IE61624B1 - Tricyclic compounds - Google Patents

Abstract

The invention is concerned with tricyclic compounds of the general formula <IMG> (I) wherein R1 is a hydrogen atom or a carboxy-protecting radical; R2 is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom; R3 and R4 independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or a substituted or unsubstituted amino radical; X is a halogen atom; and R5 and R6 are independently a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical, a lower alkoxy radical or a substituted or unsubstituted amino radical; or R5 and R6, taken together with the adjacent nitrogen atom, may form a 5 to 7 membered heterocyclic ring which may be substituted with one or more substituents at the carbon atom(s), and the heterocyclic ring may further contain -NR7-, -O-, -S-, -SO-, -SO2- or -NR7-CO-, ¢R7 is a hydrogen atom, a lower alkenyl radical, a lower alkyl or aralkyl radical which may be substituted, or a radical represented by the general formula -(CH2)nCOR8 (II) (in which n is 0 to 4 and R8 is a hydrogen atom, a lower alkoxy radical, or an amino, lower alkyl or aryl radical which may be substituted)!, as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula I or their salts. Also included is a process for the manufacture of these compounds, pharmaceutical preparations containing them and intermediates useful in said process. The end products have antimicrobial antivity. [CA1336905C]

Description

Description The present invention relates to novel pyrido[3,2,1-ij]1,3,4-benzoxadiazine derivatives, a process for their manufacture, corresponding pharmaceutical preparations and inter5 mediates usable in the process. More particularly, the invention relates to novel pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine derivatives of the general formula in which R represents 1-piperazinyl which can be substituted in the 4-posiiion by methyl, acetyl or 4-aminobenzvl; morpholino; -pyrrolidino substituted in the 3-position by amino, aminomethyl, (methyl-amino)methyl, (ethylamino)methyl, 1C methoxy or chlorine; 1-imidazolyl which can be substituted in the 4-position by methyl; or 1-piperidyl substituted in the 4-position by hydroxy or methoxy, 2θ as well as pharmaceutically acceptable salts thereof and hydrates or solvates of the compounds of formula I or of their salts. These products can be used as active ingredients in antibacterially active preparations.

The novel pyrido[3,2,1,3,4-benzoxadiazine derivatives of formula (I) and their pharmaceutically acceptable salts as well as the hydrates or solvates thereof and of their salts are manufactured in accordance with the invention by a process which is characterized by (a) reacting a compound of the general formula ΪΪ in which X represents a halogen atom; and amino, hydroxy and/or carboxy groups present may be protected, with an amine of the general formula HR III in which R has the significance given above, and, if necessary, cleaving off a protecting group present, or (b) reacting a compound of the general formula in which R has the significance given above; and amino, hydroxy and/or carboxy groups present may be protected, with formaldehyde or paraformaldehyde and, if necessary, cleaving off a protecting group present, or (c) for the manufacture of a compound of formula I in which R represents 4-acetvl-1-piperazinyl, reacting the compound of formula I in which R represents the unsubstituted 1-piperazinyl residue with an agent yielding the acetyl group, or (d) for the manufacture of a compound of formula I in which R represents 3-methoxv-1 -piperidyl, methylating the corresponding 3-hvdroxy-1-piperidyl compound of formula I, or (e) for the manufacture of a compound of formula I having a free amino group R, cleaving off the amino protecting group in a corresponding compound of formula I having a protected amino group, or (f) for the manufacture of a compound of formula I in which R represents 3-chloro-1-pyrrolidinyl, halogenating the corresponding 3-hvdroxy-1-pyrrolidinyl compound having a protected carboxy group and cleaving off the carboxy group, or (g) for the manufacture of a compound of formula I in which R represents 4-(4-aminobenzyl)-l-piperazinyl, reducing the nitro group of the corresponding 4-(4-nitrobenzyl)-1-piperazinyl compound, or (h) for the manufacture of pharmaceutically acceptable salts, hydrates or solvates or a compound of formula I or of hydrates or solvates of said salts, converting a compound of formula I into a salt, hydrate or solvate or into a hydrate or solvate of said salt.

Process A: As stated above, the compounds in accordance with the invention can be obtained by reacting a compound of the general formula in which X represents a halogen atom; and amino, hydroxy and/or carboxy groups present may be protected, with an amine of the general formula c HR III □ in which R has the significance given above, whereafter, if necessary, a protecting group present is cleaved off.

Compounds of formula (II) used in accordance with the 10 invention are novel and can be prepared e.g. according to the following Reaction Scheme a) or b). reduction H5C;OCH=(COOC;H X OH (B> χ NH K5C,OOC \xCOOC2K5 I II || OH-proieclion I H lD) OH (Ci COOC2H5 methylation ---So- COOC2H3 protecting group clcavauc (Hi COOR cycl izal ion -**-- (1 Va) n h5c2ooc VC00C2Hs cyclization OH F\i>#\X^X-COOC2Hs OH-protection OH (C) OH (J) (C.) COOC2H5 protecting group cleavage (IVa) COOR (Ila) wherein X has the significance given above; R' is a protecting group such as e.g. benzyl, methoxybenzyl, methoxymethyl. meihoxyethoxymethyl. tetrahydropvranvl, allyl, t-butyl, t-butyIdimethylsilyI, acetyl, benzoyl and the like; R is a protecting group such as e.g. formyl, acetyl, trifluoroacetvl, benzoyl, ethoxycarbonvl, 2,2,2-trichloroethoxvcarbonyl, phenoxvcarbonvl, benzyloxycarbonyl, tbutoxycarbonvl and the like; and R' is a hydrogen atom or the ethyl radical.

Compounds of formula (III) which contain an amino or monoalkylamino substituent may, if desired, be protected by an amino protecting group such as e.g. formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonvl, 2,2,2-trichloroethoxvcarbonyl, phenoxycarbonvl. benzyloxycarbonyl. t-buioxycarbonvl and the like.

The reaction of the compound of formula (II) with the amine of formula (III), which may if necessary be protected, can be carried out with or without a solvent, preferably at elevated temperature until the reaction is complete. The reaction temperature conveniently lies in the range of about 30°C to about 200°C, preferably between 80°C and 150°C, in order to obtain a sufficiently fast reaction rate.

The reaction is preferably carried out in the presence of an acid acceptor such as e.g. triethylamine, pyridine, picoline, N,Ndimethvlaniline, 1,8-diazabicvclo[5.4.0]undec-7-ene, 1,4-diazabicvclo[2.2.2]octane, alkali metal hydroxides, alkali metal carbonates and the like. Alternatively, an excess of the amine of the formula (III) can be used as the acid acceptor.

Suitable solvents for this reaction are non-reactive solvents such as e.g. acetonitrile, alcohols, dimethyl sulphoxide, dimethylformamide, dimethylacetamide, pyridine, picoline, lutidine, dimethvlpropylurea and the like. Mixture of two or more solvents can also be used.

A protecting group present can, if desired, be removed after the reaction by methods known per se. For example, the formyl group can be removed by acidic or basic hydrolysis, preferably by basic hydrolysis; while the benzyloxvcarbonvl group can be removed by hydrogenolysis.

Examples of starting compounds of formula (II) are; 9,1 O-dif I uoro -3 -methy l-7-oxo-2,3-di hvdro-7 H-pyrido [3,2,1 -ij]1,3,4-benzoxadiazine-6-carboxylic acid, ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxylate, benzyl 9,1 O-dif luoro-3-methy l-7-oxo-2,3-dihvdro-7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxvlate.

The amine of formula (III) used in accordance with the invention is, for example, piperazine, 4-methvlpiperazine, morpholine. 4-hydroxvpiperidine, 4-methoxypiperidine, 3[(methvlamino)methyl]pyrrolidine. 3-[(ethy lami no) methy I]pvrrolidine, 3-methoxypyrrolidine, 3-aminopvrrolidine, 3(benzvloxycarbonvlamino)pyrrolidine, imidazole or 4-methylimidazole.

Process B: The compounds in accordance with the invention can be obtained by reacting a compound of the formula in which amino, hydroxy and/or carboxy groups present may be protected, with formaldehyde or paraformaldehyde, whereafter, if necessary a protecting group preseni is cleaved off.

The starting compounds (IV) used in accordance with the invention are novel and can be prepared according to the above Scheme a) or b) reacting a compound (H) or (IVa) with an amine of formula III.

This reaction can, if desired, be carried out in a solvent such as e.g. in dioxan, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethyl sulphoxide, dimethylpropylurea, acetic acid and the like. Mixture of two or more of these solvents can also be used.

