SE433215B - PROCEDURE FOR PREPARING 2-PIPERAZINYL-PYRIDO- / 2,3-D / PYRIMIDINE DERIVATIVES - Google Patents
PROCEDURE FOR PREPARING 2-PIPERAZINYL-PYRIDO- / 2,3-D / PYRIMIDINE DERIVATIVESInfo
- Publication number
- SE433215B SE433215B SE7900334A SE7900334A SE433215B SE 433215 B SE433215 B SE 433215B SE 7900334 A SE7900334 A SE 7900334A SE 7900334 A SE7900334 A SE 7900334A SE 433215 B SE433215 B SE 433215B
- Authority
- SE
- Sweden
- Prior art keywords
- compound
- piperazinyl
- ethyl
- acid
- dihydro
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 40
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 241000699670 Mus sp. Species 0.000 description 20
- -1 ethyl halides Chemical class 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 229920000137 polyphosphoric acid Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012670 alkaline solution Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 229940008406 diethyl sulfate Drugs 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- CMTVXHVOYPUGET-UHFFFAOYSA-N 2-piperazin-1-ylpyrimidin-4-amine Chemical compound NC1=CC=NC(N2CCNCC2)=N1 CMTVXHVOYPUGET-UHFFFAOYSA-N 0.000 description 1
- AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102000009338 Gastric Mucins Human genes 0.000 description 1
- 108010009066 Gastric Mucins Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical group 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
POOR QUALITY 10 15 Z0 25 Il90033lv9 Z vari R] betecknar enfvöteatom eller en acylgrupp och RZ beteck- nar en ldgalkylgrupp med I till 0 kolatomer. Z wherein R 1 represents a monohydric atom or an acyl group and R 2 represents a lower alkyl group having 1 to 0 carbon atoms.
Uttrycket "acylgrupp" avser vid användning i föreliggande beskrivning och krav en kolsyra- eller karhoxylsyrnrcst, såsom en lägalkanoylgrupp, såsom formyl, acetyl, trifluoroacetyl eller propionyl, en lâgalkoxikarbonylgrupp, såsom metoxikarbonyl eller etoxikarbonyl, och en fenylsubstituerad lågalkoxikarbonylgrupp, t.ex. bensyloxikarbonyl.The term "acyl group" as used in the present specification and claims means a carbonic or carhoxylic acid radical, such as a lower alkanoyl group, such as formyl, acetyl, trifluoroacetyl or propionyl, a lower alkoxycarbonyl group, such as methoxycarbonyl or ethoxycarbonyl, and a lower alkyl alkoxycarbonyl group e.g. benzyloxycarbonyl.
Föreningen Zl] erhålles ibland såsom hydrater, vilka även innefattas. I föreliggande beskrivning beskrives dess hydrater såsom omfattande av föreningen [1] i fri form, andra än salter av föreningen LII. ' Föreningar som är relativt lika föreningen [1] beskríves i den brittiska patentskriften 1 129 358 (publicerad 2 oktober 1968) och den tyska offentliggörande skriften 2 143 369 (publi- cerad 9 mars 1972) såsom antibakteriella medel.The compound Z1] is sometimes obtained as hydrates, which are also included. In the present specification, its hydrates are described as comprising the compound [1] in free form, other than salts of the compound LII. Compounds which are relatively similar to the compound [1] are described in British Patent Specification 1,129,358 (published October 2, 1968) and German Publication No. 2,143,369 (published March 9, 1972) as antibacterial agents.
Vid arbete i försök att framställa, antíbakteriella medel som är mer användbara än de kända föreningarna har det nu visat sig att genom införing av en piperazingrupp i 2-ställningen på pyrido- 12,3-djpyrimidinkärnan kan man erhålla en förening med karakteris- tisk antibakteriell effekt (speciellt mot Pseudomonas aeruginosa).When working in an attempt to prepare antibacterial agents which are more useful than the known compounds, it has now been found that by introducing a piperazine group in the 2-position on the pyrido-12,3-dipyrimidine nucleus one can obtain a compound with characteristic antibacterial effect (especially against Pseudomonas aeruginosa).
Föreningen [I] syntetiseras på följande sätt: 1:a steget En förening med följande formel // COOR N Z /_\ /Q /I coonz R 1 ~ TV H [W] vari Rloch Rzlwr ovan angiven definition; underkastas intramolekylär ringslutning under upphettning för att ge en mcllanprodukt med följande formel i [H11 wní R, och R, hur ovan angiven definition. 10 20 'TSUUI-Säíe-å Reaktíonen utföres genom upphettning av föreningarna [lv] direkt eller i ett högkokande lösningsmedel, såsom dífenyleter, o-díklorobensen,_difeny1enoxíd, dibutylftalat eller blandningar av dessa. Lämplig upphettningstemperatur är 140-2600C.The compound [I] is synthesized as follows: 1st step A compound of the following formula // COOR N Z / _ \ / Q / I coonz R 1 ~ TV H [W] wherein Rloch Rzlwr the above definition; subjected to intramolecular cyclization during heating to give a millan product of the following formula in [H11 wní R, and R, as defined above. The reaction is carried out by heating the compounds [II] directly or in a high-boiling solvent such as diphenyl ether, o-dichlorobenzene, diphenylene oxide, dibutyl phthalate or mixtures thereof. Suitable heating temperature is 140-2600C.
