DE2811132A1 - 1-Hydroxy-2-sulphonyl-benzo-2,3,1-diaza:borine derivs. - useful as antibacterial agents against gram negative bacteria - Google Patents
1-Hydroxy-2-sulphonyl-benzo-2,3,1-diaza:borine derivs. - useful as antibacterial agents against gram negative bacteriaInfo
- Publication number
- DE2811132A1 DE2811132A1 DE19782811132 DE2811132A DE2811132A1 DE 2811132 A1 DE2811132 A1 DE 2811132A1 DE 19782811132 DE19782811132 DE 19782811132 DE 2811132 A DE2811132 A DE 2811132A DE 2811132 A1 DE2811132 A1 DE 2811132A1
- Authority
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- Germany
- Prior art keywords
- formula
- hydroxy
- benzo
- diazaborine
- atoms
- 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.)
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- 241000894006 Bacteria Species 0.000 title abstract 2
- 239000003242 anti bacterial agent Substances 0.000 title abstract 2
- 229910000085 borane Inorganic materials 0.000 title 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 title 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 8
- 150000001768 cations Chemical class 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract 3
- ZBBOOYHVEBXBIQ-UHFFFAOYSA-N 1-hydroxy-6-methyl-2-(2-methylpropylsulfonyl)-2,3,1-benzodiazaborinine Chemical compound CC1=CC=C2B(O)N(S(=O)(=O)CC(C)C)N=CC2=C1 ZBBOOYHVEBXBIQ-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- -1 alkali metal cation Chemical class 0.000 claims description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 7
- 229910052796 boron Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- VYLMBCVKHNTBIA-UHFFFAOYSA-N 1-hydroxy-2h-2,3,1-benzodiazaborinine Chemical class C1=CC=C2B(O)NN=CC2=C1 VYLMBCVKHNTBIA-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims 3
- 239000012876 carrier material Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- 208000015181 infectious disease Diseases 0.000 abstract description 3
- 241000588724 Escherichia coli Species 0.000 abstract description 2
- 241000588748 Klebsiella Species 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 abstract description 2
- 241000588770 Proteus mirabilis Species 0.000 abstract description 2
- HAQABNQQTFZFKA-UHFFFAOYSA-N 1,2,3-benzodiazaborinine Chemical compound C1=CC=C2N=NB=CC2=C1 HAQABNQQTFZFKA-UHFFFAOYSA-N 0.000 abstract 1
- 241000588767 Proteus vulgaris Species 0.000 abstract 1
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 229940007042 proteus vulgaris Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- MUCPGEPGWYOKRO-UHFFFAOYSA-N 1,3,2-diazaborinine Chemical compound B1=NC=CC=N1 MUCPGEPGWYOKRO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YAZGWGRHYJGTHK-UHFFFAOYSA-N 2,3,1-benzodiazaborinine Chemical class C1=CC=C2B=NN=CC2=C1 YAZGWGRHYJGTHK-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 description 1
- XWGJRNXMQLHUBV-UHFFFAOYSA-N 6-chloro-1-hydroxy-2-(2-methylpropylsulfonyl)-2,3,1-benzodiazaborinine Chemical compound ClC1=CC=C2B(O)N(S(=O)(=O)CC(C)C)N=CC2=C1 XWGJRNXMQLHUBV-UHFFFAOYSA-N 0.000 description 1
- WRHIUOLNAIIRNX-UHFFFAOYSA-N 6-fluoro-1-hydroxy-2-propylsulfonyl-2,3,1-benzodiazaborinine Chemical compound FC1=CC=C2B(O)N(S(=O)(=O)CCC)N=CC2=C1 WRHIUOLNAIIRNX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- WNQFYRGRLVOHEC-UHFFFAOYSA-N FC1=CC=C2B(O)N(S(=O)(=O)CCCCl)N=CC2=C1 Chemical compound FC1=CC=C2B(O)N(S(=O)(=O)CCCCl)N=CC2=C1 WNQFYRGRLVOHEC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- YMEKEHSRPZAOGO-UHFFFAOYSA-N boron triiodide Chemical compound IB(I)I YMEKEHSRPZAOGO-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 244000000058 gram-negative pathogen Species 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
64 Neue Derivate des 1-Hydroxy-henzo-2,3,1-diazaborins, diese64 New derivatives of 1-hydroxy-henzo-2,3,1-diazaborins, these
enthaltende Arzneimittel und Verfahren zu deren Herstellung In den deutschen Offenlegungsschriften 25 33 918, 26 20 776 und 26 20 777 sind 1-HVdroxV-2-alkyl-,-2-alkenyl bzw. -2-halogenalkyl-sulfonyl-benzo-2, 3, 1-diazaborine bzw. deren Herstellung beschrieben worden. Diese Verbindungen sind antibakteriell wirksam. Im Benzolkern substituierte Verbindungen dieses Typs wurden bisher noch nicht in der Literatur beschrieben.Medicinal products containing and process for their preparation In the German Offenlegungsschriften 25 33 918, 26 20 776 and 26 20 777 are 1-HVdroxV-2-alkyl -, - 2-alkenyl or -2-haloalkyl-sulfonyl-benzo-2, 3, 1-diazaborine and their preparation are described been. These compounds have an antibacterial effect. Substituted in the benzene nucleus Compounds of this type have not yet been described in the literature.
