CN1914221A - 6-11 bicyclic ketolide drivatives - Google Patents

6-11 bicyclic ketolide drivatives Download PDF

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Publication number
CN1914221A
CN1914221A CNA2003801109976A CN200380110997A CN1914221A CN 1914221 A CN1914221 A CN 1914221A CN A2003801109976 A CNA2003801109976 A CN A2003801109976A CN 200380110997 A CN200380110997 A CN 200380110997A CN 1914221 A CN1914221 A CN 1914221A
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compound
aryl
heteroaryl
formula
carbon atom
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Inventor
柯日新
王国强
方里谭
牛德强
福哈胡
邱遥龄
王燕春
马瑞那·巴沙耶克
侯英
彭钰林
金西进
刘同柱
杰伊·贾德森·法默
许国友
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Enanta Pharmaceuticals Inc
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Enanta Pharmaceuticals Inc
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    • 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

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Abstract

The present invention discloses compounds of formula i, or pharmaceutically acceptable salts, esters, or prodrugs thereof: formule (i) which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

Description

6-11 dicyclo ketone macrolide derivatives
Technical field
The present invention relates to a kind of new semi-synthetic macrolide, this macrolide has antibacterial activity and is used for the treatment of and prevents infectation of bacteria.More particularly, the present invention relates to 6-11 dicyclo ketone macrolide derivatives, contain this compound compositions and use the method for this compound, and the method for preparing this compound.
Background technology
Macrolide antibiotics is played the part of important treatment role, particularly in the appearance of new pathogenic bacteria.The size of its textural difference and lactonic ring and the number of carbohydrate are relevant with characteristic (neutral or alkalescence).The size of the classification foundation lactonic ring of macrolide (12,14,15 or 16 atoms) decision.Z microbiotic family (14-, 15-and 16-person's ring derivatives) has characteristic (antibacterium spectrum, side effect and bioavailability) widely.The most normal wherein general macrolide that uses is erythromycin, clarithromycin and Azythromycin.Have 3-oxygen functional group person among the macrolide on 3-cladinose position and be called as the ketone macrolide, its demonstration has the activity of reinforcement for Gram-negative bacteria and macrocyclic lactone bacterium gram-positive microorganism.Have about research and can resist MLSB-tolerance bacterial strain (MLS B=Macrolides-Lincosamides-type B Streptogramines) resistance to overturning, resistance and the pharmacokinetics of active Macrocyclic lactone compounds and maintenance macrolide have become important target.
Summary of the invention
The invention provides a kind of C of novel type 6-C 11Bridged erythromycin derivatives, this derivative has antibacterial activity.
In one aspect of the present invention, new bridging ketone Macrocyclic lactone compounds or its pharmacologically acceptable salts class, ester class or prodrug is provided, it is represented with following formula (I):
Wherein,
A is selected from:
a)-OH；
B)-OR p, R wherein pBe hydroxyl protecting group;
C)-R 1, R wherein 1Be independently selected from:
(1) aryl;
(2) substituted aryl;
(3) heteroaryl; And
(4) substituted heteroaryl;
D)-OR 1, R wherein 1As definition before;
E)-R 2, R wherein 2Be selected from:
(1) hydrogen;
(2) halogen;
(3) C 1-C 12Alkyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S or N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(4) C 2-C 12Alkenyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; And
(5) C 2-C 12Alkynyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
F)-OR 2, R wherein 2Independently as definition before;
G)-S (O) nR 11, wherein n=0,1 or 2, and R 11Be hydrogen, R independently 1Or R 2, R wherein 1And R 2As definition before;
H)-NHC (O) R 11, R wherein 11As definition before;
I)-NHC (O) NHR 11, R wherein 11As definition before;
J)-NHS (O) 2R 11, R wherein 11As definition before;
K)-NR 14R 15, R wherein 14And R 15Independent separately is R 11, R wherein 11As definition before; And
L)-NHR 3, R wherein 3Be amino protecting group;
B is selected from:
A) hydrogen;
B) deuterium;
C) halogen;
d)-OH；
E) R 1, R wherein 1As definition before;
F) R 2, R wherein 2As definition before; And
G)-OR p, R wherein pAs definition before,
H) condition be when B be halogen ,-OH or-OR pThe time, A is R 1Or R 2Perhaps, A is connected carbon atom on it with B with them, be selected from:
a)C＝O；
B) C (OR 2) 2, R wherein 2As definition before;
C) C (SR 2) 2, R wherein 2As definition before;
D) C[-O (CH 2) m] 2, m=2 or 3 wherein;
E) C[-S (CH 2) m] 2, wherein m is as before definition;
F) C=CHR 11, R wherein 11As definition before;
G) C=N-O-R 11, R wherein 11As definition before;
H) C=N-O-Ar 1-M-Ar 2, wherein
(1)-Ar 1-be R 31, R wherein 31Be independently selected from:
(a) R 1, R wherein 1As definition before;
(b) C 1-C 12Alkyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S or N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(c) C 2-C 12Alkenyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; Perhaps
(d) C 2-C 12Alkynyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S or N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(2)-M-do not exist or is selected from:
(a)-C 1-C 12Alkyl, it randomly comprises:
0-3 heteroatoms that is selected from O, S or N; And
0-3 is selected from-C=N-,-N=N ,-C (O)-group;
(b)-C 2-C 12Alkenyl, it randomly comprises:
0-3 heteroatoms that is selected from O, S or N; And
0-3 is selected from-C=N-,-N=N ,-C (O)-group;
(c)-C 2-C 12Alkynyl, it randomly comprises:
0-3 heteroatoms that is selected from O, S or N; And
0-3 is selected from-C=N-,-N=N ,-C (O)-group;
(d) substituted aryl;
(e) substituted heteroaryl; Perhaps
(f) substituted heterocycle alkyl; And
(3)-Ar 2Be selected from:
(a) aryl;
(b) substituted aryl;
(c) heteroaryl; Perhaps
(d) substituted heteroaryl;
I) C=NNHR 11, R wherein 11As definition before;
J) C=NNHC (O) R 11, R wherein 11As definition before;
K) C=NNHC (O) NHR 11, R wherein 11As definition before;
L) C=NNHS (O) 2R 11, R wherein 11As definition before;
M) C=NNHR 3, R wherein 3As definition before;
N) C=NR 11, R wherein 11As definition before; Or
O) C=N-N=CHR 11, R wherein 11As definition before;
One of them is selected from X and Y for another person of hydrogen:
A) hydrogen;
B) deuterium;
c)-OH；
D)-OR p, R wherein pAs definition before;
E)-NR 4R 5, R wherein 4With R 5Be selected from independently of one another:
(1) hydrogen;
(2) C 1-C 12Alkyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; Or
(3) R 4With R 5The nitrogen-atoms that is connected on it with them forms the assorted alkyl ring of 3-10 person together, and it comprises 0-2 extra heteroatoms that is selected from O, S and N;
Perhaps, X is connected carbon atom on it with Y with them, be selected from:
a)C＝O；
B) C=N-Q, wherein Q is selected from:
(1)-R 11, R wherein 11As definition before;
(2) amino protecting group;
(3)-C (O) R 11, R wherein 11As definition before;
(4)-OR 6, R wherein 6Be independently selected from:
(a) hydrogen;
(b)-CH 2O(CH 2) 2OCH 3，
(c)-CH 2O (CH 2O) nCH 3, wherein n is as before definition;
(d)-C 1-C 12Alkyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(e)-C 3-C 12Cycloalkyl;
(f)-C (O)-C 1-C 12Alkyl;
(g)-C (O)-C 3-C 12Cycloalkyl;
(h) (C (O)-R 1, R wherein 1As definition before; Or
(i)-Si (R a) (R b) (R c), R wherein a, R bAnd R cBe selected from C independently of one another 1-C 12Alkyl, aryl and substituted aryl; Or
(5) O-C (R 7) (R 8)-O-R 6, R wherein 6As definition before, condition is R 6Non-C (O)-C 1-C 12Alkyl, C (O)-C 3-C 12Cycloalkyl or C (O)-R 1, and R 7With R 8The carbon atom that connects on it with them forms C 3-C 12Naphthene group perhaps is selected from independently of one another:
(1) hydrogen; Or
(2) C 1-C 12Alkyl;
L is selected from:
a)-CH 3；
b)-CH 2CH 3；
c)-CH(OH)CH 3；
D) C 1-C 6Alkyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
E) C 2-C 6Alkenyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; Or
F) C 2-C 6Alkynyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
W is-NR 20R 21, R wherein 20And R 21Be selected from independently of one another:
A) hydrogen;
B) C 1-C 12Alkyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
C) C 2-C 12Alkenyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
D) C 2-C 12Alkynyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; Perhaps
E) R 20And R 21The nitrogen-atoms that connects on it with them forms Heterocyclylalkyl; Or Z is selected from:
A) hydrogen;
B) methyl; Or
C) halogen; And
R 2' be hydrogen or R p, R wherein pAs definition before.
In another embodiment of the present invention, pharmaceutical composition is disclosed, it comprises the combination of of the present invention arbitrary compound and the pharmaceutically acceptable carrier or the vehicle of significant quantity.Another embodiment of the present invention is to utilize the method for the bacterial-infection resisting in this medicine composite for curing individuality.The present invention also has open to appropriate carriers and compounding method.
In another aspect of the present invention, a kind of method is provided, via any route of synthesis described herein with 6 of preparation formula (I), 11-3C-bridging ketone macrolide derivatives.
Embodiment
The present invention divides first embodiment compound of the formula (I) of place definition for this reason, or its pharmacologically acceptable salts, ester or prodrug.
Representativeness of the present invention time kind is:
Compound as claimed in claim 1, it is with following formula (II) expression,
Figure A20038011099700151
Wherein A, B, R 2', Q, W and Z be defined in claim 1;
Compound as claimed in claim 1, it is with following formula (III) expression,
Wherein A, B, R 2', Q is identical with claim 1 definien with Z;
Compound as claimed in claim 1, its following formula V represent,
Wherein A, B, R 2', Q is identical with claim 1 definien with Z;
Compound as claimed in claim 1, its following formula V represent,
Figure A20038011099700154
Ar wherein 1, Ar 2, R 2', M, Q, W be identical with claim 1 definien with Z;
Compound as claimed in claim 1, it is with following formula (VI) expression,
Figure A20038011099700161
Ar wherein 1, Ar 2, R 2', M, Q be identical with claim 1 definien with Z;
Compound as claimed in claim 1, it is with following formula (VII) expression,
Ar wherein 1, Ar 2, R 2', M is identical with claim 1 definien with Z; Or
Compound as claimed in claim 1, it is with following formula (VIII) expression,
Ar wherein 1, Ar 2, R 2', M is identical with claim 1 definien with Q.
