AU767543B2 - Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin - Google Patents
Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin Download PDFInfo
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- AU767543B2 AU767543B2 AU55583/00A AU5558300A AU767543B2 AU 767543 B2 AU767543 B2 AU 767543B2 AU 55583/00 A AU55583/00 A AU 55583/00A AU 5558300 A AU5558300 A AU 5558300A AU 767543 B2 AU767543 B2 AU 767543B2
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- 150000001875 compounds Chemical class 0.000 claims description 49
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 229960001866 silicon dioxide Drugs 0.000 description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000002955 isolation Methods 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 101150041968 CDC13 gene Proteins 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000006140 methanolysis reaction Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940086542 triethylamine Drugs 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000006179 O-acylation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- NPHULPIAPWNOOH-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(2,3-dihydroindol-1-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCC2=CC=CC=C12 NPHULPIAPWNOOH-UHFFFAOYSA-N 0.000 description 1
- VXZBYIWNGKSFOJ-UHFFFAOYSA-N 2-[4-[5-(2,3-dihydro-1H-inden-2-ylamino)pyrazin-2-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC=1N=CC(=NC=1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 VXZBYIWNGKSFOJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 238000003833 Wallach reaction Methods 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Description
D ERIVATIVES OF 4'DM CRSL8-AA8-O
OYOI
Technical Field IPC: A 61 K31/70 C 07 FH 17/08 Technical Problem The present invention relates to novel compounds from the class of 17-membered azalides having an antibacterial action. More particularly, the invention relates to derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin of the fonmula I
H
3
C
I 00H 3
OCH
3
CH
3 wherein R represents CHO, CH(OCH 3 2 or CH 2
N[CH
2
(C
6
H
5 )12, R' represents C 1
-C
3 acyl, or R1 represents H when R 2 and R 3 or R 4 and R 5 together are =0, R represents OR 6and R6 represents H or C 1
-C
3 acyl, repeet H or R 2 and R 3 together represent =0, Rrepresents OH,
R
5 rersnsH or W" and R 5 together represent =0, and to a process for the preparation thereof.
Prior A rt 4'-Demycarosyl-8a-aza-a-homotyloslfl, a novel semisynthetic macrolide from the class of 17-membered azalides, was prepared by -a double transformation of C-9 -ketone of the 16-membered antibiotic 4'-demycarosyl-tylosmn L. Harmill, Antibiotics and Chemotherapy 11, _328 (196 A. Narandja et al, EP 0 287 082 Bi1; N.
Lopotar et al, EP 0 410 433 BI). By reductive amination. of C-20 aldehyde group in the presence of formic acid (Wallach reaction, J. March: "Advanced Organic Chemistry", third ed. 6-15 p. 799 Wiley, New York 1985) there was prepared 4'deyaoy-0doo2-iezlmn-aaa8-ooyoi Lopotar, HR Patent Application P940962A, 30.11.1994).
CI-C
3 acyl esters of 4'-demycarosyl-8a-aza-8a-homotylosifl and of 4'-deinycarosyl- 20-deoxo-20-dibenzylamino-8a-aza-8a-homnotylo51fl as well as 4"-deoxy-4"-oxo- and 3-deoxy-3 -oxo derivatives of 4'-demycarosyl-8a-aza-8a- homotylosmn and of 4'demycarosyl-20-deoxo-20-dibenzylanfo-8a-aza-8a-homotylosin,
CI-C
3 acyl esters thereof and a process for the preparation thereof have hitherto not been disclosed in Prior Art.
Detailed Description of the Invention Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosifl of the formula I .0.0 00 WO 00/77016 PCT/HROO/00018 3 CO- NH OH3 8a
H
3 0 o 0OH R2 H 3 R1CHH32
OCOH
3 wherein R represents CHO, CH(OCH 3 2 or CH 2
N[CH
2
(C
6
H
5 2
R
1 represents H or CI-C 3 acyl, 1(2 represents OR 6 and W 6 represents H or CI-C 3 acyl, R3 represents H or R2 and R 3 together represent =0,
W
4 represents OH, R 5 represents H or W( and R 5 together represent =0, may be prepared in such a way that 4'-demycarosy-8a-aza-8a-homotylo51fl 20-dimethylacetal of the formula Ila and 4'demycarosy1-20deoxo20dibezylamflo-8a-aza 8 ahomotylosin of the formula Ilb CO-NH OH3 8a
R
H
3 0
H
3 0 3 N(0H 3 2
OCH
3 OHH3
OH
3 Ila R CH(OCH 3 2 lb R =CH 2
N[CH
2
(C
6
H
5 2 WO 00/77016 PCT/HR00/00018 4 are subjected to A) an O-acylation with anhydrides of CI-C 3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride during 15 minutes to 1 hour at room temperature, and the obtained compounds of the formula I, wherein R represents
CH(OCH
3 2 or CH 2
N[CH
2
(C
6 Hs)] 2 R' represents COCH 3
R
2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents
OH,
are optionally subjected to Al) an O-acylation with anhydrides of CI-C 3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride in the presence of an organic base, preferably triethyl amine and 4-dimethylaminopyridine as a catalyst during 30 hours at room temperature, and the obtained compounds of the formula I, wherein R represents
CH(OCH
3 2 or CH 2
N[CH
2
(C
6
H
5 2
R
1 represents COCH 3
R
2 represents OR 6 wherein R 6 represents COCH 3
R
3 and R 5 are the same and represent H and R 4 represents OH, are optionally subjected to B) an oxidation reaction with N(3-dimethylamino-propyl)-N'ethyl carbodiimide hydrochloride in the presence of dimethylsulfoxide and pyridine trifluoroacetate as a catalyst in an inert solvent, preferably methylene chloride, during 2 to 6 hours at a temperature from 10 0 C to room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH 3 2 or CH 2
N[CH
2
(C
6 H5)] 2
R
1 represents
COCH
3
R
2 represents OR 6 wherein R 6 represents COCH 3
R
3 represents H and R 4 and R 5 together represent =0, are optionally subjected to C) methanolysis at room temperature for 2 days and the obtained compounds of the formula I, wherein R represents CH(OCH 3 2 or CH 2
N[CH
2
(C
6
H
5 2
R
1 and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 and R 4 and
R
5 together represent =0, WO 00/77016 PCT/HROO/00018 are optionally subjected to Cl) an alkaline methanolysis in a mixture of methanol and 25% ammonia at a temperature from 5 0 C to room temperature during 20 to 60 hours to obtain compounds of the formula I, wherein R represents CH(OCH 3 2 or CH 2
N[CH
2
(C
6
H
5 2 R' and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and
R
