CA1071209A - 8-oxo-2,3,5,8-tetrahydro-furo (2,3-g) quinoline-7-carboxylic acid compounds - Google Patents
8-oxo-2,3,5,8-tetrahydro-furo (2,3-g) quinoline-7-carboxylic acid compoundsInfo
- Publication number
- CA1071209A CA1071209A CA256,253A CA256253A CA1071209A CA 1071209 A CA1071209 A CA 1071209A CA 256253 A CA256253 A CA 256253A CA 1071209 A CA1071209 A CA 1071209A
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- Canada
- Prior art keywords
- group
- quinoline
- furo
- process according
- carboxylic acid
- 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.)
- Expired
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides quinoline carboxylic acid derivatives of the general formula where R1 is an alkenyl group containing 2 to 4 carbon atoms or an alkynyl group containing 2 to 4 carbon atoms and R2 is hydrogen;
an alkenyl group containing 2 to 4 carbon atoms or an alkynyl containing 2 to 4 carbon atoms and physiologically tolerable salts of such compounds. Such quinoline carboxylic acid derivatives and their salts are useful as urinary antiseptics.
The invention provides quinoline carboxylic acid derivatives of the general formula where R1 is an alkenyl group containing 2 to 4 carbon atoms or an alkynyl group containing 2 to 4 carbon atoms and R2 is hydrogen;
an alkenyl group containing 2 to 4 carbon atoms or an alkynyl containing 2 to 4 carbon atoms and physiologically tolerable salts of such compounds. Such quinoline carboxylic acid derivatives and their salts are useful as urinary antiseptics.
Description
--`1 07~ZO9 The pre~ent invention i~ concerned with new qll~noline carbo~ylic acid derivatives ha~ing ~aluable pharmacological properties as urlnary a~ti~eptic~, with a proce~ for their m3nuiacture and with ~heir use.
~he present i~vention provides ql7inoline carbo~ylic acid derivative~ o~ the general ~ormula I .
~ coo~2 (I) N
:
in which Rl represents an alkenyl group containing 2 to 4 carbon atoms and an alkynyl group containing 2 to 4 carbon atoms, and R2 represents hydrogen; an alkenyl group containins 2 to 4 carbon atoms or an alkynyl group containing 2 to 4 carbon atoms and also, when R2 represents a hydrogen atom, physiologically tolerable salts thereof with inorganic or organic bases.
As the aforesaid straight chained or branched alkenyl or alkynyl groups, there may be mentioned, for example, vinyl, allyl, l-propenyl, l-butenyl, 2-butenyl, propadienyl, butadienyl, isopropenyl, l-methylpropenyl, 2-methylpropenyl, 2-methylallyl, 3,3-dimethylallyl, ethynyl, propargyl, butynyl, and 1-methyl-2-propynyl groups.
As the aforesaid straight chained or branched saturated alkyl groups, there may be mentioned, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl and isobutyl.
~ .
~07~Z09 When R2 represents a hydrogen atom, the new compounds may be used in the form of physiologically tolerable water-soluble salts thereof with inorganic or organic bases.
For salt formation there comes into consideration inorganic and organic bases of the type that are customarily used by the expert in the art.
As bases that are preferably used in a known manner for salt formation, there comes into consideration, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, glucamine, N-methyl-glucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, N-methylmorpholine and tris-(hydroxymethyl)-methylamine.
From U.S. Patent No. 3,773,769, it has been known that
~he present i~vention provides ql7inoline carbo~ylic acid derivative~ o~ the general ~ormula I .
~ coo~2 (I) N
:
in which Rl represents an alkenyl group containing 2 to 4 carbon atoms and an alkynyl group containing 2 to 4 carbon atoms, and R2 represents hydrogen; an alkenyl group containins 2 to 4 carbon atoms or an alkynyl group containing 2 to 4 carbon atoms and also, when R2 represents a hydrogen atom, physiologically tolerable salts thereof with inorganic or organic bases.
As the aforesaid straight chained or branched alkenyl or alkynyl groups, there may be mentioned, for example, vinyl, allyl, l-propenyl, l-butenyl, 2-butenyl, propadienyl, butadienyl, isopropenyl, l-methylpropenyl, 2-methylpropenyl, 2-methylallyl, 3,3-dimethylallyl, ethynyl, propargyl, butynyl, and 1-methyl-2-propynyl groups.
As the aforesaid straight chained or branched saturated alkyl groups, there may be mentioned, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl and isobutyl.
~ .
~07~Z09 When R2 represents a hydrogen atom, the new compounds may be used in the form of physiologically tolerable water-soluble salts thereof with inorganic or organic bases.
For salt formation there comes into consideration inorganic and organic bases of the type that are customarily used by the expert in the art.
As bases that are preferably used in a known manner for salt formation, there comes into consideration, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, glucamine, N-methyl-glucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, N-methylmorpholine and tris-(hydroxymethyl)-methylamine.
From U.S. Patent No. 3,773,769, it has been known that
2,3-dihydrofuro[2,3-g]quinoline-7-carboxylic acids exhibit good inhibiting values against gram-positive and gram-negative bacteria and are thus suitable as urinary tract therapeutical agents. Compounds for this indication must exhibit an adequate elimination via the urine, because the dosage depends on this.
Only with an increase in the urine level can the administration of an active substance be effected in a lower dosage.
It has now been found that the new compounds of the general formula I coupled with a good inhibiting action against gram-positive and gram-negative bacteria exhibit as compared, for example, with 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo[2,3-g]-quinoline-7-carboxylic acid (of U.S. Patent No. 3,773,769), an increased urine elimination, as is shown in the following Table by way of example with reference to the compounds of Example 3 and Example 4 as compared with 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo[2,3-g]quinoline-7-carboxylic acid. The numerical values give the percentage content of an administered dose which is eliminated in the urine during the course of 6 hours in the case of rats at a dosage of 100 mg/kg ~ os.
Only with an increase in the urine level can the administration of an active substance be effected in a lower dosage.
It has now been found that the new compounds of the general formula I coupled with a good inhibiting action against gram-positive and gram-negative bacteria exhibit as compared, for example, with 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo[2,3-g]-quinoline-7-carboxylic acid (of U.S. Patent No. 3,773,769), an increased urine elimination, as is shown in the following Table by way of example with reference to the compounds of Example 3 and Example 4 as compared with 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo[2,3-g]quinoline-7-carboxylic acid. The numerical values give the percentage content of an administered dose which is eliminated in the urine during the course of 6 hours in the case of rats at a dosage of 100 mg/kg ~ os.
3 --. . ~ .
llD7~0~
5-Ethyl-2,3,5,8- 8-Oxo-5-(1- 8-Oxo-2,3,5,8-tetrahydro-8-oxo- propenyl)- tetrahydro-5-Compound furo[2,3-g]- 2,3,5,8- vinyl-furo-quinoline-7-car- tetrahydro- [2,3-g]quino-boxylic acid furo-[2,3-g~ line-7-car-quinoline-7- boxylic acid carboxylic . (Example 3) (Example 4) . _ Elimination (%) 0.48% 2.1% 3.4%
The new compounds may be administered in the pharma-ceutically usualforms ofapplications for example tablets, dragees, capsules, pills, solutions and suspensions. ~
The present invention also provides a process for the manufacture of a compound of the general formula I, or a physio-logically tolerable salt with an inorganic or organic base of such a compound in which R2 represents a hydrogen atom, wherein a compound of the general formula II, which may be in the tauto-meric form of the general formula II A or II B, OH
~ COOR2 ~ COOR2 . II A II B
in which R2 has the meaning given above, is reacted with a com-. pound of the general formula R"X in which: R" has the meaning given above ~or Rl or represents an alkyl group containing 1 to
llD7~0~
5-Ethyl-2,3,5,8- 8-Oxo-5-(1- 8-Oxo-2,3,5,8-tetrahydro-8-oxo- propenyl)- tetrahydro-5-Compound furo[2,3-g]- 2,3,5,8- vinyl-furo-quinoline-7-car- tetrahydro- [2,3-g]quino-boxylic acid furo-[2,3-g~ line-7-car-quinoline-7- boxylic acid carboxylic . (Example 3) (Example 4) . _ Elimination (%) 0.48% 2.1% 3.4%
The new compounds may be administered in the pharma-ceutically usualforms ofapplications for example tablets, dragees, capsules, pills, solutions and suspensions. ~
The present invention also provides a process for the manufacture of a compound of the general formula I, or a physio-logically tolerable salt with an inorganic or organic base of such a compound in which R2 represents a hydrogen atom, wherein a compound of the general formula II, which may be in the tauto-meric form of the general formula II A or II B, OH
~ COOR2 ~ COOR2 . II A II B
in which R2 has the meaning given above, is reacted with a com-. pound of the general formula R"X in which: R" has the meaning given above ~or Rl or represents an alkyl group containing 1 to
4 carbon atoms which may be straight chained or branched and ~ which is substituted by 1 or 2 halogen atoms, and X represents ., .
