GB2027433A - Aminoalkanoylaminoalkyl Phosphonic Acids - Google Patents
Aminoalkanoylaminoalkyl Phosphonic Acids Download PDFInfo
- Publication number
- GB2027433A GB2027433A GB7909676A GB7909676A GB2027433A GB 2027433 A GB2027433 A GB 2027433A GB 7909676 A GB7909676 A GB 7909676A GB 7909676 A GB7909676 A GB 7909676A GB 2027433 A GB2027433 A GB 2027433A
- Authority
- GB
- United Kingdom
- Prior art keywords
- group
- acid
- amino
- lower alkyl
- benzyloxycarbonyl
- 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.)
- Granted
Links
- 150000003009 phosphonic acids Chemical class 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 13
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 3
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 3
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 230000003115 biocidal effect Effects 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 claims description 4
- MSEBNAXFIZIHJN-YFKPBYRVSA-N [[(2s)-2-aminopentanoyl]amino]methylphosphonic acid Chemical compound CCC[C@H](N)C(=O)NCP(O)(O)=O MSEBNAXFIZIHJN-YFKPBYRVSA-N 0.000 claims description 3
- 239000007859 condensation product Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- MOQHZWFMVYEXJD-LURJTMIESA-N [[(2s)-2-amino-6-(diaminomethylideneamino)hexanoyl]amino]methylphosphonic acid Chemical compound OP(=O)(O)CNC(=O)[C@@H](N)CCCCNC(N)=N MOQHZWFMVYEXJD-LURJTMIESA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 229940088710 antibiotic agent Drugs 0.000 abstract description 5
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 abstract 1
- 235000008206 alpha-amino acids Nutrition 0.000 abstract 1
- 235000018102 proteins Nutrition 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 229910001868 water Inorganic materials 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000243 solution Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 18
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- -1 alkyl chloroformate Chemical compound 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 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 description 6
- 238000001665 trituration Methods 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000012876 carrier material Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- NMYWMOZOCYAHNC-LBPRGKRZSA-N (2s)-2-(phenylmethoxycarbonylamino)hexanoic acid Chemical compound CCCC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 NMYWMOZOCYAHNC-LBPRGKRZSA-N 0.000 description 3
- NSJDRLWFFAWSFP-NSHDSACASA-N (2s)-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CCC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 NSJDRLWFFAWSFP-NSHDSACASA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940124277 aminobutyric acid Drugs 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 102220079670 rs759826252 Human genes 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- UIQSKEDQPSEGAU-UWTATZPHSA-N (R)-(1-aminoethyl)phosphonic acid Chemical compound C[C@H](N)P(O)(O)=O UIQSKEDQPSEGAU-UWTATZPHSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical group OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- 125000005544 phthalimido group Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- GMJWAEBOPBLHBW-KZYOBBJWSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;(5s,6s)-6-[[2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.N([C@@H]1[C@@H]2SC(C(N2C1=O)C(O)=O)(C)C)C(=O)C(N)C1=CC=C(O)C=C1 GMJWAEBOPBLHBW-KZYOBBJWSA-N 0.000 description 1
- JETQIUPBHQNHNZ-NJBDSQKTSA-N (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)S(O)(=O)=O)=CC=CC=C1 JETQIUPBHQNHNZ-NJBDSQKTSA-N 0.000 description 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 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
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 description 1
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- CJQMZPYGWQCQCR-LURJTMIESA-N [[(2s)-2-aminohexanoyl]amino]methylphosphonic acid Chemical compound CCCC[C@H](N)C(=O)NCP(O)(O)=O CJQMZPYGWQCQCR-LURJTMIESA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 1
- 229950004030 cefaloglycin Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- JQXXHWHPUNPDRT-YOPQJBRCSA-N chembl1332716 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CCN(C)CC1 JQXXHWHPUNPDRT-YOPQJBRCSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 1
- FNAUIPGNLGDWRB-UHFFFAOYSA-N dimethoxyphosphorylmethanamine;hydrochloride Chemical compound Cl.COP(=O)(CN)OC FNAUIPGNLGDWRB-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- NONJJLVGHLVQQM-JHXYUMNGSA-N phenethicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C)OC1=CC=CC=C1 NONJJLVGHLVQQM-JHXYUMNGSA-N 0.000 description 1
- 229960004894 pheneticillin Drugs 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960003672 propicillin Drugs 0.000 description 1
- HOCWPKXKMNXINF-XQERAMJGSA-N propicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(CC)OC1=CC=CC=C1 HOCWPKXKMNXINF-XQERAMJGSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229940115939 shigella sonnei Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960004932 sulbenicillin Drugs 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
This invention is concerned with compounds of the formula <IMAGE> wherein R<1> represents a hydrogen atom or the methyl or hydroxymethyl group or a mono-, di- or trihalomethyl group; R<2> represents a lower alkyl, hydroxy-(lower alkyl) or guanidino- (lower alkyl) group other than the characterising group of an alpha -amino acid of the type normally found in proteins; the configuration at the carbon atom designated as (a) is (R) when R<1> represents other than a hydrogen atom; and the configuration at the carbon atom designated as (b) is (L), and pharmaceutically acceptable salts thereof, with a process for the manufacture thereof and with pharmaceutical preparations containing same. These compounds and salts have antibacterial activity and also potentiate the activity of antibiotics.
Description
SPECIFICATION
Peptide Derivatives
The present invention relates to peptide derivatives. More particularly, the invention is concerned with peptide derivatives of phosphonic acids, a process for the manufacture thereof and pharmaceutical preparations containing same.
