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WO1994004505A1 - Sulphonamide derivatives of quinolones having an antibacterial activity - Google Patents

Sulphonamide derivatives of quinolones having an antibacterial activity Download PDF

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Publication number
WO1994004505A1
WO1994004505A1 PCT/FR1993/000807 FR9300807W WO9404505A1 WO 1994004505 A1 WO1994004505 A1 WO 1994004505A1 FR 9300807 W FR9300807 W FR 9300807W WO 9404505 A1 WO9404505 A1 WO 9404505A1
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radical
general formula
quinolone
carboxylic acid
fluoro
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PCT/FR1993/000807
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French (fr)
Inventor
Claude Perrin
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Bouchara SA
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Bouchara SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of therapeutic chemistry and in particular to new anti-bacterial agents.
  • Z represents an amino radical chosen from the group consisting of the compounds of formula _ ..
  • Y represents hydrogen, a lower alkyl radical, an amino group or an acylamino radical
  • n represents 2
  • m represents 2 or 3
  • p represents 0 or 1 and in which R represents a lower alkyl, lower cycloalkyl radical , (lower cycloalkyl) lower alkyl, lower alkenyl, dihalogeno alkenyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
  • X represents a group> C-Hal or> C-0R : in which Hal is a halogen atom and R : is a lower alkyl radical and Z, R, n and m are defined as above
  • R, X and Y have the meanings previously supplied as well as their addition salts with an inorganic or organic base
  • the essential element of the invention is the presence of an arylsulfonyl substituent on nitrogen which gives the molecules a greater degree of lipophilicity and which appears to be one of the factors responsible for the anti-bacterial activity of these products.
  • an arylsulfonyl substituent on nitrogen which gives the molecules a greater degree of lipophilicity and which appears to be one of the factors responsible for the anti-bacterial activity of these products.
  • the The products of the present invention exhibit a significantly higher degree of activity and at the same time a significantly wider spectrum of activity.
  • Ciprofloxacin This is how the aryl sulfonylated derivatives of Ciprofloxacin manifest, compared to the reference product, a significantly greater in vitro and in vivo activity and above all considerably enlarged, in particular with respect to Gram positive bacteria.
  • the nitrogen group at 7 is most often a piperazine, a homopiperazine, an amino piperidine of formula
  • the nature of the substance with nitrogen in position 1 also plays a large role.
  • the ethylated or allylated compounds are very active but the cyclopropylated derivatives are appreciably more active, in particular on Gram-negative bacteria.
  • the N-difluorovinyl or dichlorovinyl derivatives are also of certain interest.
  • the carboxylic group normally remains free. However, it may be justified to salify this function with an inorganic or organic base, so as to obtain derivatives more soluble in water, an important parameter of their ability to diffuse. Mention may be made, in this regard, of the salts with an inorganic base such as the alkali metal, ammonium, alkaline earth metal, aluminum, iron or bismuth salts. Mention may also be made of the salts with an organic base such as an alkylamine, an alkanolamine, an amino sugar, a cycloalkoylamine, an amino acid, a quaternary ammonium salt or an aryl or heteroarylamine salt.
  • an inorganic base such as the alkali metal, ammonium, alkaline earth metal, aluminum, iron or bismuth salts.
  • Mention may also be made of the salts with an organic base such as an alkylamine, an alkanolamine, an amino sugar, a cycloalkoylamine, an amino acid
  • salts mention will be made most particularly of the sodium, potassium, lithium, ammonium or calcium salts; the salts of triethylamine, diethanolamine, tromethamine, dicyclopropylamine, glucosamine, sarcosine, arginine, 2-pyridylethylamine xylidine, toluidine, diphenylamine or N-methylglucamine.
  • lower alkyl designates a hydrocarbon radical having from 1 to 6 carbon atoms in a straight or branched chain such as a raethyl, ethyl, isopropyl, sec-butyl, terbutyl, neopentyl or n- hexyl.
  • a lower cycloalkyl radical is a cyclic hydrocarbon radical having from 3 to 7 carbon atoms such as a cyclopropyl, a cyclobutyl, a cyclopentyl or a cyclohexyl.
  • a lower alkenyl radical is a monounsaturated radical having from 2 to 6 carbon atoms such as a vinyl, an allyl, a butenyl, a crotyl, a dimetylallyl or a methallyl.
  • phenyl radical in 1 or the benzyl radical in 1 When the phenyl radical in 1 or the benzyl radical in 1 are substituted, they bear from 1 to 3 substituents on the benzene ring chosen from the group consisting of a lower alkyl, a halogen, a lower alkoxy, a trifluoromethyl, a trifluoromethoxy or a alcoylthio.
  • the subject of the invention is also a process for obtaining the compounds of general formula I
  • the sulfonylation reaction takes place in a polar nitrogen medium such as dimethylformamide, 4-dimethylamino pyridine, dimethyl acetamide, hexaphosphorotriamide, optionally as a mixture with a polar aprotic solvent such as dimethyl sulfoxide or acetonitrile.
  • a polar nitrogen medium such as dimethylformamide, 4-dimethylamino pyridine, dimethyl acetamide, hexaphosphorotriamide, optionally as a mixture with a polar aprotic solvent such as dimethyl sulfoxide or acetonitrile.
  • the functional derivative of arylsulfonic acid is preferably an acid halide such as a chloride or a lower alkyl ester.
  • acid chloride p is used. toluene sulfonic or p.acylaminobenzene sulfonic acid chloride.
  • the sulfonation reaction is optionally followed by a hydrolysis reaction to remove the acyl radical.
  • the compounds of general formula I can be salified by adding a mineral or organic base.
  • the compounds of general formula I can be acylated with a functional derivative of carboxylic acid having from 1 to 10 carbon atoms.
  • the acyl radical can derive from an alkyl carboxylic acid, from an aryl carboxylic acid where the aryl radical is a monocyclic compound, or alternatively from an aralkoyl carboxylic acid.
  • the compounds of general formula I are used as antibacterial drugs in the form of pharmaceutical compositions intended for administration by the general route or by the topical route. They can therefore be used in the form of bare tablets, dragees, capsules, tablets, coated tablets, powders, granules, syrups, oral suspensions, ointments, creams, gels, eggs, vaginal capsules, suppositories or eye drops.
  • the unit dosage ranges from 0.050 g to 0.500 g and preferably from 0.100 g to 0.250 g depending on the route of administration.
  • the daily dosage depends on the weight and age of the subject, the severity and the nature of the bacterial infection. It ranges from 0.200 g to 2 g.
  • the minimum inhibitory concentrations were measured by a microdilution technique (*) in a liquid medium (Mueller-Hinton broth) in a volume of 100 ⁇ l and for a concentration range from 128 to 0.06 mg / L, prepared from an antibiotic stock solution grading 512 mg / 1.
  • the preparation of these stock solutions carried out varied according to the molecules as a function of the solubility criteria.
  • the inoculation is done by adding to each cup 10 ⁇ l of a dilution in physiological water of a broth of 18 hours in broth of the brain, such that each cup contains about 10 6 bacteria / ml.
  • the minimum inhibitory concentration is read as the first concentration of non-culture-giving antibiotic, macroscopically visible after 18 h of incubation at 37 °.
  • Each tablespoon contains 10 ml of suspension, i.e. 0.25 g of active principle. 4. Gynecological tablets based on 6,8-difluoro 7- (p.methyl sulfonylamino methyl piperidinyl-1) 1-cyclopropyl quinolonyl 3-carboxylic acid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to synthesis chemistry and particularly to therapeutic chemistry. More particularly it relates to new 3-carboxylic quinolone acids having general formula (I) wherein X is a group »CHal »COR1 wherein R1 is a lower alkyl radical or hydrogen or forms with R the chain (1), Z is an amino-radical selected in the group comprised of the compounds having formula (Z1) and the compounds of formula (Z2). The compounds according to the invention are active principles of anti-bacterial drugs.