This reaction can, if necessary, be carried out in the presence of an acidic catalyst such as e.g. acetic acidl hydrochloric acid, sulphuric acid, methanesulphonic acid, ptoluenesulphonic acid, pyridinium p-toluenesulphonate, ferric chloride, zinc chloride, chlorotrimethylsilane, Nafion-H (perfluorinated sulphonic acid resin; Aldrich Chemical Co., Inc.), Amberlvst-15 (strongly acidic macroreticular resin; Aldrich Chemical Co., Inc.), and the like.

The reaction temperature can vary within a wide range. In general, the reaction is carried out at a temperature between °C and 150°C.

Preferably, about 1 mol or a molar excess of formaldehyde or paraformaldehyde is used per mol of the compound of formula (IV).

Amino or monoalkvlamino protecting groups preseni can, if desired, be removed according to methods known per se. For example, the formyl group can be removed by acidic or basic hydrolysis, preferably by basic hydrolysis; the benzyloxycarbonyl group can be removed by hydrogenolysis.

Examples of starting compounds of formula (IV) are: ο 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3 quinolinecarboxylic acid, ethyl 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4dihydro-3-quinolinecarboxylate, benzyl 6,7-difluoro-8-hydroxv-1-(meihylamino)-4-oxo-1,4di hyd ro-3-quinoli necarboxy late, 6-f I uoro-8-hydroxy-7-(1 - imidazoly 1)-1 - (methy lamino)-4-oxo1,4-dihydro-3-quinolinecarboxylic acid, ethyl 6-fluo ro-8-h yd roxv-7-(1- imidazolyl)-'!- (methylamino)-4 oxo-1,4-dihydro-3-quinolinecarboxylate, benzyl 6-f luo ro-8-hvdroxv-7-(1 - imidazoly 1)-1 - (methyl am ino)oxo-1,4-d i h yd ro-3-qui noli necarboxy late, 6- fluoro-8-hydroxv-7-( 1 -methy la mi no)-7-(4-methy 1-1 piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 7-[3-[(benzyloxycarbonylethylamino)methy|]-l-pyrrolidinyl]-6fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3quinolinecarboxylic acid, 7- [3-[(benzyloxycarbony!amino)-1 - pyrrol idiny l]-6-f luo ro-8hydroxv-1 -(methy lami no)-4-oxo-1,4-di hyd ro-3-qu ino line20 carboxylic acid. 7-[3-[(benzy loxycarbonylmeihylami no) methy I]-4-methy 1-1 pyrrolidinyl]-6-fluoro-8-hydroxy-1 - (methy lamino)-4-oxo-1,4di hydro-3-qui noli necarboxy lie acid, 7-[3- [(benzy loxy carbony lam ino) methy l]-4-ch loro-1 25 py rrolindinyl]-6-f I uoro-8-hydroxy-1 - (methy lamino)-4-oxo-1,4 dihydro-3-quinolinecarboxylic acid, and the like.

Process C: The compound of formula I in which R represents ihe group /~λ CH3CO — N N \_/ can be manufactured from the corresponding unsubstituted 1piperazinvl compound by reaction with an agent yielding the acetyl group, e.g. acetic anhydride according to Example 18 hereinafter.

Process D: The compound of formula (I) in which R represents the group can be manufactured by methylating the corresponding compound in which R represents ihe group This O-alkylation can be carried out by reaction with a compound of the general formula CH3V (V) wherein Y represents a leaving group.

Leaving groups Y are, for example, halogen atoms such as chlorine, bromine, iodine, acyloxy residues such as e.g. acetoxy; lower alkanesulphonyloxy residues such as e.g. methanesulphonyloxy, arylsulphonvloxv residues such as e.g. p-toluenesulphonvloxv, optionally nitrated phenoxy groups such as e.g. phenoxy, 4-nitrophenoxv; or succinimidooxv or phthalimidooxv. 2 The reaction can, if necessary, be carried out in a solvent, e.g. in dimethylformamide, dimethylacetamide, dimethyl sulphoxide, dimethyl-n-propvlurea, dioxan, tetrahydrofuran, pyridine and the like. Mixture οΓ2 or more of these solvents can also be used.

The reaction is preferably carried out in the presence of an acid acceptor such as e.g. triethylamine, pyridine, N.N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydride, alkali metal hydroxides, alkali metal carbonates and the like.

The reaction temperature can vary within a relatively wide range. In general, the reaction is carried out at a temperature between about 0°C and 180°C, preferably between 0°C and 110°C. Preferably 1 to 4 mol, especially 1 to 2 mol, of methylating agent is used per mol of 3-hvdroxv-1-piperidyl compound. Methyl iodide is used e.g. as the methylating agent. Preferably, a proton acceptor such as e.g an alkali metal hydride, e.g. sodium hydride is added.

Process E: Compounds of formula I having a free amino group can be manufactured from the corresponding compounds of formula I having this amino group in protected form.

Amino protecting groups are e.g. lower alkanoyl such as e.g. acetyl; benzoyl; an alkoxycarbonyl group, e.g. t-butoxvcarbonyl or ethoxycarbonyl; a substituted alkoxy group, e.g. trichloroethoxvcarbonyl; phenoxycarbonyl; benzyloxycarbonyl; p-nitrobenzvloxvcarbonyl; an aralkyl group such as e.g. trityl or benzhydryl; or a halo-alkanoyl group such as e.g. trifluoroacetyl.

The amino protecting groups are cleavable by acidic hydrolysis (e.g. ί-butoxycarbonyl or trityl) or by basic hydrolysis 3 (e.g. trifluoracetyl). Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl are cleaved oft by hydrogenolysis.

Amino protecting groups which are cleavable by acidic hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature, although slightly higher or slightly lower temperatures, e.g. in the range of about 0°C to +40°C, can also be used. Protecting groups which are cleavable using alkali are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to +30°C.

Process F: The compound of formula I in which R represents the group can be obtained by halogenating the corresponding compound in which R represents the group The halogenating agent is preferably a thionyl halide, especially thionyl chloride; or phosphorus trichloride, phosphorus oxy20 chloride or phosphorus peniachloride. The reaction temperature preferably lies between about 0°C and 80°C. Carboxy groups which may be present are preferably protected, e.g. benzylated, and subsequently, if desired, again liberated, e.g. by hydrogenation (removal of benzyl).

Process G: The compound of formula I in which R represents the group can be manufactured by reducing the nitro group of the corresponding niircrsubstituted compound of formula I. The reduction can be effected by hydrogenation in the presence of a noble metal catalyst such as palladium/charcoal. The reaction is conveniently carried out in water or a lower alkanol, e.g. methanol or ethanol, if desired in admixture with other solvents soluble therein. The reaction temperature generally lies between about 10°C and about 40°C, preferably at about room temperature.

Process H: The manufacture of pharmaceutically acceptable salts of fhe compounds of formula I or of hydrates or solvates of these salts can be carried out in a manner known per se; e.g. by reacting a carboxylic acid of formula I with an equivalent amount of the corresponding base or, conversely, by reacting a free base of formula I with an organic or inorganic acid. The reaction is conveniently carried out in a solvent, e.g. in water or in an organic solvent (e.g. ethanol, methanol, acetone or the like). The temperature of the salt formation is not critical, it generally lies at room temperature, but it can be carried out at a temperature slightly thereover or thereunder, for example in the range of 0°C to +50°C, Examples of therapeutically acceptable acids usable in the above process are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hvdroxymaleic acid, phenylacetic acid, benzoic acid. 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, aminosalicylic acid, nicotinic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, benzenesulphionic acid, p-toluenesulphonic acid, gluconic acid, glucuronic acid, galacturonic acid, aspartic acid and glutamic acid; methionine, tryptophan, lysine, arginine and the like.

The acid addition salts can be converted into the free form by treatment with a base such as e.g. a metal hydroxide, ammonia or the like.

The base salts of the compounds of formula I can be obtained by reacting a compound of formula I with a metal base or an'amine such as e.g. with an alkali or alkaline earth metal hydroxide or an organic amine. Examples of corresponding metal cations are sodium, potassium, magnesium, calcium and the like. Examples of amines are diethylanolamine, dibenzvlethylenediamine, choline, ethylenediamine and the like.

The acid addition salts or base salts of the compounds of formula I differ from the corresponding free form in certain physical properties such as e.g. by their solubility in water.

The compounds of formula I and their pharmaceutically acceptable salts can exist in unsolvated or solvated form, including hydrated form. The hydration can be effected automatically in the course of the manufacturing process or can occur 2o gradually as a result or hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous product can be exposed to a moist atmosphere, e.g. at about +1O°C io +40°C. Solvates with pharmaceutically acceptable solvents such as e.g. ethanol can be obtained, for example, during crystallization.

The compounds in accordance with the present invention exhibit a broad spectrum antibacterial activity against grampositive and gram-negative microorganisms and Mycoplasma; they can be used as agents for treatment and prophylaxis of infectious disease. The in vitro and in vivo antibacterial activity of the compounds in accordance with the present invention are illustrated as follows: 6 1. In vitro antibacterial activity The in vitro antibacterial activity of representative compounds in accordance with the invention was assayed using the agar dilution method [Chemotherapy, 22. 1126 (1974)].

