EP0738257A1 - New method for n-cyclopropylation of aromatic amines, as well as compounds and compositions obtained - Google Patents
New method for n-cyclopropylation of aromatic amines, as well as compounds and compositions obtainedInfo
- Publication number
- EP0738257A1 EP0738257A1 EP94921773A EP94921773A EP0738257A1 EP 0738257 A1 EP0738257 A1 EP 0738257A1 EP 94921773 A EP94921773 A EP 94921773A EP 94921773 A EP94921773 A EP 94921773A EP 0738257 A1 EP0738257 A1 EP 0738257A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- optionally
- quinoline
- carboxylic acid
- cyclopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
Definitions
- the present invention consists in a new method for the N-cyclo- propylation of primary and secondary aromatic amines.
- the met ⁇ hod can be used for the synthesis of several molecules. It is well adaptable in the synthesis of N-cyclopropyl-substituted quinolones and naftiridines, where the method is applicable as the last step of synthesis or previously in the course of the synthesis, before or after ring-closure of the ring carrying the nitrogen atom to be N-cyclopropylated, before or after in ⁇ troduction of other substituents of the molecule.
- R is an ester-forming group such as an C alkyl or a
- - R stands for hydrogen , C alkyl, benzyl-oxy-
- X is halogen preferably bromine -
- - X stands for a metal ion, such as alkali, favourably potassiu
- the object of the invention is a process for the introduction of a cyclopropyl group into a primary or se ⁇ condary aromatic amine, by reacting the corresponding amines or their salts so as to form the corresponding N-cyclopropyl- ( 1 '-carboxy)-derivatives of the formula (II) by way of reacting the corresponding amines or their salts a. with the reagent of general formula (I) optionally in the pre ⁇ sence of an acid binding agent or b. with 2,4-dihalogen-butiric acid ester , or c.
- the reagents of preference formula (I) are bromo-cyclopropyl-carboxylic acid, its esters and salts, but other halogen derivatives can also be used.
- the alkali salt e.g. the po ⁇ tassium or sodium salt - of the aromatic amine
- it is not ne ⁇ cessary to use an acid binding agent.
- alkali carbona ⁇ tes and hydroxides as well as amines can be used as acid bin ⁇ ding agents.
- potassium carbonate both as an acid binding agent and also to prepare the potassium salt of the amine to be cyclopropylated.
- Elimination of the l'-carboxyl group can be brought about using any known manner to eliminate carboxyl groups, preferably by way of heat treatment at temperatures between 200 - 250 oC preferably at 220 - 230oC.
- acid hydrolysis can also be used as shown below in some of the Examples.
- a preferred embodiment of the invention is the preparation of the quinolone-3-carboxylic acid derivative of the general for ⁇ mula (III) and its salts by reacting a primary or secondary amine on the course of the synthesis of the molecule before or after ring closure of the quinolone ring with the reagent of formula (I) optionally in the presence of an acid binding agent and subsequently optionally hydrolysing the ester group or groups and optionally eliminating the l'-carboxyl group in ⁇ troduced on the course of the first step from the molecule by termical treatment or hydrolysis and optionally also elimina ⁇ ting the substituent of the piperazine group.
- One important embodiment of the invention is the production of the quinoline-3-carboxylic acid derivative of the formula (III) and its salts by eliminating the 1'- carboxyl group of the ( 1 '-carboxyl )-cyclopropyl-quinoline-3-carboxylic acid deriva ⁇ tive of the formula (IV) or its salts and optionally also eli ⁇ minating the 4-substituent of the piperazine group before, af ⁇ ter or simultaneously.
- the invention comprises the process for the preparation of the quinoline-3-carboxylic acid derivative of the formula (IV) and its salts by carrying out the following steps in an optional sequence on a quinoline-3-carboxylic acid derivative of the general formula (VII) a. ) reaction according to anyof the above methods a..b. or c. e.g. with a reagent of formula (I) optionally in the presence of an acid binding agent, and optionally hydrolysing the ester groups of the (l'- carboxyl)-l-cyclopropyl quinoline-3-carboxylic acid ester deri ⁇ vative thus obtained ,
- the invention also comprises the process for the preparation of the intermediate quinoline-3-carboxylic acid derivative of the formula (IV) - which is one key intermediate of the synthesis - by N-alkylating the quinoline-3-carboxylic acid derivative of the general formula (VII) with 1-bromo-cyclopropane-carboxylic acid or its alkyl ester of formula (I), hydrolysing the quinoline-3-carboxylic acid derivative of the general formula (VIII) and 7-substituting the quinoline-3-carboxylic acid derivative of the formula (V) with piperazine or N-substituted piperazine.
- the compounds of formula (IV) are new and biolo ⁇ gically active.
- bacteriostatic products serve as the- rapeutically valuable active ingredients in pharmaceuticals especially bacteriostatic products.
- Their bacteriostatic activity corresponds to those of cyprofloxacine or enrofloxacine and they might be used when these are not effective e.g. because of resistance against some of the strains involved.
- esters primarily obtained such as the qui- n ⁇ line-3-carboxylic acid derivative of the general formula (VIII) using acidic conditions preferably aqueous sulfuric and/or acetic acid.
- acidic conditions preferably aqueous sulfuric and/or acetic acid.
- other hydrolysis methods might also be used to hydrolyse the esters.
- methanolysis especially when silylesters are present.
- Alkaline hydrolysis is also a preferred method.
- a suitable solvent for the hydrolysis step and for the step to introduce the pipe ⁇ razine- substituent it is preferable to use a suitable solvent. It has been found according to this invention that dimethyl formamide is a prefered solvent for this purpose, having a highly advantageous influence on the reaction and giving pure products. Other solvents like dimethyl sulfoxide can be used.
- Quinoline-3-carboxylic acid derivatives of formula (VIII) and piperazines are preferably reacted in the presence of pyridine. Excess of pyridine and/or piperazine after termination of the reaction may be eliminated by steam distillation.
- quinoline-3-carboxylic acid derivatives of formula (IV) and their salts are new products and are also subject of this invention.