The peptide derivatives provided by the present invention are compounds of the general formula
wherein R1 represents a hydrogen atom or the methyl or hydroxymethyl group or a mono-, di- or trihalomethyl group; R2 represents a lower alkyl, hydroxy-(lower alkyl) or guanidino-(lower alkyl) group other than the characterising group of an a- amino acid of the type normally found in proteins; the configuration at the carbon atom designated as (a) is (R) when R1 represents other than a hydrogen atom; and the configuration at the carbon atom designated as (b) is (L), and pharmaceutically acceptable salts thereof.
The term "lower alkyl" is used in this
Specification to mean a straight-chain or branched-chain alkyl group which preferably contains up to 8 carbon atoms. Examples of such lower alkyl groups are ethyl, propyl, butyl, tertbutyl, pentyl, hexyl etc. Examples of hydroxy (lower alkyl) groups denoted by R2 are 2hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like. The term "halo" means fluoro, chloro, bromo or iodo, examples of the aforementioned halomethyl groups being chloromethyl, dichloromethyl, trifluoromethyl etc.
When R' in formula I represents other than a hydrogen atom, the configuration at the carbon atom designated as (a) is (R); that is to say, the configuration which would be obtained by replacing the carboxyl group of a naturally occurring amino acid by a phosphorus moiety.
A preferred class of peptide derivatives provided by the present invention comprises compounds of formula I in which R' represents a hydrogen atom or the methyl group and pharmaceutically acceptable salts thereof. Also preferred are compounds of formula I in which R2 represents a lower alkyl group, especially the ethyl, n-propyl or n-butyl group.
Examples of compounds of formula I hereinbefore are; ( 1 R)- 1 -[L-(a-AminobuWryl)amino]- ethylphosphonic acid, (1 R)-1 -(L-norleucylamino)-ethylphosphonic acid, (L-a-Aminobutyrylamino)-methylphosphonic acid,
(L-norleucylamino)-methylphosphonic acid,
(L-norvalylamino)-methylphosphonic acid,
( 1 R)- 1 L-homoa rginylamino)-ethylphosphonic acid, and
(L-homoarginylamino)-methylphosphonic acid.
According to the process provided by the present invention, the peptide derivatives aforesaid (i.e. the compounds of formula I and pharmaceutically acceptable salts thereof) are manufactured by condensing a compound of the general formula
wherein R'O has any of the values accorded to
R1 hereinbefore or represents a protected hydroxymethyl group:R3 and R4 each represent a hydrogen atom or a lower alkyl protecting group; and the configuration at the carbon atom designated as (a) is (R) when R' represents other than a hydrogen atom; with a protected amino acid of the general formula
wherein R5 represents a protected amino group; R20 has any of the values accorded to R2 hereinbefore or represents a protected hydroxy (lower alkyl) or guanidino-(lower alkyl) group; and the configuration at the carbon atom designated as (b) is (L), cleaving off the protecting group or groups present in the condensation product and, if desired, converting a resulting compound of formula I into a pharmaceutically acceptable salt.
The protected amino group denoted by R5 in a protected-amino acid starting material of formula
Ill hereinbefore can be any protected amino group which is well-known in peptide chemistry. In a preferred embodiment of the process provided by the present invention the amino group is protected with an aralkoxycarbonyl group, particularly the benzyloxycarbonyl group, or the tert.butoxycarbonyl group. However, the amino group can also be protected with, for example, a formyl, trityl, trifluoroacetyl or 2-(biphenylyl)isopropyloxycarbonyl group or can be in the form of a phthalimido group.The protecting group present in a protected hydroxymethyl group R10 or a protected hydroxy-(lower alkyl) group R20 can be any conventional hydroxy protecting group; for example, an arnlk6xycarbonyl group (e.g. the benzyloxycarbonyl group), a lower alkanoyl group (e.g. the acetyl, propionyl and like groups), an aroyl group (e.g. the benzoyi group), a lower alkyl group (e.g. the tert.butyl group) or a lower aralkyl group (e.g. the benzyl group).
The condensation of a compound of formula II with a protected amino acid of formula Ill can be carried out according to methods known per sue in peptide chemistry; for example, according to the mixed anhyride, azide, activated ester, acid chloride, carbodiimide or EEDQ (1-ethoxycarbonyl2-ethoxy-1 ,2-dihydroquinoline) niethod.
In one method, a compound of formula II can be condensed with a protected amino acid of formula Ill in which the carboxy group is a mixed anhydride residue formed with an organic or inorganic acid. Suitably, such a protected aamino acid of formula III is treated with a tertiary base such as a tri(lower alkyl)amine (e.g.
triethylamine) or N-ethylmorpholine in an inert organic solvent (e.g. tetrahydrofuran, 1,2dimethoxyethane, dichloromethane, toluene, petroleum ether or the like) and the salt obtained is reacted with an appropriate chloroformate (e.g.
a lower alkyl chloroformate such as ethyl chloroformate orisobutyl chloroformate) at a low temperature. The mixed anhydride thus obtained is then suitably condensed in situ with a compound of formula II.
In another method, a compound of formula II can be condensed with a protected a-amino acid of formula Ill in which the carboxy group is in the form of an acid azide. This condensation is preferably carried out in an inert organic solvent such as dimethylformamide or ethyl acetate at a low temperature.
In yet another method, a compound of formula
II can be condensed with a protected a-amino acid of formula Ill in which the carboxy group is in the form of an active ester group (e.g. the 4
nitrophenyl, 2,4,5-trichlorophenyl or N
hydroxysuccinimide ester group). This
condensation is suitably carried out in an inert
solvent such as aqueous dimethylformamide or, where R3 and R4 in a compound of formula Ill both
represent a lower alkoxy group, also in a lower alkanol such as aqueous ethanol.