Soweit bisher in antibakteriell wirksamen Benzo-2,3,1-diazaborinderivaten einn Substitution des Benzolrestes durchgeführt wurde, resultierte daraus eine Wirkungsminderung im Vergleich zur im Benzolkern unsubstituierten analogen Verbindung.So far so far in antibacterial benzo-2,3,1-diazaborine derivatives a substitution of the benzene residue was carried out, this resulted in a reduction in effectiveness compared to the analogous compound unsubstituted in the benzene nucleus.
Es wurde nun überraschenderweise gefunden, daß neue 1-Hydroxybenzo-2,3,1-diazaborine der Formel worin R1 ein geradkettiger oder verzweigter, gegebenenfalls durch 1 - 3 Halogenatome, vorzugsweise Chloratome substituierter Alkylrest oder ein Alkenylrest mit 2 bis 5 Kohlenstoffatomen ist, R2 und R3 gleich oder verschieden sind und für Alkylreste mit 1 bis 4 Kohlenstoffatomen oder für Fluor-, Chlor- oder Bromatome stehen, wobei höchstens einer der Reste R2 und R3 auch für Wasserstoff stehen kann, und R4 ein Wasserstoffatom oder ein pharmazeutisch verträgliches Kation, vorzugsweise ein .P,lkalimetallkation, bedeutet, bei sehr geringer Toxizität eine hohe Aktivität gegen gramnegative Keime bzw. dadurch verursachte Erkrankungen von Mensch und Tier besitzen. Vorzugsweise steht R1 für einen geradkettigen oder verzweigten, durch ein Chloratom substituierten Alkylrest mit 3 bis 4 Kohlenstoffatomen oder einen unsubstituierten Alkylrest.mit 4 bis 5 Kohlenstoffatomen. Insbesondere bevorzugt sind solche Verbindungen der Formel I, in denen einer der Reste R2 und R3 für Wasserstoff und der andere in 6-Stellung des- Ringsystems steht. In diesem Fall steht zweckmäßig der von Wasserstoff verschiedene Rest R2 oder R3 für eine Methyl- oder eine Äthylgruppe.It has now surprisingly been found that new 1-hydroxybenzo-2,3,1-diazaborines of the formula where R1 is a straight-chain or branched alkyl radical, optionally substituted by 1 - 3 halogen atoms, preferably chlorine atoms, or an alkenyl radical with 2 to 5 carbon atoms, R2 and R3 are identical or different and for alkyl radicals with 1 to 4 carbon atoms or for fluorine, chlorine atoms or bromine atoms, where at most one of the radicals R2 and R3 can also be hydrogen, and R4 is a hydrogen atom or a pharmaceutically acceptable cation, preferably a .P, alkali metal cation, with very low toxicity, high activity against gram-negative germs or as a result have caused diseases in humans and animals. R1 is preferably a straight-chain or branched alkyl radical having 3 to 4 carbon atoms substituted by a chlorine atom or an unsubstituted alkyl radical having 4 to 5 carbon atoms. Particularly preferred compounds of the formula I are those in which one of the radicals R2 and R3 is hydrogen and the other is in the 6-position of the ring system. In this case, the radical R2 or R3 other than hydrogen is expediently a methyl or an ethyl group.
Steht R1 für einen Alkenylrest, so handelt es sich dabei vorzugsweise um einen Vinyl-, Crotyl-, Allyl- oder Methallylrest.If R1 stands for an alkenyl radical, this is preferably a vinyl, crotyl, allyl or methallyl radical.
