CA2093108A1 - 9-fluoro-7-oxo-7h-pyrido[1,2,3-de][1,4]benzoxazine-6- carboxylic acids and esters - Google Patents

Abstract

New 9-fluoro-7-oxo-7H-pyrido(1,2,3-de][1,4]benzoxazine-6-carboxylic acids and esters Abstract The present invention relates to new 9-fluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and esters, process for their preparation and their use as medicaments, in particular as antiviral medicaments.

Le A28 861

Description

20931 ~8 New 9-fllloro-7-o~o-7H=pvrido r 1,2 3-del r 1.4lbenzoxazine 6~carboxylic acids and esters The present invention relates to new 9-fluoro-7-oxo-7H-pyr.ido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and esters, process for their preparation and -their use as medicaments, in particular as antiviral medicaments.

1,8-bridged 4-quinolonecarboxylic acids having an anti-bacterial action are already known ~rom EP-A-253,235.

The present invention relates to new g-fluoro-7-oxo-7H-pyrido~l,2,3-de~[1,4]benzoxazine-6-carboxylic acids and esters o~ the general formula (I) o , CO2RI

N ~ (I), ~R2 in which R3 R1 represents hydrogen or straight-chain or branched alkyl having up ~o ~ carbon atoms, R2 represents hydrogen, methyl, ormyl, benzyl, p-Cl-benzyl, carboxyl or the -CONH2 group, or represents straight-chain or branched alkenyl or Le A 28 861 - 1 -20931~8 alkoxycarbonyl each having up -to 6 carbon a-torns, or represents straigh-t-chain or branched a].kyl having up to 6 carbon atomsl which is substikuted by carboxyl, ~enæyloxy, imidazolyl or by s-traight-chain or branched alkoxycarbony:L having up to 4 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atom~

R3 represents hydrogen, represents carboxyl or represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms, or represents straight-chain or branched alkyl having up to lO carbon atoms, which is substituted by carboxyl, phenoxy or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or represents biphenyl or a radical o~ the formula ~ ~RsR8 ~(CH~)n in which A denotes a nitrogen atom or the -CH group, R5 and R5 are identical or different and denote Le A 28 861 - 2 -~i 2~31~8 hydrogen or straight-c~hain or branched alkyl or ~cyl eaoh having up to 6 carbon atoms, R7 deno-tes hydrogen, halogen, hydroxyl or straight-chain or branched alkoxy or alkyl each 5having up to 6 carbon atoms, n denotes a number 1,2 or 3, and B denotes straight-chain or branched alkyl having up to 6 carbon atom~ or hydrogen, 0 R4 repre~ents imidazolyl or 1,4-diazacycloheptanyl bonded via N, or a radical o~ the formula (H2C)p ~ ~ ` ~J
Ra R.
or ~
/--\ HN N--R~o--N :-- y Rl2 Le A 28 861 - 3 -, .. . .
~. . . .
, : . : - ~

'. : . : '" ' ,, ':
.

2093~

in which o denotes a number 2 or 3, p denotes a number 1 or 2, D denotes the -C~2-group or an oxygen atom, RB and R9 are identical or different and denote hydrogen, methyl or et:hyl, Rl denotes cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched perfluoroalkyl hav.ing up to 6 carbon atoms, or denotes phenyl, pyridyl or pyrimidyl, each o~
which is optionally substituted by halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R11 denotes hydrogen or methyl, R12 denote straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by hydroxyl, benzyloxy, phenoxy or morpholino, and in the case in which R3 does not denote hydrogen if R2 represents hydrogen or methyl, ~0 R4 additionally represents morpholino or a radical of the formula Le A 28 861 - 4 -,: ~.. . ,, . . ; - : ~

. . " ,., ", "

. , . ,,, , . ~ , ~ 3 1 ~ 8 R"--N N--in which Rl3, R14 and Rl5 are ide~tical or different and denote hydrogen, hydroxyethyl, methyl or ethyl and their hydrates and ~alts, if appropriate in an isomeric form.

Physiologically acceptable salts of the compounds according to the invention can be salts of the sukstances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salt~, for example, are those with hydrochloric acid, hydro-bromic acid, sulphuric acid, phosphoric acid, methane-sulphonic acid, ethanesulphonic acid, toluenesu1phonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, pxopionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benæoic acid.

Physiologically acceptable salts can also be alkali metal, alkaline earth metal, silver and guanidinium salts of the compounds according to the invention.

Preferred compounds of the general formula (I) are those Le A 28 86 - 5 -, .
:. . .

.
.

. : . . .

~3~

in which Rl represents hydrogen, or represents straight-chain or branched alkyl having up to 6 carbon atoms, R2 represents hydrogen, formy:l, methyl, benzyl, p-C1-benzyl, carboxyl or the -CON~2 group, or represents straight-chain or branched alkenyl or alkoxycarbonyl each having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which i~ substituted by carboxyl, benzyloxy, imidazolyl, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl, or represent~ cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R3 represents hydrogen~
represents carboxyl, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkoxycarbonyl having up to 6 carbon atom~, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is substituted by carboxyl, phenoxy or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or represents biphenyl or a radical of the formula Le A 28 861 - 6 -~ , ; , , , : :
, ., . ~ .

2~3~

~ NFlsFI~ C~-(2)rl in which A denotes a nitrogen atom or the -CH group, R5 and R6 are identical or different and denote hydrogen or straight-chain or br a n c h e d a 1 k y 1 o r acyl each having up to 4 carbon atomst R7 denotes hydrogen, fluorine, chlorine, hydroxyl or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, n denotes a number 1 or 2, and B denotes straight-chain or branched alkyl having up to 4 carbon atoms or hydrogen, R4 represents imidazolyl or 1,4-diazacycloheptanyl bonded via N, or represents a radical of the formula Le A 28 861 - 7 -~ :' . .

. .

2~93~

N~J ~ N/

Rlo--N N-- or H: N--in which o denotes ~ number 2 or 3, p denotes a number 1 or 2, D denotes the -C~2 group or an oxygen atom, R8 and R9 are identical or different and denote hydrogen, methyl or ethyl, Rl denotes cyclopropyl, cyclopentyl or cyclohexyl, or denotes straight~chain or branched perflu-oroalkyl having up to 4 carbon atoms, or denotes phenyl, pyridyl or pyrimidyl, each of which is optionally substituted by fluorine, chlorins or straight-chain or branched alkyl or alkoxy each having up to Le A 28 861 - 8 -.

2~31~8 4 carbon atoms, Rll denotes hydrogen or methyl, Rl2 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is substituted hy hydroxyl, benzyloxy, phenoxy or morpholino, and in the case in which R3 does not denote hydroyen i~ R2 represents hydrogen or methyl, R'' additionally represents morpholino or a radical of the formula R~" N ~--in which R13, Rl4 and R15 are identical or different and denote hydrogen, hydroxyethyl, methyl or ethyl and their hydrates and salts, if appropriate in an isomeric form.

Particularly preferred compounds of the general formula Le A 28 861 - 9 -,, :
.

20~3~

( I ) are -those in which Rl represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, S R2 represents hydrogen, formyl, methyl, benzyl, p-Cl-benzyl, carboxyl or the -CONH2 group, represents vinyl, allyl, methoxycarbonyl or ethoxy-carbonyl, represents straight-chain or branched alkyl having up to 3 carbon atoms, which is sub~tituted by carboxyl, benzyloxy, imidazolyl, methoxycarbonyl or ethoxycarbonyl, or represents cyclopropyl or cyclopentyl, R3 represents hydrogen, or represents carboxyl, or represents cyclopxopyl or cyclopentyl, or represents straight-chain or branched alkoxycarbonyl having up to 4 carbon atom~, or represents straight--chain or branched alkyl ha~ing up to 6 carbon atoms, which iR substituted by carboxyl, phenoxy or by straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or represents a radical of the formula Le A 28 861 - 10 --- ..
" ~ , :.
, . :

2093t ~8 ~ NRsFIo in which A denotes a nitrogen atom or the -CH group, R5 and R6 are identical or diffe.rent and denote hydrogen, methyl, ethyl or acetyl, R7 denotes hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy, R4 represents imidazolyl or 1,4 diazacycloheptanyl bonded via N, or represents a radical o~ the formula ~N ~ ~ ~N~

~ or ~ \
R~o--N N- HN N--~-2 Le A 28 861 - 11 -,: : . . ,~ .

' ` ';, . . . . .

2~931~
in whlch o denotes the number 2, p denotes a number 1 or 2, D denotes the -CHz group or an oxygen atom, R3 and R9 are identical or different and denote hydrogen, methyl or ethyl, R10 denotes cyclopropyl or straight-chain or branched perfluoroalkyl having up to 3 carbon atoms or phenyl, pyridyl or pyrimidyl, each of which is optionally subst.ituted by fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, Rll denotes hydrogen or methyl, Rl2 denotes stxaight~chain or branched alkyl having up to 3 carbo~ atoms, which is substituted by hydroxyl, benzyloxy, phenoxy or morpholine, and in the case in which R3 does not denote hydrogen if R2 represents hydrogen or methyl, R4 additionally represents morpholino or a radical of the formula Le A 28 861 - 12 -.: . ,, . : :

: , . : , , 2093~

in which Rl3, R1~ and Rl5 are identical or different and denotehydrogen, hydroxyethyl, methyl or ethyl and their hydrates and salts, i~ appropriate in an isomeric form.

Processes for the preparation of the compounds of the general formula (I) according to the invention have additionally been found, characterised in that [A] compounds o the general formula (II) O
F ~ C02RI
T ~ N (II), ~R2 in which R2 and R3 have the abovementioned meaning, Le A 28 861 - 13 -~ . . . . . .

, .: :

2~9~08 Rl has the abovementioned meaning, but preferably represents hydrogen, and T represents halogen, preferably fluori.ne, are reacted with compounds of the general formula (III) R4-H (III), in which R4 has the aboveme~tioned meaning, in i.nert solvents, in the presence of a base, under a protective gas atmospherer or aldehydes of the general formula (IV) F ~ CO2RI (IV), in which Le A 28 861 - 14 -, -, , : . ~ . . .

. .

! .: !~

2~93~

R1 has the ~bovementloned meaning, are first reac-ted with compounds of the general formula (III) or (IIIa), preferably wit:h (IIIa) R4-H (III), W-H (IIIa), in which R4 has the abovementioned meaning, W has the abovementioned meaning of R4, one of the cyclic amine functions being protected by a protec-t.ive group, preferably tert-butoxycarbonyl or ethoxycarbonyl, in inert solverlts, in the presence of a base, with simultaneous cyclisation, and the protective group i8 removed according to a customary method or in the case in which R2, as defined above, represents substituted alkyl, [B] compounds of the general forrnula (V~

F ~ CO2RI (V), F ~ CH2 I

o Le A 28 861 ~ 15 -~. i 2~3.~g in which Rl has the abovementioned meanir~g, are reacted with compounds of the general formula (VI) Rl7-~ (VI), in which Rl7 represents the substituted alkyl mentioned under R2, which is shortened by a carbon atom, in one of the abovementioned solvents, if appropriate in the presence of a base, with simultaneous cyclisation, and in a last step the substituent R4 is introduced as described above, and in the case in which R3~H, the product is derivatised, and then, depending on the desired meaning of Rl, either an esterification or a hydrolysis is carried out by a customary method.

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

Le A 28 861 - 16 -[~] ~93~3~

o ~ HN N ~3 DMSO

F ~, CO2H

¢~ J ~CH3 [B]

F ~CO2C2Hs N

F ~ H
~C~12 ~ , oo F ~ ~ N
0~ CH2--N~=¦

F `r5~, C02H
F ~f N N --~ C~2--N~ -O

O N--~X~/ .
0~ CH2--N~=¦

Le A 28 861 - 17 -- : , . :: :

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

2~9~

Pro-tective groups in the contex-t of the invention are the groups known from pepticle chemistry such a~, for example, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, hutoxycarbonyl or isobutoxycarbonyl. Methoxy- and ethoxycarbonyl are preferred.

Suitable solvents for all the process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol monomethyl ether or glycol dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or mineral oil fraction~, or halogenohydrocar~ons such as methylene chloride, chloroform, carbon tetrachloride, or diimethyl sulphoxide, N,N-dimethylformamide, hexamethylphosphoramide, sulpholane, 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 includie, for example, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, pyridine, triethylamine, diisopropylethyl-amine or N-methylpiperidine, or bicyclic amidines such as 1,5-diazabicyclo[3.4.0]-non-5-ene (DBN), 1,5-diaza-bicyclo[3.4.0]undec-5 ene (DBU) or DABC0. Triethylamine, Le A 28 861 - 18 -. , .
` ~ ; !
,, ' . ' ` ~, ' 2~9~

diisopropylethylamine, DABCO and potassium carbonate are pre~erred.

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

The process is in general carried out in a kemperature 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 customary organic solvent. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide~ Alcohols such as methanol t ethanol, propanol or isopropanol are particularly pre~erably used.

The hydrolysis is carried out using acids such as, for example, acetic acid, hydrochloric acid, hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric acid.

Le A 28 861 - 19 -' ' : ' ` ~ ' ~ :'; : , .' ' '.' ;

2~931~g The hydrolysis i~ in general carried ou-t in a temperature range from 0c to -~130C, preferably from +20c to -~llO~C .

In general, the hydrolysis is carried out at normal pressure. However, it is also possible to work at reduced pressure or at elevated pressure (Eor example from 0.5 to 5 bar).

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

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

The esterification of the acids is carried out according to a customary method, by reacting the acids with the corresponding alcohols, i~ appropriate in one of 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 example, sulphuric acid, or inorganic acid chlorides, such as, for example, thionyl chloride.

Le A 28 861 - 20 -.

2~93~

In yeneral, 0.01 to 1 mol, preferably 0.05 to 0.5 mol, of catalyst are employed relative to 1 mol of reactan-t.

The aminoprotective groups are removed by methods known from the literature [cf. Houben-Weyl, "Methoden der organischen Chemie" (~ethods of Organic Chemistry), Synthese von Peptiden (Peptide synthesis) II, 4th Edition, Vol. 15/1, 15/2, Georg Thieme Verlag Stuttgart], preFerably using -trifluoroaceti.c acid in anisole.

The compounds of the general formula (II) are known as actual substance representatives in some cases [cf. in this connection EP 253,235 Al] or are new and can be prepaxed, for example, by reacting compounds of the general formula (VII) o F ~ C2~l6 (YII) F H
in which Rl6 represents a Cl-Cb-alkyl radical, with an ~-halogenocarbonyl compound of the general formula (VIII) R3 C~ CH~--R2 ¦ (VIII) Le A 28 861 - 21 -:
` :

~93~

in which R2 and R3 have -the abovementioned meaning and X represents halogen, preferably bromine, in one of the abovementioned solvents and bases, preferably dimethyl~ormamide ancl potassium carbonate, or by reactlng compounds o~ the general formula (IX) F ~ C ~ CO~Rj6 (IX) F Rl7 in which R16 has the abovementioned meaning and Le A 28 861 - 22 -.

21~3~8 R17 represents Cl-C"-alkoxy, with compounds of the general formula (X) 1R (X) in which ll 2 CHR,8 R2 has the abovementioned meaning and R1~ represents hydrogen or C1-C4-alkyl, in one of the abovementioned solvents, preferably ethanol, and if appropriate in the presence of an amine base also mentioned there, and then converting with dimethoxyethane and sodium hydride into the compounds of the general formula (XI) O
F ~ C2RI6 (XI~

F

CHRl8 in which Le A 28 861 - 23 -.

~09~108 R2, Rl6 and Rl8 have the abovementioned meanings, then cle~ving the double bond, by ozonolysis, to give the carbonyl function according to customary methods, and in a last step carrying out the cyclisation as described above, and in the case of the other substi-tuents mentioned above under R2 and R3, varying these according to customary methods.

The reaction with the compounds of the general formula (X) is carried out in a temperature range from -20C to +30C, preferably from 0C to 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 (IX) and (X) are known in some cases or can bé prepared according to customary methods.

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

The compounds of the general formulae (VII) and (VIII) are known per se [cf. in this connection EP-A~253,23S] or can be prepared according to a customary method.

Le A 28 861 - 24 -. .
.

.

2093~8 The compounds of -the general ~orm-llae (III) and (IIIa) are also known, in some cases commercially available or c~n be prepared according to customary methods.

The aldehydes of the general formula (IV) are known per se or can be prepared according to published methods [cf.
EP-A-253,235].

The compounds of the general formula (V) are new and can be prepared by converting compounds o~ the general formula (XII) ~ ~ CO CO2RI
F ~ F ~ (XII), in which Rl has the abovementioned meaning, by a 2-step reaction with 3-amino-4-benzyloxy-1-butene of the formula (XIII~

~ CH2-O - H2C- ~ (XIII) Le A 28 861 - 25 -.

.~

20931~

in one of the abovementioned solvents, preferably ethanol, and then with sodium hydride in anhydrous dimethoxyethane into the compound of the formula (XIV) o F ~ ~ ~ (XIV), ~H2 in which RL has the abovementioned meaning, and then carrying out an ozonolysis.

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

The compound of the formula (XIV) is new and can be prepared by the abovementioned process.

The compounds of the formulae (XII) and (XIII) are known.

The compounds of the formula tI) according to the inven-tion show an additional unforeseeable, useful spectrum of pharmacological action. Surprisingly, they are suitable Le A 28 861 - 26 -.

~ ' , ' ~ ' ' : , "' ~ ' .

2093~

for the treatment of virus-induced diseases.

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

Detection of activlty was carried out in hepatoma cells (HEP G 2.2.15) transfected with hepatitis s virus DNA.
The results of the examples listed below were determined for the HBV test system described in the following literature reference [Sells, M.A.; Chen. M.L., Acs, G., Proc. Natl. Acad. Sci. US~ ppO 1005 - 1009, Vol. 84 (1987)]:

Transfected hepatoma ce~ls (HEP G2.2.15) were incubated with various concentrations 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-natant as well as a reduction in the H~Ag level could be ~hown. It was furthermore found that the compounds according to the invention lead to a reduction o~ the replicative intermediates of hepatitis viruses. The content of HBV-DNA was determined in the supernatant of the cell cultures after PEG precipitation. This was carried out using a nonradioactively-labelled HBV genomic DNA sample [Pauly, P., 1982, Ph.D. Thesis, University of Gottingen, F.R.G.; Kochel et al., 1990, EMBL, Accession No. X 51790]. At the same time, the effect on HB~Ag formation was determined by means of a commercially available ELISA test. The IC50 value~ indicated relate to Le A 28 861 - 27 -.. ~ ... .

. .
' '1 , '~, " ' ; ,: ~ :
;:

~07~3~ ~3 the substra-te concentra-t.ions which cause a 50% inhi~ition of the HBV-DNA concentration in the s~lpernatant under the abovementioned test conditions.

Table A
Ex. No. IC50~M) SI
I 0.5 ~ 100 VIII 0.5 > 100 9 0.1 ~ 20 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 incorporati.on of radioactively labelled thymidine into the cellular DNA.

The action of the compounds according to the invention on other cells was tested by incubation of HEL and MEF
cells. No effect on the vitality of these cell5 was seen up to a concentration of 250 ~M.

As areas o~ indication for the compounds which can be used according to the invention, there can be mentioned, 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 Le A 28 861 - 28 -.. .
:.
''; ' ,, ~

20~3~
231~9-74 zos-ter viruses and IIIV.
The treatment of chronic hepatitis B virus infections and the treatment of acute hepatitis B virus infection is particularly preferred.
The present invention includes pharmaceutical prepara-tions which, besides non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (r) or (II) or which consists of one or more active compounds of the formula (I) or (II), and processes for the production of these preparations.
The active compounds of the formulae (I) and (II) should be present in the abovemen-tioned pharmaceutical prepara-tions 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 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.
The invention also extends to a commercial package containing a compound of the invention, together with instructions for its use for combating viruses.
In general, it has proven advantageous both in human and in veterinary medicine to administer the active compound .. ...
- . ~ .
:. : . -:

~:,, ::

, `' ' . , ~93~8 or compounds according to the invention in total amounts from a~out O.S to about 500 mg/kg, preferahly 1 to lOO
mg/kg, of body weight eve~y 24 ho~lr~, if appropriate in the form o~ several individual doses, to achieve the desired results. An individual dose contains the active compound or compounds preferably in amounts from about 1 to about 80 mglkg, 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 treated, the nature and the severity of the disease, the method of preparation and o-f administration of the medicament as well as the period or interval within which administration takes place.

Startinq Compounds Example I

Ethyl 9,10-difluoro-2-ethoxycarbonyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate o F ~COzC~H5 0~
co2C2HS

Le A 28 861 - 30 -.
. .
, ~9~11D8 Method [Al The compound i~ prepared either by the process published in EP-A-253,235 or via the intermediates a) and b) mentioned in the following.

Method [B]

a) Ethyl 6,7,8-trifluoro-1 (2~ethoxycarbonyl-2-propen-yl)-4-oxo-1,4-dihydroquinollne-3-carboxylate O O
F

EtO O
7 g (25.9 n~ol) of ethyl 6~7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate and 4.3 g (31.3 mmol~ of KzCO3 in 60 ml of DMF are heated at 80C for 30 minutes under argon. The heating bath is rPmoved and 5 ~
(25.9 mmol) of ethyl 2-(bromomethyl)-acrylate in 20 ml of DMF are added. The mixture is then stirred at ~0C for 4 h. After cooling, the solid is fil-tered off and the solution is concentrated. The residue is rendered acidic using lN HCl, the mixture is extractPd several times with CH~C12, and the extracts are dried over MgSO~ and concentrated. This Le A 28 861 - 31 -, . . :..... :

.
: ,: , -, ~ , :
` ~ : ~ ' : ': , :
;. :' ~0~311~

crude product fs combined with the solid ~iltered of-f and purifled by chromatography orl ~ilica gel (CH2Cl2:MeOH:NH3~aq~ = 100:5:2). After recrystallisa-tion from ethyl acetate, 5.54 g (56 % of theory) of the title compound are obt:ained.
Melting point: 188C.

b) Ethyl 6,7,8-trifluoro-1-(2-ethoxycarbonyl-2-oxo-ethyl)-4-oxo-1,4-dihydroqllinoline-3-carboxyl~te O O

F ~N
F J
0~
EtO ~ O

1 q (2.61 mmol) of the compound ~rom a) are dis-solved in 150 ml of a mixture (1:1) of C~2Cl2 and MeOH and the solution is cooled to -78C~ Ozone i5 then introduced untilthe solution is coloured blue. Excess ozone is driven off by means of oxygen gas. The mixture is treated with S ml of dimethyl sulphide, allowed to warm to room temperature and stirred until peroxides .are no longer detectahle. It is concentrated to dryness in vacuo, the residue is recrystallised from ethyl acetate and 0.785 g (78%
of theory~ of the title compound are obtained.
Melting point: 181C.

Le A 28 861 - 32 -: , : - ;., : :
.

, : , :
, .

2~31~

0.748 g (1.94 mmol) of the compound from b) and 1.54 g (11.1 ~ol) of K2CO3 ar~ treated lnder argon wlth 30 ml of DMF . After 1 h, 70 ml of water are added and the suspension is stirred for 30 minutes.
S The solid is Eiltered of~ with suction, washed twice with water and twice with ether and dried in high vacuum. 0.62 g (88% of theory) o~ the title compound is obtained (Example I).
Melting point: 245C.

Example II

Ethyl 6,7,8-trifluoro-4-oxo-1-l4-pherlyl-~ut-1-en-3-yl)-1,4-dihydroquinoline-3-carboxylate o O

~t A solution of 2.10 g (14.3 mmol) of 3-amino-4-phPnyl-l-butene is added dropwise at 0C to a solution of 4.57 g (14.3 mmol) of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benæoyl)acrylate in 20 ml of ethanol. The mixture is stirred at room temperature for 2 h and then concentrated in vacuo and the residue is dried in high vacuum. The residue is dissolved in 20 ml of anhydrou~ dimethoxy-ethanç and the solution is added dropwise at 0C to a ,~ , 20931~
susper1sior1 of fiO2 Ing (~0~ slr(~rlq~ 1oil1 ~0 Illlnol ) or so(liulll hydri(lc~ ir 50 ml of an~1ydrous dimethoxyethal-le. The mi~ture i5 stirred at 0C ~or l h, treated with 4.5 ml of ylacial acetic acid and concentrated in vacuo. The residue is partitioned between methylene chloride and water. The organic phase is dried using sodium sulphate, concen-trated and chromatographed on silica gel using tolu-ene/ethyl acetate.
Yield: 3.63 g (63%).

Example III
Ethyl l~ benzyloxy-l-butene-3-yl)-6,7,8-trifluoro~4-quinolone-3-carboxylate o F ~ CO2C2H5 A solution of l4.5 g (82 mmol) of 3-amino-4-benzyloxy-l-butene is added at OC to a solution of 26.25 g (82 mmol) of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate in 105 ml of ethanol. The mixture is stirred at room temperature for ~ h, then concentrated in vacuo and dried in a high vacuum. The residue i5 dissolved in 200 ml of anhydrous dimethoxyethane and added dropwise at 0C to a suspension of 2.93 g (97 mmol) of sodium hydride (80%
strength in oil) in 235 ml of anhydrous dimethoxyethane.
The mixture is stirred at 0C ~or l h, treated with 22 ml of glacial acetic acid and concentrated in vacuo. The residue is partitioned between methylene chloride and water. The organic phase is dried with sodium sulphate, concentrated and chromatographed on silica gel using toluene/ethyl acetate.
Yield: lS g (42%) Melting point: 61-63C.

Le A 28 861 - 34 -.

:. : :

Example IV 2093~08 Ethyl 3-benzyl-9,10-dL~lLtoro-7-oxo-7ll-pyrido[l,2~3 de][],4~benzoxazine-6-carboxylate o o '~1 Ozone i5 passed at -78C into a solution of 3.6 g (9.0 mmol) of the compound from Example II in 80 ml of methanol and 20 ml of methylene chloride until the onset of a blue co].oration. Excess ozone is driven off with nitrogen. 7.1 ml of dimethyl sulphide are added at -78C
and the mixture is allowed to come to room temperature.
It is conaentrated in vacuo, the residue i8 taken up in 50 ml of anhydrous DMF and the mixture i8 treated with 1~25 y (9.0 mmol) of potassium carhonate. ~fter 1 h ~t room temperature 5 ml of glacial acetic acid are added and then 500 ml of water, and the precipitate which deposits is filtered off with suction and dried in high vacuum.
Yield: 3-.3 g (95%); melting point: >260C~

Example V

Ethyl 3-~enzyloxymethyl-9,10-difluoro-7-oxo-7H-pyrido[1,2,3-de]rl,4]benzoxazine-6-carboxylate Le A 28 861 - 35 -. ~ .

.

` 20g31~

o o F ~E~

The title compound was prepared by use of the compound from Example III in analogy to the procedure of Example IV.
Yield: 45%.

Example VI

3-Benzyl-9,10-difluoro-7-oxo-7H-pyridoL1,2,3-de]tl,4~ben-~oxazine-6-carboxylic acid o o F` ~

3.3 g (8.6 mmol) of the compound from Examp~le IV, 47 ml of glacial acetic acid, 41 ml of water and 1 ml of concentrated sulphuric acid are heated together under reflux for 4 h. After cooling, the mixture i9 treated with water, and the precipitate which deposits is filtered off with ~uction and dried in high vacuum.
Yield 2.5 g (81%); melting point:>260C.

Le A 28 861 - 36 -: ' ,. :

., , :
' 209~8 Example VII

3-Benzyloxymethyl-9,10-dLfluoro-7-oxo~-7H-pyrido[1,2,3-d~][l,4]benzoxazine-6-carboxyllc acid o o ~o~

The title compound wa~ prepared by reaction of tho compound from Example V in analogy to the procedure of Example VI.
Yield: 77%; melting point: 168-170C.

Example VIII

Ethyl 2-(1,1-dimethyl-4-phenoxy-butyl)-9,10-difluoro-7-oxo 7H-pyrido[1,2,3-de][1,4]-benzoxazine-6~carboxylate F ~ CO2C2Hs 0~

H3C >L (CH2)~ 0 ~3 Le A 28 861 - 37 -~......... : , . : :.:. . . .

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

2~)93~

2 g (7.38 mmolj of ethyl 6,7,8-trifluoro-4-hydroxy-3--quinolonecarboxylate are ~u-qpended in 20 ml of abs. DME
under argon. 2.55 g (18.44 mmol~ of K2CO3 and 3.76 g (14.75 mmol) o~ 1-chloro-3,3-dimekhyl-6-phenoxy-2-S hexanone in 20 ml of abs. DMF are added and -the mixture is heated at 80C for 6 h. A further 1.8 g (7.38 mmol) of chloroketone are added and the mixture i5 heated at 80C for a further 14 h. After cooling, the mixture is added to 400 ml of water and acidified with lN HC1. It is extracted several times with CH2Cl2, and the organic phase is washed with water, dried over Na2SO4 and con-centrated. The residue is dissolved ln a little CH2Cl2:MeOH = 100:3 and purified on a silica gel column (same eluent).
Yield: 1.15 g (34 % of theory); melting point: 96C.

Example IX

2-(1,1-Dimethyl-4-phenoxybutyl)-9,10-difluoro-7-oxo-7H-pyridotl,2,3-de][1,4]benzoxazine-6-carboxylic acid o o F ~ OH

' O~ ~

CH3 - _H3 ~
1.1 g (2.34 mmol) of the compound from Example VIII are suspended in a mixture of l.S ml of H2SO4, 12 ml of H2O

Le A 28 861 - 38 -, .

.: ,, 209~ 8 and 18 ml of ace~ic acid and the mixt:~lre is heat~d at 120C for 4 h. It is allowed to cool, and the precipitate is filtered off with suction, washed with water and dried in high vacuum. 0.89 g (86~ of theory) of the title compound ar~ obtained.
Melting point: 212C.

Example X

9,10-Difluoro~2-(2-am.i.no-3-chloro-5-pyridyl)~7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6 carboxylic acid O n o~,~

CIJ~N

1.55 g (18.44 mmol) of K2CO3 are added under argon to 2 g (7.38 mmol) of ethyl 6,7,8~trifluoro-4-hydroxy-3-quinolonecarboxylate in 20 ml of abs. DMF. A solution of 3.7 g (14.75 mmol) of 1-ibromo-2-(2-amino-3-chloro-5-pyridyl)~2-ethanone in 20 ml of abs. DMF is added to this mixture and it is heated ~t 90C for 8 h~ The solvent i5 removed in vacuo, and the solid is stirred with water and filtered o~f with suction. 'rhe residue is taken up with acetone and the solution is concentrated until crystals form. 'rhe crude product is filtered off with suction and Le A 28 861 - 39 -'' .'. ' ' ' ' `', ~, ' ' .

2~31 ~

purified on ~ilic~ yel (eluent CH~Cl2:MeOH = 100:5).2.58 g (83~ of theory) of the title compound are obtain~d.
Mel-ting pOillt: 200C (decomposi.tion~.

Example XI

9,10 Difluoro-2-(2-amino~3-chloro-5-pyridyl)-7-oxo 7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid F ~ ~ OH
0~
~ ' '. ' CI~N

12 ml of acetic acid, 8 ml of water and 3 ml of ~2SO4 are added to 2.5 g (5.96 mmol) of the compound from Ex~nple X. The su~pension is heated at 120C for 2 h.
After cooling, it is diluted with water, and the solid is filtered off with suction and washed with water until neutral. The product is dried in high vacuum. 702 mg (30~ of theory) of the title compound are obtained.
Melting point: >230C.

Le A 28 861 - 40 -.

- ' ' . ' , , ':
' E m~e_XII 2093108 Ethyl 3~ imidazolylmethyl)-9,lO-di~luc)ro-7-oxo-7H-pyrido[l,2,3-de][l,~]benzoxazine 6-carboxy].ate O O

,~J~OEt 1==1 O ~ N ~ N

1.35 g (19.89 mmol) of imidazo:Le are added to 3.23 g (9.94 mmol) of the compound from ~xample XIII and 1.37 (9.94 mmol) of K2CO3 in 30 ml of DMF and the mixture is stirred at room temperature for 2.5 h. It i~ treated with water, and the product is iltered off with suction, washed with water and petroleum ether and dried in high vacuum. 3.~1 g (92% o theory) of the title compound are obtained.

Le A 28 861 - 41 -: : ~ . , ...... ' , :: .

,: . ,' . i , ~
. . ~ . , , ` ' . ;", ' ' , ~ , ,.: , ' ~'' , ' ,' ''. ~ . ,, ' , ~093~0~

Example XIII

Ethyl 6,7,8-trifluoro-1-(2-oxo-1-methyl~ne~ethyl)-4-quinolone-3~carboxylate o F ~,C2C2H5 ~CH2 Ozone i~ introduced at -78C into a ~olution of 30.85 g (~1.5 mmol) of the compound from Example III in 640 ml of methanol and 160 ml of methylene chloride until it is coloured blue. Excess ozone is driven of~ with nitrogen at -7~C. 57 ml of dimethyl sulphide are added, and the mixture is allowed to come to room temperature and is stirred overnight at this temperature. After concentra-tion in vacuo, the residue is chromatographed on silica gel using methylene chloride/methanol.
Yield: 22.1 g (97%) Melting point: 185-187Co Le A 28 861 - 42 -2093~

Example XIV

2 ethoxycarbonyl-3-(9,10-difluoro-6-ethoxycarbonyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-3-yl)propionic acid F ~ CO2C2H5 F ~ N ~ CO2C2Hs 1.75 g (10.9 mmol) of diethyl malonate are added to a suspension of 329 mg (10.9 mmol) of sodium hydride (80~
strength in oil) in 55 ml of anhydrous DMF. As soon as a clear solution is fo~ed, 3.55 g (10.9 mmol) of the compound from Example XIII are added and the mixture is stirred at room temperature for 4 h.5,5 ml of ylacial acetic acid and 500 ml of water are added, and the resulting precipitate is stirred overnight~ filtered off with suction and washed with w~ter. After chromatography on silica gel using methylene chloride/methanol, 3.44 g (68%) of the title compound are obtained.

Example XV

3-(6-Carboxy-9,10-difluoro 7-oxo-7H-pyrido[1,2,3-de][l,4]benzoxazin-3-yl)-propionic acid Le A 28 861 - 43 -. , ;
,: .

: ,, ., ,: , ~

.
, ,. . , - :
, : "

2093~

~ CO2H
400 mg (0.86 mmol) of the compouIId ~rom Example XIV are heated under reflux for 4 h in 12 ml of glacial acetic acid, 10 ml of water and 1 ml of sulphuric acid. After cooling, the mixture is treated wlth 100 ml of water, and the resulting precipitate i~ filtered off with suction, washed with water and dried in high vacuum.
Yield: 271 mg ~94%) Melting point: 252 254C.

Example XVI

Ethyl 1~ cyclopropyl-2-propenyl)-6~7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate o ; ~Co2c2Hs ,~7 The title compound is prepared from l-amino-1-cyclo-propyl-2-propene in analogy to the procedure of Example III.

Le A 28 861 - 44 -,, .,.~ , .

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

20931~

Example XVI:[

3-Cyclopropyl-9,10-difluoro-7-oxo-7H-pyrido[1,2,3- -de][l,4]benzoxazine 6-carboxylate X~ ~ J
o~7 The compound i.s prepared from the compound of Example XVI
in analogy to the procedure of Example IV.

Example XVIII

3-Cyclopropyl-9,10-difluoro-7-oxo-pyrido[1,2,3 de][1~4]benzoxazine-6-carboxylic acid F ~ CO2H
0~

The title compound is prepared from the compound of Example XVII in analogy to the procedure of Example VI.

Le A 28 861 - 45 -.. . . ~ "

. , - . :

. .

., ~0~3~0~

Example XIX

Bromomethyl cyclopropyl ketone Br 10.5 g (0.125 mol) of cyclopropyl methyl ketone are dissolved in 100 ml of methanol and cooled to 0C.
19.95 g (0.125 mol) of brom.ine are added in one portion and the mixture is stirred further at +10C until the solution has been completely decolorised~ It is warmed to room temperature, stirred for a further 30 min. and 40 ml o~ H20 are added. 'rhe mixture is again stirred for 15 min and added to 120 ml of H20. It is extracted four times with 100 ml of ether each ~i.me. ~he organic phases are combined and washed twice with 10% strength K2CO3 solution. They are then washed with satd. NaCl solution, dried over MgS04 and concentrated in vacuo.

The brownish crude product is distilled and 12.2 g (60%
of theory) of the title compound are obtained, B.p.12~ ~ 80-90C.

Le A 28 861 - 46 -. , :, . . :~ ~ ;

:

.

20931~

_xc~1l3 XX

Ethyl 2~cyclopropyl-9,10-diEluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate O O
F ~ ~ ` OEt 0~

5 g (18.4 mmol) of ethyl 6,7,8-trifluoro-4-hydroxy-3-~uinoline~carboxylate are suspended under argon in 100 ml of ab~. DMF. 6.37 g (46.1 mmol) of K2CO3 and 6.0 g (36.9 mmol) o~ bromomethyl cyclopropyl ketone are added and the mixture is heated at 90C for 12 h. The DMF is distilled off in racuo. The residue is taken up with CH2C12 and the solution is washed three times using 150 ml of lN HC1 each time. The organic phase i~. washed with H2O
until neutral, dried over MgSO~ and concentrated. The crude product is purified by column chromatography on silica gel (elue~t C~2Cl~MeOH:NH3(~)= 100:2:1. The product is taken up with toluene and the ~olution i9 filtered.
After concentrating again, it is recrystallised rom ethyl acetate ~nd 2.1 g (34% of theory) of the title compound are obtained.
Melting point 212C.

Le A 28 861 - 47 -.

. . .

20931~

Exa~Le XXI

2-Cyclopropyl-9-lO-difluoro--7-oxo 7EI-pyrido[1,2,3-de][1,4~benzoxazine-6-carboxylic acid O O
F ~/1 ` J\OH

F~N
0~

200 mg (0.6 mmol) of the compound from Example XX are S treated with 72 mg (3 mmol) of LioH and a mixture of 3 ml of THF and 1 ml of H2O and stirred at 40C for 90 min. The mixture iæ adjusted to p~ 1 with HCl and cooled to 0C, and the precipitate is filtered off with suctionO The residue is washed with H2O until neutral and dried in vacuo. 130 mg (71% of theory) of the title compound are obtained.
Melting point:>230C.

Le A 28 861 - 48 -. ~ , . .

20931l~
Exanll)le XXI I

3~ Imidazolylmethyl)-9,10~difluoro-7-oxo-7H-pyrido[l,2,3-de~[1,4]benzoxazine-6-carboxylicacidhydro-chloride O O

W )IJ~ x HCI

O~,N~,N

340 ml of 2N EICl are added to 3.41 g (9.13 mmol~ of the compound from Example XII and the ~ixture is heated under reflux for 4 h. It i9 filtered hot, the solution is allowed to cool, and the crystals formed are filtered off with suction and dried in high vacuum.
2.92 g (84% of theory~ of the title compound are thus obtained.

Le A ?8 861 - 49 -. . . . . . .
. : . : , , , ~ -:, :

.. . - , 20~3:t~

reparation Exam~le~

Example 1 9-Fluoro-3-~ethyl-10-(4-(2-chlorophenyl)-piperazin-1-yl)-7-oxo-7H-pyrido~1,2,3-de][1,4]benzoxazine-6-c~rboxylic ac.id o F ~ , ~ CO2H

N J O ~ CH3 Cl 300 mg (1.075 mmol) of 9,10-difluoro-3-methyl-7-oxo-7~
pyrido[l,2,3-de][1,4~benzoxazine-6-carboxylic acid are suspended in 8 ml of DMSO and treated with 520 mg t3.23 mmol) of N-(2-chlorophenyl-piperazine and the mixture is heated at 100C for 2 h. The solvent is removed in vacuum in a Kugelrohr device (bath temperature 80C), the residue is stirred with ether, and the solid is filtered off with suction and then stirred with isopropa-nol, filtered off with suction and dried.
Yield 322 mg,.(95% of theory); m.p. 7265C.

The compounds listed in Tables 1 and 2 are prepared in analogy to the procedure of Example 1:

Le A 28 861 - 50 -~ :; . :
', 2093~

able 1 :.
o ¦~ N ~N~
~ N ~J O ~ CH3 Ex. No. R' M.p~ C Yield (% of t,heory ) 2 m-OCH3 2 3 7 5 7 3 o-C2Hs 2 8 0 5 6 4 o-OC2Hs 2 6 8 7 4 p-F 260 85 Le A 28 861 - 51 -.; ~ ~. ''' ' . ' .
, - 2~931~8 rrablQ 2:

F ~,3~ CO2H

R1~ J ~CH3 Ex. No. Rl M.p.C Yield (~ of theory) 7 ~ dec. 45 N

8 /¢N~ 273 55 Example 9 10-(4-Cyclopropyl-piperazin-l-yl)9-fluoro-3-methyl-7-oxo-7H-pyrido-[1,2,3 de]~l,4~ben~oxazine~ arboxylia acid o F ~ CO~H

~ N J ~ CH3 300 mg (1.075 mmol) oliii 9,10-difluoro-3-methyl-7-oxo-7H-pyrido[l,2,3-de~1,4]benzoxazine-6-carboxylic acid are Le A 28 861 - 52 -- . .. .

' ' ' ' , ''. ~',.. ' , ' ~' '' ' ; : '.',' ' 209~8 suspended Ln 8 ml of DMSO, -treated wi~h ]39.8 mg (1.075 mmol) of 1-cyclopropylpiperazine and 240.8 mg (2.15 mmol) of DA~CO and heated at 100C for 1 h. After reaction is coMplete, the solvent is distilled off in a S Kugelrohr device under vacuurn, the resiclue is suspended with isopro-panol and the solid is filtered off with suction and dried.
Yield: 398 mg (78% of theory) as a solid; m.p.C:>265.

The compounds listed in Tables 3, 4 and 5 are obtained in analogy to the procedure of Example 9:

Table 3:

F~ ,CO2H

a~ N J o ~J~ CH3 Ex. No. R10 M.p.C Yield (~ of theory~

Le A 28 861 - 53 -.

2~93~

Table 4:

`f ~
HN~ J ~CH3 R

Ex. No. Rll Rl2 ~I.p. C Yield (% of theory ) l l H -CH2-OC6H5 dec . 5 0 12 H -~CH2)20H 183 95 13 H -H2C-N~ O dec . 2 2 .

Le A 28 861 - 54 -.

. .

20931~
Table 5:

R ')~ CO2H
~CI-13 Ex. No. R4 M.p. C Yield (~6 of theory ) ~`N--\NH
14 ~J 210 91 ;

Ç~N~
515 N~J 195 93 ~N
16 l I dec. 47 N~

17 ~P'~ >265 64 H
H
18 ~N ~ >265 95 ~o~N~

9 l >265 78 e A 28 861 - 55 -- . . . . .

2 ~

Examp:le 2 0 3-Benzyl-9-fluoro-7-oxo-10-( 1-piperazinyl ) -7H-pyrido[1, 2, 3-de ] [ 1, 4 ] benzoxazine-6-carboxylic acid O O
F ~ OH

HN ~ ~ ~

355 mg ~1.0 n~ol) of the compound from Example VI, 5 ml of DMSO, 1.7 ml of diisopropylethylamine (10 mmol) and 172 mg (2.0 mmol) of piperazine are heated under reflux for 4 h. After cooling, tha mixture is treated with ether and the precipitate which deposits is filtered off with suction.
Yield: 290 mg (6~%); meltLn~ point: 169C (dec.).

The compounds listed in Table 6 are prspared in analogy to the procedure of Example 20.

Le A 28 861 - 56 : . ' ', ..... , ,. ~ ' ' . . , '` ' ~' ' . ` ' 2093t ~

Table 6:
o F ~ COzH

HN ~,J ~ R2 R~

Ex. No. R2 Rll M.p. C Yield (% of theoxy) (dec.) 2 2 -CH2--O-CH2-c6H5 H 2 2 8 -2 3 0 6 3 (dec.) 23 -CH2-O-CH2-C6H5 -C~3 186(dec.) 44 Example 24 2-(1,1,-Dimethyl-4-phenoxy-butyl)-9-fluoro-10-pipera-zinyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-car-boxylic acid O O
F ~ OH

N ~ N
HN J O~ ~
CH3 ~ O ~

Le A 28 861 - 57 -,, .
.
` . . . . .
.

21~9~1 ~8 0.2 g (0.453 mmol) of the compound from Example IX are suspended under argon in 2 ml of abso].ute DMF. 0.11 g ( 0 906 mmol ) of diisopropylethylamine and 0.12 g ( 1. 36 mmol ) of piperazine are added and the mixture is heated at 120C for 4 h.

The solvent i9 dist.illed of~, the residue is treated with ether and the product is filtered o~f with suction. It is washed with water and dried in a high vacuum.

Exam~le 25 9 Fluoro-2-(1,1-dimethyl-4-phenoxy-butyl)-10 (3-methyl-l-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (~
F ~ ~ CO2H

f N ~ N

CH3 H3C ~ (CH~3- O

The title compound is prepared using 2-methylpiperazine in analogy to Example 24.

The examples listed in Table 7 are prepared in analogy to the compounds mentioned therein:

Le A_28 861 - 58 -., : : ;, . : , ~93~ ~8 Table 7:
~, COzH

~N ~,J O ~J
R~ IP,11 ~`N
CI~J
N~2 Ex. No. R10 Rll Rl2 M.p.C Yield % In analogy of theory to Example 26 -CH3 H H >230 60 24 27 H -CH3 H >230 67 24 28 H H H >230 59 24 29 H -CH3 -CH3 >230 40 24 Examp_e 30 Ethyl 9 fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3~de][1 t 4]benzoxazine-2,7-dicarboxylate F ~ CO2Et N ~ O

CO2Et Le A 28 861 - 59 -: , 2~93~ ~

O.S g (1.37 mmol) of the compound from Example I, 0.41 g (4.1 n~ol) of N-methy].pipera~Lne and 0.35 g (2.74 mmol) of HUnig base are treated with 15 ml of DMSO and stirred at 120C for 4 h under argon. The mixture .is concentrated in vacuo and the crude product is puri.fied by chromato-graphy on si.lica gel (CH2Cl2:MeOH:NH3(~q) = 100:2.5:1).
0.116 g (19~ of theory) of the desired compound are obtained.
Melting point: 168-170C.

Example 31 9-Fluoro-10- ( 4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [ 1, 2, 3-de ] ~ 1, 4 ] benzoxazine-2, 7 -dicarboxylic acid .
o ~--N~

CH3 . CO2H
104 mg (0.233 mmol) of the compound from Example 30 are heated at 120C for 12 hours in 5 ml of an ~OAc/H~O/H2SO4 mixture (12:8-1). The solid is filt~red off with suction and dried in a high vacuum~ 52 mg (57% of theory) of the title compound are thu~ obtained.
M~lting point: >230C.
1H-NMR(DMSO-d6): 8.95 (s lH); 7.97 (s 1~); 7.49 (d J =
11.5; lH); 3.7-3.0 (m 8H); 2.85 (s 3H).

Le A 28 861 - 60 -:~ :
: , :
:, ~. :
, ~ .:,, ' ' , , ' ' - ~

2~3~8 The compounds ].i~ted in Table 8 are prepared in analogy to -the procedure of Example 20:

Table 8:
o O ~ R

Ex. No. R4 R2 , - - -32 N ~ N-CH3 -C~z-c6H5 33 -N 3 -CH2-C6Hs -N O
34 ~ -(C~z~z-COzH

The compounds li~ted in Table 9 are prepared from the compound of Example XVIII in analogy to the procedure of Example 20.

Le A 28 861 - 61 -' ,' , ,:
.

2~.93~ ~J8 Table 9:
o F ~ 2 " ~ V

Ex. No. R4 ~N N-3 6 HO-(CH2)2-N~N

O N-37 \ J

HN N-3 8 ~
r~

3g ~

HN N-/

Le A 28 861 - 62 -.. . . .

. .
. . . , : :
:

2~93~ ~

Exampl~ 41 Ethyl 2-cyclopropyl-9-fluoro-10-(3-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]-berlzoxazine-6-carbox-ylate ~OC2Hs HN ~ ~J
Me ~, 0.5 g (1.5 mmol) of ethyl 2-cyclopropyl-9,10-di~luoro-7-oxo-7H~pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate are ~uspended under argon in 10 ml o ahs. DMSO. 0.364 g (3 m~lol) of diisopropylethylamine and 0.451 g (4.5 mmol) o~ 2-methylpiperaxine are added and the mixture is heated at 120C for 6 h.
It i~ cooled and DMSO i~ ~tripped of on a rotary evapo-rator. The residue is taken up in CH2C12, and the solution is shaken with saturated NaC1 solution, dried over MgSO4 and concentrated. The crude product is purified on silica gel (eluent CH2Cl2:MeOH:N~3(2~) - 100:2.5:1~ and yields 300 mg (48 % of theory) of the title compound.
Melting point: amorphou H-NMR(CDCl3): 8.06 (~; lH); 7.57 (d J - 12.3; lH); 6.05 (s; lH); 4.36 (q J = 7; 2H); 3.2-2.7 (m); 1.52 (m; lH) 1.39 (tr J = 7;3H); 1.07 (d J = 6; 3~); 0.90 (m; 4H).

Le A 28 861 - 63 -' . '.' - ' ' ,:
.

2~9~10~

Example 42 2-Cyclopropyl-9-fluoro-10-(3-methyl-1-pi.perazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]-ben~oxazine-6-carboxylic a~id hydrochloride O O
~ ~ N

HN~J O~
Me ~
180 mg (O.43 mmol) of -the compound from Example 41 are dissolved in a mixture of 6 ml of THF and 2 ml of H20, and khe solution is treated with 52 mg (2.17 I~mOl) 0~
LioH and stirred at 40C ~or 6 h. The p~ i~ adjusted to 1 while cooling in an ice bath and the precipitate is filtered off with suction af~er 30 min. Ik is washed with cold wa~er until neutral and dri~d in a high vacuum.
92 mg (55% o~ theory) of the yellow title compound are obtained.
Melting point:>230C.

Example 43 Ethyl 2-cyclopropyl-9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de~ 4~-benzoxazine-6-carboxylate . O

~N `o--CH3 ~N

L~

Le A 28_861 - 64 -: : ' ~3~L~8 The ti-tle compound is obtalned in 52% of theory analo-gously to the preparation of Example 41.
Melting point: 130C.

Example 44 Ethyl 2-cyclopropyl-9 fluoro-10-(4-methyl-1-pipera2inyl)-7-oxo-7H-pyrido~1,2,3-de][1,4]-benzoxazine~6-carboxylic acid hydrochloride O O

f ~ xHCl 238 mg (0.58 ~ol) of the compound from Example 43 are di~solved in 5 ml o a CH3CO~H/~2O¦HzSO4 mixture (12:8:13 and the solution is heated at 100C for 4 hours. The solvent i5 largely removed, the mixture is treated with 1 ml of conc. HCl and S0 ml of ethanol are added. It is stirred overnight and the solid is filtered off with suction in the cold~ The 95% pure crude product is purified on silica gel (eluent CH2Cl2:CH3OH:CH3CO2H =
100:25:4) and again converted into the hydrochloride (see above~. It is dried in a hiqh vacuum and 76 mg (32~ of theory) of the title compound are obtained~
Melting point:>230C.

Le A 28 861 - 65 -. , 2~931L~8 The examples listed in Table ].0 are prepared in analogy to the procedure of Example 20:

Table 10:
,~CO2H

O ~ ~ R

Ex~ No. R4 R2 ____ -N NH
/ -H2C-N~N
-NN-CH3 ~ I
46 ~ -CH2-N~N

-N NH 1=1 -CH2-N~ N

4 8 -NAO -CH2-N ~ N

49 -N N~ -CH2 N~N

~ I I

5 0 -NN-(C ~l2)2H -CH2-N ~ N

Le A 28 861 - 66 -., . -:
, ~
,, . ~ . , . . ' ~ ' ~ ' ~ '

Claims (18)

1. 9-Fluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives of the general formula in which R1 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, R2 represents hydrogen, formyl, methyl, benzyl, p-Cl-benzyl, carboxyl or the -CONH2 group, or represents straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms, or represents straight-chain or . branched alkyl having up to 6 carbon atoms, which is substituted by carboxyl, benzyloxy, imidazolyl or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, R3 represents hydrogen, represents carboxyl or Le A 28 861 - 67 -represents cycloalkyl having 3 to 8 carbon atoms, represents straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 10 carbon atoms, which is substituted by carboxyl, phenoxy or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or represents biphenyl or a radical of the formula or in which A denotes a nitrogen atom or the -CH group, R5 and R6 are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, R7 denotes hydrogen, halogen, hydroxyl or straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms, n denotes a number 1,2 or 3, and Le A 28 861 - 68 -B denotes straight-chain or branched alkyl having up to 6 carbon atoms or hydrogen, R4 represents halogen or imidazolyl or 1,4-diazacyclo-heptanyl bonded via N, or a radical of the formula , , , or in which o denotes a number 2 or 3, p denotes a number 1 or 2, D denotes the -CH2-group or an oxygen atom, R8 and R9 are identical or different and denote hydrogen, methyl or ethyl, Le A 28 861 - 69 -R10 denotes cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched perfluoroalkyl having up to 6 carbon atoms, or denotes phenyl, pyridyl or pyrimidyl, each of which is optionally substituted by halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R11 denotes hydrogen or methyl, R12 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by hydroxyl, benzyloxy, phenoxy or morpholino, and in the case in which R3 does not denote hydrogen if R2 represents hydrogen or methyl, R4 additionally represents morpholino or a radical of the formula in which R13, R14 and R15 are identical or different and denote hydrogen, hydroxyethyl, methyl or ethyl Le A 28 861 - 70 -and their hydrates and salts.

2. 9-Fluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives according to Claim 1 in which R1 represents hydrogen, or represents straight-chain or branched alkyl having up to 6 carbon atoms, R2 represents hydrogen, formyl, methyl, benzyl, p-Cl-benzyl, carboxyl or the -CONH2 group, or represents straight chain or branched alkenyl or alkoxycarbonyl each having up to 4 carbon atoms t or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is substituted by carboxyl, benzyloxy, imidazolyl, methoxy-carbonyl, ethoxycarbonyl or propoxycarbonyl, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R3 represents hydrogen, represents carboxyl, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, represents straight-chain or branched alkoxy-carbonyl having up to 6 carbon atoms, or Le A 28 861 - 71 -represents straight-chain or branched alkyl having up to 8 carbon atoms, which is substituted by carboxyl, phenoxy or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or represents biphenyl or a radical of the formula or in which A denotes a nitrogen atom or the -CH group, R5 and R6 are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, R7 denotes hydrogen, fluorine, chlorine, hydroxyl or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, n denotes a number 1 or 2, and B denotes straight-chain or branched alkyl having Le A 28 861 - 72 -up to 4 carbon atoms or hydrogen, R4 represents fluorine or imidazolyl or 1,4-diaza-cycloheptanyl bonded via N, or represents a radical of the formula , , , or in which o denotes a number 2 or 3, p denotes a number 1 or 2, D denotes the -CH2 group or an oxygen atom, R8 and R9 are identical or different and denote hydrogen, methyl or ethyl, R10 denotes cyclopropyl, cyclopentyl or Le A 28 861 - 73 -cyclohexyl, or denotes straight-chain branched perflu-oroalkyl having up to 4 carbon atoms, or denotes phenyl, pyridyl or pyrimidyl, each of which is optionally substituted by flourine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, R11 denotes hydrogen or methyl, R12 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is substituted by hydroxyl, benzyloxy, phenoxy or morpholino, and in the case in which R3 does not denote hydrogen if R2 represents hydrogen or methyl, R4 additionally represents morpholino or a radical of the formula in which Le A 28 861 - 74 -R13, R14 and R15 are identical or different and denote hydrogen, hydroxyethyl, methyl or ethyl.

3. 9-Fluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives according to Claim 1 in which R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen, formyl, methyl, benzyl, p-Cl-benzyl, carboxyl or the -CONH2 group, represents vinyl, allyl, methoxycarbonyl or ethoxycarbonyl, represents straight-chain or branched alkyl having up to 3 carbon atoms, which is substituted by carboxyl, benzyloxy, imidazolyl, methoxy-carbonyl or ethoxycarbonyl, or represents cyclopropyl or cyclopentyl, R3 represents hydrogen, or represents carboxyl, or represents cyclopropyl or cyclopentyl, or represents straight-chain or branched alkoxycar-bonyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by carboxyl, phenoxy or by straight-chain or Le A 28 861 - 75 -branched alkoxycarbonyl having up to 3 carbon atoms, or represents a radical of the formula in which A denotes a nitrogen atom or the -CH group, R5 and R6 are identical or different and denote hydrogen, methyl, ethyl or acetyl, R7 denotes hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy, R4 represents imidazolyl or 1,4-diazacycloheptanyl bonded via N, or represents a radical of the formula , , , Le A 28 861 - 76 -or in which o denotes the number 2, p denotes a number 1 or 2, D denotes the -CH2 group or an oxygen atom, R8 and R9 are identical or different and denote hydrogen, methyl or ethyl, R10 denotes cyclopropyl or straight-chain or branched perfluoroalkyl having up to 3 carbon atoms or phenyl, pyridyl or pyri-midyl, each of which is optionally substi-tuted by fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R11 denotes hydrogen or methyl, R12 denotes straight-chain or branched alkyl having up to 3 carbon atoms, which is substituted by hydroxyl, benzyloxy, phenoxy or morpholine, Le A 28 861 - 77 -and in the case in which R3 does not denote hydrogen if R2 represents hydrogen or methyl, R4 additionally represents morpholino or a radical of the formula in which R13, R14 and R15 are identical or different and denote hydrogen, hydroxyethyl, methyl or ethyl.

4. 9-Fluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives according to claim 1, 2 or 3 wherein R4 is as defined in claim 1, 2 or 3, other than halogen.

5. The compound ethyl 9,10-difluoro-2-ethoxycarbonyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.

6. The compound ethyl 2-(1,1-dimethyl-4 phenoxybutyl)-9,10-difluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.

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

8. A process for the preparation of a compound according to claim 1, or a salt thereof, which process comprises [A] reacting a compound of the general formula (II) (II), in which R1, R2 and R3 have the meaning mentioned in claim 1, and T represents halogen, with a compound of the general formula (III) R4-H (III), in which R4 has the meaning given in claim 1, in an inert solvent, in the presence of a base, under a protective gas atmosphere, or reacting an aldehyde of the general formula (IV) (IV), in which R1 has the meaning given in claim 1, with a compound of the general formula (III) or (IIIa) R4-H III), W-H (IIIa), in which R4 has the meaning given in claim 1, W has the abovementioned meaning of R4, one of the cyclic amine functions being protected by a protective group, in an inert solvent, in the presence of a base, with simultaneous cyclisation, followed by the removal of the protective group;
or [B] in the case in which R2 represents substituted alkyl, reacting a compound of the general formula (V) (V), in which R1 has the meaning given in claim 1, with a compound of the general formula (VI) R17-H (VI), in which R17 represents the substituted alkyl mentioned under R2, which is shortened by a carbon atom, in an inert solvent, with simultaneous cyclisation, and in a last step the substituent R4 is introduced as described above, and in the case in which R3?H, the product is derivatised, and, if required, esterifying an obtained compound in which R1 is hydrogen or hydrolysing an obtained compound in which R1 is other than hydrogen and, if required, converting an obtained compound into a salt thereof.

9. An antiviral composition which comprises a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.

10. A process for preparing an antiviral composition which comprises admixing a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, with a suitable diluent or carrier.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for combating viruses.

12. A commercial package containing, as active pharma-ceutical ingredient a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, together with instructions for its use for combating viruses.

13. A compound of the general formula (XI) (XI) in which R2 is as defined in claim 1, R16 represents a C1-C4-alkyl radical and R18 represents hydrogen or a C1-C4-alkyl radical.

14. A compound of the general. formula (V) as defined in claim 8.

15. A compound of the general formula (XIV) (XIV) wherein R1 is as defined in claim 1.

16. 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 7 or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16, wherein such disease is a virus infection.

18. The method according to claim 16, wherein such disease is hepatitis.