Minimum inhibitory concentrations (in pg/ml) are set forth in Tables 1 and 2. <ο <ο 0 O O o m 07 co to O co O 9— *“ CM CM 0 co fx m *— rx m CM O O ό O 0 0 0 — ό ό CM ό m to ο ο 0) 0) 0 07 o CO co 00 to to 0 m co m 07 *n co co co CM -- m — tx m in CM CM CM CO CM ό 0 ό ό O co CM co 0 — O tb co to ό tb οο ο 0 07 o O 07 07 in m co m in 07 m co 0 CO CM ·“ co CO m CM CM — CM CM co CM 0 Vll ό O O 0 0 CM tO to ro tb tb ό m tn co m ο cm in m CM tb ο ο ο vl to co co co co co 0 0 m 0 0 0 co 0 0 0 CM 0 co co 0 o O 0 co (D m 0 m 0 0 0 0 *” m rx — CM ·— 0 — m CM 0 CM 0 0 0 ό 0 0 co CM 0 ό O O ό co — tb 0 tb m ό vi vl vi — vl vl CM Antimicrobial spectrum MIC (ug/ml) C □ O rx Q.

E O O ε (Λ C (ϋ δ ο υ ο φ < Α ιΛ ΟΙ CM Ο CO moor) Ο CM CM Ο Ο Ο Ο Ο Ο co co m co co co co tD ·— 0 ο- 9— 0 o to 0 0 α 0 0 — m 0 0 ό 0 ό 0 — m to ο ο — ο co co ο ο CM ο m 0 07 O 07 O CO co 0 0 0 0 m CM 07 to co m to 0 to m O 0 CM CO CM CO CM — — — — — — 0 CO in rx 0 m CM 0 O O O O O CO co 0 0 0 0 0 0 - 0 0 - to O co m O m CM O O to in 0 m m m co 0) co C7 m CM CD m m CM 0 0 ·— O — m CM — 0 0 0 O co — CO 0 rx CM O 0 0 O O O O — to 0 0 0 0 0 0 co O O O to O co m m m — in o CM o 0 to in 0 in o o C\J co m to CM 07 in CM 0 0 CM 0 CM ·— m CM CM 0 ·- 0 f*. CM m 0 co CM 0 ό ό O 0 0 ό — to O 0 ό 0 ό ό to - 0 ό to 0 co 0 m 0 o m CM 0 rn co co 07 0 07 07 CD co co m to m 0 0 0 0 0 — co CM n co h- rx. 0 m CM ό ό 6 ό 0 ό co co 0 ό ό ό ό 6 ό ό tb ό VI CD O O O 0 cm m to 0 O co co 0 0 0 CM m to 0 0 m m CM 07 CO in to 0 0 co 0 0 CO 0 0 0 CO to m to m CO 0 0 0 in CM in GO O O O ό ό d ό O d CM to 0 d 0 ό ό co — m2 ό te CM ό Vl Vl vl vl O co co m in m co in 07 co σ» to to co »- CM CM CM 0 m O 0 co CM — co co m m m — 0 0 0 O 0 CM 5 r*. O 6 ό co 0 - m- CM co 0 0 0 O 0 0 to O 0 0 O O m σ> ο ο φ σ> co Ο co CM CM CO CO — Ο Ο Ο Ο Ο Ο (Ο ® 0 e °5) O “3 0. 2? ai 0 in cm 00 _ a DC E LL. CD (/) (/) to □ □ □ φ φ Φ δ δ δ re re re ro cm ο «σ ο σ. CM CM Or LL — vn to P Ε E δ δ 0 0 a a ω ω ra <5 V7 to to to to to — □ 0 □ O 3 — υ 0 L> (j (J 0 υ O u 0 □ O O O O 0 ω n u () u u ιΛ □ O 0 O ϋ ϋ >. >. >. >. >- JZ c £3 u re a a a a a re re re re re CD CD CD ω ω CD co co m m co co m — «— CM CM ΟΟΟ·“ Ο CO CM COOOOOO — CM CM O CM Ρχ O 0000000000000 — co — CD CO CM m tD CM 5J 07 d CM 2 (j Φ J? to u U Φ c UJ Φ > re Φ C e re O ® 5 re ω .Φ Φ Φ £3 re ρ υ re < o m to φ C Q) £ to 07 o o £ φ θ re u Φ $ ο 0 re re O 0 J to -o CM ϊ cc Z z CM <*> 0 ” if 0 0 0 CL »“ < < O re 0 Serralia marcescens IFO 12648 0 10 0 10 0 78 0.39 0.78 0 39 0 78 0 05 0 78 12 5 13 3 0.78 Salmonella lyphimurium IFO 12529 0 025 0 013 0.0033 0.10 0.05 0 025 0 10 0 0065 0.20 6.25 0.78 0.10 CD CO tD m O m 0 h- < O 0) <Ξχ < 0 - Φ ·=. 07 n re S re re -CCnjto^ a — — - C ΰ Ρ P 0 Φ 0 Φ Φ S3 - φ £ ώ ί» -0 Φ 0 □ φ □ φ c c D to to * O 0 0 UJ UJ UJ LU m ol· £ O C<1 Ο Λ ίο ?m CTf 07 CM co m cr < 2 O re re ti (/) Ε Ε E OOO 0 0 0 0 □ □ φ φ Φ to to to CL Q. U m CM Table ) (continued) Antimicrobial specirum MIC (ng/ml) Compound (Example No) Aerobic microorganism 20 22 25 Gram positive bacieria Bacillus subiilis PCI 219 0 025 0.20 0.0065 Staphylococcus aureus FDA 209P JC i 0 013 0 39 0 39 Staphylococcus aureus NR 2855 0 20 0 78 0 10 Staphylococcus aureus Smith 0. 025 0 39 0 05 Staphylococcus epidermidis IFO 12993 0 10 0.39 0.39 Staphylococcus epidermidis NR 2942 0 1 0 0 39 0.20 Enterococcus laecalis NR 2943 1 56 12 5 3 13 Gramnegaiive bacteria Alcaligenes faecalis IFO 13111 6 25 3 13 6.25 Cilrobacter Ireundii IFO 12681 0 1 0 0 10 1 56 Enterobacier aerogenes NR 2945 0 025 0 10 0.78 Enterobacter cloacae NR 2946 0 10 0 05 0 78 Escherichia coli NIHJ JC-2 0 10 - 0 10 1.56 Escherichia coli nr 2630 0 025 0 0065 0.39 Klebsiella pneumoniae FDA PCi 602 0 78 0 39 3 13 Bordetella bronchisepnca ATCC 4617 3 13 3 13 3 13 Proteus rettgeri ATCC 14505 0 78 1 56 ' 3.13 Proteus vulgaris OX19 ATCC 6898 0 .013 0.013 0.20 Pseudomonas aeruginosa A3 0 20 3 13 3.13 Pseudomonas aeruginosa NR 2950 1 56 6.25 25 Pseudomonas stutzeri IFO 12695 0 .013 0.0033 1.56 Serrafia marcescens IFO 12648 0 39 0.78 3.13 Salmonella tvphimurium IFO 12529 0 .025 0.5 1.56 --19Antibacterial spectrum MIC (yg/ml) Conmol (Examole No ) 12 Bacteroides Iragilis ATCC 23745 0.78 0.20 Bacteroides Iragilis NR 2579 3.13 1 .56 Bacteroides iragilis NR 2582 0.78 0.39 Bacteroides Iragilis NR 2583 0.39 0.10 Bacteroides Iragilis NR 2584 0.78 0.78 10 Bacteroides distasonis NR 2578 0.78 0.78 Bacteroides thetaiotaomicron NR 2588 1.56 0.78 Bifidobacterium adolescents ATCC 15703 0.39 0.10 Clostridium botulinum NR 2611 0.10 0.013 Clostridium perlrmgens NR 2612 0.39 0.10 15 Clostridium moniliforme ATCC 25546 0.78 0.10 Fusobacterium varium ATCC 8501 12.5 - Peptococcus prevotu ATCC 9321 1.56 0.39 Peptococcus variabihs ATCC 14955 0.78 0.20 Peptostreptococcus anaerobius NR 2743 0.39 0.013 20 Propionibacterium acnes ATCC 11828 Mycoplasma 0.78 0.78 Mycoplasma hominis NR 2952 0.10 0.10 2. In vivo therapeutic efficacy The in vivo antibacterial efficacy of the compounds of Examples 5, 30, 65 and 66 was tested against lethal infections of Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICR mice weighing about 20 g were infected intraperitoneally with a corresponding bacterial suspension. The test compounds were administered orally or subcutaneously at the time of infection. The mortality was observed for 5 days. The 50% effective dose (ED50, mg/kg) which protects 50% of the animals from death by the infection will be evident from Table 3.