Det är även möjligt att utföra ringslutningsreaktionen i närvaro av ett konventionellt ringslutningsmedel, sasom polyfosfor- syra, polyfosforsyraalkylester, koncentrerad svavelsyra eller fos- ~ forpentoxíd. Da polrfosforsyra, polyfosforsyraalkylester eller fosforpentoxid användes såsom ringslutningsmedel utföres reaktio- nin vanligtvis i ett lösningsmedel, såsom bensen, dioxan eller dimetylformamid. Då koncentrerad svavelsyra användeds utföres reak- tionen vanligtvis i ett lösningsmedel, såsom ättiksyraanhydrid eller ättiksyra. Naturligtvis kan ringslutningsmedlet, beroende på dess egenskaper, även användas såsom lösningsmedel. Om ring- slutningsmedel användes utföres reaktionen vid relativt låga tem- peraturer. 2:a steget Förening [lll] underkastas vidare alkyleríngsreaktion för att ge en förening med följande formel [II] och R2 har ovan angiven difinition.It is also possible to carry out the cyclization reaction in the presence of a conventional cyclization agent, such as polyphosphoric acid, polyphosphoric acid alkyl ester, concentrated sulfuric acid or phosphorus pentoxide. When polyphosphoric acid, polyphosphoric acid alkyl ester or phosphorus pentoxide is used as the cyclizing agent, the reaction is usually carried out in a solvent such as benzene, dioxane or dimethylformamide. When concentrated sulfuric acid is used, the reaction is usually carried out in a solvent such as acetic anhydride or acetic acid. Of course, depending on its properties, the cyclizing agent can also be used as a solvent. If ring closure is used, the reaction is carried out at relatively low temperatures. 2nd Step Compound [III] is further subjected to alkylation reaction to give a compound of the following formula [II] and R 2 has the above definition.
I denna reaktion kan kända alkyleringsmedel användas. Spe- vari R] ciella exempel omfatta etylhalogenider, såsom etyljodid, och etyl- ostrar, såsom díetylsulfat, etyl-p-toluensulfonat eller trietyl- fosfat.Known alkylating agents can be used in this reaction. Specific examples include ethyl halides, such as ethyl iodide, and ethyl esters, such as diethyl sulfate, ethyl p-toluenesulfonate or triethyl phosphate.
Reaktíonen utföres vanligtvis genom att man bringar före- ningen [lll] att reagera med en stökiometrisk mängd av alkylerings- medlet i ett inert lösningsmedel vid en förhöjd temperatur. Om så önskas kan alkyleringsmedlet användas i överskott. Lösningsmedlet kan vara antingen vattenfritt eller vattenhaltígt. Exempel på lösningsmedel är etanol, dioxan, dimetylformamid, dimetylsulfoxid och vatten. Reaktionen gynnas genom tillsats av en syraacceptor, exempelvis en bas, såsom ett alkalikarbonat, en alkalíhydroxid, en 10 15 U! U1 7900334-9 4 alkalimetallalkoxid, natriumhydrid, trietylamin, bensyltrimetyl- ammoniumhydroxid. Då alkyleríngsmedlet får verka i ett vatten- haltigt lösningsmedel undergâr ibland karboxylsyraesterdelen hydrolys beroende på reaktíonsbetingelserna, och överföres sa- ledes till en fri karboxylsyra. Vidare kan då föreingar med for- meln (III), vari R1 betecknar en väteatom, alkyleras, den N-ety- lerade produkten i 4-ställningen på piperazinkärnan framställas tillsammans med den N-etylerade produkten i 8-ställningen på py- rído- 2,3-d)pyrimidínkärnan. Produkterna kan naturligtvis lätt separeras fran varandra t.ex. genom omkrístallisation. 3:e steget Föreningen [ll] underkastas slutligen hydrolysreaktion och då erhålles föreningen [I] eller dess salt.The reaction is usually carried out by reacting the compound [III] with a stoichiometric amount of the alkylating agent in an inert solvent at an elevated temperature. If desired, the alkylating agent can be used in excess. The solvent may be either anhydrous or aqueous. Examples of solvents are ethanol, dioxane, dimethylformamide, dimethylsulfoxide and water. The reaction is favored by the addition of an acid acceptor, for example a base, such as an alkali carbonate, an alkali hydroxide, a 10 U! Alkali metal alkoxide, sodium hydride, triethylamine, benzyltrimethylammonium hydroxide. When the alkylating agent is allowed to act in an aqueous solvent, the carboxylic acid ester moiety sometimes undergoes hydrolysis depending on the reaction conditions, and is thus converted to a free carboxylic acid. Furthermore, when compounds of formula (III), wherein R 1 represents a hydrogen atom, are alkylated, the N-ethylated product in the 4-position on the piperazine core can be prepared together with the N-ethylated product in the 8-position on the pyridine. 2,3-d) the pyrimidine nucleus. The products can of course be easily separated from each other e.g. by recrystallization. 3rd step The compound [II] is finally subjected to hydrolysis reaction and then the compound [I] or its salt is obtained.
Hydrolyseringsreaktionen i förfarandet utföres genom att man bringar föreningen (ii) i kontakt med vatten. Vanligtvis ut- föres reaktionen, för accelerering därav, i närvaro av en kata- lysator, såsom en syra eller bas.The hydrolysis reaction in the process is carried out by contacting the compound (ii) with water. Usually, the reaction is carried out, for acceleration thereof, in the presence of a catalyst, such as an acid or base.
Exempel på syran utgör oorganiska syror, såsom saltsyra, bromvätesyra, jodvätesyra, svavelsyra eller fosforsyra, och orga- niska syror, såsom ättiksyra, oxalsyra eller toluensulfonsyra.Examples of the acid are inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid, and organic acids, such as acetic acid, oxalic acid or toluenesulfonic acid.
Exempel på basen utgör alkalimetallhydroxider, såsom nat- riumhydroxid eller bariumhydroxid, alkalímetallkarbonater, såsom natriumkarbonat eller kaliumkarbonat, och natriumacetat.Examples of the base are alkali metal hydroxides, such as sodium hydroxide or barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, and sodium acetate.