Description

Dérivés sulfonamides de quinolones à activité antibactérienne Quinolone sulfonamide derivatives with antibacterial activity

La présente invention se rapporte au domaine de la chimie thérapeutique et notamment à de nouveaux agents anti-bactériens.The present invention relates to the field of therapeutic chemistry and in particular to new anti-bacterial agents.

Elle a plus particulièrement pour objet de nouvelles aminoquinolones substituées par un radical arylsulfonylé.It more particularly relates to new aminoquinolones substituted by an arylsulfonyl radical.

Elle a spécifiquement pour objet des acides 6-fluoro 7-(sulfonyl amino) 1-alcoyl quinolonyl-3 carboxyliques de formule générale IIt specifically relates to 6-fluoro 7- (sulfonyl amino) 1-alkyl quinolonyl-3 carboxylic acids of general formula I

C00HC00H

(I)(I)

Figure imgf000003_0002
Figure imgf000003_0002

dans laquelle X représente un groupe >CHal, >C0R1 dans lequel Rx est un radical alcoyle inférieur ou de l'hydrogène ou bien forme avec R 1'enchaînement |in which X represents a group>CHal,> C0R 1 in which R x is a lower alkyl radical or hydrogen or else forms with R the chain |

— 0 CH-CH, CH,- 0 CH-CH, CH,

Z représente un radical aminé choisi dans le groupe constitué par les composés de formule _..Z represents an amino radical chosen from the group consisting of the compounds of formula _ ..

>CH - (CH2)p - NH - S02 ^Ç -γ <Zι^> CH - (CH 2 ) p - NH - S0 2 ^ Ç - γ < Z ι ^

et les composés de formule Z,and the compounds of formula Z,

>N - S0, (Z2)

Figure imgf000003_0001
4505> N - S0, (Z 2 )
Figure imgf000003_0001
4505

- 2 - dans lesquelles Y représente de l'hydrogène, un radical alcoyle inférieur, un groupe aminé ou un radical acylamino n représente 2 m représente 2 ou 3 et p représente 0 ou 1 et dans laquelle R représente un radical alcoyle inférieur, cycloalcoyle inférieur, (cycloalcoyl inférieur) alcoyle inférieur, alcenyle inférieur, dihalogéno alcényle, phényle, phényl substitué, benzyle ou benzyle substitué.- 2 - in which Y represents hydrogen, a lower alkyl radical, an amino group or an acylamino radical n represents 2 m represents 2 or 3 and p represents 0 or 1 and in which R represents a lower alkyl, lower cycloalkyl radical , (lower cycloalkyl) lower alkyl, lower alkenyl, dihalogeno alkenyl, phenyl, substituted phenyl, benzyl or substituted benzyl.

Parmi les composés de formule générale I, on distinguera plus particulièrement les sous-groupes suivants :Among the compounds of general formula I, the following subgroups will be distinguished more particularly:

- les composés de formule générale I.- the compounds of general formula I.

Figure imgf000004_0001
pour laquelle X représente un groupe >CH et pour laquelle Z, R, n et m sont définis comme précédemment avec la restriction que lorsque R est un radical cycloalcoyle Y dans la formule Z2 est un radical alcoyle inférieur ayant au moins deux atomes de carbone, un amino ou un acylamino.
Figure imgf000004_0001
for which X represents a group> CH and for which Z, R, n and m are defined as above with the restriction that when R is a cycloalkyl radical Y in the formula Z 2 is a lower alkyl radical having at least two carbon atoms , an amino or an acylamino.

les généralethe general

(IB)(I B )

Figure imgf000004_0002
dans laquelle X représente un groupe >C-Hal ou >C-0R: dans lequel Hal est un atome d'halogène et R: est un radical alcoyle inférieur et Z, R, n et m sont définis comme précédemment
Figure imgf000004_0002
in which X represents a group> C-Hal or> C-0R : in which Hal is a halogen atom and R : is a lower alkyl radical and Z, R, n and m are defined as above

- les composés de formule générale Ic - the compounds of general formula I c

Figure imgf000005_0001
Figure imgf000005_0001

dans laquelle X représente un groupe >N et n, m, R et Z sont définis comme précédemmentin which X represents a group> N and n, m, R and Z are defined as above

- les composés de formule ID - the compounds of formula I D

Figure imgf000005_0002
Figure imgf000005_0002

dans laquelle X représente l'enchaînement >C-0-CH2-CH-in which X represents the sequence> C-0-CH 2 -CH-

CH, et Z, n et m sont définis comme précédemment les composés de formule générale I,CH, and Z, n and m are defined as above the compounds of general formula I,

Figure imgf000006_0001
Figure imgf000006_0001

dans laquelle R, X et Y ont les significations fournies antérieurement ainsi que leur sels d'addition avec une base minérale ou organiquein which R, X and Y have the meanings previously supplied as well as their addition salts with an inorganic or organic base

- les composés de formule générale If - the compounds of general formula I f

Figure imgf000006_0002
Figure imgf000006_0002

dans laquelle les substituants R, X et Y ont les significations fournies antérieurement et leurs sels d'addition avec une base minérale ou organiquein which the substituents R, X and Y have the meanings previously supplied and their addition salts with an inorganic or organic base

Parmi ces composés, l'élément essentiel de l'invention est la présence d'un substituant arylsulfonylé à l'azote qui confère aux molécules un degré de lipophilie plus important et qui parait être un des facteurs responsables de l'activité anti-bactérienne de ces produits. En effet, par rapport aux analogues amino quinoloniques non sulfonylés, les produits de la présente invention présentent un degré d'activité sensiblement plus élevé et en même temps un spectre d'activité sensiblement élargi.Among these compounds, the essential element of the invention is the presence of an arylsulfonyl substituent on nitrogen which gives the molecules a greater degree of lipophilicity and which appears to be one of the factors responsible for the anti-bacterial activity of these products. Indeed, compared to non-sulfonylated amino quinolonic analogs, the The products of the present invention exhibit a significantly higher degree of activity and at the same time a significantly wider spectrum of activity.

C'est ainsi que les dérivés aryl sulfonylés de la Ciprofloxacine manifestent, par rapport au produit de référence, une activité in vitro et in vivo sensiblement plus importante et surtout considérablement élargie notamment vis-à-vis des bactéries Gram positif.This is how the aryl sulfonylated derivatives of Ciprofloxacin manifest, compared to the reference product, a significantly greater in vitro and in vivo activity and above all considerably enlarged, in particular with respect to Gram positive bacteria.

Le radical arylsulfonylé peut être un radical phénylsulfonyle mais il sera avantageusement un radical (phényl substitué) sulfonyle comme par exemple un radical p. toluène sulfonyle (Y = CH3) ou p.amino phénylsulfonyle (Y = NH2) ou p.acetamidophényl sulfonyle (Y = NHC0CH3 ) .The arylsulfonyl radical may be a phenylsulfonyl radical but it will advantageously be a (substituted phenyl) sulfonyl radical such as for example a p radical. toluene sulfonyl (Y = CH 3 ) or p.amino phenylsulfonyl (Y = NH 2 ) or p.acetamidophenyl sulfonyl (Y = NHC0CH 3 ).