- a further embodiment of the patent are compositions comprising as a biologically active ingredient the new compounds of the general formula (IV) and their salts. Their most important use is based on their bacteriostatic activity combined with their improved solubility as compared with the compounds not compri ⁇ sing the l'-carboxyl group.
- compositions for biological use as pharmaceuticals and veteri ⁇ nary products comprising the compounds of general formula (IV) with pharmaceutically acceptable carriers, auxiliary products, diluents and other additives which are known to be used in pharmaceutical products to facilitate administration for oral, parenteral, transdermal or rectal use of any kind.
- the composi ⁇ tions may be administered when related compounds are not readi ⁇ ly used because of resistance or problems of dissolution in the tissues involved.
- 1,4-dihydro-l-( 1 ' -carboxyl )- cyclopropyl-quinoline-3-carboxylic acid, 6.5 g of piperazine and 18.0 g of pyridine are heated for o 3 hours at about 75 C.
- 100 ml of water are then added and the pH value of the reaction mixture is adjusted to 10 - 11 by ad ⁇ dition of 2N aqueous sodium hydroxide.
- ⁇ nreacted pyridine and piperazine are then eliminated by steam distillation.
- the re ⁇ mainder is filtered and the pH value of the reaction mixture is o adjusted to a value of about 5 - 6 at about 70 C.
- the suspen ⁇ sion obtained is filtered, washed with water and dried.
- the suspension obtained On cooling to 20oC the suspension obtained is filtered. The precipitate is washed twice with acetone and co ⁇ vered with water. On final filtration of the crystals they are dissolved in a solution of 5 g of potassium carbonate and 100 ml of water. The solution is decolorized with carbon black and filtered. The pH value of the filtrate is adjusted to 7.5 by addition of acetic acid and the suspension obtained is cooled, filtered, washed with water and methanol and again filtered.
- Example 6 200 ml of water are added and the pH value is adjusted to 6 by addition of acetic acid, the suspen ⁇ sion is filtered, washed and dried. 13.5 g of l-(1 ' -carboxyl)- cyclopropyl- 4-oxo-l, 4-dihydro-6-fluoro-7- chloro-quinoline-3- carboxylic acid ethyl ester are obtained wich is further trea ⁇ ted as in Example 4. Example 6.
- 2,4-dibromo-butyric acid methyl ester are boiled in 200 ml of toluene until the reaction is complete.
- the suspension obtained is filtered, the solid phase is stirred in water for 1 hour.
- Example 10 Using the process of Example 10 but starting from equimolar amounts of 1, 4-dihydro-4-oxo- 6-fluoro-7-(4 '-carbomethoxy-pipe- razinyl )-quinoline- 3-carboxylic acid ethyl ester or 6-chloro- 7-(4-ethyl-piperazinyl )- 1,4-dihydro-4-oxo-quinoline- 3-carbo- xylic acid ethyl ester the products are l-(1 '-carboxy)- cyclo ⁇ propyl- 1, 4-dihydro-4-oxo- 6-fluoro- 7-piperazinyl -quinoline- 3-carboxylic acid and 1-( 1 '- carboxy)-cyclopropyl-1, 4-dihydro- 4-oxo-6-fluoro-7-(4 '-ethyl-1 '-piperazinyl )-quinoline-3-carboxylic
- Test organism Escherichia coli 14.
- Test medium ISO-Sensitest agar (pH 7.2) o Incubation: 20 hours at 37 C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Process for the introduction of a cyclopropyl group into a primary or secondary aromatic amine or into heterocyclic compounds containing a secondary nitrogen atom reacting to the corresponding amines or their salts so as to form the corresponding N-cyclopropyl-(1'-carboxy)-derivatives either with the reagent of general formula (I), optionally in the presence of an acid binding agent or with 2,4-dihalogen-butyric acid ester or with chloroacetic acid ester, whereupon the resulting N-(alkoxy-carbonyl)-methyl-derivative is treated with alkali alkylate and dihalogen-ethane to convert the alkoxy-carbonyl-methyl group into a carbalkoxy-cyclopropyl group and subsequently optionally hydrolysing the ester groups if present and optionally eliminating the 1'-carboxyl group introduced in the course of the first step, whereby the last step is carried out optionally after introducing other substituents into the aromatic ring or after eliminating other substituents from the aromatic group. The method is suitable to synthesize 1-cyclopropyl-7-piperazine-1,4-dihydro-quinolone-3-carboxylic acid derivatives. New biologically active compounds are formed including compounds of formula (IV) and their salts which are used in pharmaceutical and veterinary compositions.
Description
New Method for N-Cyclopropyl^ ation of Aromatic Amines, as well as Compounds and Compositions Obtained.
The present invention consists in a new method for the N-cyclo- propylation of primary and secondary aromatic amines. The met¬ hod can be used for the synthesis of several molecules. It is well adaptable in the synthesis of N-cyclopropyl-substituted quinolones and naftiridines, where the method is applicable as the last step of synthesis or previously in the course of the synthesis, before or after ring-closure of the ring carrying the nitrogen atom to be N-cyclopropylated, before or after in¬ troduction of other substituents of the molecule. Thus it can also be used on the course of production of certain naftiridi- ne or quinolone-3-carboxylic acid derivatives having valuable therapeutical properties, or their intermediates. The method gives the possibility to synthetize new molecules some of which are protected in this application. The new molecules are intermediates in the synthesis of known valuable chemical com¬ pounds and some of them have valuable biological activities per se.