In a further method, a compound of formula ll can be condensed with a protected a-amino acid of formula Ill in which the carboxy group is in the form of an acid chloride. This condensation is preferably carried out in the presence of a base and at a low temperature.
In yet a further method, a compound of formula
II can be condensed with a protected a-amino acid of formula Ill in the presence of a carbodiimide (e.g. dicyclohexylcarbodiimide) or
EEDQ. This condensation can be carried out in an inert organic solvent (e.g. methylene chloride or a lower alkanol such as methanol, ethanol etc) at
room temperature or at a temperature below room temperature.
The cleavage of the protecting group or protecting groups from the condensation product is carried out in accordance with methods known per se; that is to say, methods in actual use for or described in the literature on the cleavage of protecting groups. Thus, for example, an aralkoxycarbonyl group (e.g. benzyloxycarbonyl), the tert.butoxycarbonyl group or the 2-biphenylylisopropyloxycarbonyl group can be cleaved off by hydrolysis (e.g. by treatment with hydrogen
bromide in glacial acetic acid). An aralkoxycarbonyl group (e.g. benzyloxycarbonyl) can also be cleaved off by hydrogenolysis (e.g. in the presence of palladium-on-charcoal or platinum oxide). The tert.butoxycarbonyl or 2biphenylyl-isopropyloxycarbonyl group can also be cleaved off using hydrogen chloride in dioxan.
A trityl group can be cleaved off, for example, by treatment with dilute acetic acid. A phthalimido
group can be converted into the amino group by
hydrazinolysis. Lower alkyl protecting groups
denoted by R3 and R4 can be cleaved off by
treatment with hydrogen bromide in glacial acetic
acid or using trimethylchlorosilane or
trimethylbromosilane followed by aqueous
hydrolysis. It will be appreciated that where more
than one protecting group is present the cleavage
of the protecting groups can be carried out in a
single step or in more than one step depending on
the nature of said groups. However, it is preferred
to use protecting groups which can be cleaved off
in a single step.
Compounds for formula I hereinbefore are
amphoteric and form pharmaceutically acceptable
salts with pharmaceutically acceptable strong
acids (e.g. hydrochloric acid, hydrobromic acid,
sulphuric acid, methanesulphonic acid,
paratoluenesulphonic acid etc) and bases (e.g.
sodium hydroxide, potassium hydroxide etc).
The starting materials of formulae II and Ill are
known compounds or can be prepared in analogy
to the preparation of known compounds.
The peptide derivatives provided by the present
invention possess an antibacterial activity against
a wide range of gram-positive and gram-negative
bacteria such as escherichia coli, Staphylococcus
aureus, Serratia marcescens, Kiebsiella aerogenes, Streptococcus faecalis, Haemophilus influenzae, Bacillus subtilis, Salmonella
typhimurium, Proteus mirabilis, Pseudomonas
aeruginosa and Shigella sonnei. In addition, the
present peptide derivatives potentiate the activity
of antibiotics, including penicillin and
cephalosporin antibiotics and D-cycloserine.
Among the antibiotics which are potentiated by
the present peptide derivatives there may be
mentioned amoxycillin, cephradine, cephalothin,
cephalexin, carbenicillin, ampicillin, penicillin G,
sulbenicillin, cephazolin, cefoxitin, rifampicin, [(R) 1 -(2-furoyloxy)-3-methylbutyl]penicillin, (6R)-6 I[(hexahydro-l H-azepin-1 -yl)
methylene]amino}penicillanic acid,
(pivaloyloxy)methyl (6P)-6-([hexahydro-1 H
azepin-1 -yl)methylene]aminolpenicillanate, cephamandole, cephaloridin, cephaloglycin,
phenethicillin, methicillin, propicillin, ticaracillin,
amoxycillin arginine salt, phosphonomycin,
vancomycin and kanamycin.
The present invention thus also provides a
pharmaceutical preparation containing a peptide
derivative aforesaid, and, if desired, an antibiotic,
in association with a compatible pharmaceutical
carrier material.
The carrier material present in the
pharmaceutical preparations provided by this
invention can be any solid or liquid carrier
material which is compatible with the peptide derivatives aforesaid, and with the antibiotics
when such are present, and which is suitable for
therapeutic administration. The carrier material
can be an organic or inorganic carrier material
which is suitable for enteral (e.g. oral) or parenterai administration. Examples of such
carrier materials are water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, gum arabic, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragées, suppositories or capsules) or in a liquid form (e.g.
as solutions, suspensions or emulsions). The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilisation and may contain adjuvants such as preserving agents, stabilising agents, wetting agents, emulsifying agents, salts for varying the osmotic pressure or buffers. When a buffer is used, the pH of the pharmaceutical preparation will, of course, vary within the range which is well-known in pharmaceutical practice.
When the present pharmaceutical preparations contain a peptide derivative and an antibiotic, the weight ratio of peptide derivative to antibiotic can vary within wide limits. In general, the pharmaceutical preparations can contain the peptide derivative and antibiotic in a weight ratio of from 1:100 to 100:1, preferably in a weight ratio of from 1:64 to 64:1 and especially in a weight ratio of from 1:16to 16:1.
The daily dosage of peptide derivative administered alone or in combination with an antibiotic will vary within wide limits depending on factors such as the particular peptide derivative chosen, the particular antibiotic chosen, the route of administration and the infection to be treated. For example, when a peptide derivative is administered alone, a daily dosage for oral administration may amount to about 2000 mg to 4000 mg and a daily dosage for parenteral administration may amount to about 800 mg to 2000 mg. When a peptide derivative is administered in combination with an antibiotic, a daily dosage for oral administration may amount to about 750 mg to 1 500 mg of a combination of the peptide derivative and antibiotic and a daily dosage for parenteral administration may amount to about 200 mg to 2000 mg of a combination of peptide derivative and antibiotic.It will be appreciated that daily dosages can be administered in a single dosage or in divided dosages and that the dosages mentioned earlier may be varied upwards or downwards according to individual requirements and fitted to the exigencies of a particular situation as determined by the prescribing physician.