Die Verbindungen der Formel I zeichnen sich dadurch aus, daß sie ein breites Wirkungsspektrum gegenüber gramnegativen Krankheitserregern besitzen und sowohl bei oraler als auch bei peroraler Verabreichung wirksam sind. Beispielsweise beträgt die DC 50 (-das ist diejenige Dosis in mg Substanz/kg Hörpergewicht, deren Verabrichung bei 50 % der Versuchstiere Heilung der Infektion bewirkt) für das 1-Hydroxy-2(3'-chlor-npropyl-sulfonyl)-6-methyl-benzo-2,3, 1-diazaborin bei peroraler bzw. subkutaner Verabreichung in Form der Natriumverbindung (R4 = Na) an mit verschiedenen Infektionserregern infizierten Mäusen: Erreger DC 50 (mg/kg) bei Verabreichung oral subkutan E. coli 9,8 8,8 Proteus mirabilis 9,15 1 7,45 Froteus vulgaris 8,6 8,4 Klebsiella aeruginosa 9,15 6,95 Ähnliche Versuchsergebnisse wurden auch mit weiteren Verbindungen der Formel I erhalten.The compounds of the formula I are distinguished by the fact that they are a have a broad spectrum of activity against gram-negative pathogens and are effective when administered orally as well as perorally. For example the DC is 50 (-that is the dose in mg substance / kg body weight whose Administration causes the infection to cure in 50% of the test animals) for 1-hydroxy-2 (3'-chloro-npropyl-sulfonyl) -6-methyl-benzo-2,3, 1-diazaborine for peroral or subcutaneous administration in the form of the sodium compound (R4 = Na) on mice infected with various infectious agents: Pathogen DC 50 (mg / kg) when administered orally subcutaneously E. coli 9.8 8.8 Proteus mirabilis 9.15 1 7.45 Froteus vulgaris 8.6 8.4 Klebsiella aeruginosa 9.15 6.95 Similar test results were also obtained with other compounds of the formula I.
Die erfindungsgemäßen Verbindungen werden dadurch erhalten, daß man eine Verhindung der allgemeinen Formel II, worin R1 bis R3 die gleiche Bedeutung wie oben haben, mit einem ßortrihalogenid umsetzt und das unmittelbar entstandene Reaktionsprodukt zur Freisetzung der 1-Hydroxy-Gruppe hydrolysiert. Diese Umsetzung erfolgt zweckmäßig in Gegenwart eines polaren Lösungs- oder Suspensionsmittels, insbesondere in Gegenwart eines halogenierten Kohlenwasserstoffes. Als Lösungsmittel kommen also beispielsweise Dichlormethan, Chloroform oder Tetrachlorkohlenstoff, aber auch Hexan, Cyclohexan, Benzol, Toluol, Chlorbenzol und weitere Lösungsmittel in Betracht. Als ßortrihalogenid eignet sich vor allem ßortribromid, aber auch Bortrijodid oder -trichlorid. Die Umsetzung kann bei etwa Raumtemperatur bis ca. 1000C, vorzugsweise bei mäßig erhöhten Temperaturen, wie etwa 40 - 80°C, durchgeführt werden. Gegebenenfalls kann man in Gegenwart eines die Ringschlußreaktion fördernden Katalysators wie z. F. in Gegenwart eines Überschusses an Bortrihalogenid oder auch in Gegenwert von Metallhalogeniden wie Aluminiumchlorid, Zinn-, Zink- oder Eisenchlorid usw. arbeiten.The compounds according to the invention are obtained by preventing the general formula II, wherein R1 to R3 have the same meaning as above, reacts with a ßortrihalogenid and hydrolyzed the reaction product immediately formed to liberate the 1-hydroxy group. This reaction is expediently carried out in the presence of a polar solvent or suspending agent, in particular in the presence of a halogenated hydrocarbon. Suitable solvents are, for example, dichloromethane, chloroform or carbon tetrachloride, but also hexane, cyclohexane, benzene, toluene, chlorobenzene and other solvents. As a ßortrihalogenid especially ßortribromid, but also boron triiodide or trichloride is suitable. The reaction can be carried out at about room temperature to about 1000.degree. C., preferably at moderately elevated temperatures, such as about 40-80.degree. Optionally, you can in the presence of a ring closure reaction promoting catalyst such. F. work in the presence of an excess of boron trihalide or the equivalent of metal halides such as aluminum chloride, tin, zinc or iron chloride, etc.