Representative form of the present invention is:
The compound of embodiment 1. formula I: A forms C=CH with the carbon atom that B and they connect on it 2, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H, and R 2'=Ac;
The compound of embodiment 2. formula I: A forms C=CH with the carbon atom that B and they connect on it 2, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H, and R 2'=H;
The compound of embodiment 3. formula I: A forms C=O with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H, and R 2'=H;
The compound of embodiment 4. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-Ph, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 5. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-(3-pyridyl), X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 6. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-(2-pyridyl), X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 7. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-(3-quinolyl), X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 8. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-(2-quinolyl), X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 9. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2(5-pyridine-2-base thiophene-2 base), X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 10. formula I: A forms C=N-O-[3-(pyrimidine-2-base) Propargyl with the carbon atom that B and they connect on it], X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 11. formula I: A forms C=N-O-Ph with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 12. formula I: A=NHCH 2-Ph, B=H, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 13. formula I: A=NHCH 2CH 2-Ph, B=H, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 14. formula I: A forms C=CH with the carbon atom that B and they connect on it 2, X forms C=N-O-CH with the carbon atom that Y and they connect on it 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=Ac;
The compound of embodiment 15. formula I: A forms C=CH with the carbon atom that B and they connect on it 2, X forms C=N-O-CH with the carbon atom that Y and they connect on it 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=H;
The compound of embodiment 16. formula I: A forms C=O with the carbon atom that B and they connect on it, and X forms C=N-O-CH with the carbon atom that Y and they connect on it 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=H;
The compound of embodiment 17. formula I: A forms C=NOCH with the carbon atom that B and they connect on it 2-Ph, X forms C=N-O-CH with the carbon atom that Y and they connect on it 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=H;
The compound of embodiment 18. formula I: A forms C=O with the carbon atom that B and they connect on it, and X forms C=O, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=Ac;
The compound of embodiment 19. formula I: A forms C=CH with the carbon atom that B and they connect on it 2, X forms C=O, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 20. formula I: A forms C=O with the carbon atom that B and they connect on it, and X forms C=O, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 21. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-Ph, X forms C=O, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 22. formula I: A forms C=CH with the carbon atom that B and they connect on it 2, X forms C=NH, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 23. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-p-NO 2-Ph, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 24. formula I: A forms C=N-O-(CH with the carbon atom that B and they connect on it 2) 2-Ph, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 25. formula I: A forms C=N-O-(CH with the carbon atom that B and they connect on it 2) 3-Ph, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 26. formula I: A forms C=N-O-CH with the carbon atom that B and they connect on it 2-CH=CH-Ph, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H, and R 2'=H;
The compound of embodiment 27. formula I: A is NH-(CH 2) 3-Ph, B are H, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 28. formula I: A is NH-(CH 2) 4-Ph, B are H, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 29. formula I: A is CH 2-CH=CH 2, B is OH, X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 30. formula I: A is CH 2-Ph, B are OH, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 31. formula I: A is Ph, and B is OH, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 32. formula I: A is Ph, and B is OH, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 33. formula I: A is CH 2-CH=CH-Ph, B are OH, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 34. formula I: A is (CH 2) 3-Ph, B are OH, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 35. formula I: A forms C=CH-CH=CH-Ph with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 36. formula I: A is (CH 2) 3-Ph, B are H, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 37. formula I: A forms the C=CH-CH=CH-3-pyridyl with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 38. formula I: A forms the C=CH-CH=CH-3-quinolyl with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 39. formula I: A forms the C=CH-2-quinolyl with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 40. formula I: A forms the C=CH-2-quinolyl with the carbon atom that B and they connect on it, and X forms C=N-H, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 41. formula I: A forms the C=CH-4-xenyl with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 42. formula I: A forms the C=CH-3-xenyl with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 43. formula I: A forms the C=CH-4-Phenoxyphenyl with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 44. formula I: A forms C=CH-Ph with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H;
The compound of embodiment 45. formula I: A forms C=CH-2-(2 pyridyl)-thiophene-5-base with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=H and R 2'=H; Or
The compound of embodiment 46. formula I: A forms C=O with the carbon atom that B and they connect on it, and X forms C=N-Ac, L=CH with the carbon atom that Y and they connect on it 2CH 3, Z=F and R 2'=Ac.
The further representative form of the present invention is:
The embodiment compound 47-114 of formula A:
The Ar in each embodiment wherein 1, Ar 2, M, Q and Z be described in Table A:
Table A
Figure A20038011099700231
Figure A20038011099700241
Figure A20038011099700251
Figure A20038011099700271
Figure A20038011099700281
Figure A20038011099700291
The embodiment compound 115-262 of formula A1:
Figure A20038011099700301
The Ar among the embodiment wherein 1, Ar 2, M, Q and Z respectively be described in Table A 1:
Table A 1.
Figure A20038011099700302
Figure A20038011099700321
Figure A20038011099700331
Figure A20038011099700381
Figure A20038011099700391
Figure A20038011099700411
Figure A20038011099700441
Figure A20038011099700451
Figure A20038011099700461
Figure A20038011099700471
The embodiment compound 263-337 of formula A2:
Figure A20038011099700481
The Ar among each embodiment wherein 1, Ar 2, M, Q and Z be described in Table A 2:
Table A 2
Figure A20038011099700491
Figure A20038011099700511
Figure A20038011099700531
Figure A20038011099700541
Figure A20038011099700561
The embodiment compound 338-352 of formula B:
The R among each embodiment wherein 11, Q and Z be described in Table B:
Table B
Figure A20038011099700572
The embodiment compound 375-375 of formula B1:
The R among each embodiment wherein 11, Q and Z be described in Table B1:
Figure A20038011099700591
Figure A20038011099700601
Figure A20038011099700611
The embodiment compound 376-384 of formula B2:
The R among each embodiment wherein 11, Q and Z be described in Table B2:
Table B2
The embodiment compound 385-391 of formula C:
The R among each embodiment wherein 11, Q and Z be described in Table C:
Table C
Figure A20038011099700623
On the other hand, the present invention relates to a kind of method, in order to control the infectation of bacteria (for example, Mammals, people, horse, dog, cat, fish) in the individuality, this method comprises the pharmaceutical composition as herein described that gives this individual treatment significant quantity.This method comprises any compound described herein that gives individuality (comprise and being differentiated to needing the individuality of this treatment) treatment significant quantity, and any pharmaceutical composition perhaps described herein is to produce this effect.
Another aspect of the present invention relates to a kind of method, has the individuality (for example, Mammals, people, horse, dog, cat, fish) of infectation of bacteria or disease or relevant symptom with infectation of bacteria (comprising disease described herein) in order to treatment.This method comprises the compound described herein that gives these species (comprise and being differentiated to needing the individuality of this treatment) treatment significant quantity, and composition perhaps described herein is to produce this effect.Discriminating needs the individuality of this treatment and can be subjectivity (for example, opinion) or objectivity (for example measuring with test or diagnostic method) by individuality or health-care expert judgments.
Also comprise a wrapped product in the scope of the invention again.This wrapped product comprises one of aforementioned compound in a container, the container, and one the explanation that invests container (for example, one label or inset), it is the indication that treatment and infectation of bacteria diseases related is given this compound when (comprising disease described herein).
Another aspect of the invention is a method, in order to via any route of synthesis described herein to prepare any compound described herein.
Definition
Below listed person for being used to narrate various term of the present invention.Unless these definition have in special example out of the ordinary or indicate with a part than macoradical beyond, be to be applicable to the term that appears at whole part of specification sheets and claim scope.
" C used herein 1-C 3Alkyl ", " C 1-C 6Alkyl " or " C 1-C 12Alkyl " respectively refer to saturated straight chain or branch's hydro carbons radical with the family of languages between 1～3 carbon, 1～12 carbon or 1～6 carbon.C 1-C 3The example of alkyl radical comprises methyl, ethyl, propyl group and sec.-propyl radical; C 1-C 6The example of alkyl radical includes, but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, neo-pentyl and n-hexyl radical; C 1-C 12The example of alkyl radical includes, but not limited to ethyl, propyl group, sec.-propyl, n-hexyl, octyl group, decyl, dodecyl radical.
" C used herein 2-C 12Alkenyl " or " C 2-C 6Alkenyl " term means a monoradical, it wherein has a carbon-carbon double bond of removing single hydrogen atom at least derived from the hydrocarbon functional group who comprises 2～12 or 2～6 carbon atoms.Kiki alkenyl group for example includes, but not limited to, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-base etc.
" C used herein 2-C 12Alkynyl " or " C 2-C 6Alkynyl " on behalf of term, term mean a monoradical, and it wherein has a carbon carbon triple bond of removing single hydrogen atom at least derived from the hydrocarbon functional group who comprises 2～12 or 2～6 carbon atoms.Representational alkynyl group for example includes, but not limited to, ethynyl, 1-proyl, ethyl acetylene base etc.
" C used herein 1-C 6Alkoxyl group " mean as described above the C of definition 1-C 6Alkyl group is connected in its parent molecule functional group by Sauerstoffatom.C 1-C 6The example of-alkoxyl group includes, but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, tert.-butoxy, neopentyl oxygen and positive hexyloxy.
" halo " used herein reaches " halogen " term and means the atom that is selected from fluorine, chlorine, bromine and iodine.
" aryl " used herein term means the carbon-loop system of monocycle or dicyclo, and it has 1 or 2 aromatic ring, includes but not limited to phenyl, naphthyl, tetralyl, indanyl, idenyl etc.
This paper uses " arylalkyl " term to mean C 1-C 3Alkyl or C 1-C 6Alkyl residue is connected on the aryl rings.Example includes, but not limited to phenmethyl, styroyl etc.
That this paper uses " heteroaryl " term to mean is single-, two-or trinucleated aromatic series radical or ring, have 5～10 atoms on its ring, 1 annular atoms wherein is S, O and N; 0,1 or 2 annular atoms is extra heteroatoms, independently is selected from S, O and N; And other annular atoms is a carbon, and wherein any N or the S that is comprised in the ring can be by randomly oxidation.Heteroaryl includes but not limited to, pyridyl, pyrazinyl, pyrimidyl, pyrryl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl group, oxadiazole base, thienyl, furyl, quinolyl, isoquinolyl, benzimidazolyl-, benzoxazolyl, quinoxalinyl etc.