The following Examples illustrate the process provided by the present invention:
Example 1 (A) The preparation of the starting material:
5.0 g (48 mmol) of L--aminobutyric acid were dissolved in 24 ml of 2-N sodium hydroxide and the solution was cooled to OOC. 12.3 g (72 mmol) of benzyl chloroformate and 1 8 ml (72 mmol) of 4-N sodium hydroxide were added alternately and portionwise while stirring over a period of 0.5 hour in such a manner that the temperature did not exceed 100C and that the pH was maintained at ca 11. The mixture was allowed to reach room temperature slowly and was then stirred
overnight. The mixture was extracted with 50 ml
of diethyl ether and the organic and aqueous
phases were separated.The aqueous phase was
acidified to pH 2 with 5-N-hydrochloric acid to
give an oily mixture. This mixture was extracted
with two 75 ml portions of diethyl ether. The
extracts were dried over sodium sulphate and
evaporated to give 9.6 g of a colourless oil. This
oil was dissolved in 10 ml of ethyl acetate and
100 ml of petroleum ether (boiling point 40- 600C) were added to give an oily solution which
was left to stand at OOC. There was obtained a
white crystalline precipitate which was filtered
off, washed with petroleum ether and dried to
give 8.40 g (73%) of N-benzyloxycarbonyl-L-cr- aminobutyric acid of melting point 760--780C; [aj20=lO.90; [a]'2065- 20.30(c=1% in ethanol).
(B) The process:
(i) 8.30 g (35 mmol) of N-benzyloxycarbonyl-La-amino-butyric acid and 4.02 g (35 mmol) of Nhydroxysuccinimide were dissolved in 75 ml of dimethoxyethane while stirring and the solution was cooled to OOC. 7.94 g (38.5 mmol) of dicyclohexylcarbodiimide were added and the mixture was stirred at OOC for 2 hours and then left to stand at OOC overnight. The solid byproduct was filtered off. The filtrate was evaporated to give N-benzyloxycarbonyl-L--aminobutyric acid
N-hydroxy-succinimide ester in the form of a stiff gum which was used without further purification.
(ii) 4.38 g (35 mmol) of(lR)-l- aminoethylphosphonic acid were dissolved in a mixture of 40 ml of water, 7.07 g (70 mmol) of triethylamine and 40 ml of dimethylformamide while stirring. The resulting solution was cooled to OOC and a solution of 35 mmol of N benzyloxyca rbonyl-L-a-a minobutyric acid Nhydroxysuccinimide ester in 40 ml of dimethylformamide was rapidly added dropwise.
The mixture was stirred at OOC and was then allowed to come to room temperature while stirring overnight. The mixture was filtered to remove a small amount of solid. The filtrate was evaporated under an oil-pump vacuum. The residue was dissolved in a mixture of 30 ml of methanol and 10 ml of water and passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 150 g; freshly regenerated in the acid cycle), elution being carried out with the same solvent. The acid eluate was collected and evaporated to give a slightly gummy white solid. This solid was triturated with 100 ml of diethyl ether and the diethyl ether was decanted off. The residual solid was dissolved in a mixture of 100 ml of methanol and 50 ml of water and the resulting solution was titrated to pH 4.5 with 4-N aqueous benzylamine (titre 8.0 ml; theory 8.75 ml). The mixture solidified towards the end of the titration, and the precipitate was filtered off, washed with water and dried to give 8.84 g of the monobenzylamine salt of (1 P)-1-[(N- benzyloxycarbonyl-L-a-aminobutyryl)aminoj- ethylphosphonic acid of melting point 2280-- 231 0C (decomposition); [a]20=3 1.30; kr]2 5=105 (c=1% in glacial acetic acid).
(iii) 8.7 g (19.3 mmol) of the monobenzylamine salt of (1 R)- 1 -[(N-benzyloxycarbonyl-L-a- aminobutyryl)amino]-ethylphosphonic acid were stirred at room temperature for 6 hours with 20 ml of a mixture of 45% hydrogen bromide in glacial acetic acid and 8 ml of glacial acetic acid.
100 ml of ether were added, a gum precipitating.
This gum was washed by decantation with 100 ml of diethyl ether and dissolved in 100 ml of methanol. The solution was stirred and two 5 ml portions of propylene oxide were added to a pH of ca 5, there being thus obtained a white precipitate. The mixture was left to stand overnight, the precipitate was filtered off, washed successively with methanol and diethyl ether and dried to give 4.05 g of crude (1 R)-1-(L-a- aminobutyrylamino)-ethylphosphonic acid of melting point 2980C (decomposition).
Recrystallisation from a mixture of 750 ml of water and 1500 ml of ethanol gave a white crystalline precipitate which was washed with ethanol and then with diethyl ether and subsequentiy dried in vacuo. There were thus obtained 3.58 g (88%) of (1 P)-1 -(L-a- a mi nobutyrylamino)-ethyl-phosphonic acid of melting point 296 --298 C (decomposition); [a]020=-33.1 0; [a]s2065=-14 50 (c=1 -N sodium hydroxide, freshly prepared).