Denna reaktion kan även utföras genom att man direkt upp- hettar materialet i närvaro av ovan beskrivna syra, och därefter, tillsätter vatten. Lösningsmedlet utgöres vanligtvis av vatten, men beroende på materialets egenskaper kan man även använda ett vattenhaltigt lösningsmedel, såsom etanol, dioxan, etylenglykoldi- metyleter, bensen eller ättíksyra. Reaktionstemperaturen kan vara rumstemperatur, men är vanligtvis S0-ZOOOC, företrädesvis 70-120°C.This reaction can also be carried out by directly heating the material in the presence of the acid described above, and then adding water. The solvent is usually water, but depending on the properties of the material, an aqueous solvent such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid can also be used. The reaction temperature may be room temperature, but is usually SO-ZOOOC, preferably 70-120 ° C.
När denna reaktion utföres under de milda förhållandena kan antingen en acylgrupp (R1-) eller en estergrupp (RZ-)i formeln [ll] hydrolyseras. I sådant fall hydrolyseras den delvis hydrolyserade föreningen ytterligare för erhållande av föreningen Älj.When this reaction is carried out under the mild conditions, either an acyl group (R1-) or an ester group (RZ-) in the formula [II] can be hydrolyzed. In such a case, the partially hydrolyzed compound is further hydrolyzed to give the compound Älj.
Ovanstående reaktioner kan visas schematiskt på följande sätt: 790Û33lr~9 5 *m2 É i {\COORq ringslutning R1_\/1i S1/ \\\/ \\ N/ d H IV " o o I' -I ,\ . / 2 i.\ cooR, *lfl/ I, \\. alkylering If/ I *I “ | 1 “ \\~š , .,' / \ '\\ J raï-x N' \ 5 Rï-ß; \/ *N/ "N \_/ H H 2 5 III II Û k' coon N4\ L I weläè \L,/kN/\N \\__./ ÉZHS I (RT och R2 har ovan angiven definition).The above reactions can be shown schematically as follows: 790Û33lr ~ 9 5 * m2 É i {\ COORq cyclization R1 _ \ / 1i S1 / \\\ / \\ N / d H IV "oo I '-I, \. / 2 i . \ cooR, * l fl / I, \\. alkylation If / I * I “| 1“ \\ ~ š,., '/ \' \\ J raï-x N '\ 5 Rï-ß; \ / * N / "N \ _ / HH 2 5 III II Û k 'coon N4 \ LI weläè \ L, / kN / \ N \\ __./ ÉZHS I (RT and R2 have the above definition).
Utgångsföreningen ¿IYj, som användes i detta förfarande, fram- ställes genom att man bringar motsvarande 2-(1-piperazinyl)-4-amino- pyrimidin att reagera med alkoximetylenmalonat i enlighet med för- 5 farandet, som beskrives i den brittiska patentskriften 1 129 358.The starting compound used in this process is prepared by reacting the corresponding 2- (1-piperazinyl) -4-aminopyrimidine with alkoxymethylene malonate according to the procedure described in British Patent Specification 1. 129 358.
Föreningen Ål] som framställts i ovanstående förförande, kan isoleras och renas genom vanliga förfaranden. Föreningen [lf kan framställas i fritt tillstànd eller i form av salt beroende på reaktionsbetingelserna. Vidare kan föreningen [I] överföras till 10 farmaceutískt godtagbara aminsalter eller karboxylsyrasalter genom behandling med en syra eller ett alkali, eller omvänt. Syran kan utgöras av ett flertal organiska och oorganiska syror, varpå föl- jande utgör exempel: klorvätesyra, ättiksyra, mjölksyra, bärnstens- syra, oxalsyra och metansulfonsyra. 15 Den antibakteríella verkningarna av föreliggande förening [lf visas i Tabell I-IV tillsammans med de för föreningar beskrivna i 10 15 20 179003311-9 de Iidigne nämnda brittiska patontskriften eller tyska offentlig- görande skriften. _50- och LUS” het med Behrens-Kaerbcr-förfarandet (Arch. Exp. Path. Pharm., I Tabellerna [I-IV beräknades ED -värdena I enlig- lgå, 480 (19311]. Föreningarna Pa ooh AT-616 utgöres av följande Förening PA: 5,8-dihydro-8-etyl~2-pyrrolidino-5-oxopyrído-(2,3~d)pyrimidin- o-karboxylsyra utgör den mest värdefulla förening som beskrives i den brittiska patentskriften.The compound Ål] prepared in the above procedure can be isolated and purified by conventional methods. The compound [lf can be prepared in the free state or in the form of a salt depending on the reaction conditions. Furthermore, the compound [I] can be converted into pharmaceutically acceptable amine salts or carboxylic acid salts by treatment with an acid or an alkali, or vice versa. The acid can consist of a number of organic and inorganic acids, the following being examples: hydrochloric acid, acetic acid, lactic acid, succinic acid, oxalic acid and methanesulfonic acid. The antibacterial effects of the present compound [lf are shown in Tables I-IV together with those for compounds described in the British Patron's Journal or German Publication. The Behrens-Kaerbcr procedure (Arch. Exp. Path. Pharm., In Tables [I-IV), the ED values were calculated according to 480 (19311]. The compounds Pa ooh AT-616 consist of the following Compound PA: 5,8-Dihydro-8-ethyl-2-pyrrolidino-5-oxopyrido- (2,3-d) pyrimidine-o-carboxylic acid is the most valuable compound described in the British patent specification.
Förening AT-616: 5,8-dihydro-8-etyl-2-(3-hydroxipyrrolídin)-5-oxopyrido(2,3-di- pyrimidin-0~karboxy1syra utgör den mest värdefulla föreingen som beskríves i den tyska offentliggörande skriften. 1) In vitro_antibakteriell effekt mot 3 bakteríestammar Tabell 1 i “å ;' ' ' 3 = MIC (pm/mg) :Förening ~ Staphylococcus Escherichis |Pseudomonas aureus coli aeruginosa Tefal ímfl *(42 ÄÉPÉÉiJ' ííflë i -_ 1 ' so 1 i io . >~ 1! *- "" ' " PA 10 1 1 100 , E ” AT-616 30 1 f 100 Den minimala inhiberande koncentrationen (MIC) bestämdes genom det välkända-serieutspädningsförfarandet.Compound AT-616: 5,8-Dihydro-8-ethyl-2- (3-hydroxypyrrolidine) -5-oxopyrido (2,3-dipyrimidine-O-carboxylic acid is the most valuable compound described in German Offenlegungsschrift 1) In vitro_antibacterial effect against 3 bacterial strains Table 1 in 'å;' '' 3 = MIC (pm / mg): Compound ~ Staphylococcus Escherichis | Pseudomonas aureus coli aeruginosa Tefal ím fl * (42 ÄÉPÉÉiJ 'íí fl ë i -_ 1' so 1 i io.> ~ 1! * - "" '"PA 10 1 1 100, E ”AT-616 30 1 f 100 The minimum inhibitory concentration (MIC) was determined by the well-known serial dilution method.