Employed " the C of this paper 3-C 12-cycloalkyl " term means a monoradical, it is to remove single hydrogen atom from monocycle or dicyclo saturated carbon ring compound mat to derive.Example includes, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclo [2.2.1] heptyl and dicyclo [2.2.2] octyl group.
This paper employed " Heterocyclylalkyl " term means that non-aromatic 5-, 6-or 7-person ring or two or three cyclic groups condense and is, wherein (i) each ring comprises 1～3 heteroatoms, system independently is selected from oxygen, sulphur and nitrogen, (ii) each 5-person ring has 0～1 two key and each 5-person ring has 0～2 two key, (iii) nitrogen and sulfur heteroatom are randomly oxidized, (iv) nitrogen heteroatom is randomly by quaternized, and (iv) above ring arbitrarily can be fused to phenyl ring.Representational heterocycloalkyl comprises, but be not limited to, [1,3] two Evil pentanes, pyrrolidyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, piperidyl, piperazinyl, oxazolidinyl, isoxazole alkyl, morpholinyl, thiazolidyl, isothiazole alkyl and tetrahydrofuran base.
This paper employed " heteroarylalkyl " term means C 1-C 3Alkyl or C 1-C 6Alkyl residue is connected on the heteroaryl ring.Example includes but not limited to, pyridylmethyl, pyrimidinylethyl etc.
Employed " the C of this paper 1-C 6Alkoxyl group " term means the C as preceding definition 1-C 6Alkyl group is connected on the parent molecule functional group by Sauerstoffatom.C 1-C 6The alkoxyl group example includes but not limited to, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, tert.-butoxy, neopentyl oxygen and positive hexyloxy.
Employed " the C of this paper 1-C 3-alkyl-amino " term means 1 or 2 C 1-C 3-alkyl group is connected on the parent molecule functional group by nitrogen-atoms.C 1-C 3-alkyl-amino example includes, but not limited to methylamino, dimethylamino, ethylamino, diethylamino and propyl group amino.
This paper employed " alkylamino " means to have-NH (C 1-C 12Alkyl) group of structure, wherein C 1-C 12Alkyl is as before definition.
This paper employed " dialkyl amido " means to have-N (C 1-C 12Alkyl) (C 1-C 12Alkyl) group of structure, wherein C 1-C 12Alkyl is as before definition.The example of dialkyl amido includes but not limited to, dimethylamino, diethylamino, methylethyl amino, piperidino-(1-position only) etc.
This paper employed " carbalkoxy " is the representative ester group, that is, an alkoxyl group is connected in the parent molecule functional group by carbonyl, for example, methoxycarbonyl, ethoxycarbonyl etc. is arranged.
This paper employed " carboxaldehyde radicals " term means the group with formula-CHO representative.
This paper employed " carboxyl " term means the group with formula-COOH representative.
This paper employed " carboxamide " term means the (C with formula-C (O) NH 1-C 12Alkyl) or-C (O) N (C 1-C 12Alkyl) (C 1-C 12Alkyl) or-C (O) NH 2Group Deng representative.
This paper employed " hydroxy-protective group " term means a chemical functional group, and it is in this technical field is known reaction that protect hydroxyl at synthesis step time antagonism do not desire.Behind synthesis step, hydroxy-protective group as herein described can optionally be removed.General hydroxy-protective group is described in that T.H.Greene and P.G.M.Wuts show in this technical field Protective Groups in Organic Synthesis, the 3rd edition, John Wiley ﹠amp; Sons, New York (1999).The acyl group that the example of hydroxy-protective group includes, but are not limited to methyl thiomethyl, the tertiary butyl-dimethylsilyl, tert-butyl diphenyl silylation, replace with aromatic group etc.
This paper employed " protection hydroxyl " term means the hydroxyl of being protected with as the hydroxy-protective group of preceding definition, for example, comprises benzoyl, ethanoyl, trimethyl silyl, triethylsilyl, methoxyl methyl etc.
This paper employed " amido protecting group " term means a chemical functional group, and it protects the amino reaction that antagonism is not desired during at synthesis step in that this technical field is known.Behind synthesis step, amido protecting group as herein described can removing by selectivity.General amido protecting group is described in that T.H.Greene and P.G.M.Wuts show in this technical field Protective Groups in Organic Synthesis, the 3rd edition, John Wiley ﹠amp; Sons, New York (1999).The example of amido protecting group includes, but are not limited to tertbutyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzo oxygen carbonyl etc.
This paper employed " protection is amino " term means the amino of being protected with as the amido protecting group of preceding definition.
This paper employed " aprotic solvent " term means a kind of solvent, and it is to the active quite passivation of proton, that is, and can be as proton donor.Example includes, but not limited to for example for example methyl chloride, monochloroethane, chloroform etc. of hexane and toluene, halogenated hydrocarbons of hydro carbons, heterogeneous ring compound, for example tetrahydrofuran (THF) and N-N-methyl 2-pyrrolidone N-, and ethers for example ether, dimethoxy methyl ether.These seriess of compounds well known to a person skilled in the art, and to those skilled in the art obviously, for specific compound and reaction conditions, for example, factors such as solubleness, reagent react and preferred temperature range according to reagent have its preferred discrete solvent or its mixture.Further discuss to be found in organic chemistry textbook or specific disquisition for aprotic solvent, for example: Techniques of Chemistry SeriesAmong the Vol.II Organic Solvents Physical Properties and Methods of Purification, 4th ed., volumes such as John A.Riddick, John Wiley ﹠amp; Sons, NY, 1986.
This paper employed " strong acid organic solvent " term refers to a kind of solvent, and it is easy to provide proton, and for example alcohol has methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol etc.These solvents are well known to a person skilled in the art, and to those skilled in the art obviously, for specific compound and reaction conditions, for example, factors such as solubleness, reagent react and preferred temperature range according to reagent have its preferred discrete solvent or its mixture.Further discuss to be found in organic chemistry textbook or specific disquisition for the strong acid organic solvent, for example: Techniques of Chemistry SeriesAmong the Vol.II Organic Solvents Physical Properties and Methods of Purification, 4th ed., volumes such as John A.Riddick, John Wiley ﹠amp; Sons, NY, 1986.
" significant quantity " term refers to produce the compound amount of therapeutic action to the individuality of being treated.Therapeutic action can be objectively (that is, can some test or mark measure) or subjectivity (that is, individuality is indicated or felt and produces effect).Above-mentioned compound significant quantity scope can be at about 0.1mg/Kg to about 500mg/Kg, and preferred about 1 to about 50mg/Kg.Effective dose also can and be used together with other medicament and has different according to medicine-feeding way.
Substituent that the present invention looked forward to and the combination of variation thing only are to form stable compound.This paper employed " stablizing " term refers to that compound has the required stability of enough preparations and can keep enough long-standing integrity useful with the purposes that describes in detail for this paper.(for example, individuality being carried out therapeutic or preventative administration).
The synthetic compound can also further utilize for example method purifying such as column chromatography, high-pressure liquid chromatography or recrystallization by separating in the reaction mixture.The synthetic of compound shown in this paper is very usual for those skilled in the art.In addition, various synthetic steps can carry out being desired to obtain compound in differing order.Synthetic useful chemical transformation and protecting group method (protect and go and protect) for synthetic compound described herein they are known for ability in the technician, comprise, for example, R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups In Organic Synthesis, 2nd.Ed., John Wiley and Sons (1991); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wileyand Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and later release thereof are described.
This paper employed " individuality " term refers to animal.Preferred animal is a Mammals.Preferred Mammals is behaved.Individuality also can refer to, for example, and dog, cat, horse, ox, pig, guinea pig, fish, bird etc.
Compound of the present invention can be done to modify to strengthen its selectivity organism characteristic by the suitable function of apposition.These modifications are known in the field and can comprise, increase to the biological permeability (for example, blood, lymphsystem, central nervous system) of set biosystem, increase convenient oral, increase solubleness so that can be by drug administration by injection, change metabolism and change excretory speed.
Compound as herein described comprise two or more asymmetric centers and thereby produce enantiomer, non-mirror image isomerism thing and other stereoisomers, its can be defined as by the absolute stereo chemistry (R)-or (S)-, or amino acid (D)-or (L)-shape.This invention is intended to comprise all possible isomers and racemization thereof and selectivity purifying shape.Optical isomeric compound can perhaps be split with preparation by racemic mixture by preparing with above-mentioned steps from each other optical activity precursor.Fractionation can be in the presence of resolution reagent, by chromatography or by periodic crystallisation or by carrying out in conjunction with some technology well known by persons skilled in the art.Be found in Jacques etc. about fully further details, Enantiomers, Racemates, and Resolutions(John Wiley ﹠amp; Sons, 1981).Unless when compound as herein described comprises how much asymmetric centers of olefinic double bonds or other and specializes, series of compounds is intended to comprise E and two kinds of rotamerism things of Z.Same, in all tautomerism shapes also are intended to be included in.The represented any carbon-carbon double bond configuration of this paper only is convenient selected, unless this paper point out, otherwise and be not intended to indicate specified configuration; Therefore any trans carbon-carbon double bond described herein may be cis, trans or the cis of arbitrary proportion and trans mixture.
This paper employed " pharmacologically acceptable salts " refers to the salt under reasonable medical determination range, is applicable to and human body and can not cause toxicity, stimulation, anaphylaxis than the lower animal contact tissue, and has rational benefit/risk ratio.Pharmacologically acceptable salts is known in this area.For example, S.M.Berge etc. are specified in J.Pharmaceutical Sciences for pharmacologically acceptable salts, 66:1-19 (1977).These salts can be in in-situ preparing during the final separation of The compounds of this invention and purifying, or in addition individually by free base and suitable organic acid reaction are prepared.The example of pharmaceutically acceptable non-toxic acid addition of salts is by mineral acid for example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and cross chloric acid, perhaps with organic acid for example, acetate, maleic acid, tartrate, citric acid, FUMARIC ACID TECH GRADE, propanedioic acid, with the formed salt of amino, perhaps, other method of using by this area prepares, for example ion exchange method.Other pharmacologically acceptable salts class comprises adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, ten dithionates, ethane sulfonate, formate, the Hu Yansuo hydrochlorate, the glucose enanthate, glycerophosphate, the gluconate Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxyl-ethyl sulfonate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleic acid salt, malonate, methane sulfonates, the 2-naphthalenesulfonate, the nicotine hydrochlorate, nitrate, oleate, oxalate, palmitate, embonate, tartaric acid salt, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, propionic salt, stearate, fumarate, vitriol, tartrate, thiocyanate-, tosilate, the undecane hydrochlorate, valerate etc.Representational alkali or alkaline earth metal salt comprise sodium salt, lithium salts, sylvite, calcium salt, magnesium salts etc.Other pharmacologically acceptable salts class comprises, if suitable words, can be nontoxicity ammonium, quaternary ammonium and utilize the formed amine cation of opposite property ion, as halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, have 1～6 carbon atom alkyl, sulfonate and arylsulphonate.