Example 2 (A) The preparation of the starting material:
5.0 g (42.5 mmol) of L-norvaline were treated with 10.2 g (60 mmoi) of benzyl chloroformate and sodium hydroxide in the manner described in
Example 1(A). The crude oily product was crystallised from a mixture of 10 ml of diethyl ether and 20 ml of petroleum ether (boiling point 40 --60 C) to give 8.2 g (77%) of Nbenzyloxycarbonyl-L-norvaline of melting point 850--870C; [a]20=-9 90; [a]32065=-26.50 (c=1% in ethanol).
(B) The process:
(i) In a manner analogous to that described in
Example 1 (B) (i), from 8.1 g (32 mmol) of N benzyloxycarbonyl-L-norvaline, 3.68 g (32 mmol) of N-hydroxysuccinimide and 7.21 g (35 mmol) of dicyclohexylcarbodiimide there was obtained, after trituration of the oily product with 25 ml of ethanol, a white crystalline product. Addition of 25 ml of petroleum ether (boiling point 40 -- 600C) and filtration gave 9.82 g of Nbenzyloxycarbonyl-L-norvaline Nhydroxysuccinimide ester which was used directly in- the next step. A purified sample melted at 95 --97 C and showed an optical rotation [a]D20=--35.1 (c=1% in ethanol).
(ii) In a manner analogous to that described in
Example 1(B) (ii), from 9.82 g (28 mmol) of Nbenzyloxycarbonyl-L-norvaline Nhydroxysuccinimide ester and 3.75 g (30 mmol) of (1 P)-1 -aminoethylphosphonic acid, but carrying out the titration with a mixture of 150 ml of methanol and 30 ml of water in place of diethyl ether, there were obtained 7.61 g of the monobenzylamine salt of (1 P)-1 -[(N benzyloxycarbonyl-L-norvalyl)amino]- ethylphosphonic acid of melting point 225 -- 2300C (decomposition); [α]D20=--29.9 ; [(22065=98.80 (c=1% in acetic acid).
Evaporation of the filtrate and trituration of the residue with 100 ml of hot water followed by filtration and washing with ethanol and then with diethyl ether gave a second crop of 1.99 g of the monobenzylamine salt of (1 P)-1-[(N- benzyloxycaronyl-L-novaly)amino]- ethylphosphonic acid of melting point 231 -- 2340C (decomposition); [aj20=-29.70; [a]22065=-99.20 (c=1 % in acetic acid). The total yield was 9.60 g (73%).
(iii) In a manner analogous to that described in
Example 1(B) (iii), from 9.0 g (19 mmol) of the monobenzylamine salt of (1 P)-1-[N- benzyloxycarbonyl-L-norvalyl)amino]ethylphosphonic acid there was obtained, after recrystallisation from a mixture of 80 ml of water and 160 ml of ethanol, 3.54 g (82%) of (1 R)-1 -(Lnorvalylamino)-ethylphosphonic acid of melting point 260 --262 C (decomposition); [α]D20= 19.5 ; [a]23065=-75.30 (c=1% in water).
Example 3 (A) The preparation of the starting material:
5.0 g (38 mmol) of L-norleucine were treated with 9.7 g (57 mmol) of benzyl chloroformate and sodium hydroxide in a manner analogous to that described in Example 1(A). The product, N benzyloxycarbonyl-L-norleucine, was isolated in the form of an oil which was used in the process without crystallisation.
(B) The process:
(i) In a manner analogous to that described in
Example 1(B) (i), from ca 38 mmol of N benzyloxycarbonyl-L-norleucine, 4.38 g (38 mmol) of N-hydroxysuccinimide and 8.65 g (42 mmol) of dicyclohexylcarbodiimide there were obtained, after trituration of the crude oily product with 100 ml of diethyl ether, 7.47 g of Nbenzyloxycarbonyl-L-norleucine Nhydroxysuccinimide ester in the form of a crystalline solid of melting point 820--840C; [a] 020= 20.70 (c=1% in acetone).
(ii) In a manner analogous to that described in
Example 1(B) (ii), from 7.40 g (20.5 mmol) of Nbenzyloxycarbonyl-L-norleucine Nhydroxysuccinimide ester and 2.56 g (20.5 mmol) of (1 R)-1-aminoethylphosphonic acid, but carrying out the ion exchange step in methanol/water (5:1) instead of methanol/water (3:1), there was obtained, after evaporation and trituration of the crude product with ether, a solid which was digested with 150 ml of hot water, cooled and filtered to give 5.64 g (74%) of (1 P)-1- [(N-benzyloxycarbonyl-L-norleucyl)amino]-ethyl- phosphonic acid of melting point 192 --194 C (decomposition); [aj020=-37.80; [a]22065=-1 26.50 (c=0.5% in acetic acid).
(iii) In a manner analogous to that described in
Example 1 (B)(iii), from 5.20 g (14.0 mmol) of (1 R)-1 [(N-benzyloxycarbonyl-L-norleucyl)amino]- ethylphosphonic acid there were obtained, after recrystallisation from a mixture of 70 ml of water and 280 ml of ethanol, 3.02 g (91%) of (1 P)-1 -(Lnorleucylamino)ethylphosphonic acid of melting point 2540--2560C (decomposition); []D20=18.6 ; [a]23065=~70.1 (c=1% in water).
Example 4
(a) In a manner analogous to Example 1(B) (ii) and Example 2(B) (ii), from 17.4 g (50 mmol) of N-benzyloxycarbonyl-L-norvaline Nhydroxysuccinimide ester and 5.55 g (50 mmol) of aminomethylphosphonic acid, but carrying out the titration with benzylamine in a mixture of 250 ml of methanol and 50 ml of water, there were obtained 17.3 g of the crude monobenzylamine salt of the desired product, of melting point 195198 (decomp) (Crop 1). Evaporation of the filtrate and recrystallisation of the residue from a mixture of methanol (80 ml) and water (20 ml) gave a further 2.19 g of essentially pure product (talc), having a melting point of 1 80- 1850 (dec). The total yield was 19.5 g (86%).