a halogen atom, an alkane-sulphonyloxy group containing 1 to 4 carbon atoms in the alkyl group or an aryl-sulphonyloxy group (especially a benzene-sulphonyloxy group) :, -" 1071Z09 which may be substituted in the aryl part by one or more substituents selected from halogen atoms and alkyl groups containing 1 to 4 carbon atoms, and, when R" represents a halogen substituted alkyl group, the halo substituent on this group is/are split off to form an unsaturated hydrocarbon group, and then, if desired, in any order of succession, in the resulting compound any free carboxyl group is esterified and/or any esterified carboxyl group is hydrolysed and/or a carbon-to-carbon multiple bond in the group represented by Rl is rearranged and/or, when R2 represents a hydrogen atom, the resulting compound is converted into a physiologically tolerable salt thereof with an inorganic or organic base.
When R" represents a straight chained or branched alkyl group containing 1 or 2 halo substituents that is/are split off with the formation of multiple bond(s), the alkyl group may have one of the meanings given above for straight chained or branched alkyl groups. As substituents there come into consideration, fluorine, chlorine, bromine and iodine, fluorine, chlorine and bromine being especially preferred. As to the number of halogen substituents, one halogen substituent on the alkyl group represented by R" is preferred.
The symbol X in the compound of the general formula R"X
may represent the halogen atom fluorine, chlorine, bromine or iodine, fluorine, bromine or iodine being preferred, an alkane-sulphonyloxy group with alkane having the meaning methane or ethane, methane being preferred, or an aryl-sulphonyloxy group with aryl having the meaning phenyl, for example an ortho-, meta- or para-alkylphenyl (alkyl = methyl or ethyl), ortho-, meta- or para-halophenyl or naphthyl group.
~071Z09 . .
; The alkylation in accorda~ce with the procesæ o~ the present - invention iB carried out in an alkaline medium, pre~erable in water or in an org~n~c sol~ent, ior example alcohol, dimethyl sulphoxide, dioxan or tetrahydroiuran, or a mixture thereoi with water, at a temperature within the range oi ~rom 0 to 150C, preierably irom 0 to 100C, ior a reaction per~od of 005 hour to 5 day~ an alka-i~e medium there iæ u~ed, ior e~ample, 1 to 10 equivalents Or an alkall, preierably æodium hydro2ide or pota~ium hydroxide, calculated on the alkylating agent used, espe¢ially 2 to 6 equi~alents, in an aqueous alcohol or dimethyl eulphogide.
The ~-aIkylation may be carried out with an alkylating agent Or the general ~ormula R"2, in ~hich R~ is pre~ent in the meaning ri~ally desired ior the symbol ~ in the general iormula - I, or also - which is ad~antageou~ ior experimental reason~ or _ may be ne¢e~sary (ior example ~hen ~ represents a vinyl group) -i oarried out with an alkylating agent Or the general formula R~
in which R" repre~ent~ an alkyl group that i8 ~ubstituted by a group that can easily be eplit Ori with the iormation oi the iinally deslred unsQturated carbon-to-carbon bond. Starting irom such ~ubstituted Rn~-alkylating agent~ the splitting oii generally take place spontaneously under the alkylating conditions to iorm the desired end product9 oi the general iormula Io Ii the ~ubstituents pre~ent in the group xepresented by R" do not ~plit o~ simultaneoualy under the con~itions Or the alkylation, the subsequent ~plitting o~f may be carried out in a known manner with a basic reagent, ior example ~aOH, EOH, E-,,~
_,~_ . ' :
tertO-butylate, Na~, ~2C03, pyridine or an amine, in a solve~t, ior example water, alcohol, dimethyl~ormamide or dimethyl sulphogide, at a temperature within the range of irom O to 150~, preferably from 20 to 100C, during the cour~e of 0.5 to 10 hours, preierably 0.5 to 5 hours~
When the primary product of the process of the present invention does not yet contain the un~aturated carbon-to-carbon bond in the iinally de~ired position in the group represented by Rl, it can be shifted by a method generally known to the expert ior such rearrangement reaction~.
; ~he reaction can be carried out under alkaline or also acid reaction conditions. ~ basic rearr~ngement catalyst~
; there come into con~ideration, ior example, alk~l~es, ior example NaOH, EOE or E-tert.-but~late, and as an acid catalyst, *or example, triiluoracetic acid.
~ ~he baoic rearrangement ii preierableO It i~ carried out, ; ior example, at a temperature within the range oi irom O to 180C, preierably irom O to ~30C, during the course oi 0.5 to 24 hours, preierably 2 to 4 hour~, with ~- to 7N-NaOH or EOH in a solvent, - ior example water, ethylene glycol or dimethyl~ormamide.
~ he -COOR2 group in the 7-position in the product oi the proces~ oi the present in~ention may be a iree or esteriiied oarboxyl group. When R2 represents a hydrogen atom in the #tarting compound, esteriiication oi the iree carboxyl group may also take place s~multaneously under the aIkylating conditions, eepecially when R" in the aIkylating agent has the same meaning a~ ~ .
~, ,, .~,~ /
A -~-:
- . ~ .
lO~lZO9 When -COOR2 in the starting compound i~ an e~teri~ied carboxyl group, the ætability oi this ester group depend~ on the conditions of the alkylating and/or sub~tituent-splitting oii reaction(s). I* theæe reactionæ are carried out at an e~pecially high reaction temperature, the ester group i~
wholly or at least partially hydrolysed. Depending on the iin ~ly deeired mea~ing o~ ~ , by a method known er se a iree carboxyl group may be esteriiiea or re-esteriiied and an esteriiied carbogyl group may be hyarolysed.
æalt iormation may be carried out in a manner kno~n ~E ~e, ~or example, with a l-normal æolutions oi the appropriate inorganic or organic ba~e, and the ~olution so obtained i~
evaporated, and the residue remaining behind i~ recrystallized, ior example, ~rom an alcohol/water mi~ture (5-9 : 5-1).
~ sually the reaction products are obtained, owing to the mulbiple bonds in ~ and optionally aleo in R2, in the iorm oi their cis/trana-isomeric mixtures, whi¢h may be separated in the U8Ual manner into the cis- and brans-iorms, ior e~ample, by rraction~l crystA~lization or chromatographyO
~ 8 stated above, the new compo~mds oi the present invent~on may be admini~tered in the u8ual pharmaceutical iorme oi application, ior example tablet~, dragée~, capsules, pill~, solutions~suspensions~ c~.
~ he present invention accordingly ~urther provides a pharmaceutical preparation whlch compri~es a compol-n~ o~ the pre~ent invention, in admi~ture or ¢on~u~ction with a pharmaceuti-cslly ~uitable carrier.
~ 1071Z09 ~he new compound~ may be used in combination with the ; additi~es no~mally used in galenical phaxmacy, for e~ample, iormoking preparation~ active against infections o~ the urinary ' tractO
The use oi the new compounds may be carried out by means oi the u~ual pharmaceutical iorms oi application. ~he compound~
oi the invention are especially suitable ior oral administration;
thus, the pharmaceutical preparations o~ the present i~vention may be in a iorm suitable iox oral admini~tratio~, ~or e~ample a~ tablets, dragées, capsules, pills, solutions or ~uspenæion~.