In this specification the meaning of the symbols representing several substituents in the chemical formulae is always the following: 1 R is an ester-forming group such as an C alkyl or a
1-4 tri-(C )-alkyl-silyl group, or hydrogen, or a metal ion, 1-4 preferably alkali
2 - R stands for a C alkyl group and
3
- R stands for hydrogen , C alkyl, benzyl-oxy-
1-4 carbonyl, acyl or C alkoxy-carbonyl group ,
1-4
- Ar stands for an aromatic or heteroaromatic group having one or more rings and optionally having substituents and the dot¬ ted line indicates that the nitrogen also can be part of a he- terocyclic ring, 1
- X is halogen preferably bromine -
2
- X stands for a metal ion, such as alkali, favourably potassiu
It is known, that - while various cyclopropylamines are valuabl chemical compounds - the simple substitution reaction between an amine and a cyclopropyl halogenide is difficult to achieve because cyclopropyl halides are extremely resistent to nucleo — philic attack ( .Am.Chem.Soc.1951, 73, 212; Russ.Chem.Rev. 1980, 49, 549). To overcome this problem a suggestion was made to use a two-step sequence of 1-ethoxy- cyclopropylation with 1-bro- mo-1-ethoxy- cyclopropane followed by reduction of the 1-etho- xy-group with a mixture of sodium borohydride and diethoxy -bo¬ ron- trifluoride in tetrahydrofurane to prepare certain aryl N-cyclopropylamines. Variously substituted phenyl and naphthyl primary amines and phenyl-methyl-amine were thus N-cyclopropy- lated (J.Chem.Soc.Chem.Comm. 1987, 897 - 898). This laboratory method was soon after repeated according to published patent applications on anilines, naphtiridines and quinolones, without isolation and characterisation of the intermediates (EPA 332033; EPA 332930, ES 2017864, ES 20.19033, ES 2019504). According to the latter (Spanish) patents introduction of the 1-ethoxy-cyclopropyl group was accomplished using 1-ethoxy- cyclopropyl-trifluoro-methane-sulfonate (otherwise known as the triflate) .
According to the present invention a method was found according to which it was made possible to introduce the N-cyclopropyl substituent into primary or secondary aryl amines, also into naphthiridine and quinolone 3-carboxylic acid ring systems be¬ fore or after ring closure and thus a new approach of synthe¬ sis route was found which rendered the whole process safer and more economical on a production level.
More particularly the object of the invention is a process for the introduction of a cyclopropyl group into a primary or se¬ condary aromatic amine, by reacting the corresponding amines or their salts so as to form the corresponding N-cyclopropyl- ( 1 '-carboxy)-derivatives of the formula (II) by way of reacting the corresponding amines or their salts a. with the reagent of general formula (I) optionally in the pre¬ sence of an acid binding agent or b. with 2,4-dihalogen-butiric acid ester , or c. with chloroacetic acid ester whereupon the resulting N- (alkoxycarbonyl )- methyl- derivative is treated with alkali alkylate and dihalogen-ethane to convert the alkoxy-carbonyl-methyl group into a carboalkoxy- cyclopropyl group and subsequently optionally hydrolysing the ester groups if present and optionally eliminating the l'-carboxyl group in¬ troduced on the course of the first step from the molecule of the general formula (II), whereby the last step is carried out
optionally after introducing other substitutents into the aro¬ matic ring or after eliminating other substituents from the aromatic group.
When using the method a. ) the reagents of preference formula (I) are bromo-cyclopropyl-carboxylic acid, its esters and salts, but other halogen derivatives can also be used.
When using the salt - preferably the alkali salt e.g. the po¬ tassium or sodium salt - of the aromatic amine, it is not ne¬ cessary to use an acid binding agent. Otherwise alkali carbona¬ tes and hydroxides as well as amines can be used as acid bin¬ ding agents. It is preferred to use potassium carbonate both as an acid binding agent and also to prepare the potassium salt of the amine to be cyclopropylated.
Elimination of the l'-carboxyl group can be brought about using any known manner to eliminate carboxyl groups, preferably by way of heat treatment at temperatures between 200 - 250 oC preferably at 220 - 230oC. However acid hydrolysis can also be used as shown below in some of the Examples.
The new method are readily used in production of new and known naphthiridine and quinolone derivatives where the cyclopropyl group can be introduced into the molecule before or after ring closure of the naphthiridine or the quinolone ring. A preferred embodiment of the invention is the preparation of the quinolone-3-carboxylic acid derivative of the general for¬ mula (III) and its salts by reacting a primary or secondary amine on the course of the synthesis of the molecule before or after ring closure of the quinolone ring with the reagent of formula (I) optionally in the presence of an acid binding
agent and subsequently optionally hydrolysing the ester group or groups and optionally eliminating the l'-carboxyl group in¬ troduced on the course of the first step from the molecule by termical treatment or hydrolysis and optionally also elimina¬ ting the substituent of the piperazine group.
One important embodiment of the invention is the production of the quinoline-3-carboxylic acid derivative of the formula (III) and its salts by eliminating the 1'- carboxyl group of the ( 1 '-carboxyl )-cyclopropyl-quinoline-3-carboxylic acid deriva¬ tive of the formula (IV) or its salts and optionally also eli¬ minating the 4-substituent of the piperazine group before, af¬ ter or simultaneously.
The invention comprises the process for the preparation of the quinoline-3-carboxylic acid derivative of the formula (IV) and its salts by carrying out the following steps in an optional sequence on a quinoline-3-carboxylic acid derivative of the general formula (VII) a. ) reaction according to anyof the above methods a..b. or c. e.g. with a reagent of formula (I) optionally in the presence of an acid binding agent, and optionally hydrolysing the ester groups of the (l'- carboxyl)-l-cyclopropyl quinoline-3-carboxylic acid ester deri¬ vative thus obtained ,
3 b. 7-substituting with 4-R -piperazine, c. elimination of the l'-carboxyl group preferably by heat tre¬ atment or acid hydrolysis or alkaline hydrolysis, d. optionally eliminating the 4-substitutent of the piperazine preferably by way of hydrolysis.
The invention also comprises the process for the preparation of
the intermediate quinoline-3-carboxylic acid derivative of the formula (IV) - which is one key intermediate of the synthesis - by N-alkylating the quinoline-3-carboxylic acid derivative of the general formula (VII) with 1-bromo-cyclopropane-carboxylic acid or its alkyl ester of formula (I), hydrolysing the quinoline-3-carboxylic acid derivative of the general formula (VIII) and 7-substituting the quinoline-3-carboxylic acid derivative of the formula (V) with piperazine or N-substituted piperazine. The compounds of formula (IV) are new and biolo¬ gically active. Besides being intermediates they serve as the- rapeutically valuable active ingredients in pharmaceuticals especially bacteriostatic products. Their bacteriostatic activity corresponds to those of cyprofloxacine or enrofloxacine and they might be used when these are not effective e.g. because of resistance against some of the strains involved.