Compound used in the present invention comprises structural formula as herein described, is to be defined as to comprise its pharmaceutically acceptable derivates and prodrug." pharmaceutically acceptable derivates or prodrug " means the salt of any pharmacologically acceptable salts, ester, ester class or the derivative of other The compounds of this invention, and it can provide (directly or indirectly) The compounds of this invention person when lying in the recipient being offerd medicine.
When composition of the present invention comprises structural formula of compound as herein described and one or more and plants extra treatment or prevention medicament, this compound and extra medicament must exist with the dosage level between the dosage about 1～100% of normal single therapy course of treatment, and be better with about 5～95% again.Extra medicament can separate dispensing with The compounds of this invention, with the part as multiple medicament therapy.Perhaps, these medicaments also can be the part of single formulation, with compound of the present invention be single composition.
Unless specialize, this paper employed " infectation of bacteria " or " protozoal infections " comprise, but be not limited to, betide infectation of bacteria and the protozoal infections of Mammals, fish and bird, and can utilize microbiotic for example The compounds of this invention dispensing with treatment or prevention with infectation of bacteria and protozoal infections diseases associated.These infectation of bacteria and protozoal infections and include, but are not limited to following with these infection diseases associated: with pneumococcus, bloodthirsty hemophilus influenza, mucositis Mohs bacterium, streptococcus aureus or or streptococcus, relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and the mastoiditis of pseudomonal infection; Infect relevant pharyngitis, rheumatic fever and kidney glomerule ephritis with micrococcus scarlatinae, suis C and G group, diphtheria clostridium or hemorrhagic actinobacillus; Infect relevant respiratory tract infection with pneumonia mycoplasm hyopneumoniae, veteran pneumobacillus, pneumococcus, bloodthirsty hemophilus influenza or pneumonia Chlamydia; Infect relevant non-complex skin and soft tissue infection, abscess and osteomyelitis and puerperal fever with the gloomy Bartonella of streptococcus aureus, coagulase-positive staphylococci (that is, staphylococcus epidermidis, staphylococcus haemolyticus etc.), micrococcus scarlatinae, streptococcus agalactiae, suis C-F group (minute-colony streptococci), Streptococcus viridans, corynebacterium, Clostridium or the Chinese; With post rotten staphylococcus or enterococcus spp and infect the relevant acute urinary tract infection of non-complex; Urethritis and trachelitis; Reach and sand holes Chlamydia, haemophilus ducreyi, treponema pallidum, molten slurry bacterium or the relevant sexually transmitted disease of Nai Seshi micrococcus gonococcus infection of urinating; Infect relevant toxic disorder (food poisoning and toxicogenic shock symptom) with streptococcus aureus or suis A, S and C group; The ulcer relevant with Helicobacter pylori infection; Infect relevant general heating paresthesia with Spirochaeta recurrentis; Infect relevant Lyme disease with the Borrelia burgdoyferi bacterium; Infect relevant conjunctivitis, keratitis and reach dacryocystitis with sand holes Chlamydia, Nai Seshi micrococcus gonococcus, streptococcus aureus, pneumococcus, micrococcus scarlatinae, bloodthirsty hemophilus influenza or listeria; Infect relevant dispersivity mycobacterium avium group (MAC) disease with mycobacterium avium or Mycobacterium intracellulare; The gastroenteritis relevant with Cj infection; Protozoal disease in the intestines relevant with the Cryptosporidium infection; Infecting relevant tooth source sexuality with Streptococcus viridans dyes; Infect relevant Whooping cough with bordetella pertussis; Infect relevant gas subcutaneous ulcer with bacillus aerogenes capsulatus or Bacteroides; The skin infections that causes by streptococcus aureus, corynebacterium acnes; The arteriosclerosis relevant etc. with Hp or infection involving chlamydia pneumoniae.
The infectation of bacteria that can treat or prevent in animal and protozoal infections reach and include but not limited to following with these infection diseases associated: infect relevant ox respiratory disease with the special Pseudomonas of haemolysis Pasteurella, pasteurella multocida, ox mycoplasm hyopneumoniae or Boulder; Infect relevant Roll road disease with intestinal bacteria or protozoon (being coccidia, Cryptosporidium etc.); Infect relevant dairy cow breast inflammation with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, different streptococcus uberis, Cray uncle Shi Shi Bacillaceae, Corynebacterium or enterococcus spp; Belong to the relevant porcine respiratory disease of infection with actinobacillus pleuropneumoniae, pasteurella multocida or mycoplasm hyopneumoniae; The chitling road disease relevant with intestinal bacteria, lawsonia intracellularis, salmonella or dysentery characterized by blood in the stool spirochaete infection; Thin fusobacterium infects relevant cow hoof and rots; The garget relevant with coli-infection; The ox relevant with actinomyces pseudonecrophorus or nodositas infection due to Bacteroides sends out the shape wart; Infect relevant Niu Fenhong eye, infect relevant ox prematurity miscarriage with the ox catarrhalis with protozoon (that is neospora); Dog relevant and cat urinary tract infection with coli-infection; With staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus or pasteurella multocida infect relevant dog and cat skin skin and soft tissue infection; With Pseudomonas in Alcaligenes, bacterioid genus, Clostridium, the intestines, eubacterium, Peptostreptococcus, general woods zygosaccharomyces, Campylobacter, actinomyces, Rosenbach's disease Pseudomonas, Rhod, trypanosoma, cruel Proteromonas, burnt Eimeria, Toxoplasma, lung sac worm, sharp very graceful Proteromonas, and Trichomonas or the fertile Pseudomonas of Prey infect relevant dog and cat tooth or mouthfeel and dye.Other infectation of bacteria and protozoal infections and with these infect relevant can according to the inventive method treat or prevent disease " The Sanford Guide ToAntimicrobial Therapy; " with reference to people such as J.P.Sanford the 26th edition, (Antimicrobial Therapy, Inc., 1996).
Antibacterial activity
Sensitivity test can resist the external activity of set bacterial isolates in order to the antimicrobial medicament of quantitative measurment.Series of compounds mat microdilution is tested its external antibacterial activity.To observed bacterial isolates, minimum inhibition concentration (MIC) is to utilize suitable curtain Le Xidun liquid medium (Mueller Hinton Broth medium (CAMHB)) to measure on 96 micropore dishes.Antimicrobial medicament is the concentration of about 64 μ g/ml～about 0.03 μ g/ml by serial dilution (2 times) with the generation scope in DMSO.Compound after the dilution (2 μ l/ hole) then with 96 fixedly the water dropper dispenser transfer to aseptic, nonvaccinated CAMHB (0.2mL).The inoculum size utilization of each bacterial isolates and 0.5 Macfarlane turbidity standard product (McFarland turbidity standard) carry out the optics comparison to demarcate to 5 * 10 5CFU/mL.Every dish inoculation is through adjusted bacterial inoculum 10 μ l/ holes.96 porose discs are capped and are incubated under 35+/-2 ℃, under the atmospheric environment, 24 hours.After the cultivation, whether the hole in the dish has growth (muddiness) with optical method of density measurement by visual inspection.MIC is defined as the Cmin that does not have visible growth antibacterium medicament.The MIC general range of compound exhibits of the present invention is between about 64 μ g/ml～about 0.03 μ g/ml.
The governing principle that the thecalibration standards M7-A4 that all in vitro testss are announced according to the standard council of country of clinical labororatory (NCCLS) plans in the book and narrated is carried out.
Pharmaceutical composition
Pharmaceutical composition of the present invention comprises the present invention, and significant quantity compound and one or more pharmaceutically acceptable carriers or vehicle prescription be together in treatment.
This paper employed " pharmaceutically acceptable carrier or vehicle " means the prescription subsidiary of nontoxicity, inert solid, semisolid or liquid filler material, thinner, capsule material or arbitrary form with the family of languages.Some example that can be used as the pharmaceutically acceptable carrier material has carbohydrate, for example lactose, glucose and sucrose; Starch is W-Gum and yam starch for example; Mierocrystalline cellulose and derivative thereof, for example sodium carboxy methyl cellulose, ethyl cellulose and cellulose ethanoate; The powdered tragakanta; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle, for example theobroma oil and bolt wax; Oils is peanut oil, Oleum Gossypii semen, Trisun Oil R 80, sesame oil, sweet oil, Semen Maydis oil and Oleum Glycines for example; Glycols is propylene glycol for example; The ester class is ethyl oleate and Laurate ethyl for example; The agar class; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Lalgine; Non-pyrogen water; Deng a saline solution; Ringer's solution; With alcohol and phosphoric acid buffer, and other avirulent can compatible lubricant, for example Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, spices, sanitas and antioxidant also can be present in the composition according to prescriber's judgement.
Pharmaceutical composition of the present invention can via oral, through injection, through sucking spray, throwing through local topical, per rectum, intranasal, through cheek, transvaginal or via the reservoir of implanting and give, with oral or preferred to inject.Pharmaceutical composition of the present invention can comprise any traditional nontoxicity pharmaceutically acceptable carrier, adjuvant or delivery media.In some situation, the pH of prescription can utilize pharmaceutically acceptable acid, alkali or damping fluid adjustment to transport the stability of shape with enhancing compound formula or its.That the employed injection term of this paper comprises is subcutaneous, in the intracutaneous, intravenously, intramuscular, intra-arterial, jaw intraarticular, intra-arterial, Synovial joint, in the breastbone, in the canalis spinalis, intralesional and intracranial injection or perfusion technology.