Recrystallisation of a 0.5 g sample of Crop 1 from 10 ml of hot water gave a crop of 0.39 g of the pure monobenzylamine salt of (N benzyloxycarbonyl-L-norvalyl)amino- methylphosphonic acid of melting point 2032050 (dec); [(t,],20,-8.20; [a]= 21,30 (c=0.5%, in acetic acid).
(b) In a manner analogous to that described in
Example 1(B) (iii), from 18.9 g (42 mmol) of the monobenzylamine salt of (N-benzyloxycarbonyl-Lnorvalyl)-aminomethyl-phosphonic acid there was obtained, after recrystallisation from a mixture of 80 ml of water and 160 ml of ethanol, 6.65 g (75%) of L-(norvalylamino)-methylphosphonic acid of melting point 273--2750 (dec); [a]0w=+61.2O, []365=+224 (c=0.54%, H2O).
Example 5
N-Benzyloxycarbonyl-L-norvaline (45.4 g 0.181 m) was stirred in methylene dichloride solution (200 mls) as dimethyl
aminomethylphosphonate hydrochloride (31.76 g., 0.181 m) was added. The resulting suspension was cooled to -1 20C as dry triethylamine (25.3 ml 0.181 m) was added dropwise. After the addition was complete, the cold mixture was stirred for 1 5 minutes before E.E.D.Q. (56.8 g 0.23 m) in methylene dichloride (100 ml) was added rapidly. This mixture was stirred cold for 2 hours, and then stirred at room temperature over the weekend.
The mixture was washed with water (100 ml) then with 1 N hydrochloric acid (4 times, with
100 ml each time). The total acid wash was backextracted with methylene dichloride (2x50 ml).
The combined organic solution was washed again with water (100 ml) and finally with 1 5% KHCO2 solution (3x100 ml), then dried overanhydrous sodium sulphate. The solution was filtered and evaporated down. The residual oil was reevaporated down with benzene, to give a residue weighing 78.13 g.
The first signs of crystallisation were seen at this time. The oil was triturated with anhydrous ether (200 ml) in which it dissolved. Very soon crystallisation spread throughout the solution. The solution was refrigerated for 1 hour, the solid was filtered off, washed with ether and dried to constant weight in vacuo. There was obtained 58.2 g of a material having a melting point of 77-800C.
This was taken up in hot ethyl acetate (200 ml) and the solution filtered. To the cooled filtrate was added ether (200 ml). The mixture was seeded and refrigerated overnight. The solid was filtered off, washed with ether and dried in vacuo to give 50.64 g of a residue of m.p. 82-840C.
37.2 g of [(N-benzyloxycarbonyl-L norvalyl)amino]dimethylphosphonate was stirred in 45% hydrogen bromide in acetic acid (120 ml) for 5 hours. Initially carbon dioxide evolution was very rapid. Ether (500 ml) was added and this precipitated an oil. The mixture was stirred for 40 minutes, and then allowed to settle. The ether was decanted off and the oil was washed a further twice with ether, 500 ml each time.
The oil was taken up in methanol (300 ml) and the solution was stirred as propylene oxide (40 ml) was added. After about 5 minutes the product began to crystallise out. The mixture was adjusted to a pH of 4 and was refrigerated overnight.
The solid was filtered off and washed well with methanol, and then with ether. It was dried in vacuo, to give a residue of 20.13 g having a m.p.
of 288--9 OC (d).
This was taken up in hot water (200 ml) and filtered. To the filtrate was added 400 ml ethanol.
On standing, the material crystallised out. It was refrigerated for 2 hours. The solid was filtered off, washed with ethanol and then ether, and dried over phosphorus pentoxide in vacua. 16.66 9 were obtained of (L-norvalylamino)methylphosphonic acid of mp. 293-40C (d) [a]020=+62.70 (c=0.5% in water).
Example 6
(a) L-Nitro-homoarginine (2.33 g, 1 0 mmol, m.p. 227--2300 (dec)) was treated with 3.41 g (20 mmol) of benzyl chloroformate and sodium hydroxide in the manner described in Example 1(A). The crude oily product was extracted from the acidified solution with ethyl acetate (twice with 100 ml) instead of with diethyl ether. The crude oily product, N-benzyloxycarbonyl-o-nitro- L-homoarginine, obtained after drying over sodium sulphate and evaporation, was obtained as a gum which was used in the following step without further purification.
(b) In a manner analogous to that described in
Example 1(B) (i), but using dimethyl formamide (50 ml) as solvent, from ca 4.2 g (approx. 10 mmol) of the crude N-benzyloxy-carbonyl-wnitro-L-homoarginine (obtained as above), 1.15 g (10 mmol) of N-hydroxysuccinimide and 2.27 g (11 mmol) of dicyciohexylcarbodiimide there was obtained after removal of 1.73 g of dicyclohexylene and evaporation of the filtrate, the crude product N-benzyloxycarbonyl-co-nitro- L-homoarginine N-hydroxysuccinimide ester as a yellow oil which was used in the next step without further purification.
(c) In a manner analogous to that described in
Example 1(B) (ii), from ca 10 mmol of N benzyloxycarbonyl-w-nitro-l-homoarginine Nhydroxysuccinimide ester and 1.25 g (10 mmol) of (1 R)-1 -aminoethylphosphonic acid, but carrying out the treatment with ion exchange resin RS03H in 5:1 MeOH:H2O instead of 3:1. The acid eluate was evaporated and partitioned between water (300 ml) and ethyl acetate (150 ml) when some insoluble material was obtained.