Experimentella betingelser: .Experimental conditions:.
Medium: näringsmedelsbuljong, pH 7;0 (5 ml/rör) Ympmedel: 1 droppe 1: 10--utspädning av en buljongkultur; som stått över natten, per rör Inkubation temperatur och tid: 37°C i 48 h Z) Effektivitet in vivo mot systemisk infektion med Psvudomnnas aorugínosa i möss 5 10 15 20 vsoozza-9 Iflëilll T - ------- ----~ » - .___...., V , ;_,______________~_y Förening Väg nos (m§/kg) ' 5950 nr zoo 100 50 25 12,5 0,3 3,1 ;("@/kg) ¿ 1 ip _ - - 8/8 8/8 4/8 z/s 1/8 10,5 v po 8/8 4/8 0/8 - _ _ _ 100 , PÅ É íP 1 _ 0/3 - - - - - ' >1o0 P0 @°/3 - - - - - - E >z00 AT-610 : ip ; _ 3/3 _ _ _ _ _ f >,00 1 “ P0 'l/8 - - ~ - - - š>z00 1 Sífferuppgifterna i tabellen visar antalet överlevande möss/ det totala antalet möss. 0/8 betyder att alla av 8 möss dött. 8/8 avser att alla 8 möss överlevde: Uverlevnadsgraden för icke- behandlad kontroll var 0/8.Medium: nutrient broth, pH 7; 0 (5 ml / tube) Inoculum: 1 drop 1:10 - dilution of a broth culture; overnight, per tube Incubation temperature and time: 37 ° C for 48 h Z) Efficacy in vivo against systemic infection with Psvudomnnas aorugínosa in mice 5 10 15 20 vsoozza-9 I fl ëilll T - ------- - - ~ »- .___...., V,; _, ______________ ~ _y Förening Väg nos (m§ / kg) '5950 nr zoo 100 50 25 12,5 0,3 3,1; (" @ / kg) ¿1 ip _ - - 8/8 8/8 4/8 z / s 1/8 10,5 v po 8/8 4/8 0/8 - _ _ _ 100, PÅ É íP 1 _ 0 / 3 - - - - - '> 1o0 P0 @ ° / 3 - - - - - - E> z00 AT-610: ip; _ 3/3 _ _ _ _ _ f> .00 1 “P0' l / 8 - - ~ - - - š> z00 1 The figures in the table show the number of surviving mice / the total number of mice 0/8 means that all of 8 mice died 8/8 means that all 8 mice survived: The survival rate for untreated control was 0/8.
Experimentella betingelser: 3) Effektivitet in Organism: Pseudomonas aeroginosa nr 12 Möss: Hanmöss (ddY-S) med en vikt av ca 20 g Infektion: Intraperitoneal infektion med S0-100 LD50 av en bakteriell suspension i 4-procentig mag-mucín (ca 5 x 103 celler/mus) Medicinering: Två gånger, ca 5 minuter resp. 6 h efter infektcring Drog: En alkalisk lösning för parenteral administre- ring och en suspension i 0,2-procentig CMC för oral administrering Dödlighetsobservation: 7 dagar i.p: intraperitoneal administration p.o.: oral administration vivo mot systemisk infektion med Salmonella typhímurium i möss Tabell III , 8.. . ill.Experimental conditions: 3) Efficacy in Organism: Pseudomonas aeroginosa No. 12 Mice: Male mice (ddY-S) weighing about 20 g Infection: Intraperitoneal infection with S0-100 LD50 of a bacterial suspension in 4% gastric mucin (approx. 5 x 103 cells / mouse) Medication: Twice, about 5 minutes resp. 6 hours after infection Drug: An alkaline solution for parenteral administration and a suspension in 0.2% CMC for oral administration Mortality observation: 7 days ip: intraperitoneal administration po: oral administration vivo against systemic infection with Salmonella typhímurium in mice Table III , 8 ... ill.
Is _ Vi I DOS (mg/Rs) “D50 - “nl 1 av 1 °¶¿f“¥ 5 Y 100 so .zs 12,5 6,» (mg/kg) l 1 1 i 1 1 å § 1 ap \ - - 8/8 8/8 4/8 1 0,3 | I po 1 - 8/8 8/8 4/8 U/S 1 ll,5 i ! PA ip ' 9/10 s/10 3/10 0/10 - § 13,5 : po 10/10 4/10 3/10 U/10 - - 40,7 10 15 20 ZS 30 790033lP9 i Síffcrvärdena i tabellen visar antalet överlevande möss/ det totala antalet möss. 0/8 betyder att alla av S möss dött. 8/8 avser att alla 8 möss överlevt. Uverlevandegraden för icke- behandlad kontroll var 0/S.Is _ Vi I DOS (mg / Rs) “D50 -“ nl 1 av 1 ° ¶¿f “¥ 5 Y 100 so .zs 12,5 6,» (mg / kg) l 1 1 i 1 1 å § 1 ap \ - - 8/8 8/8 4/8 1 0.3 | I po 1 - 8/8 8/8 4/8 U / S 1 ll, 5 i! PA ip '9/10 s / 10 3/10 0/10 - § 13,5: po 10/10 4/10 3/10 U / 10 - - 40,7 10 15 20 ZS 30 790033lP9 i Síffcrvärdena i tabellen viser the number of surviving mice / the total number of mice. 0/8 means that all of S mice are dead. 8/8 means that all 8 mice survived. The survival rate for untreated control was 0 / S.