5 together represent =0; or the compound obtained according to process Cl of the formula I, wherein R represents CH(OCH 3 2 R' and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and R 5 together represent =0, is optionally subjected to D) a hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N hydrochloric acid for 2 hours at room temperature to obtain the compound of the formula I, wherein R represents a CHO group, R' and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and R 5 together represent =O; or compounds obtained according to process A of the formula I, wherein R represents CH(OCH 3 2 or CH 2
N[CH
2
(C
6 Hs)] 2
R'
represents COCH 3
R
2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH, are optionally subjected to oxidation in the manner disclosed in B, and the obtained compounds of the formula I, wherein R represents CH(OCH 3 2 or
CH
2
N[CH
2
(C
6 Hs)] 2 R' represents COCH 3
R
2 and R 3 together represent R 4 represents OH and R 5 represents H, are optionally subjected to methanolysis in the manner disclosed in C, WO 00/77016 PCT/IIROO/00018 6 to obtain compounds of the formula I, wherein R represents CH(OCH 3 2 or
CH
2
N[CH
2
(C
6 Hs)] 2
R
1 and R 5 are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents OH; or the compound obtained according to process B of the formula I, wherein R represents a CH(OCH 3 2 group, R' represents COCH 3
R
2 and R 3 together represent R 4 represents OH and R 5 represents H, is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents a CHO group, R' represents COCH 3
R
2 and R 3 together represent R 4 represents OH and R represents H, is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I, wherein R represents a CHO group, R' and
R
5 are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents
OH;
or the compound obtained according to process A of the formula I, wherein R represents CH(OCH 3 2 R' represents COCH 3
R
2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and
R
4 represents OH, is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, to obtain a compound of the formula I wherein R represents CHO, R' represents
COCH
3
R
2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH; or compounds obtained according to process Al of the formula I, wherein R represents CH(OCH 3 2 or CH 2
N[CH
2
(C
6
H
5 2
R'
represents COCH 3
R
2 represents OR 6 wherein R 6 represents COCH 3
R
3 and R 5 are the same and represent H and R 4 represents OH, WO 00/77016 PCT/HR00/00018 7 are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH 3 2 or
CH
2
N[CH
2
(C
6 Hs)] 2
R
1
R
3 and R 5 are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 and R 4 represents OH; or the compound obtained according to process Al of the formula I, wherein R represents CH(OCH 3 2 R' represents COCH 3
R
2 represents OR 6 wherein R 6 represents COCH 3
R
3 and R 5 are the same and represent H and R 4 represents OH, is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents CHO, R' represents COCH 3
R
2 represents OR 6 wherein R 6 represents COCH 3
R
3 and R 5 are the same and represent H and R 4 represents OH, is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I, wherein R represents CHO, R 3 and R are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 and
R
4 represents OH.
According to the present invention novel compouds are isolated by conventional processes of extraction from aqueous solutions of halogenated hydrocarbons such as methylene chloride or chloroform and by evaporating the organic solvent to a dry residue. Optionally, the separation of the reaction products or the purification of the products for spectral analyses is carried out by flash chromatography on a silica gel column (Merck Co., Silicagel 60, 230-400 mesh/ASTM) in a solvent sistem:
CH
2 Cl 2
-CH
3 0H-conc. NH 4 0H (90:9:1.5, system CH 2 C1 2
-CH
3 0H (90:9, system B) or CHCl 3
-CH
3
COCH
3 system C).
The structure of the novel compounds was confirmed by spectrometric methods and mass analysis.
WO 00/77016 PCT/HR00/00018 The novel compounds show antibacterial action and may be also used as intermediates for preparing novel 17-membered azalide antibiotics.
The invention is illustrated and in no way limited by the following Examples.
WO 00/77016 WO 0077016PCT/HROO/00018 9 Example 1 4'-Demycarosyl-2 ',4'-di-O-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (1) 4'-Demycaro syl- 8a-aza- 8a-homotylo sin 20-dimethylacetal (5.0 g, 6.02 nunol) was dissolved in dry methylene chloride (50 mil), acetic anhydride (2.0 mil) was added and it was stirred for 15 minutes at room temperature. The reaction mixture was poured into a water/ice mixture (500 mil) and extracted twvice with methylene chloride at pH The combined organic extracts were washed with a saturated NaHCO 3 solution and water, dried (K 2 C0 3 and evaporated at reduced pressure to give a TLC homogeneous product (5.38 g; 97.8%) TLC: Rf 0.44; Rf 0.22.
IR (KBr) cnf' 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
'H NMR (CDCi 3 5 ppm 7.16 5.69 5.66 4.96 (8a-NH) exchangeable with D 2 0, 4.88 4.76 4.63 4.58 4.33 4.17 3.61 (3"-OCH 3 3.47 (2"-OCHA) 3.56 (2x20-OCHA) 2.3 3 /3'-N(CH 3 2 2.05 (COCH 3 2.03 (COCH 3 1.74 1.17 (H-2 1).
1 3 C NMR (CDC1 3 5 PPM 179.1 169.8, 169.4 (2xCOCHA) 166.2 (9-CONH), 144.7 138.2 134.9 119.2 103.5 102.0 100.9 72.5 71.4 70.3 65.6 61.5 (3"-OCHA) 59.4 (2"-OCHA) 50.4 (2x20-OCHA) 42.7 42.5 41.0 3 2 40.5 34.3 21.8, 20.9 (2xCOCHA) 21.9 (C-21), 12.6 8.3 (C-18).
FAB 917.
Example 2 4'-Demycarosyl-2 ',4'-di-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (2) WO 00/77016 WO 0077016PCTIHROO/0001 8 4'-Demycarosyl-20-deoxo-20-dibenzylamino- 8a-aza-8a-homotylosmn (2.8 g, 2.90 nunol) was dissolved in dry methylene chloride (30 ml), acetic anhydride (1.3 ml, 13.76 minol) was added and it was stirred for 15 minutes at room temperature. The reaction mixture was poured into a water/ice mixture (300 ml) and extracted twice with methylene chloride at pH 6.5. The combined organic extracts were washed with a saturated NaHCO 3 solution and water, dried (K 2 C0 3 and evaporated at reduced pressure to give a TLC homogeneous product (3.02 g; 98.9%) TLC: Rf 0.38; Rf 0.23.
IR (KBr) cnf' 1749, 1651, 1633, 1548, 1454, 1374, 1231, 1169, 1059.
'H NMR (CDCl 3 5 ppm 7.25 -7.41 (phenyl), 7. 10 11), 5.70 13), 5.65 (H-b1), 4.89 (8a-NH) exchangeable with D 2 0O, 4.84 4.74 4.60 4.15 3.62 (3"-OCH 3 3.61 (20-N-CH 2 -phenyl), 3.58 (20-CH 2 -phenyl), 3.51 (2"-OCH 3 2.32 /3'-N(CH 3 2 2.06 (COCH 3 2.00 (COCH 3 1.72 (H- 22), 1.12 (H-21).