Be used for the liquor type that oral throwing gives and comprise pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and tincture.Remove the active ingredient beyond the region of objective existence, the liquor type can comprise the general inert diluent that uses in this field, for example, water or other solvent, solvating agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, phenylamino benzoic acid methyl esters, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil (particularly, Oleum Gossypii semen, peanut, corn, plumule, olive, comb fiber crops and sesame oil), glycerine, tetrahydrofurfuryl carbinol, polyoxyethylene glycol and lipid acid sorbitan ester and composition thereof.Except that not activating dilution, oral compositions also can comprise adjuvant, for example wetting Agent for Printing Inks, emulsifying and suspending agent, sweeting agent, spices.
Injection preparation, for example sterile aqueous or oiliness suspension agent can be filled a prescription with suitable dispersion or wetting Agent for Printing Inks and suspension agent according to this field known technology.Aseptic injection preparation also can be aseptic parenteral solution, suspended substance or the emulsification in nontoxicity injectable thinner or solvent, for example, and for being dissolved in the solvent in the 1,3 butylene glycol.Spendable acceptability transport instrument and solvent have water, ringer's solution, U.S.P. and etc. open sodium chloride solution.In addition, aseptic, stationarity is oily is the media of solvent or suspension for using traditionally.Can be used for any nonirritant stationarity oil of this purpose, comprise synthetic list or two glyceryl ester.In addition, lipid acid, for example oleic acid can be used for the preparation of injection.
The sterilization of injection prescription can utilize, and for example bacterium stops membrane filtration, or sterilant is added aseptic solids composition, and it can be dissolved or dispersed in sterilized water or other the aseptic injectable media before use.
For prolonging the effectiveness of medicine, wish usually the absorption of medicine by subcutaneous or intramuscularly slowed down.This can reach by using the water-soluble not good crystallinity or the liquid suspension of unsetting property material.The uptake rate of medicine depends on dissolution rate, and, depend on crystallographic dimension and crystalline form again.Perhaps, but injection throw give formulation slow down absorption also mat with medicine dissolution or be suspended in oil and transport instrument to reach.Injectable storage formulation system is used in the biodegradable polymers, polylactic acid-polyglycolic acid for example, and the microcapsule matrix that forms medicine is reached.According to ratio and the employed particular polymers characteristic of medicine, can control release rate of drugs to polymkeric substance.The embodiment of other biodegradable polymers comprises poly-(positive ester) and gather (acid anhydrides).But storage agent injection prescription also mat is overlying on pharmaceutical pack in little fat body of body tissue's compatibility or the microemulsified thing and prepares.
Rectum or vagina are thrown the composition that gives and are preferably suppository, but its preparation mat mixes The compounds of this invention with suitable non-irritating excipient or carrier, suitable non-irritating excipient or carrier for example have, theobroma oil, poly-hexylene glycol or suppository wax, it is solid in room temperature but is liquid at body temperature, so can melt in rectum or vagina and discharge active compound.
Be used for the solid dosage that oral throwing gives and comprise capsule, lozenge, powder and particle.In these solid dosages, the active ingredient system is mixed to the pharmaceutically acceptable vehicle of at least a inert or carrier for example Trisodium Citrate or Lin Suanergai, and/or a) weighting agent or extend for example starch of agent, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) wedding agent, carboxy methyl cellulose for example, alginic acid, gelatin, Polyvinylpyrolidone (PVP), sucrose and locust tree, c) wetting agent, glycerine for example, d) collapse powder, agar-agar for example, lime carbonate, potato or cassava starch, alginic acid, some silicic acid and yellow soda ash, e) dissolving slows down agent, paraffin for example, f) absorb accelerator, quaternary ammonium compound for example, g) wetting Agent for Printing Inks, for example, hexadecanol and glyceryl monostearate, h) absorption agent, as kaolin and bentonite clay and i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt and composition thereof.During for capsule, lozenge and pill, formulation also can comprise buffer reagent.
Also available vehicle of the solids composition of similar type such as lactose or and high molecular weight polyethylene glycol etc. as the bulking agent in soft and the hard capsule.
Can utilize the preparation of dressing and shell material as lozenge, sugar-coat ingot, capsule, pill and particulate solid dosage, for example enteric coating and other are at pharmacy technical other the known dressing of writing out a prescription.It randomly comprises opacifying agent and can be a kind of composition, and it is preferably with randomly, in the mode that postpones, specific enteron aisle part release of active ingredients.Available embedding composition embodiment comprises polymeric material and wax.
The local topical of The compounds of this invention and cutaneous metastatic throwing are given formulation and are comprised ointment, mashed prod, breast frost, emulsion, gel, powder, solution, spray, inhalation or paster.Activeconstituents system is mixed under sterile state with any required sanitas or required buffer reagent with pharmaceutically acceptable carrier.Ophthalmic formulations, auristillae, spongaion, powder and solution also are contained in the scope of the present invention's expection.
Ointment, mashed prod, newborn frost and gel are except that active compound of the present invention, can comprise vehicle, for example animality and vegetablefats, oil, wax, paraffin, starch, tragcanth, derivatived cellulose, polyoxyethylene glycol, silicone, wilkinite, silicic acid, talcum and zinc oxide or its mixture.
Powder and spray can comprise vehicle except that active compound of the present invention, for example lactose, talcum, silicic acid, aluminium hydroxide, Calucium Silicate powder and Silon are unconcerned or the mixture of these materials.Spray still can comprise for example chloro-fluorocarbon hydrogen compound of habitual propelling agent.
The cutaneous metastatic paster has can provide the control compound to be sent to the additional advantage of health.This formulation can be utilized this compound dissolution or be scattered in preparation in the suitable media.The absorption enhancement agent also can be used for increasing compound and can flow in the body through skin.Speed can be controlled by control speed film being provided or this compound being scattered in the polymeric matrix gel.
According to methods of treatment of the present invention, patient Yu can be treated or be prevented as human or the intravital infectation of bacteria of other animal, and mat is thrown this patient and given the The compounds of this invention that significant quantity is gone up in treatment, in this following required time of amount, can reach the result who is desired.
By " treatment significant quantity " of the present invention compound, be under the rational benefit/risk ratio that refers to be useful in any medical treatment, be used for the treatment of the capacity compound of infectation of bacteria.So, must understand, total daily dosage portion of compound of the present invention and composition can be by being determined by the attending doctor in the rational medicine determination range.And can comply with many factors and difference for the particular treatment effective dose level of given patient, comprise the severity of disease to be treated and disease; The activity of employed specific compound; Employed particular composition; Age, body weight, state of health, sex and patient's meals; The discharge rate of dispensing time, dosing way, the specific compound that uses; The treatment phase; Reach with the medicine that uses the specific compound combination or use simultaneously; In known other factor of medical circles.
For human or other animal with single or throw its amount of the total per daily dose of The compounds of this invention of giving respectively and can be, 0.01～50mg/kg body weight for example, or more generally, be 0.1～25mg/kg body weight.Single dose of composition can comprise this amount, or the dosage that repeatedly separates is to supply per daily dose.Generally speaking, the present invention is to throw with single or multiple dosage every day to give the about altogether 10mg of The compounds of this invention～about 1000mg to the employed therapeutics of this treatment of needs patient.
Compound formula as herein described can for example give with injection, intravenously, intra-arterial, intracutaneous, intraperitoneal, intramuscular or subcutaneous throwing; Or per os, through cheek, intranasal, wear mucous membrane, local topical, with eye with prepared product or suck to throw and give, dosage range is about 0.5～about 100mg/kg body weight, perhaps dosage is 1mg～1000mg/ dosage, every about 4～120 hours, or determine according to the requirement of certain drug.The method of this paper system be intended to throw give the significant quantity compound compound composition is desired to reach or shown in effect.On the typical case, but pharmaceutical composition of the present invention throw every day and to give about 1～6 time, perhaps, throw in the mode of continous pouring and to give.These throwing methods of giving can be used as chronic or acute treatment.The active principle system that can combine with carrier substance to produce single formulation decides according to the AD HOC of main body of being treated and dispensing.Typical prepared product comprises about 5%～95% (w/w) of active compound.Perhaps, these prepared products can comprise active compound about 20%～80%.
Can require the dosage lower or more higher than above-mentioned dosage.Can decide because of many factors given dose and therapeutics that given patient is required, comprise that the severity of the specific compound activity of use, age, body weight, general health state, sex, meals, dispensing time, discharge rate, drug regimen, disease and the course of disease, symptom or situation, patient are for the disposal of disease and treatment doctor's judgement.
When patient is improved, if necessary, compound of the present invention, composition or combination can be thrown with the dosage of keeping and give.Follow-up, can reduce and throw the dosage give or frequency or both, maintain the state of improvement with the symptom that will be relieved to institute's desire level.But if any illness recurrence is arranged, patient may still need treatment intermittently for a long time.
Pharmaceutical composition of the present invention can utilize pharmaceutical composition is in harmonious proportion and gives to fish with oral administration in fish meal, or pharmaceutical composition is dissolved in infected in the water at place, and this mode is commonly referred to as medical treatment and bathes.To the therapeutic dose of fish according to the purpose (disease prevention or treatment) of dispensing and types of administration, fish size and by the infection scope of treatment fish and decide.Generally, can throw every day and give 5-1000mg, be preferably 20-100mg/per kg fish body weight, can once throw and give or be divided into for several times.Essential understand, more than specified dosage only be general range, it can increase and decrease according to age of fish, body weight, the patient's condition etc.
Unless special definition, all technology used herein and scientific words system are according to ripe in the general person of this field person.All publications mentioned in this article, patent, publication application case and other reference are incorporated in this to be kept perfectly.
Abbreviation
The abbreviation and the example that use in the route narration are as follows:
Ac represents ethanoyl;
AIBN represents azo two isobutyl nitrite;
Bu 3SnH represents tributyltin hydride;
CDI represents carbonyl dimidazoles;
Dba represents diphenylmethylene acetone;
Dppb represents the phenyl phosphono-containing butane;
DBU represents 1, two heterocycle [5.4.0] 11-7-alkene of 8-phenodiazine;
DEAD represents the azoethane dicarboxylic ester;
DMAP represents dimethyl aminopyridine;
DMF represents dimethyl formamide;
DPPA represents the diphenylphosphoric acid trinitride;
EtOAc represents ethyl acetate;
MeOH represents methyl alcohol;
NaN (TMS) 2Two (trimethyl silyl) acid amides sodium of representative;
NMMO represents N-methylmorpholine N-oxide compound;
TEA represents triethylamine;
THF represents tetrahydrofuran (THF);
TPP or PPh 3Represent triphenylphosphine;
MOM represents methoxyl methyl;
Boc represents tertbutyloxycarbonyl;
Bz represents phenmethyl;
Ph represents phenyl;
POPd represents two (two-tertiary butyl phosphine-κ P) palladate (II) of dihydro dichloro;
TBS represents tertiary butyl dimethylsilyl; Or
TMS represents trimethyl silyl.