Tablets contain, ior egample, Ool to 1 gram o~ active æub~tance and 0.1 to 5 grams oi a pharmacologically inert au~iliary ~ub~tance. A~ au~iliary ~ubstances there are used, ior e~ample, ior tablets, lactoae, starches, talcum, gelatine and magnesium ~teaxate.
The compounds oi the present ln~ention can be used in the ileld both oi human and veterinary medicine.
`` ~he new aotive substances are used in quantities between Ool to 4.0 gram~ per patient per dayO
The present i~ve~tion accordingly also provides a method ior the treatment oi a urinary tract iniection, wherein a compound oi the present invention i~ a~ministered to a living beingO ~ "living being" is understood herein to exclude a human bei4g.
- The iollowing Examp_es ~77ustrate the inYentlon:-~ 9 .. `.. : . , ` - `. :
.
: 1071209 ~xample
a halogen atom, an alkane-sulphonyloxy group containing 1 to 4 carbon atoms in the alkyl group or an aryl-sulphonyloxy group (especially a benzene-sulphonyloxy group) :, -" 1071Z09 which may be substituted in the aryl part by one or more substituents selected from halogen atoms and alkyl groups containing 1 to 4 carbon atoms, and, when R" represents a halogen substituted alkyl group, the halo substituent on this group is/are split off to form an unsaturated hydrocarbon group, and then, if desired, in any order of succession, in the resulting compound any free carboxyl group is esterified and/or any esterified carboxyl group is hydrolysed and/or a carbon-to-carbon multiple bond in the group represented by Rl is rearranged and/or, when R2 represents a hydrogen atom, the resulting compound is converted into a physiologically tolerable salt thereof with an inorganic or organic base.
When R" represents a straight chained or branched alkyl group containing 1 or 2 halo substituents that is/are split off with the formation of multiple bond(s), the alkyl group may have one of the meanings given above for straight chained or branched alkyl groups. As substituents there come into consideration, fluorine, chlorine, bromine and iodine, fluorine, chlorine and bromine being especially preferred. As to the number of halogen substituents, one halogen substituent on the alkyl group represented by R" is preferred.
The symbol X in the compound of the general formula R"X
may represent the halogen atom fluorine, chlorine, bromine or iodine, fluorine, bromine or iodine being preferred, an alkane-sulphonyloxy group with alkane having the meaning methane or ethane, methane being preferred, or an aryl-sulphonyloxy group with aryl having the meaning phenyl, for example an ortho-, meta- or para-alkylphenyl (alkyl = methyl or ethyl), ortho-, meta- or para-halophenyl or naphthyl group.
~071Z09 . .
; The alkylation in accorda~ce with the procesæ o~ the present - invention iB carried out in an alkaline medium, pre~erable in water or in an org~n~c sol~ent, ior example alcohol, dimethyl sulphoxide, dioxan or tetrahydroiuran, or a mixture thereoi with water, at a temperature within the range oi ~rom 0 to 150C, preierably irom 0 to 100C, ior a reaction per~od of 005 hour to 5 day~ an alka-i~e medium there iæ u~ed, ior e~ample, 1 to 10 equivalents Or an alkall, preierably æodium hydro2ide or pota~ium hydroxide, calculated on the alkylating agent used, espe¢ially 2 to 6 equi~alents, in an aqueous alcohol or dimethyl eulphogide.
The ~-aIkylation may be carried out with an alkylating agent Or the general ~ormula R"2, in ~hich R~ is pre~ent in the meaning ri~ally desired ior the symbol ~ in the general iormula - I, or also - which is ad~antageou~ ior experimental reason~ or _ may be ne¢e~sary (ior example ~hen ~ represents a vinyl group) -i oarried out with an alkylating agent Or the general formula R~
in which R" repre~ent~ an alkyl group that i8 ~ubstituted by a group that can easily be eplit Ori with the iormation oi the iinally deslred unsQturated carbon-to-carbon bond. Starting irom such ~ubstituted Rn~-alkylating agent~ the splitting oii generally take place spontaneously under the alkylating conditions to iorm the desired end product9 oi the general iormula Io Ii the ~ubstituents pre~ent in the group xepresented by R" do not ~plit o~ simultaneoualy under the con~itions Or the alkylation, the subsequent ~plitting o~f may be carried out in a known manner with a basic reagent, ior example ~aOH, EOH, E-,,~
_,~_ . ' :
tertO-butylate, Na~, ~2C03, pyridine or an amine, in a solve~t, ior example water, alcohol, dimethyl~ormamide or dimethyl sulphogide, at a temperature within the range of irom O to 150~, preferably from 20 to 100C, during the cour~e of 0.5 to 10 hours, preierably 0.5 to 5 hours~
When the primary product of the process of the present invention does not yet contain the un~aturated carbon-to-carbon bond in the iinally de~ired position in the group represented by Rl, it can be shifted by a method generally known to the expert ior such rearrangement reaction~.
; ~he reaction can be carried out under alkaline or also acid reaction conditions. ~ basic rearr~ngement catalyst~
; there come into con~ideration, ior example, alk~l~es, ior example NaOH, EOE or E-tert.-but~late, and as an acid catalyst, *or example, triiluoracetic acid.
~ ~he baoic rearrangement ii preierableO It i~ carried out, ; ior example, at a temperature within the range oi irom O to 180C, preierably irom O to ~30C, during the course oi 0.5 to 24 hours, preierably 2 to 4 hour~, with ~- to 7N-NaOH or EOH in a solvent, - ior example water, ethylene glycol or dimethyl~ormamide.
~ he -COOR2 group in the 7-position in the product oi the proces~ oi the present in~ention may be a iree or esteriiied oarboxyl group. When R2 represents a hydrogen atom in the #tarting compound, esteriiication oi the iree carboxyl group may also take place s~multaneously under the aIkylating conditions, eepecially when R" in the aIkylating agent has the same meaning a~ ~ .
~, ,, .~,~ /
A -~-:
- . ~ .
lO~lZO9 When -COOR2 in the starting compound i~ an e~teri~ied carboxyl group, the ætability oi this ester group depend~ on the conditions of the alkylating and/or sub~tituent-splitting oii reaction(s). I* theæe reactionæ are carried out at an e~pecially high reaction temperature, the ester group i~
wholly or at least partially hydrolysed. Depending on the iin ~ly deeired mea~ing o~ ~ , by a method known er se a iree carboxyl group may be esteriiiea or re-esteriiied and an esteriiied carbogyl group may be hyarolysed.
æalt iormation may be carried out in a manner kno~n ~E ~e, ~or example, with a l-normal æolutions oi the appropriate inorganic or organic ba~e, and the ~olution so obtained i~
evaporated, and the residue remaining behind i~ recrystallized, ior example, ~rom an alcohol/water mi~ture (5-9 : 5-1).
~ sually the reaction products are obtained, owing to the mulbiple bonds in ~ and optionally aleo in R2, in the iorm oi their cis/trana-isomeric mixtures, whi¢h may be separated in the U8Ual manner into the cis- and brans-iorms, ior e~ample, by rraction~l crystA~lization or chromatographyO
~ 8 stated above, the new compo~mds oi the present invent~on may be admini~tered in the u8ual pharmaceutical iorme oi application, ior example tablet~, dragée~, capsules, pill~, solutions~suspensions~ c~.
~ he present invention accordingly ~urther provides a pharmaceutical preparation whlch compri~es a compol-n~ o~ the pre~ent invention, in admi~ture or ¢on~u~ction with a pharmaceuti-cslly ~uitable carrier.
~ 1071Z09 ~he new compound~ may be used in combination with the ; additi~es no~mally used in galenical phaxmacy, for e~ample, iormoking preparation~ active against infections o~ the urinary ' tractO
The use oi the new compounds may be carried out by means oi the u~ual pharmaceutical iorms oi application. ~he compound~
oi the invention are especially suitable ior oral administration;
thus, the pharmaceutical preparations o~ the present i~vention may be in a iorm suitable iox oral admini~tratio~, ~or e~ample a~ tablets, dragées, capsules, pills, solutions or ~uspenæion~.