When carrying out the methods of the invention it is preferable to hydrolyse the the esters primarily obtained such as the qui- nσline-3-carboxylic acid derivative of the general formula (VIII) using acidic conditions preferably aqueous sulfuric and/or acetic acid. However other hydrolysis methods might also be used to hydrolyse the esters. Thus it is possible to use methanolysis especially when silylesters are present. Alkaline hydrolysis is also a preferred method.
For the hydrolysis step and for the step to introduce the pipe¬ razine- substituent it is preferable to use a suitable solvent. It has been found according to this invention that dimethyl formamide is a prefered solvent for this purpose, having a
highly advantageous influence on the reaction and giving pure products. Other solvents like dimethyl sulfoxide can be used. Quinoline-3-carboxylic acid derivatives of formula (VIII) and piperazines are preferably reacted in the presence of pyridine. Excess of pyridine and/or piperazine after termination of the reaction may be eliminated by steam distillation. Intermediates according to the invention, more particularly quinoline-3-carboxylic acid derivatives of formula (IV) and their salts, quinoline-3-carboxylic acid derivatives of formula (VIII), and the quinoline-3-carboxylic acid of formula (V) are new products and are also subject of this invention. A further embodiment of the patent are compositions comprising as a biologically active ingredient the new compounds of the general formula (IV) and their salts. Their most important use is based on their bacteriostatic activity combined with their improved solubility as compared with the compounds not compri¬ sing the l'-carboxyl group. The object of the invention are compositions for biological use as pharmaceuticals and veteri¬ nary products comprising the compounds of general formula (IV) with pharmaceutically acceptable carriers, auxiliary products, diluents and other additives which are known to be used in pharmaceutical products to facilitate administration for oral, parenteral, transdermal or rectal use of any kind. The composi¬ tions may be administered when related compounds are not readi¬ ly used because of resistance or problems of dissolution in the tissues involved.
The reagents of general formula (I) are known or they can be synthetized with known methods.
Details of the processes according to this invention are de¬ scribed in the Examples, however without the intention of li¬ mitation to the contents of the examples. Examples Example 1-3.
Various aromatic amines (1 mole) were reacted with 1-bromo- cyclopropane-3-carboxylic acid methyl ester (1 mole) in the presence of 3 moles of potassium carbonate in dimethyl forma¬ mide as a solvent. On stirring for about 24 hours under reflux the crystalline products are filtered off. 5 moles of sodium hydroxide in water are added and the product is hydrolysed for
5 hours. Hereafter decarboxylation is accomplished at 230 to o 250 C in Dowtherm A or alkaline hydrolysis is used, whereby aqueous alkaline hydroxide is used in excess. The suspension is filtered and dried to give the following products:
Product Yield
N-cyclopropyl-aniline, 89%
N-cyclopropyl-naphthyl-amine, 92%
N-cyclopropyl-3-chloro-4-fluoro-aniline. 86%
Example 4.
27g of 6-fluoro-7-chloro-4-oxo-l,4-dihydro-quinoline-3-carboxy- lic acid ethyl ester (prepared according to known methods) are reacted with 7 g of potassium carbonate in 60 ml of dimethyl o formamide for 1 hour under reflux. On cooling to 10 C the potassium salt of the product is filtered. 50 ml of dimethyl formamide and 20 g of l-bromo-cyclopropane-3-carboxylic acid methyl ester are added to this salt and the reaction mixture is o stirred for 7 hours at about 130 C. The main amount of dimethyl
formamide is evaporated and 200 ml of water, 5 ml of cc-sulfu- ric acid and 50 ml of acetic acid are added to the remainder.
On heating for 5 hours under reflux a suspension is obtained which is cooled, filtered, washed with water until neutral, washed again with methanol and finally dried. 25 - 26 g of 6- fluoro-7-chloro-4-oxo-l, 4-dihydro-l-( 1 ' -carboxyl )-cyclopropyl- quinoline-3- carboxylic acid are isolated (yield about 80%). o Mp. : 246 - 250 C (decomp). 20 g of 6-fluoro-7-chloro-4-oxo-
1,4-dihydro-l-( 1 ' -carboxyl )- cyclopropyl-quinoline-3-carboxylic acid, 6.5 g of piperazine and 18.0 g of pyridine are heated for o 3 hours at about 75 C. 100 ml of water are then added and the pH value of the reaction mixture is adjusted to 10 - 11 by ad¬ dition of 2N aqueous sodium hydroxide. ϋnreacted pyridine and piperazine are then eliminated by steam distillation. The re¬ mainder is filtered and the pH value of the reaction mixture is o adjusted to a value of about 5 - 6 at about 70 C. The suspen¬ sion obtained is filtered, washed with water and dried. 18 19 g of 6-fluoro-7-piperazine - 4-oxo-l, 4-dihydro-l- ( 1 '-carbo¬ xyl )-cyclopropyl-quinoline-3- carboxylic acid are obtained (yi- o eld about 80 %). Mp. : 291 - 295 C. 15 g of 6-fluoro-7-piperazi- ne - 4-oxo-l,4-dihydro-l- (1'- carboxyl)- cyclopropyl- quinoline-3-carboxylic acid are heated while stirring in 100 ml of Dowtherm A ("difil oil") for 1 hour at a temperature of 220 to 230 oC. On cooling to 20oC the suspension obtained is filtered. The precipitate is washed twice with acetone and co¬ vered with water. On final filtration of the crystals they are dissolved in a solution of 5 g of potassium carbonate and 100 ml of water. The solution is decolorized with carbon black and filtered. The pH value of the filtrate is adjusted to 7.5 by
addition of acetic acid and the suspension obtained is cooled, filtered, washed with water and methanol and again filtered.