Die Verbindungen der Formel II lassen sich leicht durch Umsetzung eines Benzaldehydes der Formel III, worin R2 und R3 die gleiche Bedeutung wie oben haben, mit einem Sulfosäurehydrazid der Formel IV H2N - NH - SOz - R1 IV worin R1 die gleiche Bedeutung wie oben hat, erhalten. Gegebenenfalls kann vor der Umsetzung mit dem Bortrihalogenid auf die Isolierung der Verbindung der Formel II verzichtet und das Reaktionsgemisch eines Aldehyds der Formel III mit dem Sulfosäurehydrazid der Formel IV, vorzugsweise nach Entfernung des bei der Reaktion gebildeten Wassers, direkt mit dem Bortrihalogenid zur Umsetzung gebracht werden.The compounds of the formula II can easily be prepared by reacting a benzaldehyde of the formula III, in which R2 and R3 have the same meaning as above, with a sulfonic acid hydrazide of the formula IV H2N - NH - SOz - R1 IV in which R1 has the same meaning as above. If necessary, isolation of the compound of the formula II can be dispensed with before the reaction with the boron trihalide and the reaction mixture of an aldehyde of the formula III with the sulfonic acid hydrazide of the formula IV, preferably after removal of the water formed during the reaction, can be reacted directly with the boron trihalide .
Die Verbindungen der Formel I können auch erhalten werden, indem man eine Verbindung der Formel V, in der R2 und R3 dieselbe Bedeutung wie oben haben, mit einem Sulfosäurehydrazid der Formel IV umsetzt.The compounds of the formula I can also be obtained by adding a compound of the formula V, in which R2 and R3 have the same meaning as above, is reacted with a sulfonic acid hydrazide of the formula IV.
In einer so erhaltenen Verbindung der Formel I kann dann das Wasserstoffatom in der mit dem Boratom verbundenen Hydroxylgruppe gegen ein Kation ausgetauscht werden. Z. B. kann man Lösungen derartiger salzartiger Verbindungen dadurch herstellen, daß man eine Verbindung der Formel 1, in der R3 für Wasserstoff steht, mit verdünnter (z. B. D,1 bis ca. 2n) Natron-oder Kalilauge'mit wässrigen Amoniaklösungen oder mit Lösungen von organischen Basen wie z. B. Triäthylamin, Äthylendiamin usw. In a compound of the formula I obtained in this way, the hydrogen atom can then exchanged for a cation in the hydroxyl group connected to the boron atom will. For example, solutions of such salt-like compounds can be prepared by that a compound of formula 1, in which R3 is hydrogen, with dilute (e.g. D, 1 to approx. 2n) sodium or potassium hydroxide solution with aqueous ammonia solutions or with solutions of organic bases such as. B. triethylamine, ethylenediamine, etc.
für kurze Zeit schüttelt. Insbesondere die Alkalisalze lassen sich aus diesen Lösungen leicht z. B. durch Gefriertrocknung oder durch Verwendung von mit Wasser mischbaren Lösungsmitteln, in denen die Salze nicht löslich sind, in fester Form gewinnen. shakes for a short time. In particular, the alkali salts can be from these solutions easily z. B. by freeze drying or by using water-miscible solvents in which the salts are not soluble, in gain solid form.
Für die Therapie gramnegativer Infektionen bei Mensch und Tier "' können die Verbindungen der Formel I als solche oder nach Einarbeitung in an sich bekannte Zubereitungsformen wie Tabletten, Dragees, Sirupe, Tropfen, Injektionslösungen usw. verwendet werden. Derartige Arzneimittel, die eine Verbindung der Formel I z. B. in einer Menge von 50 - 500 mg pro Einzeldosis enthalten, gehoren ebenfalls zum Gegenstand der Erfindung. For the therapy of gram-negative infections in humans and animals "' The compounds of the formula I can be used as such or after incorporation into them known forms of preparation such as tablets, coated tablets, syrups, drops, injection solutions etc. can be used. Such medicaments containing a compound of formula I z. B. contained in an amount of 50 - 500 mg per single dose, are also included the subject of the invention.
Die folgenden Beispiele erläutern die Herstellung der Verbindungen näher. Bei der Durchführung wurde auf die Erzielung optimaler Ausbeuten kein Wert gelegt. Alle Temperaturangaben sind unkorrigiert. The following examples illustrate the preparation of the compounds closer. In carrying out this process, no value was placed on achieving optimal yields placed. All temperature data are uncorrected.