Tablets contain, ior egample, Ool to 1 gram o~ active æub~tance and 0.1 to 5 grams oi a pharmacologically inert au~iliary ~ub~tance. A~ au~iliary ~ubstances there are used, ior e~ample, ior tablets, lactoae, starches, talcum, gelatine and magnesium ~teaxate.
The compounds oi the present ln~ention can be used in the ileld both oi human and veterinary medicine.
`` ~he new aotive substances are used in quantities between Ool to 4.0 gram~ per patient per dayO
The present i~ve~tion accordingly also provides a method ior the treatment oi a urinary tract iniection, wherein a compound oi the present invention i~ a~ministered to a living beingO ~ "living being" is understood herein to exclude a human bei4g.
- The iollowing Examp_es ~77ustrate the inYentlon:-~ 9 .. `.. : . , ` - `. :
.
: 1071209 ~xample
5-~llyl-8-oxo-2,3,5,8-tetrahydro fRror2,3-g]quinoline-7-carbo~ylic acid.
- (a) 5-~llyl-8-o~o-2,3,5,8-tetrahydro-~uror2,3-g]quinoline 7-carbo~ylic acid allyl ester.
.8 Grama oi pulverized soaium hydroxide were ~u~pe~ded ~n 27 ml oi dimethyl ~ulphoxide, then ~ol gram~ oi 8-hydro~y-2,~-dihydro-~uro~2,~-g]qui~oline-7-carboxylic acid were introduced, and the whole waæ ætirred ror 10 minutes at room temperature.
; ~hen 5067 ml o~ allyl bromide were added, and the mixture waæ
stirred for 2 hour~ at room temperature, and then poured into water. ~he solid product wa~ ~iltered oY~ and recr~tallized ~rom ethanolO Melting poi~t: 100C. Yield: 205 gram3.
(b) 5-~llyl-8-oxo-2,3,5,8-tetrahydro-~uror2,3-g]quinoline-7-carbo~ylic acidO
1.0 Gram oi 5-allyl-8-o~o-2,~95,8-tetrahydro-iuro~2,~-g]
: quinol~ne-7-oarbogylic ac~d allyl ester wa~ boiled under reilux ior 10 minute~ with 10 ml oi a 2N sodium hydro~ide colutionO The solution WaB iiltered and acidi~ied. ~he precipitated product was recr~st~ zed irom dimethylrormamide.
~elting point: 264-279C. Yiela: 0O55 gramO
.:
E~m~e 2 8-Oxo-5-(1-propen~1)-2,3,5,8-tetra ~aro-iuro~2,3-g]
Qul~oline-7-carbo~ylic acid.
.
` ' " "
'`
~ 0 7 1 2 0 9 5Q0 mg oi 5-allyl-8-ogo-2,3,5,8-tetrahydro-furo~2,~-g]
quinoline-7-carboæ~lic acid were heated 1~ 5 ml of a 5N ~odium hydro~ide solution and 2~5 ml of ethylene glycol ~or 3 hours at 130Co Water and concentrated hydrochloric acid were added, and the precipitated material wa8 recrystallized ~rom dimethyl-formamide. Melting point: 263~o Yield: 0030 OEam.
E~am~le ~
~ he sodium ~alt of 8-o~o-5~ propenyl)-2,3,5,8-tetrahydro-furo~2,3-g]quinoline-7-carbo~ylic acid.
0030 Gram oi 8-ozo-5-(1-propeny1)-2,~,5,8-tetrahydro-furo~2,3-g]qui~oline-7-carbo~ylic acid wa~ dissolved in lol ml o~ a lN ~odium hydro~de ~olutio~0 ~he mixture was evaporated and the residue was recry~tall~zed from isopropanol/water 8:2.
M~lting point: 235Co Yield: 0020 gram.
~X~E~ 4 _, 8-Oæo-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quinoli~e-7-carboxylic acid.
(a) 6.0 Gram of pul~erized aodium hydroxide were su~pended in 45 ml of dimethyl sulpho~lde, 5.0 grams of 8-hydro~y-2,3-dihydro-~urot2,3-g]~uinoline-7-carboxylic acid were introduced, ~nd the whole was otirred for 10 minutes at room temperature.
8.2 gram~ of 1-bromo-2-fluorethane were added, and then the mi~ture wa~ stirred ~or 2 hours. The mixture Nas poured into water and acidi~ied with concentrated hydrochloric acid. ~he resulting solid product ~as chromatographed o~er 200 gram~ of silica gel with dio~an/conc.~40H/water 8:1:2, and the re~ulting purified ~ub~tance was recrystallizea irom dimethglformamide.
Melting point: 300_304oc (with decompo~ition)O Yield: 003 gram.
(b) 2.8 Grams of pulverized sodium hydro~ide were suspended ~n 20 ml o~ dimethyl sulpho~ide, 203 gram~ oi 8hydroxy-2,3-dihydro-~uro~2,3-g]qui~oli~e-7-carboxylic acid were introauced, and the whole waæ ~tirred ~or 10 minutes at room temperatureO
2.6 ml o~ 1,2-dibromethane were added, and the mi~ture wa~
~tirred ior 24 hours at room temperatureO. ~he miæture was poured into water ana acidi~ied with concentrated hyarochloric acidO ~he re~ulting solid product was chromatographed o~er sil~ca gel with diogan/conc.~H40H/w~ter 8:1:2, and the puriiiea .~ubstance was recryst~llized ~rom dimethyl~ormam~de.
Melting point: 300-304C (with decomposition)O Yield: 0004 gramO
(c) 2.3 Gram~ oi 8-hydro~y-2,~-dihydro-iuror2,3-g]quinoline-7-carbo~ylic acid were added to a mixture oi 2.04 grams o~
potassium hydrogide, 14.8 ml o~ water, 46 ml o~ ethanol ana 7.5 ~rams o~ 1,2-bromo~luorethane, and the whole was boiled under re~lu~ ior 5 daysO he resulting solid product was iiltered oi~ and chromatographed over 200 grams o~ silica gel with dioxan/concO~H40~/water 8:1:2, and ~a~ then recrystallized ~rom ethanol. 0.36 Gram oi 5-(2-rluorethyl)-8-oso-2,3,5,8-tetrahyaro-~uro~2,3-g]quinoli~e-7-carboxylic acid was obtained with a decompo~ition poi~t o~ 308-314ao 0.36 Gram oi 5-(2-iluorethyl)-8-oxo-2,3,5,8-tetrahydro-~urot2,3-g]~uinoline-7-oarboxylic acid was introduced into a mi2ture oi 408 grams of ~odium hydroxide and 3.5 ml of dimethyl ~ulphoxiae, and the whole wa~ stlrred ior 2 hours at 25C. ~he mixture W28 then poured into water, and acidiiied with concentrated hydrochloric --~F --~071Z09 acid, and the resulting ~olid product was chromatographed over ~ilica gel with dio~an/¢onc.~40~/water 8:1:20 0.20 ~ram oi 8-oxo-2,3,5,8-tetrahydro-5-vinyl-~uro~2,3-g]quinoline-7-carboxylic acid melting at 300-304C (with decomposition) was obtained.
_ ample_~
8-Oxo-5-propargyl-2,3,5,8-tetrahydro-~uro t 2,3-g]quinoline-7-carboxylic ac~dO
2.31 Gram~ o~ 8-hydroæy-2,3-dihydro-iuror2,3-g~quinoline-7-carboxylic acid and 4.7 ml oi 3-bromopropyne ~rere boiled under reilu~ ior 5 days in a solution o~ 1096 grams oi pota~sium hydroxide in 1402 ml oi ~rater and 40 ml oi ethanol. he product that crystalli~ed out aiter cooling ~a~ recr~stallized irom acetic acid. Melting point: 308-310C. Yield: 107 grams.
amp~,e 6 8-Oxo-5-propadieny1-2,3,5,8-tetrahydro-~uro~2,3-quinoline-7-carb~xylic aciaO
~ a) 0.54 ~ram oi 8-oxo-5-propargy1-2,3,5,8-tetrahydro-furo~2,3-g]quinoline-7-carbo~ylic acid wa~ i~troduced into a ~u~pen~ion oi 0056 gram o~ pulverized pota~ium hydroxide a~d 11 ml o~ dimethyl~ormamide at 0C. ~he mi~ture wa~ ~tirred ~or 2 hours at 0C, poured into ~rater, a~d acidiiied with hyaro-ohloric acid, and the re~ulting solid product was recry~tallized irom dimethylformamide. Melting point: 257-261Co Yield:
0.16 gram.
