CA2093107A1 - 7-oxo-7h-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and esters - Google Patents

Abstract

7-Oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and esters ABSTRACT OF THE DISCLOSURE

The present invention relates to 7-Oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carb-oxylic acids and esters, processes for their preparation and their use as medicaments, in particular as antivirally active medicaments.

Le A 28 860

Description

2~93~7 The present lnvention relates to 7-oxo-7H-pyrido[1,2,3 d,e][1,4~benzoxazine-6-carboxylic acids and esters, processes for their preparation and their use as medicaments, in particular as antivirally active medicaments.

1,8-bridged 4-quinolonecarboxylic acids having an antibacterial action have been disclosed in EP-A-Z53,235.

The present invention relate~ t:o 7-oxo~7H pyrido[l,Z,3 d,e][1,4]benzoxazine-6-carboxylic acid~ and e~ters of the general formula (I) o F ~ CO2R4 R1 ~ ~ (I) ~ 3 in which represents 1-piperidinyl or a radical of the formula A N - or H N ~ M -Le A 28 860 - 1 -. .
:

, ,," ., ; ; , ~ , . .

- 2~93~07 in which ~

A denotes a group o~ the formula -NR7, an oxygen atom or the -CH2-group, in which R7 denotes hydrogen or straight-chain or bxanched alkyl having up to 6 carbon atoms, which. is optionally ~ubstituted by hydroxyl or phenyl, Rs and R3 are identical or different and denote hydrogen, cyclohexyl, phenyl or straight-chain or branched alkyl haviny up to 4 carbon atoms, R2 represents hydrogent or represents strai~ht-chain or branched perfluoroalkyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, hydroxyl, halogen, or straight-chain or branched alkoxy or alkylthio, each having up to 3 carbon atoms, represents phenyl, pyridyl, furyl or thienyl, each of which is optionally monosubstituted by halogen or by straight chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R3 represents hydrogen, phenyl, trifluoromethyl, Le A 28 860 - ~ -, ;

: ; :

` 2~)931~7 straight chain or branched alkyl having up to 4 carbon atoms, fluoromethyl or hydroxymethyl, R'' represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and their hydrates and salts, if appropriate in an isomeric form, with the exception o~ 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7~-pyrido[1,2,3~d,e][1,4]-benzoxazine-6-carboxylic acid and its 3- and 4-methyl~1~
piperazinyl derivatives, 9-fluoro-10-(4-methyl~1-piperazinyl)-7-oxo-7~-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid and its 2-methyl derivative.

Physiologically acceptable salts o~ the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic ~cid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, malelc acld or benzolc acld.
~ .
Physiologically acceptable salts can also be alkali metal, alkaline earth metal, silver and guanidinium salts of the compounds according to the invention.

Le A 28 860 ~ 3 -:, , ~:
.
, :.

., ,:. .

~3~7 Preferred compollnds o~ the general formula (I) accor~Yng to the invention are those in which R1 represents 1-piperidinyl or a radical o~ the formula S A ~ N - or H N ~ N -in which A denotes a group of the formula -NR7, an oxygen atom or the -CH2-group, in which R7 denotes hydrogen or straLght-chain or branched alkyl having up to 4 carbon atoms, which i~ optionally substituted by hydroxyl or phenyl~

~ R5 and R6 are identical or different and denote hydrogen, cyclohexyl, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen or ~e A 28 860 - 4 -~3~7 represents straight-chain or branched perfluoroal~yl .~
having up to 4 carbon atoms, represents straight-chain or branched alkyl having up to 5 carbon atoms, which i5 optionally substituted by phenyl, hydroxyl, fluorine, chlorine or alkoxy or alkylthio each having up to 2 carbon atoms, represents phenyl, pyridyl, furyl or thienyl, each of which is optionally monosubstituted by fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R3 represents hydrogenl phenyl, trifluoromethyl, straight-chain or branched alkyl having up to 4 carbon atoms, fluoromethyl or hydroxymethyl, R4 represents hydrogen or straight-chain or branched alkyl havi~g up to 4 carbon atom~

and their hydrates and salts, if appropriate in an isomeric form.

Particularly preferred compounds of the general formula (I) according to the invention are those i-n which Rl represents 1-piperidinyl, or represents a radical of the formula Le A_28 860 - 5 -. '' ., ' , . ~ ~ : ' - , , .
:
,~ .
.: .. . ' ~:..

" 20931~7 ,. ~ .

A N - or H~N

in which A denotes a group o the formula -NR7, an oxygen atom or the -CH2-group, in which R7 denotes hydrogen or straight-chai~ or branched alkyl having up to 4 carbon atoms, which i8 optionally substituted by hydroxyl or phenyl, Rs and Rs are identical or different and denote hydrogen! cyclohexyl, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydxogen or represents straight-chain or branched perfluoroalkyl having up to 4 carbon atoms~
represents straight-chain or branched alkyl having up to 5 carbon atoms, which i~ optionally substituted by phenyl, hydroxyl, fluorine, chlorine, : methoxy, ethoxy or methylthio, represents phenyl, pyridyl or furyl, each of which . .
.

Le A 28 860 - 6 -' .
.;

~, . .~ . ~ .
. ,;- ~ ~ ;
..

.
.:
~ `' ;:

2093~7 is optionally monosubstituted by fluorine, chlorine, brornine, methyl, ethyl, methoxy or ethoxy, R3 represents hydrogen, phenyl, trifluoromethyl, straight-chain or branched alky]. having up to 4 carbon atoms, fluoromethyl or hydroxymethyl, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and their hydrates and salts, if appropriate in an isomeric form.

A process for the preparation of the compound~ o~ the general formula (I) accoxding to the inventlon has additionally been found, characterised in that [A] compounds of the general formula (II) o F ~ CO2R4 T ~ N (II) O ~ R

R

in which R2 and R3 have the abovementioned meaning, ~,.

¦ Le A 28 860 - 7 -I` .

., ' , : : . ' ~ ' '' '. ' ~ ~ ~ / ;
'` :, . ~
.

.;
: . .
.

20g31~7 R4 has the abovementioned meaning, but preferably represents hydrogen, ~
f ~P
and T represents halogen, preferably fluorine, are reacted with compounds of the general formula ~III) Rl-H (XII) in which R1 has the abovementioned meaning/

in inert solvents, in the presence of a base, under a protective gas atmosphere, or [B] in the case in which R2 and R3 represents hydrogen, aldehydes of the general formula (IV) F ~ ~02R4 F ~ N ~ (IV) F CH~-CHO
in which e A :2 8 860 - 8 -'' ' ,'`' ' ~ ' ' ~ ; ' ` `:

'- ; `

2093~0 J

R4 has the abovementioned meaning but prefera~ly represents hydrogen, are also reacted initially either with compounds o the general ~ormula (III) or (IIIa), preerably with (IIIa) Rl_H (III) W-H (IIIa) in which Rl has the abovementioned meaning and W has the abovementioned meaning of R1, where, however, one of the cyclic amine functions i~ protected by a protective group, preferably by methoxycaxbonyl, ethoxycarbonyl or tert-butoxycarbonyl, in inert solvents, in the presence of a base, with simultaneous cyclisation, the protective group is removed according to a customary method and then, according to the desired meaning of R4, either an esterification or hydrolysis is carried out according to a customary method~

Thé process according to the invention can be illustrated by way of example by the following reaction scheme:

Le A 28 860 - 9 --;

.

~, . ~ . : ' ' ~: ', ' ' ,:
. .
!, : .
' , ' ~" ' ' ' 2~93~7 [A] ~ ~;

o ~.~p F ~C02H
F ~ N + HN N - CH3 Dllt oprDpylethyl~ln-o~J \~ DMSO
C(CH3)3 F ~j~l~ CO2H
f N~f N' , N J O ~J
C(CH3)3 [B]
o F ~CO2H Boc - N NH Dli~opr~pylctbyl~in~

f ~C02H Arl1501e / tri~luorol~cc~lc ~cid , N J O ~J

F ~CO2H

HNJ o~J

Le A 28 860 - 10 -': ' ' ` .' :' ,` ,: ':: ' ' ':`- ~ ' . '` : . ;, ` ' ':' ~ . ':
.. ' . ' ~`: : ~ ' ' ` ' ` : ':' : '` " ' ' ~ :`.' ' ' ' I
:: . - : ,. '` ' : ' . :
'' ' ' . ::
"'"' ' ' ' : "
,, :', ' . ~' ~ ' , ' ' : ' ` ', 2~93~7 Protective groups in the contex-t of the invent.ion are-t~he groups known from peptide chemistry such as, for éxample, benzyloxycaxbonyl, methoxycarbonyl, ekhoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl. Methoxy- and ethoxycarbonyl are preferred.