Table 3 In vivo antibacterial activity against systemic infections in mice (ED50. mg/kg) Bacte rium Compound Escherichia Pseudomonas Streptococcus coli aeruginosa pneumoniae ML4707 4au542 6-001 s.c. p.o. p.o. p.o. Example 2 0.06 0.11 13.4 10.3 Example 12 0.10 0.62 57.0 65.9 3. Acute toxicity The LD50 values of the compounds of Examples 2, 3, 6, 7, 12 and 22 all lie above 2000 mg/kg (acute toxicity after oral administration to ICR mice).

The compounds in accordance with the invention exhibit a broad antimicrobial spectrum against gram-positive and gramnegative bacteria and Mycoplasma, especially against pathogens which are resistant to various antibiotics such as e.g. penicillins, cephalosporins, aminoglycosides, tetracyclins and the like.

Moreover, the compounds in accordance with the invention have low toxicity combined with a- potent and broad antimicrobial efficacy. The protective effect of the compounds in accordance with the invention in the case of systemic bacterial infections in mice is greater than that of synthetic antibacterial agents which are commercially available. Therefore, the compounds in accordance with the invention can be used effectively for the prevention or treatment of diseases caused by gram-positive and gramnegative bacteria, and against bacterioid microorganisms in human and veterinary medicine.

For example, diseases caused by the following microorganisms or by mixtures of the following microorganisms can be treated and/or prevented: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Lactobacillus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostreptococcus, Propionibacterium, Escherichia. Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bacteroides, Fusobacterium. Mycoplasma and other microorganisms.

The present invention also relates to pharmaceutical preparations containing one or more compounds in accordance with the invention.

The compounds in accordance with the invention can be administrated orally or non-orallv (parenterally) to human beings or animals by various conventional administration methods.

The compounds in accordance with the invention can be used as such or in formulations with adjuvants, liquid diluents, binders, lubricants, humectants etc., e.g. in the form of general medicaments such as e.g. tablets, powders, capsules, gels, dry syrups, syrups, ampoules, suspensions, liquids, emulsions, ointments, pastes, creams, suppositories and the like.

Furthermore, dissolution-delaying, absorption-accelerating, surface-active agents and the like as well as other additives can be used, i.e. any preparation form which is pharmaceutically acceptable.

The compounds in accordance with the invention can be used alone or as mixtures of two or more compound types; the amount of the compounds used being about 0.1 to 99.5%, preferably 0.5 to 95%, based on the finished medicament.

The daily dosage of a compound in accordance with the invention can vary according to the requirements of the human being or animal being treated and depending on the weight thereof and the condition being treated, but generally lies in the range of 0.5 to 500 mg per kg weight, preferably about 1 to 300 mg/kg.

The following Examples illustrate the manufacture of the compounds in accordance with the invention.

Preparations of starting compounds Reference Example Preparation of diethyl N-(3.4-difluoro-2-hydroxyohenyl)aminomethylene.malonate (a) A solution of 500 mg of 2,3-difluoro-6-nitrophenol in 7 ml of methanol is hydrogenated over 60 mg of 5% Pd/C for 6 hours. The reaction mixture is filtered in a nitrogen atmosphere and the filtrate is evaporated under reduced pressure. Crude 2-amino5,6-difluorophenol is obtained. (b) A mixture of 414 mg of 2-amino-5,6-difluorophenol and 618 mg of diethyl ethoxymethylenemalonate is heated at 130° in a nitrogen atmosphere for 5 minutes. The resulting crystalline residue is triturated with ethanol and filtered. There is obtained diethyl N-(3,4-d if I uo ro-2-h yd roxy pheny I )a mi nomethvlene23 malonate of m.p. 178-18O°C; MS m/z 315 (M+). The mother liquor is chromatographed on silica gel using chloroform/acetone (20:1) as the eluent, whereby an additional yield of crystals is obtained.

Preparation of ethyl 8-benzvloxy-6.7-difluoro-4-hydroxv-3.Gjjinolinecarboxylate_irQute- 1) (c) A mixture of diethyl M-(3,4-diiluoro-2-hydroxyphenvl)aminomethylenemalonate and 70 g of anhydrous sodium carbonate in 1.5 ml of dry dimethylformamide is treated with 30 μ I of benzyl bromide. The mixture is stirred at room temperature for hours. After evaporation of the solvent under reduced pressure the residue is dissolved in methyl chloride and the precipitate obtained is filtered off. The filtrate is washed with water, dried over anhydrous sodium sulphate and evaporated. The crystalline residue is washed with n-hexane and recrystallized from methanol. There is obtained diethyl N-(2-benzyloxv-3,4difluorophenyl)aminomethvlenemalonate of m.p. 87°C; MS m/z 405 (M+)· (d) A solution of 280 mg of the above malonate in 2.8 ml of diphenyl ether is heated at 250° for 30 minutes in a nitrogen atmosphere. After cooling the reaction mixture the ethanol produced is removed under reduced pressure. The residual dark brown solution is chromatographed on 10 g of silica gel and eluted in succession with benzene, dichloromethane and dichloromethane/acetone (30:1). The pure fractions are combined and the solvent is evaporated under reduced pressure. The crystalline residue is washed with a mixture of n-hexane and ethyl acetate; there is obtained ethyl 8-benzyloxy-6.7-difluoro-4-hydroxv-3quinolinecarboxvlate which melts at 200-201°C after recrystallization from methanol; MS m/z 359 (M+).

Preparation of ethyl 8-benzyloxy-6.7-difluoro-4-hydroxy-3qninolinecarboxvlate (route 2) A solution of 300 mg of ethyl 6,7-difluoro-4,8-dihydroxv3-quinolinecarboxylate in 6 ml of dry dimethylformamide is treated in succession with 308 mg of anhydrous potassium carbonate and 145 μ I of benzyl chloride. The mixture is stirred at 55-65°C for 11 hours. The reaction mixture is diluted with ml of water and extracted with chloroform. The extract is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on 7 g of silica gel using acetone/chloroform (1:20) as an eluent. There is obtained ethyl 8-be nzv lox y-6,7-dif luo ro-4-h ydroxv-3-quino linecarboxvlate which melts at 200-201 °C after recrystallization from methanol; MS m/z 359 (M+).

Preparation of ethvl 8-benzvloxy-6.7-difluoro-1-fformylmethvlamino)-4-oxo-1, 4-di hyd ro-3-aui nol inecarboxv late (e) A mixture of 410 mg of ethyl 8-benzyloxv-6,7-difluoro-4hydroxy-3-quinolinecarboxylate and 315 mg of anhydrous potas15 sium carbonate in 10 ml of dry dimethylformamide is stirred at room temperature for 3 hours and subsequently treated with 260 mg of 0-(2.4-dinitrophenyl)hvdroxylamine. The reaction mixture is stirred at room temperature for a further 6.5 hours. After removing the solvent under reduced pressure 12 ml of water are added and the mixture is stirred at room temperature for 3 hours. The resulting precipitate is filtered off and washed in succession with cold water and ether. There is obtained 1amino-8-benzylox v-6,7-difluoro-4-oxo-1,4-dihy dro-3-quinolinecarboxvlate which melts at 143-144°C after recrystallization from methanol; MS m/z 374 (M+). (f) 1.51 ml of acetic anhydride are treated at 0°C with 0.6 ml of 98% formic acid. The mixture is stirred at 0°C for 15 minutes and at 50°C for 15 minutes and then cooled to 0°C. This solution is treated dropwise with a solution of 400 mg of the above amine in 2.1 ml of 98% formic acid. The mixture is stirred at room temperature for 2 days. The reaction mixture is evaporated under reduced pressure and the crystalline residue is recrystallized from ethanol. There is obtained ethyl 8-benzvloxv-6,7-difluoro1 -(formylamino)-4-oxo-1,4-dihvdro-3-quinolinecarboxylate of m.p. 188-190°C; MS m/z 402 (M+). (9) A mixture of 400 mg of the above formamide, 275 mg of anhydrous potassium carbonate and 17 ml of anhydrous dimethylformamide is stirred at room temperature for 1,5 hours. The reaction mixture is treated with 0.19 ml of methyl iodide and stirred for a further 2.5 hours. The solvent is removed under reduced pressure and the residue is partitioned between chloroform and water. The organic phases are dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The-residue is recrvsiallized from ethanol; there is obtained ethyl 8-benzyloxv-6,7-difluoro-1-(forrnylmethylamino)4-oxo-l,4-dihydro-3-quinolinecarboxylate of m.p. 180-181°C; MS m/z 416 (M+).

