DK151624B - Analogifremgangsmaade til fremstilling af et 1-ethyl-6,8-difluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinolinderivat eller farmaceutisk acceptable salte deraf. - Google Patents
Analogifremgangsmaade til fremstilling af et 1-ethyl-6,8-difluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinolinderivat eller farmaceutisk acceptable salte deraf. Download PDFInfo
- Publication number
- DK151624B DK151624B DK098582A DK98582A DK151624B DK 151624 B DK151624 B DK 151624B DK 098582 A DK098582 A DK 098582A DK 98582 A DK98582 A DK 98582A DK 151624 B DK151624 B DK 151624B
- Authority
- DK
- Denmark
- Prior art keywords
- compound
- formula
- piperazinyl
- dihydro
- ethyl
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 6
- PRZQONJSCXATCT-UHFFFAOYSA-N 1-ethyl-6,8-difluoro-7-piperazin-1-ylquinolin-4-one Chemical class C(C)N1C=CC(C2=CC(=C(C(=C12)F)N1CCNCC1)F)=O PRZQONJSCXATCT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 32
- -1 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) quinazoline derivative Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 241000894006 Bacteria Species 0.000 description 7
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 7
- 229960000210 nalidixic acid Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 6
- 229960001732 pipemidic acid Drugs 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000192125 Firmicutes Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- VDHHZWTYFFZYBM-UHFFFAOYSA-N 1-(4-nitrobenzyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CN1CCNCC1 VDHHZWTYFFZYBM-UHFFFAOYSA-N 0.000 description 1
- YHRXPOLYCUTZAM-UHFFFAOYSA-N 1-ethyl-6,8-difluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 YHRXPOLYCUTZAM-UHFFFAOYSA-N 0.000 description 1
- LJTUWMSADLDOBG-UHFFFAOYSA-N 1-ethyl-6,8-difluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 LJTUWMSADLDOBG-UHFFFAOYSA-N 0.000 description 1
- JZHSDNJZRQZNPJ-UHFFFAOYSA-N 1-ethyl-6,8-difluoro-7-[4-[(4-nitrophenyl)methyl]piperazin-1-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N(CC1)CCN1CC1=CC=C([N+]([O-])=O)C=C1 JZHSDNJZRQZNPJ-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000589291 Acinetobacter Species 0.000 description 1
- 241000588986 Alcaligenes Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000588919 Citrobacter freundii Species 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000588772 Morganella morganii Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241001221452 Staphylococcus faecalis Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 238000010227 cup method (microbiological evaluation) Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000012543 microbiological analysis Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 1
- 229960004444 piromidic acid Drugs 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 229940115939 shigella sonnei Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940098232 yersinia enterocolitica Drugs 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
i
DK 151624 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af et 1-ethyl-6,8-difluor-1,4-dihydro-4-oxo-7-(l-piperazinyl)-quinolinderivat eller farmaceutisk acceptable salte deraf, som har en kraftig antibakteriel virkning.
5 Antibakterielle midler såsom nalidixidsyre, piromididsyre og pipemi-didsyre har vist sig at være særdeles effektive i behandlingen af infektioner, der skyldes gramnegative bakterier, men sådanne midler har den alvorlige ulempe, at de kun har svag virkning mod de fleste grampositive bakterier. Forbindelsen ifølge den foreliggende opfindelse 10 er. særlig nyttig, fordi den har kraftig antibakteriel virkning mod såvel grampositive som gramnegative bakterier.
Den hidtil ukendte forbindelse, der er fremstillet ifølge den foreliggende opfindelse, er et quinolincarboxylsyrederivat med formlen I
O
»I
WCOOH
* w W F ' C2H5 eller de farmaceutisk tolerable salte deraf.
