, preferably 1 to 2 moles, per 1 mole of the I compound The basic compound is usually used in an r tif ,I tamount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound The compound wherein R is the group: -COR 9 is subjected to the reaction for removal of the group: -COR 9 in a suitable solvent in the presence of a basic compound. The t t j t solvent includes ethers diethyl ether, dioxane, Stetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), aliphatic hydrocarbons n-hexane, heptane, cyclohexane, etc.), aprotic polar solvents DMF, DMSO, HMPA, etc.), and the like. The basic compound includes ammonia gas, aqueous ammonia, primary or secohdary amines ethylamine, diethylamine, piperidine, etc.), and the like. The reaction is usually carried out at a temperature of from 00 to 150 0 C, preferably from room temperature to 100 0 C, for 1 to 20 hours.

LL.

I>I

I Vi C t C C i 12 The compound wherein R4 is a group: -COOR 1 0 is subjected to the reaction for removal of the group: -COOR 1 0 in an aqueous solution in the presence of an acid catalyst. The acid catalyst includes mineral acids (e.g.

hydrochloric acid, sulfuric acid, etc.) and organic acids p-toluenesulfonic acid, etc.). The reaction is usually carried out at a temperature of from 00 to 150 0

C,

preferably from room temperature to 100 0 C, for 1 to hours.

The reaction of the R group-removed compound and the compound is carried out in a suitable solvent. The solvent may be any solvents which are used in the above reaction for the removal of the R 4 group. The reaction is usually carried out at a temperature of from 00 to 200 0

C,

preferably from 0° to 150 0 C, for 0.5 to 10 hours. The comound is usually used in an equimolar to large excess amount, preferably 1 to 2 moles per 1 mole of the compound In case of using a compound wherein R is a lower alkoxy group, the reaction may also be carried out by using acid anhydrides acetic anhydride) as a sulvent as well as above-mentioned solvents at a temperature of from 0° to 200°C, preferably 00 to 1700C.

The reaction of the compound and the compound is carried out in a suitable solvent The solvent may be any conventional solvents unless they give any undesir- (:t x1cr 13 able effect on the reaction, and includes, for example, alcohols methanol, ethanol, propanol, etc.), ethers diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), aliphatic hydrocarbons nhexane, heptane, cyclohexane, ligroin, etc.), halogenated hydrocarbons chloroform, methylene chloride, carbon tetrachloride, etc.) and aprotic polar solvents (e.g.

DMF, DMSO, HMPA, etc.). The reation is usually carried out at a temperature of from 0° to 1500C, preferably o' from room temperature to 100°C, for 0.5 to 15 hours. The compound is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound [73. In the reaction, a basic compound may optionally be 0*o$ a added and such basic compound may be any basic compounds which are used in the above reaction of the compound and the compound The cyclization of the compound is carried out in a suitable solvent in the presence of a basic compound.

4 The solvent may be any conventional solvents unless they give any undesirable effect on the reaction, and includes, for example, ethers diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aliphatic hydrocarbons n-hexane, heptane, ligroin, etc.), halogenated hydrocarbons chloroform, methylene chloride, carbon R tetrachloride, etc.) and aprotic polar solvents (e.g.

C 1 14 DMF, DMSO, HMPA, etc.). The basic compound includes inorganic bases metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, etc.), metal alcoholates sodium methylate, sodium ethylate, etc.), and organic bases (e.g.

1,8-diazobicyclo[5.4.0]undecene-7 (DBU), N-benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, etc.).

I The reaction is usually carried out at a temperature of from 00 to 150 0 C, preferably from room temperature to 120°C, for a< 0.5 to 5 hours. The basic compound is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound The hydrolysis of the compound [10] can be carried out under the conditions of conventional hydrolysis, for instance, in the presence of a basic compound sodium o hydroxide, potassium hydroxide, barium hydroxide, potassium S" carbonate, etc.), a mineral acid sulfuric acid, hydrochloric acid, nitric acid, etc.) or an organic acid acetic acid, aromatic sulfonic acids, etc.) in a solvent such as water, alcohols methanol, ethanol, O 0 isopropanol, etc.), ketones acetone, methyl ethyl ketone, etc.), ethers dioxane, ethylene glycol, etc.), acetic acid, or a mixture thereof. The reaction is usually carried out at a temperature of from room temperature to 2000C, preferably from room temperature to 150 0 C, for 0.1 to hours. By the reaction, there is produced the compound [1a3.

L a) C-l 15 [Reaction Scheme-II] 0 F COOR 13

R

2 H [11] FC 13 4 N 2 N X R2 R 3

A

3 [1b] [Ib'] wherein R 3 is as defined above, X 4 is halogen atom, and R 1 3 is hydrogen atom or a group of the formula:

-OCOR

1 4 S.-B 0COR (wherein R and R15 are each an alkyl).

B 'OCOR 1 5 The reaction of the compound [1b] and the comound [11] is carried out in an inert solvent, wherein both compounds are used in a wide range of ratio, and the compound [11] is usually used in an amount of at least 1 C mole, preferably 1 to 5 moles, per 1 mole of the compound The solvent includes, for example, water, alcohols methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), ethers tetrahydrofuran, Sdioxane, diglyme, etc.), dimethylacetamide, DMF, DMSO, HMPA, N-methylpyrrolidone, and a mixture thereof. Among these solvents, the preferred one is DMF, DMSO, HMPA, and Nmethylpyrrolidone. The reaction may also be carried out in the presence of an acid-removing agent, such as inorganic carbonates sodium carbonate, potassium carbonate, 16 sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) or organic bases pyridine, quinoline, triethylamine, etc.). An alkaline methal halide (e.g.

potassium fluoride, etc.) may also be added in the reaction mixture. The reaction is usually carried out under a pressure of from 1 to 20 atm., preferably from 1 to 10 atm., at a temperature of from room temperature to 2500C, preferably from room temperature to 200°C, for 0.5 to S° hours.

The compound wherein R 13 is a group:

-B

-B OCOR15 can be converted into the corresponding compound

OCOR

1 5 0 00 wherein R 13 is hydrogen atom by treating the former compound with an acid or a base to decompose the chelate i compound. The acid includes mineral acids (e.g.

hydrochloric acid, sulfuric acid, etc.) and organic acids acetic acid, p-toluenesulfonic acid, etc.) and the base includes mineral bases sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, etc.) and organic S bases triethylamine, etc.). The reaction is preferably carried out at a temperature of from 0 0 C to 150°C, preferably from 00C to 100°C. The acid or the base may be used in an amount of at least 1 mole, preferably 1 to moles, per 1 mole of the starting compound.

V o 17 [Reaction scheme-III] 0 0 F COOH R1 6

X

5 [12] F COOH |W "NN W? N N

SR

3 I 3

I

(CH

2 )n (CH 2 )n [ic [1d] wherein R 3 is as defined above, either Z or W is S; -CH 2 and the other is -NH, n is an integer of 1 to 3, R 1 6 is a (lower) alkyl; a cycloalkyl; a phenyl (lower) alkyl in which phenyl ring may be substituted by a (lower) alkoxy, nitro or amino; a phenyl which may be substituted by a halogen atom, a (lower) alkyl or a (lower) alkyl substituted by 1 to 3 of halogen atoms; a pyridyl; a (lower) alkyl having 1 to 3 substituents selected from the group consisting of hydroxy, amino, a (lower) alkoxy and a halogen atom, said amino being optionally substituted by a (lower) alkyl, a (lower) alkanoyl, a cycloalkyl or a (lower) alkoxycarbonyl; a (lower) alkanoyl which may be substituted c- tby 1 to 7 of halogen atoms; a (lower) alkenylcarbonyl having S: 1 to 3 substituents selected from the group consisting of a halogen atom and a carboxy; a (lower) alkoxycarbonyl; an aminocarbonyl which may be substituted by a (lower) alkyl; a phenyl (lower) alkoxycarbonyl; an amino (lower) alkanoyl which may be substituted by a phenyl (lower) alkoxycarbonyl; a (lower) alkoxycarbonyl (lower) alkyl; a carboxy (lower) 18 alkyl; an anilinocarbonyl (lower) alkyl; a (lower) alkylsulfonyl which may be substituted by 1 to 3 halogen atoms; a sulfo (lower) alkyl; a (lower) alkenyl or a (lower) alkynyl, X 5 is a halogen atom, and either Z' or W' is -CH 2 16 and the other is -NR.

The reaction of the compound [1c] and the compound [12] is carried out in a suitable solvent in the presence of a hydrogen halide-removing agent. The solvent includes j ;water, alcohols methanol, ethanol, isopropanol, etc.), 'in' ketones acetone, methyl ethyl ketone, etc.), ethers diethyl ether, dioxane, etc.) and aromatic o, hydrocarbons benzene, toluene, xylene, etc.). The hydrogen halide-removing agent includes inorganic bases sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.), alkline metals (e.g.

I sodium, potassium, etc.), and organic bases pyridine, 4, t piperidine, etc.). If necessary, copper powders, copper t halides copper iodide, etc.) or alkaline metal halides sodium iodide, potassium iodide, etc.) may be employed. The compound [1c] is usually used in an equimolar S' to lirge excess amount, preferably 1 to 3 moles, per 1 mole of the compound The reaction is usually carried out at a temperature of from room temperature to 150 0

C,

preferably 50°C to 120 0 C, for 1 to 12 hours.

r 19 [Reaction scheme IV] F COOH R 17

COR

18 [13] W N N \CH 2)n Cic] 0

COO

H

.I e] t[ wherein R 3 Z, W and n are as defined above, R 1 7 and

R

1 8 are each hydrogen atom or a lower alkyl, and either Z' I R17 or W' is -CH 2 and the other is -N-CH' 18 2 1 8 The reaction of the compound [1c] and the compound [13] is carried out in the presence or absence of a solvent f in the presence of a reducing agent. The solvent includes, for example, water, alcohols methanol, ethanol, isopropanol, etc.), lower alkanoic acids formic acid, acetic acid, etc.), ethers dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.) and aromatic hydrocarbons benzen, xylene, toluene, etc.). The reducing agent includes formic acid, alkaline metal or alkaline earth metal salts of formic acid sodium formate, etc.), reducing agents for hydrogenation sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.) and 20 catalysts for catalytic reduction palladium b]ack, palladium carbon, platinum oxide, platinum black, Raney nickel, etc.). In case of using formic acid as a reducing agent, the reaction is usually carried out at a temperature of from room temperature to 200°C, preferably from 500 to 150°C, for 1 to 10 hours. Formic acid is preferably used in a large excess amount to the compound Besides, in case of using a reducing agent for hydrogenation, the reaction is usually carried out at a :o °temprature of from -300 to 100°C, preferably from 00 to 700C, for 30 minutes to 12 hours. The reducing agent for o0 Shydrogenation is usually used in an amount of from 1 to Smoles, preferably from 1 to 6 moles, per 1 mole of the compound In dase of using lithium aluminum hydride as a reducing agent, a preferable solvent includes ethers (e.g.

0 4 diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) and aromatic hydrocarbons benzene, toluene, xylene, etc.). In case of using a catalyst for catalytic reduction, the reaction is usually carried out under a hydrogen pressure of from 1 to 20 atm., preferably from 1 to t 10 atm., at a temperature of from -300 to 100°C, preferably from 00 to 600C, for 1 to 12 hours. The catalyst is usually used in an amount of from 0.1 to 40% by weight, preferably from 0.1 to 20% by weight, of the compound The compound [13] is usually used in an amount of at least 1 mole, preferably 1 mole to a large excess amount, per 1 mole of the compound [1l].

I 0 21- In the reaction scheme-I, the starting compounds of the formula are novel or known compounds, which can be prepared, for example, by the process as shown in the following reaction scheme-V.

[Reaction scheme-V] Haloenatg. get Fh21 2 C: X R E 1 4 N 2 1 4 a I N X 4.

@4 9.w e4 0 o 0 o beC b*#e 9 00 @4 0 be 9440 1

CH

2

SR

2 R21 r NH 2 MCN 17]1

CHSR

20 ~I 9 C 16]1 9944 C 4 0~4 4 0440 *1 0 0 94 4 be C .9.4 400009 0 *C C o 90 1 18]

-F

19]

CH

2 1 19

CH

2 1 19 [2a] 22 wherein R 2 and X 2 are as defined above, X 5 and X 6 are each a halogen atom, R 19 is hydrogen atom or a lower alkyl and R 20 is a lower alkyl, in which R 19 and R 2 0 may be taken together to form a heterocylclic ring, and M is an alkaline metal sodium, potassium, etc.) or a metal silver, calcium, copper, etc.).

In case that R and R of the compound [16] are taken together to form a heterocyclic ring, R 19 of the compound [20) is -R 19

-R

20

-H.

The compound [16] can be prepared by reacting a 00 starting aniline derivative of the formula [14] with a 0000 halogenating agent 3nd then reacting the resultant compound of the formula [14a] with a thio compound of the formula [153.

The reaction of an aniline derivative [I4] and a halogenating agent is usually carried out in a suitable solvent. The solvent may be any conventional solvents unless they give any undesirable effect on the reaction, and includes, for example, halogenated hydrocarbons (e.g.

chloroform, dichloromethane, etc.), ethers dioxane, SL,diethyl ether, tetrahydrofuran, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), lower alcohols (e.g.

methanol, ethanol, isopropanol, etc.), and polar solvents DMSO, HMPA, acetonitrile, etc.). The halogenating agent may be any conventional halogenating agents and includes, for example, N-bromosuccinlmide, N-chloro- 23 succinimide, sodium hypobromite, sodium hypochlorite, bleaching powder, thionyl chioride and tert-butyl hypochlorite. The halogenating agent is usually used in an amount of at least 1 mole, preferably 1 to 6 moles, per 1 mole of the starting material. The reaction is usually carried out at a temperature of from -78 0 C to room temperature, preferably from -600 to 15 0 C, and usually completes within a few minutes. By the reaction, there is produced the intermediate of the formula [14a]. While the t resultant compound [14a] may be separated from the reaction r mixture to provide it for a subsequent reaction, the reaction mixture is usually provided for the reaction with a i*t' thio compound of the formula [15] without separating it from the reaction mixture.

The reaction of the compound [14a] and the t t wi compound [15] is carried out in the same solvent as abovementioned in the presence of a basic compound. The basic t t l compound includes inorganic bases potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen t l carbonate, sodium amide, sodium hydride, etc.), and organic iI bases such as tertiary amines triethylamine, tripropylamine, pyridine, quinoline, etc.). The compound is usually used in an amount of at least 1 mole, preferably 1 to 1.5 moles, per 1 mole of the compound [14a]. The reaction is usually carried out at a temperature of from room temperature to 150 0 C, preferably from room

I

2 p I r 24 i f Ctt C Ct t (I I

CI,

II temperature to 1000C, for 1 to 5 hours. The reaction of the compound [16] and the compound [17] is carried out in a suitable solvent in the presence or absence of a basic compound. The solvent includes water, alcohols (e.g.

methanol, ethanol. isopropanol, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), ethers dioxane, tetrahydrofuran, diglyme, etc.), polar solvents DMF, DMSO, HMPA, N-methylpyrrolidone, etc.), or a mixture thereof. The basic compound includes inorganic carbonates sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), organic bases pyridine, quinoline, triethylamine, etc.) and phase transition catalysts phenyltriethylammonium chloride, tetramethylammonium chloride, etc.). The compound [17] is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound The reaction is usually carried out at a temperature of from room temperature to 200°C, preferably from room temperature to 1800C, for 0.5 to 10 hours.

The desulfuration of the compound [18] for preparing the compound [19] is usually carried out in a solvent in the presence of a suitable catalyst. The catalyst includes, for example, aluminum-amalgam, lithiumlower alkylamine, Raney nickel, Raney cobalt, triethyl phosphite and triphenyl phosphine and preferable one is Raney nickel. The solvent includes alcohols (e.g.

L,

-A

25 methanol, ethanol, isopropanol, etc.) and ethers (e.g.

diehtyl ether, dioxane, tetrahydrofuran, etc.). The reaction is usually carried out at a temperature of from 00 to 200°C, preferably from room temperature to 100°C, for minutes to 5 hours. The catalyst is usually used in an amount of from 1 to 10-fold by weight of the compound [18].

4.' It

II

ft P14 44 1 I 4.

st t 4444 I I 4 .4 4 4. 5I 4. I 4 i 43 The reaction of converting the compound [19] into the compound [20] is carried out by reacting the compound [19] with a metallic salt of nitrous acid sodium nitrite, potassium nitrite, etc.) in a suitable solvent in the presence of an acid, and then reacting the resultant product with a metal halide potassium iodide, copper chloride, copper bromide, etc.) without separating it from the reaction mixture. The acid includes mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid. The solvent includes water, alkanoic acids acetic acid, etc.), ethers dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons benzen, toluene, xylene, etc.), alcohols methanol, ehtanol, isopropanol, etc.), halogenated hydrocarbons (e.g.

chloroform, dicnioromethane, dichloroethane, etc.), aprotic polar solvents DMF, DMSO, HMPA, etc.), and a mixture thereof. The metallic salt of nitrous acid and the metal halide each is usually used in an amount of at least 1 mole, preferably 1 to 1.5 moles, per 1 mole of the compound

L,

26 The reaction is usually carried out at a temperature of from 0° to 150 0 C, preferably from 00 to 100 0 C, for minutes to 5 hours.

The hydrolysis of the compound [20] can be carried out in the presence of a suitable hydrolysis catalyst, for instance, a mineral acid sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) or a basic compound sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.) in the presence or absence of a solvent. The solvent includes, for example, water and a mixture of water and a ,lower alcohol methanol, ehtanol, etc.). The reaction is usually carried out at a temperature of from 500 to 2000C, preferably 700 to 1800C, for 1 to 10 hours.

In the reaction scheme-II, the compounds of the i 1

OCOR

1 4 formula [1b] wherein R 13 is a group: -B C 15 can be prepared, for example, by the process as shown in the following reaction scheme-VI.

C

I- 27 [Reaction scheme-VI] 0 F COOR 5

/OCOR

1 4

B-OCOR

1 5 [21]

'OCOR

2 1 R3 [If] F COOR 1 3

X

4

N

t t: wherein R 3

X

4

R

14 and R 15 are as defined above, R 5 is a lower alkyl or hydrogen atom, R 13 is a group: 14t

/OCOR

1 -B and R 21 is a lower alkyl.

OCOR

15 The reaction of the compound Elf] and the compound C t [21] is carried out in a suitable solvent. The solvent ,r includes, for example, the solvents employed in the reaction of the R 4 group-removed compound and the compound in the above reaction scheme-I. The reaction is usually carried out at a temperature of from room temperature to 200 0

C,

I t preferably from room temperature to 150 0 C, for 10 minutes to hours. The compound [21] is usually used in an amount of at least 1 mole, preferably 1 to 10 moles, per 1 mole of the compound [lf].

The compounds employed in the reaction scheme- Y -28 I are novel or known compounds, which can be prepared, for example, by the process as shown in the following reaction scheme-VII.

[Reaction scheme-VII]

(X

7 )m (X7)m

M'N

3 [23]3 CO2H 'CON [22] [24]

SM"N

3 [23a] (X7)m (X 7 )m

R

22

OH

25]

NHR

2 2

NH

[26] [27]

N

S' wherein X7 is a halogen atom, R 22 is a phenyl (lower) alkoxycarbonyl, R 2 2 is a phenyl (lower) alkyl, m is an integer of 1 to 3, M' is an alkaline metal such as sodium and potassium, and is hydrogen atom or M'.

490 The reaction of the compound [22] and the compound 4 t [23] can be carried out under a reaction condition usually employed in a reaction for forming an amide bond. Processes for forming an amide bond include, for example, a mixed acid anhydride process: a process comprised of reacting the carboxylic acid [22] with an alkyl halocarboxylate to obtain a mixed acid anhydride, and then reacting the resultant anhydride with the azide an active ester process: a process comprised of converting the carboxylic acid [22] into an active ester such as p-nitrophenyl ester, Nhydroxysuccinimide ester or 1-hydroxybenzotriazole ester, 29 and then reacting the resultant ester with the azide [23]; a carbodilmide process: a process comprised of condensing the carboxylic acid [22] and the azide [23] in the presence of an activating agent such as dicyclohexylcarbodiimide or carbonyldiimidaxole and the other processes: a process comprised of converting the carboxylic acid [22] into the carboxylic anhydride using a dehydration agent such as acetic anhydride, and then reacting the resultant anhydride with the azide a process comprised of reacting an ester of the carboxylic acid [22] and a lower alcohol with the azide [23] under a high pressure in a high temperature; or a process comprised *6 of reacting an acid halide of the carboxylic acid [22] (i.e.

acyl halide) with the azide [23].

The mixed acid anhydride is obtained by a "conventional Schotten-Baumann reaction, and the resultant anhydride is allowed to react with the azide usually without separating it from the reaction mixture, to prepare the compound The Schotten-Baumann reaction is carried out in the presence of a basic compound usually employed in said reaction. The basic compound includes, for example, organic bases triethylamine, trimethylamine, pyridine, dimethylamiline, N-methylaorpholine, nonene-5 (DBN), 1,8-diazabicyclo undecene-7 (DBU), 1,4-diazabicyclo octane (DABCO), etc.), and inorganic bases potassium carbonate, sodium carbonate, o potassium hydrogen carbonate, sodium hydrogen carbonate, etc.). The reaction is usually carried out at a temperature of from -200 to 100 0 C, preferably from 00 to 500C, for minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction of the resultant mixed acid anhydride and the azide [23] is usually carried out at a temperature of from -200 to 150 0 C, preferably from 00 to 50 0 C, for 5 minutes to hours, preferably 5 minutes to 5 hours. The mixed acid anhydride process is usually carried out in a solvent usually employed in said process. The solvent includes i o water, halogenated hydrocarbons dichloromethane, chloroform, dichloroethane, etc.), aromatic hydrocarbons a 0e benzene, toluene, xylene, etc.), ethers diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g.

methyl acetate, ethyl acetate, etc.), ketones acetone, aprotic polar solvents DMF, DMSO, HMPA, etc.), and a mixture thereof. The alkyl halocarboxylate used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloro)formate, ethyl bromoformate and isobutyl chloroformate. The azide [23] is usually used in an amount of at least 1 mole, preferably 1 to 1.7 mles, per 1 mole of the carboxylic acid [22].

In case of using the process comprised of reacting an acyl halide with the azide [233, the reaction is carried out in the presence of a basic compound in a suitable which may be substituted by a phenyl (lower) alkoxycarbonyl; a (lower) alkoxycarbonyl (lower) alkyl; a carboxy (lower) R 1 31 solvent. The basic compound may be any known basic compounds, and includes, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, and metal alcoholates such as sodium methylate and sodium ethylate, in addition to the basic compound employed in the above Schotten-Baumann reaction.

The solvent includes, for example, alcohols methanol, ethanol, propanol, butanol, 3-methoxy-l-butanol, ethyl cellosolve, methyl cellosolve, etc.), pyridine, acetone, Sacetonitrile, the solvents employed in the above mixed acid anhydride process, and a mixture thereof. Although the ratio of the azide [23] and an acyl halide employed is not limited, the acyl halide is usually used in an amount of at least 1 mole, preferably 1 to 5 moles, per 1 mole of the azide The reaction is usually carried out at a tt' temperature of from -300 to 180°C, preferably from 00 to I 7 1500C, for 5 minutes to 30 hours. The compound [24] thus prepared may be used in a subsequent reaction without separating it from the reaction mixture.

*The reaction of the compound [24] and the compound is usually carried out at a temperature of from 0° to 150°C, preferably from room temperature to 100°C, for 1 to hours, in the presence or absence of a suitable solvent. The compound [25] is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound [24].

I 32 32 The reaction of converting the compound [26] into the compound [27] can be carrie.d out under the same reaction condition as used in a reaction for removing a phenyl (lower) alkyl group or a phenyl (lower) alkoxycarbonyl group on the heterocyclic ring attached to the above compound The reaction of directly converting the compound [22] into the compound [27] is generally referred to as Schmidt reaction, and carried out in a suitable solvent in the presence of an acid. The acid includes mineral acids i sulfuric acid, hydrochloric acid, etc.), phosphorus

S,,

1 compounds phophorus oxychloride, phosphorus S, pentachloride, phosphorus trichloride, phosphorus pentoxide, etc.), thionyl chloride, iron [III] chloride, 4 aluminum chloride, stannic chloride, sulfoacetic acid and t phosphoric acid. The solvent includes aromatic hydrocarbons benzene, toluene, xylene, etc.) and halogenated hydrocarbons chloroform, dichloromethane, carbon tetrachloride, etc.). The reaction is usually carried out at a temperature of from 0°C to 150'C, preferably from 0°C to 100*C, for 0.5 to hours. The compound [23a] is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound [22].

I 1: S- 33- [Reaction scheme-VIII] 0

R

23 1

CH

2

X

8 F

/COOH

T rr 0 0 7z\ W NN N 0 3 I [28]

(CH

2 )n

A

[1c] 0 F COOH

S/-

"(CH 2 n

R

3 [lh] wherein R 23 is phenyl, a lower alkyl or hydrogen atom, X8 is a halogen atom, either or is -CH 2 and the other is 1 23 a group: -N-CH 2

R

2 and R 3 Z, Wx, and n are as .0 0 o 94 0 1> 0 defined above.

The reaction of the compound [1c] and the compound [28] can be carried out under the same reaction condition as employed in the reaction of the compound i[1b] and the compound [11] in the above reaction scheme-II.

S.1 In the compounds the compound in which the heterocyclic ring is substituted by a C 1

-C

6 alkanoyl; a Cl-C 6 alkoxycarbonyl; a 2-oxo-l, 3dioxolemethyl which may be substituted by CI-C 6 alkyl can I be converted into the compound in which the S• Iheterocyclic ring is not substituted, for example, using the following methods.

Trhe compound in which the heterocyclic ring is substituted by 1 or more of the substituents to (c) can be converted into the compound in which the heterocyclic ring is not substituted, by hydrolyxing the former compound under the same reaction condition as employed in the hydrolysis of the above compound

I-

S I---l b compound (13) is usually used in an amount of at least 1 mole, preferably 1 mole to a large excess amount, per 1 mole of the compound [1c].

4 34 [Reaction scherne-IX: F n

NO

2

NH

2 £29] R3' £37] )CH-C (COOR 2 4 2 I It t 4 I gt.

I 'C R280H 00

R

2 6

R

R28OCHIO7 R 27 0 02 R 2 [323 2 t NO 2

COOR

2 4~ C00R24

N-CH

1 31] Cycli zat .on I-It I I-Itt LI-It I- I I II I- I I-I I C I; I-I 4 0 Cyciization 430 Ij 3 wherein R 2 as defined above, RV' is a group: -~!hSR2 (hri R 1 anR 20 are as defined above) or

R

3 (wherein R 3 is as defined -above), and R 2 4, R 2 5

R

2 6

R

2 7 and R 28are each a lower alkyl, and X 9 is a halogen atom.

35 The reaction of the compound [37] and the compound can be carried out under the same reaction condition as employed in the reaction of the compound [1b] and the compound [11] in the above reaction scheme-II.

The reaction of the compound [29] and the compound or [30b] is carried out in the presence or absence of a solvent, preferably in the absence of any solvent. The solvent includes, for example, alcohols methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g.

benzene, toluene, etc.), polar solvents acetonitrile, S DMF, DMSO, HMPA, etc.). The compound [30a] or [30b] is usually used in an amount of at least 1 mole, preferably 1 to 1.5 moles, per 1 mole of the compound The reaction is usually carried out at a temperature of from room temperature to 2000C, preferably from 600 to 2000C, for r* t to 25 hours.

The cyclization of the compound [31] or [32] can be carried out according to various known methods such as a heating method, a method using an acidic compound (e.g.

phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, cone. sulfuric acid, a t Spolyphosphoric acid, etc.). In case of using the heating method, the reaction is usually carried out in a high b.p.

solvent such as a high b.p. hydrocarbon or a high b.p. ether tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc.) at a temperature of from 1000 to 2500C,

F

agent may be any conventional halogenating agents and includes, for example, N-bromosuccinimide, N-chloro-

I..

36

F

tf V rif preferably from 1500 to 200 0 C. In case of using the method using an acidic compound, the acidic compound is usually used in an equimolar to a large excess amount, preferably to 20 moles, per 1 mole of the compound [31] or and the reaction is usually carried out in the presence or absence of a suitable solvent at a temperature of from room temperature to 150 0 C for 0.1 to 6 hours. The solvent includes acid anhydrides acetic anhydride, etc.) in addition to the solvents employed in the cyclization of the above compound The hydrolysis of the compound [1i] can be carried out under the same reaction condition as employed in the hydrolysis of the compound [10] in the above reaction scheme-I.

R19 The compound [1j] in which R 3 is a group: -CHSR 2 0 can be coverted into the corresponding compound in which R 3 is -CH2R 1 9 by treating the former co-.pound under the same reaction condition as employed in the reaciton wherein the compound [18] is converted into the compound [19] in the above reaction scheme-V.

The compound [29] employed as the starting material in the above reaction scheme-IX can be prepared, for example, by the processes as shown in the follwing reaction schemes-X to XII.

[14a]. The reaction is usually carried out at a temperature of' from room temperature to 150 0 C, preferably from room 1- ~.Ai 1 c 4 37 [Reaction scheme-X] Nr NH 2

CH-SR

20

R

1 9 [163 1 9 133]

R

2 Nr NHR 2 9

OH

2 Ri 9 INitrat ion R21

NHR

29

CH

2

R

1 9 Nitration

'NO

2 36 36 1 phosphite arnd triphenyl phosphine arid preferable one is Raney nickel. The solvent includes alcohols (e.g.

4

L

38 N 02

.X

9

CH

2 1 19 R3a C8] 1 20C95

CH

2

SR

20 F N0 2

R

2

NH-I

CH

2 1 19 [29a]

NO

2 IP L F 0 R21a -61 t r ~c1~ t C I C CI

A

[3 9a] I Halogenation [29b] 11(1 C C 1.11' tC C F NO 2 R2N NH< 1393 NH2-'<[8] F N0 2 R2 a [38] wherein R 2 1, R1 9

R

20 and X6are as defined above, R29 is a (lower) alkanoyl, arnd X9is a halogen atom.

The desulfuration of the compound E16D>or [29b] can be carried out under the same reaciton conditions as employed in the desulfuration of' the above compound [18].

The reaction of' converting the compound [33] into the compound [31] is carried out in the presence of' a (lower) alkanoylating agent such as a (lower) alkanoic acid 2' 1*

N,

Ilfi ~~lc~ tIC It*a C Ir r( CL I '1 pl

I

Nr O'i 39 formic acid, acetic acid, propionic acid, etc.), a (lower) alkanoic acid anhy-ride acetic anhydride, etc.) or a (lower) alkanoic acid halide acetyl chloride, propionyl bormide, etc.). In the case of usingan acid anhydride or an acid halide as the (lower) alkanoylating agent, a basic compound may be employed. The basic compound includes, for example, alkali metals (e.g.

metallic sodium, metallic potassium, etc.), and hydroxides, carbonates or hydrogen carbonates thereof and organic bases pyridine, piperidine, etc.). The reaction is carried out in the presence or absence of a solvent, usually in the presence of a suitable solvent. The solvent includes, for example, ketones acetone, methyl ethyl ketone, etc.), ethers diethyl ether, dioxane, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), acetic acid, acetic anhydride, water and pyridine.

The (lower) alkanoylating agent is used in an amount of at least 1 mole per 1 mole of the compound [333, usually in equimolar to a large excess amount. The reaction is usually carried out at a temperature of from 00 to 1500C, preferably from 00 to 100 0 C, for 5 minutes to 10 hours. In case of using a (lower) alkanoic acid as the (lower) alkanoylating agent, a dehydrating agent is preferably employed. The dehydrating agent includes mineral acids sulfuric acid, hydrochloric acid, etc.) and sulfonic acids p-toluenesulfonxc acid, benzenesulfonic acid, ethanesulfonic acid, etc.). The reaction is

L-

~I ;p 40 preferably carried out at a temperature of from 500 to 1200C.

The nitration of the compound [33] or [34] is carried out by treating the said compound with a nitrating agent such as fuming nitric acid, cone. nitric acid, a mixed acid nitric acid plus sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride, etc.), an alkali metal nitrate plus sulfuric acid, an anhydride of nitric Sacid and an organic acid acetyl nitrate, benzoyl nitrate, etc.), nitrogen tetraoxide, nitric acid plus ooo mercury nitrate, nitrate of acetone cyanohydrin, an alkyl S. nitrate plus sulfuric acid or a polyphosphoric acid, in the presence or absence of a solvent such as acetic acid, acetic anhydride or sulfuric acid.

The nitrating agent is preferably used in an amount of 1 to 1 .5 moles per 1 mole of the compound [33] or The reaction is usually carried out at a temperature of from -100 to 70°C for 1 to 24 hours.

The hydrolysis of the compound [35] is carried out 4under the same reaction conditions as employed in the Shydrolysis of the above compound The reaction of the compound [37a] or [38] with the compound can be carried out under the same reaction conditions as employed in the reaction of the compound [1b] and the compound [11] in the above reaction scheme-II.

The halogenation of the compound [39] can be RA, carried out under the same reaction conditions as employed

T

AP

41 in the halogenation of the above compound [14].

The reaction of the compound [39a] and the compound [15] can be carried out under the same reaction conditions as employed in the reaction of the compound [14a] and the compound [153.

The convertion of the compound [29b] into the compound [29a] can be carried out under the same conditions as i, the convertion of the compound [18] into the compound S[19].

The reaction of converting the compound [36] into the compound [37] can be carried out by converting the former compound into a diazonium salt thereof using sodium nitrite and an acid sulfuric acid, hydrochloric acid hydrobromic acid, boron fluoride, etc.) in a solvent such as a (lower) alkanoic acid acetic acid), water, etc., and 6 then reacting the diazonium sal: with a copper powder or a copper halide cuprous bromide, cuprous chloride, t cupric chloride, etc.) in the presence of a hydrohalogenic acid hydrobromic acid, hydrochloric acid, etc.), or with potassium iodide in the presence or absence of a copper 1 powder, preferably with a copper halide in the presence of a hydrohalogenic acid. The sodium nitrite is usually used in an amount of 1 to 2 moles, preferably 1 to 1.5 moles, per 1 mole of the compound and the copper halide is usually used in an amount of 1 to 5 moles, preferably 1 to 4 moles, per 1 mole of the compound The reaction is usually carried out at a temprature of from -200 to 100oC, 42 preferably from -50 to 10000, for 10 minutes to 5 hours.

The halogen atom oflX in the compound [37a] can be converted into each other.

[Reaction scheme-XI] F

NO

2 R2

NHR

2 9 -Hydroly LLis F N0 2 R 2

H

2 Halogenation t t r t t r t

R

1 9

NO

2

CH

2

SR

2 [15]1

R

2

NH

R aNH] 41]1 F NO0 2 R2 NH 2

CHSR

20

R

1 9 4 3]3 Y-N02 41 ~4 1* 1 41

SI

R

1 9 [37] rt t I t t; wherein R 2 1, R1 9

R

20

R

29

X

6 and X9are as defined above.

The hydrolysis of the compound can be carried out under the same reaction conditions as employed in the hydrolysis of the above compound The halogenation of the compound can be carvied out under the same reaction conditions as employed inorganic bases potassium carbonate, sodium carbonate, -43 in the halogenation of the compound [114] in the above reaction scheme-V.

The reaction of the compound [C42] and the compound can be carr-ied out under the same reaction conditions K as employed in the reaction of the compound [114a] and the compound [1 The desulfuration of the compound [413 can be carried out under the same reaction conditions as employed t f rin the desulfuration of the compound [18] in the above f (4 treaction scheme-V.

[Reaction scheme-XII] IItF F NO 2 mA)COOH (A)COOH [441] ;1451 3 Reduction\ Reduction F R 3 5 FR3 RI R 1 [146] [147] F R 35 N' C1 F. N0 2

R

2 X9-1 R 2 1 NH'K (A)MiCH 3 inCH 3 [148] [29b] 7 44 [Reaction scheme-XIIIJ F 0 IN02

(A)MCH

2 0H [146]

R

2 X9O 3 (A )MCH 2

O

3 [52] 52]1 Hydrolysis Acylation 0@ ~*f 4, 4 4Qtt 4, 4 9.4 *9S* o 4 4* 4 .4 9 4 [52] (A )mCH 2 N\(R3 [511 [52] F

NO

2

R

2

X

9 (A)mCH 2

X

1 S NO 2 HS-R 3 10 C51] o C C 9. 4 4.

4 C 24 CS (A)MCH2

R

3 1 50]1 4 4*0*4 4 C

C

C.

0* (A)MCH2 SR3 14 C[53)1 wherein R 2 'and X9 are aa defined above, A is a (lower) alkylene, m is 0 or 1, X 10 is a halogen atom, or a phenylsulfonyloxy which may be substituted by a lower alkyl,

R

3 0 is a (lower) alkyl, R 3 1 is a (lower) alkanoyloxy, R 32 and R 3 3 are the same or different and each r'epresents hydrogen atom or a (lower) alkyl, R 3 4 is a lower alkyl, and

R

35 is hydrogen atom or nitro group.

The nitration of the compound [44] in the above reaction scheme-XII can be carried out under the same reaction conditions as employed in the nitration of the compound [34] in the above reaction scheme-X.

The reaction of the compound [44] or [45] is usually carried out using a hydride reducing agent such as sodium borohydride, lithium abluminum hydride or diborane, @0a and the reducing agent is usually used in an amount of at *"least 1 mole, preferably 1 to 3 moles, per 1 mole of the compound [44] or The reduction reaction is usually carried out in a suitable solvent, for example, water, (lower) alcohols methanol, ethanol, isopropanol, Setc.), ethers tetrahydrofuran, diethyl ether, diglyme, t i t etc.) or DMSO, at a temperature of from -60* to 800C, preferably from -30°C to 50 0 C, for 10 minutes to hours. In case of using lithium aluminum hydride or diborane as a reducing agent, an anhydrous solvent such as Sdiethyl ether, tetrahydrofuran or diglyme is preferably employed.

The reaction of converting the compound [46] into the compound [47] wherein X 1 0 is a halogen atom by halogenation is carried out under any reaction conditions usually employed in halogenation of hydroxy group, and may R 46 be carried out, for example, by reacting the compound [46] with a halogenating agent in the presence or absence of a suitable inert solvent. The halogenating agent includes, for example, hydrohalogenic acids hydrochloric acid, hydrobromic acid, etc.), N,N-diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphrus oxychloride, thionyl chloride and diethylaminosulfur trifluoride (DAST). The inert solvent includes, for example, ethers dioxane, tetrahydrofuran, etc.) and halogentated hydrocarbons (e.g.

Schloroform, dichloromethane, carbon tetrachloride, etc.), The halogenating agent is used in an amount of at least 1 mole per 1 mole of the compound usually in an equimolar to an excess amount, the reaction is usually carried out at a temperature of from 00 to 150 0 C, preferably from 00 to 80°C, for 10 minutes to 15 hours. In case of using DAST as a halogenating agent, a basic compound such as triethylamine may be employed.

When the compound [46] is reacted with a phenylsulfonyl halide which may have a lower alkyl substituent on S',the phenyl ring, it may be converted into a compound [47] wherein X 10 is a phenylsulfonyloxy which may be substituted with a lower alkyl. The reaction can be carried out in the same manner as in the method for the conversion of the compound [46] into the compound [49] as mentioned hereinafter.

I heterocyclic ring is not substituted, by hydrolyxing the former compound under the same reaction condition as employed in the hydrolysis of the above compound

T

II II L 1 III 47 The compound [48] wherein R 35 is hydrogen atom is firstly converted into a compound [48] wherein R 35 is nitro by the same nitration reaction of the compound and thereafter, it is reacted with the compound The reaction of the compound [48] thus converted and the compound can be carried out under the same reaction conditions as employed in reaction of the compound [1b] and the compound [11] in the above reaction scheme-II.

The reaction of converting the compound [47] into 4 t n, 1 the compound [48] can be carried out under the same reaction conditions as employed in the reduction of the 9* it above compound The reaction of converting the compound [46] into the compound [49] in the above reaction scheme-XIII can be carried out by various methods, for example, by reacting the compound [46] with a compound: R34X 11 (wherein R34 is a it t (lower) alkyl and X 1 1 is a halogen atom) in a suitable solvent in the presence of a basic compound, or (ii) by reacting the compound [46] with a (lower) alcohol a straight chain or branched chain C 1

-C

6 alcohol such as methanol, ethanol, isopropanol or butanol in the presence of an acid.

The solvent used in the above method includes, for example, ethers diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), alcohols (e.g.

methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons I group: -CHSR' (wherein R' and R c V are as defined above) or SRA R 3 (wherein R 3 is as defined above), and R 2 4, R 25

R

26

R

2 7 28 and R 2 8 are each a lower alkyl, and X 9 is a halogen atom.

-Lu 48 48 benzene, toluene, xylene, etc.), aliphatic hydrocarbons n-hexane, heptane, cyclohexane, ligroin, etc.), amines pyridine, N,N-dimethylaniline, etc.), halogenated hydrocarbons chloroform, dichloromethane, carbon tetrachloride, etc.), aprotic polar solvents (e.g.

DMF, DMSO, HMPA, etc.), and a mixture thereof. The basic compound includes inorganic bases metallic sodium, metallic potassium, metallic magnesium, sodium hydride, i sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, l etc.), metal alcoholates sodium methylate, sodium ethylate, etc.) and organic bases pyridine, piperidine, quinoline, triethylamine, N,N- dimethylaniline, etc.). The reaction is usually carried out at a temperature of from 0° to 120 0 C, preferably from room tempereture to 100 OC, for 0.1 to 5 hours. The compound: t

R

3 4X 11 is usually used in an amount of at least 1 mole, preferably 1 to 3 moles, per 1 mole of the compound [46].

The acid used in the above method (ii) includes, S for example, mineral acids hydrochloric acid, sulfuric St acid, hydrobromic acid, etc.). The reaction is usually carried out at a temperature of from room temperature to 1500C, preferably from 500 to 120 0 C, for 1 to 50 hours. The (lower) alcohol is usually used in a large excess amount.

The acylation of the compound [46] can be carried out under the same reaction conditions as employed in the .7J 7\ I*,i x -49reaction of converting the compound [33] into the compound [34] in the above reaction scheme-X.

The reaction of the compound [50] or [47] with the compound and the reaction of the compound [47] with the compound [54] both can be carried out in the presence or absence of a suitable solvent in the presence or absence of a basic compound. The solvent and the basic compound may be the same solvents and basic 1 compounds as employed in the reaction of the compound [3] and the compound in the above reaction scheme-I. In the reaction of the compound [50] or [47] with the compound the compound [52] may be used in a large excess amount which functions also as a basic compound.

The compound [52] and [54] is each used in an amount of at least 1 mole per 1 mole of the starting material, specifically the compound [50] or preferably in a large excess amount. The reaction is Carried out at a temperature of from 0* to 150*C,preferably from room temperature to 100 0 C, for 3 to 15 hours.

The hydrolysis of the compound [50] can be carried out under the same reaction conditions as employed in the hydrolysis of the above compound nI.l VJS 50 Among the above compounds 15], [31] and the compounds wherein R 2 is a heterocyclic ring having oxo group can be converted into the compounds wherein R 2 is a heterocyclic ring having hydroxy group, by reducing the former compounds. The reduction can be carried out in a suitable solvent in the presence of a reducing agent for hydrogenation. The reducing agent includes, for example, sodium borogydirde, lithium aluminum hydride, diborane, and the like, and is usually used in an amount of at least 1 mole, preferably 1 to 5 moles, per 1 mole of the starting material to be reduce. The solvent includes, 15 for example, water, (lower) alcohols methanol, ethanol, isopropanol, etc.) and ethers (e.g.

tetrahydrofuran, diethyl ether, diglyme, etc). The reaction is usually carried out at a temperature of from -60° to 50°C, preferably from -30°C to room temperature, for 10 minutes to 5 hours. In case of using lithium aluminum hydride or diborane as the reducing agent, it is preferred to employ an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme. In case of using sodium borobydride as the reducing agent, an inorganic base such as sodium hydride may also be added in the reaction mixture.

The compounds wherein R 2 is a heterocyclic ring ihaving at least one -NH- in the ring can be converted into the compounds wherein R 2 is a heterocyclic ring S 30 substituted by at least one C 1

-C

6 alkanoyl, by reacting the former compounds under the same reaction conditions as employed in the reaction of converting the compound [33] into the compound [34] in the above reaction scheme-

X.

900" 900507.50 51 The compounds [47] and [48] wherein R 3 is hydrogen atom can be converted into the corresponding compounds wherein R 35 is nitro by the same nitration reaction of the compound [44].

The compounds [44] and [45] can be prepared by the process as shown in the following reaction scheme.

9 0£ 1 r t 900507,51 -52- [Reaction scheme.-XIV] F R 35 Reduction F R 3 R2 X R 2 1' X MCOOH )mCH 2 0H [56] FR3 71 0 0 H

COOR

36 CH [58]3 MCN [17] F R 35 F R 3 (A')mCH CH 0'COR 36 CH CN [59] Hydrolysis 1'Hydrolysis 0F R 35 FR3 R R *0 )mCH 2

CH

2 COOH )rCH 2

COOH

[61] [62] wherein R 21

R

35

X

9 M and mT are as defined above, and A' is a lower alkylene, provided that the groups (A')MCH 2 and (AI)M CH 2

CH

2 have not more than 6 carbon atoms, R 36 is a ,A lower alkyl, and X11is a halogen atom.

j -52- [R~eaction scheme-XIV] F R 35 Reduction F R 3 MOOOH (A')mC 2 0 [56] F

R

3 mCH X 1 [57] /000R 3 6

/CH\

3 [58] MON [17] F R5F R 3 xII R -P

OOR

3 6 (A')mCH CH (A'I )mCH ON m 2 OOOR 36 2 [59] Hydrolysis jHydrolysis FR 3 5 F R 3

R

2 R 2 mOH 2

OH

2 COOH (A')MCH 2

COOH

C61] [62] wherein R 2 1, R 35

X

9 M and m are as defined above, and A' is a lower alkylene, provided that the groups ()mOH 2 and (A')MOCH 2

OH

2 have not more than 6 carbon atoms, R3 6 is a Q I lower alkyl, and X11is a halogen atom.

53 The reduction of the compound [55] is carried out under the same conditions as in the reduction of the compound [44] or Besides, the halogenation of the compound [56] can be carried out under the same conditions as in the halogenation of the compound [46].

The reaction of the compound [57] and the compound [58] is usually carried out in an appropriate solvent in the presence of a basic compound at a temperaure of from room temperature to 200 0 C, preferably from 60 to 120 0 C, for 1 to 24 hours. The solvent includes, for example, ethers (e.g.

o ?dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether, etc.), aromatic hydrocarbons benzene, toluene, xylene, etc.), lower alcohols methanol, i ethanol, isopropanol, etc.) and polar solvents (e.g.

S dimethyl formamide, dimethylsulfoxide, etc.). The Sbasic compound includes, for example, inorganic bases (e.g.

calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, t sodium methlate, sodium ethylate, etc.) and amines (e.g.

triethylamine, tripropylamine, pyridine, quinoline, etc.), The reaction proceeds favorably by using an alkali metal iodide potassium iodide, sodium iodide etc.). The compound [58] is usually used in an equimolar to excess amount, preferably 1 to 5 moles, more preferably 1 to 1.2 mole, per 1 mole of the compound [57].

54 The reaction of the compound [57] and the compound [17] can be carried out under the same conditions as in the reaction of the compound [16] and the compound [17].

Besides, the hydrolysis of the compound [59] or [60] can be carried out under the same conditions as in the hydrolysis of the compound The compounds [10] in the reaction scheme-I and O othe compounds [1b] and in the reaction scheme-II are o' useful not only as an intermediate for preparing the present O «o compounds having antimicrobial activities, but also as an antimicrobial agent because they also have antimicrobial activities.

In the compounds of the present invention there are optical and geometrical isomers, and the present invention includes also these isomers.

The compounds can easily be converted into a salt thereof by treaing them with a pharmaceutically acceptable acid or base. The acid includes inorganic acids hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.) and organic acids oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric '7

A

o 96I o am 0o ,o a Be a 9 55 acid, lactic acid, benzoic acid, methanesulfonic acid, propionic acid, etc.). The base includes sodium hydroxide, potassium hydrocid, clacium hydrocide, sodium carboante and potasium hydrogen carbonate.

The compound thus obtained can easily be isolated by conventional methods, such as extraction with solvents, dilution method, recrystallization, column chromatography, preparative thin layer chromatography, and the like.

The compounds of the present invention or salts thereof show excellent antimicrobial activity against Pseudomonas aeruginosa, anaerobic bacteria, resistant cells against various antimicrobials, clinically isolated bacteria, and gram negative and gram positive bacteria (e.g.

Enterococcus faecalis, Staphylococcus pyogenes, etc.), and hence, are useful as an antimicrobial agent for the treatment of diseases induced by these microorganisms.

These compounds show also low toxicity and less side effect and are characteristic in good absorbability and in sustained activity. Moreover, the compounds are highly excreted via urine and hence are useful for the treatment of urinary infectious diseases, and further because of easy excretion via bile, they are also useful for the treatment of intestinal infectious diseases. Besides, the compounds of this invention show improved absorbability into body by using them in the form of a salt such as lactate, hydrochloride, etc.

I 19 Ull..i.. 56 ;jtt

I

The compounds of the present invention are usually used in the form of a usual pharmaceutical preparation. The pharmaceutical preparation can be prepared in admixture with conventional pharmaceutically acceptable diluents or carriers, such as fillers, weighting agents, binding agents, wetting agents, disintegrators, surfactants and lubricating agents. The pharmaceutical preparation includes various preparations suitable for treatment of the diseases, for example, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories and injections (solution, suspensions, etc.) In the preparation of tablets, there may be used any conventional carriers, for example, excepients (e.g.

lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose, silicate, etc.), binding agents water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters quaternary ammonium salts, sodium lauryl- A r.

k egjRAC7,

OC;

57 sulfate, etc.), wetting agents glycerin, starches, etc.), adsorbents starches, lactose, kaolin, bentonite, colloidal silicates, etc.) and lublicants (e.g.

purified talc, stearates, boric acid powder, polyethylene glycol, etc.). The tablets may also be coated with conventional coating agents, for example, may be in the form of a sugar coated tablet, a gelatin-coated tablets, an enteric coating tablet, a film coating tablet, or a double or multiple layers tablet. In the preparation of pills, there may be used conventional carries, such as excipients glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binding agents (e.g.

gum arabic powder, tragacanth powder, gelatin, ethanol, too. etc.) and disintegrators laminaran, agar, etc.) In the preparation of suppositories, there may be used conventional carriers, such as polyethylene glycol, 0 6 cacao butter, higher alcohols, higher alcohol esters, gelatin and semi-synthetized glycerides. In the preparation of injections, the solutions, emulsions or suspensions of the compounds are sterilized and are preferably made isotonic with the body liquid. These solutions, emulsions and suspensions are prepared by admixing the active compound with a conventional diluent, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitan -58 fatty acid esters. The preparations may also be incorporated with sodium chloride, glucose or glycerin in an amount sufficient to make them isotonic .ith the body liquid. The preparations may also be incorported with conventional solubilizers, buffering agents, anesthetizing agents, and further, with coloring agents, preservatives, perfumes, flavors, sweeting agents, and other medicaments.

The preparations in the form of a paste, cream or gel may be a 4, *oa 4 prepared by using as a diluent white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, so silicone or bentonite.

o" The pharmaceutical preparation of the present invention may also be in the form of an infusable or injectable solution containing the above compound or a salt thereof lactate, etc.), and an acid not producing a precipitate. The acid not producing a precipitate includes, for example, lactic acid, methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid, and the like, preferably lactic acid. In case of using lactic acid, 0 the acid is usually used in an amount of from 0.1 to 10% by weight, preferably from 0.5 to 2% by weight, based on the weight of the above infusable or injectable solution. In case of using an acid other than lactic acid, the acid is usually used in an amount of from 0.05 to 4% by weight, preferably from 0.3 to 2% by weight, based on the weight of the above solution. Moreover, a conventional additive may 1 59 optionally be added to the above infusable or injectable solution. The additive includes, for example, a thickener, an absorption promoter or inhibitor, a crystallization inhibitor, a complex-forming agent, an antioxidant, an isotonicity-giving agent, or a hydrating agent.

The pH of the solution can properly be adjusted by adding an alkali such as sodium hydroxide, and is usually adjusted within the range of from 2.5 to 7. The infusable or injectable solution thus prepared has an excellent stability, and can be stored and preserved for a long time with retaining the solution state.

1 The active compounds or salts thereof may be contained in any amount in the preparations, and are usually contained in an amount of 1 to 70 by weight based on the whole weight of the preparations.

The pharmaceutical preparations of the present invention can be administered in any methods. Suitable method for administration may be selected in accordance with the preparation form, age and sex of the patients and St degree of severity of the diseases. For instance, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered in oral route. In case of injection, it is administered intravenously alone or together with an auxiliary liquid glucose, amino acid solution, etc.). The injections may also be administered in intramuscular, intracutaneous, subcutaneous, or intra- 60 peritoneal route. Suppositories are administered in intrarectal route.

The dosage of the pharmaceutical preparations of the present invention may vary according to administration methods, age and sex of the patients and severity of the diseases, but is usually in the range of about 0.2 to 100 mg of the active compound or a salt thereof per 1 kg of body weight of the patient per day. The preparation is usually administered by dividing into 2 to 4 times per day.

The present invention is illustrated by the .oo* following Reference Examples, Examples, Preparations, and Experiments.

Reference Example 1 To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) in anhydrous dichloromethane (1.2 liter) is added gradually N-chlorosuccinimide (90 g) at below 15 0 C, and thereafter is further added in portions triethylamine (93 ml) at 15 0 C. After the addition, the mixture is refluxed for 7 hours. After cooling, 10 aqueous sodium hydroxide (one liter) is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane n-hexane 1 The product is 61 recrystallized from n-hexane to give 6-bromo-3,4-difluoro-2methylthiomethylaniline (52 g) as a white crystal, m.p. 60 61 C.

Reference Example 2 A mixture of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (99 HMPA (130 g) and copper cyanide (48 g) is heated at 150 0 C for 4 hours. After cooling, the reaction mixture is poured into a solution of ethylenediamine (50 ml) in water (500 ml), and the mixture is heated at 60 0 C for one hour. After cooling, the mixture is extracted with ethyl j acetate, and the extract is dried over magnesium sulfate and concentrated. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane nhexane 1 and the product is recrystallized from K ethanol to give 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (28 as a white crystal, m.p. 109 1100C.

Reference Example 3 To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol (80 ml) are added S Raney nickel (40 ml) with etha--l (80 ml). The mixture is stirred at 40 50°C for 30 minutes, and then filterd. To the filtrate is added water, the reaction mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated. The product is recrystallized from n-hexane to give 2-amino-4,5-difluoro-3methylbenzonitrile (2.4 as a white crystal, m.p. 114 116 0

C.

N.I

II

I

2 I "cl~lR~cmrr*rPm~lc~mr~~ i ii ^I r t

I,

62 Reference Example 4 Sodium nitrite (5.6 g) is added to conc. sulfuric acid (59 ml) at below 700C. The mixture is heated at 700C for 10 minutes and then cooled, and thereto is added dropwise a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123 ml) at below 40 0 C. The mixture is stirred at the same temperature for 30 minutes and then added in portions to a solution of cuprous chloride (20 g) in cone. hydrochloric acid (200 ml), and thereafter is heated at 800C for 30 minutes. After cooling, to the reaction mixture is added ice water, and ethyl acetate is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane nhexane 1 1) to give 2-chloro-4,5-difluoro-3-methylbenzonitrile (8.0 as a white crystal, m.p. 59 610C.

Reference Example To 2-chloro-4,5-difluoro-3-methylbenzonitrile g) is added 60 sulfuric acid (20 ml), and the mixture is heated at 140 1500C for 3 hours. After cooling, the reaction mixture is poured into ice water, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off. To the residue is added n-hexane, and the precipitate is separated by filtration to give 2-chloro-4,5-difluoro-3methylbenzoic acid (3.1 as a white crystal, m.p. 121 1220C.

J

rtr 7 63 Reference Example 6 To 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g) is added thionyl chloride (6 ml), and the mixture is reflexed for one hour. The mixture is concentrated under reduced pressure to give 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g).

Separately, metallic magnesium (0.38 g) is suspended in anhydrous ethanol (0.8 ml) and thereto is added a few drops of carbon tetrachloride. When the reaction is started, a mixture of diethyl malonate (2.3 ml), anhydorus ethanol (1.5 ml) and anhydrous toluene (6 ml) is added portionwise at 50 60 0 C. Thereto is added dropwise a solution of the above 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g) in anhydrous toluene (5 ml) at 0 0 C. After the addition, the mixture is stirred at room temperature for minutes. To the raction mixture is added a mixture of cono. sulfuric acid (0.4 ml) and water (8 ml) and the mixture is extracted with diethyl ether. The extract is dried over magnesium sulfate and the solvent is then distilled off to give diethyl 2-chloro-3-methyl-4,5difluorobenzoylmalonate (5.1 g).

Reference Example 7 To diethyl 2-chloro-3-methyl- 4 malonate (5.1 g) are added water (10 ml) and p-toluenesulfonic acid (30 ml), and the mixture is refluxed for 4 hours. After cooling, the mixture is extracted with diethyl II :E::t

S.L

-s

L_

64 Reference Example 8 To ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate (3.9 g) are added triethoxymethane (3.1 g) and acetic anhydride (3.4 and the mixture is heated at 150 0

C

for one hour. The mixture is concentrated to give ethyl 2- (2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate.

cyclopropylamine (1.1 ml) at room temperture, and the mixture is stirred for 30 minutes. Ethanol is distilled off to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3cyclopropylaminoacrylate. To the product is added anhydrous dioxane (30 ml) and thereto is added portionwise 60 sodium hydride (0.6 The mixture is stirred at room temperature for 30 minutes and then refluxed for one hour. The reaction mixture is poured into aquoeus saturated ammonium chloride and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated to give ethyl 1cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxylate (2.2 g).

*i f t NMR (CDC1 3 6: 8.64 (1H, 8.10 t, Hz), 4.36 (2H, q, J=7.5 Hz), 3.76-4.10 (1H, 2.76 (3H, d, Hz), 1.37 (3H, t, J=7.5 Hz), 0.86-1.30 (4H, m).

1111___ZAXMAn~sjbdouwjj!!J6jGp:cjo

II

jjjj 2 5 11111.4 ZkXMAnsOdoNW1NrIHOA3D9V 'id Ot .5 Referencexmpe 9 To ethyl l-cyclopropyl-6,7-dif luoro-8-nethyl- 1 4dihydro-)4-oxoquinoline-3-carboxylate (2.2 g) are added cone.

V hydrochloric acid (5 ml), water (2 ml) and acetic acid ml), and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are separated by filtration, and washed with water, ethanol and diethyl ether in this order to give 1-cyclopropyl-6,7-difluoro-8-methyl- V 1,4-dihyvdro-4-oxoquinoline-3-carboxylic acid (1.8 g) as a white crystal, m.p. 240-243'C.

L Reference Example To 1-cyclopropyl-6,7-difluoro-8-methyl-1,4dihydro-'I-oxoquinoline--3-carboxylic acid (1.0 g) Ere added Vtriacetylborone [B(0COCH 3 3 (1.0 g) and acetic anhydride 14(10 ml) and the mixture is heated at 1400C for 15 minutes.

After the reaction, the mixture is concentrated and to the resulting residue is added diethyl ether and the crystals are separated by filtration to give 6,7-difluoro-lcyclopropyl-8-methyl-1 4l-dihydro-4-oxoquinoline-3-carboxyliLc acid -B(000CH 3 chelate (1.2 g).

NMR (CD Cl 3 9.32 (1H, 8.23 (1H, t, J=9 Hz), 4.30-4.58 (1H, in), 2. 97 (3H, d J3 Hz) 2. 03 (6H, 3) 13 1.60 (4H, in).

Reference Example 11 2 2 -Dichloro-l-oyclopropylcarboxylic acid (4.0 g) is suspended in water (5 ml), and thereto is added an 66 appropriate amount of acetone to give a completely uniform solution. The solution is cooled to 0 0 C and thereto is added a solution of triethylamine (3.0 g) in acetone ml). While keeping the temperature of the mixture at 0°C, a solution of ethyl chlorocarbonate (3.54 g) in acetone ml) is added dropwise thereto. After the addition, the mixture is stirred at 0 0 C for 30 minutes, and thereto is added dropwise a solution of -sodium azide (2.51 g) in water ml). The mixture is further stirred at 0°C for one s" t hour, and then the reaction mixture is poured into ice water, and the mixture is extracted with diethyl ether. The a c, extract is dried over magnesium sulfate and concentrated.

To the resulting 2,2-dichloro-l-cyclopropylcarbonylazide Iare added benzyl alcohol (3.35 g) and anhydrous benzene nat mil), and the mixture is refluxed with stirring for 10 hours.

S..

i After completion of the reaction, the reaction mixture is concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, ethyl acetate n-hexane 1 30), and then recrystallized from dichloromethane to give 2,2-dichloro-1-benzyloxycarbonylaminocyclopropane (2.8 as colorless needles, m.p. 79.5- 80.50C.

By using appropriate starting materials, there are prepared the following compounds in the same manner as described in Reference Example 11.

2-Chloro-1-benzyloxycarbonylaminocyclopropane (a 41,I mixture of cis and trans isomers) 67- NMR (CDCl 3 5: 1.10-1.32 (2H, in), 2.76-3.10 (2H, in), 4.73-5-13 (OH, in), 5. 11 (2H, 7.35 (5H, s) 2-Fluoro-1-benzyloxycrbonylaminocyclopropane (a mixture of cis and trans isomers) NMR (CDCl 3 60 MHz) 6: 0.60-1.60 (2H, in), 2.50- 3.-17 1IIH, in), 4.07-4.30 and 4.53-5.00 (2H, in), 5.08 and 5.11 (2H, 7.33 (5H, s) 4 Reference Example 12 To 2,2-dichloro-1-benzyloxycarbonylaminocyclo- 4 et0 4 propane (1.5 g) are added 5 Pd-C (0.15 ethanol (15 ml) and conc. hydrochloric acid (1.5 ml), and the mixture is subjected to catalytic reduction at room temperature under atmospheric pressure. After the reaction;- the catalyst is removed by filtration, and the filtrate is concentrated.

The resulting residue is recrystallized from ethanolsot*%diethyl ether to give 2,2-dichloro-1-aninocyclopropane hydrochloride (0.7 g) as white powder, in.p. 1147 i148 0

C

(decomp.).

By using appropriate starting materials, there are prepared the following compounds in the same manner as described in Reference Example 12.

2-Chloro-1-aininocyclopropane hydrochloride (a mixture of cis and trans isomers) NMR (DMSO-d 6 6 :1.16-1.73 (2H, in), 2.83-3.10 (1H, mn), 3.57-3.80 (1H, in), 8.6o-9.26 (3H, m) ~~i~xAL ~2-Fluoro-1-aminocyclopropane hydrochloride (a w' R -7 Lt,

I

68 mixture of cis and trans isomers) NMR (DMSO-d 6 200 MHz) 6: 1.00-1.60 (2H, 2.47- 2.68 and 2.88-3.17 (1H, 4.65-4.88 and 4.96-5.20 (1H, m), 8.30-9.00 (3H, m) Reference Example 13 To a solution of ethyl 2-(2,4,5-trifluorobenzoyl)- 3-ethoxyacrylate (1.78 g) and triethylamine (0.60 g) in ethanol (10 ml) is added dropwise a solution of 2-fluoro-1cyclopropylamine hydrochloride (0.60 g) in ethanol (10 ml) at room temperature with stirring. After the addition, the t t mixture is stirred at the same temperature for one hour and concentrated to give ethyl 2-(2,4,5-trifluorobenzoyl)-3-(2fluoro-1-cyclopropyl)aminoacrylate. To the product are added 60 sodium hydride (0.3 g) and anhydrous dioxane ml), and the mixture is stirred at room temperature for one t. thour. After concentrating the reaction mixture, water is added to the resulting residue, and the mixture is extracted with dichloromethane. The extract is washed with water and dried and then the solvent is distilled off to give ethyl 1- (2-fluoro-l-cyclopropyl)-6,7-difluoro-1,4-dihydro-4oxoquinoline-3-carboxylate (a mixture of cis and trans isomers) (1.02 g).

NMR (CDC1 3 60 MHz) 6: 1.36 (3H, t, J=8 Hz), 1.44- 2.27 (2H, 3.50-3.83 (1H, 4.28 (2H, q, J=8 Hz), 4.55- 4.86 and 5.26-5.53 (1H, 7.58 (1H, dd, J=11 Hz, 6 Hz), 7.98 (1H, dd, J=10 Hz, 9 Hz), 8.31 and 8.51 (1H, s) Ii -69- By Using appropriated starting materials, there 1 are prepared the following compounds in the same manner as described in Reference Example 13.

Ethyl 1- chloro- 1- cyclopropyl )-67-dif luoro- 14dihydro-4-oxoquinoline-3-oarboxylate (a mixture of cis and trans isomers) NMR (CDCl 3 60 MHz) 6: 1 .37 (3H, t, J=7 Hz) 1 .70 Ii 2.20 (2H, in), 3.40-3.80 (2H, mn), 4.31 (28, q, J=7 Hz), 7.55 (1H, dd, J=114 Hz, 6 Hz), 8.07 (1H, dd, J=9 Hz, 9 Hz), 8.32 and 8.314 (1H, s) Ethyl 1-(2-methyl-1-cyclopropyl)-6,7-difluoro-1,4- ,dihydro- 1 4-oxoqui nolline-3- carboxyl ate (a mixture of cis and trans isomers) NMR (CDCl 3 60 MHz) 6: 1.00-2.00 (3H, in), 1.39 (3H, t, J=7 Hz), 1.141 (38, 3.00-2.27 (Hi),1.37 O1H, qJ7Hz), 7.55 (1H, dd, J=11 Hz, 6 Hz), 8.20 (1H, dd, J=9 Reference Example 114 To ethyl 1- (2-fluoro-1-cyclopropyl)-6,7-difluoro- 1,4-dihydro-4-oxo quinoline-3- carboxyl ate 1 .02 g is added acetic acid conc. hydrochloric acid (14 1, 20 ml), and the mixture is refluxed with stirring for one hour.

After concentrating, to the resulting residue is added water. The precipitated crystals are separated by filtration and washed with ethanol and diethyl ether and then dried to give 1-(2-fluoro-l-cyclopropyl)-6,7-difluoro-1,4- 70 dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) (0.58 g).

NMR (DMS0-d 6 200 MHz) 6: 1.63-2.17 (2H, in), 3.75- 3.97 and 4.20-4.50 1H, in), 5.09-5.35 and 5.41-5.63 IH, in), 8.12 (dd, j=l'i.85 Hz, 6.67 Hz), 8.39 (dd, J=12.08 Hz, 7.3 Hz) 8 .30 (dd J=1 0.-38 Hz, 8. 62 Hz) 8. 28 (dd J. 12. 18 Hz, 10.42 Hz) 8.73 and 8.65 (1Hi, s) By Using appropriate starting materials, there are prepared the following compounds in the same mariner as described in Reference Example 14.

1-(2-Chloro-l-cyclopropyl)-6,7-difluoro-1 1 4dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) NMR (DMSO-d 6 200 MHz) 6: 1.80-1.99 and 2.04~-2.23 (2H, in), 3.914-14.07 O1H, in), 4.19-14.34 (1H, mn), 7.98 dd, J=11 .84 Hz, 6.6'4 Hz), 8.31 (1H, dd;' J=10.34 Hz, 8.66 Hz) 8.69 (1H, s) 1-(2-Methyl-l-cyclopropyl)-6,7-difluoro-1,4dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) NMR (trifluoroacetic acid-d 6 60 MHz) 6: 1.33-2.10 (3H, in), 1.58 (3M, 3.66-14.00 (1H, in), 8.38 (IM, dd, Hz, 6 Hz), 8.53 (1H, dd, J=9 Hz, 9 Hz), 9.48 (1H, s) Reference Example To a solution of ethyl 7-( 14 -iethyl--piperazinyl)s~AL~1 1-cyclopropyl-6-fluoro-8-methylthiomnethyl- 1, 4-dihydro- 1 4- 71 oxoquinoline-3-carboxylate (8.09 g) in ethanol (80 ml) is added Raney nickel (40 ml) together with ethanol (80 ml), the mixture is stirred at 40 50 0 C for 30 minutes and then filtered. To the resulting filtrate is added water, and the mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated to give ethyl 7-( 4 -methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl- 1,4-dihydro-4-oxoquinoline-3-carboxylate (2.5 g).

Reference Example 16 Into a solution of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (6.00 g) in ethanol (120 ml) is suspensed S° Raney nickel (70 ml), and the mixture is stirred at 50 0 C for minutes. -After removing Raney nickel by filtration, the filtrate is concentrated to give 3,4-difluoro-2-methylaniline (3.77 g) as a colorless oil.

^NMR (CDCI 3 6: 6.72 (1H, ddd, J=10.2 Hz, 10.2 Hz, 8.7 Hz), 6.27 (1H, ddd, J=10.2 Hz, 6.0 Hz, 2.7 Hz), 3.43 (2H, br), 2.02 (3H, d, J=2.4 Hz).

Reference Example 17 To 3,4-difluoro-2-methylaniline (3.27 g) is added y- acetic anhydride (50 ml), and the mixture is sirred for minutes. After distilling off acetic anhydride, the resulting residue is extracted with dichloromethane. The extract is washed with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride in Sthis order, and then dried over anhydrous magnesium sulfate.

N OT 72 After distilling off dichloromethane, the residue is recrystallized from ethyl acetate n-hexane to give 3,4difluoro-2-methylacetanilide (3.86 g) as colorless needles, m.p. 145.5 146.00C.

Reference Example 18 3,4-Difluoro-2-methylacetanilide (100 mg) is added to ice-cooled conc. sulfuric acid (0.3 ml) and thereto is added cone. nitric acid (0.1 ml) under ice cooling, and the I t mixture is stirred at room temperature for 2 hours. To the mixture is further added cone. nitric acid (0.1 ml), and the mixture is sitrred at room temperature overnight. To the reaction mixture is added a large amount of water, and the mixture is extracted with dichloromethane. The extract is washed with water, aqueous saturated sodium hydrogen w «carbonate and aqueous saturated sodium chloride in this St order and then dired over anhydrous magnesium sulfate.

After distilling off dichloromethane, the residue is recrystallized from ethyl acetate n-hexane to give difluoro-6-methyl-2-nitroacetanilide (80.7 mg) as yellow needles, m.p. 152.1 152.6°C.

Reference Example 19 4 ,5-Difluoro-6-methyl-2-nitr'oacetanilide (81 mg) is dissolved in acetic acid (2 ml) and thereto is added cone. hydrochloric acid (1 ml) at 0 0 C. The mixture is stirred at 100 0 C overnight and then concentrated. The residue i3 neutralized with aqueous saturated sodium r 73 hydrogen carbonate and extracte< with dichloromethane. The extract is washed with aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate. Dichloromethane is distilled off to give 4,5-difluoro-6-methyl-2-nitroaniline (59 mg) as orange prisms, m.p. 87.2 88.00C.

Reference Example Sodium nitrite (30 mg) is added portionwise to cone. hydrochloric acid (0.32 ml), and the mixture is stirred at 70 0 C for 10 minutes and cooled to room tempero 00 ature and thereto is added dropwise a solution of "o difluoro-6-methyl-2-nitroanline (59 mg) in acetic acid 0 ,0 ml) at the same temperature. The mixture is stirred at room temperature for 30 mintues and thereto is added dropwise a solution of cuprous chloride (107 mg) in cone. hydrochloric acid (1.0 ml). The mixture is stirred at 80 0 C for minutes. To the reacti-n mixture is added water and the mixture is extracted with ethyl acetate. The extract is washed with water, aqueous saturated sodium hydrogen caronate and aqueous saturated sodium chloride in this order and then dried over anhydrous magnesium sulfate. Ethyl o° acetate is distilled off to give 2-chloro-5,6-difluoro-3nitrotoluene (54 mg).

NMR (CDCI 3 6: 7.58 (1H, dd, J=11.0 Hz, 8.0 Hz), 2.40 (3H,s) Reference Example 21 To 2 -chloro-5,6-difluoro-3-nitrotoluene (54 mg)

N%,

:7" I 74 are added ethanol (0.3 ml) and water (0.03 ml) at 0OC and thereto further added dropwise a solution of N-methylpiperazine (0.04 ml) and triethylamine (0.06 ml) in ethanol (0.1 ml) at room temperature. The mixture is stirred at room tempeature for 5 hours, at 600C for 5 hours and further at 80°C overnight. The reaction mixture is acidified with 2N hydrochloric acid and washed with a small amount of diethyl ether and then neutralized with aqueous saturated S sodium hydrogen carbonate and extracted with dichloromethane. The extract is washed with water and aqueous saturated sodium chloride in this order and dried over o anhydrous magnesium sulfate, and then dichloromethane is disilled off to give 2-chloro-5-fluoro-6-(4-methyl-1.piperazinyl)-3-nitrotoluene (35 mg).

.r NMR (CDC13) 6: 7.46 (1H, d, J=11.2 Hz), 3.15 (4H, br), 2.55 (4H, br), 2.46 (3H, 2.73 (3H, s) Reference Example 22 To a solution of 2-chloro-5-fluoro-6-(4-methyl-1piperazinyl)-3-nitrotoluene (17 mg) in dimethylsulfoxide ml) are added potassium fluoride (110 mg) and cyclo- 4" propylamine (1.0 ml) and the mixture is stirred at 100 0 C for 13 hours. The reaction mixture is diluted with dichloromethane, and the mixture is washed with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then dichloromethane is disilled off. The product is purified by preparative thin layer S- ichromatography (developer, methanol-dichloromethane 1 to give N-cyclopropyl-4-fluoro-2-methyl-3-(4-methyl-1piperazinyl)-6-nitrotoluene (11 mg).

NMR (CDC1 3 6: 7.69 (1H, d, J=13 Hz), 7.59 (1H, br), 3.45-3.08 (4H, 2.85-2.75 (1H, 2.70-2.43 (4H, 2.45 (3H, 2.36 (3H, 1.0-0.5 (4H, m) Reference Example 23 To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60 0 C. The mixture is stirred at 0 C for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitrog1" 4,5-difluoroaniline (54 g).

NMR (CDC1 3 6: 5.76-6.40 (2H, 6.60 (1H, dd, J=12 Hz, 7 Hz), 7.97 (1H, dd, J=10.5 Hz, 8.5 Hz) Reference Example 24 To a solution of 2-nitro-4,5-difluoroaniline g) and dimethylsulfide (1.79 g) in dichloromethane (40 ml) Sis added gradually N-chlorosuccinimide (3.82 g) with

I

I

76 stirring at below 15 0 C. The mixture is stirred for minutes, and thereto is added triethylamine (2.89 and the mixture is refluxed for 21 hours. After allowing to cool, the reaction mixture is washed with 10 aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried. The solvent is removed by concentration, and the resulting residue is purified by silica gel column chromatography (solvent, n-hexane ethyl acetate 30 1) and then recrystallized from n-hexane to give 2-nitro-4,5i difluoro-6-methylthiomethylaniline (0.47 g) as yellow Sneedles, m.p. 110 111.50C.

e Reference Example Sodium nitrite (0.15.g) is added to conc. sulfuric acid (15 ml) and the mixture is stirred at 'fOoC for tl* minutes. To the mixture is added dropwise a solution of 2nitro-4,5-difluoro-6-methylthiomethylaniline (0.45 g) in acetic acid (4.5 ml). The mixture is stirred at the same temperature for 45 minutes, and thereto is further added dropwise a solution of cuprous chloride (0.52 g) in cone.

hydrochloric acid (5.2 ml). The mixture is stirred at 800C for 1.5 hour, and the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water and aqueous saturated sodium chloride in this order and dried, and then the solvent is disilled off. The resulting residue is purified by silica gel column chromatography (solvent, n-hexane ethyl acetate 30 1) 77 to give 2-chloro-3-methylthio-4,5-difluoro-l-nitrobenzene (0.16 g).

NMR (CDC13) 6: 2.15 (3H, 3.92 (2H, dd, J=3 Hz), 7.67 (1H, dd, J=8.5 Hz, 8 Hz) Reference Example 26 2,3,6-Trifluorobenzolc acid (21.0 g) is added to cone. sulfuric acid (120 ml) under ice-cooling. To the mixture is added dropwise a solution of potassium nitrate (14.5 g) in cone sulfuric acid (30 ml) at below 200C. After the addition, the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice water and extracted with diethyl ether. The extract is dried over magnesium sulfate, and:then the solvent is distilled off.

The residue is recrystallized from dichloromethane nhexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22 g), as colorless prisms, m.p. 98 990C.

NMR (CDC13) 6: 8.11-8.23 (1H, 9.10 (1H, brs) Reference Example 27 To a solution of sodium boron hydroxide (44 g) in anhydrous tetrahydrofuran is added a solution of 2,5,6- S trifluoro-3-nitrobenzoic acid (22 g) in anhydrous tetrahydrofuran (40 ml) at below 100C, and thereto is further added dropwise a solution of boron trifluoride etherate ml) in anhydrous tetrahydrofuran (40 ml) at below 100C.

Aftei' the addition, the mixture is stirred at room To temperature for one hour. The reaction mixture is poured

TO

i 78 t

I

into ice water and extracted with diethyl ether. The extract is dried, and then the solvent is distilled off to give 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g).

NMR (CDCl 3 6: 2.56 (1H, brs), 4.88 (2H, t, J-1.8 Hz), 7.92-8.04 (1H, m) Reference Example 28 To a solution of 2,5, 6 -trifluoro-3-nitrobenzyl alcohol (14 g) in ethanol (64 ml) and water (7 ml) is added a mixture of 4-ethoxycarbonylpiperazine (11 triethylamine (12.5 g) and ethanol (18 ml) at one time. The mixture is stirred at room temperature overnight, and the resulting precipitates are separated by filtration. The crystals are washed with a-small amount of diethyl ether and recrystallized from ethanol to give 3, 6 -difluoro-2-(4-ethoxycarbonylalcohol (8.7 as yellow needles, m.p. 147 1490C.

Reference Example 29 To a solution of 3, 6 -difluoro-2-(4-ethoxycarbonylalcohol (8.5 g) in chloroform ml) is added thionyl chloride (2.7 ml) at room temperature. The mixture is stirred at the same temperature for mintues, and the reaction mixture is poured into ice water, and then neutralized with sodium hydrogen carbonate and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off to give 2-( 4 -ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5- Lc -L 1i tu t LI-EI ut:rx am pie i i.

2 -Chloro-l-benzyloxycarbonylaminocyclopropane (a mixture of cis and trans isomers) Nor- 4 t t 79 nitrobenzyl chloride (8.1 g) NMR (CDC1 3 6: 1.28 (3H, t, J-7-1 Hz), 3.08-3.33 (4H, in), 3.446-3.75 1 4H, in), 4 .18 (2H, q, J-7.1 Hz), 4.77 (2H, d, J=2.5 Hz), 7.82 (1H, dd, J=9.2 Hz, 7.2 Hz) Reference Example To a solution of 3,6-difluoro-2-( 1 4-ethoxycarbonyl- 1-piperazinyl )-5-nitrobenzyl chloride (8.1 g) in dimethylsulfoxide (90 ml) is added gredually sodium boron hydride (1.8 g) at below 3000. The mixture iS stirred at the same temperature for one hour, and the reaction mixture is poured into ice water, and then acidified with conc. hydrochloric acid and extracted with diethyl ether. The solvent is distilled off to give 2-(4-ethoxycarbonyl-1-piperazinyl)- 3,6-difluoro-5-nitrotoluene (7.1 g).

NMR (CDC1 3 6: 1.26 (3H, t, J=7.1 Hz), 2.30 (3H, d, J=3 Hz), 2.76-3.27 (5H, in), 3.50-3.75 1 4H, in), 4.,17 (2H, q, J=7-1 Hz), 7.60 (1H, dd, J=9.3 Hz, 7.2 Hz) Reference Example 31 To 3,6-difluoro-2-( 1 4-ethoxycarbonyl-1-pipeirazin- (7.1 g) are added anhydrous dimethylsulfoxide (23 ml), potassium fluoride (2.0 g) and cyclopropylamine (1.5 and the mixture is heated at 600C for 6 hours. The reaction mixture is poured into ice water, and extracted with dichloromethane. The solvent is distilled off and the residue is recrystallized from ethanol to give N-cyclopropyl-2-methyl-3- (4-ethoxycarbonyl-l-plperazinyl fluoro-6-nitroaniline (7.4 as orange red prisms, M.P. 97 ~TR4~ y~x 7

A

ILI, II/ -1D -5O Usi, fl), 8.60-9.26 (3H, m) 2 -Fluoro-l-aminocyclopropane hydrochloride (a 80 98 0

C.

*coo 000 CO00 0*0 0 0 NMR (CDCl1 3 6: 0.50-0.54 (2H, in), 0.66-0.74 (2H, in), 1.28 (3H, t, J-7.1 Hiz), 2.143 (3H, 2.63-2.90 O1H, mn), 3.07-3.28 1 4H, in), 3.147-3.77 1 4H, in), 4.20 (2H, q, J=7.1 Hz), 7.53 (1H, brs), 7.70 (1H, dd, J=.13 Hz) Reference Example 32 To N-cyclopropyl-2-methyl-3-(14-ethoxycarbonyl-1piperazinyl)-]4-fluoro-6-nitroaniline (7.1 g) is added diethyl ethoxymethyleneinalonate (14.6 and the mixture is reacted at 150 170 0 C for 17 hours. After cooling, the solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography (solvent, dichloromethane :n-hexane 2 1 -*dichloromethane) to give diethyl [N-cyclopropyl-N-[3-(14-ethoxycarbonyl-lpiperazinyl )-2-iethyl-4-fluoro-6-nitrophenyllaninomethylenelinalonate (5.14 g).

Reference Example_33 To a solution of diethyl EN-cyclopropyl-N-[3-(4ethoxycarbonyl-l-piperazinyl)-2-nethyl-14-fluoro-6-nitrophenyllaininomethylenerlalonate (1.0 g) in acetic anhydride ml) is added conc. sulfuric acid (2 ml) with keeping at 700C. After stirring for 30 minutes, the reaction mixture is poured into ice water, and neutralized with potassium carbonate. The mixture is extracted with ethyl acetate, and the solvent is distilled off, and the resulting residue is purified by silica gel column chromatography -81- (solvent, dichioromethane methanol 10 1) and then recrystallized from ethyl acetate to give ethyl 1cYcloPrOPYl-7-(4-ethoxycarbonyl-l-piperazinyl)- 6 -fluoro- 8 methyl-1,4-dihydro-4-oxoquifoline-3-carboxylate (0.19 as colorless prisms, m.p. 200 202 0

C.

In the same manner as described in Reference Example 33 by using appropriate starting materials, there are prepared the same compounds as in Reference Examples 8, and 13.

Reference Examples 34l In the same manner as described in Reference Example 28 by using appropriate starting material, there is prepared the following compound: 3 6-Dif luoro-2- (4-benzYl- 3 -methyl- 1 -piperazi nyl) alcohol NR(CDCl 3 6: 1.18 (3H, d, J=6 Hz), 2.20-2.38 (1H, in), 2.55-2.72 (1H, mn), 2.72-2.91 (1H, mn), 3.06-3.44 4.09 (1H, d, J-13 Hz), 4.77 (2H, br), 7.12-7.140 mn), 7.71 dd, J=9.5 Hz, 7.2 Hz) Reference Examples C~ L the same manner as described in Reference Example 29 by using appropriate starting material, there is prepared the following compound: 2- (4-BenzY1- 3 methyl- 1- piperazi nyl-3, 6- di f1uorochloride NMR (cDC 3 6: 1.21 (3H, d, J=6 Hz), 2.214-2.50

"KS

Ii

I

I

t 111 1t c I L' 82 (1H, 2.60-3.00 (2H, 3.00-3.46 (5H, 4.11 (1H, d, J-13 Hz), 4.75 (2H, brs), 7.26-7.45 (5H, 7.79 (1H, dd, Hz, 7.3 Hz) Reference Examples 36 In the same manner as described in Reference Example 30 by using appropriate starting material, there is prepared the following compound: 2-(4-Benzyl-3-methyl- -piperazinyl)-3,6-difluoro- NMR (CDC13) 6: 1.18 (3H, d, J=6 Hz), 2.25 (3H, d, J=3.3 Hz), 2.30-2.48 (1H, 2.50-3.38 (7H, 4.08 (1H, d, J=13 Hz), 7.15-7.46 (5H, 7.58 (1H, dd, J=7.5 Hz, Hz) Reference Examples 37 In the same manner as described in Reference Example 31 by using appropriate starting material, there is prepared the following compound: N-Cyclopropyl-2-methyl-3-(4-benzyl-3-methyl-1piperazinyl)-4-fluoro-6-nitroaniline NMR (CDC13) 6: 0.52-0.68 (2H, 0.70-0.87 (2H, 1.28 (3H, d, J=6 Hz), 2.22-2.40 (1H, 2.38 (3H, s), 2.58-3.37 (8H, 7.26-7.44 (5H, 7.60 (1H, brs), 4.11 (1H, d, J=13 Hz), 7.77 (1H, dd, J=13.2 Hz) Reference Examples 38 In the same manner as described in Reference Examples 32 and 33 by using appropriate starting material, there is prepared the following compound:

C

4 t t L9 ation and washed with ethanol and diethyl ether and then dried to give 1-( 2 -fluoro-1-cyclopropyl)-6,7-difluoro-1,4-

F

-83ii Ir

~I

3: Ethyl 1-cyclopropyl-7-(4-benzyl-3-methyl-1piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylate, m.p. 172 173 0 C, white powder (recrystallized from ethyl acetate) Reference Examples 39 In the same manner as described in Reference Example 28 by using appropriate starting material, there is prepared the following compound: 3,6-Difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol, m.p. 117.0 118.5 0 C, orange prisms (recrystallized from ethyl acetate n-hexane), Reference Example To 3,6-difluoro-2-(3-amino-l-pyrrolidinyl)-5nitrobenzyl alcohol (43 mg) is added acetic anhydride ml) at room temperature. The mixture is stirred at the same temperature for 10 minutes, and the reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane methanol dichloromethane 1 12) and then recrystallized from dichloromethane to give 2-(3-acetylamino-1-pyrrolidinyl)-3,6alcohol (40 mg), as yellow prisms, m.p. 142.5 143.50C.

4. c 4. 4.

4.

L- i -84- Reference Examples 41 In the same manner as described in Reference Example 29 by using appropriate starting material, there is prepared the following compound: 2-(4-Acetylamino-l-pyrrolidinyl)-3,6-difluoro-5nitrobenzyl chloride NMR (CDC13) 6: 7.74 (1H, dd, J=12.0 Hz, 7.5 Hz), 6.16 (1H, d, J=5.4 Hz), 4.78 (1H, dd, J=11.3 Hz, 3.0 Hz), 4.69 (1H, dd, J=11.3 Hz, 3.0 Hz), 4.62-4.50 (1H, 3.97- S, 3.69 (2H, 3.67-3.50 (1H, 3.49-3.32 (1H, 2.40- J t 2.18 (1H, 2.12-1.93 (1H, 1.98 (3H, s) Reference Examples 42 In the same manner as described in Reference Example 30 by using appropriate starting material, there is prepared the following compound: 4 t C 2-(3-AGetylamino-1-pyrrolidinyl)-3,6-difluoro-5nitrotoluene, m.p. 139.0 140.3°C, yellow needles (recrystallized from dichloromethane) Reference Examples 43 In the same manner as described in Reference Example 31 by using appropriate starting material, there is prepared the following compound: N-Cyclopropyl-2-methyl-3-(3-acetylamino-1-pyrrolidinyl)-4-fluoro-6-nitroaniline, m.p. 162.5 164.00C, orange prisms (recrystallized from ethyl acetate nhexane), Reference Examples 414 In the same manner as described in Reference Example 32 by using appropriate starting material, there is prepared the following compound: Diethyl [N-cyclopropyl-N-[(3-acetylamino-l-pyrrolidinyl)-l'i-fluoro-2-methyl-6-nitrophenylaminoinethylene]mal onat e NMB (CDCl 3 6: 7.73 (1H, 7.68 (1H, d, J=11.6 Hz), 5.97 br), 4.62-4.145 (18, mn), 4.12 (148, q, J=7.2 Hz), 3.85-3.15 (5H, in), 2.142-1.95 (5H, in), 1.98 (3H, s), 1 .29 (6H, t, J=7.2 Hz), 0.93-0.52 (14H, m) Reference Examples In the same manner as described in Reference Example 33 by using appropriate starting material, there is prepared the following compound: Ethyl 1-cyclopropyl-7-(3-acetylamino-l-pyrrolidinyl )-6-.fluoro-8-methyl-1 4-dihydro-4-oxoqunoline-3carboxylate, in.p. 215.5 217.0 0 C, white powder (recrystallized from ethanol ethyl acetate -diethyl ether) Reference Example 46 3,6-Difluoro-2-(14-ethoxycarbonyl-l-piperazinyl)-5nitrobenzyl alcohol (1 .5 g) is dissolved in dichloromethane (18 ml), and thereto is added dropwise a solution of diethylaminosulfur trifluoride (DAST) (0.7 ml) and triethylaine (0.78 inll in dichloromethane (3 ml) over a period of 5 minutes while stirring at 000 in ice bath. The f 86 mixture is stirred at 0°C for 1.2 hour, and thereto is further added DAST (0.3 ml). After 5 minutes, the reaction mixture is poured into ice water, and the organic layer is separated. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (solvent, ethyl acetate n-hexane 1 1 5 v/v) to give 2,5-difluoro-3-fluoromethyl-4-(4ethoxycarbonyl-1-piperazinyl)nitrobenzene (1.1 g).