Synthetic method
Compound of the present invention and method and following more easily understanding of synthetic route binding, the method that can prepare The compounds of this invention is explained by route system.
With a kind of preferred intermediate product of the series of compounds shown in the following formula (IX) in order to compound shown in the preparation formula (I).
R wherein 6And R 2' as previously defined.
With the 2nd preferred intermediate product of the series of compounds shown in the following formula (X) in order to compound shown in the preparation formula (I).
Figure A20038011099700962
Wherein X, Y, R 2', R 4" and R 6' as previously defined.
Route 1-4 narration is in order to prepare the method for intermediate product, and these intermediate products are useful for preparation compound of the present invention.
The compound of formula (1-2) is useful as initial substance in preparation during The compounds of this invention, and its method that can utilize following route 1 and route 2 to be described in detail is synthetic.Erythromycin derivatives (1-2) is to utilize United States Patent (USP) 4,990,602,4,331,803,4,680,386,4,670,549 and the method narrated of European patent application EP 260,938 prepare by erythromycin.
Route 1
Erythromycin derivatives ( 1-2) then react with alkylating agent, alkylating agent is a following formula again:
R 13-OC(O)O-CH 2[C＝CHR 11]CH 2-OC(O)-OR 13( 1-3)
R wherein 13Be C 1-C 12-alkyl, and R 11As definition before.
The expection of most of palladiums (0) catalyzer can be used on present method.Some palladium (II) catalyzer, acid chloride (II) for example, it also can act on by changing palladium (0) class in position into phosphine reaction.Referring to, for example, Beller etc., Angew.Chem.Int.Ed.Engl., 1995, 34(17), 1848.Palladium catalyst can be selected from, but is not limited to, and comprises the group that acid chloride (II), four-(triphenylphosphine) palladium (0), three (diphenylmethylene acetone) two palladiums, four or two (diphenylmethylene acetone) two palladiums etc. are formed.To present method, palladium on the carbon and palladium (II) halide catalyst is time good selection compared with other palladium catalyst.
Suitable phosphine includes, but not limited to triphenylphosphine, two (diphenylphosphine) methane, two (diphenylphosphine) ethane, two (diphenylphosphine) propane, 1, two (diphenylphosphine) butane of 4-, two (diphenylphosphine) pentane and three (o-tolyl) phosphine etc.
Reaction ties up in the aprotic solvent to be carried out, and is good to heat down, for example, and at 50 ℃ or higher.Suitable aprotic solvent comprises, but be not limited to, tetrahydrofuran (THF), N, dinethylformamide, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, hexamethyl phosphoric triamide, 1,2-dimethoxy ethane, methyl tert-butyl ether, heptane, acetonitrile, isopropyl acetate and ethyl acetate.Best solvent is tetrahydrofuran (THF) or toluene.
To the useful alkylating agent of the inventive method be two carbonic acid ( 1-3).Generally speaking, alkylating agent have formula as discussed previously ( 1-3).Preferred alkylating agent is R wherein 13Be the tertiary butyl, sec.-propyl or isobutyl-person.Alkylating agent can make glycol and all cpds reaction prepare to quote two carbonic acid groups.These compounds include, but are not limited to tertiary butyl chloride formic acid, two-tertiary butyl, two carbonic acid and 1-(tertbutyloxycarbonyl) imidazoles, and this reaction lies in organic or inorganic alkali and carries out under existing.Temperature of reaction is by-30 ℃ to about 30 ℃ approximately.Alkylating agent is preferred with two-tertiary butyl, two carbonic acid.
Another kind comprises with phosgene or the pure two-chloroformic acid derivative with the preparation glycol of triphosgene processing the method that alcohol changes carbonic acid into.This two-chloroformic acid derivative is then changed into two carbonic acid, according to Cotarca, and L., Delogu, P., Nardelli, A., Sunijic, V, Synthesis, 1996,553 described methods.This reaction can be carried out in various organic solvents, and for example methylene dichloride, toluene, ether, ethyl acetate and chloroform exist down in alkali.Suitable alkali includes, but not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide, yellow soda ash, salt of wormwood, volatile salt, dimethyl aminopyridine, pyridine, triethylamine etc.Temperature condition can be by 0 ℃～about 60 ℃.Reaction is carried out finishing in about 3～5 hours usually.
Macrolide ( 1-4) cladinose group can by rare-acid water separate or the catalyzer hydrolysis remove with obtain formula ( 1-5) compound.Representational acid comprises dilute hydrochloric acid, sulfuric acid, crosses chloric acid, Mono Chloro Acetic Acid, dichloro acetic acid or trifluoroacetic acid.This reaction appropriate solvent comprises methyl alcohol, ethanol, Virahol, butanols etc.Reaction times is generally 0.5～24 hour.Temperature of reaction is preferred with-10 ℃～80 ℃.
Route 2
Formula ( 1-4) compound, wherein R 6Be ethanoyl, can be changed into corresponding imines as shown in Scheme 2.But the selectivity of oxime goes the protection mat to carry out basic hydrolysis reach in protonic solvent.Representational basic cpd comprises lithium hydroxide, sodium hydroxide, potassium hydroxide etc.Appropriate solvent includes, but not limited to tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane, Virahol, ethanol, butanols and composition thereof.Temperature of reaction is preferred with 0～35 ℃, and the reaction times is preferred with 0.5～8 hour.
With similar approach, can go protection simultaneously to oxime and 2 ' hydroxyl under the various conditions.De-protected condition includes, but not limited to be handled to backflow with alcoholic solvent by room temperature, or with for example butylamine processing of primary amine.Being used for de-protected preferred alcohols solvent is methyl alcohol and ethanol.To removing the more thorough discussion of protecting group step, reagent and condition narration is arranged in the literature, for example T.W.Greene and P.G.M.Wuts are in " Protective Groups in Organic Synthesis " 3 RdEd., John Wiley ﹠amp; Son, Inc, 1999.
With formula ( 2-1) under reductive condition the deoxidation meeting obtain formula ( 2-2) macrolide imines.Many reductive agents can be used for carrying out this transformation, include, but not limited to lithium aluminum hydride, titanous chloride, borine and various sulfide, for example, and Sodium sulfhydrate and Sodium Nitrite.For the more detailed narration of oxime reduction, see J.March institute " Advanced Organic Chemistry " 4 ThEd., Wiley ﹠amp; Son, Inc, 1992.
A kind ofly be used to make oxime to be reduced to the corresponding useful especially method of imines, use a kind of sulphurous acid reducing agent, for example sodium bisulfite under acidic conditions, is generally the proton agent.Representational acid includes, but are not limited to acetate, formic acid, dilute hydrochloric acid, dilute phosphoric acid, dilute sulphuric acid etc.Suitable protonic solvent includes, but not limited to the mixture of water and methyl alcohol, ethanol, Virahol or butanols.This reaction is carried out under 50～110 ℃ usually, and is preferred to carry out 1～10 hour.
The hydrolysis of cladinose group can utilize before 1 narrator of route reach with obtain formula ( 2-3) compound.
Formula ( 2-3) additional compounds can be directly by formula ( 2-1) compound is via with TiCl 3Handle in alcoholic solvent to form, alcoholic solvent is preferably methyl alcohol or ethanol.
Formula ( 2-3) imines can use suitable acylating agent to carry out acylation reaction under alkaline condition in aprotic solvent.Typical acylating agent includes, but not limited to Acetyl Chloride 98Min., diacetyl oxide, Benzoyl chloride, benzoyl oxide and benzene first chloroformic acid.
Aprotic solvent for example has, methylene dichloride, chloroform, tetrahydrofuran (THF), N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide, its mixture or with the mixture of these solution and ether, tetrahydrofuran (THF), 1,2-dimethoxy ethane, 1, mixing such as 2-ethylene dichloride, acetonitrile, ethyl acetate, acetone.Aprotic solvent can't have disadvantageous effect to this reaction.This solvent is to be selected from methylene dichloride, chloroform, N, and dinethylformamide, tetrahydrofuran (THF), N-N-methyl 2-pyrrolidone N-or its mixture are preferred.
Typical alkali includes, but not limited to pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-crassitude, 2,6-lutidine, 1, two heterocycle [5.4.0] 11-7-alkene of 8-phenodiazine.Acylation condition is discussed in more detail, seen, for example, T.W.Greene and P.G.M.Wuts, " Protective Groups in Organic Synthesis " 3 RdEd., John Wiley ﹠amp; Son, Inc, 1999.
Route 3
Figure A20038011099701011
Figure A20038011099701021
The step that forms 6-11 bridge formation macrolide can be as described in the route 3.In similar mode as discussed previously, this step comprise with formula ( 1-4) compound and suitable alkylating agent reaction.As before, formula ( 1-4) the erythromycin derivatives system and the alkylating agent reaction of following formula:
R 13-OC(O)O-CH 2[C＝CHR 11]CH 2-O-R p( 3-1)
R wherein 13Be C 1-C 12-alkyl, and R 11And R pWith definition before.
As previously discussed, most palladium (0) catalyzer can be expected at this method effect and be reflected in the aprotic solvent and carry out, and is preferably under heating and carries out, at 50 ℃ or high temperature more.Best solvent is tetrahydrofuran (THF) and toluene.
In the method for the present invention useful alkylating agent be blended silane ether carbonic acid ( 3-1).Usually, alkylating agent have formula ( 3-1), as previously mentioned.Preferred alkylating agent is R 13For the tertiary butyl, sec.-propyl or isobutyl-and Rp are tertiary butyl dimethylsilyl, tri isopropyl silane base, tert-butyl diphenyl silylation etc.