Suitable solvents ~or all the process steps are the customary inert solvents whi.ch do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol monomethyl ether or glyco:L dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbon~ such as benzene, toluene, xylene, cyclohexane or mineral oil fractions, or halogenohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulphoxide, N,N-dimethylformamide, hexamethylphosphoramide, sulfolane, ethyl acetate, pyridine, triethylamine, N-methylpyrrolidine, anisole or picoline. It is also possible to use mixtures of the solvents mentioned.
Dimethyl sulphoxide and N,N-dimethylformamide are preferred.

Suitable bases are the customary basic compounds. These preferably include alkali metal or alkaline earth metal hydroxides, pyridine, triethylamine, diisopropylethyl-amine or N-methylpiperidine, or ~icyclic amidines such as 1,5-diazabicyclo[3.4.0]-non-5-ene (DBN), 1,5-diaza-bicyclo[3.4.03undec-5-ene (DBU) or DABC0. Triethylamine, diisopropylethylamine and DABC0 are preferred.

Le A 28 860 '. ' : "

" ! .

2093~7 The bases are in general ~mployed in an amount from~ to 3 mol, preferably from 1 to 1.5 mol, relative to~ mol of the corresponding carboxylic acid.

The processes ~A] and [B] are in general carried out in a temperature range from +0C to ~150C, preferably from +0C to +120C.

In general, the process is carried out at normal pressure. However, it is also possible to carry out the process at reduced pressure or at elevated pressure (for example in a range from 0.5 to 5 bar).

Suitable solvents for the hydrolysis are water or water in combination with a cu tomary organic solvent. These preferably include alcohols such as methanol, ethanol, propanol, i~opropanol or butanol, or ether~ such as tetrahydrofuran or dioxane, or dimethylformamide, or dimethyl sulphoxide, or acetic acid. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used.

The hydr~lysis is carried out using acids such as, for example, hydrochloric acid, acetic acid, hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric a~id.

The hydrolysis is in general carried out in a temperature range from 0C to 130C, preferably from 20C to 110C.

Le A 28 860 ~ 12 -. , , ' ' :

' : ' : ' ' : .~ ' , . , ' , . : ': '' : ' 20~3:~ ~)7 In general, the hydrolysis is carried out at no~nal pre~sure. However, it is also possible to work at~reduced pressure or at elevated pressure (for example from 0.5 to S bar).

When carrying out the hydrolysis, the acid is in general employed in an amount from 1 to 3 rnol, preferably from 1 to 1.5 mol, relative to 1 mol of the ester. Molar amounts of the reactants are partlcularly preferably used.

The hydrolysis of tert-butyl esters is in general carried out using acids, such as, for example, hydrochloric acid or trifluoroacetic acid, in the pre~ence o~ one of the abovementioned solvents and/or water or mixtures thereo, preferably with dioxane or tetrahydrofuran.

The esterification of the acids is carried out according to a customary method, ~y reacting the acids with the corresponding alcohols, if appropriate in one o~ the abovementioned solvents in the presence of a catalyst.
The corresponding alcohol is preferably then also employed as a solvent.

Catalysts which can be employed are inorganic acids, such as, for exarnple, sulphuric acid or inorganic acid chlorides, such as, for example, thionyl chloride.

In general, 0.01 to 1 mol, preferably 0.05 to 0.5 mol, of catalysts are employed relative to 1 mol of reactant.

~e A 28 860 - 13 -~ ;

2093:1~7 The aminoprotective group~ are removed by methods kh~n from the literature [cf. Houb~n-Weyl, "Metho~en der organischen Chemie" (Method~ of Organic Chemistry), Synthe~e von Peptiden (Peptide synthesis) II, 4th Edition, Vol. 15/1, 15/2, Georg Thieme Verlag~, preferably using trifluoroacetic acid in anisole.

The compounds of the general formula (II) are known in some cases ~cf. in this connection ~P 253,235 A1;
J. Heterocycl. J. Chem. 28, 106~ (1991)] or are new and can be prepared, for example, by reacting compounds of the general formula (V) o F ~ CO2R8 (V) F H
in which Ra repxesents a C1-C4-alkyl radical, with an ~-halogenocarbonyl compound of the general formula (VI) ¦ (VI) B

in which Le A 28 860 - 14 -' '' :' ' ': ' ~
. ,:
: . . . ':
.:

~: ' ' ~ ': : ' '' , ' ~ : '~

2093~

R2 and R3 have the abovementioned meaning _,;
;i~, .~
and B represents halogen, prefer~bly bromine, in one of the abovementioned solvents and bases, preferably d.imethylformamide and potassium carbonate, or by reacting compounds of the general formula (VII) F ~ F ~ ~9 (VII) in which R8 has the abovementioned meaning and R9 represents C1-C4-alkoxy, with compounds of the general formula (VIII) Le A_28 860 - 15 -2~3~

NH2 - f`;
~ R3 ~ .r~

in which CHRI
R3 has the abovementionsd meaning and Rl represents hydrogen or Cl-C4-alkyl, in one of the abovementioned solvent~, pre~erably ethanol, and if appropriate in the presence of an amine base also mentioned there, and then converting with dimethoxyethane and sodium hydride into the compound~ of the general formula ~IX) O
F ~ C02R8 F ~ R3 (I~) CHRl ln which R8, R3 and Rl have the abovementioned meanings, then cleaving the double bond by ozonolysis to give ths Le A 28 860- 16 -~" ' ". ' ' ' , ' ' ;
' ' ~ ~' ' , ' .. ' ' ' ', ' ' ' ., ; ' ` , ~ . : '' ~
` . . ~ "

' ~ "''.' ` `
' . ' ~ , , ' , ` , ' ' ' ' , ' ~, '. "
' , ' I `, ' ~3 :L07 carbonyl function according to customary methods, and in a last step carrying out the cyclisation as d~cribed above, and in the case of the other substituents mentioned above under R2 and R3, varying these according to customary methods.

The reaction with the compounds of the general formula (VIII) is carried out in a temperature range from -20C
to +30C, pre~erably from 0C ko room temperature, and at normal pressure.

The ozonolysis is in general carried out at -78C in a solvent mixture of methanol/methylene chloride and under a protective gas atmosphere.

The compounds of the general formulae (VII) and (VIII) are known in some cases or can be prepared according to customary methods.

The compounds of the general formula (IX) are mainly new and can be prepared according to the process descrihed above.

; The compounds of the general formulae (V) and (VI) are known per se [cf. EP-A-253,235] or can be prepared according to known methods.

The compounds of the general formulae (III) and (IIIa) are also known, in some cases commercially available or can be prepared according to customary methods.

Le A 28 860 - 17 -. ' ' ` `, .
, " , ,, ` ~ ' ` ~' .
~, '~ ., , `
~ ` ' ': `

" ~ ' ' ' ` '' " '' , ` ' .`, ' , ,' , , `, '~'` ' ~`'' , 2 0 9 31~ I

The aldehydes of the general ormula (~V) are known per se or can be prepared according to published methods [cf.
EP A-253l235].

The compounds according ko the invention show an additional unforeseeable, useful spectrum of pharmacological action. Surprisingly, they are suitable for the treatment of virus-induced diseases.

The intermediates of the general formula (II) can also exhibit this spectrum of action.

Detection of activity was carried out in hepatoma cells ~HEP G2.2.15) transfected with hepatitis B viru~ DNA. The results of the examples listed below were determined for the H~V test system described in the following literature reference ~Sells, M.A.; Chen. M.L., Acs, G., Proc, Natl.
Acad. Sci. USA pp~ 1005 - 1009, Vol. 84 (1987)]:

Transfected hepatoma cells (HEP G2.2.15) were incubated with various concentration~ of the respective compound.
By treatment of the transfected hepatoma cell line HEP
G2.2.15 with the compounds according to the invention~
the reduction of virus-specific HBV-DNA in the super-n~tant a~ well as a reduction in the-HBsAg level could be shown. It was furthermore found that the compounds according to the invention lead to a reduction of the replicative intermediates of hepatitis viruses. The content of HBV-DNA was determined in the supernatant of Le A 28 860 - 18 -. .

~' .

20931q)7 the cell cultures after PEG precipitation. Thi ~as carried out using a non-radioactively label~d HBV
genomic DNA sample [Pauly, P., 1982, Ph.D. Thesis, University of Gottingen, F.R.G.; Kochel et al., 1990, EMB~, Accession No. X 51790]. At the same time, th~
effect on HBsAg formation was determined by means of a commercially available Elisa test. The TC50 values indicated relate to the substrate concentrations which cause a 50% inhibition of the H~V-DNA concentrat:ion in 10 the supernatant under the abovementioned test conditions.

Table A
Ex. No. IC50 (~M) SI
0 . 1 >100 33 0.5 >20 39 0.1 >100 At the same time, any cytotoxic effect of the compounds according to the invention that might be present was determined by means of staining with Crystal Violet or via the incorporation of radioactively labelled thymidine into the cellular DNA.

The action of the compounds according to the invention on other cells was tested by incubation o~ HEL and MEF
cells. No effect on the vitality of the cells was seen up to a concentration of 250 ~M.

Le A 28 860 - 19 -. ~ .
, ' .
' ' 2 ~ 9 ~

As areas of indication for the compounds which ca~fbe used according to the invention, there can be me.~ ionèd, for example:

The treatment of acute and chronic virus infections which can lead to hepatitis, for example infections with hepatitis viruses; also virus infections with herpes viruses Types 1 and 2, cytomegaloviruses, varicella zoster viruses and HIV.

The treatment of chronic hepatitis B virus infections and the treatment of acute hepatitis B virus infection i~
particularly preferred.

The present invention includes pharmaceutical preparations which, besides non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formulae (I) and/or (II) or which consist of one or more active compound~ of the formulae (I) and/or (II), and processes for the production of these preparations.

The compounds of the formulae (I) and ~II) should be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight, of the total mixture.

The abovementioned pharmaceutical preparations can also contain further pharmaceutical active compounds in Le A 28 860 - 20 -.

':

; ' ' ' .

': . , . " ; ' ' 2 0 ~ 3 1 ~ 7 23189-7~85 addition to the compounds of the formulae (I) and (II).
The abovementioned pharmaceutical preparations are prepared in a customary manner by known methods, for example by mixing the active compound or compounds with the excipient or excipients.
In general, it has proven advantageous both in human and in veterinary medicine to administer the active compound or compounds in total amounts from about 0.5 to about 500 mg/kg, preferably 1 to 100 mg/kg, of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose contains the active compound or compounds preferably in amounts fromakout l to akout 80 mgtkg, in particular 1 to 30 mg/kg, of body weight. However, it may be necessary to depart from the doses mentioned, namely depending on the nature and the body weight of the subject to be treatedl the nature and the severity of the disease, the method of preparation and of administration of the medicament as well as the period or interval within which administration takes place.
The invention also extends to a commercial package containing a compound of the invention, together with instructions for its use for combating viral diseases.

. . ~

, .

2~1~31~37 Startinq Compounds ~;
i~ i,d,~
Example I

Ethyl 9,10-difluoro~2-(~ m~t:hoxy-phenyl~-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylate O O
F ~ ~ o ~ CH3 0~ ;

~ ~ O~C~3 0.7 g (2.58 mmol) of ethyl 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate, 0.892 g ~6.45 mmol) of K2CO3 and 1.183 g (5.16 mmol) of 2-bromo-2'-methoxy-acetophenone in 40 ml of ~bs. DMF are heated at 90C for 6 h under argon.
The solvent is removed in vacuo. The residue is taken up with CH2C12 and shaken 3 times with 50 ml of lN HCl. The combined organic phase is washed twice with water, dried over sodium sulphate and concentrated in vacuo. The crude product is purified on silica gel (elu~nt CH2Cl2 Le A 28 860 - 22 -.
': :

2~3 ~ ~7 MeOH = 100 : l) and recrystallised from toluene. ~;
Yield: 300 mg (29% of theory) M.p.: ~230C

Example II

Ethyl 9,10-difluoro-7-oxo-2-(2-propyl)-7H-pyrido[1,2,3-d,e][l,4~benzoxazine-6-carboxylate O O
F~JI~o~cH3 0~
~ 1 2 g (7.38 mmol) of ethyl 6,7,8-trifluoro-4-hydroxy-3-quinoline-carboxylate are suspended in 50 ml of abs. DMF
under argon. 2.55 q (18.4~ mmol) o K2CO3 and 2.43 g (14.75 mmol) of l~bromo-3-methyl-2-butanone in 10 ml of abs. DMF are added and the mixture is heated at 90C for 1 8 h. It is cooled and poured into ice-water. The ¦ p~ecipitated product is filtered off with suction and washed with water. It is washed with petroleum ether and dried in vacuo. The crude product is purified by column chromatography on silica gel (eluent CHzCl2 : MeOH =
100 : 1.5) and l.S g t61% of theory) of the title .1 Le A 28 860 - 23 -' -' , ' :" ' ' 20~3l2~7 compound are obtained. ;
M.p~: 170C

xample III

Ethyl 2-tert-butyl-9,10-difluoro-7~oxo-7H~pyrido[1,2,3-d,e][l,4]benzoxazine-6-carboxylelte O O
F ~ ~ O'-~CH3 o~
C(CH3)3 2.55 g (18.44 mmol) of K2CO3 and 2.64 g (14.75 mmol) of 1-bromo-3,3-dimethyl-2-butanone are added under argon to 2 g (7.38 mmol) of ethyl 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate in 100 ml abs. DMF and the mixture is heated at 90C for 4 h. The solvent is removed in vacuo, and the solid stirred with water and filtered off.
The aqueous phase is extracted with CH2C12, the extract is dried over Na2SO4 and the solvent is removed in vacuo. The combined crude product is purified on silica gel (eluent CH2Cl2 : MeOH = 100 : 1.5). It is then recrystallised from CHC 13 .
Yield: 1.24 ~ (48% of theory) M.p.: 185C

Le A 28 860 - 24 -. . .

.,~ t ,: ..

-,: ,` '" ' :
~ ~ , '` . . ' ' ; :

2~931~7 Example IV ~
,~
Ethyl 2-(4-chloxophenyl)-9,10-difluoro-7-oxo-7H-pyrido[l,2,3~d,eJ[1,4]benzoxa2ine-6-carboxylate F ~ ~ ,COOC~Hs F ~ N
0~ .

The title compound is obtained analogously to Example I.
M.p.: 213C

Example V

Ethyl 9,10-difluoro-2-(4-methoxy-phenyl)-7-oxo-7H-pyrido[l,2,3-d,e]~1,4]benzoxazine-6-carboxylate F ~ COOC~Hs~

Le A 28 860 ~ 25 -. rL,~....
'': , - : , . . .~ ,. . . .

: :

: . ~ ,, : , ' .
.~ : .
. .
~ .
:~ ' - '. `` :.
: ' . . ~ ' ' " - ~ . ' 2093~0~

1~9 g (7 mmol) of ethyl 6,7,8-tri~luoro~ hydrox~ t;3-quinoline-carboxylate, 3.Z g (14 mmol) of 2-b~ mo-4'-methoxyacetophenone and 2.43 g (18 mmol) of K2CO3 are heated at 90C for 6 hours in 14 ml of DMF. The solvent is distilled off in vacuo and the residue is stirred with water. The crude product i.s purified by column chromatography.
Yield: 2.48 g (89~ of theory) M.p.: 214C

Example VI

2-(tert-Butyl)-9,10-difluoro-7-oxo-7H pyrido~1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid O
F ~ COOH

F ~ N
~ , ~(CH3)3 2 ml of acetic acid, 1.3 ml of water and 0.17 ml of ~2S4 are added to 393 mg (1.12 mmol~ of the compound from Example III and the mixture is boiled under reflux for 2 h. After cooling, it is treated.with water and the solid is filtered off. It is washed with waterO The product is dried and recrystallised from chloroform.
Yield: 230 mg (64% of theory) M.p.: ~230C

Le A 28 860 - 26 -.
.
, j;
~.~

, 2~)193~7 Example VII - _ G~;
t A ~
9,10-Difluoro-2~(2-methoxy-phenyl)-7-oxo-7H-pyrido[1,2,3-d,e]~1,4]benzoxa~ine-6-carboxyl:ic acid O O

F ~N
0~ .

~ `CH3 9 ml o acetic acid, 6 ml o~ water and 0.8 ml of H2SO4 are added to 500 mg (1.25 mmol) of the compound from Example I and the mixture is boiled under reflux for 3 h.
After cooling, the solid is filtered off and washed with water. The product is dried in a high vacuum~
Yield: 450 mg (97% of theory) M.p.: >230C

The compounds listed in Table I are prepared in analogy to the procedures of Examples VI and VII:

Le A 28 860 - 27 -~,:~ .. , -. . - , . . . . .
.,-,, ~, , ' , . ~

-- , . .
., ' ` :
~' ' , . ' :

2~9~ ~7 Table I: ~

F ~,CO H

~Fl3 Ex. No. R2 R3 M.p. C

VIII -C6H4-p-Cl H >300 IX -C6H4-p-OCH3 H >300 X -CH(CH3)2 H >230 Example_XI

10-(4-Butoxycarbonyl-l-piperazinyl)-9-fluoro-7-oxo~7H-pyrido[l,2,3-d,e~[1,4]benzoxazine-6 carboxylic acid O O
F ~ OH

B~ ' J J
500 mg (1 75 mmol) of 6,7,8-trifluoro-1-formylmethyl- . :

4-oxo-4H-quinoline-3-c~rboxylic aci~ and 652 mg (3,50 mmol) of l-butoxycarbonyl-piperazine are heated under reflux for 4 h in a mix~ure of 3.0 ml of diiso-propylethylamine and 2.5 ml of DMSO. After cooling, the mixture is treated with ether, the solvent is decanted : .

Le A 28 860 - 28 -. ' " " ' ~ ' ' ' ' ' : ~ ' ' " ' , , . , '~
.' ! : . . ~ ' ~ :
.
:. . . ' ~ , :. ' , . ~ . .~: ., , 2 0 9 310 1~

off and the resi~ue is triturated with ethyl acetate and ethanol. ~ -Yield: 282 mg (37% of theory) lH-NMR (DMSO-d6): ~= 6.93 and 7.10 (2d, ~ = 5 Hz; each lH, 2-H and 3-H); 7.45 (d, J = 12~5 Hz; lH, 8-H); 8.75 (s, lH, 5-H).

Example XII

Ethyl 6,7,8-trifluoro-(1-(1'-methyl-ethyl)-2-propenyl)~
4-oxo-4H-quinoline-3-carboxylate O O
F ~ ~ OEt F ~ CH3 I

1.41 g (14.2 mmol) of 3-amino-4-methyl-1-pentene in 20 ml of ethanol are added dropwise at 0C to a solution of 4.55 g (14.2 mmol) of ethyl 3-ethoxy-2 (2,3,4,5-tetrafluoro-benzoyl)acrylate and 4.95 ml (28.4 mmol) of diisopropylethylamine in 20 ml of ethanol. After 1.5 h at room temperature, the mixture is concentrated in vacuo, the residue is partitioned between water and methylene chloride, and the organic phase is dried using sodium sulphate and concentrated again.

~e_A 28 860 - 29 -' -'- ~. .

2~93i~7 The residue i9 dissolv~ in 20 ml of anhydrous dimethoxy-ethane and added dropwise at 0C to a suspensio~S~of 552 mg (18.3 mmol) of sodium hydride (80~ strength) in 45 ml of anhydrous dimethoxyethane. After 1 h at 0C, 4 ml of glacial acetic acid are added, the mixture is concentrated and the residue i5 partitioned between methylene chloride and water. The organic phase is dried using sodium sulphate, concentrated and chromatographed on silica gel using toluene/ethyl acetate.
Yield: 3.35 g (67%);
M.p.: 65-67C.

Example_XIII

Ethyl 6,7,8-trifluoro-4-oxo-1-(1-phenyl-3-propenyl)-~H-quinoline-3-carboxylate O O
F ~ OEt F ~ N
F

~.
The title compound was prepared irom 3-amino-3-phenyl-l-propene in analogy to the procedure of Example XII.
Yield: 36%;
M.p.: 120C

Le A 28 860 - 30 -i, .~
.

.

~a~3l0 l7 Example XIV
,~
Ethyl 1~ ethyl-2-propenyl)-6,7,8~trifluoro~-oxo-4H-quinoline-3-carboxylate O C) F ~ ~ OEt F ~ (,H3 I

The title compound was prepared from 3-amino-1-pentene in analogy to the procedure of Example XII.
Yield: 50%;
M p.: 99GC.

E m le XV

Ethyl 9,10-difluoro-3-(1-methyl-ethyl)-7-oxo-7H-pyrido-[1,2,3-de][1,4~benzoxazine-carboxylate O O
F ~ OEt O ~ CH3 ~e A 28 860 - 31 -;' :; , , ,: , 2~931~7 Ozone is passed into a solution of 3.35 g (9.5 mmol~ of the compound from Example XII in 85 ml of meth~norrand 21 ml of methylene chloride at -78C unt:il it is coloured blue. Excess ozone is driven off with nitrogen. 7.5 ml of dimethyl sulphide are added, and the mixture is allowed to come to room temperature and is concentrated in vacuo after about 5 h. The residue is dissolved in 50 ml of anhydrous DMF, treate~ with 1.:31 g ~9.5 mmol) of K2CO3 and stirred at room temperature or 1 h. 5 ml of glacial acetic acid and 500 ml of water are added~ and the precipitate which deposits is filtered with suction, washed with water and dried in vacuo.
Yield: 2.50 g (79%), lH-NMR:(DMSO-d6): 1.19 (d, J = 7 Hz; 3'-CH3), 1.28 (t, J
= 7 Hz; 3H, 6'-CH3), 2r99 (h, J = 7 Hz; lH, 3'-H), 4.24 (q, J = 7 Hz; 2H, 6'-CH2), 6.77 (s; lH, 2-H), 7,56 (dd, J
= 8 Hz, J = 11 Hz; lH,¦8-H), 8.36 (5; lH, 5-H).
!

Exam~le XVI

Ethyl 3-ethyl-9,10-dif~uoro-7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-car~oxylate O O
OEt O ~ CH3 The title compound was prepared from the compound of e A 28 850 _ 3~ _ :.

: . . . :, ,, ~;
' . .

2 ~ 9 ~ 7 Example XIV in analogy to the procedure of Example XV.
Yield: 69%;
.~*

H-NMR (DMSO-d6): 1.14 and 1.28 (2t, J = 7 Hz; each 3H, 3'-C~3 and 6'-CH3), 4.24 (q, J = 7 Hz; 2H, 6'-CH2), 6.79 (s; 1~, 2-H), 7.55 (dd, J = 8 Hz, J ~ Iz; lH, 8-H), 8.28 (s; lH, 5-H).

Exam~l_ XVII

9,10-Difluoro-7-oxo-3-(1-methyl-ethyl)-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid O O
F ,~ OH

o ~ C~3 2.50 g (7.5 mmol) of the compound from Example XV are heated under re~lux for 4 h in a mixture of 100 ml of water, 110 ml of glacial acetic acid and 10 ml of s~lphuric acid. After cooling, the~ mixture i5 treated with water. The precipi~ate which deposits is filtered off with suction and dried in vacuo.
Yield: 1.76 g (77%);
M.p., 253-255C.

Le A 28 860 ~ 33 _ ' - . .

2093.~7 ~ Ir;

3-Ethyl-9,10-difluoro-7-oxo-7H~pyrido[1,2,3-de][1,4~-ben~oxa~ine-6-carboxylic acid O O
F / ~ N

O ~ ~ CH3 The title compound is prepared :Erom the compound of Example XVI in analogy to the procedure of Example XVII.
Yield: 68%;
M.p.: 246C.

Example XIX

9, 10-Di:Eluoro-3-methyl-7-oxo -7H-pyrido~ 1, 2, 3-d,e][~,4]benzoxazine-6-carboxylic acid o F ~ COOH

~ C`H3 Le A 28_86Q - 34 -'. :' ~ ' ~ I
' ~ ` ' '' ~ , ' ` ,:

, .

2~931~7 l l o O g of 6,7,8~trifluoro-1,4-dihydro-4-oxo-1-(1-met~y1-2-oxo-ethyl ~3-quinolinecarboxylic acid are heated to boiling for 3 hours in 110 ml of tert-butanol with 4.62 g of ~cotsu. After cooling to room temperature, the mixture i8 added to water and acidified and the precipitated solid is isolated.
Yield: 8.5 g;
M.p.: 258-260C.

Example XX

10-(4-Ethoxycarbonyl-1-piperazinyl)-9-fluoro-3-methyl-7 oxo-7H-pyrido[1,2,3-d,e~[1,4]benzoxazine-6-carboxylic acid F ~ ,COOH

~ N J ~ CH3 OC2Hs 0.21 g of 9,10-difluoro~3-methyl-7-oxo-7H-pyrido[1,2,3-d~e][1,4]benæoxazine-6-carboxylic acid and 0.36 g of ethoxycarbonylpiperazine are heated at 120~C for 3 hours in 7.5 ml of DMSO. All the volatile components are distilled off in high vacuum and the residue is stirred with ethanol.

Le A 28 860 - 35 -, . .

2~93~ ~7 Yield: 0 . 22 g; ';M.p.: 290-292C.

Example XXI

Ethyl 9,10-difluoro-2-(4-methyl-phenyl)-7-oxo-7H-pyrido[l~2~3-d~e][l~]ben2oxazi~ne-6-carboxylate O O
F ~ o ^ CH3 0~ .
¢~

Analogously to Example III, 0.52 g (5~% of theory) of the title compound are obtained using 2-bromo-4~-methyl-acetophenone.
M.p.: 237C.
-I.e A 28 860 - 36 -' ,:

20~3.~7 Exam~le XXII
'~;' ' Ethyl 2-ethyl-9,10~difluoro-7-oxo-7H-pyrido[1,2,~-de]-[1,4]benzoxazine-6-carboxylate O O
~ O CH3 F N
~

Analogously to Example II, 0.9 g (38% of theory) of the title compound are obtained using l~bromo-2-butanone.
M.p.: 210C.

The compounds listed in Table II are prepared in analogy to the procedures of Examples VI and VII:

Le A 28 860 37 _ .: , , .
, , ~, . . . . .

2~9~i7 F ~ CO~H

O ~ H
, R

Exam~le No. R2 M.p.C
XXIII -C2Hs : >230 XXIV -C6H~-p-CH3 >230 Example XXV

Ethyl 2-[1,1-bis(fluoromethyl~-ethyl]-9,10-difluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate O O
F~o o~
r . F C~3 F

The title compound is obtained in 23~ of theory in analogy to the procedure of Example III.
M.p.: 225C.

.

Le A 28 860 _ 3~ _ : , . ' ' , ' ' ~ , ' .
,' j ' ' ' ' ',' . ,; : ~ .
,.
,' ~ ' ~ ' ' ' ~' ;` ';' ' 2~93~7 Example XXVI ~
~ ~p 2-[1,1-~is(fluoromethyl)-ethyl]-9,10-difluoro-70xo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-car.boxylic acid O O
; ~ ^`~'-OH
0~ .

The title compound is obtained in 85% of theory in analogy to the procedure of Example VI.
M.p.: >230C.

Exam~le XXVII

Ethyl 9,lO~Difluoro-7-oxo 3~phenyl-7H-pyrldo[1,2,3-de~-[1,4]benzoxazine-6-carboxylate F ~ ~ CO2C2Hs ~ C~H5 The title compound is prepared from the compound of Example XIII in analogy to the procedure of Example XV.

Le A 28_860. - 39 ~

~ . . . ~. - - - ~ :
, : .

.... . .
., ,. ~ . ~.

20g31~7 Example XXVIII
~ d'' 9,10-Difluoro-7-oxo 3-phenyl-7EI pyrido~1, 2, 3-d,e][l,4]benzoxazine-6-carboxyl:ic acid o F ~ ~ CO211 C6Hs The title compound is prepared from the compound of Example XXVII in analogy to the procedure of Example XVII.

_ ample XXIX
Ethyl 1-(2-ethyl-1 propyl-2-propenyl)-6,7,8-trifluoro-4-oxo-~H-quinoline-3-carboxylate o F ~ CO2C2~s H3C ~ CH3 The title compound is prepared from 3-amino-2-ethyl-1-hexene in analogy to the procedure of Example XII.

Le A 28 860 - 40 -~' ' "' :' ~:' ':

~93~7 ~L~ _ 9, Ethyl 2-Ethyl-9,10-difluoro-7-oxo-3-propyl-7H-pyrido-[1,2,3-de][1,4]benzoxazine-6-carboxylate O
F ~ CO2C2Hs F ~ ,~,~

~\ (CH2)2-CH3 C2Hj The title compound is prepared from the compound of Example XXIX in analogy to the procedure of Example XV.

Example XXXI
Ethyl 1-(1,2-dimethyl-2-propenyl)-6,7-8-trifluoro-7-oxo-4~-quinoline-3-carboxylate F ~ CO2C~Hs F
H3C ~ CH3 CH~ -The title compound is prepared from 3-amino-2-methyl-1-butene in analogy to the procedure of Example XII.
M.p.C: 122.

. , Le A 28 860 - 41 -, "

. ,-,: :,~ .~ :, 2~3~7 Example XXXII

2-Ethyl-9~10-difluoro-7-oxo-3-propyl-7H-pyrido[~ 2,3-de]-[1,4]benzoxazine-6-carboxylic acid F ~ CO2H

F ~ N
0~
(CH2)2-C~3 C2Hs The title compound is prepared from the compound of Example XXX in analogy to the procedure of Example XVII.
M~poC 170.

Exam~le XXXIII

Ethyl 9,10-difluoro-2,3-dimethyl-7-.oxo-7H-pyrido[1,2,3-d,e][l,4]benzoxazine-6-carboxylate e A 28 860 - 42 -2~9~7 o ~j.
F ~ CO2c2Hs The title compound is prepared from the compound of Example XXXI in analogy to the procedure o Example XV.
M.p.C: 186.

Example XXXIV

9,lO-Di1uoro-2,3-dimethyl~7-oxo-7H-pyrido~1,2,3-d,e]tl,4]benzoxazine-6-carboxylic acid o F ~ CO2H

F ~ N

. C~3 The title compound is prepared rom th0 compound o~
Example XXXIII in analogy to the procedure of Example XVII.

. ~ .

..

Le A_28 860 - 43 -: ,, ,, . : ,; , : :

2n93~7 Exam~le XXXv Ethyl 1~ (1'1'-dimethylethyl)~2-propenyl)-6,7,8-trifluoro-9-oxo-9H-quinoline-3-carboxylate F ~ CO2C2Hs F ~ CH3 H~C CH3 The title compound is prepared from 3-amino 4,4-dimethyl 1-pentene in analogy to the procedure of Example XII.

Exam~le_XXXVI

Ethyl 3-(1,1-dime~hyl-1-ethyl)-9,10-difluoro-7-oxo-7H-pyrido[1,2,3-de]~1,4]~enzoxazine-6-carboxylate o F ~ CO2C2H5 .
The title compound is prepared from the compound of Example XXXV in analogy t2 ~he procedure of Example XV.

. .

~e A 28 860 - 44 ~

:~ ,, . :

~0~3 : ~
; 3-(1,1 Dimethyl-l-ethyl)-9,10~difluoro-7-oxo 7H~.~yrlao r . [1,2,3-de][1,4]benzoxazine-6-carboxylic acid O
P ~ CO~H

~CCHH33 ,l C~3 .l The title compound lS prepared from the compound of 1 5 Example XXXVI in analogy to the procedure of I Example XVII.

. Prçparation Examples . Example _l 2-tert Butyl-9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]-benzoxazine-6-carboxylic acid O O

~ N ~
H3C' J ~
- C(CH3)3 .e A 28 860 - 45 -`:
,' ~' ' '~ i' : . , ' .