Experimentella betingelser: Organism: Salmonella typhimurium S-9 Möss: Hanmöss (ddY-S) med en vikt av ca 20 g Infektion: lntraperitoneal infektion med S0-100 LD 0 av en bakteríell suspension i näringsmeâels- buljong (ca 105 celler /mus) Medicinering: Två gånger per dag i 4 dagar från dagen för infektionen.Experimental conditions: Organism: Salmonella typhimurium S-9 Mice: Male mice (ddY-S) weighing about 20 g Infection: Intraperitoneal infection with S0-100 LD 0 of a bacterial suspension in nutrient broth (about 105 cells / mouse) Medication: Twice daily for 4 days from the day of infection.
En alkaliskt lösning för parenteral administre- Drog: ring och en suspension i 0,2-procentig CMC för oral administrering Observation: 14 dagar i.p.: intraperitoneal administrering p.o.: oral administrering 74) Akut toxícitet i möss Abeii v l Dos tmg/kgrwuww_ LD i' . rören' ' " -50 i ing 5 Vag , g imon zooo__g__1ooo son (mg/kg) 5 I 1 i iv 6 i - _ o/6 6/6 700 po i 6/6 6/6 i - - >4ooo Siffervärdena i tabellen visar antalet överlevande möss/det totala antalet möss. O/6 betyder att alla av 6 möss dött och 6/6 avser att alla möss överlevt. 7 I Förening var i alkalisk lösning för intravenös administre- ring och för oral administrering i en suspension, som innehöll 0,2 % CMC, och administrerades till hanmöss (ddY-S) med en vikt av ca 20 g. Efter 7 dagar registrerades dödsfrekvensen oc LD50- värdet uppskattades. i.v.: intravenös administrering p.o.: oral administrering Den kliniska doseringen av föreningen I beror på kroppsvikt, ålder och administeringsväg, men ligger i allmänhet inom området 100 mg - 5 g/dag. företrädesvis 200 mg - 3 g/dag.An alkaline solution for parenteral administration Drug: ring and a suspension in 0.2% CMC for oral administration Observation: 14 days ip: intraperitoneal administration po: oral administration 74) Acute toxicity in mice Abeii vl Dose tmg / kgrwuww_ LD i ' . tubes '' "-50 i ing 5 Vag, g imon zooo__g__1ooo son (mg / kg) 5 I 1 i iv 6 i - _ o / 6 6/6 700 po i 6/6 6/6 i - -> 4ooo The numerical values in the table shows the number of surviving mice / the total number of mice. U / 6 means that all of 6 mice died and 6/6 means that all mice survived.7 In Compound was in alkaline solution for intravenous administration and for oral administration in a suspension, containing 0.2% CMC, and administered to male mice (ddY-S) weighing about 20 g. After 7 days, the mortality rate was recorded and the LD50 value was estimated iv: intravenous administration po: oral administration The clinical dosage of Compound I depends on body weight, age and route of administration, but is generally in the range of 100 mg - 5 g / day, preferably 200 mg - 3 g / day.
Följande exempel åskådliggör framställningen av föreningar [1] och de nya mellanprodukterna därav. lU 15 20 30 35 79003344 Exempel_l Htyl-1-(J-acetyl-l-piperazinyl)-5,8-dihydro-5-oxopyrido(2,3-d)- pyrimidin-0-karhoxylat Till 16 ml difenyleter, som upphettats till 250-ZSSOC, sattes under omröring 2,0 g dietyl-N-12-(4-acetyl-1-piperazínyll-4-pyri~ midinyl]-umínometylenmalonat, försiktig återflödning fortsattes i 10 min och därefter fick blandningen svalna till rumstemperatur.The following examples illustrate the preparation of compounds [1] and the novel intermediates thereof. Example 20 1 Ethyl 1- (J-acetyl-1-piperazinyl) -5,8-dihydro-5-oxopyrido (2,3-d) -pyrimidine-O-carhoxylate To 16 ml of diphenyl ether heated to 250-ZSSOC, 2.0 g of diethyl N-12- (4-acetyl-1-piperazinyl-4-pyrimidinyl] -uminomethylene malonate was added with stirring, gentle reflux was continued for 10 minutes and then the mixture was allowed to cool to room temperature.
Till blandningen sattes 12 ml n-hexan och den erhållna fällníngen uppsamlades, tvättades med etanol och omkrístallíserades ur etanol för erhållande av 1,52 g av produkten med smältpunkten 300-SUZOC.To the mixture was added 12 ml of n-hexane, and the resulting precipitate was collected, washed with ethanol and recrystallized from ethanol to obtain 1.52 g of the product, m.p. 300-SUZOC.
Exempel 2 Följande föreningar framställdes på ett liknande sätt som det i exemplet I: etyl-5,8-dihydro-2-(4-formyl-piperazinyl)~5-0xopyrido-¿É,3-d]- pyrimidin-6-karboxylat (smp. över SOOOC), _ etyl-5,8-dihydro-2-(4-etoxikarbonyl-1-piperazinyl)-5-oxopyrido- ZÉ,3-djpyrimidin-6-karboxylat (smp över SOOOC), etyl~5,8~dihydro-Z-(4-trifluoroacetyl-1-piperazinyl)-5-oxopyrido- 12,3-dfpyrimidín-6-karboxylat, etyl-5,8-dihydro-Z-(1-piperazinyl)-5-oxopyridolí,3-d]pyrimidin- 6-karboxylat.Example 2 The following compounds were prepared in a similar manner to that of Example I: ethyl 5,8-dihydro-2- (4-formyl-piperazinyl) -5-oxopyrido-β, 3-d] -pyrimidine-6-carboxylate (m.p. above SOOOC), ethyl 5,8-dihydro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-oxopyrido-ZÉ, 3-dipyrimidine-6-carboxylate (m.p. above SOOOC), ethyl-5 , 8-dihydro-Z- (4-trifluoroacetyl-1-piperazinyl) -5-oxopyrido-12,3-dipyrimidine-6-carboxylate, ethyl 5,8-dihydro-Z- (1-piperazinyl) -5-oxopyridolyl , 3-d] pyrimidine-6-carboxylate.