This was filtered off and dried to give 1.36 g of crude product having a m.p. of 190--1930 (dec), as characterised by tic and N.M.R. (Crop 1).
The filtrate solvent layers were separated, the aqueous layer was evaporated to dryness and the residue was triturated with acetone (50 ml) to give a white precipitate. This precipitate was filtered off and washed with acetone, and dried to give a further 1.43 g (m.p. 184--8 (dec)) of the product, (1 R)-1 [(N-benzyloxycarbonyl-w-nitro-L- homoarginyl)amino]-ethylphosphonic acid (Crop 2). Crops 1 and 2 were used in the next step without further purification.
(d) In a manner analogous to that described in
Example 1 (B)(iii), from 2.7 g (ca 5.7 mmol) of (1 R)-l -[(N-benzyl-oxyca rbonyl-o-n itro-l- homoarginyl)amino]-ethylphosphonic acid (Crops
1 and 2 above) there were obtained, after recrystallisation from a mixture of 15 ml of water and 150 ml ethanol, 1.23 g of (1 P)-1-(L-w-nitro- homoarginylamino)-ethylphosphonic acid of m.p.
ca 1900 (dec); [α]D20= 10.6 ; [a]22065=-43.50 (c=0.53%, H2O).
Evaporation of the filtrate and recrystallisation from water (5 ml) and ethanol (100 ml) gave a further 0.14 g of product having an m.p. ca 1900
(dec); [Cg]DO=11.2 ; [a]220s5=-43.20 (c=0.51% H20).
The total yield was 1.37 g (71%).
(e) 1.2 g (3.5 mmol) of (1 P)-1 -L-w-nitro- homoarginylamino-ethylphosphonic acid,
prepared as above, was taken up in 50 ml of
water, and 0.35 g of 10% Pd/charcoal was added.
The mixture was hydrogenated at ambient
temperature and pressure until uptake ceased,
(about 5 hours). The mixture was filtered to
remove the catalyst and the filtrate was
evaporated. The gummy solid residue was taken
up in 15 ml of cold water and the solution was filtered and treated with 120 ml of ethanol to give
a precipitate which was allowed to stand for 1
hour and then filtered off.There was obtained
0.76 g of (1 R)-1-(L-homoarginylamino)
ethylphosphonic acid of melting point ca 1 950 (dec); [a]20=1 190 (c=0.5%, H2O)- Example 7
(i) In a manner analogous to that described in
Example 1(B) (ii), from a solution of 45 mm,ol of N-benzyloxycarbonyl-L-α-aminobutyric acid Nhydroxysuccinimide ester in 40 ml dimethylformamide and 4.44 g (40 mmol) of aminomethylphosphonic acid, but using methanol:water of 4:1 instead of 2:1, there were obtained 14.1 g of the monobenzylamine salt of [(N-benzyloxyca rbonyl-L-x-aminobutryl)amino]- methylphosphonic acid of m.p. 185195 (dec).Evaporation of the filtrate and recrystallisation of the residue from a mixture of 50 ml of water and 50 ml of methanol gave as a white crystalline precipitate a further 1.6 g of product of m.p. 205208 (dec); [α]D20-6.1 0; [a]23065-21 .10 (c=0.51%, CH3COOH).
(ii) In a manner analogous to that described in
Example 1(B) (iii) from 15.6 g (ca 36 mmol) of the monobenzylamine salt of [(N-benzyloxycarbonyl L-a-aminobutyryl)amino]-methylphosphonic acid, prepared as above, there was obtained 5.92 g of crude product of m.p. 253255 (dec).
Recrystallisation from a mixture of 60 ml of water and 120 ml of ethanol gave 4.93 g of (L-a- aminobutyryiamino)-methyiphosphonic acid of m.p. 263265 (dec); [α]D20+57.0 ; [a]22065+2120 (c=0.51%, H20).
Example 8
(i) In a manner analogous to that described in
Example 3(B) (ii), from 2.52 g (7 mmol) of N benzyloxycarbonyl-L-norleucine Nhydroxysuccinimide ester and 0.78 g (7 mmol) of aminomethylphosphonic acid, but carrying out the ion exchange step in methanol/water of 2:1 instead of 5:1 and titrating the acid eluate directly with benzylamine (omitting evaporation and trituration with ether followed by dissolving in methanol/water again), there were obtained, after stirring with 1 00 ml of acetone, 0.56 g of the monobenzylamine salt of [(N-benzyloxycerbonyl- L-norleucyl)amino]-methylphosphonic acid having an m.p. of 1 85-1 890 (dec). Evaporation of the filtrate and trituration with 50 ml of diethyl ether gave a further 1.9 g of product, m.p. 170180 (dec).
(ii) In a manner analogous to that described in
Example 1(B) (iii), from 2.40 g (ca 5.2 mmol) of the monobenzylamine salt of [(Nbenzyloxycarbonyl-L-norleucyl)amino]methylphosphonic acid, prepared as above, and using both crops, there was obtained 1.04 g of crude product of melting point 263266 (dec).
Recrystallisation from a mixture of 20 ml of water and 120 ml of ethanol gave 0.88 g of (Lnorleucylamino)-methylphosphonic acid of m.p.
272274 (dec); [a]20+6340; [a]32065+2310 (c=0.5%, H20).