15 Forbindelsen med formlen I er særdeles effektiv i behandlingen af infektioner, der skyldes grampositive og gramnegative bakterier, og det har vist sig, at forbindelsen med formlen I heldigvis delvis meta-boliseres til 1-ethyl-6,8-difluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinolin-3-carboxylsyre, der har en fremragende virkning mod gram-20 negative bakterier, når den administreres til dyr.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved hydrogenering af en forbindelse med formlen II
DK 151624B
2
O
Π
/ \ ^ \ \ II
°2N-( y CH2 -Nv > '-' i? C2H5
Hydrogeneringen foretages ved katalytisk hydrogenering med palladium på kul, Raney-nikkei, platinoxid eller lignende som katalysator i et inert opløsningsmiddel såsom alkoholer, ethere eller organiske syrer, eller ved reaktion med metal såsom jern, tin eller zink, eller 5 halogenidet eller sulfatet i nærværelse af en syre såsom saltsyre, svovlsyre eller eddikesyre.
Udgangsmaterialet med formlen II fås ved reaktion af en forbindelse med formlen ill 0
II
F-p jj-COOH
F C2H5
hvor X er en fraspaltelig enhed såsom halogen eller sulfonyloxy, med 10 N-(p-nitrobenzyl)piperazin eller ved behandling af en forbindelse med formlen V
O
ti • \ v
HN N-^ J
W T ? F C2H5
DK 151624 B
3
med en forbindelse med formlen VI
°2N^ y>CH2X< VI
hvor X’ er halogen.
Saltene såsom methansulfonat, benzensulfonat, acetat, maleat, citrat, malat, lactat, hydrochlorid, sulfat, phosphat, natriumsalt, kaliumsalt 5 eller aminsalte af forbindelse I fås på sædvanlig måde.
Forbindelsen med formlen I eller saltet deraf administreres til mennesker eller dyr, sædvanligvis i området på fra 1-100 mg/kg/dag, ad oral eller parenteral vej. Forbindelsen med formlen I eller saltet deraf kan anvendes i form af farmaceutiske præparater såsom tabletter, 10 kapsler, sirupper, injektioner, granuler, pulvere, suppositorier eller emulsioner. De farmaceutiske præparater kan indeholde forbindelsen iblandet en adjuvans og formes på sædvanlig måde.
De følgende eksempler tjener til at belyse opfindelsen.
EKSEMPEL 1 15 En blanding af 6,7 g 1-ethyl-6,8-difluor-1,4-dihydro-4-oxo-7-(1-pipe-razinyl)quinolin-3-carboxylsyre-hydrochlorid, 5,45 g triethylamin, 5,8 g p-nitrobenzylbromid og 200 mi dimethylformamid omrøres ved 90°C i 10,5 timer. Opløsningsmidlet afdampes, og remanensen behandles med vand. Det faste stof filtreres, vaskes med vand, tørres og omkry-20 stalliseres af en blanding af dimethylformamid og ethanol, hvorved fås 6,9 g 1-ethyl-6,8-difluor-1,4-dihydro-7-[4-(p-nitrobenzyl)-1-pipera-zinyl]-4-oxoquinolin-3-carboxylsyre. Smeltepunkt 241-242°C.
DK 151624B
4
Analyse:
Beregnet for C23H22F2N4°5: C 58,47 H 4,69 N 11,86
Fundet: C 58,50 H 4,59 N 11,95 EKSEMPEL 2 5 En blanding af 6,0 g 1-ethyl-6,8-difluor-1,4-dihydro-7-[4-(p-nitro-benzyl)-1-piperazinyl]-4-oxoquinolin-3-carboxylsyre, 150 ml eddikesyre og 1,0 g 5%'s palladium på kul hydrogeneres. Opslæmningen filtreres, og filtratet inddampes til tørhed. Remanensen behandles med vand, neutraliseres med en vandig natriumhydroxidopløsning og 10 ekstraheres med dichlormethan. Den organiske fase tørres og inddampes. Remanensen chromatograferes på silicagel. Ved eluering med en blanding af chloroform og ethanol (20:1) og omkrystallrsering af en blanding af chloroform og ethanol fås 7-[4-(p-aminobenzyl)-1-pipera-zinyl]-l-ethyl-6,8-difluor-l,4-dihydro-4-oxoquinoIin-3-carboxylsyre.
15 Smeltepunkt 220-221 °C.
Analyse:
Beregnet for C23H24F2N403: C 62,43 H 5,47 N 12,66
Fundet: C 62,53 H 5,36 N 12,68
Forsøg 1: Antibakteriel virkning (in vitro) 20 Den mindste inhiberende koncentration (MIC) af forbindelsen med formlen I mod standardstammer af grampositive og gramnegative bakterier bestemmes ved en agarfortyndingsteknik (Japan Society of Society of Chemotherapy's standardmetode).