` ~ . '. ' ~ '"' ' ' i' ~' ~

20g3~7 ~ 100 mg (0.31 mmol) of the compound from Exampl~ VI, 80~mg I (O.62 mmol) of diisopropyl-ethylamine and 93 rii~ (O.93 ¦ mmol) of N-methylpiperazine are heated at 140C for 3 h under argon in 2 ml of abs. DMSO. A:Eter cooling, the ¦ 5 mixture is treated with water and the solid is stirred and then filtered. The crude product is washed with water I and dried in high vacuum.
Yield: 88 mg (70% of theory) M.p.: >230C

Example 2 9-Fluoro-7-oxo-10-(1-piperazinyl)-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid O O
F ~ OH

HN J O ~J

130 mg (0.30 mmol~ of the compound from Example XI are treated at room temperature for 1 h with a mixture of 1 ml of anisole and 10 ml of trifluoroacetic acid. The mixture is concentrated in vacuo, and the residue is treated with ether and filtered off with suction. The solid is dissolved in water, and the solution is adjusted Le A 28 860 ~ 46 -2093~

to p~ 5 using sodium acetate and chromatographed ~n RP~18 using water/acetonitrile/acetic acid. ,.r.
Yield: 35 mg (35% of theory) 1H-NMR (CF3CO2D): b - 7.02, (s; 2H, 2-H and 3-H); 7.88 (d, J = 11 Hz; lH, 8-H); 8.37 (s; lH, S-H).
' Exam~le 3 9-Fluoro-10-(3-methyl~l~E~iperazinyl)-7-oxo-7~-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid O O
H3C ~ ~ OH
~ HNJ o~

1.0 g (3.5 mmol) o~ 6~7,8-trifluoro-1-forr,lylmethyl-4-oxo-4H-~uinoline-3-carboxylic acid and 0.7 g (7.0 mmol) of 2-methylpiperazine ~re heated under reflux for 4 h in a mixture of 5 ml of DMSO and 6 ml of diisopropyl-ethylamine. After cooling, the mixture is treated with ~ ether, the solvent is decanted off and the residue is - 15 triturated with ethyl acetate and ethanol. For purification, the residue is dissolved in water and chromatographed on RP-18 using water/acetonitrile~acetic acid.
Yield: 25 mg (2% of theory~
1H-NMR (DMSO-d6): ~ - 0.96 (d, 3 = 6 Hz; 3H, CH3); 6.94 Le A 28 860 - 47 -:
.'~.: ' ' . `
..... : , ~ , , , 2093~07 and 7.08 (2d, J = 5 H2; each 1 H, 2-H and 3-H); 7.42.(d, J = 12.5 Hz; lH, B-H); 8.72 (s; lH, 5-H)~

Exam~le 4 : 10-(3,5-Dimethyl-1-piperazi.nyl)-9-fluoro-7-oxo-7H-pyrido[1,2,3 d,e][1,4]benzoxazine-6-carboxylic acid C) O
OH

, HN ~ O
}~ C

The title compound was prepared analogously to Example 3.
Yield: 15%
H~NMR (DMSO-d6): 6 - 1.30 (d, J = 6 H~; 3H, CH3); 6.98 and 7.13 (2d, J - 5 ~z; each lH, 2-H and 3-H); 7.48 (d, J = 13 H;, lH, 8-H);,8.76 (s; lH, 5-H).

Exam~le 5 10-(4-Ethyl-l-plperazinyl)-9-fluoro-3-methyl-7-oxo-7H-I pyrido[1,2,3-de][1,4~enzoxazine-6-carboxylic acid F ~ ~ CO2H

H5c2 - J ~ CH3 ,' : Le A 28 860 - 48 --' ' - ' : ' :
.. . .

2~93~e~7 300 mg (1.075 mmol) of 9,10-difluoro-3-methyl-7-oxo-?H-pyrido[1,2,3 d,e][1,4]benzoxaz:ine-6 carboxylic ~id are suspended in 8 ml o~ DMSO, treated with 139.8 mg (1.075 mmol) of 1-ethyl-piperazine and 240.8 mg (2.15 mmol) of DABCO and heated at 100C for 1 h. After reaction is complete, the solvent is distill~d off in a ~: high vacuum, the residue is suspended using isopropanoland the solid is filtered off with suction and dried, Yield: 354 mg (85% of theory) i~s a solid The compounds listed in Tables 1, 2, 3, 4, 5 and 6 are prepared in anaiogy to the procedures of Examples 1-5, the esters of the corresponding precursors being directly reacted in the case o the ester~ (R4 ~ H):

Le A 28 860 49 -., .

: ' . . .
' , . , .

20931 ~

Table I
O t~
'~ F`,I~ C02H

R"N~ `CH3 Rs Ex . No, Rs R6 R7 M . p . C Yield ( %
o~
theory ) 6 H H -CH2-C6Hs 237 82 7 El H - (C:EI2)2-OH 183 83 8 H H H3C-CH(OH)-cH2- 238 64 9 H ~3 -CH ( C6Hs ) -CH3 210 5 0 ll H ~C6Hll H 1~5 53 : 12 -H3C -H3C H >2S0 73 14 H -C(CH3)3 H 145 31 Table 2:
o F ~,11~, C02H

O`~cH
:' s ., .

., .

:
~ . .

: ~e A 28 860 - 50 -.'''. . , ' , :. ' , :, . .. ~ , ~ .

, 2093~7 Ex . No . Rs R3 M . p . C Yield ( % o:~
Y ) I~,r 15 -CH3 -CH3 ~ 2 51 51 16 H H >265 83 Table 3:

F ~,3~ CO2H
R~ ~N
J~ CH3 Ex . No . Rl M. p . C Yield ~ % of ~N~ theory ) 17 ~J 247 31 Table 4:

F ~ CO2H

, N ~J 0,~

Le A 28 860 - 51 -: ' , , , ,' ~. ~ .

.' ., ~. ...

2~3~

Ex. No. Rs R6 R7 R' M.p. C Yield ( 5 of ~Y~theory ) 18 H H -CH3 o-OCH3 >2 3 02 3 19 H H H o-OCH3 >230 25 -CH3 -CH3 H o-OCH3 >230 96 2 3 -CH3 H H m-CH3 >2 3 041 Table 5:

F ~,U~, CO2 R4 ~N~N~J
R~N~j t~
Rs R2 Ex. ~' R2 R4 RS B6 R7 ln analo8Y M.p. C Y~ ~ld (X o to oxaQple theory ) 24 -C(C~3)3 -C2ds -CH3 ~ d 1 110 70 -C(C~3)3 -C2E5 3 E~ -C~3 1 160 S7 :) 26 -CEl~CB3)2 -C2~S a g -c~33 1 lD3 55 27 -CB~C~3)2 3 ~ ~3 -Q33 1 ~230 50 23 -c8~c3 ) d -C63 3 a 1 >230 17 29 -Cd(C~33)2 1~ c.33 C~3 ~ 1 ~230 25 Le A 28 860 - 52 -' , ' ' ' , ' ' ' ' ' . ~, , ' , ' .

:
.
.~ ; ' 2~931~7 Table 6 o ,~ R,~C2 F~4 ~ 3 Ex. No. R1R2 R3 R4 M.p. C

HN N - -C6H4-p-Oc~3 H ~C2~s 31 HN N - -C6H4-P-cl H ~C2Hs 32 H3C.N N - C6H4 p Cl H ~C2Hs HN N--33 \__/ H ~CH3 -CH3 280 (d.. ) Example 34 2-tert-Butyl-10-(3/5-dimethyl-1-piperazinyl)-9-fluoro 7-oxo-7H pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid O O
F ~ OH

H3C~f N~N
' H ~ ~
f'L~
.3 C(CH3)3 Analogously to Example 1, 96 mg (54% of theory) of the title compound are obtained using 2,6-dimethylpiperazine.
~.p.: >~30C.

-I Te A 28 860 - 53 ~
I

20~31~7 E_ mple 3~5 ~
1.'~?
2-tert-~utyl-9-fluoro-10-(3-methyl-l-piperazinyl)~7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid o o F ~/~ ~ o~

H,N ~fJ O
CH3 C(CH3)3 Analogously to Example 1, 72 mg (58% of theory) of the title compound are obtained using 2-methyl-piperazine.
M.p.: >230C.