13 C NMR (CDCl 3 5 PPM 173.4 169.9, 169.5 (2xCOCHA) 166.1 (9-CONH), 144.8 137.9 135.2 119.3 102.3 101.0 72.5 71.4 70.4 66.0 61.5 (3"-OCH 3 59.5 3 52.2 42.9 42.4 41.0 /3'-N(CH 3 2 38.7 29.4 19), 21.8 21.1, 21.0 (2xCOCHA) 12.7 8.4 18), 2
C
6
H
5 2 139.8, 129.1, i28.0, 126.6, 57.9.
FAB 1052.
Example 3 4'-Demycarosyl-2 ',4',4"-tri-O-acetyl-8a-aza-8a-homotylosin (3) Compound 1 (4.0 g, 4.37 mmol) was dissolved in dry methylene chloride (100 ml), triethyl amine (7.0 ml), 4-dimethylaniinopyridine (0.12 g) and acetic anhydride (0.42 ml, 4.45 mmol) were added and then the reaction solution was left to stand for 26 WO 00/77016 PCT/HROO/00018 11 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 1 to give a TLC homogeneous product (4.08 g; 97.7 TLC: Rf(A) 0.65; Rf(C) 0.54.
IR (KBr) cm-' 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.
'H NMR (CDC13) 5 ppm 7.16 5.69 5.65 4.89 (8a-NH) exchangeable with D 2 0, 4.88 4.76 4.64 4.59 4.33 4.18 3.52 (3"-OCH 3 3.46 (2"OCH 3 3.36 (20-OCH 3 3.35 (20-OCH 3 2.33 /3'-N(CH 3 2 2.12 (COCH 3 2.05 (COCH 3 2.03
(COCH
3 1.74 1.16 (H-21).
3 C NMR (CDC1 3 5 ppm 173.1 170.1, 169.8, 169.4 (3xCOCH 3 166.1 (9-CONH), 144.7 138.0 134.9 119.2 103.7 102.1 100.9 74.5 71.4 70.3 65.6 61.3 (3"-OCH 3 59.3 (2"-OCH 3 53.7 (20-OCH 3 50.6 (20-OCH 3 42.7 42.6 41.0 /3'-N(CH 3 2 40.5 34.5 21.9, (C- 21), 21.1, 21.0, 20.7 (3xCOCH 3 12.7 8.3 (C-18).
FAB 959.
Example 4 4'-Demycarosyl-2',4',4"-tri-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (4) Compound 2 (2.8 g, 2.66 mmol) was dissolved in dry methylene chloride (60 ml), triethyl amine (3.7 ml), 4-dimethylaminopyridine (0.07 g) and acetic anhydride (0.25 ml, 1.64 mmol) were added and then the reaction solution was left to stand for 26 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 1 to give a TLC homogeneous product (2.7 g; 92.9 TLC: Rf(B) 0.55; Rf(C) 0.47.
IR (KBr) cm' 1747, 1651, 1632, 1538, 1453, 1372, 1233, 1170, 1051.
'H NMR (CDC13) 5 ppm 7.22 7.41 (phenyl), 7.10 5.70 5.65 WO 00/77016 PCT/HR00/00018 12 4.91 (8a-NH) exchangeable with D 2 0, 4.86 4.74 4.66 4.46 4.15 3.61 (2x20-N-CH 2 -phenyl), 3.53 (3"-OCH 3 3.50 (2"-OCH 3 2.32 /3'-N(CH 3 2.12 (COCH 3 2.06 (COCH 3 2.00 (COCH 3 1.72 1.12 0.78 (H-18).
13C NMR (CDC13) 5 ppm 173.3 170.1, 169.9, 169.5 (3xCOCH 3 166.1 (9-CONH), 144.8 137.9 135.2 119.3 102.3 101.0 74.6 71.4 70.4 66.0 61.5 (3"-OCH 3 59.3 (2"-OCH 3 52.2 42.9 42.4 41.0 /3'-N(CH 3 2 38.7 29.4 21.8 21.1, 21.0, 20.7 (3xCOCH 3 12.7 8.4 (C-18), 2
C
6 H5) 2 139.8, 129.1, 128.0, 126.6, 57.9.
FAB (MH 1094.
Example 4'-Demycarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin dimethylacetal A solution of pyridine trifluoroacetate (1.0 g, 5.24 mmol) in methylene chloride ml) was added drop by drop at 15 0 C to a solution of the compound 1 (1.0 g, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.22 mmol) and dimethyl sulfoxide (1.0 ml, 14.10 mmol) in methylene chloride (20 ml).
The reaction mixture was stirred for 3 hours at room temperature, then poured into water (150 ml) and after separating the organic layer, it was extracted two more times with methylene chloride. The combined organic extracts were washed with a saturated NaHCO 3 solution and water, dried (K 2 C0 3 and evaporated at reduced pressure to a dry residue. The obtained crude product (0.95 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (0.45 g).
TLC: Rf(B) 0.52.
IR (KBr)cm- 1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.
WO 00/77016 WO 0077016PCT/HROO/00018 13 'H1 NMR (CDCI 3 8 ppm 7.16 5.71 5.64 4.97 (8a-NH) exchangeable with D 2 0, 4.88 4.76 4.60 4.63 4.33 4.17 3.98 3.78 3.58 (3"-OCH 3 3.52 (2"-OCH 3 3.3 6 (20-OCHA) 3.3 5 (20-OCHA) 3.3 0 2.3 3 -N(CH 3 2 2.05 (COCHA) 2.03 (COCHA) 1.76 1.3 4 1. 17 (H-2 1).
3 C NMR (CDCl 3 6 ppm 202.4 173.1 169.9, i69.5 (2xCOCH 3 166.i (9-CONH), 144.6 i37.6 135.3 119.5 103.6 103.0 102.1 85.3 84.2 73.3 71.3 70.3 65.6 60.2 (3"-OCH 3 59.1 (2"-OCH 3 53.7 50.5 (20-OCHA) 42.7 42.6 41.0 /3-'-N(CH 3 2 40.7 34.4 21.9 21.1, 21.0 (2xCOCHA) 14.0 C-12.7 8.3 18).
FAB 915.
Example 6 4'-Demycarosyl-2 ',4'-di-O-acetyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzyl amino- 8a-aza-8a-homotylosin (6) A solution of pyridine trifluoroacetate 6 g, 3. 11 mmnol) in methylene chloride (6 ml) was added drop by drop at 15'C to a solution of the compound 2 (0.6 g, 0.57 mmol), i-(3-dimethylaminopropyl)-3-ethylcarbodiiide hydrochloride (0.6 g, 3.14 mmol) and dimethyl sulfoxide (0.45 ml, 6.35 mmnol) in methylene chloride (20 ml). The reaction mixture was stirred for 5 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (0.54 g) was purified by flash chromatography on a silica gel colun using the solvent system B to give a TLC homogeneous product (0.28 g).