Beispiel 1 Zu einer siedenden Losung von 0,4 g wasserfreiem FeCl3 in 200 ml Methylenchlorid läßt man unter intensivem Rühren in einer Stickstoffatmosphäre gleichzeitig eine Lösung von 9,0 g m-Tolyl-isobutylsulfonylhydrazon in 500 ml Methylenchlorid sowie eine Lösung von 10,0 ml Bortribromid in 30 ml Methylenchlorid in 2 Minuten zufließen. Das Gemisch wird 5 Minuten unter Rückfluß erwärmt und aann schnell auf 0 - 50C abgekühlt.Example 1 To a boiling solution of 0.4 g of anhydrous FeCl3 in 200 ml of methylene chloride is left with vigorous stirring in a nitrogen atmosphere at the same time a solution of 9.0 g of m-tolyl-isobutylsulfonylhydrazone in 500 ml of methylene chloride and a solution of 10.0 ml of boron tribromide in 30 ml of methylene chloride in 2 minutes flow in. The mixture is refluxed for 5 minutes and then quickly absorbed Cooled down to 0 - 50C.
Nach dem Abkühlen gießt man auf 300 ml Eiswasser, trennt die wäßrige Phase ab -und wäscht die org. Phase zweimal mit je 50 ml Wasser. Die org. Phase wird anschließend dreimal mit je 200 ml 1nNaOH extrahiert und der alkalische wäßrige Extrakt mit Sal-zsäure angesäuert. Man schüttelt die saure wäßrige Phase mit Methylenchlorid aus, trocknet den organischen Extrakt mit Magnesiumsulfat und dampft ein, wobei das Produkt als Oel anfällt. Das ölige Produkt wird unter Erwärmen in wenig Äthanol aufgenommen. Beim Erkalten kristallisiert das 1-Hydroxy-Z-isobutylsulfonyl-6-methyl-benzo-Z,3,1-diazaborin aus.After cooling, it is poured into 300 ml of ice water and the aqueous solution is separated Phase off and washes the org. Phase twice with 50 ml of water each time. The org. phase is then extracted three times with 200 ml of 1N NaOH each time and the alkaline aqueous Extract acidified with hydrochloric acid. The acidic aqueous phase is shaken with methylene chloride off, the organic extract dries with magnesium sulfate and evaporated, whereby the product is obtained as an oil. The oily product is heated in a little ethanol recorded. On cooling, the 1-hydroxy-Z-isobutylsulfonyl-6-methyl-benzo-Z, 3,1-diazaborine crystallizes the end.
Ausbeute: 33 % der Theorie Schmp.: 89 - 900C Durch Neutralisation mit der berechneten Menge 2nNaOH und anschließende Gefriertrocknung der wäßrigen Lösung wurde das Natriumsalz erhalten.Yield: 33% of theory, melting point: 89-900 ° C. By neutralization with the calculated amount of 2nNaOH and subsequent freeze-drying of the aqueous Solution, the sodium salt was obtained.
Beispiel 2 Ausgehend von dem 3-Chlorpropansulfonylhydrazon des m-Tolylaldehyds und Bortribromid wurde analog dem in Beispiel 1 beschriebenen Vorgehen das nyl)-6-methyl-benzo-Z,3,1-diazaborin hergestellt.Example 2 Starting from the 3-chloropropanesulfonylhydrazone of m-tolylaldehyde and boron tribromide was analogous to the procedure described in Example 1, the nyl) -6-methyl-benzo-Z, 3,1-diazaborine manufactured.
Ausbeute: 50 % der Theorie Schmp.: 128 - 13Q0C.Yield: 50% of theory, melting point: 128-13 ° C.
Durch Neutralisation mit der berechneten Menge 2nNaOH und anschließende Gefriertrocknung der wäßrigen Lösung wurde das Natriumsalz erhalten.By neutralization with the calculated amount of 2nNaOH and then Freeze-drying the aqueous solution gave the sodium salt.
Beispiel 3 Man verfährt wie im Beispiel 1 beschrieben, verwendet jedoch das n-Propylsulfonylhydrazon des 3-Fluorbenzaldehyds und Bortribromid, wobei man das 1-Hydroxy-2-(n-propylsulfonyl)-6-fluor-benzo-2,3,1-diazaborin erhält. Durch Umfällen aus Toluol/Petroläther (1:3) wird es in reiner Form gewonnen.Example 3 The procedure described in Example 1 is repeated, but using the n-propylsulfonylhydrazone of 3-fluorobenzaldehyde and boron tribromide, whereby one 1-hydroxy-2- (n-propylsulfonyl) -6-fluoro-benzo-2,3,1-diazaborine is obtained. By Reprecipitation from toluene / petroleum ether (1: 3) it is obtained in pure form.