Formula ( 3-1) the long-pending system of alkanisation reacts glycol to introduce the carbonic acid group with many kinds of compounds in regular turn, is reacting to introduce silane group, with preparation with chemical compound lot.Alkylating agent includes, but not limited to tertiary butyl chloride formic acid, di-t-butyl two carbonic acid and 1-(tertbutyloxycarbonyl) imidazoles.Wherein silanizing agent includes, but are not limited to tertiary butyl dimethylsilyl chlorine, tertiary butyl dimethylsilyl triflate, tertiary butyl dimethylsilyl prussiate and tertiary butyl methyl-monosilane base imidazoles.Both reactions are all carried out under organic or inorganic alkali exists.Temperature of reaction can be from-30 ℃～30 ℃ variations approximately.Preferred person, alkylating agent is di-t-butyl two carbonic acid and silanizing agent is a tertiary butyl dimethylsilyl chlorine.
The free oxime ( 3-3) be utilize with go to protect oxime ( 1-4) main identical step preparation, wherein R 6Be the Ac in the route 2.
Formula ( 3-4) compound can be directly by formula ( 3-3) compound by use previous described be used to make formula ( 2-1) oxime be reduced to corresponding ( 2-2) step of imines is to form.
Protecting group (Rp) then by by formula ( 3-4) hydroxyl of compound removes, and it utilizes T.W.Greene and P.G.M.Wuts, " Protective Groups in Organic Synthesis " 3 RdEd., John Wiley ﹠amp; Son, Inc, 1999 described felicity conditions.For example, if protecting group is TBS, can use tetra-n-butyl Neutral ammonium fluoride, hydrofluoric acid or trifluoroacetic acid.Use standard conditions, primary hydroxyl can be changed into tertiary butyl carbonic acid, and then make the aforesaid palladium of 11-hydroxyl mat (0) catalyzer alkanisation.In this way easily preparation formula ( 3-6) compound.
Cladinose remove can as reach as described in the route 1 before with obtain formula ( 1-5) compound.
Route 4
Figure A20038011099701031
In the invention ( 5-1) but the compound mat with secondary alcohol oxidation preparation, its utilization is crossed iodine alkane (Dess Martin periodinane) as oxygenant for Si Mading.Reaction is carried out in 0～25 ℃ in aprotic solvent usually.Reaction times was generally between 1～12 hour.
Perhaps, oxidizing reaction can utilize pyridinium chlorochromate, sulphur three oxy picolinate mixtures to finish in dimethyl sulfoxide (DMSO), four n-propyl ammoniums are crossed ruthenic acid and N-methylmorpholine N-oxide compound, history literary composition oxide compound etc.The discussion more thorough to the secondary alcohol oxidation is found in J.March, " Advanced OrganicChemistry " 4 ThEd., Wiley ﹠amp; Son, Inc, 1992.
Route 5
Figure A20038011099701041
Route 5 explanations other method of the present invention is in order to prepare compound of the present invention.With fat alkene ( 6-1) change into ketone ( 6-2) can utilize and make fat alkene be exposed to ozone ozonide is decomposed with suitable reductive agent and to finish, as described in route 3.Reaction is carried out in inert solvent usually, for example, but is not limited to, and methyl alcohol, ethanol, ethyl acetate, Glacial acetic acid, chloroform, METHYLENE CHLORIDE or hexane or its mixture, preferred with methyl alcohol, be preferably at-78～-20 ℃.The reductive agent of representative for example has, triphenylphosphine, and trimethyl phosphite, thiocarbamide and dimethylsulphide, preferred with triphenylphosphine.Decompose and the more thorough visible J.March of discussion of condition " Advanced Organic Chemistry " 4 for ozone ThEd., Wiley ﹠amp; Son, Inc, 1992.
Another be used to prepare ketone ( 6-2) method comprises that earlier fat alkene dihydroxy being remake glycol cuts.Glycol ( 6-3) utilize earlier make fat alkene with ( 6-1) perosmic anhydride prepared in reaction.The perosmic anhydride reaction that this reaction can utilize and measure, or as if the oxygenant that exists as hydrogen peroxide, tert-butyl peroxide or N-methylmorpholine-N-oxide compound, can react with the perosmic anhydride of catalytic amount.These reactions can be carried out in all kinds of SOLVENTS, comprising: 1, and 4-dioxane, tetrahydrofuran (THF), the trimethyl carbinol and ether are preferably at 0 ℃.
Glycol can utilize many reagent to cut, and includes but not limited to periodic acid, tetraethyllead, magnesium dioxide, potassium permanganate, sodium metaperiodate and N-iodine maleoyl amine.According to cutting agent, can use all ingredients.Preferred incision agent is a sodium metaperiodate, and solvent is preferably ethanol, methyl alcohol, acetone or 1, the mixture of 4-dioxane and water, and temperature of reaction is 0～25 ℃.
Route 6
Figure A20038011099701051
Route 6 formulas ( 7-1) can use halogenating agent handle change into formula ( 7-2) step.This reagent act as with halogen atom and replaces hydrogen atom in the C-2 position of ketone macrolide.Many halogenating agents are useful to this step.
Fluorizating agent include, but not limited to the inferior acid amides of N-fluorobenzene sulfo group in alkali exist down, 10%F2 in formic acid, 3,5-two chloro-1-fluorine pyridinium tetrafluoroborates, 3,5-two chloro-1-fluorinated pyridine triflate, (CF 3SO 2) 2NF, N-fluoro-N-methyl para toluene sulfonamide in alkali exist down, N-fluorinated pyridine triflate, N-fluoro perfluor pyridine exist down in alkali.
Chlorizating agent includes, but not limited to hexachloroethane and has following, CF in alkali 3CF 2CH 2ICl 2, SO 2Cl 2, SOCl 2, CF 3SO 2Cl exists down in alkali; Cl 2, NaOCl exists down in acetate.
Bromizating agent includes but not limited to, Br 2Pyridine HBr, Br 2/ acetate, N-bromine fumaroyl imines exist following, LDA/BrCH in alkali 2CH 2Br or LDA/CBr 4
Suitable iodinating agent is that N-iodine maleimide exists down or I in alkali 2
To halogenating reaction need suitable bases for example be alkalimetal hydride, as NaH and KH, or amine alkali, for example, LDA or triethylamine.Different reagent may need multi-form alkali, but all known in this field.
Preferred halogenating agent is that N-fluorobenzene sulfimide exists down in sodium hydride.
Appropriate solvent is dimethyl formamide, dimethyl sulfoxide (DMSO), pyrrolidone etc.
The operator who is familiar with this field should be appreciated that the C-2 halogenated products corresponding as if needs, formula ( 7-1) or ( 7Before compound-2) can replace ( 6-1) or ( 6-2) compound.
Route 7
Figure A20038011099701061
For ease of explanation, in route 7, only show 6-11 crosslinked group according to each specific compound of formula I, must understand, this is to be used to illustrate a kind of compound according to formula I, it has specific crosslinked group.Formula of the present invention ( 6-1) reach ( 6-2) compound can further utilize variety of way to make functionalization.Route 7 is detailed shown with ketone ( 6-2) change into formula ( 7The step of oxime-7).The formation of oxime can utilize suitable substituted hydroxy amine, under acidity or alkaline condition in all kinds of SOLVENTS to reach.Representational acid includes, but not limited to hydrochloric acid, phosphoric acid, sulfuric acid, tosic acid and pyridine tosic acid.Same, useful alkali for example has, triethylamine, pyridine, diisopropyl ethyl amine, 1,5-lutidine etc.Appropriate solvent includes, but are not limited to methyl alcohol, ethanol, water, tetrahydrofuran (THF), 1,2-dimethoxy ethane and ethyl acetate.This reaction is so that to utilize triethylamine be alkali and be embodied as preferred in ethanol.Temperature of reaction is generally 25 ℃, and the reaction times is 1～12 hour.
Ketone ( 6-2) also can be further via the reductive amination step transitions be amine ( 7-9) utilize.Therefore, ketone is existed down in reductive agent to handle with amine, with obtain product amine ( 7-9).This reaction can be following the carrying out of adding or not adding acid.The common example of acid that uses comprises hydrochloric acid, phosphoric acid, sulfuric acid, acetate etc.Reductive amination is reacted effective reductive agent include, but are not limited to hydrogen and catalyzer, zinc and hydrochloric acid, SODIUM CYANO BOROHYDRIDE, sodium borohydride, pentacarbonyl iron and alcohol potassium hydroxide.The general alcohol solvent that uses.Preferred condition system uses SODIUM CYANO BOROHYDRIDE in methyl alcohol and add acetate.
Another kind further make ketone ( 6-2) method of functionalization system via add Grignard reagent with form formula ( 7-8) alcohol.Route 8 has been described this step.Required Grignard reagent can be easily via various alkyl or aryl halogenide T and magnesium (are seen B.S.Furniss in standard conditions, A.J.Hannaford, P.W.G.Smith, and A.R.Tatchell " Vogel ' s Textbook of PracticalOrganic Chemistry " 5 ThEd., Longman, 1989) descend reaction to obtain.This addition reaction lies in the inert solvent to be carried out, and generally ties up under the low temperature.Appropriate solvent includes, but are not limited to tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and hexane.Preferred solvent is tetrahydrofuran (THF) or ether.Reaction is to carry out to good under-78～0 ℃.
In a similar manner, with other organometallic reagent reaction can obtain type ( 7-8) alcohol.The example of spendable organometallic reagent includes, but are not limited to organoaluminum, organolithium, organic cerium, organic zinc, organic thallium and organoboron reagent.The discussion more thorough for organometallic reagent is found in B.S.Furniss, A.J.Hannaford, and P.W.G.Smith, A.R.Tatchell " Vogel ' sTextbook of Practical Organic Chemistry " 5 ThEd., Longman, 1989.
Moreover, formula ( 7-14) alcohol can utilize with the ketone of correspondence ( 6-2) also original preparation (seeing Hudlicky, M.Reductions in Organic Chemistry, Ellis HorwoodLimited:Chichester, 1984) under various conditions.Institute's deutero-alcohol can further modify again with obtain formula ( 7-15) compound.Production ( 7-15) method includes, but are not limited to: with pure alkanisation, or change alcohol into leaving group with electrophilic reagent, for example, triflate, tosylate, phosphonate, halogenide etc. are replaced with heterocycle nucleophilic reagent (for example, amine, alkoxide, sulfide etc.) again.
Skilled person can examine know compound ( 6-1) reach ( 6-2) unsaturated compound of representative can be reduced to form corresponding saturated compound (seeing Hudlicky, M.Reductionsin Organic Chemistry, Ellis Horwood Limited:Chichester, 1984).