TLC: Rf 0.48; Rf 0.33.
IR (KBr) cm-' 1747, 1651, 1633, 1548, 1454, 1372, 1231, 1058.
'H1 NMR (CDC1 3 6 ppm 7.25 -7.41 (phenyl), 7.12 11), 5.70 (H-i13), 5.65 1), 4.94 (8a-NH) exchangeable with D 2 0, 4.82 4.74 4.65 WO 00/77016 WO 0077016PCT/HROO/00018 14 4.15 3.98 3.78 3.62 (20-N-CH 2 -phenyi), 3.58 2 -phenyl), 3.55 (3"-OCH 3 3.49 (2"-OCH 3 2.32 /3'-N(CH 3 2 2.06 (COCHA) 2.00 (COCHA) 1.74 1.36 1. 12 (H-2 1).
1 3 C NMR (CDC1 3 8 ppm 202.4 173.4 i69.8, 169.3 (2xCOCHA) i66.1 (9-CONH), 144.6 (C-i1, 137.0 i35.6 119.6 103.0 102.2 85.3 84.8 73.3 7i.4 70.4 65.9 60.3 (3"-OCHA) 59.1 (2"-OCHA) 52.2 42.9 42.4 40.9 /3'-N(CH 3 2 3 8.7 29.4 19), 2i.8 21.i, 21. 0 (2xCOCHA) 14. 0 12.8 8.4 (C-i18), 2
C
6 H5) 2 139.6, 129.9, 128.0, 126.6, 57.8.
FAB 1050.
Examiple 7 4 '-Demycarosyl-2 ',4"-tri-O-acetyl-3-deoxy-3-oxo-8a-aza-8a-h omotylosin dimethylacetal (7) A solution of pyridine trifluoroacetate (3.0 g, 15.72 mmol) in methylene chloride ml) was added drop by drop at 15 0 C to a solution of the compound 3 (2.0 g, 2.09 mmoi), 1-(3-dimethylaniinopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 15.66 mmoi) and dimethyl sulfoxide (2.9 ml, 40.89 mmoi) in methylene chloride (50 ml).
The reaction mixture was stirred for 3 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (1.95 g) was purified by flash chromatography on a silica gel column using the solvent system C to give a TLC homogeneous product (1.3 g).
TLC: Rf 0.58.
IR (KBr) cm'1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.
'H NMR (CDCI 3 8 ppm 6.90 5.76 5.43 4.96 (8a-NH) exchangeable with D 2 0, 4.89 4.79 4.66 4.40 4.18 3.55, 3.32 3.52 (3"-OCH 3 3.49 (2"-OCH 3 3.30 WO 00/77016 PCT/HROO/00018 3 3.29 (20-OCHA) 2.34 /3'-N(CH 3 2 2.12 (COICHA) 2.06 (COCHA) 2.03 (COCHA) 1.75 1. 10 1.07 18).
1 3 C NMR (CDC1 3 5 ppm 205.6 172.9 170.1, 169.8, 169.4 (3xCOCHA) 166.1 (9-CONH), 144.1 138.0 134.9 119.6 103.7 102.1 100.9 74.5 71.4 70.3 61.3 (3"-OCH 3 59.3 (2"-OCH 3 53.7 (20-OCR 3 50.6 (20-OCR 3 46.5 44.2 42.0 41.0 /3'-N(CH 3 2 34.5 21.9, (C-21), 21.1, 21.0, 20.7 (3xCOCH 3 17.6 18), 12.7 (C-22).
FAB 957.
Example 8 4'-Demycarosyl-2,4,4"-tri-O-acety-3-deoxy-3-oxo-2deoxo-2O-dibenzylamilo- 8a-aza-8a-homotylosifl (8) A solution of pyridine trifluoroacetate (2.0 g, 10.36 mmol) in methylene chloride ml) was added drop by drop at 15'C to a solution of the compound 4 (1.0 g, 1.09 nimol), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g, 10.44 nimol) and dimethyl sulfoxide (1.6 ml, 22.56 mmol) in methylene chloride (20 ml).
The reaction mixture was stirred for 6 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (0.96 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (0.62 g).
TLC: P1 0.60.
IR (KBr) cm-1 1748, 1633, 1538, 1454, 1373, 1231, 1052.
'H NMR (CDCI 3 8 ppm 7.22 -7.40 (phenyl), 6.89 11), 5.66 5.49 13), 4.96 (8a-NH) exchangeable with D 2 0, 4.81 4.74 4.66 4.42 4.15 4.12 3.78, 3.38 3.51 (2x20-N-CH 2 phenyl, 3"-OCH 3 3.48 (2"-OCH 3 2.32 13'-N(CH 3 2 1, 2.22 2.09
(COCH
3 2.06 (COCH 3 2.00 (COCH 3 1.72 1.10 1.08 18).
WO 00/77016 PCT/HROO/00018 16 3 C NMR (CDC1 3 5 ppmn 206.7 172.7 170.1, 169.9, 169.5 (3xCOCHA) 166.1 (9-CONH), 144.0 136.5 135.0 119.9 102.7 100.9 74.6 71.3 70.3 61.3 (3"-OCH 3 59.3 (2"-OCH 3 51.7 47.7 44.5 42.0 41.0 /3'-N(CH 3 2 28.6 22.0 21.0, 20.7 (3xCOCH 3 17.8 13.1 (C-22), 2
C
6
H
2 140.1, 128.9, 128.0, 126.4, 57.9.
FAB 1092.
Example 9 4'-Demycarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homfOtylOSifl 20-dimethylacetal (9) The compound 5 (0.65 g, 0.71 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 48 hours. To the reaction solution a saturated NaHCO 3 solution was added and it was extracted twice with chloroform. The combined organic extracts were dried (K 2 C0 3 and evaporated at reduced pressure to a dry residue. The obtained crude product (0.45 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (0.20 g).
TLC: Rf 0.27.
IR (KBr) cm'1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.
'H NMR (CDC1 3 5 ppm 7.16 5.72 5.67 4.99 (8a-NH) exchangeable with D 2 0, 4.60 4.63 4.33 4.17 3.98 3.78 3.58 (3"-OCH 3 3.52 (2"-OCHA) 3.46 3.36, 3.35 (2x20-OCHA) 3.30 3.06 2.33 /3'-N(CH 3 2 1.76 (H-22), 1.34 1. 17 (H-2 1).
1 3 C NMR (CDCl 3 5 ppmn 202.4 173.1 166.1 (9-CONH), 144.6 (C-li1), 137.6 135.3 119.5 103.6 103.0 102.1 85.3 84.2 73.3 65.6 60.2 (3"-OCH 3 59.1 (2"-OCH 3 53.7 (20-OCHA) 50.5 (20-OCHA) 42.7 42.6 41.0 WO 00/77016 WO 0077016PCT/HROO/O001 8 17 /3'-N(CH 3 2 40'.7 34.4 21.9 14.0 12.7 (C-22), 8.3 18).
FAB 83 1.
Example 4'-DemycarosyI-4"-deoxy-4"-oxo-20-deoxo-20-dibelYamino-8a-aza- 8 ahomotylosin The compound 6 (0.30 g, 0.73 nimmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 30 hours. After addition of water (50 ml) the product was isolated by a gradient extraction with chloroform at pH 4.5 and 7.5. The combined chloroform extracts at pH 7.5 were dried (K 2 C0 3 and evaporated at reduced pressure and the obtained product (0.17 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (10) (0.08 g).
TLC: P1 0.49.
IR (KBr) cm-1 1715, 1655, 1619, 1542, 1454, 1377, 1168, 1082.
'H NMR (CDC 3 5 ppm 7.25 -7.41 (phenyl), 7.12 11), 5.70 13), 5.65 1), 4.94 (8a-NH) exchangeable with D 2 0, 4.84 4.74 4.60 4.15 3.98 3.78 3.62 (3"-OCHA) 3.61 (20-N-C- 2 phenyl), 3.58 (20-CH 2 -phenyl), 3.51 (2"-OCH 3 3.46 3.01 2.32 13'-N(CH 3 1.72 1.12 (H-21).
1 3 C NMR (CDC1 3 5 ppm 202.4 173.4 166.1 (9-CONH), 144.7 11), 137.1 135.6 119.7 104.2 103.0 85.4 84.9 73.3 66.4 59.8 (3"-OCH 3 58.6 (2"-OCH 3 52.2 43.3 42.3 41.5 /3'2-N(CH 3 2 3 8.7 29.4 19), 22. 0 14. 1 12.8 9. 1 (C-i18), 2
C
6
H
5 2 139.8, 129.1, 128.0, 126.6, 58.0.
FAB 967.
WO 00/77016 WO 0077016PCT/HROO/0001 8 18 Example 11 4 '-Demycarosyl-4"-O-acetyl-3-deoxy-3-oxo-8a-aza-8a-hom otylosin dimethylacetal (11) The compound 7 (0.70 g, 0.73 nimol) was dissolved in methanol (50 ml) and left to stand at room temperature for 24 hours. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtaied crude product (0.62 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (11) (0.40 g).
TLC: Rf 0.44.
IR (KBr) cm-1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
'H NMR (CDC1 3 5 ppm 6.87 5.77 5.44 5.18 (8a-NH) exchangeable with D 2 0, 4.88 4.64 4.44 4.30 4.17 3.93 3.89 3.53 (3"-OCH 3 3.50, 3.26 3.48 (2"'-OCH 3 3.30 (20-OCHA) 3.29 (20-OCHA) 2.53 /3'-N(CH 3 2 2.12 (COCH3) 1.75 1.25 (H-18).
1 3 C NMR (CDCl 3 5 ppm 205.4 172.9 170.1 (COCHA) 167.4 (9- CONH), 143.4 (C-il1), 13 6.2 12), 13 4.6 (C-i13), 120.7 104.2,(C-1F), 103.9 100.8 74.5 70.9 70.5 61.3 OCHA) 59.0 (2"-OCH 3 52.6 (20-OCHA) 52.1 (20-OCHA) 45.9 44.4 42.5 41.4 /3'-N(CH 3 2 33.8 22.0 20.7 (COCHA) 17.5 18), 12.9 (C-22).
FAB 873.
Example 12 4'-Demycarosyl-4"-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino- 8 a-aza- 8a-homotylosin (12) WO 00/77016 PCT/HR00/00018 19 The compound 8 (1.20 g, 10.99 mmol) was dissolved in methanol (100 ml) and left to stand at room temperature for 24 hours. To the reaction solution water (100 ml) was added and it was extracted with methylene chloride at pH 6.5. The combined organic extracts were dried (K 2 C0 3 and evaporated at reduced pressure and the obtained crude product (1.0 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (12) (0.52 g).
TLC: Rf(A) 0.65.
IR (KBr) cm 1 1745, 1650, 1622, 1537, 1454, 1373, 1233, 1166, 1058.
'H NMR (CDC13) 5 ppm 7.25 7.41 (phenyl), 6.90 5.67 5.52 (H-13), 4.98 (8a-NH) exchangeable with DzO, 4.67 4.45 4.17 4.02 3.61 (20-CH 2 -phenyl), 3.53 (3"-OCH 3 3.52 (20-CH 2 -phenyl), 3.50 (2"-OCH 3 3.76, 3.32 2.52 /3'-N(CH 3 2 2.12 (COCH 3 1.73 (H- 22), 1.21 1.08 (H-21).
13C NMR (CDCl 3 5 ppm 205.3 172.5 170.1 (COCH 3 167.2 (9- CONH), 143.9 135.9 135.4 120.0 103.9 100.9 74.6 70.7 70.4 61.3 (3"-OCH 3 59.3
OCH
3 51.6 46.1 44.5 43.3 41.5 /3'-N(CH 3 2 28.8 22.0 20.7 (COCH 3 17.8 12.9
N(CH
2
C
6
H)
2 139.9, 128.8, 128.0, 126.5, 58.0.
FAB (MH 1008.
Example 13 4'-Demycarosyl-4"-O-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (13) The compound 3 (0.5 g, 0.52 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 24 hours. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.43 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (13) (0.32 g).
wo oon7016 WO 0077016PCTIHROO/00018 TLC: Rf 0.32.
IR (KBr) cm'1 1739, 1656, 1616, 1541, 1455, 1376, 1237, 1170, 1062.
'H NMR (CDCI 3 5 ppm 7.15 5.71 5.66 4.97 (8a-NH) exchangeable with D 2 0, 4.64 4.62 4.44 4.24 4.18 3.53 (3"-OCHA) 3.47 (2"-OCH 3 3.37 (20-OCHA) 3.36 OCHA) 2.50 13'-N(CH 3 2 1, 2.12 (COCH 3 1.75 1.17 (H-2 1).
FAB 875.
Example 14 4'Dmcrsl4--ctl2-ex-0-iezlmn-aaa8-ooyoi (14) The compound 4 (0.75 g, 0.69 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 24 hours. The isolation of the product was carried out in the manner disclosed in Example 12 and the obtained crude product (0.66 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (14) (0.45 g).
TLC: Rf 0.50.