10.5 - 11.0 g of l-cyclopropyl-6-fluoro-7-piperazine-4-oxo-
1,4-dihydro- quinoline-3-carboxylic acid (cyprofloxacine) are o obtained. Mp. : 257 - 258 C (decomp.). Yield about 83 -85%.
Example 5.
10.4 g of l-potassium-4-oxo-l, 4-dihydro-6-fluoro-7-chloro-qui- noline-3-carboxylic acid ethyl ester, 23.7 g of 1-bromo-cyclo- propane-carboxylic acid trimethyl silyl-ester and 7.0 g of po¬ tassium carbonate are reacted in 100 ml of dimethyl formamide o for 8 hours while stirring at 80 C excluding humidity of the air. To the mixture containing l-( 1 '-trimethyl-silyl-carboxy) - 1,4-dihydro-6- fluoro-7- chloro - 4- oxo -quinoline-3-carbo- xylicacid ethyl ester 4.0 g of methanol were added. On further stirring for 1 hour the solvent is distilled off in vacuo. The remainder contains the potassium salt of l-(1 '-carboxyl )-cyclo¬ propyl- 4-oxo-l, 4-dihydro-6- fluoro-7-chloro-quinoline-3-car- boxylic acid ethyl ester. 200 ml of water are added and the pH value is adjusted to 6 by addition of acetic acid, the suspen¬ sion is filtered, washed and dried. 13.5 g of l-(1 ' -carboxyl)- cyclopropyl- 4-oxo-l, 4-dihydro-6-fluoro-7- chloro-quinoline-3- carboxylic acid ethyl ester are obtained wich is further trea¬ ted as in Example 4. Example 6.
27 g of 4-oxo-l, 4-dihydro-6-fluoro-7- chloro- quinoline- 3-car- boxylic acid ethyl ester are refluxed with 20 g of N-carbetho- xy-piperazine and 8.0 g of potassium carbonate in 150 ml of o dimethyl formamide for 4 hours under reflux at about 150 C. The
mixture is filtered while hot and 34 g of 4-oxo-l, 4-dihydro-6-fluoro-7-(4 ' -ethoxy-carbonyl- piperazino) -quinoline-3-car-boxylic acid ethyl ester are isolated on cry¬ stallization and filtration. 20 g of 4-oxo-l, 4-dihydro-6- fluoro-7- (4 '-carbethoxy- piperazino) -quinoline-3-carboxylic acid ethyl ester, 10 g of 1-bromo-cyclopropane-carboxylic acid acid methyl ester and 5 g of potassium carbonate are refluxed in 80 ml of dimethyl formamide for 24 hours. On cooling to 5 o 10 C crystals precipitate which are filtered and dried. 23 g of l-( 1 '-methoxy-carbonyl )-cyclopropyl- 4-oxo-l, 4-dihydro—6-fluo- ro-7-(4 ' -ethoxy-carbonyl- piperazino) -quinoline-3-carboxylic acid ethyl ester are obtained. 20 g of
1—( 1 '-methoxy-carbonyl )-cyclopropyl- 4-oxo-l,4-dihydro--6-fluo- ro-7-(4 '-ethoxy- carbonyl-piperazino) -quinoline-3-carboxylic acid ethyl ester are refluxed with 10 g of sodium hydroxide in
100 ml of water. Concentrated hydrochloric acid is added to adjust the pH value to 1 - 2 and the mixture is further boiled for 5 hours. The suspension obtained is adjusted to 6 - 7 using a 10% sodium hydroxide solution. On stirring for 30 minutes the suspension is filtered, the crystals are washed and dried. 10 g of 1- cyclopropyl - 4-σxo-l,4-dihydro- 6-fluoro-7-piperazino o -quinoline-3- carboxylic acid are obtained. M.p. : 255 - 257 C.
Example 7.
1.8 g of sodium hydroxide are dissolved in 60 ml of methanol and 8 g of 1-bromo-cyclopropyl- methyl ester are added. On ref- luxing for 4 hours the mixture is evaporated to dryness and 9 g of 7-chloro- 6-fluoro- 1, 4-dihydro-4- oxo quinoline 3- carbo¬ xylic acid ethyl ester are added, together with 3 g of potassi¬ um carbonate in 75 ml of dimethyl formamide. On 8 hours reflux
the mixture is cooled and filtered. The product is added to the solution of 150 ml of water and 10 g of sodium hydroxide. On 2 hours of reflux both hydrolysis and decarboxylation take pla¬ ce. On decolorizing with carbon the filtrate is adjusted to pH
2 to 3 with 20% hydrochloric acid in water, the suspension ob- o tained is filtered at 10 C, washed and dried. 7.5 g of 1-cyclo- propyl- 7-chloro- 6-fluoro-1, 4- dihydro-4- oxo- quinoline-3- carboxylic acid are obtained in excellent quality.
Example 8.
27 g of 6-fluoro -7-chloro-l, 4-dihydro-4-oxo-quinolone- 3- carboxylic acid ethyl ester, 20 g of potassium carbonate and 30 g of 2, 4-dibromo-butyric acid methyl ester are reacted in 100 o ml of dimethyl formamide about 5 hours at 70 C until the unreacted quinoline ester disappears. The transformation is followed by way of TLC analysis (8 parts of chloroform, 5 parts carbon tetrachloride, 1 part methanol). On heating for 7 hours o o at 120 to 130 C the suspension is cooled under 100 C, the potassium carbonate is filtered off and the filtrate is evaporated in vacuo. 200 ml of water are added to the remainder. On stirring for an hour the suspension is filtered, the crystals washed until neutral and dried. 32 g of 1-( 1 '- carbomethoxy)-cyclopropyl-6-chloro-7-fluoro-1,4-dihydro -4-oxo- quinoline-3-carboxylic acid ethylester are obtained. Mp.: 224- o 226 C.
Example 9.