' 1 ~ 71 2 0 9 (b) 0~20 Gram o~ 8-oxo-5-propargy1-2,3,5,8-tetrahydro-~uro~2,~-g]quinoline-7-carbo~ylic acid wa~ stirred in 10 ml o~ tri~luoracetic acid ~or 20 hours at room temperature, ana the mi~ture was poured into water, and the re~ulting solid product ~ra~ recryRtallized ~rom dimethyl~ormamideO Melting point: 257-261C~ Yield: OolO gramO
am~le 7 5-(2-~utenyl)-8-o~o-2,3,5,8-tetrahydro-~uro~2,3-g~
quinoline-7-car~oæylic acid.
(a) 5-(2-Butenyl)-8-oxo-2,3,5,8-tetrahydro-~uro~2,3-g]
qui~oline-7-carboxylic acid 2-butenyl ester.
2.5 Grams o~ 8-h~droxy-2,~-dihgdro-~uro~2~3-g]~uinoline-7-carboxylic acid were introduced ~t room temperature into 2 ~uepen~ion o~ 300 grams o~ sodium hydro~ide i~ 2108 ml o~
dimethyl sulphoxiae, and then 404 gram~ of crotyl bromiae were addedO The mixture wa~ stirred ~or 2 hours at room temperature, and poured into water, and the re~ulting solid product was re¢rystallized ~rom ethanol. Melting point: ~11C.
Yleld: 0.85 gram.
(b) 5-(2-~utenyl)-8-o~o-2,3,~,8-tetrahydro-~urot2,3-g]
quinoline-7-¢ar~o~ylic acid.
0075 Gram of 5-(2-buten~yl)-8-oxo-2,3,5,8-tetrah~dro-~uror2,3-g~quinol~ne-7-carbo~licl2-butenyl ester ~a~ bo~led under reilw~ in 10 ml of a 2N ~odium hydro~ide solutio~ îor 10 minutesO ~he mi~cture wa~ ~iltered, and acidi~ied with hydro-chloric acld, and the re~ulting solid product wa~ recry~tall~zed irom dimethylformamideO Melting point: 276-286Co Yield: 0.43 gram.
_ ~ _ ~ 0 7 1 Z 0 9 Exam~le 8 5~ uten~ 8-oxo-2,3,5,8-tetrahydro-~uro~2,3-g~
~uinoline-7-carbo~ylic acid.
0.30 Gram o~ 5-(2-~ute~y1)-8-o~o-2,3,5,8-tetrahydro-~uror2,3-g~quinoline-7-carbo~ylic acid was heatea in 3 ml o~
a 5N ~odium hydroxide solution and 105 ml o~ ethylene gl~col ~or 4 hour~ at 130Co The mi~ture wa~ diluted with some water, and ac~di~ied with hydrochloric acid, and the re~ulting ~olid product wae recry~talllzed ~rom dimethyl ~ulphoæide/waterO
Melti~g point: 270-271C. Yield: 0.11 gramO
~amP~e ~
5-(2-Methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-~uror2,3-g3quinoline-7-carboxylic acidO
(a) ~-(2-Methyl-2-propen~1)-8-oxo-2,3,5,8-tetrahydro-furo~2,3-g]quinoline-7-carboxylic acid (2-methyl-2-propenyl) e~ter.
203 Grame o~ 8-hydro~y-2,3-dihydro-~uro~2,3-g]quinoline-7-carboxylic acid were introduced into a suspensio~ of 3.0 gram~ o~ sod~um hydroxide and 20 ml o~ dimethyl sulpho~ide, and then 6.0 gram~ of methallyl bromide were added. The m~Yture wa~ ~tirred for 2 hour~ at room temperature, and poured into water, and the resulting solid product was recrystallized ~rom ethanol. Melting poi~t: 169-172Co Yield: 0.80 gramO
(b) 5-(2-Methy1-2-propeny1)-8-oxo-2,3,5,8-tetrahydro-~Uro~2,~-g3quinoline-7-carbo~ylic acid.
.
. . . - -, ~071209 0.75 Gram o~ 5-(2-methyl-2-propenyl)-8-ogo-2,3,5,8-tetrahydro-~uro~2,3-g]quinoline-7-carboxylic acid (2-methy1-2-propenyl) ester was æuspended in 10 ml of a 2N ~odium hydroæide solution and boiled under re~lux ~or 10 minu~e~0 ~he mixture wa~ iiltered, and acidiiied with hydrochloric acid, and the resulting 801ia product was recrystallized ~rom dimet~yl~ormamideO
Melting point: 265-272Co Yield: 0030 gramO
:3~camPle 10 5-(2-Methyl-l-propenyl)-8-o~o-2,3,5,8-tetrahydro-~uro-C2.3-g]quinoline-7-carboxylic acid.
0025 Gram oi 5-(2-methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-iuro~2,3-g]quinoline-7-carbo~ylic acid wa~ heated in 3 ml o~ a 5N ~oaium hydroxide 301ution and L5 ml 0~ ethylene glycol for 3 hours at 130C. The mixture was diluted with some water, and acidi~ied with hydrochloric acid, and the resulting oolid produc~ ~a~ recry~tallized irom dimeth~liormamide.
Nelting point: 293-295Co Yield: 0.16 gram.
Exam~le 11 ~ he ~odium Balt o~ 8-oxo-2,3,5,8-tetrahydro-5-~inyl-~uro ~2, 3-g]quinoline-7-carbo~yll c acid .
O. 23 ~ram o~ 8-oxo-2, 3, 5,8-tetrahydro-5-rinyl- euro t 2, 3-g]
quinoline-7-oarbo~yllc acid wa8 dissolved in 0.9 mi o~ a 1 eodium h;ydroxide solutionO ~he mixture waa concentrated ~, va,cuo, and the re~idue wa~ recry~tallized ~rom i~opropanol/water 8:20 Melting point: 253-257C. Yield: 0.13 gram.
~ IG
- (a) 5-~llyl-8-o~o-2,3,5,8-tetrahydro-~uror2,3-g]quinoline 7-carbo~ylic acid allyl ester.
.8 Grama oi pulverized soaium hydroxide were ~u~pe~ded ~n 27 ml oi dimethyl ~ulphoxide, then ~ol gram~ oi 8-hydro~y-2,~-dihydro-~uro~2,~-g]qui~oline-7-carboxylic acid were introduced, and the whole waæ ætirred ror 10 minutes at room temperature.
; ~hen 5067 ml o~ allyl bromide were added, and the mixture waæ
stirred for 2 hour~ at room temperature, and then poured into water. ~he solid product wa~ ~iltered oY~ and recr~tallized ~rom ethanolO Melting poi~t: 100C. Yield: 205 gram3.
(b) 5-~llyl-8-oxo-2,3,5,8-tetrahydro-~uror2,3-g]quinoline-7-carbo~ylic acidO
1.0 Gram oi 5-allyl-8-o~o-2,~95,8-tetrahydro-iuro~2,~-g]
: quinol~ne-7-oarbogylic ac~d allyl ester wa~ boiled under reilux ior 10 minute~ with 10 ml oi a 2N sodium hydro~ide colutionO The solution WaB iiltered and acidi~ied. ~he precipitated product was recr~st~ zed irom dimethylrormamide.