Example 36 .
2-tert-Butyl-9-fluoro-10-(1-piperazinyl)-7~oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid O O
F ~ OH
~ N ~ N

H,NJ ~
C(CH3)3 Analogously to Example 1, 90 mg (37% o~ theory) of the title compound are obtained using piperazine.
M.p.: >230C.

: Le A 28 860 - 54 _ ,' ' ' ~ ` ` ''';

.

~0931 ~7 Example 37 ~

Ethyl 10-(3-amino-1 pyrrolidinyl)-2-(4-chlorophenyl)-9-fluoro-7-oxo-7H-oyrido[1,2,3-d,eJ[1,4]benzoxazine 6-carboxylate hydrochloride F ~ COOC2Hs ~ N ~ N
H2N ~ xHCI

Cl `( :
0.4 g (1 mmol) of ethyl 2-(4-chlorophenyl)-9,10-difluoro-7 oxo-7H-pyrido[1,2,3-d,e][1,4]-benzoxazine-6-carboxylate, 0.31 g (1.6 mmol) of 3-tert-butoxycarbonylaminopyrrolidine and O.22 g (2 mmol) of 1,4-diazabicyclo[2.2.2]octane are heated at 1409C for 2 h in 10 ml of N-methylpyrrolidone. The mixture is ~, 10 treated with water and the crude product is isolated. It is 1 purified by column chromatography. 0.4 g of the product are then stirred in a mixture of 3.7 ml of methanol and 3,7 ml of conc. hydrochloric acid for 2 h. The solvents are distilled I off in vacuo and the residue is stirred with isopropanol.
¦ 15 Yield: 0.23 g M.p.: 271C (dec.).

,:
., Le A 28 860 _ 55 _ :' , . , ' ,~ ~ '' , '. , ,,,. , ., '" .', . ' ::
" . ~ .

: ~ ~

2093~07 x_mple 38 ~~
f'~
Ethyl 10-(3wamino-1-pyrrolidinyl)-9-fluoro-2~(4-methoxyphenyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylate hydrochloride o F ~ cooc2Hs ~ N ~ N
H N ~ ~ . xHCI
[~ ' S Analogously to Example 37, the title compound can be obtained starting from ethyl 9,10-difluoro-2-(4-methoxyphenyl ) -7-oxo-7H-pyrido[1,2, 3-d, e][1,4]benzoxazine-carboxylate.
M.p.:250C(dec.).

The compounds listed in Table 7 are prepared in analogy to the procedures of Examples 5, 37and38:

Le A_~i8 860 - 56 -~, , , : ' ' ~: ; ' ' 2093~17 ~able 7~
". 4, o F ~ co21 ~ CH3 Ex. No. R1 5alt M.p.C
39 HN N HCl >300 The compounds listed in Table 8 are p.repared in analogy to the examples given therein:

Table 8:
o ..
F ~ CO

6~f NJ~N~
7 ~IJ
Fis R2 Ex. No. R2 R5 R3 R7 In analogy M.p.C Yield of example (% of ~) -CH(CH3) H H H 1 >230 44 41 -C2H5 H H H 1 >230 43 42 -C2H5 -CH3 H H 1 ~230 47 43 -C2~5 -CH3 -CH3 H 1 ~230 75 44 -C2H5 H H -CH3 1 >230 35 Le A 28 860 - 57 -;

;';' "`; ' .,: ~, .
.. : . : : ~

~3~ 7 Exam~le 45 9-Fluoro-3~ methyl-ethyl)-7-oxo-10~ piperazin~
7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid " O O

; ,N J ~ CH3 CH~
.,; .
: 307 mg (1.0 mmol) of the compound from Example XVII, 5 ml of DMSO, 1.7 ml of diisopropylethylamine and 172 mg (2.0 mmol) of piperazine are heated undex reflux for 4 h.
~ After cooling, 50 ml of ether are added, and the : precipitate i.s filtered off with suction, washed with ether and dried in vacuo.
Yield: 298 mg; (80%).

Example 46 3-Ethyl-9-fluoro-10-(4-methyl-l-piperazinyl)-7-oxo-7H-pyrido[l,2,3-d,e][1,4~benzoxazine-6-carboxylic acid O O
OH
CH3-N J ~ CH3 ~e A 28 86.0 - 58 -`

2~9~

The title compound is prepared in arlalogy to t.h~
procedure of Example 45. i~
Yield: 23% of theory.

Example 47 3-Ethyl-9-fluoro-10 (N-morpholino)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid O O
OH
oJ O ~ CH3 The title compound is prepared in analogy to the procedure of Example 45.
Yield: 25% of theory.

The compounds listed in Table 9 are prepared in analogy to the procedure of Example 45:

Table 9:
F ~ CO2H
~N~N~J
R7 N~ o~l~
Rs Le A 28 860 - 59 -.... .. ,~ . .

~ . . .

2~93:1 ~7 Ex. No. R3 Rs R7 Yield (% of theory) 48 -CH(CH3)2 -CH3 H 55 49 -~2H5 H H 58 'H-N~R data are available for the compounds.

The compounds listed in Table 10 are prepared in analogy to the procedure of Example 1 Table 10:
o F~,CO2H
o~
C(CH3)3 Ex. No. Rl M.p.C

51 - N ~ o >250 52 _N~ >250 Le A 28 860 60 -.

2 0 ~

Exampl e 53 2 - [ 1, 1 -Bis ( f luoromethyl ) -1 -ethyl ] -10- ( 3, 5 -dimethyl- 1-pipera~inyl ) -9-f luoro-7-oxo-7H-pyrido [ 1, 2, 3-d, e] [ 1, 4 ]benzoxazine-6 carboxylic acid hydrochloride O O

~ ~ x HCI
HN~ o~
Me r I -F C~3 F

200 mg (0.56 Ir~nol) of the compound from Example XXVI, 145 mg ( 1.12 mmol ) o E diisopropylethylaIrine and 192 mg (1.68 mmol) oE 2,6-dimethylpiperazine are heated under argon at 140C for 4 hour~ in 2 ml of abs. DMSO. The mixture is allowed to cool and is treated with 15 ml of ether. The precipitate is filtered of f with suctian and washed with ether . ~he solid is dissolved in 1. 5 ml of conc. ~Cl, 75 ml of ethanol are added and the mixture is stirred overnight. The product is filtered off with suction and dried in a high vacuum. 51 mg (19% of theory) of the title compound are obtained.
Melting point: >2 3 0 C .

Le A 28860 - 61 --,"- , , ~ , . ~,-,, , , : :" - : ,, : ~ : :

- , , ~ : .

- ~ ", , ` :` . .... .
':

2~93~ 7 ~ ~, ,~
2~[1,1-Bis(fluoromethyl)-1-ethyl] 9-fluoro-10-(4-methyl-1-piperazinyl ) -7-oxo-7H-pyrido[l, 2, 3-d,e][1,4]benzoxazine-6-carboxylic acid hydrochloride O O

~ ~ I HCI
CH3'NJ o~J

89 mg (34P6 of theory) of the title compound are obtained in analogy to the procedure of Example 53.
Melting point: >230C

Example 55 9-Fluoro-2-methyl-10-(3-methyl-1-piperazinyl)-7-oxo-7~I-pyrido[1,2,3-d,e]~1,4]benzoxazine-6-carboxylic acid O O
F ~ ~'OH

~N~N
HN~ ~
Me CH3 Le A 2~ 860 - 62 :. :

'' ' ~'' "
. .

2~93~ 07 200 mg (0.72 mmol) of the starting material preparecl analogously to Example 13 of EP 253,235 are suspended i~
6 ml of DMSO with 174 mg (1.43 mmol) of diisop~pylethyl~nir~ and 215 mg (2.15 mmol) of 2-methylpiperazine and the mixture is heated at 140C under argo:n for 5 hours. After cooling, the DMSO is removed in vacuo. The residue is treated with some water and adjusted to pH 3. The precipitated solid is filtered ofi with suction and dried in vacuo. 97 mg (38% of theory) of the title compound are obtained.
Melting point: >230C.