Preparation of 6.7-difluoro-8-hvdroxy-1-(methylamino)-4-oxo1,4-dihvdro-3-quinolinecarboxylic acid (h) 330 mg of ethyl 8-benzvloxy-6,7-difluoro-1-(formvlmet hy lam ino )-4-oxo-1 ,4-dihydro-3-quinolinecarboxvlate (330 mg) are hydrogenated over 50 mg of 5% Pd/C in 14 ml of chloroform for 4 hours. The reaction mixture is diluted with 14 ml of methanol and filtered. The filter cake is washed with chloroform/methanol 1:1. The combined filtrates are evaporated and the residue is recrvstallized from ethanol. There is obtained ethyl 6,7-dif luoro-1 - (formyl methy lamino)-8-hydro xy-4-oxo-1,4dihydro-3-quinolinecarboxylate of m.p. 221-225°C (dec.); MS m/z 326 (M+). (i) A mixture of 210 mg of the above ester and 5.2 ml of 0.5N aqueous sodium hydroxide solution is heated at 100°C for 2 hours in a nitrogen atmosphere. The reaction mixture is acidified with 0.16 ml of acetic acid. The precipitate obtained is filtered off, washed with water and dried under reduced pressure. There is obtained 6,7-dif luo ro-8-hydroxy-1 - (methylamino)-4-oxo-1,4dihydro-3-quinolinecarboxylic acid which melts ai 248-250°C (dec.) after recrystallization from ethanol; MS m/z 270 (M*)· Of Examples 1-32 hereinafter. Examples 1-14 and 18-32 illustrate the compounds in accordance with the invention and, respectively, their manufacture. Examples 15-17 serve to complete the disclosure.

Example 1 Manufacture of 9.10-difluoro-3-methyl-7-oxo-2.3-dihydro-7Hpyridof3.2.1-iil-1,3.4-benzoxadiazine-6-earboxylic acid A mixture of 105 mg of 6,7-difluoro-8-hvdroxv-1-(methvlamino)-4-oxo-1,4-dihydro-3-quinolinecarboxvlic acid (from Reference Example (i)). 150 mg of paraformaldehyde and 5 ml of dry dioxan is heated at 100°C for 3 hours in a nitrogen atmosphere. After removing the solvent under reduced pressure 20 ml of dimethylformamide are added, the mixture is stirred for 20 minutes and then filtered. The filtered cake is washed with dimethylformamide and the filtrate is evaporated under reduced pressure. The residue is triturated with water and filtered.

There is obtained 9,10-difluoro-3-methyl-7-oxo-2,3-dihvdro7 H-pyrido [3,2.1 -ij]-1,3,4-benzoxadiazine-6-carboxvlic acid which melts at 290-292°C with decomposition after reerystallization from dimethylformamide; MS m/z 282 (M+).

Example 2 Manufacture of 9-fluoro-3-methyl-10-(4-methyl-1-Diperazinyl)7-oxo-2.3-dihydro-7H-pyridoi3.2.1 -ii]-1,3.4-benz oxadiazine-6carboxylic acid A mixture of 30 mg of 9,10-difluoro-3-methyl-7-oxo-2,3di hvdro-7 H-pyrido [3,2,1 - i j] -1.3,4-benzoxadiazine-6-carboxvlic acid (from Example 1), 47 μ I of N-methylpiperazine and 3 ml of dry pyridine is heated at 100-110°C for 9 hours in a nitrogen atmosphere. The pyridine is removed under reduced pressure and the residue is recrvsiallized from methanol. There is obtained 9fluoro-3-methyl-10-(4-methvl-1-piperazinyl)-7-oxo-2,327 di hyd ro-7H-pyrido [3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxylic acid of m.p. 268-269°C (dec.); MS m/z 362 (M+).

The following compounds are obtainable in analogy io Example 2: Example R Number r~\ HN N — N— N=/ Melting point °C Recrystallization MS m/s solvent 240-245 (dec.) >300 256-258 242-244 (dec.) 251-252 (dec.) 239-241 (dec.) 284-286 (dec.) 280-284 (dec.) fVfeOH 349 (MH4·)' EtOH/CHCl3 349 (M+) MeOH/CHCl3 353 (M+) DMF EtOH EtOH DMF 377 (MH*)‘ 391 (ΜΗ*)' 405 (ΜΗ*)’ 350 (MH+)’ MeOH/CHCl3/Et2O 34S5(MH + )' FAB-MS Example 11 Manufacture of 1 0-f3-fbenzyloxycarbQnylaminoT-_1 -ovrrolidinvlL· 9-fluoro-3-methvl-7-oxo-2.3-dihydro-7H-pvridQf3.2.1 -iil-1.3.4A mixture of 28 mg of 9,10-ditluoro-3-meihyl-7-oxo-2,3dihvdro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxylic acid (from Example 1), 94 mg of 3-(benzvloxycarbonylamino)pvrrolidine and 3 ml of dry pyridine is heated at 100°C for 3 hours in a nitrogen atmosphere. The pyridine is removed under reduced pressure and the residue is recrystallized from methanol. There is obtained 10-[3-(benzyloxycarbonylamino)-1pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7Hpyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxvlic acid of m.p. 227-230°C; MS m/z 482 (M+).

Example 12 Manufacture of 10-(3-amino-1 -pyrrolidinylt-9--flU-Oro-3-methy_l· 7-oxo-2.3-dihydro-7H-oyridof3.2,1 - iil-1.3.4-benzoxadiazine-6carboxvlic acid mg of 10-[3-(benzyloxycarbonylamino)-1-pvrrolidinyl]S-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4benzoxadiazine-6-carboxylic acid (from Example 11) are hydrogenated over 10 mg of 5% Pd/C in 2 ml of dimethylformamide for 4.5 hours. After removing the catalyst by filtration the filtrate is evaporated under reduced pressure. The residue is recrystallized from methanol. There is obtained 10-(3-amino-1pyrrolidinyl)-9-fluoro-3-meihyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxvlic acid of m.p. 230234°C (dec.); MS m/z 348 (M+).

Example 13 Manufacture of 9-fluoro-10-(3-methoxy-1-pyrrolidin_ylUL· methy l-7-o xo-2.3-d i hydro-7 H-ovrido [3.2,1 -iil-1.3.4-benzoxadiazine-6-carboxylic acid A suspension of 100 mg of 9-fluoro-10-(3-hydroxv-1 pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 - ij]1,3,4-benzoxadiazine-6-carboxvlic acid (from Example 9) in 10 ml of dry dimethylformamide is treated with 30 mg of 60% sodium hydride (in oil) and 40 μ I of methyl iodide. The mixture is stirred at room temperature for 2 hours, subsequently treated with an additional 30 mg of 60% sodium hydride in oil and 40 μΙ of methyl iodide and stirred at 45°C for 3 hours. The solvent is evaporated under reduced pressure. The residue is evaporated under reduced pressure. The residue is treated with 2 ml of cold water and 2.3 ml of 0.5N aqueous sodium hydroxide solution and the resulting suspension is heated at 100°C for 2 hours. The reaction mixture is cooled to room temperature, neutralized with acetic acid and diluted with water. The mixture is extracted with chloroform and the extract is washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crystalline residue is chromatographed on silica gel using acetone/chloroform 1:9 as the eluent. After recrystallization from methanol there is obtained S-fluoro-10-(3methoxy-1 -py rrolidi nyl )-3-methy l-7-oxo-2,3-dih ydro-7Hpvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxvlic acid of m.p. 233-234°C; FAB-MS m/z 364 (MH+).

Example 14 Manufacture of 9-fluoro-10-(4-methoxy-1-oiperidyl)-3-methyl7-oxo-2.3-di hvdro-7 H-ovrido [3,2.1 -iil-1.3.4-benzoxadiazine-6carboxvlic acid 9-Fluoro-10-(4-methoxy-l-piperidvl)-3-methyl-7-oxo2,3-dihydro-7H-pyrido[3,2,1 - ij]-1,3,4-benzoxadiazine-6-carboxvlic acid is manufactured from 9-fluoro-10-(4-hydroxv-1 31 p i per idy I)-3-met hyl-7-0 χ 0-2,3-di hvdro-7H-pyrido[3,2,1 -ij]1,3,4-benzoxadiazine-6-carboxylic acid (from Example 5) in analogy to Example 13. The compound is recrystallized from chloroform/n-hexane and then melts at 229-233°C (dec.); MS m/z 377 (M+).