Le groupement azoté en 7 est le plus souvent une pipérazine, une homopipérazine, une amino piperidine de formuleThe nitrogen group at 7 is most often a piperazine, a homopiperazine, an amino piperidine of formula

^r CH2 CH2 NH2 avec p = 1^ r CH 2 CH 2 NH 2 with p = 1

ou bien ^T CH2 NH2 or ^ T CH 2 NH 2

avec p = 0with p = 0

La longueur de la chaine joue un rôle important pour l'activité et les composés pour lesquels p = 0 sont souvent plus actifs que les composés pour lesquels p = 1, qui restent cependant à un niveau d'activité important.The length of the chain plays an important role for the activity and the compounds for which p = 0 are often more active than the compounds for which p = 1, which however remain at an important level of activity.

Pour les composés de formule générale I, la nature du substance à l'azote en position 1 joue également un grand rôle. Les composés éthylés ou allylés sont bien actifs mais les dérivés cyclopropylés sont sensiblement plus actifs, notamment sur les bactéries Gram-négatif. On pourra également noter le bon niveau d'activité des dérivés N-benzylés ou N-benzyl substitué comme par exemple les dérivés o-chlorobenzyle, o.fluorobenzyle ou dichlorobenzyle ou encore diméthoxybenzyle. Les dérivés N-difluorovinyliques ou dichlorovinyliques présentent également un intérêt certain.For the compounds of general formula I, the nature of the substance with nitrogen in position 1 also plays a large role. The ethylated or allylated compounds are very active but the cyclopropylated derivatives are appreciably more active, in particular on Gram-negative bacteria. We can also note the good level of activity of the N-benzylated or N-benzyl substituted derivatives such as for example the o-chlorobenzyl, o.fluorobenzyl or dichlorobenzyl or dimethoxybenzyl derivatives. The N-difluorovinyl or dichlorovinyl derivatives are also of certain interest.

Le groupement carboxylique reste normalement libre. Toutefois, il peut s'avérer justifié de salifier cette fonction par une base minérale ou organique, de façon à obtenir des dérivés plus solubles dans l'eau, paramètre important de leur aptitude à diffuser. On pourra citer, à cet égard, les sels avec une base minérale comme les sels de métal alcalin, d'ammonium, de métal alcalino-terreux, d'Aluminium, de fer ou de bismuth. On pourra citer également les sels avec une base organique comme une alcoylamine, une alcanolamine, un sucre aminé, une cycloalcoylamine, un acide aminé, un sel d'ammonium quaternaire ou un sel d'aryl ou d'hétéroarylamine.The carboxylic group normally remains free. However, it may be justified to salify this function with an inorganic or organic base, so as to obtain derivatives more soluble in water, an important parameter of their ability to diffuse. Mention may be made, in this regard, of the salts with an inorganic base such as the alkali metal, ammonium, alkaline earth metal, aluminum, iron or bismuth salts. Mention may also be made of the salts with an organic base such as an alkylamine, an alkanolamine, an amino sugar, a cycloalkoylamine, an amino acid, a quaternary ammonium salt or an aryl or heteroarylamine salt.

Parmi les sels, on citera tout particulièrement les sels de sodium, de potassium, de lithium, d'ammonium ou de calcium; les sels de triéthylamine, de diéthanolamine, de trométhamine, de dicyclopropy- lamine, de glucosamine, de sarcosine, d'arginine, de pyridyl-2 éthylamine de xylidine, de toluidine, de diphénylamine ou de N-méthylglucamine.Among the salts, mention will be made most particularly of the sodium, potassium, lithium, ammonium or calcium salts; the salts of triethylamine, diethanolamine, tromethamine, dicyclopropylamine, glucosamine, sarcosine, arginine, 2-pyridylethylamine xylidine, toluidine, diphenylamine or N-methylglucamine.

Parmi les composés de formule générale I, on pourra citer les composés suivants, actuellement préférés :Among the compounds of general formula I, mention may be made of the following compounds which are currently preferred:

- l'acide 6,8-difluoro 1-éthyl 7-(p.aminophényl sulfonyl aminométhyl pipéridinyl-1) quinolone 3-carboxylique- 6,8-difluoro 1-ethyl 7- (p.aminophenyl sulfonyl aminomethyl piperidinyl-1) quinolone 3-carboxylic acid

l'acide 6,8-difluoro 1-éthyl 7-[(p.aminophényl sulfonylamino) pipéridinyl-1] quinolone 3-carboxylique6,8-difluoro 1-ethyl 7 - [(p.aminophenyl sulfonylamino) piperidinyl-1] quinolone 3-carboxylic

l'acide 6,8-difluoro 1-éthyl 7-[4-p.aminophényl sulfonyl pipérazinyl-1] quinolone 3-carboxylique6,8-difluoro 1-ethyl 7- [4-p.aminophenyl sulfonyl piperazinyl-1] quinolone 3-carboxylic acid

l'acide 6-fluoro 7-(4-p.aminophényl sulfonyl pipérazinyl-1) 1-cyclopropyl quinolone 3-carboxylique l'acide 6-fluoro 1-éthyl 7-(4-p.aminophényl sulfonyl pipérazinyl-1) quinolone 3-carboxylique6-fluoro 7- (4-p.aminophenyl sulfonyl piperazinyl-1) 1-cyclopropyl quinolone 3-carboxylic acid 6-fluoro 1-ethyl 7- (4-p.aminophenyl sulfonyl piperazinyl-1) quinolone 3-carboxylic acid

l'acide 6-fluoro 1-cyclopropyl 7-[(4-p.aminophényl sulfonyl) pipérazinyl-1] quinolone 3-carboxylique6-fluoro 1-cyclopropyl 7 - [(4-p.aminophenyl sulfonyl) piperazinyl-1] quinolone 3-carboxylic

l'acide 6,8-difluoro 1-cyclopropyl 7-[ (4-(p.aminophényl sulfonyl aminométhyl) pipéridinyl-1] quinolone 3-carboxylique6,8-difluoro 1-cyclopropyl 7- [(4- (p.aminophenyl sulfonyl aminomethyl) piperidinyl-1] quinolone 3-carboxylic

l'acide 6,8-difluoro 1-cyclopropyl 7-[(4-(p.aminophényl sulfonyl) piperazinyl-1] quinolone 3-carboxylique6,8-difluoro 1-cyclopropyl 7 - [(4- (p.aminophenyl sulfonyl) piperazinyl-1] quinolone 3-carboxylic acid

l'acide 6,8-difluoro 1-isopropyl 7-[4-(p.aminophényl sulphonyl aminométhyl) pipéridinyl-1] quinolone 3-carboxylique6,8-difluoro 1-isopropyl 7- [4- (p.aminophenyl sulphonyl aminomethyl) piperidinyl-1] quinolone 3-carboxylic

l'acide 6-fluoro 1-éthyl 7-[4(p.aminophényl sulfonyl) pipérazinyl-1] 4-oxo naphtyridine 3-carboxylique6-fluoro 1-ethyl 7- [4 (p.aminophenyl sulfonyl) piperazinyl-1] 4-oxo naphthyridine 3-carboxylic

l'acide 6-fluoro l,8-(2ξ-méthyl tétrahydro oxazinyl) 7-[4(p.amino phényl sulfonyl) pipérazinyl-1] quinolone 3-carboxylique6-fluoro 1, 8- (2ξ-methyl tetrahydro oxazinyl) 7- [4 (p.amino phenyl sulfonyl) piperazinyl-1] quinolone 3-carboxylic acid

l'acide 6-fluoro 7-[4(p.aminophényl sulfonyl aminométhyl) pipéridinyl-1] l,8-(2ξ-méthyl tétrahydro oxazinyl) quinolone 3-carboxylique6-fluoro 7- [4 (p.aminophenyl sulfonyl aminomethyl) piperidinyl-1] l, 8- (2ξ-methyl tetrahydro oxazinyl) quinolone 3-carboxylic acid