Som vist i tabel 1 har nalidixidsyre og pipemididsyre hovedsagelig 25 antibakteriel virkning over for gramnegative bakterier og er uvirksomme over for mange stammer af grampositive bakterier. Derimod er forbindelsen med formlen I mere virksom end nalidixidsyre og pipemididsyre mod såvel grampositive som gramnegative bakterier. Især er den antibakteriel le virkning af forbindelsen med formlen I mere virk-
DK 151624B
5 som mod grampositive bakterier, der indeholder Streptococcus spp., som ikke påvirkes af nalidixidsyre og pipemididsyre.
Forsøg 2: Antibakteriel virkning (in vivo)
Den antibakterielle virkning in vivo af forbindelsen med formlen I 5 bestemmes ved systemisk infektion af mus.
Den systemiske infektion frembringes i hanmus ICR (kropsvægt 19 ± 2 g) ved at pode intraperitonealt med Staphylococcus aureus Smith og E. col i ML4707.
Forbindelserne administreres oralt i delte doser ved 0 og 4 timer efter 10 infektion. Lægemidlernes terapeutiske virkning bedømmes ud fra det antal mus, der overlever efter 7 dages observation. Der foretages en sammenligning af antibakteriel aktivitet in vivo på grundlag af den gennemsnitlige virkningsfulde dosis (EDcjq) beregnet ved Litchfield's og Wilcoxon’s metode.
15 Som vist i tabel 2 har den antibakterielle virkning in vivo af forbindelsen med formlen I signifikant større virkning end nalidixidsyrens og pipemididsyrens virkning mod S. aureus Smith. Virkningen af forbindelsen med formlen I er 172 gange større end nalidixidsyrens virkning og 62 gange større end pipemididsyrens virkning.
20 Forsøg 3: Vævsniveauer af forbindelsen med formlen I efter en enkelt oral administration på 50 mg/kg i mus og rotter Vævsniveauerne af forbindelsen med formlen I bestemmes ved mikrobiologisk analyse, der benytter tyndtlags-kopmetoden med Bacillus subtilis ATCC6633 som forsøgsorganisme. Serum- og vævsniveauerne 25 af forbindelsen med formlen I beregnes ud fra en standard kurve, der fremstilles i henholdsvis forsøgsdyreartens normale serum og M/15-phosphatpuffer (pH-værdi 7,5). Forsøgsresultaterne vises i tabel 3.
6 DK 1516248
Efter en enkelt oral administration på 50 mg/kg af forbindelsen med formlen I til mus og rotter nås et maksimalt serumniveau på henholdsvis 8,6 og 5,3 yg/ml inden for 30-60 minutter.
Niveauet af forbindelsen med formlen I i lunger, levér og nyre er 5 højere end serumniveauerne hos begge arter.
Evnen hos forbindelsen med formlen I til at overføres i væv er fremragende.
Forsøg 4: Akut toxicitet af forbindelsen med formlen I
Den akutte toxicitet af forbindelsen med formlen I undersøges i mus 10 (ICR-stamme, 7 uger gamle). Observationsperioden er 7 dage efter en enkelt oral og intravenøs administration.
Som vist i tabel 4 har forbindelsen med formlen I en lav toxicitet.
Tabel 1
Antibakteriel virkning in vitro af nærværende forbindelse 15____—
Organisme MIC (ug/ml) ** ***
Gram Nærvæ- Metabo- ΝΑ PPA
* rende lit forbin- 20 delse
Bacillus subtilis PCI 219 + 0,1 0,2 6,25 6,25
Staphylocnr „us 25 aureus 20bP + 0,1 0,78 100 25 S. aureus 1ID670 (Terajima) + 0,2 0,78 >100 25 S. epidermidis IID866 + 0,2 0,78 30 Streptococcus pyogenes 1ID692 + 0,78 3,13 >100 >100 S. pyogenes S-8 + 0,78 12,5 >100 >100
DK 151624B
7
Tabel 1 fortsat S. pneumoniae IID552 ♦ 0,39 6,25 >100 >100 S. faecalis 5 IID682 + 0,78 3,13 >100 >100 E. coii NIHJ JC-2 - 0,20 0,05 3,13 1,56 E. coli ATCC10536 - 0,39 0,05 3,13 1,56
Haemophilus influenzae JID986 - 0,20 0,025 1,56 3,13 10 Klebsiella pneumoniae IF03512 - 0,1 0,05 1,56 1,56
Proteus vulgaris IF03167 - 1,56 0,05 3,13 3,13 P. mirabilis IID994 - 1,56 0,05 15 P. morganii IID602 - 1,56 0,1
Enterobacter cloacae IID977 - 1,56 0,1
Citrobacter freundii I1D976 - 1,56 0,1 20 Shigella sonnei IID969 - 0,39 0,05 1,56 1,56
Salmonella enteri- tidis IID604 - 1,56 0,1 12,5 12,5
Yersinia entero- 25 colitica IID981 - 1,56 0,1
Serratia marcescens IID618 - 3,13 0,1
Pseudomonas aeruginosa V-1 - 12,5 0,78 100 12,5 30 P. aeruginosa IF012689 - 25 1,56 >100 25
Acinetobacter enitratus IID876 -. 0,78 0,78
Alcaligenes faeca- 35 lis 0104002 - 3,13 0,78 g
Indpodningsstørrelse: 10 celler/ml
Tabel 2
DK 151624B
8
Antibakteriel virkning in vivo af nærværende forbindelse
Stamme Infektions- Forbindelse MIC ^50 dosis (vg/ml) (mg/kg) 5 (celler/dyr) 5
Staphylococcus 2,4x10 nærværende aureus Smith (i BHl - forbindelse 0,05 3,7 holdigt NA 25 635 10 mucin) PPA 12,5 231 7 E. coli ML4707 1,2x10 nærværende (i salt- forbindelse 0,39 13,8 opløs- NA 3,13 38,3 15 ning PPA 1,56 38,9 * = hjerne-hjerte infusion ** = nalidixidsyre *** = pipemididsyre 20 Tabel 3 Vævsniveauer af nærværende forbindelse
Koncentration (vg/ml)
Dyr Væv Tid efter administration (timer) 25 0,5 1,0 2,0 4,0 6,0 serum 8,6 6,5 5,0 2,7 1,8 lunge 12,8 9,5 5,5 4,3 2,8 mus lever 22,5 17,5 12,0 9,0 5,8 30 -r/re 13,0 13,0 7,8 4,6 4,6 serum 4,8 5,3 1,2 0,2 0,2 lunge 6,0 8,6 2,1 0,6 ND* rotte lever 14,0 15,4 6,2 2,2 0,8 35 nyre 6,6 6,8 2,7 1,0 0,3 ( * = ikke påvist
Claims (1)
10 Analogifremgangsmåde til fremstilling af et 1-ethyl-6,8-difluor-l,4-dihydro-4-oxo-7-(l-piperazinyl)quinazolinderivat med formlen I 0 il WCOOH , F Ks eller farmaceutisk acceptable salte deraf, kendetegnet ved hydrogenering af en forbindelse med 15 formlen II 0 _ FfY>C00H v/V,_n\ 11 2 2 \__/ ; . C2H5 hvorefter forbindelsen om ønsket omdannes til et farmaceutisk acceptabelt salt deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56032274A JPS57145862A (en) | 1981-03-06 | 1981-03-06 | Quinolinecarboxylic acid derivative |
| JP3227481 | 1981-03-06 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK98582A DK98582A (da) | 1982-09-07 |
| DK151624B true DK151624B (da) | 1987-12-21 |
| DK151624C DK151624C (da) | 1988-06-27 |
Family
ID=12354397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK098582A DK151624C (da) | 1981-03-06 | 1982-03-05 | Analogifremgangsmaade til fremstilling af et 1-ethyl-6,8-difluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinolinderivat eller farmaceutisk acceptable salte deraf. |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4429127A (da) |
| JP (1) | JPS57145862A (da) |
| KR (1) | KR880000689B1 (da) |
| AR (1) | AR228085A1 (da) |
| AT (1) | AT382146B (da) |
| AU (1) | AU544761B2 (da) |
| BE (1) | BE892388A (da) |
| CA (1) | CA1215986A (da) |
| CH (1) | CH649290A5 (da) |
| DE (1) | DE3205655A1 (da) |
| DK (1) | DK151624C (da) |
| ES (1) | ES510163A0 (da) |
| FR (1) | FR2501204B1 (da) |
| GB (1) | GB2094305B (da) |
| HU (1) | HU187449B (da) |
| IN (1) | IN155968B (da) |
| IT (1) | IT1150198B (da) |
| MX (1) | MX167628B (da) |
| NL (1) | NL192618C (da) |
| PH (1) | PH17166A (da) |
| SE (1) | SE446984B (da) |
| ZA (1) | ZA821027B (da) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
| JPS59155381A (ja) * | 1983-02-22 | 1984-09-04 | Kyorin Pharmaceut Co Ltd | ベンゾキノリジンカルボン酸誘導体及びその製造法 |
| DE3308908A1 (de) * | 1983-03-12 | 1984-09-13 | Bayer Ag, 5090 Leverkusen | Bakterizide mittel |
| DE3318145A1 (de) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| NZ208470A (en) * | 1983-07-18 | 1988-06-30 | Abbott Lab | 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives and antibacterial compositions containing such |
| AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| US4774246A (en) * | 1984-01-26 | 1988-09-27 | Abbott Laboratories | Quinoline antibacterial compounds |
| EP0154780B1 (en) * | 1984-01-26 | 1990-04-11 | Abbott Laboratories | Quinoline antibacterial compounds |
| DE3409922A1 (de) * | 1984-03-17 | 1985-09-26 | Bayer Ag, 5090 Leverkusen | 1,7-diamino-1,4-dihydro-4-oxo-3-(aza)chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie ihre verwendung bei der bekaempfung bakterieller erkrankungen |
| DE3571974D1 (en) * | 1984-12-06 | 1989-09-07 | Pfizer | Substituted dihydroquinolone carboxylic acids, anti-bacterial compositions containing them |
| US4851535A (en) * | 1985-01-23 | 1989-07-25 | Toyama Chemical Co., Ltd. | Nicotinic acid derivatives |
| US4755513A (en) * | 1985-01-30 | 1988-07-05 | Otsuka Pharmaceutical Company, Limited | Antimicrobial 1-substituted phenyl-4-oxoquinoline-3-carboxylic acid compounds |
| DE3504643A1 (de) * | 1985-02-12 | 1986-08-14 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-1,4-dihydro-4-oxo-7-(4-(2-oxo-1,3-dioxol-4-yl-methyl)-1-piperazinyl)-3-chinolin carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| US4689325A (en) * | 1985-12-23 | 1987-08-25 | Abbott Laboratories | Isoxazolo-pyrido-phenoxazine and isothiazolo-pyrido-phenoxazine derivatives |
| US4687770A (en) * | 1985-12-23 | 1987-08-18 | Abbott Laboratories | Isoxazolo-pyrido-benzoxazine and isothiazolo-pyrido-benzoxazine derivatives |
| US4940710A (en) * | 1986-01-17 | 1990-07-10 | American Cyanamid Company | 7-(substituted)piperazinyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| US4692454A (en) * | 1986-02-03 | 1987-09-08 | Warner-Lambert Company | Opthalmic use of quinolone antibiotics |
| CA2114981A1 (en) | 1993-02-09 | 1994-08-10 | Kazumi Ogata | Quinolonecarboxylic acid derivatives |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5312889A (en) | 1976-07-22 | 1978-02-04 | Dainippon Pharmaceut Co Ltd | P-aminobenzylpiperazine dervatives |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| CA1175836A (en) | 1977-09-20 | 1984-10-09 | Marcel Pesson | Production of 1,4-dihydroquinoline-3-carboxylic acid derivatives |
| JPS5845426B2 (ja) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | 置換キノリンカルボン酸誘導体 |
| GB2030562B (en) * | 1978-10-04 | 1982-10-27 | Kyorin Seiyaku Kk | Substituted quinolinecarboxylic acid |
| JPS5653656A (en) | 1979-10-05 | 1981-05-13 | Tanabe Seiyaku Co Ltd | Quinoline derivative and its preparation |
-
1981
- 1981-03-06 JP JP56032274A patent/JPS57145862A/ja active Granted
-
1982
- 1982-02-12 AU AU80451/82A patent/AU544761B2/en not_active Expired
- 1982-02-16 NL NL8200582A patent/NL192618C/nl not_active IP Right Cessation
- 1982-02-17 DE DE19823205655 patent/DE3205655A1/de active Granted
- 1982-02-17 US US06/349,660 patent/US4429127A/en not_active Expired - Lifetime
- 1982-02-17 ZA ZA821027A patent/ZA821027B/xx unknown
- 1982-02-24 IT IT19831/82A patent/IT1150198B/it active
- 1982-03-01 MX MX013592A patent/MX167628B/es unknown
- 1982-03-02 IN IN242/CAL/82A patent/IN155968B/en unknown
- 1982-03-03 PH PH26938-AA patent/PH17166A/en unknown
- 1982-03-04 GB GB8206376A patent/GB2094305B/en not_active Expired
- 1982-03-04 FR FR8203594A patent/FR2501204B1/fr not_active Expired
- 1982-03-04 CH CH1335/82A patent/CH649290A5/de not_active IP Right Cessation
- 1982-03-05 AR AR286639A patent/AR228085A1/es active
- 1982-03-05 HU HU82687A patent/HU187449B/hu unknown
- 1982-03-05 SE SE8201386A patent/SE446984B/sv not_active IP Right Cessation
- 1982-03-05 KR KR8200951A patent/KR880000689B1/ko not_active Expired
- 1982-03-05 DK DK098582A patent/DK151624C/da not_active IP Right Cessation
- 1982-03-05 BE BE0/207490A patent/BE892388A/fr not_active IP Right Cessation
- 1982-03-05 ES ES510163A patent/ES510163A0/es active Granted
- 1982-03-05 CA CA000397700A patent/CA1215986A/en not_active Expired
- 1982-03-08 AT AT0089982A patent/AT382146B/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK98582A (da) | 1982-09-07 |
| MX167628B (es) | 1993-03-31 |
| FR2501204B1 (fr) | 1986-03-28 |
| ATA89982A (de) | 1986-06-15 |
| ES8306484A1 (es) | 1983-06-01 |
| KR880000689B1 (ko) | 1988-04-23 |
| IT1150198B (it) | 1986-12-10 |
| KR830009084A (ko) | 1983-12-17 |
| SE8201386L (sv) | 1982-09-07 |
| ES510163A0 (es) | 1983-06-01 |
| DK151624C (da) | 1988-06-27 |
| GB2094305A (en) | 1982-09-15 |
| GB2094305B (en) | 1984-08-01 |
| PH17166A (en) | 1984-06-13 |
| NL192618C (nl) | 1997-11-04 |
| CH649290A5 (de) | 1985-05-15 |
| JPH0145468B2 (da) | 1989-10-03 |
| HU187449B (en) | 1986-01-28 |
| AR228085A1 (es) | 1983-01-14 |
| NL8200582A (nl) | 1982-10-01 |
| CA1215986A (en) | 1986-12-30 |
| JPS57145862A (en) | 1982-09-09 |
| SE446984B (sv) | 1986-10-20 |
| FR2501204A1 (fr) | 1982-09-10 |
| IN155968B (da) | 1985-04-13 |
| ZA821027B (en) | 1983-01-26 |
| IT8219831A0 (it) | 1982-02-24 |
| DE3205655A1 (de) | 1982-09-23 |
| AT382146B (de) | 1987-01-12 |
| DE3205655C2 (da) | 1988-12-08 |
| AU544761B2 (en) | 1985-06-13 |
| NL192618B (nl) | 1997-07-01 |
| BE892388A (fr) | 1982-09-06 |
| US4429127A (en) | 1984-01-31 |
| AU8045182A (en) | 1982-09-09 |
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| PUP | Patent expired |