Ausbeute: 55,6 % Schmp.: 79 - B1OC Durch Behandeln mit der berechneten Menge 2nNaOH und anschließende Gefriertrocknung der wäßrigen Lösung wurde das Natriumsalz erhalten.Yield: 55.6% m.p .: 79 - B1OC By treating with the calculated The amount of 2N NaOH and subsequent freeze-drying of the aqueous solution became the sodium salt obtain.
Nach den vorstehend in Beschreibung und Beispielen geschilderten Verfahren kann man z. B. auch folgende Verbindungen der Formel I herstellen: 1-Hydroxy-2-(3'-chlor-n-propylsulfonyl)-6-fluor-benzo-2,3,1-diazaborin 1-Hydroxy-2-allylsulfonyl-6-methyl-henzo-2,3,1-diazaborin 1-Hydroxy-2-(3'-chlor-n-propylsulfonyl)-5,7-dimethyl-benzo-2,3, 1-diazaborin 1-Hydroxy-2-(3'-brom-n-propylsulfonyl)-6-methyl-benzo-2,3,1-diazaborin 1-Hydroxy-2-(isobutylsulfonyl,-6-fluor-benzo-Z,3,1-diazaborin 1-Hydroxy-2-(α-chloräthylsulfonyl)-6-methyl-benzo-2,3,1-diazaborin 1-Hydroxy-Z-(crotylsulfonyl)-6-methyl-Lenzo-Z,3,1-diazaDorin 1-Hydroxy-2-(vinylsulfonyl)-5-3thyl-benzo-Z,3,1-diaz2horin 1-Hdroxy-2-(methallylsulfonyl)-6-methyl-benzo-2, 3, 1-diazaborin 1-Hydroxy-2-(isobutylsulfonyl)-6-chlor-benzo-2,3,1-diazaborin und weitere entsprechende Verbindungen sowie deren Salze mit Basen.According to the methods outlined above in the description and examples you can z. B. also produce the following compounds of formula I: 1-Hydroxy-2- (3'-chloro-n-propylsulfonyl) -6-fluoro-benzo-2,3,1-diazaborine 1-Hydroxy-2-allylsulfonyl-6-methyl-henzo-2,3,1-diazaborine 1-Hydroxy-2- (3'-chloro-n-propylsulfonyl) -5,7-dimethyl-benzo-2,3, 1-diazaborine 1-hydroxy-2- (3'-bromo-n-propylsulfonyl) -6-methyl-benzo-2,3,1-diazaborine 1-Hydroxy-2- (isobutylsulfonyl, -6-fluoro-benzo-Z, 3,1-diazaborine 1-Hydroxy-2- (α-chloroethylsulphonyl) -6-methyl-benzo-2,3,1-diazaborine 1-hydroxy-Z- (crotylsulphonyl) -6-methyl-Lenzo-Z, 3,1-diazaDorine 1-Hydroxy-2- (vinylsulfonyl) -5-3thyl-benzo-Z, 3,1-diaz2horin 1-Hydroxy-2- (methallylsulfonyl) -6-methyl-benzo-2, 3, 1-diazaborine, 1-hydroxy-2- (isobutylsulfonyl) -6-chloro-benzo-2,3,1-diazaborine and further corresponding compounds and their salts with bases.
Claims (11)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782811132 DE2811132A1 (en) | 1978-03-15 | 1978-03-15 | 1-Hydroxy-2-sulphonyl-benzo-2,3,1-diaza:borine derivs. - useful as antibacterial agents against gram negative bacteria |
| US05/928,589 US4199573A (en) | 1976-07-26 | 1978-07-27 | Diazaborines and drug compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782811132 DE2811132A1 (en) | 1978-03-15 | 1978-03-15 | 1-Hydroxy-2-sulphonyl-benzo-2,3,1-diaza:borine derivs. - useful as antibacterial agents against gram negative bacteria |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2811132A1 true DE2811132A1 (en) | 1979-09-20 |
Family
ID=6034438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19782811132 Withdrawn DE2811132A1 (en) | 1976-07-26 | 1978-03-15 | 1-Hydroxy-2-sulphonyl-benzo-2,3,1-diaza:borine derivs. - useful as antibacterial agents against gram negative bacteria |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2811132A1 (en) |
-
1978
- 1978-03-15 DE DE19782811132 patent/DE2811132A1/en not_active Withdrawn
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