Exemgel 3 Etyl~2-(4-acetyl-1-piperazinyl)-S,8-dihydro-8-etyl-5-oxopyrído- /É,3-dfpyrimidin-6-karboxylat Till en suspension av 4,0 g etyl-2-(4-acetyl-1-piperazinyl)- 5,8-dihydro-5-oxopyridolí,3-dfpyrímidin-6-karboxylat och 6,0 g kaliumkarbonat i 100 ml 50-procentig vattenhaltíg etanol sattes totalt 5,5 ml dietylsulfat i tre portioner under omröring och bland- ningen fick reagera i 2 h vid rumstemperatur.Example 3 Ethyl 2- (4-acetyl-1-piperazinyl) -S, 8-dihydro-8-ethyl-5-oxopyrido [1,3-d] pyrimidine-6-carboxylate To a suspension of 4.0 g of ethyl 2- (4-Acetyl-1-piperazinyl) -5,8-dihydro-5-oxopyridoline, 3-dipyrimidine-6-carboxylate and 6.0 g of potassium carbonate in 100 ml of 50% aqueous ethanol were added a total of 5.5 ml of diethyl sulfate in three portions while stirring and the mixture was allowed to react for 2 hours at room temperature.
Reaktionsprodukten extraherades med kloroform och extraktet torkades över vattenfritt magnesiumsulfat, följt av avdunstning av lösníngsmedlet för erhållande av en kristallín återstod, var- till n-hexan sattes. Krístallerna uppsamlades och omkristallise- rades ur en blandning av n-hexan och aceton för erhållande av 3,4 g av produkten med smältpunkten 208-2l0°C under sönderdelning.The reaction product was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to give a crystalline residue, to which was added n-hexane. The crystals were collected and recrystallized from a mixture of n-hexane and acetone to obtain 3.4 g of the product, m.p. 208-210 ° C with decomposition.
Exemgcl 4 Etyl-2-(1-piperazinyll-5,8-dihydro-8-etyl-5-oxøpyridoéí,3-d]py- rimidin-6-karhoxvlat Till en lösning av 1,5 g ctyl-5,8-dihydro-2-(l~piperu:inyll I0 15 20 25 30 35 40 vsoozza-9 10 -5~oxopyrido[É,3-dfpyrimidin-6-karboxylat i 60 ml av en l0~procen- tig vuttenhaltig lösning av natriumkurbonat sattes tre 10 ml por- tioner dietylsulfat. Efter avslutande av reaktionen neutraliscrndcs den erhållna blandningen med ättikšyra. Fällningen uppsamlades och omkristallíserades ur dímetylformamid för erhållande av 0,8 g etyl-2-(1-piperazinyl)-5,8-dihydro-8-etyl-S-oxopyridolí,3-d7py- rimídin-6-karboxylat, smp; 156-158°C.Example 4 Ethyl 2- (1-piperazinyl-5,8-dihydro-8-ethyl-5-oxoepyridoyl, 3-d] pyrimidine-6-carhoxylate To a solution of 1.5 g of ethyl-5,8- dihydro-2- (1-piperu: inyl Io 15 20 25 30 35 40 40-oxopyrido [3,3-d] pyrimidine-6-carboxylate in 60 ml of a 10% aqueous solution containing sodium carbonate was added After completion of the reaction, three 10 ml portions of diethyl sulphate neutralize the resulting mixture with acetic acid. The precipitate was collected and recrystallized from dimethylformamide to give 0.8 g of ethyl 2- (1-piperazinyl) -5,8-dihydro-8- ethyl S-oxopyridolyl, 3-d-pyrimidine-6-carboxylate, mp 156-158 ° C.
Exemgel 5 5,8-dihydro-8-etyl-Z-(1-píperazinyl)-5-oxopyridolí,3-d]pyrimidin- 6-karboxylsyra (förening ÜJJ 5,0 g etyl-5,8-dihydro-8~etyl-5-oxo-2-(1-píperazínyl)pyrido- ¿É,3-dfpyrimidin-6-karboxylat upplöstes i 30 ml av en 7-procentíg vattenhaltig lösning av natriumhydroxid genom upphettning till QOOC i 20 min. Efter avkylning neutraliserades den bildade lös- ning med ättiksyra för erhållande av en fällning, som uppsamla- des och omkristalliserades ur dimetylformamid. Man erhöll 4,3 g av produkten med smältpunkten 253-2S5°C. ußxemgel 6 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-etyl-5-oxopyrido[?,3-d] pyrimidin-6-karboxylsyra 1 5,0 g etyl-2-(4-acetyl-1-píperazinyl)-5,8-dihydro-8-etyl-S- oxopyridolï,3-djpyrimidin-6-karboxylat upplöstes i 35 ml av en I0-procentig vattenhaltig lösning av natriumkarbonat genom upphett- ning till 90°C i 30 min. Den erhållna lösningen filtrerades för avlägsnande av olösligt material och filtratet neutraliserades med ättiksyra för erhållande av en fällning som uppsamlades och om- kristalliserades ur en blandning av bensen och kloroform. Man er- höll därvid 4,1 g av produkten med smältpunkten 298-300°C.Example 5 5,8-Dihydro-8-ethyl-Z- (1-piperazinyl) -5-oxopyridolyl, 3-d] pyrimidine-6-carboxylic acid (compound ÜJJ 5.0 g ethyl-5,8-dihydro-8 Ethyl 5-oxo-2- (1-piperazinyl) pyrido [3,3-d] pyrimidine-6-carboxylate was dissolved in 30 ml of a 7% aqueous solution of sodium hydroxide by heating to QOOC for 20 minutes. After cooling, it was neutralized. formed solution with acetic acid to give a precipitate which was collected and recrystallized from dimethylformamide to give 4.3 g of the product, m.p. 253 DEG-25 DEG C., Example 6 2- (4-acetyl-1-piperazinyl) -5,8-dihydro-8-ethyl-5-oxopyrido [1,3-d] pyrimidine-6-carboxylic acid 1 5.0 g of ethyl 2- (4-acetyl-1-piperazinyl) -5,8-dihydro -8-Ethyl-S-oxopyridolyl, 3-dipyrimidine-6-carboxylate was dissolved in 35 ml of an 10% aqueous solution of sodium carbonate by heating to 90 ° C for 30 minutes. The resulting solution was filtered to remove insoluble matter. and the filtrate was neutralized with acetic acid to give a precipitate as up was collected and recrystallized from a mixture of benzene and chloroform. 4.1 g of the product with a melting point of 298-300 ° C were obtained.