l'acide 6,8-difluoro 1-cyclopropyl 7-[4-(p.amino phenylsulfonyl amino) pipéridinyl-1] quinolone 3-carboxylique6,8-difluoro 1-cyclopropyl 7- [4- (p.amino phenylsulfonyl amino) piperidinyl-1] quinolone 3-carboxylic

l'acide 6,8-difluoro 1-cyclopropyl 7-[4-(p.amino phenyl sulfonyl) perhydrodiazepinyl-1] quinolone 3-carboxylique6,8-difluoro 1-cyclopropyl 7- [4- (p.amino phenyl sulfonyl) perhydrodiazepinyl-1] quinolone 3-carboxylic

l'acide 6,8-difluoro 1-cyclopropyl 7-[(p.butyrylamino phényl sulfonyl) perhydrodiazepinyl-1] quinolone 3-carboxylique Dans ce qui suit, le terme alcoyle inférieur désigne un radical hydrocarboné ayant de 1 à 6 atomes de carbone en chaine droite ou ramifiée comme un raéthyle, un éthyle, un isopropyle, un sec-butyle, un terbutyle, un neopentyle ou un n-hexyle.6,8-difluoro 1-cyclopropyl 7 - [(p.butyrylamino phenyl sulfonyl) perhydrodiazepinyl-1] quinolone 3-carboxylic In what follows, the term lower alkyl designates a hydrocarbon radical having from 1 to 6 carbon atoms in a straight or branched chain such as a raethyl, ethyl, isopropyl, sec-butyl, terbutyl, neopentyl or n- hexyl.

Un radical cycloalcoyle inférieur est un radical hydrocarboné cyclique ayant de 3 à 7 atomes de carbone comme un cyclopropyle, un cyclobutyle, un cyclopentyle ou un cyclohexyle.A lower cycloalkyl radical is a cyclic hydrocarbon radical having from 3 to 7 carbon atoms such as a cyclopropyl, a cyclobutyl, a cyclopentyl or a cyclohexyl.

Un radical alcenyle inférieur est un radical mono-insaturé ayant de 2 à 6 atomes de carbone comme un vinyle, un allyle, un butenyle, un crotyle, un dimétylallyle ou un méthallyle.A lower alkenyl radical is a monounsaturated radical having from 2 to 6 carbon atoms such as a vinyl, an allyl, a butenyl, a crotyl, a dimetylallyl or a methallyl.

Lorsque le radical phényle en 1 ou le radical benzyle en 1 sont substitués, ils portent de 1 à 3 substituants sur le cycle benzénique choisis dans le groupe constitué par un alcoyle inférieur, un halogène, un alcoxy inférieur, un trifluoromethyle, un trifluorométhoxy ou un alcoylthio.When the phenyl radical in 1 or the benzyl radical in 1 are substituted, they bear from 1 to 3 substituents on the benzene ring chosen from the group consisting of a lower alkyl, a halogen, a lower alkoxy, a trifluoromethyl, a trifluoromethoxy or a alcoylthio.

L'invention a également pour objet un procédé d'obtention des composés de formule générale IThe subject of the invention is also a process for obtaining the compounds of general formula I

Figure imgf000010_0001
Figure imgf000010_0001

dans laquelle X, Z et R sont définis comme précédemmentin which X, Z and R are defined as above

qui consiste en ce que l'on fait réagir une 6-fluoro 7-halogéno quinolone de formule générale II 04505which consists in reacting a 6-fluoro 7-halo quinolone of general formula II 04505

Figure imgf000011_0001
dans laquelle R et X ont les significations fournies précédemment et Hal est un atome de fluor ou de chlore
Figure imgf000011_0001
in which R and X have the meanings given above and Hal is a fluorine or chlorine atom

avec un compoé aminé de formule générale IIIwith an amino compound of general formula III

(CH2)n(CH 2 ) n

/ \/ \

Z NH (III)Z NH (III)

\ /\ /

(CH2)m(CH 2 ) m

dans laquelle Z représente >CH-(CH2)p-NH2 ou >NH s. ou p est défini comme précédemmentin which Z represents> CH- (CH 2 ) p-NH 2 or> NH s. where p is defined as above

pour former une quinolone de formule générale IVto form a quinolone of general formula IV

Figure imgf000011_0002
Figure imgf000011_0002

Figure imgf000011_0004
dans laquelle R, X et Z sont définis comme précédemment
Figure imgf000011_0004
in which R, X and Z are defined as above

que l'on fait réagir avec un dérivé fonctionnel d'acide arylsulfoniquethat we react with a functional derivative of arylsulfonic acid

R2

Figure imgf000011_0003
dans laquelle Y représente de l'hydrogène, un radical alcoyle inférieur, un radical amino ou un radical acylamino et R2 représente un atome d'halogène ou un alcoyle inférieurR 2
Figure imgf000011_0003
in which Y represents hydrogen, a lower alkyl radical, an amino radical or an acylamino radical and R 2 represents a halogen atom or a lower alkyl

pour obtenir le dérivé sulfonyle correspondant de formule générale I.to obtain the corresponding sulfonyl derivative of general formula I.

La réaction de sulfonylation a lieu en milieu azoté polaire comme le diméthylformamide, la 4-diméthylamino pyridine, le diméthyl acétamide, l'hexaphosphorotriamide, éventuellement en mélange avec un solvant polaire aprotique comme le diméthylsulfoxyde ou l'acétonitrile.The sulfonylation reaction takes place in a polar nitrogen medium such as dimethylformamide, 4-dimethylamino pyridine, dimethyl acetamide, hexaphosphorotriamide, optionally as a mixture with a polar aprotic solvent such as dimethyl sulfoxide or acetonitrile.

Le dérivé fonctionnel d'acide arylsulfonique est de préférence un halogénure d'acide comme un chlorure ou un ester d'alcoyle inférieur.The functional derivative of arylsulfonic acid is preferably an acid halide such as a chloride or a lower alkyl ester.

D'une manière tout à fait préférée, on utilise le chlorure d'acide p. toluène sulfonique ou un chlorure d'acide p.acylaminobenzène sulfonique.Most preferably, acid chloride p is used. toluene sulfonic or p.acylaminobenzene sulfonic acid chloride.

La réaction du sulfonation est éventuellement suivie d'une réaction d'hydrolyse pour éliminer le radical acyle.The sulfonation reaction is optionally followed by a hydrolysis reaction to remove the acyl radical.

Les composés de formule générale I peuvent être salifiés par addition d'une base minérale ou organique.The compounds of general formula I can be salified by adding a mineral or organic base.

Lorsque Y est égal à NH2 , les composés de formule générale I peuvent être acylés par un dérivé fonctionnel d'acide carboxylique ayant de 1 à 10 atomes de carbone.When Y is equal to NH 2 , the compounds of general formula I can be acylated with a functional derivative of carboxylic acid having from 1 to 10 carbon atoms.

Le radical acyle peut dériver d'un acide alcoyl carboxylique, d'un acide aryl carboxylique où le radical aryle est un composé monocyclique, ou bien encore d'un acide aralcoyl carboxylique.The acyl radical can derive from an alkyl carboxylic acid, from an aryl carboxylic acid where the aryl radical is a monocyclic compound, or alternatively from an aralkoyl carboxylic acid.

Les composés de formule générale I sont utilisés comme médicaments antibactériens sous forme de compositions pharmaceutiques destinées à l'administration par voie générale ou par voie topique. Ils peuvent donc être utilisés sous forme de comprimés nus, de dragées, de gélules, de tablettes, de comprimés enrobés, de poudres, de granulés, de sirops, de suspensions buvables, de pommades, de crèmes, de gels, d'ovules, de capsules vaginales, de suppositoires ou de collyres.The compounds of general formula I are used as antibacterial drugs in the form of pharmaceutical compositions intended for administration by the general route or by the topical route. They can therefore be used in the form of bare tablets, dragees, capsules, tablets, coated tablets, powders, granules, syrups, oral suspensions, ointments, creams, gels, eggs, vaginal capsules, suppositories or eye drops.