~elting point: 264-279C. Yiela: 0O55 gramO
.:
E~m~e 2 8-Oxo-5-(1-propen~1)-2,3,5,8-tetra ~aro-iuro~2,3-g]
Qul~oline-7-carbo~ylic acid.
.
` ' " "
'`
~ 0 7 1 2 0 9 5Q0 mg oi 5-allyl-8-ogo-2,3,5,8-tetrahydro-furo~2,~-g]
quinoline-7-carboæ~lic acid were heated 1~ 5 ml of a 5N ~odium hydro~ide solution and 2~5 ml of ethylene glycol ~or 3 hours at 130Co Water and concentrated hydrochloric acid were added, and the precipitated material wa8 recrystallized ~rom dimethyl-formamide. Melting point: 263~o Yield: 0030 OEam.
E~am~le ~
~ he sodium ~alt of 8-o~o-5~ propenyl)-2,3,5,8-tetrahydro-furo~2,3-g]quinoline-7-carbo~ylic acid.
0030 Gram oi 8-ozo-5-(1-propeny1)-2,~,5,8-tetrahydro-furo~2,3-g]qui~oline-7-carbo~ylic acid wa~ dissolved in lol ml o~ a lN ~odium hydro~de ~olutio~0 ~he mixture was evaporated and the residue was recry~tall~zed from isopropanol/water 8:2.
M~lting point: 235Co Yield: 0020 gram.
~X~E~ 4 _, 8-Oæo-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quinoli~e-7-carboxylic acid.
(a) 6.0 Gram of pul~erized aodium hydroxide were su~pended in 45 ml of dimethyl sulpho~lde, 5.0 grams of 8-hydro~y-2,3-dihydro-~urot2,3-g]~uinoline-7-carboxylic acid were introduced, ~nd the whole was otirred for 10 minutes at room temperature.
8.2 gram~ of 1-bromo-2-fluorethane were added, and then the mi~ture wa~ stirred ~or 2 hours. The mixture Nas poured into water and acidi~ied with concentrated hydrochloric acid. ~he resulting solid product ~as chromatographed o~er 200 gram~ of silica gel with dio~an/conc.~40H/water 8:1:2, and the re~ulting purified ~ub~tance was recrystallizea irom dimethglformamide.
Melting point: 300_304oc (with decompo~ition)O Yield: 003 gram.
(b) 2.8 Grams of pulverized sodium hydro~ide were suspended ~n 20 ml o~ dimethyl sulpho~ide, 203 gram~ oi 8hydroxy-2,3-dihydro-~uro~2,3-g]qui~oli~e-7-carboxylic acid were introauced, and the whole waæ ~tirred ~or 10 minutes at room temperatureO
2.6 ml o~ 1,2-dibromethane were added, and the mi~ture wa~
~tirred ior 24 hours at room temperatureO. ~he miæture was poured into water ana acidi~ied with concentrated hyarochloric acidO ~he re~ulting solid product was chromatographed o~er sil~ca gel with diogan/conc.~H40H/w~ter 8:1:2, and the puriiiea .~ubstance was recryst~llized ~rom dimethyl~ormam~de.
Melting point: 300-304C (with decomposition)O Yield: 0004 gramO
(c) 2.3 Gram~ oi 8-hydro~y-2,~-dihydro-iuror2,3-g]quinoline-7-carbo~ylic acid were added to a mixture oi 2.04 grams o~
potassium hydrogide, 14.8 ml o~ water, 46 ml o~ ethanol ana 7.5 ~rams o~ 1,2-bromo~luorethane, and the whole was boiled under re~lu~ ior 5 daysO he resulting solid product was iiltered oi~ and chromatographed over 200 grams o~ silica gel with dioxan/concO~H40~/water 8:1:2, and ~a~ then recrystallized ~rom ethanol. 0.36 Gram oi 5-(2-rluorethyl)-8-oso-2,3,5,8-tetrahyaro-~uro~2,3-g]quinoli~e-7-carboxylic acid was obtained with a decompo~ition poi~t o~ 308-314ao 0.36 Gram oi 5-(2-iluorethyl)-8-oxo-2,3,5,8-tetrahydro-~urot2,3-g]~uinoline-7-oarboxylic acid was introduced into a mi2ture oi 408 grams of ~odium hydroxide and 3.5 ml of dimethyl ~ulphoxiae, and the whole wa~ stlrred ior 2 hours at 25C. ~he mixture W28 then poured into water, and acidiiied with concentrated hydrochloric --~F --~071Z09 acid, and the resulting ~olid product was chromatographed over ~ilica gel with dio~an/¢onc.~40~/water 8:1:20 0.20 ~ram oi 8-oxo-2,3,5,8-tetrahydro-5-vinyl-~uro~2,3-g]quinoline-7-carboxylic acid melting at 300-304C (with decomposition) was obtained.
_ ample_~
8-Oxo-5-propargyl-2,3,5,8-tetrahydro-~uro t 2,3-g]quinoline-7-carboxylic ac~dO
2.31 Gram~ o~ 8-hydroæy-2,3-dihydro-iuror2,3-g~quinoline-7-carboxylic acid and 4.7 ml oi 3-bromopropyne ~rere boiled under reilu~ ior 5 days in a solution o~ 1096 grams oi pota~sium hydroxide in 1402 ml oi ~rater and 40 ml oi ethanol. he product that crystalli~ed out aiter cooling ~a~ recr~stallized irom acetic acid. Melting point: 308-310C. Yield: 107 grams.
amp~,e 6 8-Oxo-5-propadieny1-2,3,5,8-tetrahydro-~uro~2,3-quinoline-7-carb~xylic aciaO
~ a) 0.54 ~ram oi 8-oxo-5-propargy1-2,3,5,8-tetrahydro-furo~2,3-g]quinoline-7-carbo~ylic acid wa~ i~troduced into a ~u~pen~ion oi 0056 gram o~ pulverized pota~ium hydroxide a~d 11 ml o~ dimethyl~ormamide at 0C. ~he mi~ture wa~ ~tirred ~or 2 hours at 0C, poured into ~rater, a~d acidiiied with hyaro-ohloric acid, and the re~ulting solid product was recry~tallized irom dimethylformamide. Melting point: 257-261Co Yield:
0.16 gram.
' 1 ~ 71 2 0 9 (b) 0~20 Gram o~ 8-oxo-5-propargy1-2,3,5,8-tetrahydro-~uro~2,~-g]quinoline-7-carbo~ylic acid wa~ stirred in 10 ml o~ tri~luoracetic acid ~or 20 hours at room temperature, ana the mi~ture was poured into water, and the re~ulting solid product ~ra~ recryRtallized ~rom dimethyl~ormamideO Melting point: 257-261C~ Yield: OolO gramO
am~le 7 5-(2-~utenyl)-8-o~o-2,3,5,8-tetrahydro-~uro~2,3-g~
quinoline-7-car~oæylic acid.
(a) 5-(2-Butenyl)-8-oxo-2,3,5,8-tetrahydro-~uro~2,3-g]
qui~oline-7-carboxylic acid 2-butenyl ester.
2.5 Grams o~ 8-h~droxy-2,~-dihgdro-~uro~2~3-g]~uinoline-7-carboxylic acid were introduced ~t room temperature into 2 ~uepen~ion o~ 300 grams o~ sodium hydro~ide i~ 2108 ml o~
dimethyl sulphoxiae, and then 404 gram~ of crotyl bromiae were addedO The mixture wa~ stirred ~or 2 hours at room temperature, and poured into water, and the re~ulting solid product was re¢rystallized ~rom ethanol. Melting point: ~11C.
Yleld: 0.85 gram.
(b) 5-(2-~utenyl)-8-o~o-2,3,~,8-tetrahydro-~urot2,3-g]
quinoline-7-¢ar~o~ylic acid.
0075 Gram of 5-(2-buten~yl)-8-oxo-2,3,5,8-tetrah~dro-~uror2,3-g~quinol~ne-7-carbo~licl2-butenyl ester ~a~ bo~led under reilw~ in 10 ml of a 2N ~odium hydro~ide solutio~ îor 10 minutesO ~he mi~cture wa~ ~iltered, and acidi~ied with hydro-chloric acld, and the re~ulting solid product wa~ recry~tall~zed irom dimethylformamideO Melting point: 276-286Co Yield: 0.43 gram.
_ ~ _ ~ 0 7 1 Z 0 9 Exam~le 8 5~ uten~ 8-oxo-2,3,5,8-tetrahydro-~uro~2,3-g~
~uinoline-7-carbo~ylic acid.
0.30 Gram o~ 5-(2-~ute~y1)-8-o~o-2,3,5,8-tetrahydro-~uror2,3-g~quinoline-7-carbo~ylic acid was heatea in 3 ml o~
a 5N ~odium hydroxide solution and 105 ml o~ ethylene gl~col ~or 4 hour~ at 130Co The mi~ture wa~ diluted with some water, and ac~di~ied with hydrochloric acid, and the re~ulting ~olid product wae recry~talllzed ~rom dimethyl ~ulphoæide/waterO
Melti~g point: 270-271C. Yield: 0.11 gramO
~amP~e ~
5-(2-Methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-~uror2,3-g3quinoline-7-carboxylic acidO
(a) ~-(2-Methyl-2-propen~1)-8-oxo-2,3,5,8-tetrahydro-furo~2,3-g]quinoline-7-carboxylic acid (2-methyl-2-propenyl) e~ter.
203 Grame o~ 8-hydro~y-2,3-dihydro-~uro~2,3-g]quinoline-7-carboxylic acid were introduced into a suspensio~ of 3.0 gram~ o~ sod~um hydroxide and 20 ml o~ dimethyl sulpho~ide, and then 6.0 gram~ of methallyl bromide were added. The m~Yture wa~ ~tirred for 2 hour~ at room temperature, and poured into water, and the resulting solid product was recrystallized ~rom ethanol. Melting poi~t: 169-172Co Yield: 0.80 gramO
(b) 5-(2-Methy1-2-propeny1)-8-oxo-2,3,5,8-tetrahydro-~Uro~2,~-g3quinoline-7-carbo~ylic acid.
.
. . . - -, ~071209 0.75 Gram o~ 5-(2-methyl-2-propenyl)-8-ogo-2,3,5,8-tetrahydro-~uro~2,3-g]quinoline-7-carboxylic acid (2-methy1-2-propenyl) ester was æuspended in 10 ml of a 2N ~odium hydroæide solution and boiled under re~lux ~or 10 minu~e~0 ~he mixture wa~ iiltered, and acidiiied with hydrochloric acid, and the resulting 801ia product was recrystallized ~rom dimet~yl~ormamideO
Melting point: 265-272Co Yield: 0030 gramO
:3~camPle 10 5-(2-Methyl-l-propenyl)-8-o~o-2,3,5,8-tetrahydro-~uro-C2.3-g]quinoline-7-carboxylic acid.
0025 Gram oi 5-(2-methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-iuro~2,3-g]quinoline-7-carbo~ylic acid wa~ heated in 3 ml o~ a 5N ~oaium hydroxide 301ution and L5 ml 0~ ethylene glycol for 3 hours at 130C. The mixture was diluted with some water, and acidi~ied with hydrochloric acid, and the resulting oolid produc~ ~a~ recry~tallized irom dimeth~liormamide.
Nelting point: 293-295Co Yield: 0.16 gram.
Exam~le 11 ~ he ~odium Balt o~ 8-oxo-2,3,5,8-tetrahydro-5-~inyl-~uro ~2, 3-g]quinoline-7-carbo~yll c acid .
O. 23 ~ram o~ 8-oxo-2, 3, 5,8-tetrahydro-5-rinyl- euro t 2, 3-g]
quinoline-7-oarbo~yllc acid wa8 dissolved in 0.9 mi o~ a 1 eodium h;ydroxide solutionO ~he mixture waa concentrated ~, va,cuo, and the re~idue wa~ recry~tallized ~rom i~opropanol/water 8:20 Melting point: 253-257C. Yield: 0.13 gram.
~ IG
Claims (33)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process of preparing a quinoline carboxylic acid derivative of the general formula (I) (I) where: R1 represents an alkenyl group containing 2 to 4 carbon atoms or an alkynyl group containing 2 to 4 carbon atoms, and, R2 represents hydrogen; an alkenyl group containing 2 to 4 carbon atoms or an alkynyl group containing 2 to 4 carbon atoms or, a physiologically tolerable salt of a compound of formula (I) where R2 is a hydrogen atom with an inorganic or organic base, comprising: treating a compound of at least one of the general tautomeric formulae (IIA) and (IIB) (IIA) (IIB) where R2 has the meaning given above, with a compound of the formula R"X where R" represents an alkenyl group containing 2 to 4 carbon atoms; an alkynyl group containing 2 to 4 carbon atoms; or an alkyl group containing 1 to 4 carbon atoms substituted with 1 or 2 halogen atoms, and X represents a halogen atom, an alkane-sulphonyloxy group containing 1 to 4 carbon atoms in the alkyl residue or an unsubstituted benzene sulphonyloxy group or a benzene sulphonyloxy group substituted with at least one substituent selected from halogen atoms and alkyl groups contain-?g 1 to 4 carbon atoms, and, thereafter, when R" represents a group, splitting off the halo substituent or substituents therefrom to form at least one multiple bond, and, thereafter, when the compound to be prepared is required to be an ester and -COOR2 in the reaction product represents a free carboxyl group, esterifying the free carboxyl group,when R2 in the compound to be prepared is required to represent a hydrogen atom and -COOR2 in the reaction product represents an esterified carboxyl group, hydrolysing the esterified carboxyl group, when the group attached to the nitrogen atom in the 5-position contains at least one multiple bond, at least one of which is in other than the required position effecting rearrangement thereof, when the compound to be prepared is required to be a salt and -COOR2 after said reaction is a free carboxyl group, reacting the free carboxyl group with an organic or inorganic base which yields a physiologically tolerable cation, and when the compound to be prepared is required to be a salt and -COOR2 after said reaction is an esterified carboxyl group, hydrolysing the esterified carboxyl group thereby producing a free carboxyl group and reacting the free carboxyl group with an organic or inorganic base which yields a physiologically acceptable cation.
2. A compound of the general formula (I) given in claim 1 where R1 and R2 are as in claim 1 or a physiologically tolerable salt thereof with an inorganic or organic base when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
3. A process according to claim 1, wherein:
(a) in the reactants, R2 represents a hydrogen atom or an allyl group and R" represents an allyl group, (b) in the reactants, R2 represents an allyl group and R"
represents a 1-propenyl residue, and, after said reaction the double bond in the 1-propenyl residue is rearranged to convert the 1-propenyl residue into an allyl group, (c) in the reactants, R2 represents an allyl group and R"
represents an n-propyl residue substituted by one halogen atom and, after said reaction, the halogen atom is split off to form a double bond in the 2,3-position thereby converting the n-propyl residue into an allyl group, or (d) in the reactants, R2 represents an allyl group and R"
represents an n-propyl residue substituted by one halogen atom and, after said reaction, the halogen atom is split off to form a 1-propenyl group and the double bond in the 1-propenyl group is rearranged to convert the 1-propenyl group into an allyl group.
(a) in the reactants, R2 represents a hydrogen atom or an allyl group and R" represents an allyl group, (b) in the reactants, R2 represents an allyl group and R"
represents a 1-propenyl residue, and, after said reaction the double bond in the 1-propenyl residue is rearranged to convert the 1-propenyl residue into an allyl group, (c) in the reactants, R2 represents an allyl group and R"
represents an n-propyl residue substituted by one halogen atom and, after said reaction, the halogen atom is split off to form a double bond in the 2,3-position thereby converting the n-propyl residue into an allyl group, or (d) in the reactants, R2 represents an allyl group and R"
represents an n-propyl residue substituted by one halogen atom and, after said reaction, the halogen atom is split off to form a 1-propenyl group and the double bond in the 1-propenyl group is rearranged to convert the 1-propenyl group into an allyl group.
4. A process according to claim 3, comprising reacting 8-hydroxy-2,3-dihydro-furo[2,3-g] quinoline-7-carboxylic acid with allyl bromide.
5. 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g] quinoline -7-carboxylic acid allyl ester when prepared by a process according to claim 3 or 4 or an obvious chemical equivalent thereof.
6. A process according to claim 3, further comprising hydrolysing the 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid allyl ester produced.
quinoline-7-carboxylic acid allyl ester produced.
7. 5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g] quinoline -7-carboxylic acid when produced by a process according to claim 6 or an obvious chemical equivalent thereof.
8. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with allyl bromide and the reaction product is hydrolysed.
9. 5-allyl 8-oxo-2,3,5,8-tetrahydro-furo-[2,3-g]
quinoline-7-carboxylic acid when produced by a process according to claim 8 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid when produced by a process according to claim 8 or an obvious chemical equivalent thereof.
10. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with allyl bromide and the reaction product is hydrolysed and the double bond in the allyl group in the hydrolysed reaction product is rearranged to convert the allyl group into a 1-propenyl group.
11. 8-oxo-5-(1-propenyl)-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid when produced by a process according to claim 10 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid when produced by a process according to claim 10 or an obvious chemical equivalent thereof.
12. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with allyl bromide and the reaction product is hydrolysed, the double bond in the allyl group in the hydrolysed reaction product is rearranged to convert the allyl group into a 1-propenyl group and the free carboxyl group is reacted with sodium hydroxide.
13. The sodium salt of 8-oxo-5-(1-propenyl)-2,3,5,8-tetrahydro-furo[2,3-g] when prepared by a process according to claim 12 or an obvious chemical equivalent thereof.
14. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with 1-bromo-2-fluoroethane or 1,2-dibromoethane and a halogen atom is split off the ethyl group attached to the nitrogen atom in the reaction product.
15. 8-Oxo-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quino-line-7-carboyxlic acid when prepared by a process according to claim 5 or an obvious chemical equivalent thereof.
16. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with 3-bromopropine.
17. 8-oxo-5-propargyl-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid when prepared by a process according to claim 16 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid when prepared by a process according to claim 16 or an obvious chemical equivalent thereof.
18. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with 3-bromopropine and the triple bond in the 5-propargyl group in the reaction product is rearranged to convert the 5-propargyl group into a 5-propadienyl group.
19. 8-Oxo-5-propadienyl-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid when prepared by a process according to claim 18 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid when prepared by a process according to claim 18 or an obvious chemical equivalent thereof.
20. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with crotyl bromide.
21. 5-(2-Butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid 2-butenyl ester when prepared by a process according to claim 20 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid 2-butenyl ester when prepared by a process according to claim 20 or an obvious chemical equivalent thereof.
22. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with crotyl bromide and the esterified carboxyl group in the reaction product is hydrolysed.
23. 5-(2-Butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid when prepared by a process according to claim 22 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid when prepared by a process according to claim 22 or an obvious chemical equivalent thereof.
24. A process according to claim 1, wherein 8-hydroxy-2,3-dihdyro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with crotyl bromide, the esterified carboxyl group in the reaction product is hydrolysed and the double bond in the 2-butenyl group is rearranged to convert the 2-butenyl group into a 1-butenyl group.
25. 5-(1-Butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]
quinoline-7-carboxylic acid when prepared by a process according to claim 24 or an obvious chemical equivalent thereof.
quinoline-7-carboxylic acid when prepared by a process according to claim 24 or an obvious chemical equivalent thereof.
26. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with methallyl bromide.
27. 5-(2-Methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinoline-7-carboyxlic acid (2-methyl-2-propenyl) ester when prepared by a process according to claim 26 or an obvious chemical equivalent thereof.
28. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboyxlic acid is reacted with methallyl bromide and the esterified carboxyl group in the reaction product is hydrolysed.
29. 5-(2-Methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinoline-7-carboxylic acid when prepared by a process according to claim 28 or an obvious chemical equivalent thereof.
30. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with methallyl bromide, the esterified carboxyl group in the reaction product is hydrolysed and the double bond in the 2-methyl-2-propenyl group attached to the nitrogen atom is rearranged to convert the 2-methyl-2-propenyl group into a 2-methyl-1-propenyl group.
31. 5-(2-Methyl-1-propenyl)-8-oxo-2,3,5,a-tetrahydro-furo[2,3-g]quinoline when prepared by a process according to claim 30 or an obvious chemical equivalent thereof.
32. A process according to claim 1, wherein 8-hydroxy-2,3-dihydro-furo[2,3-g]quinoline-7-carboxylic acid is reacted with 1-bromo-2-fluoroethane or 1,2-dibromoethane, a halogen atom is split off the ethyl group attached to the nitrogen atom in the reaction product and the free carboxyl group is reacted with sodium hydroxide.
33. The sodium salt of 8-oxo-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quinoline-7-carboxylic acid when prepared by a process according to claim 32 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752530412 DE2530412A1 (en) | 1975-07-04 | 1975-07-04 | CHINOLINCARBONIC ACID DERIVATIVES II |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071209A true CA1071209A (en) | 1980-02-05 |
Family
ID=5950957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA256,253A Expired CA1071209A (en) | 1975-07-04 | 1976-07-05 | 8-oxo-2,3,5,8-tetrahydro-furo (2,3-g) quinoline-7-carboxylic acid compounds |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5223096A (en) |
| BE (1) | BE843738A (en) |
| CA (1) | CA1071209A (en) |
| CH (1) | CH626894A5 (en) |
| DE (1) | DE2530412A1 (en) |
| DK (1) | DK142949C (en) |
| FR (1) | FR2315932A1 (en) |
| IE (1) | IE43256B1 (en) |
| IL (1) | IL49967A0 (en) |
| LU (1) | LU75294A1 (en) |
| NL (1) | NL7607417A (en) |
| PT (1) | PT65299B (en) |
| SE (1) | SE7607515L (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2030899A1 (en) * | 1970-06-18 | 1971-12-23 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Quinoline carboxylic acid derivatives |
-
1975
- 1975-07-04 DE DE19752530412 patent/DE2530412A1/en not_active Withdrawn
-
1976
- 1976-06-30 CH CH838876A patent/CH626894A5/en not_active IP Right Cessation
- 1976-06-30 PT PT65299A patent/PT65299B/en unknown
- 1976-07-01 SE SE7607515A patent/SE7607515L/en not_active Application Discontinuation
- 1976-07-02 BE BE168601A patent/BE843738A/en not_active IP Right Cessation
- 1976-07-02 LU LU75294A patent/LU75294A1/xx unknown
- 1976-07-02 DK DK300076A patent/DK142949C/en not_active IP Right Cessation
- 1976-07-04 IL IL49967A patent/IL49967A0/en unknown
- 1976-07-05 IE IE1476/76A patent/IE43256B1/en unknown
- 1976-07-05 JP JP51079782A patent/JPS5223096A/en active Pending
- 1976-07-05 CA CA256,253A patent/CA1071209A/en not_active Expired
- 1976-07-05 FR FR7620428A patent/FR2315932A1/en active Granted
- 1976-07-05 NL NL7607417A patent/NL7607417A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2315932B1 (en) | 1979-07-20 |
| FR2315932A1 (en) | 1977-01-28 |
| DK142949C (en) | 1981-10-05 |
| PT65299B (en) | 1977-12-13 |
| JPS5223096A (en) | 1977-02-21 |
| CH626894A5 (en) | 1981-12-15 |
| DE2530412A1 (en) | 1977-01-20 |
| PT65299A (en) | 1976-07-01 |
| DK300076A (en) | 1977-01-05 |
| BE843738A (en) | 1977-01-03 |
| NL7607417A (en) | 1977-01-06 |
| SE7607515L (en) | 1977-01-05 |
| DK142949B (en) | 1981-03-02 |
| IE43256L (en) | 1977-01-04 |
| IE43256B1 (en) | 1981-01-14 |
| LU75294A1 (en) | 1977-02-23 |
| IL49967A0 (en) | 1976-09-30 |
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