27g of 6-chlσro-7-fluoro-1, 4-dihydro-4-oxo-quinoline- 3-carbo- xylic acid ethyl ester, 20 g of potassium carbonate and 30 g of
2,4-dibromo-butyric acid methyl ester are boiled in 200 ml of
toluene until the reaction is complete. The suspension obtained is filtered, the solid phase is stirred in water for 1 hour.
The crystals are filtered, washed with water until neutral and dried. 31 g of 1-( 1 'carbomethoxy)-cyclopropyl-6-chloro-7-fluoro-
1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethylester are obtained. Purification can be brought about by recrystallizati- on from ethanol. 27g of l-( 1 ' -carbomethoxy)-cyclopropyl-6-chlo- ro-7-fluoro- 1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid et- o hylester are obtained. M.p.: 224- 226 C.
Example 10.
45.6 g of 6-fluoro-7-chloro-l, 4-dihydro-4-oxo-quinoline- 3-car- boxylic acid ethyl ester, 40 g of potassium carbonate, 4 g of tetrabutyl ammonium chloride, 1 g of potassium iodide and 30 g of chloro-acetic acid methyl ester are refluxed in 200 ml of toluene for 16 hours. The reaction mixture is filtered, the solid phase admixed with 500 ml of water under stirring while adjusting the pH to about 7 with acetic acid. The suspension is filtered, the crystals washed with water and dried. 48 g of 1- (methoxy-carbonyl )- methyl-4-oxo-6 fluoro-7-chloro-quinoline-3- carboxylic acid ethyl ester are obtained.
5 g of sodium are dissolved in 150 ml of ethanol, and 34.2 g of 1-(methoxy-carbonyl )- methyl-4-oxo-6-fluoro-7-chloro- quinoline- 3-carbσxylic acid ethyl ester added and the mixture is stirred for 15 minutes. 20 g of dibromo- ethane are added o dropwise at 35 - 40 C and the reaction mixture is heated until the pH value is about neutral. 70 ml of ethanol are distilled off from the suspension obtained. 600 ml of water are added to o the remainder and on stirring for 20 minutes at 20 C and fil¬ tration the solid is washed with water and dried. 32g of l-(
-carbomethoxy)-cyclopropyl- 1,4-dihydro-4-oxo- 6-fluoro- 7- chloro-quinoline- 3-carboxylic acid ethyl ester are obtained. 3,7 g of the above product are refluxed with 30 ml of water, 15 ml of acetic acid and 5 ml of concentrated hydrochlo¬ ric acid for 2 hours. The reaction mixture is filtered at room temperature, washed neutral and dried. 2.9 g of l-( 1 '-carbox )- cyclopropyl- 1,4-dihydro-4-oxo- 6-fluoro- 7-chloro- quinoline- 3-carboxylic acid are obtained. Example 11 and Example 12.
Using the process of Example 10 but starting from equimolar amounts of 1, 4-dihydro-4-oxo- 6-fluoro-7-(4 '-carbomethoxy-pipe- razinyl )-quinoline- 3-carboxylic acid ethyl ester or 6-chloro- 7-(4-ethyl-piperazinyl )- 1,4-dihydro-4-oxo-quinoline- 3-carbo- xylic acid ethyl ester the products are l-(1 '-carboxy)- cyclo¬ propyl- 1, 4-dihydro-4-oxo- 6-fluoro- 7-piperazinyl -quinoline- 3-carboxylic acid and 1-( 1 '- carboxy)-cyclopropyl-1, 4-dihydro- 4-oxo-6-fluoro-7-(4 '-ethyl-1 '-piperazinyl )-quinoline-3-carboxylic acid respectively. Example 13.
7.7 g of 6-fluoro-7-chloro-4-oxo-l,4-dihydro-l-( 1 '-carboxyl )- cyclopropyl-quinoline-3- carboxylic acid, 40g of pyridine, 2,5g of N-ethyl-piperazine are refluxed for 8 hours. On evaporation in vacuo 40 ml of acetic acid, 30 ml of water and 2 ml of cc. sulfuric acid are added. After refluxing.3 hours water is added to 150 ml. The precipitate is filtered, washed with water and dried. 4.6 g of l-( 1 ' -carboxyl )-cyclopropyl- 4-oxo-l,4-di- hydro- 6-fluoro-7-(4 '-ethyl-1 'piperazine) -quinoline-3- carbo¬ xylic acid are obtained.
The above product is heated while stirring in 50 ml of Dowtherm A ("difil oil") for half and hour at 240 oC. The resulting so¬ lution is extracted twice with 20 mis each of a 25% aqueous hy- o drogen iodide solution at 70 C. The aqueous phase is diluted with 70 ml of ethanol, cooled and filtered. The precipitate is washed with ethanol and dried. 3.2 g of l-cyclopropyl-4-oxo-l,4- dihydro-6-fluoro-7-(4'ethyl-1 '-piperazinyl )- quinoline-3-carboxy lie acid hydroiodide salt are obtained. Mp. : 333-335 oC (demp).
Example 14.
The following samples were subjeced to in vitro bacteriostatic tests: l-( 1 '-carboxy)- cyclopropyl- 1, 4-dihydro-4-oxo- 6-fluoro- 7- piperazinyl -quinoline- 3-carboxylic acid,
1-(1'- carboxy)-cyclopropyl-l, 4-dihydro- 4-oxo-6-fluoro-7-(4 '- ethyl-1 '-piperazinyl )-quinoline-3-carboxylic acid, cyprofloxacine, nalidixic acid.
Test organism: Escherichia coli 14.
Test medium: ISO-Sensitest agar (pH 7.2) o Incubation: 20 hours at 37 C.
Concentration: 2 mg/liter.
Results: The antibacterial effect was similar in all cases tested: the microorganisms were killed during the test period.
Similar results can be obtained with other noxious bacteria.
Claims
1 .