La posologie unitaire s'échelonne de 0,050 g à 0,500 g et de préférence de 0,100 g à 0,250 g selon la voie d'administration.The unit dosage ranges from 0.050 g to 0.500 g and preferably from 0.100 g to 0.250 g depending on the route of administration.

La posologie journalière dépend du poids et de l'âge du sujet, de la sévérité et de la nature de l'infection bactérienne. Elle s'échelonne de 0,200 g à 2 g.The daily dosage depends on the weight and age of the subject, the severity and the nature of the bacterial infection. It ranges from 0.200 g to 2 g.

Les exemples suivants illustrent l'invention sans toutefois la limiter :The following examples illustrate the invention without however limiting it:

EXEMPLE IEXAMPLE I

Acide 1-cyclopropyl 6-fluoro 7-[(4-méthyl phenyl sulfonyl)-4 pipérazinyl-1] quinolone 3-carboxylique Composé la1-Cyclopropyl 6-fluoro 7 - [(4-methyl phenyl sulfonyl) -4 piperazinyl-1] quinolone 3-carboxylic acid Compound

On dissout 0,5 g d'acide 1-cyclopropyl 6-fluoro 7-(pipérazinyl-l) quinolone 3-carboxylique dans 20 ml de soude IN à 40'C. On ajoute 0,6 g de chlorure de p. toluène sulfonyle et on maintient 90 mn sous bonne agitation à la même température. On ramène ensuite le pH à 5 par addition d'acide acétique. L'acide recherché précipite, on le sépare par filtration, on l'essore, on le lave par filtration, on l'essore, on le lave à l'eau puis on le reprend 30 ml d'éthanol bouillant, on filtre l'insoluble et on le sèche. On recueille 0,65 g de produit pur PFK >260°C (Rdt = 73%) .0.5 g of 1-cyclopropyl 6-fluoro 7- (piperazinyl-1) quinolone 3-carboxylic acid is dissolved in 20 ml of IN sodium hydroxide solution at 40 ° C. 0.6 g of p chloride is added. toluene sulfonyl and is maintained 90 minutes with good stirring at the same temperature. The pH is then reduced to 5 by addition of acetic acid. The desired acid precipitates, it is separated by filtration, it is filtered, it is washed by filtration, it is filtered, it is washed with water and then it is taken up 30 ml of boiling ethanol, the insoluble and dried. 0.65 g of pure product K K is collected> 260 ° C (yield = 73%).

L'acide 1-cyclopropyl 6,8-difluoro 7[(4-méthyl phényl sulfamoyl) aminométhyl-4] pipéridinyl-1 quinolone 3-carboxylique est préparé de la même façon avec un rendement de 68% (PFK = 222°) - Composé lb 1-cyclopropyl-6,8-difluoro 7 [[(4-methyl phenyl sulfamoyl) aminomethyl-4] piperidinyl-1 quinolone 3-carboxylic acid is prepared in the same way with a yield of 68% (mp K = 222 °) - Compound l b

Les composés suivants ont été préparés de la même façon : 2. l'acide 6,8-difluoro 7-[(p.aminophényl sulfonylamino methyl) pipéridinyl-1] 1-éthyl quinolone 3-carboxylique fondant à 260°C (Rdt = 70%) (Composé 2)The following compounds were prepared in the same way: 2. 6,8-difluoro acid 7 - [(p.aminophenyl sulfonylamino methyl) piperidinyl-1] 1-ethyl quinolone 3-carboxylic melting at 260 ° C (Yield = 70%) (Compound 2)

3. l'acide 6,8-difluoro 7-[4-p.aminophényl sulfamoyl) pipérazinyl-1] 1-éthyl quinolone 3-carboxylique fondant au-dessus de 260°C (Rdt = 81%)3. 6,8-difluoro 7- [4-p.aminophenyl sulfamoyl) piperazinyl-1] 1-ethyl quinolone 3-carboxylic acid melting above 260 ° C (Yield = 81%)

4. l'acide 6,8-difluoro 7-(4-p.aminophényl sulfamoylamino) pipérazinyl-1) 1-éthyl quinolone 3-carboxylique fondant à 224°C (Rdt = 38%)4. 6,8-difluoro 7- (4-p.aminophenyl sulfamoylamino) piperazinyl-1) 1-ethyl quinolone 3-carboxylic acid melting at 224 ° C (yield = 38%)

5. l'acide 6-fluoro 7-(4-p.aminophényl sulfonyl pipérazinyl-1) 1-cyclopropyl quinolone 3-carboxylique fondant au-dessus de 260°C (Rdt = 70%) (Composé 5)5. 6-fluoro 7- (4-p.aminophenyl sulfonyl piperazinyl-1) 1-cyclopropyl quinolone 3-carboxylic acid melting above 260 ° C (Yield = 70%) (Compound 5)

6. l'acide 6-fluoro 7-[(4-p.aminophényl sulfonyl) pipérazinyl-1] 1-éthyl quinolone 3-carboxylique fondant au-dessus de 260°C (Rdt = 79%)6. 6-fluoro 7 - [(4-p.aminophenyl sulfonyl) piperazinyl-1] 1-ethyl quinolone 3-carboxylic acid melting above 260 ° C (Yield = 79%)

7. l'acide 6-fluoro 7-[(4-(p.aminophényl sulfamoyl methyl) pipéridinyl-1] 1-cyclopropyl quinolone 3-carboxylique fondant à 262°C (Rdt = 40%)7. 6-fluoro acid 7 - [(4- (p.aminophenyl sulfamoyl methyl) piperidinyl-1] 1-cyclopropyl quinolone 3-carboxylic melting at 262 ° C (yield = 40%)

8. l'acide 6,8-difluoro 7-[(4-(p.aminophényl sulfamoyl methyl) piperidinyl-1] 1-cyclopropyl quinolone 3-carboxylique fondant à 225-230°C (Rdt = 50%) (Composé 8)8. 6,8-difluoro acid 7 - [(4- (p.aminophenyl sulfamoyl methyl) piperidinyl-1] 1-cyclopropyl quinolone 3-carboxylic melting at 225-230 ° C (Yield = 50%) (Compound 8 )

9. l'acide 6,8-difluoro 7-[(p.aminophényl sulphanoyl méthyl) pipéridinyl-1] 1-isopropyl quinolone 3-carboxylique fondant à 220°C (Rdt = 20%)9. 6,8-difluoro acid 7 - [(p.aminophenyl sulphanoyl methyl) piperidinyl-1] 1-isopropyl quinolone 3-carboxylic melting at 220 ° C (Yield = 20%)

10. l'acide 6,8-difluoro 7-[(4-méthylphényl sulfonylamino) méthyl pipéridinyl-1] 1-cyclopropyl quinolone 3-carboxylique 11. l'acide 6-fluoro 7-[(4-méthyl phényl sulfonyl) pipérazinyl-4] 1-éthyl naphtyridine 3-carboxylique10. 6,8-difluoro 7 - [(4-methylphenyl sulfonylamino) methyl piperidinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid 11. 6-fluoro acid 7 - [(4-methyl phenyl sulfonyl) piperazinyl-4] 1-ethyl naphthyridine 3-carboxylic

12. l'acide 6-fluoro 7-[4(p.aminophényl sulfonyl aminométhyl) pipérazinyl-1] 1-éthyl naphtyridinyl A-one 3-carboxylique12. 6-fluoro 7- [4 (p.aminophenyl sulfonyl aminomethyl) piperazinyl-1] 1-ethyl naphthridridyl A-one 3-carboxylic acid

13. l'acide 6,8-difluoro 7-[5-(4-méthylphenyl sulfonyl) perhydro diazepinyl-1] 1-cyclopropyl quinolone 3-carboxylique13. 6,8-difluoro 7- [5- (4-methylphenyl sulfonyl) perhydro diazepinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid

14. l'acide 6,8-difluoro 7-[(4-p.amino phenyl sulfonyl) pipérazinyl-1] 1-cyclopropyl quinolone 3-carboxylique fondant au-dessus de 260°C (Rdt 25%)14. 6,8-difluoro acid 7 - [(4-p.amino phenyl sulfonyl) piperazinyl-1] 1-cyclopropyl quinolone 3-carboxylic melting above 260 ° C (yield 25%)

15. l'acide 6,8-difluoro 7-[(4-p.aminophényl sulfonyl) perhydro- diazepinyl-1] 1-cyclopropyl quinolone 3-carboxylique15. 6,8-difluoro 7 - [(4-p.aminophenyl sulfonyl) perhydro-diazepinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid

16. l'acide 6-fluoro 7-( [5-(p.aminophényl sulfonyl) perhydrodiazepinyl-1] 1-cyclopropyl quinolone 3-carboxylique16. 6-fluoro 7- ([5- (p.aminophenyl sulfonyl) perhydrodiazepinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid

17. l'acide 6-fluoro 7-[(p.méthylphényl sulfonyl) perhydrodiazepinyl-1] 1-cyclopropyl quinolone 3-carboxylique17. 6-fluoro 7 - [(p.methylphenyl sulfonyl) perhydrodiazepinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid

18. l'acide 6,8-difluoro 7-[ (p.aminophényl sulfonylamino) pipéridinyl-1] 1-cyclopropyl quinolone 3-carboxylique18. 6,8-difluoro 7- [(p.aminophenyl sulfonylamino) piperidinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid

19. l'acide 6-fluoro 1-cyclopropyl 7-[(4-aminophényl sulfonyl) pipérazinyl-1] quinolone 3-carboxylique19. 6-fluoro 1-cyclopropyl 7 - [(4-aminophenyl sulfonyl) piperazinyl-1] quinolone 3-carboxylic acid

ETUDE BACTERIOLOGIQUE DES COMPOSES SELON L'INVENTIONBACTERIOLOGICAL STUDY OF THE COMPOUNDS ACCORDING TO THE INVENTION

Matériel et Méthodes :Material and methods :

Les produits ont été testés vis-à-vis de 7 souches de référence : *4 espèces à gram-positifThe products have been tested against 7 reference strains: * 4 gram-positive species

- Bacillus subtilis ATCC 9372- Bacillus subtilis ATCC 9372

- Staphylococcus aureus ATCC 25923- Staphylococcus aureus ATCC 25923

- Streptococcus faecalis ATCC 8043- Streptococcus faecalis ATCC 8043

- Staphylococcu aureus CB 951- Staphylococcu aureus CB 951

*3 espèces à gram-négatif* 3 gram-negative species

- Escherichia coli ATCC 25922- Escherichia coli ATCC 25922

- Pseudomonas aeruginosa ATCC 22853- Pseudomonas aeruginosa ATCC 22853

- Acinetobacter calcoaceticus variété anitratum ATCC 17903- Acinetobacter calcoaceticus variety anitratum ATCC 17903

La mesure des concentrations minimales inhibitrices a été faite par une technique de microdilution (*) en milieu liquide (bouillon de Mueller- Hinton) sous un volume de 100 μl et pour une gamme de concentration allant de 128 à 0,06 mg/L, préparé à partir d'une solution-mère d'antibiotique titrant 512 mg/1. La préparation de ces solutions-mères effectuée a varié selon les molécules en fonction des critères de solubilité.The minimum inhibitory concentrations were measured by a microdilution technique (*) in a liquid medium (Mueller-Hinton broth) in a volume of 100 μl and for a concentration range from 128 to 0.06 mg / L, prepared from an antibiotic stock solution grading 512 mg / 1. The preparation of these stock solutions carried out varied according to the molecules as a function of the solubility criteria.

L'inoculation se fait en ajoutant dans chaque cupule 10 μl d'une dilution en eau physiologique d'un bouillon de 18H en bouillon coeur cervelle telle que chaque cupule contienne environ 106 bactéries/ml.The inoculation is done by adding to each cup 10 μl of a dilution in physiological water of a broth of 18 hours in broth of the brain, such that each cup contains about 10 6 bacteria / ml.

La concentration minimale inhibitrice est lue comme la première concentration d'antibiotique ne donnant pas de culture, macroscopiquement visible après 18 h d'incubation à 37°.The minimum inhibitory concentration is read as the first concentration of non-culture-giving antibiotic, macroscopically visible after 18 h of incubation at 37 °.

(* = microplaques et inoculateur Dynatech)

Figure imgf000017_0001
(* = Dynatech microplates and inoculator)
Figure imgf000017_0001

Figure imgf000017_0002
Figure imgf000017_0002

Exemple de réalisations pharmaceutiquesExample of pharmaceutical achievements

1. Comprimés d'acide 6,8-difluoro 7-(p.aminophényl sulfonyl pipérazinyl-1) 1-cyclopropyl quinolone 3-carboxylique à 0,250 g.1. 6,8-Difluoro 7- (p.aminophenyl sulfonyl piperazinyl-1) 1-cyclopropyl quinolone 3-carboxylic acid tablets at 0.250 g.

- principe actif 250 g- active ingredient 250 g

- Amidon de mais 107 g- Corn starch 107 g

- Amidon de blé 51 g- Wheat starch 51 g

- Ethyl cellulose 12 g- Ethyl cellulose 12 g

- Carboxyméthyl cellulose 18 g- Carboxymethyl cellulose 18 g

- Stéarate de Magnésium 12 g- Magnesium stearate 12 g

pour 1000 comprimés terminés au poids moyen de 0,450 gper 1000 finished tablets at an average weight of 0.450 g

2. Gélules d'acide 6-fluoro 7-[4-(4-méthylphényl sulfonyl) perhydro- diazépinyl-1] 1-cyclopropyl quinolone 3-carboxylique à 200 mg.2. 6-fluoro 7- [4- (4-methylphenyl sulfonyl) perhydro-diazepinyl-1] 1-cyclopropyl quinolone 3-carboxylic acid capsules at 200 mg.

- principe actif 200 g- active ingredient 200 g

- Lactose 100 g- Lactose 100 g

- Talc 5 g- Talc 5 g

pour 1000 gélulesper 1000 capsules

3. Suspension buvable d'acide 6-fluoro 7-[(p.méthylphényl sulfonyl) pipérazinyl-1] 1-cyclopropyl quinolone 3-carboxylique3. Oral suspension of 6-fluoro acid 7 - [(p.methylphenyl sulfonyl) piperazinyl-1] 1-cyclopropyl quinolone 3-carboxylic

- principe actif 2,50 g- active ingredient 2.50 g

- Carboxyméthyl cellulose 0,50 g- Carboxymethyl cellulose 0.50 g

- Hydroxypropyl méthyl cellulose 0,25 g- Hydroxypropyl methyl cellulose 0.25 g

- Arôme café 0,25 g- Coffee flavor 0.25 g

- Ethyl vanilline 0,20 g- Ethyl vanillin 0.20 g

- Aspartame 0,008 g- Aspartame 0.008 g

- Eau purifiée q.s.p 100 ml- Purified water q.s.p 100 ml

Chaque cuillère à soupe contient 10 ml de suspension, soit 0,25 g de principe actif. 4. Comprimés gynécologiques à base d'acide 6,8-difluoro 7-(p.méthyl sulfonylamino méthyl pipéridinyl-1) 1-cyclopropyl quinolonyl 3-carboxyliqueEach tablespoon contains 10 ml of suspension, i.e. 0.25 g of active principle. 4. Gynecological tablets based on 6,8-difluoro 7- (p.methyl sulfonylamino methyl piperidinyl-1) 1-cyclopropyl quinolonyl 3-carboxylic acid