Reference Example 47 3,6-Difluoro-2-( 4 nitrobenzyl alcohol (1.0 g) is dissolved in pyridine ml), and thereto is added with stirring acetic anhydride (2 ml) at room temperature, and the mixture is stirred at the same temperature for 2 hours. To the reaction mixture is added water (20 ml), and the mixture is stirred for minutes. The mixture is extracted with dichloromethane and the organic layer is washed with 10 hydrochloric acid and aqueous saturated sodium hydrogen carbonate and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 3-acetoxymethyl-2,5-difuoro-4-(4ethoxycarbonyl-1-piperazinyl)-nitrobenzene (1.2 g).

Reference Examples 48 In the same manner as described in Reference Example 31 by using appropriate starting material, there are prepared the following compounds: N-Cyclopropyl-2-acetoxymethyl-3-(4-ethoxycarbonyl- 1 87 1-piperazlnyl)-4-fluoro-6-nitroanllne N-Cyclopropyl-2-methoxymethyl-3- (4-methyl-ipiperazinyl)-4-fluoro-6-nitroaniline NMR (CDCl 3 6: 0.47-0.55 (2H, 0.69-0.78 (2H, 2.36 (3H, 2.51-2.61 (4H, 2.88-2.98 (1H, i), 3.22-3.31 (4H, 3.34 (3H, 4.67 (2H, 7.29 (1H, s), 7.70 (1H, d, J=12.7 Hz) N-Cyclopropyl-2-methoxynethyl-3- (L-ethoxycarbonyl- 1-piperazinyl)-4-fluoro-6-nitroaniline, orange red needles, m.p. 89 900C (ethanol water) Reference Examples 49 In the same manner as described in Reference Example 32 by using appropriate starting material, there are prepared the following compounds:: Diethyl [N-cyclopropyl-N-[3-(4-ethoxycarbonyl-1pi perazinyl )-2-acetoxym ethyl-4- f1 uor nitrophenyl laminoiethylenelmalonate Diethyl [N-cyclopropyl-N-[3-(4-methyl-1-piperazinyl )-2-methoxymethyl-4-fluoro-6-nitrophenyl aminomethylene]malonate NMR (CDC1 3 6: 0.50-1.10 (4H, 1.23 (3H, t, Hz), 2.37 (3H, 2.39-2.60 (4H, 3.0-3.20 (1H, 3.10-3.50 (4H, 3.39 4.15 (2H, q, J=7.0 Hz), 4.30-4.55 (2H, 7.55-7.90 (2H, m) Diethyl [N-cyclopropyl-N-r3-(4-ethoxycarbonyl-lpiperazinyl)-2-methoxymethyl-4-fluoro-6-nitrophenylamino- -88 methyl enelmalonate NMR (ODd 3 6: 0.55-0.73 (2H, i) .511 2 mn), 1.15-1.145 (9H, in), 3.0-3.15 (1H, in), 3.15-3.35(4H, in), 3.140 (3H, in), 3.45-3.70 in,1.05-1.4 6,i) 410 4.60 (2H, mn), 7.65-7.90 (2H1, in) Reference Examples In the same manner as described in Reference Example 33 by using appropriate starting material, there are prepared the following compounds: Ethyl 1-cyclopropyl-7-(14-ethoxycarbonyl-1piperazinyl )-6-fluoro-8-acetoxymethyl- 1, 4-dihydro-14-oxoquinoline-3-carboxylate, yellow powder, 172 173 0

C

Methyl 1-cycloproPyl-7-(14-ethoxyca rbonyl-1piperazinyl)-6-fluoro-8-nethoxymethyl-1,4-dihydro-14-oxoquinoline-3-carboxylate NMR (CDd 3 6: 0.80-0.95 (2H, in), 1.10-1.22 (211, in), 1.30 (3H, t, J=7.1 Hz), 3.13 (3H1, 3.08-3.30 (14H, in), 3.50-3.85 (5H, in), 3.92 (3H, 4.19 (2H1, q, J-7.1 Hz), 5.12 (2H, 8.09 d, J=12.14 Hz), 8.67 (1H, S) Ethyl 1-cycloPropyl-7-(14-methyl-l-piperazlnyl)-6fluoro-8-acetoxyinethyl-1,14-dihydro-14-oxoquinoline-3carboxylate, in.p. 122 1250C, yellowish white powder Methyl 1-cyclopropyl-7-(14-ethoxyoarbonyl-lpiperazinyl )-6-fluioro-8-hydroxyinethyl- 1 ,4-dihydro-4oxo quinolime- 3-carboxyl ate BA4/Ethyl 1-cyclopropyl-7-(14-ethoxycarbonyl-1- -Si

Q-

NToO 89 piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4oxoquinoline-3-carboxylate Reference Examples 51 In the same manner as described in Reference Example 28 by using appropriate starting material, there is prepared the following compound: 3,6-Difluoro-2-(4-methyl-1-piperazinyl)-5nitrobenzyl alcohol, m.p. 138 1390C, yellow prisms Reference Example 52 3,6-Difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5nitrobenzyl alcohol (7.14 g) is dissolved in methanol (770 ml), and thereto is added dropwise conc. sulfuric acid (145 ml) while cooling on an ice bath. The mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and is poured into ice water (1.5 liter), and then extracted with dichloromethane. The extract is dried over magnesium sulfate and sodium sulfate, and then the solvent is distilled off under reduced pressure to give 3methoxymethyl-2,5-difluoro-4-(4-ethoxycarbonyl-1- S' piperazinyl)nitrobenzene (7.39 g) as yellow powder, m.p. 860C.

In the same manner as described above by using an appropriate starting material, the following compound is prepared.

3-Methoxymethyl-2,5-difluoro-4-(4-methyl-1piperazinyl)nitrobenzene ,!1 90 Vt t T

V

V

V f NMR (CDC1 3 6: 2.37 (3H, 2.45-2.60 in), 3.32-3.42 1 4H, in), 3.48 (3R, 4.53 (2H, d, J=3.5 Hz), 7.78 (1H, dd, J=7.3 Hz, J-s11.8 Hz) Reference.Example 53 To a solution of ethyl 1-cycloPropyl-7-(14-ethoxycarbonyl-l-piperazinyl)-6-fluoro-8-acetoxymethyl-1,4dihydro- 1 4-oxoquinoline-3-carboxylate (300 mg) in methanol (3 ml) is added 1N aqueous potassium carbonate (0.8 ml), and the mixture is stirred at room temperature for 3.25 hours.

The reaction mixture is poured into water, and extracted with dichioromethane and chloroform. The organic layers are combined and then dried over anhydrous sodium sulfate and the solvent is distilled off to give a mixture of methyl 1cyclopropyl-7- ethioxycarbonyl-1- pi perazinyl )-6-fl uoro-8hydroxymethyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylate and ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-l-piperazinyl fluoro-8-hydroxymethyl-1 4-dihydro-4-oxoqulnollne-3carboxylate (2 1) (280 mng).

Without separating them, to the mixture are added methanol (7 ml) and conc. sulfuric acid (1.14 ml), and the mixture is refluxed for ~4 hours. The reaction mixture is poured into ice water (50 ml), and then adjusted to below pH 8 with potassium carbonate and extracted with dichlovomethane. The extract is dried over anhydorus sodium sulfate, and then the solvent is distilled off under reduced pressure to give methyl 1-cycloproPYl-7-( 1 4-etuhoxyoarbonyl-lt t

K

K

91piperazinyl)-6-fluoro-8-methoxymfethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (159 mg).

NMR (CDCl 3 6: 0.80-0.95 (2H, in), 1.10-1.22 (2H, in), 1.30 (3H, t, J=7.1 Hz), 3.13 (3H, 3.08-3.30 in), 3.50-3-65 (5H, mn), 3.92 (3M, 4.19 (2H, q, J-7.1 Hz), 5.12 (2H, 8.09 (1H1, d, J=12.14 Hz), 8.67 O1H, s) Reference Examples 514 In the same manner as described in Reference Example 28 by Using appropriate starting material, there are prepared the following compounds: 3,6-Difluoro-2-morpholino-5-nitrobelzyl alcohol NMR (CDCl 3 6: 7,79 (OH, dd, J=11.9 Hz, 7,2 Hz), 4i.86 (2H, 4.02-3.66 1 4H, mn), 3.142-3.20 1 4H, in), 3.30- 3.02 O1H, br) in.p. 87 89 0 C (recrystallized from n-hexane ethyl acetate), yellow plates 2, 5-Difluoro-3-,methoxymethyl-4-inorpholino-nitrobenzene, m.p. 61.5 620C (recrystallized from n-hexane ethyl acetate), yellow needles 3, 6-Difluoro-2- (3-acetainidoinethyl-1 -pyrrolidinyl alcohol, m.p. 120 121 0 C, yellow crysals NMR (CDCl DSd6'6: 1.55-1.83 (1H, in), 1.95 (3H, 1.99-2.10 (1H, in), 2.39-2.57 O1H, in), 3.114-3.82 (6H, mn), 4.72 (2H, d, J=2.6 Hz), 7.31 (1H, brs), 7.70 O1H, dd, J=7.5 Hz, 13.5 Hz) 3,6-Difluoro-2-(14-benzyl-l-piperazinyl)-5-nitro- 4 4 t t .1 ~T r,~ 92 benzyl alcohol NMR (CDCl 3 6: 2.50-2.72 (4H, 3.20 (1H, br), 3.25-3.38 (4H, 3.58 (2H, 4.75-4.90 (2H, 7.20- 7.45 (5H, 7.76 (1H, dd, J=7.2 Hz, 11.6 Hz) 2,5-Difluoro-3-methoxymethyl-4-(4-benzyl-1piperazinyl)-nitrobenzene NMR (CDCl 3 6: 2.45-2.68 (4H, 3.30-3.45 (4H, o o 3.42 (3H, 3.58 (2H, 4.52 (2H, d, J=3.4 Hz), a V-o 7.26-7.40 (5H, 7.78 (1H, dd, J=7.3 Hz, 11.9 Hz) 2,5-D i fluo r o- 3 methoxym e t h yl 4 benzyl- 3 me ethylo a 1-piperazinyl)-nitrobenzene 9 P NMR (CDC1 3 6: 7.77 (1H, d, J=7.4 Hz, 11.9 Hz), 7.41-7.18 (5H, 4.52 (2H, 4.11 (18, d, J=13.0 Hz), 3.45-2.89 (4H, 3.42 (3H, 3.21 (18, d, J=13.0 Hz), 4 2.89-2.73 (1H, 2.73-2.54 (1H, 2.39-2.20 (1H, m), 1.19 (3H, d, J=6.2 Hz) 3,6-Difluoro-2-[3-(N-methyl-N-benzylamino)-1alcohol NMR (CDC1 3 6: 7.75 (1H, dd, J=7.5 Hz, 13.1 Hz), 7.41-7.20 (5H, 3.85-3.60 (4H, 3.62 (1H, d, J=13.1 Hz), 3.52 (18, d, J=13.1 Hz), 3.25-3.05 (1H, 2.35-1.92 (3H, 2.20 (3H, s) Reference Examples In the same manner as described in Reference Example 29 by using appropriate starting material, there are prepared the following compounds: A/T 0' _7 off and the residue is recrystallized Ifrom ethanol to give ST~, 1 N-cyclopropyl-2-methyl-3- (4--ethoxycar'bonyl- 1-pt perazinyl fluoro-6-nitroaniline as orange red prisms, m.p. 97 -93- 2-Morpholino-3,6-difluoro-5-nitrobenzyl chloride NMR (CDC1 3 6: 7.814 (1H, dd, J=11.3 Hz,7.3 Hz), 4.79 (2H, d, J=2.6 Hz), 4.00-3.78 mn), 3.40-3.15 (14H, mn) 2,5-Difluoro-3-chloromethyl-14-[3-(N-methyl-Nbenzylamino -pyrrol idinyl )-ni trotoluene NMR (CDC1 3 6: 7.78 (1H, dd, J=7.6 Hz, 13.14 Hz), 7.142-7.22 (5H, mn), 4.78 (1W, dd, J=2.7 Hz, 12.1 Hz), 4.67 (1H, dd, J=2.7 Hz, 12.1 Hz), 3.92-3.55 1 4H, mn), 3.67 (1H, d, J=13.1 Hz), 3.53 (1H, d, J=13.1 Hz), 3.30-3.10 (1H, mn), 2.35-1.88 (2H, mn), 2.22 (3H, s) 2,5-Difluoro-3-chloronethyl-4-(3-acetanidonethyl- 1-pyrrolidinyl)nitrotoluele, in.p. 914 98 0 C, yellow crystal, NMR (ODd 3 DMSO-d 6 6: 1.68-1.90 (1W, mn), 2.07 (3W s, .0-2.25 .50-2.68 (1 mi), 3.20-3.79 (6H, mn), 4.78 (2W, d, J=2.6 Hz), 7.78 (1H, dd, J=7.5 Hz, 13.5 Hz), 8.18 -brs) Reference Example 56 In the same mnanner as described in Reference Example 30 by using appropriate starting materials, there are prepared the following compounds.

2-Morpholino-3,6-difluoro-5-nitrotoluene, orange needles, m.p. 120.5 121.50C (recrystallized from n-hexane) 3,6 -D ifl1uoro-5- ni tro-2-[3- (N-methyl-N- ben zv.amino)-l1-pyrrolidinyljtoluene, NMR (CDC1 3 6: 7.65 (1H, dd, J=7.1 Hz, 12.8 Hz), 7.38-7.20 (5H, in), 3.79-3145 (14H, in), 3.62 (1H, d, J=13.14 acetate, and the solvent is distilled off, and the resulting residue is purified by silica gel column chromatography 94- Hz) 3. 50 (1H, d J-1 3. 4 Hz) 3. 30-3.-06 (1H, in), 2. 35-2. 13 O1H, in), 2.25 (3H, d, J=3.2 Hz), 2.20 (3H, 2.11-1.88 (1H, mn) 3, 6 -Difluoro-5-nitro-2-(3-acetamidomethyl-lpyrrolidinyl )-toluene, in.p. 82 84*C, yellow crystals NMR (CDCl 3 6: 1.60-1.78 OlH, mn), 2.00 (38, s), 2.02-2.20 (1H, mn), 2.2~4 (3H, d, J=3.2 Hz), 2.240-2.66 (1H, in), 3.20-3.62 (6H, in), 5.67 brs), 7.63 (1H, dd, Hz, 13.5 Hz) Reference Examples 57 In the same manner as described in Reference a Example 31 by using appropriate starting material, there are prepared the following compounds: N-Cyclopropyl-2-inethyl-3-morphol ino-24-fluoro-6nitroaniline, red flakes, m.p. 101.5 102 0 C (recrystallized f rom n-hexane) ~~~N-Cyclopropyl -iethoxymethyl3-(-ezy a::.piperazinyl)-4-fluoro-6-nitroaniline NMR (CDCl 3 6: 0.245-0.57 (28, 0.65-0.77 (28, mn), 2.248-2.65 (4H, mn), 2.86-3.00 (1H, in), 3.20-3.30 (24H, m), *a3.32 (3H, 3.58 (28, 41.81 (28, 7.25-7.38 (5H, mn), 7.70 (1H, d, J=12.8 Hz) N-Cyclopropyl-2-uiethoxyinethyl-3-(3-nethyl-24benzyl-1-piperazinyl)-24-fluoro-6-nitroaniline NMR (CDCl 3 6: 7.70 (18, d, J-12.9 Hz), 7.240-7.19 (58, mn), 4.65 (28, 4.11 (1H, d, J=13.3 Hz), 3.32 (28, chloride NMR (CDC 3 65: 1.21 O3H, d, J=6 Hiz), 2.24-2.50

F'

r 95 t t~t C s) 3. 40-2.88 (5H, m) 3. 22 1H, di, J-1 3.3 Hz) 2. 88-2.72 0 H, mn), 2. 72-2. 53 (1 H, in), 2.38-2.20 (1 H, mn), 1 .20 (3H, d J=6.2 Hz), 0.80-0.63 (2H, mn), 0.60-0.45 (2H, m) N-C yclo propyl- 2- methyl-3- methyl-N- ben zylamino)- 1-pyrrolidinyl]-4-fluoro-6-nitroaniline NMR (CDCl 3 6: 7.87 O1H, 7.69 (1H, di, J-11.7 Hz), 7.40-7.22 (5H, in), 3.81-3.41 (4H, mn), 3.65 (1H, d, J=10.6 Hz), 3.55 (1H, d, J=10.6 Hz), 3.24-3.08 (1H, in), 2.86-2.72 O1H, mn), 2.32-2.10 (1H, mn), 2.29 (3H, 2.21 (3H, 2.08-1.90 (1H, mn), 0.88-0.56 (3H, in), 0.51-0.41 (1H, mn) N-Cyclopropyl-2-inethoxymethyl-3-inorphol ino-4fluoro-6-nitroaniline, m.p. 57 60 0 C (recrysallized from nhexane), red powder N-Cyclopropyl-2-methyl-3- (3-acetamidoinethyl-lpyrrolidinyl)-4-fluoro-6-nitroaniline NMR (ODC1 3 6: 0.40-0.85 O4H, in), 1 .60-1 .83 (1H, mn), 2.01 O3H, 2.04-2.20 (1H, in), 2.28 (3H, 2.42-2.60 O1H, mn), 2.70-2.88 O1H, in), 3.20-3.65 (6H, mn), 5.89 O1H, brs), 7.65 (1H, di, J=14.6 Hz), 7.86 (1H, brs) Reference Examples 58 In the same manner as described in Reference Example 32 by using appropriate starting material, there are prepared the following compounds: Diethyl [N-cyclopropyl-N-[3-(4-benzyl- 1-piperazinyl )-2-inethoxymethyl-4-fluoro-6-nitrophenyllaninoinethylene]- 4.~tIEI

C

I I 4~

-V

~z U 96 ialonate NMR (CDCl 3 6: 0.55-0.90 (4H, 1.15-1.35 (6H, 2. 47-2.70 (4H, 3.05-3.45 (4H, 3.37 (38, 3.58 (28, 4.15 q, J=7 Hz), 4.20-4.55 k3H, 7.20-7.38 (58, 7.63-7.90 (2H, m) Diethyl [N-cyclopropyl-N-[3-( 4 -benzl-3-methyl-1piperazinyl)-2-methoxynethyl-4-fluoro-6-nitrophenylainomethylenelialonate NMR (CDC1 3 6: 7.80 (18, d, J=12.7 Hz), 7.78 (1H, e: 7.47-7.15 (5H, 4.55-3.98 3.65-2.88 (6H, m), 3.38 (3H, 2.86-2.70 (1H, 2.70-2.47 (18, 2.32- 2.18 (18, 1.50-1.08 (6H, 1.19 (38, d, J=5.0 Hz), 1.01-0.141 (4H, m) Diethyl [N-Cyclopropyl-N-[3-[3-(N-benzyl-N-methylamino )-1-pyrrolidinyl 1-2-iethyl-4-fluoro-6-nitrophenylJaminoiethyleneIialonate NMR (CDCl 3 6: 7.85-7.60 (28, 7.40-7.16 mn), 4.25-4.06 (2H, 3.80-3.05 (88, 2.19 (68, s), 2.3-1.89 (28, 1.23 (6H, t, J=7.1 Hz), 1.12-0.41 (4H, m) Diethyl CN-cyclopropyl-N-[3-morpholino-2-iethyl-4fluoro-6-nitophenyl]aminoiethylenelmaILnate ReferenceExamples 59 In the same manner as described in Reference Example 33 by using appropriate starting material, there are prepared the following compounds: Ethyl ccyclop ropyl-7-m orpholino-6 fluoro 8

-Y

t L~ alcohol (40 mg), as yellow prisms, m.p. 142.5 143.5*C.

4 09 a 9 0* 0 4, see, as@ 97 methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, colorless powder, m.p, 205 206 0 C (recrystallized from ethyl acetate r-hexane) Ethyl 1-cyclopropyl-7-(14-benzyl-1-piperazinyl acetoxymethyl-6-fluoro-1 ,4-dihydro-4-oxoquinoline-3carboxylate, NMR (CDCl1 3 6: 0.85-1.00 (2H, in), 1.10-1.25 (2H, mn), 1.141 (3H, t, J=7.1 Hz), 2.03 (3H, 2.45-2.30 (J4H, in), 3.10-3.45 (4H, in), 3.60 (2H, 3.85-14.03 1H, in), 4.39 (2H, q, J=7.1 Hz), 5.79 (2H, 7.23-7.145 (5H, in), 8.11 (1H, d J=1 2.3 Hz) 8. 65 (1 H, s) Ethyl 1-cyclopropyl-7-inorpholino-8-acetoxyinethyl- 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, in.p. 176- 1780C (recrystallized from ethyl acetate diethyl ether n-hexane), pale yellow prisms Ethyl 1-cyclopropyl-7-(14-methyl-l-piperazinyl fluoro-8-hydroxymethyl-1 ,4-dihydro- 1 I-oxoquirioline-3carboxylate, in.p. 216-2180C, pale yellow powder Ethyl 1 -cYclopropyl-7- (4-methyl--piperazinyl fluoro-8-nethoxyinethyl-1,4-dihydro-14-oxoquinc-line-3carboxylate, m.p. 200-20140C, pale yellow powder Ethyl 1-cyclopropyl-7-(14-benzYl-3-inethyl-1piperazinyl)-6-fluoro-8-acetoxymethyl-1,4-dihydro-4oxoquinoline-3-carboxylate, m.p. 170-172.5*C (decoinp.) (recrystallized from ethyl acetate diethyl ether), pale brown powder orange prisms (recrystallized from ethyl acetate nhexane), ii 98 Ethyl 1-cyclopropyl-7-E3-(N-benzyl-N-methylamino> 1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 145-148.50C (decomp.) (recrystallized from ethyl acetate diethyl ether), pale yellow powder Ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate m.p.

212-216 0 C, pale yellow powder Ethyl 1-cyclopropyl-7-rorpholino-6-fluoro-8-(lpyrrolidinylmethyl 1, 4-dihydro-4-oxoquinoline-3- 0S carboxylate, m.p. 227-2320C, pale yellow powder 0:0 Ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 165-1670C (recrystallized from dichloromethane diethyl ether), pale yellow needles *s Ethyl 1-cyclopropyl-7-(3-acetamidometlyl-l- 0Wo* e f py r rolid inyl)-6- -fl uoro- 8 -metthyl- 1 ,4 -d ihyd ro- 4 -oxo quiinoliine- :1 3-carboxylate, m.p. 208-210 0 C (recrystallized from ethanol), white crystals Reference Example ro a To a solution of ethyl 1-cyclopropyl-7-(4-methyl- 1-piperazinyl)-6-fluoro-8-acetoxyme thyl-1 ,4-dihydro-4oxoquinoline-3-carboxylate (142 mg) in ethanol (10 ml) is added 2N aqueous potassium carbonate (1 ml), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is extracted with chloroform. The extract is dried 99 over magnesium sulfate and the solvent is distilled off.

The residue is crystallized by adding thereto diethyl ether to give ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6fluoro-8-hydroxymethyl-1, 4 -dihydro-4-oxoquinoline-3carboxylate (101 mg), as pale yellow powder, m.p. 216 218oC.

Reference Example 61 To a solution of ethyl 1-cyclopropyl-7-(4-methyl- 1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4oxoquinoline-3-carboxylate (160 mg) in methanol (10 ml) is added cone. sulfuric acid (2 ml), and the mixture is refluxed for 6.5 hours. The reaction mixture is adjusted to below pH 8 with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The exttract is washed with aqueous saturated sodium chloride and then dried over Smagnesium sulfate and the solvent is distilled off. The residue is crystallized by adding thereto diethyl ether to give methyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3carboxylate (125 mg), as pale yellow powder, m.p. 200 f ,204 C.

Reference Example 62 To a solution of 3,6-difluoro-2-(4-benzyl-1alcohol (15.4 g) in methanol (400 ml) is added gradually cone. sulfuric acid (80 ml) with stirring under ice cooling. After the addition, the mixture prepared the following compounds: N-Cyclopropyl-2-acetoxymethyl-3- (4-ethoxycarbonyl- 100 $0 00 *000 400 0 .0" 006 is refluxed for 30 hours, and thereto is further added conc.

sulfuric acid (10 ml), and the mixture is further refluxed for 20 hours. After cooling to room temperature, the reaction mixture is adjusted to below pH 8 with aqueous saturated potassium carbonate and aqueous saturated sodium hydrogen carbonate and then extracted with ethyl acetate.

The extract is dried over magnesium sulfate, and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane) to give 2,5-difluoro-14-(4-benzyl-l-piperazinyl)-3-methoxymethylnitrobenzene (12.9 g).

NMR (CDCl 3 6: 2.415-2.68 in), 3.30-3.415 (41H, in), 3.142 (3H, s),,3.58 (2H1, 41.52 J=3.14 Hz), 7.26-7.140 (5H, in), 7.78 O1H, dd, J=7.3 Hz, 11.9 Hz) Reference Example 63 To a solution of ethyl 1-cyclopropyl-7-morpholino- 6-fluoro-8-acetoxymethyl- 1 ,4-dihydro-14-oxoquinoline-3-, carboxylate (550 mng) in ethanol (10 ml) is added 2N aqueous potassium carbonate (1 ml), and the mixture is stirred at room temperature for 41 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The extract is dried and concentrated. The residue is crystallized by adding thereto diethyl ether to give ethyl 1-oyclopropyl-7-inorpholino'- 6 -fluoro-8-hydroxymethyl-~J 4dihydro-11-oxoquinolifle-3-Oarboxylate (353 mng), as pale yellow powder, m.p. 212 2160c.

I

101 Reference Example 64 To ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate mg) is added thionyl chloride (1 ml), and the mixture is stirred at room temperature for 4 hours and further at 500C for one hour. The solvent is concentrated under reduced pressure to give crude ethyl 1-cyclopropyl-7-morpholino-6fluoro-8-chloromethyl-, 4-dihydro-4-oxoquinoline-3carboxylate (84 mg).

Without purifyting the product, pyrrolidine (1 ml) is added thereto, and the mixture is stirred at room Stemperature overnight. The reaction mixture is extracted with dichloromethane, and the extract is washed with water and aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography (solvent, dichloromethane methanol 10 to give 1cyclopropyl-7-morpholino-8-(1-pyrrolidinylmethyl )-6-fluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (31.8 mg), as pale yellow powder, m.p. 227 232"C.

o t tReference Example To ethyl 1-cyclopropyi-7-morpholino-6-fluoro-8hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (101 mg) is added thionyl chloride (1.5 ml), and the mixture is stirred at room temperature for 5.2 hours. The solvent is removed by concentration under reduced pressure. To the oxoquinoline-3-carboxylate Ethyl 1-cyclopropyl-7-(4-ethoxycarbonyl-1- C 0 A/To m i 102resulting crude ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate are added ethanethiol (1.5 ml) and triethylamine (30 pl), and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with dichloromethane and the extract is washed with water and aqueous saturated sodium chloride in this order and then dried over magnesium sulfate. The solvent is removed by concentration under reduced pressure, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane 9 J methanol 15 1) and then recrystallized from dichloromethane diethyl ether to give ethyl 1-cyclopropyl-7morpholino-6-fluoro-8-ethylthiomethyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylate (49 mg), as pale yellow needles, m.p. 165 167 0

C.

Reference Example 66 1 To 2-chloro-5,6-difluoro-3-nitrotoluene (1.0 g) are added spray-dried potassium fluoride (1.4 anhydrous dimethylsulfoxide (10 ml) and benzene (10 ml), and the moisture is removed by azeotropic distillation together with benzene. Subsequently, the mixture is stirred at 170 180 0 C under argon stream for 3.5 hours. After cooling, the reaction mixture is poured into ice water and extracted with diethyl ether. The extract is washed with water, dried and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent, n-hexane) to menoxymetny±-2,5-difluoro-4-(4-methyl- 1piperazinyl)nitrobenzene 103 give 2,5,6-trifluoro-3-nitrotoluene (0.45 g).

NMR (CDCl 3 6: 2.34-2.37 (3H, 7.75-8.00 (1H, m) Reference Example 67 To a solution of 3-amino-1-benzyl-4-methylpyrrolidine (9.5 g) in methanol (190 ml) is added anhydrous t-butoxycarboxylic acid (13.0 g) at room temperature, and the mixture is stirred for one hour. Methanol is distilled off under reduced pressure, and to the resulting residue is added water. The mixture is extracted with dichloromethane, and the extract is dried over magnesium sulfate and then dichloromethane is distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane methanol 19 1) to give 3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (isomer A) (4.4 as colorless prisms, m.p. 131.5 132.7 0

C.

NMR (CDCI 3 6: 1.09 (3H, d, J=6.7 Hz), 1.43 (9H, 1.86-2.02 (2H, 2.62 (2H, d, J-6.1 Hz), 2.93-3.05 (1H, 3.56 (2H, 3.68 (1H, brs), 4.84 (1H, brs), 7.20- 7.37 (5H, m) Reference Examples 68 To 3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (3.9 g) are added ethanol (50 ml) and 10 Pd-C (780 mg), and the mixture is subjected to catalytic reduction at 60°C under atmospheric pressure. After the catalytic reduction, the catalyst is removed off by ^^t 'pp ;e ana Tnen Lne solvent is distilled off under reduced pressure to give methyl 1-cyclopropyl-7-(4-ethoxycarbonyl-1- 104 ether to give 3-(t-butoxyamino)-4-methylpyrrolidine (isomer A) (2.01 as colorless prisms, m.p. 86.8 870C.

NMR (CDC1 3 6: 1.08 (3H, d, J-6.8 Hz), 1.45 (9H, 1.83-1.97 (1H, 2.10 (IH, brs), 2.43-2.52 (1H, m), i2.52-2.81 (1H, 3.10-3.35 (2H, 3.53-3.73 (1H, m), 4.69 (1H, brs) Reference Example 69 S104 itetrahydrofuran (500 ml) is added dropwise a solution of ml) with stirring at below 1000, and thereto is further added dropwise a solution of BF 3

.(C

2

H

5 )0 (232 ml) in tetrahydrofuran (500 ml) under ice cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water (1.5 liter) and is extracted with diethyl ether. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl alcohol (112.7 as pale yellow •oil, b.p. 11200 (30 mmHg).

Reference Example STo a solution of 2 ,3 6 -trifluorobenzyl alcohol (41 g) in dichloromethane (100 ml) is added dropwise a solution of thionyl chloride (50 ml) in dichloromethane (80 ml) under ice cooling with stirring, and the mixture is stirred at 105 room temperature overn To the mixture is added triethylamine (10 ml), and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 as colorless oil, b.p. 63 0 C (13 mmHg).

NMR (CDCI 3 6: 4.66 (2H, 6.62-6.93 (1H, m), 7.04-7.26 (1H. m) Reference Example 71 To a solution of sodium cyanide (1.94 g) in water (4 ml) is added phenyltriethylammonium chloride (0.09 g), and thereto is added with stirring 2,3,6-trifluorobenzyl chloride (5.0 and the mixture is stirred at 90 to 1000C for 40 minutes. The reaction mixture is poured into water ml) and is extracted with diethyl ether. The extract is dried over potassium carbonate and the solvent is distilled off to give 2-(2,3,6-trifluorophenyl)acetonitrile (3.1 g), b.p. 80 850C (5 mmHg).

s *NMR (CDC1 3 6: 3.76 (2H, d, J=0.8 Hz), 6.89-6.98 (1H, 7.11-7.26 (1H, m) Reference Example 72 2-(2,3,6-Trifluorophenyl)acetonitrile (13.3 g) is dissolved in ethanol (20 ml), and thereto is carefully added conc. sulfuric acid (8.5 ml), and the mixture is refluxed at 125C0 for 7 hours. After cooling, the reaction mixture is fractionated with diethyl ether and water. The ether layer is washed with aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced V °7 i

I

prepared the following compounds: 4 4I 106 pressure to give ethyl 2-(2,3,6-trifluorophenyl)acetate (16.3 as colorless oil.

NMR (CDCl 3 6: 1.27 (3H, t, J-7.1 Hz), 3.72 (2H, d, J=1.2 Hz), 4.19 (2H, q, J=7.1 Hz), 6.78-6.90 (1H, m), 7.00-7.16 (1H, m) Reference Example 73 Ethyl 2-(2,3,6-trifluorophenyl)acetate (16.2 g) is dissolved in ethanol (60 ml). The mixture is stirred and thereto is added 3N sodium hydroxide (200 ml), and the mixture is stirred at 70°C for one hour. After cooling, 6N hydrochloric acid (120 ml) is added to the mixture. The 1 resulting white powdery precipitates are dissolved by adding I thereto diethyl ether. The diethyl ether layer is separated and dried over magnesium sulfate and then concentrated under Sreduced pressure to give 2-(2,3,6-trifluorophenyl)acetic i acid (13.9 as white crystals.

NMR (CDC 3 1 S: 3.79 (2H, 6.79-6.91 (1H, m), 7.02-7.18 (1H, 9.75 (1H, s) Reference Example 74 Lithium aluminum hydride (0.8 g) is suspended in dry diethyl ether (5 ml) and the mixture is stirred. To the l mixture is added dropwise a solution of 2-(2,3,6-trifluorophenyl)acetic acid (2.0 g) in dry diethyl ether (15 ml), and the mixture is refluxed for 30 minutes. To the reaction mixture are added water (0.8 ml), 10 aqueous sodium hydroxide (0.8 ml) and water (1.6 ml) in this order, and the T ON r 1 107 mixture is stirred at room temperature. To the mixture is added diethyl ether (10 ml), and the resulting precipitates are separated by filtration and washed with tetrahydrofuran. The washing liquid and the filtrate are combined and then concentrated under reduced pressure to give 2-(2,3,6-trifluorophenyl)ethyl alcohol (1.9 as colorless oil.

NMR (CDCI 3 6: 1.75 (1H, 2.98 (3H, t, J=6.7 Hz), 3.85 (2H, t, J=6.7 Hz), 6.74-6.87 (1H, 6.93-7.09 (1H, m) Reference Example To a solution of 2-(2,3,6-trifluorophenyl)ethyl alcohol (1.5 g) in methylene chloride (10 ml) are added with stirring p-toluenesulfonyl chloride (2.2 g) and triethylamine (2.0 ml), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into water and is extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) and recrystallized from diethyl ether n-hexane to give 1-[2- (p-toluenesulfonyloxy)ethyl]-2,3,6-trifluorobenzene (3.4 g), as colorless prisms, m.p. 73 74°C.

NMR (CDC1 3 6: 2.44 (3H, 3.03 (3H, t, 4.65 (2H, 4.11 (1H, d, J=13.3 Hz), 3.32 (2H, 108 Hz), 4.23 (2H, t, J-6.5 Hz), 6.70-6.82 (1H, 6.93-7.09 (1H, 7.29 (2H, d, J-8.5 Hz), 7.70 (2H, d, J=8.5 Hz) Reference Example 76 Lithium aluminum hydride (5.6 g) is suspended in dry diethyl ether (70 ml) and thereto is added dropwise with stirring a solution of 1-[2-(p-toluenesulfonyloxy)ethyl]- 2 3,6-trifluorobenzene (23.3 g) in dry diethyl ether (170 ml) at below 10 0 C, and the mixture is stirred at room temperature for one hour. To the reaction mixture are added water (5.6 ml), 10 aqueous sodium hydroxide (10.0 ml) and water (5.6 ml) in this order, and the mixture is stirred at room temperature for 30 minutes. The resulting white precipitates are filtered off, and the filtrate is concent- '-i rated under atmospheric pressure to give 2,3,6-trifluoro-1ethylbenzene (13.2 as colorless oil.

NMR (CDCl 3 6: 1.22 (3H, t, J=7.1 Hz), 2.72 (2H, S= q, J=7.1 Hz), 6.71-6.82 (1H, 6.87-7.03 (1H, m) Reference Example 77 2,3,6-Trifluoro-l-ethylbenzene (1.09 g) is dissolved in conc. sulfuric acid (5.5 ml), and thereto is added with stirring a mixture of potassium nitrate (0.83 g) C (c in cone. sulfuric acid (4 ml) at room temperature, and the mixture is stirred at the same temperature for one hour.

The reaction mixture is poured into cold water (100 ml) and is extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium chloride and dried over I ~1LIIUII-I~*I-~^IIIYlf--)ll-~l_~- i ~I l-iLI_ 109 magnesium sulfate and then concentrated under reduced pressure to give 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.14 as yellow oil.

NMR (CDCl 3 6: 1.27 (3H, t, J=7.6 Hz), 2.77-2.89 (2H, 7.83 (1H, dd, J=8.0 Hz, 16.2 Hz) Reference Example 78 To 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.02 g) are added ethanol (4.5 ml) an-d water (0.5 ml) and the mixture is stirred. To the mixture is added with stirring a mixture of 1-methylpiperazine (0.83 ml), triethylamine ml) and ethanol (0.6 ml), and the mixture is refluxed for hours. To the reaction mixture is furthr added 1-methyl- K piperazine (1.0 ml), and the mixture is refluxed for 3 hours. The mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) to give 3ethyl-2,5-difluoro-4- (4-methyl-1- piperazinyl)nitrobenzene (1.12 as yellow oil.

NMR (CDCI 3 6: 1.21 (3H, t, J=7.5 Hz), 2.37 (3H, 2.42-2.67 (4H, 2.81 (2H, dq, J=2.8 Hz, 7.5 Hz), 3.05-3.23 (4H, 7.63 (1H, dd, J=7.1 Hz, 11.3 Hz) Reference Example 79 To 3-ethyl-2,5-difluoro-44(4-methyl-1-piperazinyl)nitrobenzene (1.12 g) are added potassium fluoride (0.24 N,N-dimethylsulfoxide (3.5 ml) and cyclopropylamine (0.4 ml), and the mixture is stirred at 80 to 850C for 110 hour. The reaction mixture is diluted with ethyl acetate, and the organic layer is washed with water and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give Ncyclopropyl-2-ethyl-3-( 4 -methyl-1-piperazinyl)-4-fluoro-6nitroaniline (1.00 as viscous oil.

NMR (CDC1 3 6: 0.45-0.55 (2H, 0.66-0.78 (2H, 1.14 (3H, t, J=7.4 Hz), 2.37 (3H, 2.40-2.62 (4H, m), 2.62-2.85 (1H, 3.00 (2H, q, J=7.4 Hz), 3.05-3.23 (4H, 6.82 (1H, 7.54 (1H, d, J=12.4 Hz) SReference Example t In the same manner as described in Reference SExample 67 by using an appropriate starting material, there is prepared the following compound.

3-(t-Butoxycarbonylamino)-1-benzyl-4-methylt pyrrolidine (isomer colorless needles, m.p. 83 83.5°C (recrstallized from n-hexane) NMR (CDC13) 6: 0.93 (3H, d, J=6.98 Hz), 1.44 (9H, 2.14-2.54 (3H, 2.60-2.93 (2H, 3.58 (2H, dd, J=13.03 Hz, 14.91 Hz), 4.07-4.31 (1H, 4.61-4.82 (1H, m), 7.14-7.39 (5H, m) Reference Example 81 In the same manner as described in Reference Example 68 by using an appropriate starting material, there is prepared the following compound.

3-(t-Butoxyamino)-4-methylpyrrolidine (isomer B), 111 b.p. 106 109 0 C (0.25 mmHg) NMR (CDC13) 6: 0.97 (3H, d, J=6.9 Hz), 1.45 (9H, 1.93 (1H, brs), 2.10-2.33 (1H, 2.61-2.79 (1H, m), 3.04-3.33 (2H, 3.97-4.21 (1H, 4.63-4.87 (1H, m) Reference Example 82 In the same manner as described in Reference Example 32 by using an appropriate starting material, there is prepared the following compound.

Diethyl [N-cyclopropyl-N-[3-(4-methyl-1-piperazinyl)-2-ethyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate Reference Example 83 In the same manner as described in Reference ,4 Example 33 by using an appropriate starting material, there is prepared the following compound.

Ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6t t Sfluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 201 203°C, white powder (recrystallized from ethanol) Example 1 To 6,7-difluoro-1-cyclopropyl-8-methyl-1,4dihydro-4-oxoquinoline-3-carboxylic acid B(OCOCH 3 2 S, chelate (1.2 g) are added benzylpiperazine (1.6 g) and dimethylacetamide (6 ml), ar'd the mixture is reacted at 50 0

C

for 20 hours. After concentrating, the resulting residue is dissolved in acetone (20 ml) and thereto is added cone.

hydrochloric acid (5 ml), and the mixture is stirred at room temperature for 30 minutes. After the solvent is distilled mixture is extracted with chloroform. The extract is dried AT 112 off, to the residue is added water, and the mixture is extracted with dichloromethane. The aqueous layer is taken and neutralized with aqueous sodium hydrogen carbonate, and is extracted with dichloromethane. The extracts are combined and dried over magnesium sulfate. After removing the solvent, to the resulting residue is added a mixture of diethyl ether and ethanol, and the resulting precipitates are separated by filtration to give 7-(4-benzyl-l-piperazino yl)- -cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 as white crystals, m.p.

e e 209 211 C.

NMR (CDC 3 1 6: 8.86 (1H, 7.85 (1H, d, J=12 o 3 SHz), 7.35 (5H, bs), 3.93-4.26 (1H, 3.62 (2H 3.13- 3.50 (4H, 2.76 (3H, 2.53-2.83 (4H, 0.73-1.40 (4H, m) 'P44 Example 2 Sfluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (84 mg) are added acetic acid (3 ml) and 10 Pd-C (10 mg), and the mixture is subjected to catalytic reduction at 700C I for one hour. After the catalytic reduction, the reaction mixture is cooled and the catalyst is filtered off. The filtrate is concentrated, and to the residue is added aqueous sodium hydrogen carbonate, and the resulting precipitates are separated by filtration to give 7-(1piperazinyl -cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4- -113 oyoquinollne-3-carboxylic acid (45 mg), as white crystals, mp. 291 295'C (decomp.).

NMR (DMSO-d 6 6: 8.84 O1H, 7.85 (1H, d, J=12.5 Hz), 4.30-4.148 (1H, in), 3.16-3.50 (8H, in), 2.78 s), 1.12-1.28 (2H, in), 0.814-0.96 (2H, mn) Example 3 6,7-Difluoro-l-cyclopropyl-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxylic acid (1.8 g) is suspended in Nmethylpyrrolidone (5 ml) and thereto is added piperazine (1.8 and the mixture is stirred at 150 0 C for 3 hours.

After the reaction, the reaction mixture is concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane methanol =3 :1) to give 7-(l-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl- 1, 4-dihydro-4--oxoquinoline-3-carboxylic acid (0.06 as, v white crystals, m.p. 291 295 0 C (decomp.).

NMR (DMSO-d 6 6: 8.84 (iH, 7.85 (1H, d, J-12.5 Hz), 4.30-14.48 (1H, in), 3.16-3.50 (8H, in), 2.78 (3H, s), 1.12-1.28 (2H, in), 0.84-0.96 (2H, mn) J Example 4 In the same manner as described in Example 1 by using appropriate starting material, there are prepared the following compounds: 7-(4-Methyl-l-piperazinyl)-l-cyclopropyl--6-fluoro- 8-inethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, in.p.

S- R, 219 220.5 0 C (recrys tall ized from ethanol), pale yellow 7 FPI-~" m e (AI XLL1i. meilli

I

ii 0" o rt@ 0a0 00r ob 0 480 tt'lot r t 114 7- 4-D iazabi cycloC 4. 3.ol non an- 44-yi -cyclopropyl-6-fluoro-8-methyl-1 -dihydro-4-oxoquinoline-3carboxylic acid, m.p. 208 212 0 C (recrystallized from dichloromethane diethyl ether), pale yellow powder 7-(l-Piperazinyl)-1-(2,2-dichloro-1-cyclopropyl)- 6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(1-Piperazinyl)-1l-(2-fluoro-l-cyclopropyl)-6fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Example 1-Cyclopropyl- 6 -fluoro-8-methyl-7-(1-piperazinyl)- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.20 g) and potassium hydrogen carbonate (70 mg) are suspended in dimethylformamide (3 ml), and thereto is added 4-bromomethyl-3-methyl-1,3-dioxolen-2-one (0.13 g) under icecooling, and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure, and to the resulting residue is added water, and the mixture is extracted with dichloromethane.

The extract is distilled under reduced pressure, and the resulting residue is recrystallized from dichloromethane and diethyl ether to give 7-4-(5-methyl-2-oxo-1,3-dioxolen-4yl)methyl-l-piperazinyl]-1-cyclopropyl-6-fluoro8-methyl.

1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.24 as pale yellowish white crystals, m.p. 174 177 0

C.

lzs

CRA

removed by concentration under reduced pressure. To the 115- Example 6 To 6,7-difluoro-1-cyclopropyl-8-methyl-1,4dihydro-4-oxoquinoline-3-carboxylic acid B(OCOCH 3 2 chelate (3.4 g) are added dimethylacetamide (10 ml) and 4benzyl-3-methylpiperazine (6.8 and the mixture is reacted at 50 0 C for 3 hours. After the reaction, the solvent is distilled off, and to the resulting residue are added acetone (30 ml) and cone. hydrochloric acid (5 ml), and the mixture is stirred at room temperature for minutes. After the solvent is distilled off, to the residue is added water, and the crystals are separated by filtra- .,ft tion. The aqueous layer is neutralized with sodium hydrogen carbonate and is extracted with dichloromethane. The dichloromethane is distilled off, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane methanol 20 1) and recrystallized from ;ethanol to give 7-(4-benzyl-3-methyl-l-piperazinyl)-1cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid (0.45 as pale yellow powder, m.p. 170 171 0 Example 7 To 7-(4-benzyl-3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid (0.30 g) are added acetic acid (10 ml) and Pd-C (50 mg), and the mixture is subjected to catalytic reduction at 70°C under atmospheric pressure for one hour.

i, -k L LI. ±CU by silica gel column chromatography (solvent, n-hexane) to 116 After the catalytic reduction, the reaction mixture is cooled and the catalyst is removed by filtration. The filtrate is concentrated, and to the residue is added water, and the mixture is adjusted to about pH 7.5 with sodium hydrogen carbonate, and then is extracted with dichloromethane. The dichloromethane is distilled off, and to the residue is added diethyl ether, and the resulting precipitates are separated by filtration and recrystallized from ethanol to give 7-(3-methyl-l-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinollne-3carboxylic acid (0.16 as pale yellow powder, m.p. 206 208 0

C.

Example In the same manner as described in Examples 1, 3 and 9 by using appropriate starting material, there are prepared the following compounds.: 1) 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6fluoro-8-methyl- ,4-dihydro-4-oxoquinoline-3-carboxylic S acid, m.p. 201.5 203.0OC, pale yellow powder (reorystal- S' lized from ethanol diethyl ether) i 1

I--

117 2) 1-Cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fl4oro-8-hydroxymethyl- ,4-dihydro- 4 -oxoquinoline-3ca'boxylic acid, m.p. 234 235 0 C (recrystallized from methanol), white needles 3) 1-Cyclopropyl-7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid, m.p. 218 220 0 C (recrystallized from ethanol), pale yellow prisms 4) 1-Cyclopropyl-7-(4-methyl-1-piperazinyl)-6fluoro-8- hydroxymethyl- 1, 4-dihydro-4-oxoquinoline-3carboxylic acid, m.p. 197 201 0 C, pale yellow powder 1-Cyclopropyl-7-(1-piperazinyl)-6-fluoro-8hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 149 152 0 C (recrystallized from ethanol acetone dichloromethane), white powder 6) 1-Cyclopropyl *I-(4-methyl-1-piperazinyl)-6fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid, m.p. 208 210 0 C (recrystallized from ethanol diethyl ether), white powder 7) 1-Cyc9 opropyl 7-(1-piperazinyl)-6-fluoro-8methoxymethyl-1 ,-dihydro- 4 -oxoquinoline-3-carboxylic acid 8) 1-Cyclopropyl-7-(4-methyl--piperazinyl)-6fluoro-8-fluoromethyl-1, 4-dihydro-4-oxoquinoline-3carboxylic acid, m.p. 187 189 0 C (decomp.) (recrystallized from diethyl ether dichloromethane), pale yellow powder 9) 1-Cyclopropyl-7-(l-piperazinyl)-6-fluoro-8fluoromethyl-1 4 2 -dihydro- 4-oxoquinoline-3-carboxylic acid

F

118 1-Cyclopropyl-7-(4-methyl-l-piperazlnyl)-6fl.uoro-8-difluoromethyl- 1 ,4-dihydro-4-oxoquinoline-3carboxylic acid 11) 1-Cyclopropyl-7-(l-piperaznyl)-6-fluoro-8difluoromethyl-1 ,-dihydro-4-oxoquinoline-3-carboxylic acid 12) 1-Cyclopropyl-7-(4-hydroxy-l-piperidyl)-6fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid, n.p. 234 236 0 C (recrystallized from chloroform ethanol), pale yellow crystals 13) 1-Cyclopropyl-7-(3-amino-4-methyl-1pyrroli dinyl fluoro-8-methyl- 1 ,4 dihydro-4-o xoqui nol ine- .11. 3-carboxylic acid hydrochloride (isolmet; m.p. 226 232 0 C, yellow powder (recrystallized from ethyl acetate ethanol) NMR (DMSO-d 6 6; 1.18 (3H, d, J=6.7 Hz), 2.62 (3H, 7.72 (1H, d, J=13.4 Hz), 8.79 (1H, s) 14) 1-Cyclopropyl-7-(3-aminomethyl-l-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid hydrochloride, m.p. 195 200 0 C (recrystalj ,lized from ethyl acetate methanol), yellow crystals 1-Cyclopropyl-7-(3-methylamino--pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid, m.p. 185.5 187.50C (decomp.) (recrystallized from ethanol diethyl ether), white powder 16) 1-Cyclopropyl-7-(4-cyclopropyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- 119 carboxylic acid, m.p. 2214 225.51C (decomp.) (recrystallized from ethanol), pale yellow prisms 17) 1-Cyclopropyl-7-[3-(5-methyl-2-oxo-1 ,3dioxolen-4-yl)methylamino-l-pyrrolidinyl]-6-fluoro-8-methyl- I 1, 4 -dihydro-4-oxoquinoline-3-carboxylic acid 18) 1-C yclopropyl-7--morpholino-6-fluoro-8-methyl- 1,4-dihydr.o-4-oxoquinoline-3-carboxylic acid, m.p. 227.5- V 2280C (recrystallized from ethanol), pale yellow flakes 19) 1-Cyclopropyl-7-morpholino-6-fluoro-8hydroxymethyl-1,'I-dihydro-'4-oxoquinoline--3-carboxylic acid, m.p. 218 220 0 C (recrystallized from methanol), pale yellow prisms 1-CycloproPYl-7-(l4-benzyl--1-piperazinyl fluoro-8-hydroxymethyl-1, 1 4-dihydro-'4-oxoquinoline-3carboxylic acid, m.p. 229 231 0 C (recrystallized from p dichioromethane diethyl ether), pale yellow leaves 1 21) 1-Cyclopropyl-7-( 2 4-benzyl-3-methyl-lpiperazinyl )-6-fluoro-8-hydroxymethyl-1 ,4-dihydro-4- I oxoquinoline-3-carboxylic acid, rn.p. 208 209 0 C (recrystallized from ethanol diethyl ether), pale orange powder 22) 1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6fluoro-8-hydroxymethyl-1 ,4-dihydro- 4 -oxoquinoline-3carboxylic acid, m.p. 180 183 0 C (recrystallized fromV ethanol ethyl acetate diethyl ether), white powder 23) I-CycloPropyl-7-[3-(N-benzyl-N-methylamino)- 1-pyrrolidinyl-6-'fluoro-8-methyl-,14-dihydro.-4-oxohydroxide (0.8 ml) and water (1.6 ml) in this order, and the -120quinoline-3-carboxyllc acid, m.p. 160.8 -161 (recrystallized from ethanol diethyl ether) pale yellow pow der 2'4) 1-Cyclopropyl-7-morpholino-6-fluoro-8- (1pyrrolidinylmethyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 232 -23600 (decomp.) (recrystallized from diethyl. ether -ethanol dichloromethane) pale yellow prisms 1 Cycl1opropyl- 7-morphol ino- 6 -fl1uoro-8 ethylthiomethyl-1 4--dihydro-'4-oxoquinolinE- 3-carboxylic acid, m.p. 206 20800 (recrystallized f rom n-hexaneethanol), pale yellow prisms v26) 1 -Cyclopropyl- 7 (4-oxo- 1-pi peri dyl -f luoro- 8-methyl-1, 1 4-dihydro- 2 4-oxoquinoline--3-carboxylic acid, m.p.

247 25000 (recrys tall ize' from chloroform ethanol), white crystals 27) 1 -Cyclopropyl-7- (3-acetamidomethyvl-1 pyrrolidinyl )-6-fluoro-8-methyl- 1 2 -dihydro-4-oxoquinoline- 3-carboxyllc acid, m.p. 192 19140C (recrystallized from chloroform methanol), white crystals 28) 1 C Y C10Pro0P YI- 7- 3 -t -b uto x yca r b onylaminooxoquinoline-3--carboxylic acid, m.p. 131 1350C (recrystallized from methanol), white powder 29) 1-Cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl )-6-fluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3- 121 carboxylic acid hydrochloride, m.p. 195 2000C (recrystallized from ethyl acetate methanol), white powder 1-Cyclopropyl-7-[3-(N-ethylacetamido)methyl- 1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxylic acid, m.p. 167 1690C (recrystallized from ethanol), pale yellow crystals 31) 1-Cyclopropyl-7-(3-ethyl aminomethyl-lpyrrolidinyl fluoro-8-methyl- 1 dihydro-4-oxoquinoline- 3-carboxylic acid hydrochloride, m.p. 267 27100 -(recrystallized from methanol acetonitrile), yellow powder 32) 1-Cyclopropyl-7-(4-acetyl-3-methyl-lpiperazinyl)-6-fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3carboxylic acid, m.p. 219 220 0 C (recrystallized from methanol), white powder *tic 33) 1-Cyclopropyl-7-(4-formyl-3-methyl-lpiperazinyl)-6-fluoro-8-methyl-1 4-dihydro- 4-oxoquinoline-3carboxylic acid, m.p. 236 2390C (recrystallized from methanol), white powder 34) 1-Cyclopropyl-7-(3,4-dimethyl-l-piperazinyl)- 6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 181 18300 (recrystallized from ethyl acetate), pale yellow powder 1-Cyclopropyl-7-(3,5-dimethyl-l-piperidyl)-6fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 176 1790C (recrystallized from ethanol), pale yellow prisms 06 6, 1 122 36) 1 -CycloPropyl-7- (3-methylmorphol ino) -6 fluoro-8-methyl- 1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid m p. 199.-5 201 IC (recrystall ized f rom ethanolethyl acetate), colorless needles 37) 1-CycloproPYl-7-(3-aminomethylmorpholino)-6fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid 38) I-Cyclopropyl-7-(3-fluoromethylmorpholino)-6fluoro-8-methyl-1 ,4 1 -dihydro-4-oxoquinoline-3-carboxylic acid 39) 1-CycloPropyl-7-(3-chloromethylrnorpholino)-6fluoro-8-methyl- 1 ,4-dihydro- 1 4-ooquinoline-3-carboxylic acid 1 -Cyclopropyl-- I- (4-ethyl- 1-piperazinyl fluoro-8-methyl--1, 1 4-dihydro-L-oxoquinoline-3-carboxylic acid, m.p. 208 2101C (recrystallized from dimethylacetamide diethyl ether), pale yellow prisms 41l) 1-Cyclopropyl-7- (4-fluoro-l1-piperidinyl fluoro-8-methyl-1 ,4-dihydro--4-oxoquinoline-3-carboxylic acid, m.p. 208 210 0 C (recrystallized from ethanol), colorless needles 42) 1-Cyclopropyl-7-[3-(5-methyl-2-oxo-1 ,3dioxolen-'4-yl )methylamino-1-pyrrolidiriyl]-6-fluoro-8-methyl- 1,4-dihydro-4-oxoquino'.ine-3-carboxylic acid J43) 1 -CYclopropyl-7- (4-methyl- 1-piperazinyl fluoro-8-ethyl-1 4-dihydro-4-oxoquinollne-3-carboxylic acid, m.p. 239 2'420C (decomp.) (recrystallized from diethyl ether ethanol), white powder 44) 1-CYoloPropyl-7-(3-methyl-l-piperazinyl)-6- 123 fluoro-8-ethyl-1,4-dihydro-4-oxoqunoline-3-carboxylic acid 1-Cyclopropyl-7-(3-amino-1-pyrrolidinyl fluoro-8-ethyl-1,14-dihydro-4-oxoquinoline-3-carboxylic acid 46) 1-Cyclopropyl-7- (3-amino-4--ethyl-1pyrrolidinyl)-6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid 47) I-Cyclopropyl-7-(3-amino-4-methyl-lpyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid hydrochloride (isomer m.p. 209 2130C (recrystallized from ethyl acetate ethanol), yellow powder NMR (DMS0-d 6 6: 1.15 (3H, d, J=6.9 Hz), 2.76 (3H, 7.70 (1H, d, J=13.7 Hz), 8.77 (1H, s) 48) 1 C ycl o pro py 1 7 3 t buto xycar bonyl ami no 4 methyl-l-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxyiic acid (isomer m.p. 157 1600C (recrystallized from ethyl acetate), yellow crystal NMR (CDC1 3 6: 1.20 (3H, d, J=6.6 Hz), 2.57 (3H, 7.91 (1H, d, J=13.3 Hz), 9.15 (1H, s) 49) 1-Cyclopropyl-7- butoxycar bonylamino- 4methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxylic acid (isomer m.p. 199 2020C (recrystallized from ethyl acetate), yellow powder NMR (CDC1 3 6: 1.12 (3H, d, J=6.6 Hz), 2.58 (3H, 7.85 (1H, d, J=13.6 Hz), 8.87 (1H, s) 1-Cyclopropyl-7-(3-t-butoxycarbonylamino-lpyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid, m.p. 117 1200C (recrystallized from 124 ethanol), pale yellow prisms 51) 1-Cyclopropyl-7-morpholino-6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p.

189 192 0 C (decomp.) (recrystallized from n-hexane -acetonitrile), pale yellow powder Example 11 To 1-cyclopropyl-7-(4-benzyl-1-piperazinyl)- 6 fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid (132 mg) are added 10 Pd-C (68 mg) and ethanol (10 ml), and the mixture is subjected to catalytic reduction under hydrogen gas atmosphere at 60 0 C for hours. After filtering off the catalyst, the filtrate is concentrated. The resulting residue is recrystallized from ethanol acetone dichloromethane to give 1-cyclopropyl-7r (1-piperazinyl)-6-fluoro-8-hydroxymethyl-1 ,4-dihydro-4oxoquinoline-3-carboxylic acid (34.2 mg), as white powder, m.p. 149 152 0

C.

Example 12 1-Cyclopropyl-7-(4-oxo-l-piperidyl)-6-fluoro-8 methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.25 g) is dissolved in 1 aqueous sodium hydroxide (28 ml), and thereto is added sodium boron hydroxide (0.1 g) at room temperature. The mixture is stirred at the same temperature for 30 minutes, and the resulting mixture is poured into ice water and then acidified with cone. sulfuric acid. The mixture is extracted with dichloromethane, and the solvent is distilled off. The resulting residue is crystallized by V: 125 adding thereto ethyl acetate, and then recrystallized from chloroform methanol to give 1-cyclopropyl-7-(4-hydroxy-1piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid (0.16 as pale yellow crystals, m.p. 234 236 0 Example 13 To 1-cyclopropyl-7-[3-(t-butoxycarbonylaminomethyl)-1-pyrrolidinyll-6-fluoro-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxylic acid (0.1 g) are added 10 hydrochloric acid (4 ml) and ethanol (2 ml), and the mixture is reacted at 70 0 C for 10 minutes. After concentrating, the resulting residue is crystallized by adding thereto diethyl ether and then recrystallized from ethyl acetate methanol to give 1-cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6a fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (45 mg), as yellow crystals, m.p. 195 200 0

C.

Example 14 To 1-cyclopropyl-7-[3-(N-ethylacetamido)methyl-1pyrrolidinyl]-6-fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline- 3-carboxylic acid hydrochloride (0.22 g) is added 5 aqueous sodium hydroxide (10 ml), and the mixture is refluxed for 24 hours. After cooling, the insoluble materials are filtered off, and the filtrate is acidified with cone. hydrochloric acid. The mixture is extracted with dichloromethane, and the aqueous layer is made alkaline with aqueous sodium hydroxide, and thereto is added t-butoxy- Scarboxylic anhydride (200 mg). The mixture is sitrred at 126 room temperature for 30 minutes. The reaction mixture is acidified with 10 hydrochloric acid and is extracted with dichloromethane. After removing the solvent by concentration, to the resulting residue are added 10 hydrochloric acid (5 ml) and methanol (10 ml), and the mixture is heated at 70 0 C for 30 minutes. After concentrating, the resulting residue is recrystallized from methanol acetonitrile to I. give 1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6- Example 1 -Cyclopropyl-7-(3-methyl--piperazinyl)-6-fluoro- 8-methyl-1,4-dihydro-4-oxoquinoline-3.-carboxylic acid (0.3 g) is dissolved in 10 aqueous sodium hydroxide (5 ml), and there, is added acetic anhydride (0.3 ml) at room temperature, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is acidified with cone. hydrochloric acid and is extracted with Sdichloromethane. After removing the solvent by concentrato ation, the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane) and then recrystallized from methanol to give 1-cyclopropyl-7-(4acetyl-3-methyl-l-piperazinyl)-6-fluoro-8-methyl-1,4dihydro-4-oxoquinoline-3-carboxylic acid (0.1 as white powder, m.p. 219 221 C.

Example 16 1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro- 127 8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is added to a mixture of formic acid (1.7 ml) and acetic anhydride (2.2 ml) at 0°C. After the addition, the mixture is heated at 800C for 2 hours. To the reaction mixture is added water, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from .O methanol to give 1-cyclopropyl-7-(4-formyl-3-methyl-1- So piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- 0 carboxylic acid (0.13 as white powder, m.p. 236 o a., 2390C.

o' Example 17 To 1-cyclopropyl-7-(3-methyl-1-piperazinyl)-6fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) are added formic acid (3 ml), 37 formalin (3 ml) and sodium formate (0.4 and the mixture is refluxed for 4 5 hours. After cooling, the reaction mixture is poured into ice water and adjusted to below pH 8 with aqueous sodium hydrogen carbonate, and the mixture is extracted with 400000 o. o dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from ethyl acetate to give 1-cyclopropyl-7-(3,4-dimethyl-l-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylic acid (0.12 as pale yellow powder, m.p. 181 1830C.

In the same manner as described in Example 17 -128 using appropriate starting materials, there are prepared the same compounds as 1st compound in Example 4, 3rd and compounds in Example 8, 4th, 6th, 15th, 23rd, 31st and n Example Preparation 1 An injection preparation is prepared from the following components.

Components Amount 7-(1--Piperazinyl)-l-cyclopropyl-6fluoro-8-methyl-1 ,4-dihydro- 1 4-oxo quinoline-3-carboxylic acd200 mg Glucose 250 mg Distilled water for injection q.s.

ATotally 5 ml 7-(l-Piperazlnyl )-l-cyclopropyl-6-fluoro-8-methyl- 1,'-dihydro-4-oxoqunoline-3-carboxyllc acid and glucose are dissolved in distilled water for injection, and' the solution is added to a 5 ml ampoule, which is purged with nitrogen gas and then subjected to sterilization at 121 0 C for minutes to give an injection preparation.

3 Preparation 2 Film coated tablets are prepared from the following components.

Components Amount 7-(1 -Piperazlnyl)-l-cyolopropyl-6f luoro-8--methyl- 1 ,4-dihydro-4I-oxo quinoline-3-carboxylic acid 100 g _L -I.II1ICII IIIl~UIIFII~ tit 129 Avicel (tradename of microcrystalline cellulose, manufactured by Asahi Chemical, Japan) Corn starch Magnesium stearate (tradename of hydroxypropyl methylcellulose, manufactured by Shinetsu Kagaku Kogyo, 40 g 30 g 2 g j

P

i f r Ij j:6I

/I

'i t, *l 4 D 49 4 44 o 00 St t i (I1 4. Japan) 10 g Polyethylene glycol 6000 3 g Castor oil 40 g Ethanol 40 g 7-(1-Piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, Avicel, corn starch and magnesium stearate are mixed and kneaded and the mixture is tabletted using a conventional pounder (R 10 mm) for sugar coating (manufactured by Kikusui Seisakusho Co., Ltd., Japan). The tablets thus obtained are coated with a film coating agent consisting of TC-5, polyethylene glycol 6000, castor oil and ethanol to give film coated tablets.

Preparation 3 An ointment is prepared from the following components.

Components 7-(1-Piperazinyl)-1-cyclopropyl-6fluoro-8-methyl-1,4-dihydro-4-oxoquioline-3-carboxylic acid Purified lanolin Bleached beeswax White vaseline Totally Amount 2 g 5 g 88 g 100 g -130- 4 Bleached beeswax is made liquid by heating, and thereto are added 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro- 4 8-methyl-1,LJ-dihydro-4-oxoquinoline-3-carboxylic acid, purified lanolin and while vaseline, and the mixture is Iheated until it becomes liquid. The mixture is stirred until it is solidified to give an ointment.

Experiment (Antimicrobial activity in in vitro) The antimicrobial activity of the test compounds as mentioned below was tested by measuring minimum inhibitory concentration (NIC) by the serial dilution method on agar plate [cf. Chemotherapy, 22, 1126-1128 (19724)]. The microorganisms were used in a concentration of 1 x 108 cells/n) 660 mij,- 0.07-0.16) and. 1 x 106 cells/n) (100 pfolds dilution). When S. penumoniae type II and S.

pneum niae type III were used as the test microorganism, the I medium contained 5 horse blood. The results are shown in Table 1.