Process for the introduction of a cyclopropyl group into a pri¬ mary or secondary aromatic amine or into heterocyclic compounds containing a secondary nitrogen atom, c h a r a c t e r i z e d b y reacting the corresponding amines or their salts so as to form the corresponding N-cyclopropyl-( 1 ' -carboxy)-derivatives of the formula (II) where
Ar stands for an aromatic or heteroaromatic group containing one or two rings which are optionally substituted and
- the dotted line indicates that the nitrogen atom can also be a member of a heterocyclic ring and 1 R is hydrogen, a metal ion or an ester-forming group such as a C alkyl or a tri-(C )-alkyl-silyl group, 1-4 1-4 by way of reacting the corresponding amines or their salts a. with the reagent of general formula (I) 1
- R has the same meaning as indicated above,
1
- X is halogen preferably bromine optionally in the presence of an acid binding agent or b. with 2,4-dihalogen-butiric acid ester or c. with chloroacetic acid ester whereupon the resulting N-(alkoxy- carbonyl)- methyl- derivative is treated with alkali alkylate and dihalogen-ethane to convert the alkoxy-carbonyl-methyl group into a carbalkoxy- cyclopropyl group and subsequently optionally hydrolysing the ester groups if present and optionally eliminating the l'-carboxyl group intro¬ duced on the course of the first step from the molecule of the general formula (II), where 1
- Ar and R are the same as above - whereby the last step is carried out optionally after introducing other substitutents into the aromatic ring or after eliminating other substituents from the aromatic group.
2.
Process according to claim 1. for the preparation of the qui- noline-3-carboxylic acid derivative of the formula (III) and its salts where in the formula 3
- R stands for hydrogen , C alkyl, benzyl-oxy-carbonyl,
1-4 acyl or C alkoxy-carbonyl group , 1-4 c h a r a c t e r i z e d b y reacting a primary or secon¬ dary amine on the course of the synthesis of the molecule befo¬ re or after ring closure of the quinolone ring a. with the reagent of general formula (I) where 1 1 R and - X are the same as above - optionally in the presence of an acid binding agent or b. with 2, 4-dihalogen-butiric acid ester or c. with chloroacetic acid ester whereupon the resulting N-
(alkoxycarbonyl )- methyl- derivative is treated with alkali alkylate and dihalogen-ethane to convert the alkoxy-carbonyl-methyl group into a carboalkoxy-cyclopropyl group and subsequently optionally hydrolysing the ester groups if present and optionally eliminating the l'-carboxyl group intro¬ duced on the course of the first step from the molecule by termical treatment or hydrolysis and optionally also elimina¬ ting the substituent of the piperazine group.
3. Process for the preparation of the quinoline-3-carboxylic acid derivative of the formula (III) and its salts 3
- R stands for the same as above - c h a r a c t e r i z e d b y eliminating the 1'- carboxyl group of the ( 1 '-carboxyl )-cyclopropyl-quinoline-3-carboxylic acid derivative of the formula (IV) or its salts and optionally also eliminating the 4-substituent of the piperazine group be¬ fore, after or simultaneously.
4. Process according to any of claims 1 to 3 c h a r a c t e r i z e d b y eliminating the 1'- carboxyl o group by way of heat treatment at 200 - 250 C preferably at o 220 - 230 C, or by acidic or alkaline hydrolysis.
5.
Process according to any of claims 1 to 3 for the preparation of the new quinoline-3-carboxylic acid derivative of the formu¬ la (IV) and its salts c h a r a c t e r i z e d b y carrying out the following steps in an optional sequence on a quinoline-3-carboxylic acid derivative of the general formula
(VII) where in the formula 2
- R stands for a C alkyl group and
1-4
- X stands for hydrogen or a metal ion such as alkali, favourably potassium - a. treating according any of the methods a., b., or c. of claim 1. and optionally hydrolysing the ester groups of the (l'-car¬ boxyl )-l-cyclopropyl quinoline-3-carboxylic acid derivative,
3 b. 7-substituting with 4-R -piperazine 3
- R stands for the same as above - c. eliminating of the l'-carboxyl group by heat treatment or acid hydrolysis or alkaline hydrolysis, d. optionally eliminating the 4-substitutent of the piperazine.
6.
Process according to claim 5 . c h a r a c t e r i z e d b y
N-cyclopropylating a quinoline-3-carboxylic acid derivative of the general formula (VII) 2 2
- R and X stand for the same as above - with the methods a., b., or c. of claim 1, optionally hydroly¬ sing the compound of formula (VIII) obtained, 1 2
- R and R stand for the same as above -
7-substituting the quinolone derivative of general formula (V) o
3 tained with 4-R -piperazine, 3
- R stands for the same as above -
1 '-decarboxylizing the product obtained by termical treatment
3 or hydrolysis and optionally eliminating the R substituent by hydrolysis together or before eliminating the carboxyl group.
7.
Process according to claims 1 to 6 c h a r a c t e r i z e d b hydrolysing the quinoline-3-carboxylic acid derivative of the general formula (VIII) 1 2 - R and R stand for the same as above - using acidic conditions preferably aqueous sulfuric and/or acetic acid.
8.
Process according to any of claims 3 to 7 c h a r a c t e r i z e d b y carrying out reactions in the presence of dimethyl formamide.
9.
Process according to any of claims 3 to 7 c h a r a c t e r i z e d b y reacting the quinoline-3-car- boxylic acid derivative of the general formula (VIII) and pi¬ perazine in the presence of pyridine and eliminating the ex¬ cess of pyridine and/or piperazine after termination of the re¬ action by steam distillation.
10.
The quinoline-3-carboxylic acid derivative of formula (IV) and its salts and pharmaceutical compositions containing the same along with pharmaceutically acceptable additives and auxiliary materials.
11.
The quinoline-3-carboxylic acid derivative of the general for¬ mula (VIII) 2 2 - R and X stand for the same as above .
12.