- principe actif 1000 g- active ingredient 1000 g

- Lactose 1275 g- Lactose 1275 g

- Croscarmellose sodique 25 g- Croscarmellose sodium 25 g

(commercialisée sous la marque ACDISOL)(marketed under the ACDISOL brand)

- Perhydrosqualène 10 g- Perhydrosqualene 10 g

- Stéarate de Magnésium 190 g- Magnesium stearate 190 g

pour 10.000 comprimés terminés au poids moyen de 0,250 g per 10,000 finished tablets at an average weight of 0.250 g

Claims

R E V E N D I C A T I O N SR E V E N D I C A T I O N S L'invention a pour objet :The subject of the invention is: 1°- les acides 6-fluoro 7-sulfonylamino 1-alcoyl quinolonyl-3 carboxyliques de formule générale I1 ° - 6-fluoro 7-sulfonylamino 1-alkyl quinolonyl-3 carboxylic acids of general formula I
Figure imgf000020_0001
Figure imgf000020_0001
 dans laquelle X représente un groupe >CH >C-Hal, ≥C-OR! , >N ou bien forme avec R un enchaînement |in which X represents a group>CH> C-Hal, ≥C-OR ! ,> N or else forms with R a sequence | -0 CH-CH3 CH2 -0 CH-CH 3 CH 2 dans lequel Rx est un radical alcoyle inférieur ou de l'hydrogène Z représente un radical aminé choisi dans le groupe constitué par :in which R x is a lower alkyl radical or hydrogen Z represents an amino radical chosen from the group consisting of: - les composés de formule Zλ - the compounds of formula Z λ >CH - (CH2)p - NH - S02 -^ ^~Y W> CH - (CH 2 ) p - NH - S0 2 - ^ ^ ~ Y W et - les composés de formule Z-and - the compounds of formula Z- >N - S0 ï (Z.)
Figure imgf000020_0002
05> N - S0 ï (Z.)
Figure imgf000020_0002
05 19 - dans lesquels Y est de l'hydrogène, un radical alcoyle inférieur, un radical aminé ou un radical acylaminé n représente 2 m représente 2 ou 3 p représente 0 ou 1 et R représente un radical alcoyle inférieur, cycloalcoyle inférieur, (cycloalcoyle inférieur) alcoyle inférieur, alcenyle inférieur, dihalogénoalcenyle, phényle, phényl substitué, benzyle ou benzyle substitué.19 - in which Y is hydrogen, a lower alkyl radical, an amino radical or an acylamine radical n represents 2 m represents 2 or 3 p represents 0 or 1 and R represents a lower alkyl radical, lower cycloalkyl, (lower cycloalkyl ) lower alkyl, lower alkenyl, dihaloalkenyl, phenyl, substituted phenyl, benzyl or substituted benzyl. °- Un acide 6-fluoro 7-sulfonylamino 1-alcoyl quinolonyl 3-carboxylique selon la revendication 1°, ayant la formule générale IA ° - A 6-fluoro 7-sulfonylamino 1-alkyl quinolonyl 3-carboxylic acid according to claim 1 °, having the general formula I A
Figure imgf000021_0001
Figure imgf000021_0001
 dans laquelle X représente le groupe >CH et n, m, Z et R sont définis comme précédemmentin which X represents the group> CH and n, m, Z and R are defined as above °- Un acide 6-fluoro 7-sulfonylamino 1-alcoyl quinolonyl 3-carboxylique selon la revendication 1° ayant la formule générale° - A 6-fluoro 7-sulfonylamino 1-alkyl quinolonyl 3-carboxylic acid according to claim 1 having the general formula
Figure imgf000021_0002
X représente un groupe >C-Hal ou C-ORj^ dans lequel Hal est un atome d'halogène et R: est un radical alcoyle inférieur et Z, n et m sont définis comme précédemment.
Figure imgf000021_0002
X represents a group> C-Hal or C-OR j ^ in which Hal is a halogen atom and R : is a lower alkyl radical and Z, n and m are defined as above. °- Un acide 6-fluoro 7-sulfonylamino 1-alcoyl quinolonyl-3 carboxylique selon la revendication 1° ayant la formule générale° - A 6-fluoro 7-sulfonylamino 1-alkyl quinolonyl-3 carboxylic acid according to claim 1 having the general formula
Figure imgf000022_0001
Figure imgf000022_0001
 dans laquelle X est un groupe, N et n, m, R et Z sont définis comme précédemment.in which X is a group, N and n, m, R and Z are defined as above. °- Un acide 6-fluoro 7-sulfonylamino quinolonyl-3 carboxylique selon la revendication 1° répondant à la formule générale ID ° - A 6-fluoro 7-sulfonylamino quinolonyl-3 carboxylic acid according to claim 1 ° corresponding to the general formula I D
Figure imgf000022_0002
dans laquelle X représente l'enchaînement
Figure imgf000022_0002
in which X represents the sequence >C-0-CH2-CH-> C-0-CH 2 -CH- CH3 CH 3 Z, n et m sont définis comme précédemment °- Un acide 6-fluoro 7-sulfonyl perhydrodiazépinyl quinolonyl-3 carboxylique selon la revendication 1° répondant à la formule générale IE Z, n and m are defined as above ° - A 6-fluoro 7-sulfonyl perhydrodiazepinyl quinolonyl-3 carboxylic acid according to claim 1 ° corresponding to the general formula I E
Figure imgf000023_0001
Figure imgf000023_0001
Figure imgf000023_0002
dans laquelle X, R et Y sont définis comme précédemment
Figure imgf000023_0002
in which X, R and Y are defined as above Un acide 6-fluoro 7-(sulfonyl amino pipéridinyl-1) quinolonyl 3-carboxylique selon la revendication 1° répondant à la formule générale IF A 6-fluoro 7- (sulfonyl amino piperidinyl-1) quinolonyl 3-carboxylic acid according to claim 1 corresponding to the general formula I F
Figure imgf000023_0003
Figure imgf000023_0003
 dans laquelle X, R et Y sont définis comme précédemmentin which X, R and Y are defined as above °- Les sels des composés selon l'une des revendications 1 à 7° avec une base minérale ou organique.° - The salts of the compounds according to one of claims 1 to 7 ° with a mineral or organic base. e- Un composé selon l'une des revendications 1 à 8° dans lequel Y est un radical méthyle °- Un composé selon l'une des revendications 1 à 8° dans lequel Y est un radical amino e - A compound according to one of claims 1 to 8 ° in which Y is a methyl radical ° - A compound according to one of claims 1 to 8 ° in which Y is an amino radical °- Un composé selon l'une des revendications 1 à 10° choisi dans le groupe constitué par :° - A compound according to one of claims 1 to 10 ° chosen from the group consisting of: l'acide 6,8-difluoro 1-éthyl 7-(p.aminophényl sulfonyl aminométhyl pipéridinyl-1) quinolone 3-carboxylique6,8-difluoro 1-ethyl 7- (p.aminophenyl sulfonyl aminomethyl piperidinyl-1) quinolone 3-carboxylic acid - l'acide 6,8-difluoro 1-éthyl 7-[(p.aminophényl sulfonylamino) pipéridinyl-1] quinolone 3-carboxylique- 6,8-difluoro 1-ethyl 7 - [(p.aminophenyl sulfonylamino) piperidinyl-1] quinolone 3-carboxylic l'acide 6,8-difluoro 1-éthyl 7-[4-(p.aminophényl sulfonyl) pipérazinyl-1] quinolone 3-carboxylique6,8-difluoro 1-ethyl 7- [4- (p.aminophenyl sulfonyl) piperazinyl-1] quinolone 3-carboxylic acid l'acide 6,8-difluoro 1-cyclopropyl 7-[(4-(p.aminophényl sulfonyl) aminométhyl) pipéridinyl-1] quinolone 3-carboxylique6,8-difluoro 1-cyclopropyl 7 - [(4- (p.aminophenyl sulfonyl) aminomethyl) piperidinyl-1] quinolone 3-carboxylic l'acide 6,8-difluoro 1-cyclopropyl 7-[4-(p.amino phenyl sulfonyl) perhydrodiazepinyl-1] quinolone 3-carboxylique6,8-difluoro 1-cyclopropyl 7- [4- (p.amino phenyl sulfonyl) perhydrodiazepinyl-1] quinolone 3-carboxylic °- Un procédé d'obtention des composés de formule générale I selon la revendication° - A process for obtaining the compounds of general formula I according to claim