Examole 15 Manufacture of 9-fluoro-3-methyl-7-oxo-10-f4-(2-oxo-noroovh-1 -oioerazinvn-2.3-di hyd ro-7H-Dvrido (3,2,1 -ii]-1.3.4benzoxadiazine-6-carboxylic acid A mixture of 50 mg of 9-fluoro-3-methyl-7-oxo-10-(1 piperazinyl)-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (from Example 3), 17 μΙ of chloroacetone, 40 μ I of triethylamine and 1 ml of dry dimethylformamide is heated ai 80°C for 3.5 hours. The volatile components are then removed under reduced pressure and the residue is suspended in water. The precipitate obtained is isolated by filtration and recrvsiallized from a mixture of dichloromethane and methanol. There is obtained 9-fluoro-3-meihyl-7-oxo-10[4-(2-oxo-n-propv 1)-1 - piperazinvl]-2,3-dihydro-7H-pv rido[3,2,1 20 ij]-1,3,4-benzoxadiazine-6-carboxylic acid of m.p. 225-229°C (dec.); FAB-MS m/z 405 (MH+).

The following compound (Example 16) is obtainable in analogy to Example 15.

Example No. R1 Melting Recrystall- FAB-MS m/z point ization - °C solvent 275-276 EtOH (dec.) 484 (ΜΗ*) Example 17 Manufacture of 10-[4-(3-carboxypropionyl)-1-oiperazinyl1-9fluoro-3-methy l-7-oxo-2.3-dihydro-7H-pyrido[3,2,1 - iil-1.3,4benzoxadizine-6-carboxylic acid A mixture of 50 mg of 9-fluoro-3-methyl-7-oxo-10-(1 1 θ piperazinyl)-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxylic acid (from Example 3), 21.6 mg of succinic anhydride, 40 μ I of triethylamine and 4 ml of dry dimethylformamide is heated at 80°C for 2 hours. The solvent is evaporated under reduced pressure and the residue is suspended in water.

The precipitate is filtered off and recrystallized from a mixture of dichloromethane and methanol. There is obtained 10-(4-(3carboxypropionvl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2,3dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxvlic acid of m.p. 257-259°C (dec.); FAB-MS m/z 449 (MH*). on Example 18 Manufacture of 10-(4-acetyl-1-Diperazinyl)-9-fluoro-3-methvl7-ΟΧΟ-2.3-dihydro-7H-pyrido [3,2.1 - iii-1.3.4-benzoxadiazine-6carboxvlic acid -(4-Acetyl-1-piperazinyl)-9-fluoro-3-meihyl-7-oxo2,3-dihvdro-7H-pyrido[3,2,1 - ij]-1,3,4-benzoxadiazine-6-carboxylic acid is manufactured from 9-fluoro-3-methyl-7-oxo-10(1 -piperazinyl)-2,3-dihydro-7H-pyrido[3,2,1 - ij]-1,3,4-benzoxa5 diazine-6-carboxylic acid (from Example 3) and acetic anhydride in analogy to Example 17. After recrystallrzaiion from dichloromethane/methanol the compound melts at 2S4-296°C (dec.); FABMS m/z 391 (MH+).

-S-carboxylate of m.p. 260-263°C (dec.); ΊΗ-ΝΜΑ (D2O)_8:2.98 (3H,s), 3.05 (4H,m), 3.39 (4H,m), 3.84 (2H,s), 5.18 (2H,s), 7.55 (1H,d,J=13.4 HZ), 8.34 (1H,s).

Example 19 Manufacture of l0-f4-(4-aminobenzyl)-1-pioerazinyl1-9-fluoro3-methyl-7-oxo-2.3-dJhydro-7H-pyridof3.2.1-ii1-1.3.4-benzoxa15 diazine-6-carboxylic acid 100 mg of 9-fluoro-3-methyl-10-[4-(4-nitrobenzyl)-1piperazinyl]-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4benzoxadiazine-6-carboxylic acid (from Example 16) is hydrogenated over 10 mg of 5% Pd/C in dichioromethane/ methanol 1:1 for 2 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol and there is obtained l0-[4-(4-aminobenzvl)1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pvrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid of m.p. 23725 238°C (dec.); FAB-MS m/z 454 (MH+).

Example 20 Manufacture of 10-f3-(aminomethyl)-1-pyrrolidinyn-9-fluoro-3methvl-7-oxo-2.3-dihydro-7H-Dyridof3.2.1 -iil-1,3,4-benzoxadiazine-6-carboxvlic acid A mixture of 40 mg of 10-[3-(acetylaminomeihvl)-1pvrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido34 [3,2,1-ij]-1,3.4-benzoxadiazine-6-carboxylic acid (from Example 8) and 2.5 ml of IN aqueous sodium hydroxide is heated at 100°C for 3 hours. After cooling to room temperature the reaction mixture is neutralized with acetic acid and the precipitate which separates is filtered_off and recrystallized from methanol. There is obtained 10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-3methyl-7-oxo-2,3-d ihvdro-7H-pyr id o [3,2,1 -ij]-1,3,4-benzox adiazine-6-carboxylic acid of m.p. 177-180°C (dec.); FAB-MS m/z 363 (MH+).

Example 21 Manufacture of 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-(methylamino)-4-oxo-1.4-dihvdro-3-quinolinecarboxylic acid A solution of 50 mg of 6,7-difluoro-8-hydroxv-1 -(methylamino)-4-oxo-1,4-dihvdro-3-quinolinecarboxylic acid (from Reference Example (i)) in 2 ml of dry dimethylformamide is treated with 32 mg of carbonvldiimidazole while stirring. Stirring is continued at room temperature for 2 hours and then at 80°C for 5 hours. The solvent is then evaporated under reduced pressure, the residue is suspended in- water and the pH is adjusted to pH 5 with acetic acid. The precipitate which separates is filtered off and washed with methanol. There is obtained 6fluoro-8-hydroxy-7-(1-imidazolyl)-1-(meihylamino)-4-oxo-1,4dihydro-3-quinolinecarboxylic acid as a pale yellow powder, FABMS m/z 319 (MH+); 1 H-NMR (d6-DMSO) δ: 2.82 (3H,s), 7.10 (1H, d, J=10.7 Hz), 7.61 (IH, d). 7.75 (1H, d), 8.62 (1H,s), 8.92 (1H,s), .33 (1H, br.s) Example 22 Manufacture of 9-fluoro-10-(1-imidazolyl)-3-methyl-7-oxo-2.3di hydro-7 H-pyrido [3,2.1 -iij-1,3.4-benzoxadiazine-6-carboxylic acid A suspension of 15 mg of 6-fluoro-8-hydroxv-7-(1 -imidazolvl)-1-(methylamino)-4-oxo-1,4-dihvdro-3-quinolinecar35 boxylic acid (from Example 21) in a mixture of 1 ml of 35% formalin and 1 ml of dioxan is heated at 100-110°C for 1.5 hours in a nitrogen atmosphere. The solvent is evaporated under reduced pressure and the crystalline residue is washed with methanol. There is obtained 9-fluoro-10-(1-imidazolyl)-3methyl-7-oxO-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadizine-6-carboxylic acid as a pale pink powder. After recrystallization from dimethylformamide and ether the compound melts at >300°C; FAB-MS m/z 331 (MH+). 9-Fluoro-10-(1-imidazolyl)-3-methyl-7-oxo-2,3-dihydro7H-pyrido[3,2,1 -ij]-1,3.4-benzoxadiazine-6-carboxvlic acid is also obtainable from 9,10-difluoro-3-meihvl-7-oxo-2,3-dihydro 7H-pvrido[3,2,1 -ijj-1,3,4-benzoxadiazine-6-carboxylic acid and imidazole in dimethyl sulphoxide in analogy to Example 2.

Example 23 Manufacture of benzyl 9-fluoro-10-(3-hydroxv-1-oyrrolidinvl)3-methvl-7-oxo-2.3-dihydro-7H-oyridof3.2· 1 - iil-1.3.4-benzoxadiazinerfl-carboxylate A mixture of 10 mg of 9-fluoro-10-(3-hydroxy-1-pvrro2o lidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pv rido [3,2,1- ij]-1,3,4benzoxadiazine-6-carboxylic acid (from Example 9), 8 mg of anhydrous potassium carbonate and 0.5 ml of dimethylformamide is stirred at room temperature for 1.5 hours and then treated with 10.8 mg of benzyl bromide. The mixture is stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue is suspended in water and extracted with chloroform. The extract is evaporated to dryness under reduced pressure. The residue is triturated with ether. There is obtained benzyl 9-fluo ro-10-(3-hyd roxv-1-pyr rol id invl)-3-met hyl-7-oxo30 2,3-dihvdro-7H-pyrido[3.2,1 - ij]-1,3,4-benzoxadiazine-S-carboxylate of melting point of 196-198°C (dec.); FAB-MS m/z 440 (MH+).

Example 24 Manufacture of benzyl 10-(3-chloro-1-pyrrolidinyl)-9-.fl.U-g_ro-3methyl-7-oxo-2.3-dihvdro-7H-oyridof3.2.1 - iil-1,3.4-ben-Zfl.xadiazine-6-carboxvlate mg of benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 - ij]-1,3,4-benzoxadiazine-6-carboxylate (from Example 23) are dissolved in 0.2 ml of thionvL chloride and stirred at 60°C for 15 minutes. The reaction mixture is diluted with water and extracted with chloroform.