[Test compound]: 7-(l-Piperazinyl)-1-cyclopropyl-6-fluoro-8methyl-1, 1 4-dihydro-4-oxoquinoline-3-carboxylic acid 2. 7- (4-Methyl-1 -pi perazi nyl)- 1 -cycl opropyl-6 fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3-car boxylic acid 3. 7-(1 ,4-Diazabicyclo[ 2 4.3.0]nonan- 1 4-yl)-1--cyclopropyl-6-fluoro-8-methyl- 1 4 1 -dihydro-4-oxoquinoline-3carboxylic acid J4. 7-[ 1 -(5-Methyl-2-oxo-1,3-dioxolen-4--yl)methyl-

I.

ii 1;

I

it ii 131 r I t t 1-piperazinyl]-l-cyclopropyl-6-fluo'o-8-methyl-1,4-dihydro- ~4-oxoquino1 ine-3- carboxylic acid 5. 7-(3-Methyl-l-plperazinyl)-1-cyclopropyl-6fluoro--8-methyl- 1 4-dihydro-4-oxoquinoline-3- carboxylic acid 6. 7-(1l-Piperazinyl)-1-(2--fluoro-1-cyclopropyl)- 6-fluoro-1 ,4-dihiydro-4-oxoquinoline-3-carboxylic acid 7. 7-(3-Amino-l-pyrrolidinyl)-1-cyclopropyl-6fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3-car'boxylic acid 8. 7-( 1 -Methyl-l-p'perazinyl)-l-cyclopropyl-6fluoro-8-hydroxymethyl-1 ,4-dihydro-I4-oxoquinoline-3carboxylic acid 9. 1-Cyclopropyl-7-mrorpholino-6-fluoro-8-methyl- 1 ,4-dihydro-4-oxoquiroline-3-carboxylic acid 1-Cyclopropyl-7-morpholino-6-fluoro-8hydroxymethyl-1 ,4-dihydro- 1 4-oxoquinoline--3-carboxylic acid 11. 1-Cyclopropyl--7-(3--acetamidomethyl-lpyrrolidinyl)-6-fluoro-8-methyl-1 ,4-dihydro- 1 4-oxoquinoline- 3-carboxylic acid 12. 'i-Cyclopropyl-7-(3-methyl-IJ-benzyl-lpipet'azinyl.) -6-fluioro-8-hydroxymethyl- 1 ,4-dihydro-1oxoquinoline-3-carboxyl.ic acid 13. Vi-Cyclopropyl-7-('4-oxo--piperidinyl)-6- VJluoro-8-methyl-1 ,'-dihydro-4J-oxoquirioline-3--carboxylic acid 14. I-Cyclopropyl-7-('-hydroxy--piperidinyl)-6f'Luoro-8-rnethyl-1 1 1 [dihydro-4--oxoquinoline-3--carboxylic acid I-Cyclopropyl-7-[3-(t-butoxycarbonylamino- C t I t Cs Z ,'V -132rethy)--pyrrolidinyl]-6-fluoro-8-methyl-1,'4-dihydro-4oxoquinoline-3-carboxyllc acid 16. 1-Cyclopropyl-7-(3-aminomethy-l-pyrrolidinyl)-6-fluor'o-8-methyl-1 4 1 -dihydro-4-oxoquinoline-3car'boxylic acid 17. 1 -Cyclc propyl-- (N-methyl- N- ben zyl ami no)- 1-pytrolidinyl]-6-fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid 18. 1-Cyclopr'opyl-7-(3-methylamino-l-pyrrolidinyl )-6-f'luoro-8-methyl- 1 4 1 -dihydro-4-oxoquinoline-3- .060 carboxylic acid 000.19. 1-Cyclopropyl-7-(4-acetyl-3--methyl-1piperazinyl f luoro-8.methyl- 1 4-dihydro- 1 4-oxoquinol ine-3carboxylic acid :2 20. 1 -Cyclopropyl-7- (3 -ethyl aninomethyl-1 pyrrolidinyl fluoro-8-methyl- 1,4I-dihydro-4-oxoquinoiine- 0 3-carboxylic acid 21. 1-Cyclopropyl-7-( 1 4-formyl-3-methyl-lpiperazinyl.)-6-fluoro-8-methyl-1 ,4-dihydro-4-oxquinoline-3carboxylic acid 22. 1-Cyclopropyl-7-(3, 4-dimethyl-l-piperazinyl) 6-f'luoro-8-methyl-1 ,4-dihydro-4-oxquinoine-3-carboxylic acidL 23. 1-Cyclopropy-7-(4-ethy-l-piperaziny1)-6fluoro-8-methyl- 1 ,4-dihydro-4-oxoquinloline-3-carboxylic acid 24. 1-Cyclopropy1-7-C(-cycopropy--piperazin- -133yl )-6-fluoro--8- met hyl1-1 ,4-dihydro-4-oxoqui no.ine-3carboxylic acid 1-Cyclopropyl-7-(3-methylmorpholino)-6fluoro-8-methyl-1 ,I-dihydro-4-oxoquinoline--3-carboxylic acid 26. 1-Cyclopropyl-7--(3-amino- 1 4-methyl-lpyrrolidinyl)-6-fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline- 3--carboxylic acid hydrochloride (isomer A) 27. 1-Cyclopiropyl-7- (3,5-dirnethyl-1-piperidinyl 6-t'luoro-8--methyl-1 ,4-dihydro- 1 -oxoquinoline-3-carboxylic acid 28. 1-Cyclopropyl-7-( 1 4-fluoro-l-piperidinyl)-6fluoro-8-methyl-1 1 -dihydro- 1 -oxoquinoline-3-carboxylic acid [Test microorganisms]: A: Staphylococcus aureus FDA 209A B: Staphylococcus pyrogens IID S-23 C: Staphylococcus pneumoniae type II D: Staphylococcus pneumoniae type III E: Pseudomonas aeruginosa E-2 00F: Bacteroides fragilis GM7000 Eubacterium limosum ATCC 8'496 H: Peptococcus anaecobis GM1003 I: Propionibacterium acnes ATCC 6919 J: Propionibacterium granulosum ATCC 25564 K: Enterococcus faecalls .134 Table 1

C

C

C C .t C Test Test Compd. Test Compd. Test Compd. Test Compd.

micro- No. 1 No. 2 No.3 No. 4 organiss 1 x j0b 1 x 10 6 1 x 106 1 x 16 cells/mi cells/mi cells/mi, cell/mi, A 0.2 0.1 0.1 0.05 B 0.39 0.39 0.39 0.2 C 0.78 0.39 0.78 0.39 D 1.56 0.39 0.39 0.39 E 0.39 0.78 1.56 0.39 F 0.78 0.2 0.1 0.2 u0.78 H 1.56 0.78 0.39 0.1 1 0.39 0.2 0.2 0.05 J 0.2 0.39 0.2 0.1 K 0.39 0.39 1.56 1.56 to be continued C. I K~ L

~K~LT

135 Table 1 (Continue) It it t ti~

CAL

Test Test Compd. Test Compd. Test Compd. Test Compd.

micro- No.5 No.6 No.7 No.8 organiss x1 6 1 x 106 1 x 106 1 x 106 cells/mi cells/mi cells/mi cell/mi A 0.2 0.78 0.0'48 0.39 B 0.39 0.39 0.0418 0.78 C 0.39 D 0.39 E 0.78 0.39 0.195 1.56 F 0.2

G

H 0.39 1 0.2 1 0.2 K 0.78 to be continued-

*SS*

4'*OC 4**C Cl

ICC

'I

-136 Table 1 (Continue) 00 0 40 *940 04 o oq# t000 0 0 0 *0 0 o 04 0000 0000 t 0 *000 00 to a a 0~ 0 0 00 0.4 0 *t000 4 0 00 0 O 9 00 Test Test Compd. Test Compd. Test Compd. Test Compd.

micro- No.9 No.10 No. 11 No. 12 organ- 6 6 i sms 1 x 10 1 x 106 1 x 106 1 x o cells/mi cells/mi cells/mi cell/mi A 0.012 0.0148 0.024 0.39 B 0.0148 0.78 0.0214 0.0148

C

D

E 0.78

F

G

H

K

-to be continued-

I

-I

i

I

ii 11 137 Table 1 (Continue) 44 440 4 44 44.44 4 444 4444 4 4 44 4-44 4444 04 44 4 tA Test Test Comp micro- No.13 organ-6 i.sins 1 x10u cells/mi A ,.0.006 B 0.097

C

D

E 1 .56

F

G

H

K

di. Test Compd.

No.1 1 4 Test Compd.

No.15 1 x 10 cells/ml 1 x 1 6 cells/mi Test Compd.

No.16 1 x 10 6 cell/mi 0.01 2 0.0118 0.78 0. 048 0.1 95 006 <0.006 0.39 to be continued -138 Table 1 (Continue) Test Test Compd. Test Compd. Test Compd. Test Compd.

micro- No.17 No. 18 No. 19 No. organ- 1x0666 6 i sms 1 x 10 1 x 10 1 x 106 cells/mi cells/mi cells/mi cell/mi 0.0148 0.195 0.024 0.0148 0.0148 0.097 006 0.012 t ,#t 0.39 0.78 to be continued 1.39 Table 1 (Continue) t T etst Test Compd. Test Compd. Test Compd. Test Comnpd.

micro- No.21 No.22 No.23 No.24 organ-6666 isms 1 x 10 6 1 x 106 1 x 106 1 x 106 cells/mi cells/mi cells/mi cell/mi A 0.024 0.097 0.097 0.0148 B 0.097 0.39 0.39 0.39

C

D

E 1.56 1.56-

F

G

H

K

-to be continued- 140 Table 1 (Continue) 4 0 0*4 o 4 4 4*4 Off 0 4 0 4 44.

4 0 0040 4 0 et 04 #844.

44.

'C

Tes t Test Compd. Test Compd. Test Compd. Test Compd.

micro- No.25 No.26 No.27 No.28 organ 1 x 10 6 1 x 106 1 x 106 1 x 10 6 cells/mi cells/mi cells/mi cell/mi A 0.012 0.0214 0.097 0.012 B 0.097 0.024

C

D

E 1.56 0.195 -0.78

F

G

H

K

Claims (32)

1. A compound of the formula: 0 I F 1COOH IJ 1l 1 1 R2 Ri wherein when R 3 is methyl or ethyl group, R 2 is a 1- R pyrrolidinyl group of the formula: -N wherein R I is ap 99o9 amino C 1 -C 6 alkyl group, said amino group being optionally substituted by one C 1 -C 6 alkyl group; or an amino group which is optionally substituted by one C1-C 6 alkyl group and R J is hydrogen atom; a Cl-C 6 alkyl group; *o or a piperazinyl group which has optionally one substituent selected from the group consisting of oxo, o hydroxy and a halogen; or a heterocyclic group selected from the group consisting of the following groups: RD RG N-RB -N N-RC, -N N-R, and -N N in which R B is a 2-oxo-l,3-dioxolenemethyl substituted by a C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl; RC is hydrogen, a C 1 -C 6 alkyl, a C1-C 6 alkoxycarbonyl, or a phenyl (C 1 C 6 )alkyl; RD is hydrogen or a C 1 -C 6 alkyl; RG is a C1-Cg alkyl; and RH is a C 1 -C 6 alkanoyl; S O 508dblet.018.dbl228720.cla.1 fc r RK -N 0 or a group of the formula wherein RK is hydrogen or a C 1 -C 6 alkyl group or a morpholino group which is subsituted by one to three C1-C 6 alkyl groups where each of the alkyl group is substituted by 1 to 3 substituents selected from the group consisting of -NH 2 and a halogen; or when R 3 is methyl having 1 to 3 halogens, -CH 2 OH, 1 0 -CH 2 -N a (Cl-C 6 )alkylthiomethyl, or a (C 1 -C 6 )alkoxy- RD methyl, R 2 is a group of the formula: -N NRC (wherein R C and RD are as defined above), or -N 0, or a pharmaceutically acceptable salt thereoi.

2. A compound according to claim 1, wherein R 3 is ,o. methyl.

3. A compound according to claim 1, wherein R 3 is ethyl. u*

4. A compound according to claim 1, wherein R2 is a group of the formula: -N N-RB o r D R -N NRB -N N-RC or -N N-RH SI wherein RB, RC, RD, RG and RH are as defined in claim 1. A compound according to claim 4, wherein R 2 R F is a group of the formula: -N NH wherein RF is a C 1 -C 6 alkyl group. 'VI O 08,dblet.018,dbl228720.c1a,2 143

6. A compound accroding to claim 4, wherein R 2 D C D is a group of the formula: -N N-R wherein R is a -C alkyl group, and R is a C 1 -C 6 alkyl group.

7. A compound according to claim 5, wherein R 3 is methyl

8. A compound according to claim 5, wherein R 3 is ethyl.

9. A compound according to claim 6, wherein R 3 is methyl. 0 o. A compound according to claim 6, wherein R 3 is o ethyl.

11. A compound according to claim 4, wherein R 2 is a group of the formula: -N N-RB, RB is a 2-oxo-1,3- dioxolenemethyl group substiTuted by a C 1 -C 6 alkyl group. 0 0

12. A compound according to claim 4, wherein R 2 is a group of the formula: RB is a C3-C 8 -N N-RB cycloalkyl.

13. A compound according to claim 11, wherein R 3 is methyl.

14. A compound according to claim 11, wherein R 3 is ethyl. A compound accorcing to claim 1, wherein R 2 is a 1-pyrrolidinyl group of the formula: R I -N wherein R I and R J is as defined in claim 1. 9 0 9 08,dblet.O18,db1228720.cla,3 W-I I- 144

16. A compound according to claim 15, wherein R I is an amino group which may be substituted by one C1-C 6 alkyl group.

17. A compound according to claim 15, wherein R I is a C 1 C 6 alkyl having one amino group, said amino group being substituted by one C 1 -C 6 alkyl group, and R J is hydrogen atom.

18. A compound according to claim 16, wherein R 3 is methyl.

19. A compound according to claim 17, wherein R 3 is ethyl. A compound according to claim 1, wherein R 2 is a group of the formula: R K wherein RK is hydrogen atom or a C 1 -C 6 alky.1 group. N 0 ,-8

21. A compound according to claim 20, wherein R 3 is methyl. 'a* 44 aO 20 0

22. A compound according to claim 1, wherein R 2 is 1-piperidinyl group which i3 substituted by one halogen atom.

23. A compound according to claim 22, wherein R 3 is methyl.

24. A compound according to claim 22, wherein R 3 is ethyl. A compound according to claim 1, wherein R 2 is 1-pipezidinyl group which is substituent selected from hydroxy group and oxo group. )6S08, dblet.018,dbl228720.cla,4 N;~L_ -145

26. A compound according to claim 1, wherein R 2 is >1 a group of the formula: -N NR 3 is methyl group.

27. A compound according to claim 16, wherein R3 is ethyl.

28. A compound according to claim 17, wherein R3 is ethyl.

29. A compound according to claim 1, wherein R 3 is methyl having 1 to 3 halogens, -CH 2 0H, -OH 2 N] ,a Cl- alkylthiomethyl group, or a 01-06 alkoxymethyl group, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, wherein R 2 is agroup of the formula: RD wherein RC and RD are as O~

31. A compound according to claim 4, wherein R 2 is a group of the formula: RG wherein RG and RH are as defined in claim 1. -N N=H 9 -N N- 32, A compound according to claim 1, wherein R 2 is0 a ~a 1-piperidinyl group which has optionally one substituent selected from the group consisting of oxo, hydroxy and a halogen. 0

33. 7-[4-(5-Me-thyl-2-oxo--l,3-dioxolen-4-yl) methyl- 1- piperazinyl]-l-cylcopropyl6fluoro8methyl14- dihydro-4-oxoquinoline-3-carboxylic acid.

34. 7 3 fluoro-8-methyl-1, 4 -dihydro-4-oxoquinoline-3-carboxylic acid. 9'V dblet.018,db1228720.cla.5 4, -146- 7-(3-Amino-1-pyrrolidifyl)lcyclopropyl- 6 fluoro-8-methyl-l, 4-dihydro-4-oxoquifolie3-carboxylic acid.

36. I-Cyclopr'opyl-7-(3-aminomethyl-l-pyrrolidin- yl1 f1u o ro 8- me th y 1- 1 4- d ihyd r o-4 ox o qu in ol11ne -3 carboxylic acid.

37. 1-CYcloPr'OPYl-7-(3-methylamino-1-pyrr'olidin- yl)-6-fluoro-8-methyl-1 ,4-dihydro-4-oxoquinoline-3- car'boxylic acid.

38. 1-CycloproPYl-7-(3-ethylaminomethyl-l- pyr'rolidinyl.)-6-fluor'o-8-rnethyl- 1 ,-dihydr'o-4-oxoquinoJine- 3-carboxylic acid. 39 .1-CyclopropYl-7-(3-amino-4I-rethyl-1-0 pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 09 3-carboxylic acid. 1-Cyclopropyl-7-(4-fluoro-l-piperidinyl)-6- fluoro-8-methyl-1, 1 4-dihydro-4-oxoquinoline-3-carboxylic 6 acid. 41 .1-Cyclopropyl-7-morpholino-6-fluoro-8-methyl- 1,4-dihydro-4-oxoquinolifle-3-carboxylic acid. 42 .1-Cyclopropyl-7-(3-methylmorpholino)-6-fluoro- 8-methyl- ,4-dihydro- 1 -oxoquinoline-3-carboxylic acid.

43. A process for preparing a compound according to claim 1, which comprises subjecting a compound of the formula: 147 0 F C COOR R2 X 2 NH-< R 3 wherein R 2 and R 3 are as defined in claim 1, X 2 is a halogen atom, and R 5 is a lower alkyl, to cyclization reaction to give a compound of the formula: 0 F COOR R 2 R 3 wherein R 2 and R 3 are as defined in claim 1, and R 5 is as defined above, optionally followed by hydrolysis of the above compound, reacting a compound of the formula: 0 0 0 0 0 F COOR13 A 00 4 N R 3 A wherein R 3 is as defined in claim 1, X 4 is a halogen atom, and R 1 3 is hydrogen atom or a group of the formula: ,OCOR 1 -BC (wherein R1 4 and R 1 5 are each an alkyl), OCOR 1 with a compound of the formula: R 2 H wherein R 2 is as defined in claim 1 to give a compound of the formula: V ILV -C pr d 148 F 0 0 1 3 F COOR /N R 2 R 3 t R 3 A wherein R 2 and R 3 are as defined in claim 1, and R 1 3 is as defined above, optionally followed by converting the compound where R 13 is a group of the formula: /OCOR 1 4 into a compound where R 13 is hydrogen atom, reacting a compound of the formula: 0 FI 00C00 0 0 W N N j (CH 2 )n R 3 A wherein R 3 is as defined in claim 1, either Z or W is -CH 2 and the other is -NH, n is an integer of 1 to 3, with a compound of the formula: R1 6 X5 00 wherein R 16 is a (lower) alkyl; a cycloalkyl; a phenyl 00 (lower) alkyl in which phenyl ring may be substituted by a (lower) alkoxy, nitro or amino; a phenyl which may be substituted by a halogen atom, a (lower) alkyl or a (lower) alkyl substituted by 1 to 3 of halogen atoms; a pyridyl; a (lower) alkyl having 1 to 3 substituents selected from the group consisting of hydroxy, amino, a (lower) alkoxy and a halogen atom, said amino being optionally substituted by a 149 (lower) alkyl, a (lower) alkanoyl, a cycloalkyl or a (lower) alkoxycarbonyl; a (lower) alkanoyl which may be substituted by 1 to 7 of halogen atoms; a (lower) alkenylcarbonyl having 1 to 3 substituents selected from the group consisting of a halogen atom and a carboxy; a (lower) alkoxycarbonyl; an aminocarbonyl which may be substituted by a (lower) alkyl; a phenyl (lower) alkoxycarbonyl; an amino (lower) alkanoyl which may be substituted by a phenyl (lower) alkoxycarbonyl; a (lower) alkoxycarbonyl (lower) alkyl; a carboxy (lower) alkyl; an anilinocarbonyl (lower) alkyl; a (lower) o a alkylsulfonyl which may be substituted by 1 to 3 halogen atoms; a sulfo (lower) alkyl; a (lower) alkenyl or a (lower) alkynyl, and X5 is a halogen atom, to give a compound of the formula: 0 F COOH N N N 46a I '.4 (CH2)n R 3 A wherein R 3 is as defined in claim 1, n is as defined above, and either Z' or W' is -CH 2 and the other is 1 16 -NR 16 reacting a compound of the formula: 0 F COH W N- N (CH 2 )n 3 R -I -150- wherein R 3 is as defined in claim 1, and W, Z and n are as defined above, with a compound of the formula: R 17 C0R 1 8 wherein R 1 7 and Ri are each hydrogen atom or a lower alkyl, to give a compound of the formula: 0 F COOH /11 R 3 _I n A wherein R 3 is as defined in claim 1, n is as defined above, and either Z11 or W11 is -C2and the other is" L R9 CN CH 0 F CO0HC W N N '0 (CH 2 )n R3. C 2) A wherein R 3 is as defined in claim 1, and W, Z and n are as defined above, with a compound of the formula: 0 0 0~ -151- F COOM /-ZI Wf N N wherein R 3 is as defined in claim 1, n is as det ined above, either or is1 -CH 2 and the other is a group: -N-CR 2 R 23 2 is as defined above), 0 0 (f subjecting a compound of the formula: :F NO2 00 R21 -C 0 R 26 *wherein R 2 1 is halogen ~Ri 1'atom or the same as R 2 RP is a group: HSR2 (wherein R 9 and R 2 are as def ined above) or R 3 (wherein R 3 is as defined In claim 1) and R 2 6 and R 2 7 are each a lower alkyl to a cyclization reaction to give a compound of the formula: F COOH 2 N H 3 wherein R 2 and RV' are as defined above, or are as det Ined above, or /VT 152 subjecting a compound of the formula: F NO 2 COOR 2 4 SCOOR 2 R 3 2 N-CH wherein R 2 and R 3 are as defined above, and R 2 4 is a lower alkyl, to give a compound of the formula: SF coa F COOR24 1 II 0 R2 N 2 3 1' I wherein R2',R 3 and SR 2 4 are as defined above, optionally followed by hydrolysis thereof.

44. An antimicrobial composition which comprises as an essential active ingredient an effective amount of a compound I according to claim 1 together with a pharmaceutically acceptable diluent or carrier. Compounds of the formula methods for their J manufacture or antimicrobial compositions containing them, substantially as hereinbefore described with reference to any one of the Examples. DATED this 13th day of August, 1990 Otsuka Pharmaceutical Company Limited R 4 By Its Patent Attorneys DAVIES COLLISON T O