Figure imgf000024_0001
Figure imgf000024_0001
 dans laquelle n, m, X, Z et R sont définis comme précédemment qui consiste en ce que l'on fait réagir une 6-fluoro 7-halogéno quinolone de formule générale II
Figure imgf000025_0001
dans laquelle R et X ont les significations fournies précédemment et Hal est un atome de fluor ou de chlore avec un composé aminé de formule générale III (CH2)nin which n, m, X, Z and R are defined as above which consists in reacting a 6-fluoro 7-halo quinolone of general formula II
Figure imgf000025_0001
in which R and X have the meanings given above and Hal is a fluorine or chlorine atom with an amino compound of general formula III (CH 2 ) n / \/ \ Z NH (III)Z NH (III) \ /\ / (CH2)m dans laquelle Z représente >CH-(CH2)p-NH2 ou >NH n et m sont définis comme précédemment et p est égal à 0 ou 1 pour former une quinolone de formule générale IV(CH 2 ) m in which Z represents> CH- (CH 2 ) p-NH 2 or> NH n and m are defined as above and p is equal to 0 or 1 to form a quinolone of general formula IV
Figure imgf000025_0002
Figure imgf000025_0002
 dans laquelle R, X, n et m sont définis comme précédemment et Z est un groupe >CH-(CH2)n-NH2 ou >NH que l'on fait réagir avec un dérivé fonctionnel d'acide arylsulfoniquein which R, X, n and m are defined as above and Z is a group> CH- (CH 2 ) n-NH 2 or> NH which is reacted with a functional derivative of arylsulfonic acid R2
Figure imgf000025_0003
dans laquelle Y représente de l'hydrogène, un radical alcoyle inférieur, un radical amino ou un radical acylamino et R2 représente un atome d'halogène ou un alcoyle inférieur pour obtenir le dérivé sulfonyle correspondant de formule générale I.R 2
Figure imgf000025_0003
in which Y represents hydrogen, a lower alkyl radical, an amino radical or an acylamino radical and R 2 represents a halogen atom or a lower alkyl to obtain the corresponding sulfonyl derivative of general formula I. °- Un procédé selon la revendication 12° dans lequel la réaction de sulfonylation a lieu en milieu azoté polaire.° - A process according to claim 12 ° wherein the sulfonylation reaction takes place in a polar nitrogen medium. °- Un procédé selon la revendication 12° qui comporte l'étape supplémentaire, lorsque Y est égal à NH2-, d'acylation par un dérivé fonctionnel d'acide carboxylique ayant de 1 à 10 atomes de carbone en présence d'un catalyseur d'acylation.° - A process according to claim 12 ° which comprises the additional step, when Y is equal to NH 2 -, of acylation with a functional derivative of carboxylic acid having from 1 to 10 carbon atoms in the presence of a catalyst acylation. °- Compositions pharmaceutiques caractérisées en ce qu'elles renferment à titre de principe actif au moins un composé de formule générale I selon l'une des revendications 1 à 11°° - Pharmaceutical compositions characterized in that they contain, as active principle, at least one compound of general formula I according to one of claims 1 to 11 °
Figure imgf000026_0001
Figure imgf000026_0001
 dans laquelle X représente un groupe >CH >C-Hal, ≥C-OR! , >N ou bien forme avec R un enchaînement |in which X represents a group>CH> C-Hal, ≥C-OR ! ,> N or else forms with R a sequence | -0 ^CH-CH, \ / 3 -0 ^ CH-CH, \ / 3 CH2 dans lequel _\ est un radical alcoyle inférieur ou de l'hydrogène Z représente un radical aminé choisi dans le groupe constitué par : - les compoés de formule Zx CH 2 in which _ \ is a lower alkyl radical or hydrogen Z represents an amino radical chosen from the group consisting of: - the compounds of formula Z x >CH - (CH, )p - NH - S02 - - γ Zι >> CH - (CH,) p - NH - S0 2 - - γ Z ι> et - les compoés de formule Z2 and - the compounds of formula Z 2
Figure imgf000027_0001
Figure imgf000027_0001
 dans lesquels Y est de l'hydrogène, un radical alcoyle inférieur, un radical aminé ou un radical acylaminé n représente 2 m représente 2 ou 3 p représente 0 ou 1 et R représente un radical alcoyle inférieur, cycloalcoyle inférieur, (cycloalcoyl inférieur) alcoyle inférieur, alcenyle inférieur, dihalogénoalcenyle, phényle, phényl substitué, benzyle ou benzyle substitué en association ou en mélange avec un excipient inerte, non toxique, pharmaceutiquement-acceptable.in which Y is hydrogen, a lower alkyl radical, an amino radical or an acylamine radical n represents 2 m represents 2 or 3 p represents 0 or 1 and R represents a lower alkyl radical, lower cycloalkyl, (lower cycloalkyl) alkyl lower, lower alkenyl, dihaloalkenyl, phenyl, substituted phenyl, benzyl or substituted benzyl in combination or in admixture with an inert, non-toxic, pharmaceutically acceptable excipient. Une composition pharmaceutique selon la revendication 15° dans laquelle la teneur en principe actif s'échelonne de 0,050 à 0,500 g par prise unitaire. A pharmaceutical composition according to claim 15 in which the content of active principle ranges from 0.050 to 0.500 g per unit dosage.
PCT/FR1993/000807 1992-08-14 1993-08-12 Sulphonamide derivatives of quinolones having an antibacterial activity Ceased WO1994004505A1 (en)

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EP0610896A1 (en) * 1993-02-09 1994-08-17 Senju Pharmaceutical Co., Ltd. Quinolonecarboxylic acid derivatives as antibacterials
WO2001003698A1 (en) * 1999-07-09 2001-01-18 Ortho-Mcneil Pharmaceutical, Inc. Taste masked pharmaceutical liquid formulations
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses

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EP0117473A1 (en) * 1983-02-25 1984-09-05 Bayer Ag Quinolone carboxylic acids, process for their preparation and antibacterial compositions containing them
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0610896A1 (en) * 1993-02-09 1994-08-17 Senju Pharmaceutical Co., Ltd. Quinolonecarboxylic acid derivatives as antibacterials
WO2001003698A1 (en) * 1999-07-09 2001-01-18 Ortho-Mcneil Pharmaceutical, Inc. Taste masked pharmaceutical liquid formulations
US6482823B1 (en) 1999-07-09 2002-11-19 Ortho-Mcneil Pharmaceutical, Inc. Taste masked pharmaceutical liquid formulations
US6586012B2 (en) 1999-07-09 2003-07-01 Ortho-Mcneil Pharmaceutical, Inc. Taste masked pharmaceutical liquid formulations
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses

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