IR (KBr) cm-' 1740, 1657, 1621, 1538, 1454, 1373, 1236, 1169, 1054.
'H NMR (CDC1 3 5 ppm 7.25 -7.41 (phenyl), 7.10 (H-i 5.69 5.65 4.96 (8a-NH) exchangeable with D 2 0, 4.66 4.45 4.14 4.07 3.59 (20-N-CH 2 -phenyl), 3.56 (20-CH 2 -phenyl), 3.53 (3 "-OCHA) 3.50 (2"-OCHA) 2.49 13'-N(CH 3 2 2.12 (COCHA) 1.73 1. 11 (H-2 1), 0.94 (H-18).
FAB 1010.
Example 4'-Demycarosy-3-deoxy-3-oxo-8a-aza- 8 a-homlotyIosin 20-dimethylacetal WO 00/77016 PCT/HR00/00018 21 The compound 11 (0.40 g, 0.46 mmol) was dissolved in a methanol/conc. NH 4
OH
mixture 50 ml) and left to stand for 60 hours at the temperature of 5 0 C. The reaction solution was evaporated to an oily residue and then a product was isolated in the manner disclosed in Example 9. The obtained crude product (0.25 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (15) (0.15 g).
TLC: Rf(A) 0.39.
IR (KBr)cm- 1 1739, 1714, 1650, 1620, 1544, 1455, 1375, 1170, 1063.
'H NMR (CDCl 3 5 ppm 6.87 5.77 5.44 5.18 (8a-NH) exchangeable with D 2 0, 4.60 4.64 4.33 4.17 3.93 3.89 3.53 (3"-OCH 3 3.50, 3.26 3.48 (2"-OCH 3 3.30 (20-OCH3), 3.29 (20-OCH3), 2.33 /3'-N(CH 3 2 1.75 1.25 (H-18).
FAB (MH 831.
Example 16 4'-Demycarosyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8ahomotylosin (16) The compound 12 (0.78 g, 0.77 mmol) was dissolved in a methanol/conc. NH 4
OH
mixture 50 ml) and left to stand for 24 hours at room temperature. To the reaction solution water (80 ml) was added and it was extracted twice with methylene chloride at pH 7.5. The combined organic extracts were dried (K 2 C0 3 and evaporated at reduced pressure and the obtained product (0.66 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (16) (0.32 g).
TLC: Rf(A) 0.55.
IR (KBr) cm- 1739, 1714, 1650, 1622, 1538, 1454, 1376, 1167, 1082.
'H NMR (CDC13) 6 ppm 7.25 7.41 (phenyl), 6.90 5.66 5.53 5.28 (8a-NH) exchangeable with D 2 0, 4.61 4.16 4.03 WO 00/77016 WO 0077016PCT/HROO/00018 22 3.62 (20-N-CH 2 -phenyl), 3.61 (20-CH 2 -phenyl, 3"-OCH 3 3.51 (2"-OCH 3 3.78, 3.3 8 2.5 /3'-N(CH 3 2 2.3 8 1.72 1.21 18), 1.08 (H-2 1).
1 3 C NMR (CDC1 3 5 ppm 205.3 172.5 167.2 (9-CONH), 143.9 11), 135.9 135.6 120.0 103.9 101.0 72.5 70.7 70.4 61.5 (3"-OCH 3 59.5 (2"-OCH 3 51.7 46.1 44.5 43.3 41.5 13'-N(CH 3 2 1, 28.8 19), 22.0 (C-2 1), 17.8 18), 12.9 (C-22), 2
C
6
H)
2 140.0, 128.8, 128.0, 126.5, 58.0.
FAB 967.
Example 17 4'I-Demyca rosy-3-d eoxy-3-oxo-8a-aza-8 a-h o mloIsin (17) The compound 15 (0.5 g, 0.60 mmol) was dissolved in an acetonitrile/0. 1 N HCI mixture 1, 35 ml]) and stirred for 2 hours at room temperature. To the reaction solution a saturated NaHCO 3 solution was added and it was extracted twice with methylene chloride. The combined organic extracts were dried (K 2 C0 3 and evaporated at reduced pressure and the obtained product (0.42 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (17) (0.25 g).
TLC: P1 0.35.
IR (KBr) cm- 1 1739, 1719, 1657, 1620, 1545, 1455, 1376, 1169, 1082.
'H NMR (CDC 3 5 ppmn 9.78 7.19 (H-il1), 5.72 5.70 13), 5.06 (8a-NH) exchangeable with D 2 0, 4.58 4.18 4.23 3.68, 3.32 3.62 (3"-OCH 3 3.49 (2"-OCH 3 2.49 /3'-N(CH 3 2 1.75 (H-22), 1. 25 18), 1.18 (H-2 1).
1 3 C NMR (CDCI 3 5 ppm 205.3 203.8 173.5 166.9 (9-CONH), 145.1 138.2 135.1 129.3 103.7 101.1 72.8 71.0 70.4 61.5 (3"-OCHA) 59.5 (2"-OCH 3 wo oon7016 WO 0077016PCT/HROO/00018 23 46.6 19), 46.1 44.5 43.3 41.5 /3'-N(CH 3 2 22.4 (C-2 1), 17.8 18), 12.9 (C-22).
FAB 785.
Example 18 4'-Demycarosyl-2 ',4'-di-O-acetyl-8a-aza-8a-homotylosifl (18) The compound 1 (0.5 g, 0.55 mmol) was dissolved in an acetonitrile/0. 1 N HCl mixture 1, 3 5 ml) and stirred for 2 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC homogeneous product (18) (0.34 g).
TLC: P1 0.35.
IR (KBr) cm'1 1749, 1657, 1620, 1548, 1455, 1375, 1231, 1170, 1059.
'H NMR (CDC 3 5 ppm 9.75 7.21 (H1-li1), 5.72 5.71 13), 5.08 (8a-NH) exchangeable with D 2 0, 4.89 4.74 4.58 4.26 3.61 (3"-OCHA) 3.49 (2"'-OCH 3 2.33 /3'-N(CH 3 2 2.05 (COCH 3 2.03 (COCHA) 1.74 1.18 (H-2 1).
1 3 C NMR (CDCl 3 6 ppmn 203.6 173.3 169.9, 169.5 (2xCOCHA) 166.5 (9-CONH), 145.2 138.3 135.0 119.0 101.6 100.9 72.5 70.6 70.3 65.6 61.5 -OCHA) 59.5 (2"-OCH 3 46.3 42.5 41.0 /3'-N(CH 3 2 38.5 21.6 21.1, 21.0 (2xCOCH 3 12.7 8.1 18).
FAB 871.