The compounds listed in Table 11 are obtained analogously to the procedure of Example 1.

Table 11:

Re ~`N ~.~J
, N ~J O ~J

CH, Ex. No. R5 R5 R7 M.p. C Yield (% of theory) 56 -CH3 -CH3 H >230 64 57 -CH3 H H >230 50 I,e A 28 860 - 63 -:, , ' ~

2(~)310r7 The compounds listed in Table 12 are prepared in analo~gy to the procedure of ~xample ~5 Table 12:
o F ~ COzH
o~3 R~
Ex. No. Rl R2 R3 M.p.~C Starting compound 58 - Nr~N - CH3 H -CH(CH3)2 >250 XVII

S9 _Nr-~O ~ -CH(CH3)2 230 XVII

61 - N\__~NH H -C6Hs XXVIII

62 _ N~ - ~0 H -C6H5 XXVIII

63 _ Nr~N - CH3 H _~6Hs XXVIII

64 _Nr ~ NH -C2H5 -(CH~)2-CH3 >250 XXXII
65--Nr ~ NH -C2H5 -(CH2)2-CH3 XXXII

Le A_28 860 - 64 -' :' 2~9~7 Tab e 12 (continuati.on) x. No. Rl R~ R3 M.p. C Starting "~
compound 66 - Nr - ~ -C2H5 -(CH2)2-CH3 XXXII

67 - N NH -C~13 --C~3 ~XXIV
68 ~ N N - C~3 -CH3 -CH3 x~xrv 69 - N NH -CH3 -C~3 XXXIV

70 _ N~O -CH3 -CH3 XXXIV

71 - N NH H -C(CH3)3 XXXVII

72 _ N~N - CH3 H -C(CH3)3 XXXVII

The compounds listed in Table 13 are pxepared in analogy to the procedure of Example 5:

Le A 28 860 - 65 -.

. ..
.

20~3.~7 Table 13 ~
O -~?

F ~ CO2H
R; ~,J
Rs C(CH~)3 Ex. No. R7 R5 M,p. C
73-cH2c6H5 H ~250 7q- CH- CH3 H >250 OH
76 H C2H5 >250 77- CH2 CH- CH3 H :~250 OH

Example 7 8 2-tert~Butyl-9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-d,e~1,4]benzoxazine-6-carboxylic acid hydrochloride O O
F ~ OH

~ N ~ N ~ xHCI
CH N J O ~
: C(CH3)3 Le ~A_28 860 - 66 , .
, " , " , -,, : ~ . . . .. .

2 ~ 7 5.5 g (13.71 mmol) of the compound from Example 1 ar~ .
dissolved in 57 ml of conc. HCl. 1.6 1 of ethan~ are added and the mixture i5 stirred overnight. The precipitated product is filtered off with siuction and dried in a high vacuum.
Yield: 4.2 g (70% of theory) Melting point: >230C.

Le_A 28 860 - 67 -- :

. ~ , , , ~ . ;
,

Claims (19)

1. 7-Oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid derivatives of the general formula in which R1 represents halogen, 1-piperidinyl or a radical of the formula or in which A denotes a group of the formula -NR7, an oxygen atom or the -CH2-group, in which R7 denotes hydrogen or straight-chain Le A 28 860 - 68 -or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or phenyl, R5 and R6 are identical or different and denote hydrogen, cyclohexyl, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen, or represents straight-chain or branched perfluoroalkyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, hydroxyl, halogen, or straight-chain or branched alkoxy or alkylthio, each having up to 3 carbon atoms, represents phenyl, pyridyl, furyl or thienyl, each of which is optionally monosubstituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R3 represents hydrogen, phenyl, trifluoromethyl, straight-chain or branched alkyl having up to 4 carbon atoms, fluoromethyl or hydroxymethyl, Le A 28 860 - 69 -hydrates and salts, with the exception of 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido[a],2,3-d,e][1,4]-benzoxazine-6-carboxylic acid and its 3-and 4-methyl-1-piperazinyl derivatives, 9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid and its 2-methyl derivative.

2. 7-Oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-caxboxylic acid derivatives according to Claim 1, in which R1 represents fluorine, 1-piperidinyl or a radical of the formula or in which A denotes a group of the formula -NR7, an oxygen atom or the -CH2-group, in which R7 denotes hydrogen or straight-chain Le A 28 860 - 70 -or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or phenyl, R5 and R6 are identical or different and denote hydrogen, cyclohexyl, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen or represents straight-chain or branched perfluoroalkyl having up to 4 carbon atoms, represents straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl, hydroxyl, fluorine, chlorine or alkoxy or alkylthio each having up to 2 carbon atoms, represents phenyl, pyridyl, furyl or thienyl, each of which is optionally monosubstituted by fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R3 represents hydrogen, phenyl, trifluoromethyl, straight-chain or branched alkyl having up to 4 carbon atoms, fluoromethyl or hydroxymethyl, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.
Le A 28 860 - 71 -

3. 7-Oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid derivatives according to Claim 1, in which R1 represents 1-piperidinyl, or represents a radical of the formula or in which A denotes a group of the formula -NR7, an oxygen atom or the -CH2-group, in which R7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or phenyl, R5 and R6 are identical or different and denotes hydrogen, cyclohexyl, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, Le-A 28 860 - 72 -R2 represents hydrogen or represents straight-chain or branched perfluoroalkyl having up to 4 carbon atoms, represents straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl, hydroxyl, fluorine, chlorine, methoxy, ethoxy or methylthio, represents phenyl, pyridyl or furyl, each of which is optionally mono-substituted by fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R3 represents hydrogen, phenyl, trifluoromethyl, straight-chain or branched alkyl having up to 4 carbon atoms, fluoromethyl or hydroxymethyl, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.

4. The compound 2-tert-butyl-9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid or a salt thereof.

5. The compound 9-fluoro-3-methyl-10-(morpholin-4-yl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid or a salt thereof.

6. The compound methyl 9-fluoro-3-methyl-10-(1-piper-azinyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylate or a salt thereof.

7. The compound ethyl 10-(3-amino-1-pyrrolidinyl)-9-fluoro-2-(4-methoxyphenyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]-benzoxazine-6-carboxylate or a salt thereof.

8. The hydrochloride salt of ethyl 10-(3-amino-1-pyrrolidinyl)-9-fluoro-2-(4-methoxyphenyl)-7-oxo-7H-pyrido-[1,2,3-d,e][1,4]benzoxazine-6-carboxylate.

9. A salt of 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid.

10. The hydrochloride salt of 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid.

11. A process for the preparation of a 7-oxo-7H-pyrido-[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid derivative according to claim 1, which process comprises [A] reacting a compound of the general formula (II) (II) in which R2, R3 and R4 have the meanings given in claim 1 and T represents halogen, with a compound of the general formula (III) R1-H (III) in which R1 has the meaning given in claim 1, in an inert solvent, in the presence of a base, under a protective gas atmosphere, or [B] in the case in which R and R represents hydrogen, reacting an aldehyde of the general formula (IV) (IV) in which R4 has the meaning given in claim l, with a compound of the general formula (III) or (IIIa) R1-H (III) W-H (IIIa) in which R1 has the meaning given in claim 1 and W has the meaning given in claim 1 of R1, where, however, except for one, the amine functions are protected by protective groups, in an inert solvent, in the presence of a base, with simultaneous cyclisation, followed, if necessary, by removal of a protective group and, if required, according to the desired meaning of R4, either an esterification or hydrolysis and, if required, by converting an obtained compound into a salt thereof.

12. An antiviral composition which comprises a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.

13. A process for preparing an antiviral composition which comprises admixing a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, with a suitable diluent or carrier.

14. Use of a compound according to any one of claims 1 to 10 for combating a viral infection.

15. A commercial package containing, as active pharma-ceutical ingredient, a compound according to any one of claims 1 to 10 or a physiologically acceptable salt thereof, together with instructions for its use for combating a viral infection.

16. A compound of the general formula (IX) wherein R3 is as defined in claim 1, R represents C1-C4 alkyl and R10 represents hydrogen or C1-C4 alkyl.

17. A method of combating a disease in a patient in need thereof which comprises administering to such patient an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17, wherein such disease is a virus infection.

19. The method according to claim 17, wherein such disease is hepatitis.