Exempel 7 _ 5,8-dihydro-8-etyl-2~(1-piperazinyl)-5-oxopyrido-12,3-djpyrimidin- 6-karboxylsyra (förening E11) (A) 2,0 g 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-etyl-S- oxopyridolï,3-d]pyrimidin-6-karboxylsyra upplöstes i 40 ml av en 10 procentig vattenhaltig lösning av natriumhydroxid genom upphett-_ ning till 90-95°C i 1,5 h. Den bildade lösningen behandlades med - avfärgandc kol och filtrerades. Filtratet neutraliscrades med ättiksyra för erhållande av 1,6 g av produkten i rent tillstånd och med smältpunkten 252-ZSSOC.Example 7 - 5,8-Dihydro-8-ethyl-2- (1-piperazinyl) -5-oxopyrido-12,3-dipyrimidine-6-carboxylic acid (Compound E11) (A) 2.0 g 2- (4- acetyl-1-piperazinyl) -5,8-dihydro-8-ethyl-5-oxopyridolyl, 3-d] pyrimidine-6-carboxylic acid was dissolved in 40 ml of a 10% aqueous solution of sodium hydroxide by heating to 90- 95 ° C for 1.5 hours. The resulting solution was treated with decolorizing carbon and filtered. The filtrate was neutralized with acetic acid to give 1.6 g of the product in the pure state and with a melting point of 252-ZSSOC.
(Bl 1,0 g etyl-Z-(4-ncetyl-I-piperazinyl)-5,8-dihydro-8- cry]-S-oxopyrido¿É,3-dfpyrímidin-6-knrboxylat upplöstes i 30 ml 10 7900334-9 11 av en 10-proccntig vattenhaltig lösning av natriumhydroxíd genom upphcttníng till 90-950C i 1 h. Neutralísering av reaktionsblund- ningen med ättiksyra under kylníng_gav en rå fast substans, som omkristalliserades ur dimetylformamid för erhållande av 1,1 g av produkten í rent tillstånd. Éšemgel 8 5,8-díhydro-8-etyl-2-(1-piperazinyl)-5-oxopyrídolfi,3-d]pyrímídín- 6-karboxylsyra (föreníng[í]) Man följde förfarandet som beskrevs i exemplet 7 (A) med användning av 5,8-díhydro-Z-(4-etoxíkarbonyl-1-piperazíny1)-8- etyl-5-oxopyrído¿2,3-Q?pyrhmdin-6-karboxylsyra och erhöll därvid 5,8-díhydr0-8-ety1-2-(1-píperazínyl)-5-oxopyrídoíí,3-d]pyrimídín- 6-karhoxylsyra med smältpunkten 253-255°C.(B1 1.0 g of ethyl Z- (4-acetyl-1-piperazinyl) -5,8-dihydro-8-cry] -S-oxopyrido [3,3-d] pyrimidine-6-carboxylate was dissolved in 30 ml of 7900334 Neutralization of the reaction mixture with acetic acid under cooling gave a crude solid which was recrystallized from dimethylformamide to give 1.1 g of the product in sodium hydroxide solution by heating to 90 DEG-95 DEG C. for 1 hour. Example 5 5,8-Dihydro-8-ethyl-2- (1-piperazinyl) -5-oxopyridol fi, 3-d] pyrimidine-6-carboxylic acid (compound [í]) The procedure described in Example 7 was followed. (A) using 5,8-dihydro-Z- (4-ethoxycarbonyl-1-piperazinyl) -8-ethyl-5-oxopyrido [2,3-c] pyrimidine-6-carboxylic acid to give 5,8- dihydro-8--ethyl-2- (1-piperazinyl) -5-oxopyridolyl, 3-d] pyrimidine-6-carboxylic acid, m.p. 253-255 ° C.