Example 19 4'-Demycarosyl-2 ',4',4"-tri-O-acetyl-8a-aza-8a-homotylosiii (19) The compound 3 (0.5 g, 0.52 mmol) was dissolved in an acetonitrile/0. 1 N HCI mixture 1, 3 5 ml) and stirred for 2 hours at room temperature. The isolation of the WO 00/77016 WO 0077016PCTIHROO/00018 24 product was carried out in the manner disclosed in Example 17 to give a TLC homogeneous product (19) (0.47 g).
TLC: Rf 0.60; Rf 0.50.
IR (KBr) cm'1 1748, 1659, 1621, 1538, 1455, 1373, 1232, 1171, 1052.
'H NMR (CDCl 3 8 ppm 9.74 7.16 (H-il1), 5.69 5.65 13), 4.89 (8a-NH) exchangeable with D 2 0, 4.88 4.76 4.64 4.44 4.33 4.18 3.52 (3"-OCHA) 3.46 (2"-OCH 3 2.33 /3'-N(CH 3 2 1, 2.12 (COCHA) 2.05 (COCHA) 2.03 (COCHA) 1.74 1.16 (H-21).
1 3 C NMR (CDC1 3 5 ppm. 203.6 173.1 170.1, 169.8, 169.4 (3xCOCH 3 166.1 (9-CONH), 144.7 138.0 134.9 119.2 103.7 102.i 100.9 74.5 71.4 70.3 65.6 61.3 (3"-OCH 3 59.3 (2"-OCH 3 46.3 42.7 42.6 41.0 13'-N(CH 3 2 40.5 3 4.5 19), 21.9 (C-2 21.1, 21.0, 20.7 (3xCOCHA) 12.7 8.3 (C-i18).
FAB 913.
Example 4'-Demycarosyl-2 ',4'-di-O-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin The compound 5 (0.7 g, 0.77 mmol) was dissolved in an acetonitrile/0. 1 N HC1 mixture 1, 50 ml) and stirred for 1 hour at room temperature. The isolation of the product was carried out in the manner disclosed i Example 17 to give a TLC homogeneous product (20) (0.36 g).
TLC: Rf 0.48.
IR (KBr) cm'1 1749, 1656, 1619, 1543, 1458, 1375, 1230, 1172, 1058.
'H NMR (CDCI 3 5 ppm 9.75 7.21 (H-il1), 5.72 5.70 5.08 (8a-NH) exchangeable with D 2 0, 4.88 4.74 4.58 4.30 4.17 3.98 3.78 3.58 (3"-OCH 3 3.48 (2"I-OCHA) WO 00/77016 WO 0077016PCTIHROO/0001 8 3.30 2.33 /3'-N(CH 3 2 2.05 (COCH 3 2.03 (COCH 3 1.76 (H-22), 1.34 1. 17 (H-2 1).
1 3 C NMR*(CDC1 3 5 ppm 203.0 202.4 173.1 169.9, 169.5 (2xCOCH 3 166.5 (9-CONH), 145.0 138.1 135.1 119.0 102.1 100.9 85.3 84.2 73.3 71.3 70.3 65.6 61.5 (3"-OCH 3 59.4 (2"-OCH 3 46.3 (C-19), 42.5 4 1. 0 /3J'-N(CH 3 3 8.5 21.9 21.1, 21.0 (2xCOCH 3 14. 0 12.7 8.3 (C-i1).
FAB 869.
Example 21 4'-Demycarosyl-4"1-O-acetyl-8a-aza-8a-homotylosin (21) The compound 19 (0.30 g, 0.33 mmol) was dissolved in methanol (20 ml) and left to stand for 24 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.25 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (21) (0.19 g).
TLC: Rf 0.28.
IR (KBr) cm-1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
'H NMR (CDCl 3 5 ppm 9.78 7.20 (H-li1), 5.72 5.70 13), 5.12 (8a-NH) exchangeable with D 2 0, 4.88 4.64 4.44 4.18 4.12 3.93 3.89 3.53 (3"-OCH 3 3.48 (2"-OCHA) 2.49 /3'-N(CH 3 2 1, 2.12 (COCH 3 .75 (H-22).
FAB 829.
Example 22 4' -Demycarosyl-4"-deoxy-4-oxo-8a-aza-8a-homotyosin (22) The compound 20 (0.23 g, 0.27 mmol) was dissolved in methanol (20 ml) and left to stand for 24 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.14 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (22) (0.095 g).
TLC: Rf(A) 0.30.
IR (KBr) cm 1717, 1655, 1625, 1542, 1454, 1378, 1170, 1062.
1 H NMR (CDC13) 6 ppm 9.76 7.20 5.72 5.70 5.12 (8a-NH) exchangeable with D 2 0, 4.64 4.33 4.18 3.98 3.78 3.58 (3"-OCH 3 3.46 (2"-OCH 3 3.30 3.06 2.33 /3'-N(CH 3 2 1.74 1.34 1.16 (H-21).
3 C NMR (CDC1 3 5 ppm 203.7 202.5 173.4 166.6 (9-CONH), 144.9 137.6 135.4 119.4 102.1 100.9 71.4 70.3 66.3 61.5 (3"-OCH 3 59.7 (2"-OCH 3 46.2 42.7 42.1 41.5 /3'-N(CH 3 2 39.8 21.7 (C-21), 14.0 12.7 8.7 (C-18).
FAB 785.
.s A reference herein to a prior art document is not an admission that the document forms •part of the common general knowledge in the art in Australia.
•o*
Claims (12)
1. Compounds of the general formula I CH 3 I OCH 3 OCH 3 V. 9
9. 9O9 .9 9.* 9 9 .9 9e 49 9 9 O r O0 *9 9 *9 4G S@ wherein R represents CHO, CH(OCH 3 2 or CH 2 N[CH 2 (C 6 H)] 2 R 1 represents C 1 -C 3 acyl, or R' represents H when R 2 and R 3 or R 4 and R 5 together are =0, R 2 represents OR 6 and R 6 represents H or C 1 -C 3 acyl, R 3 represents H or R 2 and R 3 together represent =0, R 4 represents OH, R 5 represents H or R 4 and R 5 together represent =0. 2. A compound according to claim 1, characterized in that R represents CH(OCH 3 2 R' represents COCH 3 R 2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH. 3. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R' represents COCH 3 R 2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH. 4. A compound according to claim 1, characterized in that R represents CH(OCH 3 2 R 1 represents COCH 3 R 2 represents OR 6 wherein R 6 represents COCH 3 R 3 and R 5 are the same and represent H and R 4 represents OH. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R' represents COCH 3 R 2 represents OR 6 wherein R 6 represents COCH 3 R 3 and R 5 are the same and represent H and R 4 represents OH. 6. A compound according to claim 1, characterized in that R represents CH(OCH 3 2 R 1 represents COCH 3 R 2 and R 3 together represent R 4 represents OH and R 5 represents H. 7. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R 1 represents COCH 3 R 2 and R 3 together represent R 4 represents OH and R 5 represents H. 8. A compound according to claim 1, characterized in that R represents i' CH(OCH 3 2 R' represents COCH 3 R 2 represents OR 6 wherein R 6 represents COCH 3 3 R 3 represents H and R 4 and R 5 together represent =0. 9. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R' represents COCH 3 R represents OR 6 wherein R 6 represents COCH 3 R 3 represents H and R 4 and R 5 together represent =0.
10. A compound according to claim 1, characterized in that R represents CH(OCH 3 2 R' and R 5 are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents OH.
11. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R' and R 5 are the same and represent H, R 2 and R 3 together represent =0 and R 4 represents OH.
12. A compound according to claim 1, characterized in that R represents CH(OCH 3 2 R' and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 and R 4 and R 5 together represent =0.
13. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R 1 and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents COCH 3 and R 4 and R 5 together represent =0.
14. A compound according to claim 1, characterized in that R represents CH(OCH 3 2 R 1 and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and R 5 together represent =0. A compound according to claim 1, characterized in that R represents CH 2 N[CH 2 (C 6 H 5 2 R 1 and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and R 5 together represent =0.
16. A compound according to claim 1, characterized in that R represents CHO, R' and R 3 are the same and represent H, R 2 represents OR 6 wherein R 6 represents H, and R 4 and R 5 together represent =0.
17. A compound according to claim 1, characterized in that R represents CHO, R 1 represents COCH 3 R 2 represents OR 6 wherein R 6 represents H, R 3 and R 5 are the same and represent H and R 4 represents OH.
18. A compound according to claim 1, characterized in that R represents CHO, R' represents COCH 3 R 2 represents OR 6 wherein R 6 represents COCH 3 R 3 and R 5 are the same and represent H and R 4 represents OH.
19. A compound according to claim 1, characterized in that R represents CHO, R' represents COCH 3 R 2 and R 3 together represent R 4 represents OH and R 5 represents H. A compound according to claim 1, characterized in that R represents CHO, R' and R 5 are the same and represent H, R 2 and R 3 together represent =O and R 4 represents OH.
21. A compound according to claim 1, substantially as herein described with reference to any one of the Examples. Dated this 24th day of September 2003 PLIVA D.D. By its Patent Attorneys GRIFFITH HACK e
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR990192A HRP990192A2 (en) | 1999-06-11 | 1999-06-11 | 4'-DEMICAROZYL-8a-AZA-8a-HOMOTHILOSINE DERIVATIVES |
| HRP990192A | 1999-06-11 | ||
| PCT/HR2000/000018 WO2000077016A1 (en) | 1999-06-11 | 2000-06-06 | DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5558300A AU5558300A (en) | 2001-01-02 |
| AU767543B2 true AU767543B2 (en) | 2003-11-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU55583/00A Ceased AU767543B2 (en) | 1999-06-11 | 2000-06-06 | Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1189914A1 (en) |
| JP (1) | JP2003502338A (en) |
| AU (1) | AU767543B2 (en) |
| CA (1) | CA2375812A1 (en) |
| CZ (1) | CZ20014362A3 (en) |
| EA (1) | EA200200026A1 (en) |
| HR (1) | HRP990192A2 (en) |
| HU (1) | HUP0201610A3 (en) |
| NO (1) | NO322424B1 (en) |
| SK (1) | SK17572001A3 (en) |
| UA (1) | UA66930C2 (en) |
| WO (1) | WO2000077016A1 (en) |
| YU (1) | YU87401A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| TW200420573A (en) | 2002-09-26 | 2004-10-16 | Rib X Pharmaceuticals Inc | Bifunctional heterocyclic compounds and methods of making and using same |
| EP1599491A1 (en) * | 2003-03-05 | 2005-11-30 | Rib-X Pharmaceuticals, Inc. | Bifunctional heterocyclic compounds and methods of making and using the same |
| US7365174B2 (en) | 2003-08-22 | 2008-04-29 | Meiji Seika Kaisha, Ltd. | Azalide and azalactam derivatives and method for producing the same |
| CN102816194A (en) | 2004-02-27 | 2012-12-12 | 瑞伯-X医药品有限公司 | Macrocyclic compounds and methods of making and using the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI8710674B (en) * | 1987-04-14 | 1998-06-30 | Pliva | Process for preparation of 10,11,12,13-tetrahydro derivatives of tylosin |
| SI8911498B (en) * | 1989-07-26 | 1998-10-31 | Pliva | Process for the preparation of tylosin derivatives |
| CZ211798A3 (en) * | 1997-07-16 | 1999-02-17 | Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmetička Industrije, Dioničko Društvo | Linear 8a-secoazalides and process for preparing thereof |
-
1999
- 1999-06-11 HR HR990192A patent/HRP990192A2/en not_active Application Discontinuation
-
2000
- 2000-06-06 EA EA200200026A patent/EA200200026A1/en unknown
- 2000-06-06 HU HU0201610A patent/HUP0201610A3/en unknown
- 2000-06-06 EP EP00940676A patent/EP1189914A1/en not_active Withdrawn
- 2000-06-06 AU AU55583/00A patent/AU767543B2/en not_active Ceased
- 2000-06-06 UA UA2001129085A patent/UA66930C2/en unknown
- 2000-06-06 CA CA002375812A patent/CA2375812A1/en not_active Abandoned
- 2000-06-06 JP JP2001503873A patent/JP2003502338A/en active Pending
- 2000-06-06 YU YU87401A patent/YU87401A/en unknown
- 2000-06-06 CZ CZ20014362A patent/CZ20014362A3/en unknown
- 2000-06-06 WO PCT/HR2000/000018 patent/WO2000077016A1/en not_active Application Discontinuation
- 2000-06-06 SK SK1757-2001A patent/SK17572001A3/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| AU5558300A (en) | 2001-01-02 |
| CZ20014362A3 (en) | 2002-04-17 |
| NO322424B1 (en) | 2006-10-02 |
| HUP0201610A3 (en) | 2003-03-28 |
| YU87401A (en) | 2004-07-15 |
| EP1189914A1 (en) | 2002-03-27 |
| UA66930C2 (en) | 2004-06-15 |
| NO20016030L (en) | 2002-01-30 |
| SK17572001A3 (en) | 2002-04-04 |
| EA200200026A1 (en) | 2002-06-27 |
| HRP990192A2 (en) | 2001-04-30 |
| CA2375812A1 (en) | 2000-12-21 |
| HUP0201610A2 (en) | 2002-10-28 |
| NO20016030D0 (en) | 2001-12-10 |
| JP2003502338A (en) | 2003-01-21 |
| WO2000077016A1 (en) | 2000-12-21 |
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