The extract is evaporated under reduced pressure. The residue is chromatographed on 2 g of silica gel with chloroform. There is obtained benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3methyl-7-oxo-2,3-dihydro-7H-pvrido[3,2,1 -ij]-1 ,3,4-benzoxadiazine-6-carboxylate of m.p. >300°C; FAB-MS m/z 458 (MH+),460 (MH+2)+.

Examole 25 Manufacture of 10-(3-chloro-1-pvrrolidinvl)-9-fluoro-3-methvl7-oxo-2.3-dihydro-7H-oyridof3.2.1 - iil-1,3 ^-benzoxadiazine-GG&rkoxxiate 2.5 mg of benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 - ij] -1,3,4benzoxadiazine-6-carboxylate (from Example 24) are hydrogenated over 1 mg of 5% Pd/C in chloroform. The catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure, and the residue is recrystallized from ethanol. There is obtained 10-(3-chloro-1 -pyrrolidinyl)-9-fluoro-3methvl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4benzoxadiazine-6-carboxylic acid of m.p. 269-272°C (dec.); FAB-MS m/z 368 (MH+), 370 (MH+2)+.

Example 26 Manufacture of 9-fluoro-3-methyl-tO-(4-methyl-1-Qioerazinyl)7-oxo-2.3-dihydro-7H-pyridof3.2.1 - ii]-1 ,3.4-benzoxadiazine-6carboxvlic acid via the fluoroborane intermediate (a) A mixture of 100 mg of 9,10-difluoro-3-methyl-7-oxo2,3-di hyd ro-7H-pyrido [3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxvlic acid (from Example 1) and 1 ml of 60% aqueous fluoroboric acid is heated at 90°C for 12 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off, washed with methanol and dried under reduced pressure. There is obtained crude 9,10-difluoro-6-[[(difluoroborvl)oxy]carbonyl]-3methvl-2,3-dihydro-7H-pyrido[3,2,1 - ij]-1,3,4-benz ox ad i azin-7one; FAB-MS m/z 331 (MH+). (b) A solution of 33 mg of the above borane intermediate in ml of dimethyl sulphoxide is treated while stirring with 15 μΙ of N-methylpiperazine and 20 ul of triethylamine. After stirring at room temperautre for 3 hours the reaction mixture is lyophilized. The residue is crystallized from methanol and there is obtained 6-[[(difluoroboryl)oxy]carbonyl]-9-fluoro-3-methvl1 0-(4-methy 1-1 - piperaz iny I)-2,3-di hvdro-7 H-pyrido[3,2,1-ij]1.3.4- benzoxadiazin-7-one as yellow crystals of m.p. 228-230°C (dec.); FAB-MS m/z 411 (MH+). (c) A solution of 5 mg of the above borane intermeidate in ml of 95% ethanol is treated with 3 μ I of triethylamine. After heating under reflux conditions for 4 hours the reaction mixture is cooled to room temperature. The precipitate which separates is filtered off and there is obtained 9-fluoro-3-meihyl-10-(4met hyl-1- piperaz inyl)-7-oxo-2,3-dihydro-7H-pvrido [3,2,1-ij]1.3.4- benzoxadiazine-6-carboxylic acid of m.p. 268-269°C (dec.).

Example 27 Manufacture of 9-fluoro-3-methyl-10-(4-mefhyl-1-pioerazinyl)7-oxo-2,3-dihydro-7H-oyrido[3.2.1 - iil-1.3.4-benzoxadiazine-6carboxvlic acid via the acetoxvborane intermediate (a) A mixture of 100 mg of 9,10-difluoro-3-methyl-7-oxo2,3-dihydro-7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxylic acid (from Example 1), 1 ml of acetic anhydride and 100 mg of triacetoxvborane is heated at 140°C for 15 minutes. The reaction mixture is evaporated under reduced pressure. The residue is triturated with acetone and filtered. There is obtained 6-[[(diacetoxvboryl)oxy]carbonyl]-9,1 0-difluoro-3-methvl-2,3dihydro-7H-pvrido[3,2.1 -ij]-1,3,4-benzoxadiazine-7-one; FAB-MS m/z 411 (MH+). (b) A solution of 41 mg of the above borane intermediate tn 1 ml of dimethyl sulphoxide is treated with 15 μΙ of Nmethylpiperazine and 20 μ I of triethylamine. The reaction mixture is stirred at room temperature for 2 hours and then lyophilized. The residue is crystallized from methanol/ether; there is obtained 6-[[(diacetoxyboryl)oxy]carbonvl]-9-fluoro-3methvl-10-(4-meihyl-1-piperazinyl)-2,3-dihydro-7Hpvrido[3,2,1-ij]-1,3,4-benzoxadiazin-7-one as yellow crystals; m.p. 156-157°C (dec.); FAB-MS m/z 491 (MH+). (c) 5 mg of the above borane intermediate are suspended in 0.1 ml of acetone and treated with 2.5 μΙ of concentrated hydrochloric acid. The reaction mixture is stirred at room temperature for 30 minutes and then cooled an ice bath. The precipitate which separates is filtered off and dissolved in 0.1 ml of 95% ethanol. The solution is treated with 2 μΙ of triethylamine and the mixture is held under reflux conditions for 1 hour. The solution is cooled to room temperature and the precipitate which separates is filtered off. There is obtained 9fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3dihvdro-7H-pyrido[3.2,1 -ij]-1,3,4-benzoxadiazine-S-carboxylic acid of m.p. 268-269°C (dec.).

Example 28 Manufacture of 10-(3-amino-1 -pyrrolidinyJ)-9-flujirQ-3-methvl7-oxo-2.3-dihvdro-7H-pvridof3.2.1 -iil-1,3.4-benzoxadiazine-6carboxvlic acid hydrochloride The pH value of a solution of 20 mg of 10-(3-amino-1pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7Hpvrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxvlic acid (from Example 12) is adjusted to 1.0 with 6N hydrochloric acid. The clear soluton is lyophilized and the residue is crystallized from water/ethanol 1:2. There is obtained 10-(3-amino-1pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihdyro-7Hpvrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxvlic acid hydrochloride of m.p. 226-228°C (dec.).

Example 29 Manufacture of 9-fluoro-3-methyl-10-(4-methyl-1-oioerazinvl)7-oxo-2.3-dihydro-7H-oyridof3.2.1 - iil-1.3.4-benzoxadiazine-6carboxvlic acid hydrochloride 9-Fluo ro-3-methyl-10-(4-methvl-1-piperazinyl)-7-oxo2.3- di hydro-7 H-pyrido [3,2,1 -ij]-1,3,4-benzoxadiazine-620 carboxylic acid hydrochloride is obtained in analogy to Example 28, m.p. 264-266°C (dec.).

Example 30 Manufacture of sodium 9-fluoro-3-methyl-1Q-morpholino-7-oxo2.3- dihydro-7H-pvridof 3.2,1 - iij-1,3.4-benzoxadiazine-6-car25 kmM&is mg of 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3dihydro-7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxylic acid (from Example 4) are suspended in 0.4 ml of water and treated while stirring with 40 μ I of 1N aqueous sodium hydroxide. The clear solution is lyophilized and the residue is crystallized from water/ethanol (1:4). There is obtained sodium 9-fluoro-3-methy 1-1 0-morpholino-7-oxo-2,3-dih yd ro-7H5' pyrido[3,2,1 -ij]-1.3.4-benzoxadiazine-6-caxboxylate of m.p. >300°C.

Example 31 Manufacture of 9-fluoro-3-(2-fluoroethyl)-10-(4-methvl-1piDerazinyl)-7-oxo-2.3-dihydro-7H-oyridoi3.2,1 - iil-t ,3,41 o benzoxadiazine-6-carboxylic acid 9-Fluoro-3-(2-fluoroethyl)-10-(4-methyl-1-piperazinyl)7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6carboxylic acid is manufacured from ethyl 8-benzyloxy-6,7diiluoro-1 - (formy lam ι no )-4-oxo-1.4 -di hydro-3-qui noli n ecar15 boxylate (from Reference Example (f)) using the methods given in Reference Examples (g), (h) and (i) (using 1-bromo-2-fluoroethane instead of methyl iodide), Example 1 and Example 2, The product is obtained as crystals, m.p. 220-224°C; MS m/z 394 (M+), after recrvstallization from methanol.