Claims (1)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8128872A JPS5336478B2 (en) | 1972-08-14 | 1972-08-14 | |
| JP12802272A JPS5617352B2 (en) | 1972-12-19 | 1972-12-19 | |
| JP26973A JPS569507B2 (en) | 1972-12-22 | 1972-12-22 | |
| JP733108A JPS569508B2 (en) | 1972-12-26 | 1972-12-26 | |
| JP73570A JPS578110B2 (en) | 1972-12-27 | 1972-12-27 | |
| JP5890973A JPS565754B2 (en) | 1973-05-25 | 1973-05-25 | |
| JP6965173A JPS5616796B2 (en) | 1973-06-19 | 1973-06-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE7900334L SE7900334L (en) | 1979-01-15 |
| SE433215B true SE433215B (en) | 1984-05-14 |
Family
ID=27563068
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7900334A SE433215B (en) | 1972-08-14 | 1979-01-15 | PROCEDURE FOR PREPARING 2-PIPERAZINYL-PYRIDO- / 2,3-D / PYRIMIDINE DERIVATIVES |
Country Status (10)
| Country | Link |
|---|---|
| AR (5) | AR202799A1 (en) |
| CA (1) | CA1073456A (en) |
| CH (3) | CH601293A5 (en) |
| DE (1) | DE2341146A1 (en) |
| FI (1) | FI54481C (en) |
| FR (1) | FR2196159B1 (en) |
| GB (2) | GB1451911A (en) |
| NL (1) | NL181483C (en) |
| NO (1) | NO137966C (en) |
| SE (1) | SE433215B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1484138A (en) * | 1974-03-14 | 1977-08-24 | Bellon Labor Sa Roger | Pyrido pyrimidine derivatives |
| GB1553436A (en) * | 1976-09-17 | 1979-09-26 | Bellon R Lab | Derivatives of pipemidic acid |
| JPS53141286A (en) | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| DE2903850A1 (en) * | 1979-02-01 | 1980-08-07 | Bayer Ag | 2-AMINO-8-CYCLOPROPYL-5-OXO-5,8- DIHYDRO-PYRIDO CORNER CLAMP ON 2,3-D CORNER CLAMP FOR -PYRIMIDINE-6-CARNONIC ACIDS, METHOD FOR THE PRODUCTION AND USE THEREOF |
| FR2453157A1 (en) * | 1979-04-02 | 1980-10-31 | Fabre Sa Pierre | 2-Undecyl imidazole salts - having Gram positive and negative antibacterial activity |
| DE3028520A1 (en) * | 1980-07-28 | 1982-02-25 | Dynamit Nobel Ag, 5210 Troisdorf | METHOD FOR PRODUCING CHINOLINES, NAPHTYRIDINES AND OTHER NITROGEN BI-HETEROCYCLES |
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| NZ210847A (en) * | 1984-01-26 | 1988-02-29 | Abbott Lab | Naphthyridine and pyridopyrimidine derivatives and pharmaceutical compositions |
| AT392789B (en) * | 1985-01-23 | 1991-06-10 | Toyama Chemical Co Ltd | METHOD FOR PRODUCING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES |
| US4851535A (en) * | 1985-01-23 | 1989-07-25 | Toyama Chemical Co., Ltd. | Nicotinic acid derivatives |
| EP0224121A3 (en) * | 1985-11-19 | 1987-11-11 | ROTTAPHARM S.p.A. | 7-[4-amino-piperazinyl]- or 7-[4-chloro-piperazinyl]quinolinone derivatives, a process for the preparation thereof and pharmaceutical compositions containing them |
| US4687770A (en) * | 1985-12-23 | 1987-08-18 | Abbott Laboratories | Isoxazolo-pyrido-benzoxazine and isothiazolo-pyrido-benzoxazine derivatives |
| US4689325A (en) * | 1985-12-23 | 1987-08-25 | Abbott Laboratories | Isoxazolo-pyrido-phenoxazine and isothiazolo-pyrido-phenoxazine derivatives |
| US7196200B2 (en) * | 2004-01-21 | 2007-03-27 | Abbott Laboratories | Antibacterial compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR7582M (en) * | 1965-09-08 | 1970-01-12 |
-
1973
- 1973-08-08 GB GB3762173A patent/GB1451911A/en not_active Expired
- 1973-08-08 GB GB1539276A patent/GB1451912A/en not_active Expired
- 1973-08-10 FI FI2519/73A patent/FI54481C/en active
- 1973-08-13 NO NO733211A patent/NO137966C/en unknown
- 1973-08-13 CA CA178,687A patent/CA1073456A/en not_active Expired
- 1973-08-14 FR FR7329718A patent/FR2196159B1/fr not_active Expired
- 1973-08-14 NL NLAANVRAGE7311190,A patent/NL181483C/en not_active IP Right Cessation
- 1973-08-14 CH CH1169473A patent/CH601293A5/xx not_active IP Right Cessation
- 1973-08-14 CH CH316577A patent/CH605948A5/xx not_active IP Right Cessation
- 1973-08-14 DE DE19732341146 patent/DE2341146A1/en not_active Withdrawn
- 1973-08-14 CH CH316477A patent/CH605947A5/xx not_active IP Right Cessation
- 1973-08-14 AR AR249573A patent/AR202799A1/en active
-
1974
- 1974-08-30 AR AR255407A patent/AR200347A1/en active
- 1974-08-30 AR AR255408A patent/AR203047A1/en active
-
1975
- 1975-06-30 AR AR259398A patent/AR203165A1/en active
- 1975-06-30 AR AR259397A patent/AR203164A1/en active
-
1979
- 1979-01-15 SE SE7900334A patent/SE433215B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2196159A1 (en) | 1974-03-15 |
| NL7311190A (en) | 1974-02-18 |
| AR200347A1 (en) | 1974-10-31 |
| FI54481C (en) | 1978-12-11 |
| AR203047A1 (en) | 1975-08-08 |
| CH605948A5 (en) | 1978-10-13 |
| CA1073456A (en) | 1980-03-11 |
| AU5909273A (en) | 1975-02-13 |
| CH601293A5 (en) | 1978-07-14 |
| FI54481B (en) | 1978-08-31 |
| GB1451911A (en) | 1976-10-06 |
| CH605947A5 (en) | 1978-10-13 |
| SE7900334L (en) | 1979-01-15 |
| NO137966C (en) | 1978-05-31 |
| NL181483C (en) | 1987-09-01 |
| NO137966B (en) | 1978-02-20 |
| NL181483B (en) | 1987-04-01 |
| DE2341146A1 (en) | 1974-02-28 |
| FR2196159B1 (en) | 1978-09-15 |
| AR203164A1 (en) | 1975-08-14 |
| AR203165A1 (en) | 1975-08-14 |
| AR202799A1 (en) | 1975-07-24 |
| GB1451912A (en) | 1976-10-06 |
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