The quinoline-3-carboxylic acid derivative of the formula (V).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2000593 | 1993-07-13 | ||
| HU9302005A HUT67395A (en) | 1993-07-13 | 1993-07-13 | Method for the n-cyclopropylation of primary and secondary aromatic amines |
| PCT/HU1994/000025 WO1995002573A2 (en) | 1993-07-13 | 1994-07-12 | New method for n-cyclopropylation of aromatic amines, as well as compounds and compositions obtained |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0738257A1 true EP0738257A1 (en) | 1996-10-23 |
Family
ID=10983778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP94921773A Ceased EP0738257A1 (en) | 1993-07-13 | 1994-07-12 | New method for n-cyclopropylation of aromatic amines, as well as compounds and compositions obtained |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0738257A1 (en) |
| KR (1) | KR960704875A (en) |
| AU (1) | AU7236494A (en) |
| CA (1) | CA2167151A1 (en) |
| HU (1) | HUT67395A (en) |
| WO (1) | WO1995002573A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113912551B (en) * | 2021-10-09 | 2023-04-18 | 浙江新和成股份有限公司 | Recyclable aromatic amine reagent and preparation and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3509546A1 (en) * | 1985-03-16 | 1986-09-25 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1- (SUBST.CYCLOPROPYL) -1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| US5281596A (en) * | 1986-02-19 | 1994-01-25 | Bayer Aktiengesellschaft | Antibacterial drugs for fish |
| DE3808118A1 (en) * | 1988-03-11 | 1989-09-21 | Bayer Ag | METHOD FOR PRODUCING 1-CYCLOPROPYL-QUINOLON CARBONIC ACIDS AND THEIR DERIVATIVES |
| DE3808117A1 (en) * | 1988-03-11 | 1989-09-21 | Bayer Ag | N-CYCLOPROPYLANILINE AND THE USE THEREOF IN METHOD FOR THE PRODUCTION OF 1-CYCLOPROPYL-CHINOLONIC CARBONIC ACIDS AND THEIR DERIVATIVES |
| FR2655545B1 (en) * | 1989-12-11 | 1994-06-10 | Rhone Poulenc Sante | NEW THERAPEUTIC APPLICATION OF FLUOROQUINOLONE DERIVATIVES. |
-
1993
- 1993-07-13 HU HU9302005A patent/HUT67395A/en unknown
-
1994
- 1994-07-12 WO PCT/HU1994/000025 patent/WO1995002573A2/en not_active Application Discontinuation
- 1994-07-12 EP EP94921773A patent/EP0738257A1/en not_active Ceased
- 1994-07-12 CA CA002167151A patent/CA2167151A1/en not_active Abandoned
- 1994-07-12 KR KR1019960701140A patent/KR960704875A/en active IP Right Grant
- 1994-07-12 AU AU72364/94A patent/AU7236494A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9502573A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2167151A1 (en) | 1995-01-26 |
| HUT67395A (en) | 1995-04-28 |
| WO1995002573A3 (en) | 1995-03-09 |
| KR960704875A (en) | 1996-10-09 |
| AU7236494A (en) | 1995-02-13 |
| HU9302005D0 (en) | 1993-10-28 |
| WO1995002573A2 (en) | 1995-01-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU1635898A3 (en) | Process for preparing quinoline derivatives or pharmaceutically acceptable esters thereof, or pharmaceutically acceptable salts of these derivatives or esters | |
| CA1214465A (en) | Substituted quinoline carboxylic acid derivatives | |
| KR870001016B1 (en) | Process for preparing 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivatives | |
| IE70302B1 (en) | Process for the preparation of imidazo[4,5-c]quinolin-4-amines | |
| HU210051B (en) | New process for the production of 1h-imidazo(4,5-c)quinolin derivatives | |
| HU199821B (en) | Process for production of derivatives of in 8 position substituated quinoline carbonic acid and medical compositions containing them | |
| JPS60208987A (en) | Antibacterial pyridobenzothiazine derivative, manufacture and antibacterial medicine composition | |
| NL193375C (en) | Process for preparing quinolinecarboxylic acid derivatives. | |
| FI90874B (en) | Quinoline carboxylic acid boric anhydrides and process for their preparation | |
| JPH0477B2 (en) | ||
| NO163329B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF 7- (PYRROL-1-YL) -1-ETHYL-1,4-DIHYDRO-4-OXO-QUINOLIN-3-CARBOXYLIC ACID AND 7- (PYRROL-1-YL) Ethyl 1,4-dihydro-4-oxo- (1,8-naphthyridine) -3-carboxylic acid. | |
| WO1995002573A2 (en) | New method for n-cyclopropylation of aromatic amines, as well as compounds and compositions obtained | |
| US3873543A (en) | 3-Substituted-as-triazino(5,6-c) quinoline derivatives | |
| RU2166504C2 (en) | Coumarinquinolone carboxylic acids and method of their synthesis | |
| FI84072B (en) | Intermediate for preparing norfloxacin, and process for preparing it | |
| US4791118A (en) | Quinolonecarboxylic acid derivatives and their preparation | |
| EP0221541A2 (en) | Quinolonecarboxylic acid derivatives and their preparation | |
| US5597924A (en) | Coversion of substituted 8-chloroquinolines to substituted 8-hydroxyquinolines | |
| JPH05112554A (en) | New quinolonecarboxylic acid derivative | |
| FI89045B (en) | Process for the preparation of quinoline carboxylic acid derivatives | |
| JPS6259263A (en) | Quinolonecarboxylic acid derivative | |
| SE449488B (en) | 8-CYANO-6,7-DIHYDRO-5-METHYL-1-OXO-1H-, 5H-BENZO (IJ) QUINOLIZIN-2-CARBOXYLIC ACIDS AND PROCEDURE FOR PREPARING THEREOF | |
| EP0482481A1 (en) | Method for the preparation of 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepines | |
| JP2640967B2 (en) | Quinolonecarboxylic acid derivatives and salts thereof | |
| Pintilie et al. | Synthesis and antibacterial activity of some novel fluoroquinolones |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19960208 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
| AX | Request for extension of the european patent |
Free format text: SI PAYMENT 960207 |
|
| RAX | Requested extension states of the european patent have changed |
Free format text: SI PAYMENT 960207 |
|
| 17Q | First examination report despatched |
Effective date: 19970619 |
|
| GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
| GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
| 18R | Application refused |
Effective date: 19991009 |