The following Example illustrates a typical pharmaceutical preparation containing the peptide derivatives provided by the present invention:
Example A
A parenteral formulation containing the following ingredients can be prepared:
Per
1000 ml
Peptide derivative 50.0 g
Chlorocresol 1.0 g Glacial acetic acid 1.2 g
Sodium hydroxide solution (0.1-N) q.s. ad pH 4.5
Water for injection ad 1000 ml
Claims (30)
1. Compounds of the general formula
wherein R1 represents a hydrogen atom or the methyl or hydroxymethyl group or a mono-, di- or trihalomethyl group; R2 represents a lower alkyl, hydroxy-(lower alkyl) or guanidino-(lower alkyl) group other than the characterising group of an a- amino acid of the type normally found in proteins; the configuration at the carbon atom designated as (a) is (R) when R' represents other than a hydrogen atom; and the configuration at the carbon atom designated as (b) is (L), and pharmaceutically acceptable salts thereof.
2. Peptide derivatives as claimed in claim 1, wherein R' represents a hydrogen atom or the methyl group.
3. Peptide derivatives as claimed in claim 1 or claim 2, wherein R2 represents a lower alkyl group.
4. Peptide derivatives as claimed in claim 3, wherein R2 represents the ethyl, n-propyl or nbutyl group.
5. (1 P)-1 -[L-(a-Aminobutyryl)amino]- ethylphosphonic acid.
6. (1 R)-1-(L-Norieucylamino)-ethylphosphonic acid.
7. (1R)-l -(L-Norvalyiamino)-ethylphosphonic acid.
8. (L-a-Aminobutyrylamino)-methyl- phpsphonic acid.
9. (LNorleucylamino)-methylphosphonic acid.
1 0. (L-Norvalylamino)-methylphosphonic acid.
11. (1P)-1-(L-Homoarginylamino)- ethylphosphonic acid.
1 2. (L-Homoarginylamino)-methylphosphonic acid.
1 3. A process for the manufacture of the peptide derivatives claimed in claim 1, which process comprises condensing a compound of the general formula
wherein R'O has any of the values according to
R1 hereinbefore or represents a protected hydroxy group; R3 and R4 each represent a hydrogen atom or a lower alkyl protecting group; and the configuration at the carbon atom designated as (a) is (R) when R'O represents other than a hydrogen atom, with a protected er-amino acid of the general formula
wherein R20 has any of the values accorded to R2 hereinbefore or represents a protected hydroxy-(lower alkyl) or guanidino-(lower alkyl) group;R5 represents a protected amino group; and the configuration at the carbon atom designated as (b) is (L), claving off the protecting group or groups present in the condensation product and, if desired, converting a resulting compound of formula I into a pharmaceutically acceptable salt.
14. A process as claimed in claim 13, wherein a peptide derivative in which R' represents a hydrogen atom or the methyl group is manufactured.
1 5. A process as claimed in claim 1 3 or claim 14, wherein a peptide derivative in which R2 represents a lower alkyl group,is manufactured.
1 6. A process as claimed claim 15, wherein a peptide derivative in which R2 represents the ethyl, n-propyl or n-butyl group is manufactured.
1 7. A process for the manufacture of the peptide derivatives claimed in claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 8.
18. A peptide derivative as claimed in claim 1, when manufactured by the process claimed in any one of claims 13 to 1 6 inclusive or by an obvious chemical equivalent thereof.
1 9. A pharmaceutical preparation containing a peptide derivative as claimed in any one of claims 1 to 12 inclusive in association with a compatible pharmaceutical carrier material.
20. A pharmaceutical preparation containing a peptide derivative as claimed in any of claims 1 to 12 inclusive and an antibiotic in association with a compatible pharmaceutical carrier material.
21. A pharmaceutical preparation as claimed in claim 20 wherein said antibiotic is an antibiotic as specified hereinbefore.
22. Compounds of the general formula
wherein R3, R4, R5, Rlq and R20 have the significance given in claim 13 and the configuration at the carbon atoms designated as (a) and (b) is as specified in claim 13.
23. (1 R)-1-[(N-Benzyioxywarbonyl-L-cg- aminobutyryl)aminoj-ethylphosphonic acid.
24. (1 R)- 1 -[(N-Benzyloxycarbonyl-Lnorvalyl)amino]-ethylphosphonic acid.
25. (1 R)-1-[(N-Benzyloxycarbonyl-L- norleucyl)amino]ethylphosphonic acid.
26. [(N-Benzyloxycarbonyl-L-a- aminobutyryl)amino]-methylphosphonic acid.
27. [(N-Benzyloxycarbonyl-L-norleucyl)amino]- methylphosphonic acid.
28. [(N-Benzyloxycarbonyl-L-norvalyl)amino]- methylphosphonic acid.
29. (1 R)-1 -[N-Benzyloxycarbonyl-so-nitro-L- homoarginyl)amino]-ethylphosphonic acid.
30. [(N-Benzyloxycarbonyl-w-nitro-L- homoarginyi)amino]-methylphosphonic acid.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7909676A GB2027433B (en) | 1977-12-20 | 1979-03-20 | Aminoalkanoylaminoalkyl phosphonic acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB5293877 | 1977-12-20 | ||
GB7909676A GB2027433B (en) | 1977-12-20 | 1979-03-20 | Aminoalkanoylaminoalkyl phosphonic acids |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2027433A true GB2027433A (en) | 1980-02-20 |
GB2027433B GB2027433B (en) | 1982-11-03 |
Family
ID=26267168
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7909676A Expired GB2027433B (en) | 1977-12-20 | 1979-03-20 | Aminoalkanoylaminoalkyl phosphonic acids |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2027433B (en) |
-
1979
- 1979-03-20 GB GB7909676A patent/GB2027433B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB2027433B (en) | 1982-11-03 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |