AU688462B2 - 8-amino-pyrido (1,2,3-d,e)(1,3,4) benzoxadiazine derivatives - Google Patents

Description

Our Ref: 547344 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT .too .:#Go *0

U.

00 C C

C..

9*O

C

Applicant(s):

CC..

of 1 Bayer Aktiengesellschaft D-51368 LEVERKUSEN

GERMANY

Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 8-Amino-pyrido benzoxadiazine derivatives The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 I 'I 0 The present invention relates to new 8-amino-pyridotl,2,3-d,e] [1,3,4]benzoxadiazine derivatives, processes for their preparation, and antibacterial compositions containing these compounds.

It has already been disclosed that pyridobenzoxadiazinecarboxylic acids are antibacterially active. Examples of these are found in EP-0 259 804, EP-O 343 524 and in the European Journal of Medicinal Chemistry 26, 889 (1991).

I

10 a The present invention relates to: 1. New 8-amino-pyrido[1,2,3-d,e] [1,3,4]benzoxadiazine derivatives of the general formula (I) A 0

COOB

s(I), *a a *0 0 0* 0 a in which A represents amino or alkylamino,

R

1 represents hydrogen or Ci-C 3 -alkyl which is optionally substituted by hydroxyl or halogen, Le A 30 351 1

I-

1 00

R

2 independently of R 1 represents hydrogen or methyl,

R

3 represents hydrogen or Ci-C 4 -alkyl, B represents hydrogen, alkyl having 1 to 4 carbon atoms, which is optionally substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino, or (5-methyl-2-oxo-1,3-dioxol-4yl)-methyl,

X

1 represents hydrogen or halogen, Z represents radicals with the structures

R

4 R

NC~N

ara a aa a a aoaaaa a a R N R9

R

14

N'

s Ris

N-

N./ N- Le A 30 351 2

I,

in which R 4 represents hydrogen, straight-chain or branched Cl-C 4 -alkyl which is optionally substituted by hydroxyl or methoxy, cyclopropyl, acyl having 1 to 3 C atoms,

R

5 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R 6 represents hydrogen or C 1 4 -alkyl, R 7 represents hydrogen or C, 1 4 -alkyl, Ra represents hydrogen or C3- 4 -alkyl,

R

9 represents hydrogen, methyl or _CH 2 -NR 7 R8, 10 represents hydrogen, C 1 4 -alkyl., amino, alkyl- or dialkylanino having 1 or 2 C atoms in the alkyl moitty and optionally substituted by hydroxyl, amino- C,.

4 -alkyl,

C

1 4 alkyl -amino- C 1 4 -alkyl or 1-imidazolyl,

R

11 represents hydrogen, hydroxyl, methoxy, rnethylthio, halogen, methyl, hydroxymethyl, R 12 represents hydrogen or methyl, Le A 30 351-3 3

R

13 represents hydrogen or C 1 -4-alkyl,

R

14 represents hydrogen or C 1 4 -alkyl and represents hydrogen or C 1 -4-alkyl, in the form of racemates or as enantiomerically pure compounds, their pharmaceutically utilizable hydrates and acid addition salts, and their salts with bases.

2. Process for the preparation of the compounds of the formula (I) A 0 X COOB R in which A represents amino or alkylamino, R1>"XR in which A represents amino or alkylamino,

R

1 represents hydrogen or C 1

-C

3 -alkyl which is optionally substituted by hydroxyl or halogen,

R

2 independently of R 1 represents hydrogen or methyl, Le A 30 351 4

II

R 3 represents hydrogen or C: 1

-C

4 -alkyl, B represents hydrogen, alkyl havi.ng 1 to 4 carbon atoms, which is optionally substituted by hydroxyl, methoxy, amino, methylamino or dimethylexmiino, or (5-methyl-2-oxo-l, 3-dioxol-4yl) -methyl,

X

1 represents hydrogen or halogen, Z represents radicals with the structures a a a a a a a **aa R N'!5 T R N'D .1-1 r

N

N

H 2 C

C

N

R 1 0

CN-

a. a

N

R is in which Le A 30 351-5 5

R

4 represents hydrogen, straight-chain or branched C 1

C

4 -alkyl which is optionally substituted by hydroxcyl or methoxy, cyclopropyl, acyl havirr%, 1 to 3 C atoms, Rs represents h~ydrogen, methyl, phenyl, thienyl or pyridyl,

R

6 represents hydrogen or C,, 4 -alkyl, R 7 represents hydrogen or C 1 4 -alkyl, *.Re represents hydrogen or C 1 4 -alkyl,

R

9 represents hydrogen, methyl or C2N7R,

R

10 represents hydrogen, C 1 4 -alkyl, amino, ~:alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety and optionally substituted by hydroxcyl, amino-C..

4 -alkyl,

C

1 4 -alkyl-amino-Cl.

4 -alkyl or 1-imidazolyl,

R'

1 represents hydrogen, hydroxyl, methoxy, methylthio, halogen, methyl, hydroxymethyl, R 1 2 represents hydrogen or methyl, R 13 represents hydrogen or C 1 4 -alkyl, Le A 30 351-- 6 R 3 4 represents hydrogen Or C 1 4 -alkyl and R's represents hydrogen or C 1 4 -alkyl, characterized in that compounds of the formula (11) NH 2 0 x 2 N

(T

0 N~ R 3 5. in which

R

1 R 2 R 3 B and X 1 have the meaning given above and x 2 represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula ((III)

Z-H(II

in which Z has the meaning given above, if appropriate in the presence of acid acceptors.

3. Compourds of the formula (II) Le A 30 351 7 x 2 NI I 0 N ,R R1>R 2 in which

R

1 R 2 R1, B and X1 have the meaning given above and x 2 represents halogen, in particular fluorine or chlorine.

Process for the preparation of the compounds of the *formula (11)

NH

2 0 COGL3 X N RII3

R

in which R3-, R 2 R1, B, and X 1 have the meaning given above and x 2 represents halogen, in particular fluorine or chlorine, characterized in that compounds of the formala (IV) Le A 30 351-8 8

M

X ^COOB

S(IV),

X N O N 3 R R2 R in which

R

1

R

2

R

3 B, X 1 and X 2 have the meaning given above, are reacted with nitrating reagents such as nitric 5 acid and nitrates in a solvent such as, for example, water, sulphuric acid, acetic acid, acetic anhydride or their mixtures at -50°C to 200°C, perferably at -20°C to 100°C, and the nitro compounds obtained are then reduced.

10 The compounds according to the invention are suitable as active compounds for human and veterinary medicine.

Preferred compounds of the formula are those in which A represents amino,

R

1 represents hydr.gen or Ci-C 3 -alkyl which is optionally substituted by hydroxyl,

R

2 independently of R 1 represents hydrogen or methyl, Le A 30 351 9 I L-p R 3 represents hydrogen, methyl or ethyl, B represents hydrogen, alkyl having 1 to 4 carbon atoms, which is optionally substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino, or methyl-2-oxo-l,3-dioxol-4-yl) -methyl, X1 represents hydrogen, fluorine or chlorine, Z represents radicals with the structures 4 .4 4 4 0* 4 4 4*4 I .4 4

I

S

a.

5*

I

41 .4 7 R

N

R 0 R'1 0 R

N-

RI

N N 6 R 1 r N

N

N l in which R 4 represents hydrogen, straight-chain or branched

C,-C

3 -alkyl op tionally substituted by hydroxyl, or methoxy,

R

5 represents hydrogen, methyl or phenyl, R6 represents hydrogen or methyl, Le A 30--35-1 -1 10

R

7 represents hydrogen or methyl,

R

9 represents hydrogen, methyl or -CH 2

NH

2

R

10 represents hydrogen, methyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl or ethylaminomethyl,

R

1 represents hydrogen, hydroxyl, methyl, fluorine, methyl or hydroxymethyl,

R

13 represents hydrogen or methyl,

R

1 4 represents hydrogen or methyl, 10 R 15 represents hydrogen or methyl, 9 and their pharmaceutically utilizable hydrates and acid addition salts, and their alkali metal, alkaline earth metal, silver and guanidinium salts.

Particularly preferred compounds of the formula are 15 those 9* 9 in which A represents amino,

R

1 represents hydrogen or methyl which is optionally substituted by hydroxyl, Le A 30 351 11 R 2 R 3

B

X1 z represents represents.

represents represents represents R N -T

R

5 0-) in which hydrogen, methyl or ethyl, hydrogen, methyl or ethyl, fluorine, radicals with the structures R R 4.-1

N

R 10

R

1 2112Nr:N N represents hydrogen, methyl, ethyl optio'aally subst,4.tuted by hydroxyl, represents hydrogen or methyl, represents hydrogen or methyl, represents hydrogen or methyl, Le A 30 351 12

R

9 represents hydrogen, methyl or -CH 2

NH

2

R

10 represents hydrogen, methyl, amino, methylamino, aminomethyl or ethylaminomethyl,

R

11 represents hydrogen, hydroxyl or methoxy,

R

13 represents hydrogen or methyl,

R

14 represents hydrogen or methyl,

R

15 represents hydrogen or methyl, and their pharmaceutically utilizable hydrates and acid addition salts, and the alkali metal, alkaline earth metal, silver and guanidinium salts of the carboxylic acid on which they are based.

If, for example, 8-amino-9,10-difluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido[l,2,3] [1,3,4]benzoxadiazine-6carboxylic acid and piperazine are used in the process for the preparation of compounds of the formula the course of the reaction can be represented by the follow- 0o s ing equation:

NH

2 0 NH2 0 HN NH F COOH F COOH F Y.N N N O N HNO ,N0 Le A 30 351 13 s q The compounds of the formula (II) used as starting compounds are new. They can be prepared by reacting compounds of the formula (IV) 0 XA COOB 2 N

(IV),

X N RO R in which R 1

R

2

R

3 B, X 1 and X 2 have the meaning given above, °Po.

o 0 with nitrating reagents such as nitric acid and nitrates in a solvent such as, for example, water, sulphuric acid, acetic acid, acetic anhydride or mixtures thereof at -50 0 C to 200°C, preferably at -20°C to 1000C, and then reducing the nitro compounds obtained.

e Metal hydrides, transition metals and transition metal salts can be employed for the reduction of the nitro group; preferably hydrogen is used in the presence of 15 catalysts such as, for example, palladium-carbon, Raney nickel and platinum. Solvents which can be used are, for example, water, hydrochloric acid, alcohols, acetic acid or alternatively mixtures thereof.

Compounds of the formula (II) can also be prepared according to the following reaction scheme, in which R 1

R

2

R

3 B, X 1 and X 2 have the meaning given above: Le A 30 351 14 g NEW J. Med. Chem. 34, 1142 (1991) COOEt F QEt 1) H 2 N-N(R )BOC 2) Base

(CHO),,

S

S S *SS S S S 5*5S S S

SS

55 3 F HN, R 3

SS

15 IBu4

NF

,COOEt 1) NaOH 2) R 1 (R 2

)C=O

1) activation 2) B-OH

NO

2 0 X1 COOH X 2 N

{H

2 ICat.

NH

2 0 X COOH X 2) N

S

S

.5.559 They can optionally be employed as racemates, enantiomers or pure diastereomers.

Examples which may be mentioned are: Le A 30 351 -1 16 8-amino-9, 10-dif luoro-3-methyl-7-oxo-2,3-dihydro-71Fpyrido[1,2,3-d,eJ El,3,4]benzoxadiazine-6-carboxylic acid, 8-amino-9,10-difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7Hpyrido[1,2,3-d,e] [1,3,4]benzoxadiazine-6-carboxylic acid, 8-amino-9,10-difluoro-2-(hydroxymethyl) -3-methyl-7-oxo- 2,3-dihydro-7H-pyrido[l,2,3-d,eI [1,3,4Jbenzoxadiazine-6carboxylic acid, 8-amino-9,10-difluoro-3-ethyl-7-oxo-2,3-dihydro-7Hpyrido[l,2,3-d,eJ E1,3,4]benzoxadiazine-6-carboxylic acid, ethyl 8-amino-9,1C-difluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido[1,2,3-d,e3 [1,3,4]benzoxadiazine-6-carboxylate.

The amines of the formula (III) used as starting comnpounds are known. Chiral amines can be employed both as racemates, and as enant.iomerically or diastereomerically pure compounds.

Examples which may be mentioned are: piperazile, 1 -methylpiperazine, 2 -ethylpiperazine, 2-methylpiperazine 2, 6-dimethylpiperazine, 1- cyclopropylpiperazine, 2 -phenylpiperazine, 1, 2 -dime thylpipera. ine, 2,5-diazabicyclo[2.2.llheptane1 2-methyl-2,5-diazabicyclo[2 .2 .ljheptane, 17 2, 5-diazabicyclo octane, 2-methyl-2,5-diazabicyc.*l.- T2.2]21octane, 1,4-diazabicyclo octane morpholine, 2, G-dimethylmorpholine, 2- aminomethylmorpholine, imidazole, pyrrole, 3 -aminomethyl-2, 3-aminomethyl-4-methyl-2, pyrrolidine, 3-me thylpyrrolidine, *3 -amino-4 -methylenepyrrolidine, 7-a~mino-5-azaspiro heptane, 3-aniinopyrrolidine, 3-tert-butoxycarbonylamino-pyrrolidine, fee:3-methylamino-pyrrolidine, 3- dimethylamino -pyrrolidine, 3- aiinomethyl.-pyrrolidine, 3-tert-butoxycarbonylaxninomethyl-pyrrolidine, 4 -chloro-3 -tert-butoxycarbonylaminomethyl-pyrrolidine, 3- tert-butoxycarbonylaminomethyl -3-methyl -pyrrolidine, 3 -tert-butoxycarbonylaznino-4-methyl-pyrrolidine, eq 3- tert -butoxycarbonylaiinomethyl.-3 -methoxy-pyrrolidine, 3 -methylaminomethyl-pyrrolidine, 3- ethylaminomethyl-pyrrolidine 4- tert -butoxycarbonylamino -2 -methyl.-pyrrol idine, 2 -methyl -3 -methylamino -pyrrolidine, 2 -methyl-4-methylani no-pyrrolidine, 3- (2-hydroxyethylamino) -pyrrolidine, Le A .30- 351 -118 3 -hydroxy-pyrrolidine, 3 -hydroxymethyl -pyrrolidinE,, 4-amino-3 -hydroxy-pyrrolidine, 3 -hydroxy-4 -methylaniino-pyrrolidine, 3 -tert-butoxycarbonyamino-4-methoxy-p7,vrroidile, 3 -methylaminomethyl-3-hydroxy-pyrrolidine, 3 -dimethylaniinomethyl- 3-hydroxy-pyrrolidine, 3 -diethylaniinomethyl -3 -hydroxy-pyrrolidine 3-tert-butylaminomethyl-3 -hydroxy-pyrrolidine, 3 -methylamino-4-hydroxymethyl-pyrrolidile, 4 -methoxy- 3-methylamino-pyrrolidine, 3 -methoxy- 3-methylaminomethyl -pyrrolidine, 3 -amino-4-methoxy-2-methyl-pyrroidile, 3 -methyl-4-tert-butoxycarbonylaminomethy-pyrroidile and .15 3 -methoxy-4 -tert-butoxycarbonylaminomethyl-pyrroidile, Le A 30 351 19 The following compounds of the formula (1a) may be mentioned specifically:

NH

2 0 x COOR4 1 1 Z N R (1a) 4 4 0 0 0 40004i *4 4 0 9 04 94 4 JIR3R 4 z x H Me H

H

2 N

F

N-

H Me H H2N )C -F 2

C

H Me H 0 N-

H

2 N H Ime Et

F

H3C-N H Et Et

F

HGC-N \jN- Me Methyl Et Ethyl Le A _3 0 -351 20 Continuation: NH 2 0 0 N, R R H (Ia)

R

3

Z

Me Me H

H

3 C-N Me Me H H2N a a-CH 2 OH Me H ka II3 II~ 21 Continuation: NH 2 0 x COOR4 Z) N R H (1a)

R

1

R

H CH 3 Ethyl H 2

N

0- 5 H C 3

-CH

2

-C

2

-NH

2 3HC-N

N

CH

3

-CH

2

-CH

2

-OCH

3 H3C-N \-jN-

*CH

3

CH

3

-H

2

N

N-

Le A 30 351 22 Continuation: NH 2 0 x COOR4 ZI IN U NR3 Rl~2 RR 3 R e H (Ta)

R

3 3 H Me H

H

3 ~C-N1 H Me H HN~1J, H Et H H 2

N

23 Continuation:

NH

2 0 x ICOOR 4 Z) N o N R 3 R IxH (Ia) *0*000 l R 4 zX H Me H H 3 C.

F

N N H Me H H 2

NF

3 C H Me H H N 3

CO

H Me H

HNF

H Me H H

F

H

3 C

C

Le. A 3 0 :35 I 4 24 Continuation: COOR 4 (1a) a a a a a 0# a a a a a a a 4 a a.

a. a a a a Ph Phenyl Le A 30 351 25

,COOR

4 (Ia) *0 0 0000 00 0 0 000 0 00 000 0 00 0 0 000000 00 0 0*0 0 00.

0 0 0000 0* 00 0 0 000000 0 26 The reaction of compounds of the formula (II) with compounds of the formula (III), in which the compounds (III) can also be employed in the form of their salts, such as e.g. the hydrochlorides, is preferably carried out in a diluent such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphoramide, sulpholane, acetonitrile, water, an alcohol such as methanol, ethanol, n-pr'panol, isopropanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used.

The acid-binding agents used can be all customary inorganic and organic acid-binding agents. These preferably include the alkali metal hydroxides, alkali metal carbon- Se*. ates, organic amines and amidines. The following may be 15 mentioned in detail as being particularly suitable: triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine

(III).

o S*(111) The reaction temperatures can be varied within a rela- 20 tively wide range. In general, the reaction is carried out between about 20 and 2000C, preferably between 80 and 180 0

C.

C

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, the reaction is carried out at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.

Le A3 0 35.1 27 II I I -I When carrying out the process according to the invention in general, 1 to 15 mol, preferably 1 to 6 mol, of the compound (III) are employed relative to 1 mol of the compound (II) Free amino groups can be protected during the reaction by a suitable amino protective group, for example by the tert-butoxycarbonyl radical, and liberated again after completion of the reaction by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Volume E4, page 144 (1983); J.F.W. McOmie, Protective Groups in O&ganic Chemistry (1973), page 43).

The esters according to the invention are obtained by reaction of an alkali metal salt of the carboxylic acid on which they are based, which can optionally be protected on the N atom by a protective group such as the tert-butoxycarbonyl radical, with suitable halogenoalkyl derivatives in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea at temperatures of about 0 to So 100°C, preferably 0 to 50 0

C.

i The acid addition salts of the compounds according to the invention are prepared in a customary manner, for example by dissolving the betaine in an adequate amount of aque- 25 ous acid and precipitating the salt using a watermiscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent amounts of betaine 28 -I e L I__ and acid can also be heated in water or an alcohol such as glycol monomethyl ether and then evaporated to dryness or the precipitated salt filtered off with suction.

Pharmaceutically utilizable salts are to be understood as meaning, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. The compounds according to the invention can also be bound to acidic or basic ion exchangers.

The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in insufficient 15 alkali metal or alkaline earth metal hydroxide solution, filtering undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable salts are those of sodium, potassium or calcium. The corresponding silver salts are obtained by reaction of an alkali metal or alkaline earth metal salt with a suitable silver salt d.;o such as silver nitrate.

The compounds according to the invention have a strong antibiotic action and exhibit, together with low toxicity, a wide antibacterial spectrum against Gram-positive and Gram-negative microorganisms, in particular even against those which are resistant to various antibiotics, such as e.g. penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines.

29 I, _~U These useful properties make possible their use, as chemotherapeutic agents in medicine and veterinary medicine and as substances for the preservation of inorganic and organic materials, in particular of organic materials of all types, e.g. polymers, lubricants, dyes, fibres, leather, paper and wood, foodstuffs and water.

The compounds according to the invention are active against a very wide spectrum of microorganisms. Gramnegative and Gram-positive bacteria and bacteria-like microorganisms can be controlled using them and the diseases caused by these pathogens prevented, ameliorated and/or cured.

*ooo The compounds according to the invention are distinguished by increased action on dormant and resistant 15 microorganisms. In the case of dormant bacteria, i.e.

bacteria which exhibit no detectable growth, the compounds act below the concentrations of similar substances. This relates not only to the amount to be employed, but also to the rates of destruction. It was 20 possible to observe such results in Gram-positive and -negative bacteria, in particular in Micrococcus luteus and Acinetobacter.

The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms.

They are therefore particularly highly suitable for the prophylaxis and chemotherapy in human and veterinary medicine of local and systemic infections which are Le A30 351 30 _g g caused by these pathogens.

The compounds are further suitable for the control of protozoonoses and helminthoses.

The compounds according to the invention can be used in various pharmaceutical preparations. Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, injections and oral administerable solutions, suspensions and emulsions, and also pastes, ointments, gels, creams, lotions, powders and sprays.

o The active compounds have favourable toxicity to warmblooded animals and are preferably suitable for the control of bacterial diseases which occur in productive, breeding, zoo, laboratory and experimental animals and 4 pets in animal keeping and animal breeding. They are active here against all or individual stages of development and against resistant and normally sensitive strains. By control of the bacterial diseases, illness, cases of death and yield decreases in the production of meat, milk, wool, hides, eggs, honey etc.) should be decreased, so that more economical and simpler animal keeping is possible as a result of the use of the active compounds.

The productive and breeding animals include mammals such as e.g. cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur- 31 bearing animals such as e.g. mink, chinchilla, racoon, birds suh as e.g. hens, geese, turkeys, ducks, doves and species of birds for keeping at home and in zoos. They further include productive and ornamental fish.

The laboratory and experimental animals include mice, rats, guinea-pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

The fish include productive, breeding, aquarium and ornamental fish of all ages, which live in fresh and salt 10 water. The productive and breeding fish include e.g.

carp, eel, trout, whitefish, salmon, bream, roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanese eel (Anguilla japonica), red seabream (Pagurus major), sea bass (Dicentrarchus labrax), grey mullet (Mugilus eephalus), pompano, gilthread seabream (Sparus auratus), Tilapia spp,, Chichlidae species such as e.g. Plagioscion, channel catfish.

S

The agents according to the invention are particularly suitable for the treatment of fry, e.g. carp of 2 4 cm body length. The agents are also very highly suitable in eel breeding.

9 9 Administration can be carried out both prophylactically and therapeutically.

Administration of the active compounds is carried out directly or enterally, parenterally, dermally or nasally L9_ A30 351 32 I in the form of suitable preparations.

Enteral administration of the active compounds is carried out e.g. orally in the form of powders, suppositories, tablets, capsules, pastes, drinks, granules, drenches, boli, medicated feed or drinking water. Dermal administration is carried out e.g. in the form of dipping, spraying, bathing, washing, spraying-on and spotting-on and dusting. Parenteral administration is carried out e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

P.o see 0 .11 s**s g* on 0 :15 9 06 020 Suitable preparations are: solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, sprayon formulations, gels; emulsions and suspensions for oral or dermal administration and for injection; semi-solid preparations; formulations in which the active compound is processed in an ointment base or in an oil-in-water or water-in-oil emulsion base; solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boli, capsules; aerosols and inhalants, active compound-containing moulded articles.

33

I

Injection solutions are administered intravenously, intramuscularly and subcutaneously.

Injection solut.ons are prepared by dissolving the active compound in a suitable solvent and adding possible additives such as solubilizers, acids, bases, buffer salts, antioxidants or preservatives. The solutions are sterile filtered and bottled.

Solvents which may be mentioned are: physiologically tolerable solvents such as water, alcohols such as ethanol, butanol, benzyl acohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, and mixtures thereof.

The active compounds can optionally also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.

Solubilizers which may be mentioned are: solvents which promote the solution of the active compound in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyethoxylated castor oil, polyethoxy- 20 lated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid esters, n-butanol.

Oral solutions are administered directly. Concentrates are administered orally after prior dilution to the 34 I -I administration concentration. Oral solutions and conceatrates are prepared as described above uvder the injection solutions, it being possible to dispense with sterile operation.

Solutions for use on the skin are applied in drops, spread on, rubbed in, sprayed on, splashed on or applied by dipping, bathing or washing. These solutions are prepared as described above under injection solutions.

It may be advantageous to add thickening agents during preparation. Thickening agents are: inorganic thickening agents such as bentonites, colloidal silica, aluminium monostearate, organic thickening agents such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.

Gels are applied to or spread on the skin or introduced into body cavities. Gels are prepared by treating solutions which have been prepared as described under injection solutions with an amount of thickening agent such that: a clear material having an ointment-like consistency results. The thickening agents employed are the thickening agents given-further above.

Pouring-on formulations are lured onto or sprayed ontor restricted areas of the skin, the active compound either penetrating the skin and acting systemically or being distributed on the body surface.

35 Pouring-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable skin-compatible solvents or solvent mixtures. Other auxiliaries such as colorants, absorption-promoting substances, antioxidants, light screens or adhesives are optionally added.

Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylens glycols, glycerol, aromatic alcohols such as renzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic 15 and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone or 2dimethyl-4-oxy-methylene-1,3-dioxolane.

Colorants are all colorants permitted for use on animals and which can be dissolved or suspended.

Absorption-promoting substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides or fatty alcohols.

Antioxidants are sulphites or metabisulphites such as potassium metabisulphite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole and tocopherol.

36

I-

Light screens are e.g. substances of the benzophenone class or novantisolic acid.

Adhesives are e.g. cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, and gelatine.

Emulsions can be administered orally, dermally or as injections.

Emulsions are either of the water-in-oil type or of the oil-in-water type.

10 They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and homogenizing this with the solvent of the other phase with the aid of suitable emulsifiers and optionally other auxiliaries such as colorants, absorption-promoting substances, preservatives, antioxidants, light screens and viscosity-increasing substances.

Hydrophobic phases (oils) which may be mentioned are: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic 20 triglycerides such as caprylic/capric acid biglyceride, triglyceride mixture with vegetable fatty acids of chain length C 8 .12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids possibly also containing hydroxyl groups, mono- and diglycerides of Ce/C, 1 -fatty acids.

L~e A30r 351 37

I

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length containing saturated fatty alcohols of chain length C 16

C

1 i, isopropyl myristate, isopropyl palmitate, caprylic/ capric acid esters of saturated fatty alcohols of chain length C 1 2

-C

18 isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters such as dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, inter alia fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol and oleyl alcohol.

Fatty acids such as e.g. oleic acid and their mixtures.

S

Hydrophilic phases which may be mentioned are: 15 water, alcohols such as e.g. propylene glycol, glycerol, sorbitol and their mixtures.

Emulsifiers which may be mentioned are: non-ionic surfactants, e.g. polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glyceryl nonostearate, polyoxythsyl stearate, alkylphenol polyglycol ether; ampholytic surfactants such as di-Na N-lauryl-p-iminodipropionate or lecithin; anionic surfactants, such as Na laurylsulphate, fatty alcohol ether sulphates, mono/dialkyl polyglycol ether I orthophosphoric acid ester monoethanolamine salt; cationic surfactants such as cetyltrimethylammonium chloride.

Further auxiliaries which may be mentioned are: viscosity-increasing and emulsion-stabilizing substances such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances mentioned.

Suspensions can be administered orally, dermally or as an injection. They are prepared by suspending the active S..compound in a vehicle, optionally with the addition of other auxiliaries such as wetting agents, colorants, absorption-promoting substances, preservatives, antioxidants light screens.

Vehicles which may be mentioned are all homogeneous solvents and solvent mixtures.

20 Wetting agents (dispersing agents) which may be mentioned are the surfactants given further above.

Further auxiliaries which may be mentioned are those given further above.

LeA30-351 39

I"-

Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only by their higher viscosity.

For the production of solid preparations, the active compound is mixed with suitable excipients, optionally with the addition of auxiliaries, and brought into the desired form.

Excipients which may be mentioned are all physiologically tolerable solid inert substances. All such serve inorganic and organic substances. Inorganic substances are e.g. sodium chloride, carbonates such as calcium carbono ate, hydrogen carbonates, aluminas, silicic acids, clays, precipitated or colloidal silica, phosphates.

Organic substances, e.g. sugar, cellulose, foodstuffs and feeds such as milk powder, animal meals, cereal flours and meals, starches.

Auxiliaries are preservatives, antioxidants and colorants which have already been mentioned above.

Other suitable auxiliaries are lubricants and glidants 20 such as e.g. magnesium stearate, stearic acid, talc, bentonites, disintegration-promoting substances such as starch or crosslinked polyvinylpyrrolidone, binding agents such as e.g. starch, gelatine or linear polyvinylpyrrolidone, and dry binding agents such as microcrystalline cellulose.

40 The active compounds can also be present in the preparations in a mixture with synergists or with other active compounds.

Ready-for-use preparations contain the active compound in concentrations of 10 ppm 20 per cent by weight, preferably from 0.1 to 10 per cent by weight.

Preparations which are diluted before use contain the active compound in concentrations of 0.5 90 per cent by weight, preferably of 1 to 50 per cent by weight.

10 In general, it has proven advantageous to administer 0o amounts of about 0.5 to about 50 mg, preferably 1 to mg, of active compound per kg of body weight per day to achieve effective results.

The active compounds can also be administered together 15 with the feed or drinking water of the animals..

Feed and foodstuffs contain 0.01 to 100 ppm, preferably 0.5 to 50 ppm, of the active compound in combination with a suitable edible material.

Such a feed and foodstuff can be used both forcurative purposes and for prophylactic purposes.

Such a feed or foodstuff is prepared by mixing a concentratz or a premix which contains 0.5 to 30%, preferably 1 to 20% by weight, of an active compound in a mixture with 41

I

an edible organic or inorganic carrier with customary feeds. Edible carriers are e.g. maize flour or maize and soyabean flour or mineral salts which preferably contain a small amount of an edible dust-preventing oil, e.g.

maize oil or soya oil. The premix obtained in this process can then be added to the complete feed before feeding it to the animals.

The minimum inhibitory concentrations (MIC) of the compounds according to the invention were determined by serial dilution methods on Iso-Sensitest agar (Oxoid).

For each test substance, a series of agar plates were prepared which contained decreasing concentrations of the active compound at, in each case, double dilution. The agar plates were inoculated with a multipoint inoculator 15 (Denley). For -inoculation, overnight cultures of the pathogens were used which had previously been diluted such that each inoculation point contained about 104 colony-forming particles. The inoculated agar plates were *o incubated at 37*C, and the growth of microorganisms was read off after about 20 hours. The MIC value (ig/ml) indicates the lowest active compound concentration at which no growth was to be detected with the naked eye.

The MIC values of some of the compounds according to the invention are shown in the table below.

Le A30 351 42 Table: MIC values Species Strain Example No.

2 3 5 E. ccli Neumann 0.015 0.06 0.015 0.06 ATCC 25922 0.015 0.06 0.03 0.06 Kiebsiella 8085 0.06 0.12 0.25 0.12 pneumoniae Acineto- 14068 0.015 0.015 0.015 0.015 bacter Micrococcus 9341 0.015 0.015 0.015 0.015 luteus

S.

S S SSS S S 555 5 *5

S

S

S5

S

0 00 43 Preparation of the active compoQunds 8-Amino-9.-fluoro-3 -methyl-lO- (l-piperazinvl)I2.-oz.- 2.3-dihvdro-7H-pyrido[1.2.3-d~e1 r13.41benzoaiazine- 6-carboxylic acid 100 mg (0.337 ramol) of 8-amino-9,10-difluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e] -benzoxadiazine-6-carboxylic acid are heated at 120*C under argon 10 fe -r two hours with 58 mg (0.673 inmol) of piperazine in 3 ml of DMASO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 112 mg (92% of theory) Melting point: >300*C- 44 .xmple 2

NH

2 0 F OOOH N N MeN 0 NM 8 -Amino- 9- fluaro-3 -methyl-10 (4 -methyl- -piVerazinyl) 2-oxo-2. 3-dihydro-7H-vrdirl.3-d.ei rl.4benzoxadiazine-6-carbxy1icqaaI4 100O mg (0.337 mmol) of 8 -amino- 9, 10-dif luoro-3 -methy- 7-oxo-2,3-dihydro-7H-pyrido[l,2,3-d,eJ [1,3,4J -benzoxadiazine-6-carboxylic acid are heated at 120*C under argon *too*:for four hours with 67 mg (0.673 nimol) of 1-methylpiperazine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 100 mg (79% of theory) 0:0. Melting point: >300 0

C

NH

2 0 F COOH

I

3

I

H 3 C" N)

N"

3y 45 ~0

U

e U. U 8-Amino-9-fluoro-3-methyl-1o- (3-methyl-l-riperalzinyl) 7-oxo-2,3-dihvdro-7H-pyridor2.3-d~el [j,__4jlbenZoXadi- Azine-6-carb~oxylji acid 100 mg (0.337 mmol) of 8 -amino- 9, 10-dif luoro-3 -methyl- 7-oxo-2,3-dihydro-7H-pyrido[l,2,3-d,e '1 -ben-oxadiazine-6-carboxylic acid are heated at l20*C'under argon for four hours with 67 mg (0,673 mmol) of 2-methylpiperazine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 96 mg (76% of theory) Melting point: 280*C (with decomposition)

NH

2 0 F COOH

H

3 C N N

H

3

C

vl)-7-oxo-2 3dihydrc-7H-Pyridorl.2.-3-d~eI rl.3j.4gzoxa- LAL~ U 100 mg (0.337 mmol) of 8 -amino- 9, 10-dif luoro-3 -methyl 7-oxo-2,3-dihydro-7U--pyrido El,2,3-d,eI LA0 35 46 benzoxadiazine-6-carboxylic acid are heated at 120 0

C

under argon for two hours with 77 mg 673 mmol) of 2, 6dimethylpiperazine in 3 ml of DMSO. The mixture is concentrated in high vacuum, and the rasidue is recrystallized from ethanol and dried.

Yield: 108 mg (82% of theory) Melting point: 280*C

NH

2 0 F, CQOH N N

HO

Me mn-- lur--ehl1.( hyrw--yrldnj g(.37mo)o 8-amino-9,1-dfluoro-3-methyl-1-3hdox1proiin) 7-oxo-2,3-dihydro-7H-pyrido[l,2,3-d,eI [l,3,4J -benzoxadi- :15 azine-6-carboxylic acid: are heated at 120 0 C under argon for two hours with 59 mg (0.673 mmol) oZ 3-hydrox,.jpyrrolidine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 93 mg (76% of theory) Melting point: >300 0

C

Le A3-35471 47 .1 Ex'WPJ1p. 6 F COOH 6~Y N Me jmino -9-fluoro-3-methyl-10- (1-pr.r.1idinyl) -7-oxo 2,3-dihydro-7B-Pyriogr.2.3-d l r1, 3.41 benzoxai njQ 6-arbo xlic acid 100 mg (0.337 mmol) of 8-amino-9,l0-difluoro-3 -methyl-7oxo-2,3-dihydro-7H-pyrido[l,2,3-d,eI [1,3,41 -benzoxadi- *.*azine-6-carboxylic acid are heated at 1200C under argon for two hours with 48 mg (0.673 nmol) of pyrrolidine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 80 mg (68% of theory) Melting point: >300 0

C

-NH 2 0 F COOH

I

N #N 0j 0, N, M Le A30 351 -48 s~ Y a-Amino-9-fluor--mty-O-(moroin)--o- 2.3-dihydro-7H-py3ridotfl,2.3-d~eI T1.3,A41 Nenzoxadiazine= 6-carboxylic acid 100 mng (0.337 nmol) of 8-amino-9,1O-difluoro-3-met-hyl- 7-oxo-2,3-dihydro-7H-pyrido[l,2,3-d,eI [1,3,4J -benzoxcadiazine-6-carboxylic acid are heated at 120"C under argon for four hours with 59 mg (0.673 znmol) of morpholine in 3 ml of DNSO. The mixture is concentrated in a high vacuumn, and the residue is recrystallized from ethanol and dried.

Yield: 99 mg (81% of theory) 0 Melting point: >300*C 0OH 0 0 0 0 9

CO

NH3 C4' -N 0 N 000CC g.ty--mrhln 100 mg(,30ml f8aio91-:f.ur--ehl 7l-oxo-23-dihydro-7H-pyrido[12,3ddel r1.3,41bezx- Le A30 351 49 benzoxadiazine-6-carboxylic acid are heated at 120 0

C

under argon for four hours with 78 mg (0.673 mmol) of 2,6-dimethylmorpholine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 88 mg (81% of theory) Melting point: >3000C NH 0 1 2 N N EtN O N'e eoeMe 8-Amino-9-fluoro-3-methyl-1O-(4-ethylpipeirazinyl)-7-oxo- 2,3-dihydro-7H-pyridofl. 23 -d.el rl.3.4benzoxadiazine- 6- carboxylic acid 100 mg (0.337 mmol) of 8-amino-9,10-difluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e] -benzoxadi- 15 azine-6-carboxylic acid are heated at 120 0 C under argon S:...for two hours with 77 mg (0.673 mmol) of 1-ethylpiperazine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 118 mg (90% of theory) Melting point: >3000C 50 I 8-Amino-9--fluoro-3-methyl-10-(ls,4S)-5-.methyl-2,5-diazabicyclo E2.2.11 hept-2-y1) -2-oxo-2.3-dihydro-7H-pyridorl23-d.el r1.3,41benzoaizn--abxlcai 100 mg (0.337 inmol) of 8 -amino- 9, 10-difluoro- 3-methyl 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,eJ [1,3,41 -benzoxadiazize-6-carboxylic acid are heated at 120*W% under argon for two hours with 76 mg (0.673 mmol) of (1S,4S) -5-methyl-2,5-diazabicyclo[2.2.1]heptane in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 112 mg (85% of theory) Melting point: 270WC (decomposition) 15 x le1 NH 2 0 F, COOH 1LA30 351 51 8-Amino- 9-f hro-3-methvl-1 (1-imidazolyl) 7 -rAQ 2,3-di1ivdro-7H-p2yridor,2.3-d.eI rl,3.4benZoxadia-zzn.e- 6-carboxylic acid 100 mg (0.337 mmol) of 8-amino-9,10-difjluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e] [1,3,41 -benzoxadiazine-6-carboxylio. acid are heated at 120*C under argon for six hours with 46 mg (0.673 mmol) of imidazole in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 60 mg (76% of theory) Melting point: >300*C

NH

2 0 F COOH

N

~.:H2N N NI N, Me 8-Amino-9-fluoro-3-metbv-1-10-(3-amino-l-pyrrolidinyl) 7-oxo-2,3-dihydroQ-7H-pyridolrl,2,3-d.eI fl.3.4lbenzoQxadiazing-6-c rbozylic aci trifluoroacetatg a) 8-Amino-9-fluoromethyl-10- (tert-butoxycarbonylamino) -1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido- [1,2,3-d,eJ [1,3,4]benzoxadiazine-6-carboxylic acid 52

I

100 mg (0.337 mmol) of 8-aznino-9,10-difluoro-3-inethyl-7oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e] -benzoxadiazine-6-carboxylic acid are heated at 120*C under argon for two hours with 125 mg (0.673 im~ol) of 3- (tert-butoxycarbonylamnino)-pyrrolidine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 122 mg (78% of theory) Melting point: 275*C b) 8-Amino-9-fluoromethyl-10-(3-amino.-l-pyrrolidinyl) 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,eI [1,3,4]benzoxadiazine-6-carboxylic acid trifluororacetate 80 mg (0.17 mmol) of the product from stage a) are dissolved in 2 ml of trifluoroacetic acid with icecooling, the solution is concentrated in vacuo, and the residue is crystallized from ethanol and dried.

Yield: 70 mg (86% of theory) Melting point: 260*C Examle 13

NH

2 0 *F COOH

N

N N1 HN0 0 N, Me MeO 53 B-Ami.no-9-fluoro-3-methyl-10- (3-methoxy-3-methyaInomethyl-I-pyrrglidinyl) -7-oxo-2.3-dihydro-7H.pyridor1.2.3d.el rI.3.41benzoxpdiazin arboxylic acid 100 mg (0.337 mmol) of 8-amino-9,10-difluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[l,2,3-d,e] -benzoxadiazine-6-carboxylic acid are heated at 1201C under argon for two hours with 97 mg (0.673 mmol) of 3-methoxy- 3-methylaniinomethylpyrrolidine in 3 ml of DMSO. The mixture is concentrated in a high vacuum, and the residue is recrystallized from ethanol and dried.

Yield: 106 mg (75% of theory) Melting point: 238-240*C Preparation of startinr compounds 9,10-Difluro- 3-methyl 8-nitro- 7-oxo-_2,3_-dihydro- 71{-pyridorI,2,3-d~gI [1.3.41 -benzoxadiazine-6-carboxyrlic acid 3.7 g (36.6 mmol) of potassium nitrate are added in portions to 7.0 g (24.8 mmol) of 9,l0-difluro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,eJ -benzoxadiazine-6-carboxylic acid-, dissolved in 90 ml of concentrated sulphuric acid, and stirred at room temperature for one hour. The reaction mixture is added to 270 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried.

Yield: 6.9 g (85% of theory) Melting point: >300*C 54 8-Amino-9,10-diftluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido el l. 3.41benzoxadiazine-6 -carboxylic g (12.2 mmol) of 9,10-difluro-3-methyl-8-nitro-7-oxo- 2,3-dihydro-7H-pyrido[l,2,3-d,e] [1,3,4 -benzoxadiazine- 6-carboxylic acid and 1.2 g of palladium on active carbon palladium) are suspended in 280 ml of ethanol and hydrogenated at room temperature under normal pressure for two days. The reaction mixture is treated with 280 ml of water and then adjusted to pH 10-11 with 2N sodium hydroxide solution. The hydrogenation catalyst is filtered off and the filtrate is adjusted to pH 5-6 with 2N hydrochloric acid. The resulting precipitate is filtered off, washed with methanol and dried (Fraction A).

15 The hydrogenation catalyst filtered off is heated under reflux for one hour three times in 100 1 of dimethylformamide (DMF) each time and then filtered off again.

The combined DMF solutions are concentrated in vacuo and dried (Fraction B).

Yield: 3.0 g (83% of theory) Melting point: >300 0

C

Le A30 351 55 I st---1 I

Claims (5)

1. 8-Amino-pyrido[l,2,3-d,eJ [1,3,4Jbenzoxadiazine derivatives of the general form,,xla (I) .COOB (I),1 5 in which A represents amino or alkylamino, R 1 represents hydrogen or C 2 -C 3 -alkyl which is optionally substituted by hydroxyl or halogen, R 2 independently of R' represents hydrogen or methyl, R 3 represents hyarogen or Cl-C 4 -alkyl, B represents hydrogen, alkyl having 1 to 4 carbon atoms, which is optionally substituted by hydroxyl, methoxy, amino, methylainino or di- methylainino, or (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl, S 351 56 X1 represents hydrogen or halogen, Z represent~i radicals with the structures 1 I~, 'R R N R 4 ND N .qY 6 6 *6t 66 4 S 0** 4 S 6t 4 Ir 6 NR' 0 R 1 N- R 9 R 1 2 R R 14 1 N R i R 1 N- N- in which R 4 represents hydrogen, straight-chain or branched C,-C 4 -alkyl which is optionally substituted by hydroxyl or methoxy, cyclopropyl, acyl having 1 to 3 C atoms, 57 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R 6 represents hydrogen or C 1 4 -alkyl, R 7 represents hydrogen or C 1 4 -alkyl, R8 represents hydrogen or C 1 4 -alkyl, R 9 represents hydrogen, methyl or -CH 2 -NR 7 R 8 3, R 10 represents hydrogen, C 1 4 -alkyl, amino, alkyl- or dialkylamino having 1 or 2 C ~:atoms in the alkyl moiety and optionally .10 substituted b, hydroxyl, amino-C.. 4 -alkyl, 1 4 -alkyl-amino-Cl- 4 -alkyl or 1-imidazolyl, R1- represents hydrogen, hydroxyl, methoxy, methylthio, halogen, methyl, hydroxy- methyl, R 12 represents hydrogen or methyl, R 3 represents hydrogen or C 1 4 -alkyl, R 4 represents hydrogen or C 1 4 -alkyl and R's represents hydrogen or C 1 4 -alkyl. in the form of racemates or as enantiomerically pure 58 Vat* compounds, their pharmaceutically utilizable hydrates and acid addition salts, and their salts with bases.

2. Process for the preparation of the compounds of the formula (I) A 0 9 9 *999

9. 9 in which A represents amino or alkylamino, R 1 represents hydrogen or C 1 -C 3 -alkyl which is optionally substituted by hydroxyl or halogen, R 2 independently of R' represents hydrogen or methyl, R 3 represents hydrogen or CI-C 4 -alkyl, B represents hydrogen, alkyl having 1 to 4 carbon atoms, which is optionally substituted by hydroxyl, methoxy, amino, methylamino or Le A30 351 59 ~p-I dixnethylamino, or (5-methyl-2-oxo-:l,3-ditoxol-4- yl) -methyl, represents hydrogen or halogen, represents radicals with the structures R

11-1 R 4.-NT N N r 8* S *5 S 0t S S d 0 S S. 5* 9 S R 9 R 2 N- N N R 13 R~ 14NN N R /i in which R 4 represents hydrogen, straight-chain or branched Le A30 351 -6 60 CY 1 -C-alkyl which is optionally substituted by hydroxyl or methoxy, cyclopropyl, acyl having 1 to 3 C atoms, R 5 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R6 represents hydrogen Or C 1 4 -alkyl, R7 represents hydrogen or C 1 4 -alkyl, Re represents hydrogen or C,. 4 -alkyl, R 9 represents hydrogen, methyl or -CH 2 NRR', 3- 0 represents hydrogen, C 1 4 -alkyl, amino, alkyl- or dialkylainino having 1 or 2 C atoms in the alkyl moiety and optionally ~:substituted by hydroxyl, amino-CI- 4 -alkyl, *C 1 4 alkyl -amino- C 1 4 alkyl or 1-imidazolyl, R" rep!''sents hydrogen, hydroxyl, inethoxy, methylthio, halogen, methyl, hydroxy- methyl, R 12 represents hydrogen or methyl, R 1 3 represents hydrogen or C 1 4 -alkyl, R 14 represents hydrogen or C 1 4 -alkyl and 6 R 15 represents hydrogen or C 1 4 -alky., characterized in that compounds of the formula (II) A 0 x 0 N R R XIR)2 in which K: R 2 B and X1 have the meaning given above and x 2 represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula ((III) Z-H (III) .Z.L0 in which Z has the meaning given above, if appropriate in the presence of acid acceptors. 3. Compounds of the formula (11) 62 '~N 0 N- R 3 RIXKR 2(I in which R 1 R 2 R 3 B and X 1 have the meaning given above and *x2 represents halogen, in particoular fluorine or S. chlorine, 4. Process for the preparation of the compounds of the formula (11) NH 2 0 CB N 0 R 3 R R in which R 1 R 2 R 3 B and XI have the menning given above and 63 S S 6*S S~ X 2 represents halogen, in particular fluorine or chlorine, characterized in that compounds of the formula (IV) 0 COOB I I O NI 3 SR1 R R R (IV), in which R 1 R 2 R 3 B, X 1 and X 2 have the meaning given above, are reacted with nitrating reagents such as nitric acid and nitrates in a solvent such as, for example, water, sulphuric acid, acetic acid, acetic anhydride or their miP, ures at -50°C to 200°C, preferably at 0 C to 100°C, and the nitro compounds obtained are then reduced. 5. Compounds of the formula according to-Claim 1, in which A represents amino, R I represents hydrogen or Ci-C 3 -alkyl which is S Le A30 351 64 optionally substituted by OH, R 2 independently of R 1 represents hydrogen or methyl, R 3 represents hydrogen, methyl or ethyl, B represents hydrogen, alkyl having 1 to 4 carbon atoms, which is optionally substituted by hydroxyl, methoxy, amino, methylamino or dimeth- ylamino, or (5-methyl-2-oxo-l,3-dioxol-4-yl)- methyl, 10 X L represents hydrogen, fluorine or chlorine, Z represents radicals with the structures R N R NN N R4/ R4/N R 4 S* R 5 R 6 10 R14 R 13 i* N R1"N R N N- N N- R 9 R in which 65 I R' represents hydrogen, straight-chain or branched C 1 -C 3 -alkyl optionally substituted by hydroxyl, or methoxy, R 5 represents hydrogen, methyl or phenyl, R' represents hydrogen or methyl, R 7 represents hydrogen or methyl, R 9 represents hydrogen, methyl or -CH 2 NH,, R 1 0 represents hydrogen, methyl, amino, methyl- amino, dimethylamino, aminomethyl, methylamino- S0L methyl or ethylaminomethyl, R 1 1 represents hydrogen, hydroxyl, methyl, fluor- S" ine, methyl or hydroxymethyl, R 1 3 represents hydrogen or methyl, t. R 14 represents hydrogen or methyl, R 15 represents hydrogen or methyl. 6. Medicaments containing compounds of the formula (I) according to Claim 1. 9 7. Use of compounds of the formula according to Claim 1 for the production of medicaments. Le A30 351 66 I '3008T/yls

67- 8. Use of compounds of the formula according to Claim 1 in antibacterial compositions. 9. A method for the treatment of prophylaxis of bacterial diseases in animals or fish which comprises administering to said animals or fish a therpeutically effective amount of at least one compound according to any one of claims 1 to 6 optionally in association with one or more pharmaceutically or veterinary carriers and/or excipients. An antibacterial composition which comprises a compound of the formula according to claim 1 in association with one or more pharmaceutical or veterinary carriers and/or excipients. 11. An animal or fish foodstuff which contains at least one compound of the forumula according to claim 1. 12. A compound of the formula according to claim 1 substantially as hereinbefore described with reference to the Examples. 13. Compounds according to any one of claims 1 to 5 methods for their manufacture or pharaceutical/veterinary compositions or methods of treatment involving/containing them, substantially as hereinbefore described with reference to the Examples. DATED this 19th day of APRIL 1995 BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys DAVIES COLLISON CAVE s. 8-Amino-pyridorl,2.3-d~el F.3.41benzoxadiazine deriva- tives A bs tr ac t The present invention relates to new 8-amino-pyrido- [l,2,3-d,el [1,3,4Jbenzoxadiazine derivatives of the general formula (1) .*0 9 0 I I 0 XN R IKR 2 (I),I in which A represents amino or alkylamino, and the other radicals have the meaning given in the description, processes for their preparation and their use in antibacterial comapositions. Le 30