Example 32 Manufacture of sodium 9-fluoro-3-methyl-10-(4-methyl-1piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2.1-ii1-1,3,4benzoxadiazine-6-carboxylate 520 mg of 9-fluoro-3-methyl-10-(4-methvl-1 2 5 piperazinvl)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 - ij]-1,3,4benzoxadiazine-6-carboxylic acid are dissolved in 2.88 ml of 0.5N aqueous sodium hydroxide. The clear solution is evaporated under reduced pressure; the pale yellow powder obtained is recrystallized from ethanol and there is obtained, after drying under reduced pressure at 80°C for 2 days, sodium 9-fluoro-3methyl-10-(4-meihyl-l-piperazinyl)-7-oxo-2,3-dihydro-7Hpyrido[3,2,1-ij]-l ,3,4-benzoxadiazine-6-carb0xylate of m.p. 252254°C (dec.), FAB-MS m/z 385.

The following Examples illustrate pharmaceutical preparations containing a compound in accordance with the invention: Example A Gelatine capsules containing the following ingredients are manufactured in a conventional manner: 9- Flu oro-3- methy 1-1 0-(4- methv 1-1 -piperazinyl)-7-oxo-2,3-dihydro-7Hpv rido [3,2,1 -ij]-1,3,4-benzoxadiazine- 6-carboxylic acid 200 mg 200 mg Luviskol (water-soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mo 257 mg Example B Tablets containing the following ingredients are manufactured in a conventional manner: 9-Fluoro-3-methyl-10-(4-methvl-1piperaz inyl) -7-oxo- 2,3-d i hvdro-7 Hpv rido [3,2,1 -ij]-1,3.4-benzoxadiazine6-carboxvlic acid Starch 200 mg mg Carboxymethylcellulose calcium Crystalline cellulose Magnesium stearate mg 40 mg 320 mg

Claims (24)

Claims

1. Pvrido[3,2,ij]-1,3,4-benzoxadiazine derivatives of the general formula in which R represents 1-piperazinyl which can be substituted in the 4-position by methyl, acetyl or 4-aminobenzyl; morpholino; 1 -pvrrolidino substituted in the 3-position by amino, arninomethyl, (methyl-amino)methyl, (ethylamino)methvl, methoxy or chlorine; 1-imidazolyl which can be substituted in the 4-position by methyl; or 1-piperidyl substituted in the 4-position by hydroxy or methoxy, as well as pharmaceutically acceptable salts thereof and hydrates or solvates of the compounds of formula I or of their salts.

2. Compounds according to claim 1, characterized in that R represents the group ch 3 n nw

3. Compounds according to claim 1, characterized in that R represents the group

4. A compound according to claim 1, characterized in that it is 9-fluoro-3-methvl-1 0-(4-methyl-1-piperazinvl)-7oxo-2,3-dihydro-7H-pyrido{3,2,ij]-1,3,4-benzoxadiazine-6carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate of solvate of one of these compounds.

5. A compound according io claim 1, characterized in that it is 9-fluoro-3-methvl-7-oxo-1 0-(1-piperazinyl)-2,3d i h yd ro-7 H - py r i do [3.2, i j] -1,3,4-benzoxadiazine-6-carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate of solvate of one of these compounds.

6. A compound according to claim 1, characterized in that it is 10-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-9-fluoro3-meihyl-7-oxo-2,3-dihvdro-7H-pyrido[3,2,ij]-1,3,4benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate of solvate of one of these compounds.

7. A compound according to claim 1, characterized in that it is 10-(3-amino-1-pyrrolidinvl)-9-fluoro-3-methyl-7oxo-2,3-dihvdro-7H-pyrido[3,2.1-ij]-1,3.4-benzoxadiazine-6carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate of solvate of one of these compounds.

8. A compound according io claim 1, characterized in that it is 9-fluoro-3-methyl-10-[3-[(methylamino)methyl]-1pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido[3,2,ij]-1,3,4benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate of solvate of one of these compounds.

9. A compound according to claim 1, characterized in that it is 10-[4-(4-aminobenzvl)-1-piperazinyl]-9-fluoro-3meihvl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1 - ij]-1,3,4benzoxadiazine-6-carboxylic acid or a hydrate of solvate of one of these compounds.

10. A compound according to claim 1, characterized in that it is 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6-carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

11. A compound according to claim 1, characterized in that it is 9-fluoro-10-(3-methoxy-1-pyrrolidinyl)-3-methyl-7oxo-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

12. A compound according to claim 1, characterized in that it is 10-[3-(aminomethyl)-1-pyrrolidinvl)-9-fluoro-3methvl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

13. A compound according io claim 1, characterized in that it is 9-fluoro-10-(1-imidazolyl)-3-meihyl-7-oxo-2,3dihydro-7H-pyrido[3.2,1 -ij] -1,3,4-benzoxadiazine-6-carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

14. A compound according to claim 1, characterized in that it is 9-fluoro-3-methyl-10-(4-methyl-1-imidazolyl)-7oxo-2,3-dihydro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

15. A compound according to claim 1, characterized in that it is 9-fluoro-10-(4-hydroxy-1-piperidyl)-3-methyl-7-oxo2.3- dihydro-7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

16. A compound according to claim 1, characterized in that it is 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-meihyl-7oxo-2,3-dihydro-7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

17. A compound according to claim 1, characterized in that it is 10-(4-acetyl-1-piperazinyl)-9-fluoro-3-methvl-7oxo-2,3-dihydro-7H-pvrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

18. A compound according to claim 1. characterized in that it is 9-fluoro-1 0-(4-methoxy-1-piperidyl)-3-methyl-7-oxo2.3- dihvdro-7H-pyrido[3,2,1 -ij]-1,3,4-benzoxadiazine-6carboxvlic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of one of these compounds.

19. Compounds of the general formula 4Ί in which X represents a halogen atom.

20. Compounds of the general formula OK nhck 3 in which R represents 1-piperazinyl which can be substituted in the 4-position by methyl, acetyl or 4-aminobenzyl; morpholino; 1-pyrrolidino substituted in the 3-position by amino, aminomethyl, (methyl-amino)methyl, (ethylamino)methyl, methoxy or chlorine; 1-imidazolyl which can be substituted in the 4-position by methyl; or 1-piperidyl substituted in the 4-position by hydroxy or methoxy.

21. Compounds according to any one of claims 1-18 as pharmaceutically active substances.

22. Compounds according to any one of claims 1-18 as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases.

23. A process for the manufacture of the compounds in accordance with any one of claims 1-18, characterized by (a) reacting a compound of the general formula in which X represents a halogen atom; and amino, hydroxy and/or carboxy groups present may be protected, with an amine of the general formula HR III in which R has the significance given in claim 1, and, if necessary, cleaving off a protecting group present, or (b) reacting a compound of the general formula in which R has the significance given in claim 1; and amino, hydroxy and/or carboxy groups present may be protected, with formaldehyde or paraformaldehyde and, if necessary, cleaving off a protecting group present, or (c) for the manufacture of a compound of formula I in which R represents 4-acetyl-1-piperazinyl, reacting the compound of formula I in which R represents the unsubstituted 1-piperazinyl residue with an agent yielding the acetyl group, or (d) for the manufacture of a compound of formula I in which R represents 3-methoxy-l-piperidyl, methylating the corresponding 3-hydroxv-1-piperidyl compound of formula I, or (e) for the manufacture of a compound of formula I having a 5 free amino group R, cleaving off the arntno protecting group in a corresponding compound of formula I having a protected amino group, or (f) for the manufacture of a compound of formula I in which R represents 3-chloro-1-pyrrolidinyl, halogenating the 10 corresponding 3-hydroxy-1-pyrrolidinyl compound having a protected carboxy group and cleaving off the carboxy group, or (g) for the manufacture of a compound of formula I in which R represents 4-(4-aminobenzyl)-1-piperazinyl. reducing the nitro group of the corresponding 4-(4-nitrobenzyl)-1-piperazinvl 15 compound, or (h) for the manufacture of pharmaceutically acceptable salts, hydrates or solvates of a compound of formula I or of hydrates or solvates of said salts, converting a compound of formula I into a salt, hydrate or solvate or into a hydrate or solvate of said salt. 20 24. A pharmaceutical preparation, characterized in that it contains a compound in accordance with any one of claims 1-18. 25. A pharmaceutical preparation for the treatment and prophylaxis of infectious diseases, characterized in that it contains a compound in accordance with any one of claims 1-18. 25 26. The use of the compounds in accordance with any one of claims 1-18 for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases. 27. A compound according to. claim i, substantially as hereinbefore described and exemplified. . i ; Ί 28. A process for the manufacture Of a.compound ·':*» ? according to claim 1, substantially as hereinbefore 5 described and exemplified. 29. A compound according to claim 1, whenever manufactured by a process claimed in a preceding claim. 30. A compound according to claim 21, substantially as hereinbefore described and exemplified. 10 31. A compound according to claim 22, substantially as hereinbefore described and exemplified. 32. A pharmaceutical preparation according to claim

24. ,, substantially as hereinbefore described and exemplified.