Glycol ( 7-5) can utilize with alkene ( 6-1) with the perosmic anhydride prepared in reaction.This reacts quantifiable perosmic anhydride and carries out, and perhaps, if in the presence of oxygenant such as hydrogen peroxide, tetrabutyl hydrogen peroxide or N-methylmorpholine-N-oxide compound, reacts with the perosmic anhydride of catalytic amount.These reactions can be carried out in all kinds of SOLVENTS, comprise, and 1,4-dioxane, tetrahydrofuran (THF), the trimethyl carbinol and ether are preferably at 0 ℃.Institute's deutero-glycol can for example (be seen B.S.Furniss with the electrophilic reagent selectivity with the primary alconol alkanisation by further again mat, A.J.Hannaford, P.W.G.Smith, and A.R.Tatchell " Vogel ' s Textbook of Practical Organic Chemistry " 5 ThEd., Longman, 1989) with modification obtain formula ( 7-12) compound.
Formula ( 7-10) epoxide can utilize and change primary alconol into leaving group for example triflate, tosylate, phosphonate, halogenide etc., again with the intramolecularly nucleophilic reagent (see TetrahedronLett., 1983,661-664).Formula ( 7-10) epoxide can be further via making functionalization with various nucleophilic reagent open loops.Representational nucleophilic reagent includes, but are not limited to amine, alkoxide, sulfide, organometallic reagent etc.Reaction can have or not have the Lewis acid activation agent, as carrying out (seeing (a) J.Med Chem. under silver carbonate, triflate silver, boron trifluoride diethyl etherate, the aluminum chloride etc., 1997,2762-2769, (b) J.Amer.Chem.Soc., 1999,10251-10263, (c) Tetrahedron Lett., 2000,4229-4234).
Route 8
Figure A20038011099701091
According to formula ( 6-1) The compounds of this invention also further functionalization to produce compound of the present invention.Alkene ( 6-1) can be in the presence of palladium catalyst [Pd (0) or Pd (II)] with aryl halide or aryl triflate handle with provide compound ( 9-3): (see (a) Heck, PalladiumReagentsin Organic Synthesis, Academic Press:New York, 1985, Chapter 1; (b) Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters2,4; (c) Sonogashira, Synthesis 1977,777.), under sea gram coupling (Heck coupling) condition, two keys can be selected isomery and optical isomerization.Perhaps, compound ( 6-1) can through with the vinyl aromatic derivative utilize ruthenium catalyst carry out mutual transposition reaction with obtain formula ( 9Compound-2) (see (a) J.Org.Chem.2000,65,2204-2207; (b) Reviews:Synlett.1999,2,267; (c) Reviews:Ivin, K.J.; Mol, J.C.Olefin Metathesis and Metathesis Polymerization, 2 NdEd.; AcademicPress:New York, 1997; (d) J.Org.Chem.1999,64,4798-4816; (e) Angew.Chem., Int.Ed.Engl.1997,36,2036-2056; (f) Tetrahedron 1998,54,4413-4450).
Route 9
Can examine know formula ( 6-2) ketone can with Shi Dang De phosphonium salt in the presence of alkali via dimension base of a fruit reaction (Wittig reaction) change into formula ( 9-2) reach ( 8Alkene-1) (see (a) Burke, TetrahedronLett., 1987,4143-4146, (b) Rathke and Nowak, J.Org.Chem., 1985,2624-2626, (c) Maryanoff andReitz, Chem.Rev., 1989,863-927).Moreover, formula ( 8-1) vinyl halide can utilize in the presence of palladium catalyst, copper halide and amine alkali with fat alkynes carry out the rope slave add hila coupling (Sonogashira coupling) with obtain ( 8Compound-2) (see (a) Sonogashira, Comprehensive Organic Synthesis, Volume 3, and Chapters 2,4; (b) Sonogashira, Synthesis 1977,777.).In a similar manner, formula ( 9-2) fat alkene can by vinyl halide ( 8-1) in the presence of palladium catalyst and alkali, obtains via the mutual coupling of Suzuki (Suzuki cross coupling) with organoboron reagent, or in the presence of palladium catalyst, obtain (seeing (a) Suzuki via the mutual coupling in history Tilly (Stille cross coupling) with organotin, J.Organomet.Chem.1999,576,147-168, (b) Stille, Angew.Chem.Int.Ed.Engl, 1986,508-524 (c) Farina, J.Am.Chem.Soc., 1991,9585-9595).
Be familiar with this field person and can examine and know, compound ( 9-2) reach ( 8-2) unsaturated compound of representative can be reduced to form corresponding saturated compound (seeing Hudlicky, M.Reductions inOrganic Chemistry, Ellis Horwood Limited:Chichester, 1984).
Route 10
Figure A20038011099701111
Can examine know compound of the present invention comprise with formula ( 10-1) 3 ' N on the compound is modified.Formula ( 10-2) compound can be via United States Patent (USP) the 6th, 034, and No. 069 and the 6th, 387, No. 885 described method preparations.
The reference that all this paper quote, no matter be printing, polarity formula, computer-readable modus ponens storage medium or other form person, be contained in this especially to preserve its integrity, it comprises, but be not limited to summary, paper, periodical, publication, proposition, special, world-wide web website, database, patent and patent disclosure case.
Embodiment
Compound of the present invention and method utilization and following embodiment link and can more be understood, and these embodiment are intended to explanation and non-limiting scope of the present invention.The concrete example that is disclosed is done various changes and modified for being familiar with this art person is apparent, and these changes and only modify otherwise can depart from the present invention's spirit and appended claim all can be carried out, chemical structure, substituent, derivative, prescription and/or the method for being correlated with including but not limited to the present invention.
Embodiment 1
The compound of formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=Ac
The compound of step 1a: formula 1-2: R 6=Ac, R 2'=Ac, and R 4"=Ac
Under room temperature erythromycin A-9 oxime (74.9g, 0.1mol) in the solution of THF 400ml, add acetic anhydride (35.9ml, 0.38mol), triethylamine (55.7ml, 0.4mol) and DMAP (3.7g, 0.03mol).This mixture was stirred 16 hours and was concentrated into about 200ml under room temperature, and with ethyl acetate 300ml dilution, again with resulting mixture with saturated NaHCO 3(500ml * 4) and bittern (500ml) clean, again with anhydrous sodium sulfate drying.With solvent evaporates and with residue by the compound (78g) of ethyl acetate recrystallize to obtain title.
MS(ESI)m/z 875(M+H) +.
13C NMR(CDCl 3)：δ178.5，175.4，170.6，170.2，168.2，100.2，96.1，83.3，79.3，78.7，75.2，74.5，72.9，70.0，67.6，63.4，63.2，60.6，49.5，44.7，40.9，35.4，31.8，28.5，22.8，21.7，21.6，21.5，21.3，21.2，21.1，19.9，18.6，18.4，16.7，14.9，14.4，14.3，10.8，9.2
Step 1b: formula 1-3 compound: R 11=H and R 13=t-Bu:
In 2-methylene-1, ammediol (5.28g, 0.06mmol) with two-tertiary butyl, two carbonic acid (35g, 0.16mol) in the solution of methylene dichloride, add 6N NaOH (70ml) and TBuA hydrosulfate (3.4g, 10mmol).With stirred overnight under this mixture room temperature.Organic layer is separated, with NaHCO 3(200ml * 3) and bittern (200ml) clean, again with anhydrous MgSO 4Drying, and concentrated reaching with vacuum-drying obtain title compound.
1H NMR(CDCl 3)：δ5.20(s，2H)；4.44(s，4H)；1.18(s，18H).
13C NMR(CDCl 3)：δ153.3，138.5，117.3，82.3，66.9，27.8.
Step 1c: formula 1-4 compound: R 6=Ac, R 11=H, R 2'=Ac and R 4"=Ac
In erythromycin oxime 2 ', 4 from step 1a ", the 9-nitrilotriacetic (112g, 128mmol), from the compound of step 1b (44.3g, 154mmol) and dppb (1.71g 4mmol) in the solution of THF (500ml), adds Pd down in nitrogen 2(dba) 3(1.83g, 2mmol).With this mixture backflow 5 hours and concentrated.With residue with flash chromatography instrument purifying (SiO 2Hexane: acetone/2: 1) to obtain title compound (110g).
MS(ESI)m/z 927.64(M+H) +
13C NMR(CDCl 3)：δ176.5，175.9，170.7，170.1，169.9，141.6，124.7，100.4，96.0，79.1，78.7，78.2，78.0，77.4，76.5，73.5，73.0，72.4，72.1，67.8，66.1，63.4，63.3，49.6，44.1，41.2，40.9，37.3，35.4，35.1，31.3，29.5，28.5，27.1，23.4，21.7，21.3，21.1，20.9，20.3，18.8，18.3，17.4，15.7，13.4，12.7，8.6.
Step 1d: formula 2-1 compound: R 11=H, R 2'=H, and R 4"=Ac
The compound (32g) of step 1c was concentrated in the solution backflow of methyl alcohol 400ml in 48 hours then.With residue with flash chromatography method purifying (SiO 2, CH 2Cl 2: 2M ammonia in methyl alcohol=95: 5) to obtain title compound (28.5g).
MS(ESI)m/z 843(M+H) +
13C NMR(CDCl 3)：δ176.2，170.8，168.8，142.0，124.2，102.5，95.9，79.4，78.7，78.1，78.0，76.6，73.0，71.8，71.1，68.2，65.6，63.2，49.7，44.2，41.7，40.5，37.7，35.0，34.4，29.3，25.8，23.5，21.9，21.3，21.1，19.0，18.1，17.5，15.3，13.2，12.7，8.7.
Step 1e: formula 2-2 compound: R 11=H and R 2'=H
With titanous chloride (40ml, 20% in 3% hydrochloric acid) spend 10 minutes and splash into from step 1d compound (9.5g, 11.3mmol) and ammonium acetate (17.4g, 226mmol) 0 ℃ in methyl alcohol 120ml stirs in the solution.This reaction mixture is risen again to room temperature and stirred overnight.Utilize the slow 3N of interpolation aqueous sodium hydroxide solution that the pH of reaction mixture is adjusted into pH=10.This aqueous solution is cleaned once with saturated Sodium Hydrogen Carbonate (200ml) with ethyl acetate (200ml) extraction and with organic phase,, and solvent removed with vacuum again with dried over sodium sulfate.With residue with flash chromatography method purifying (SiO 2, CH 2Cl 2: 2M ammonia in methyl alcohol/95: 5) to obtain title compound (3.0g).
MS(ESI)m/z：627(M+H).
13C-NMR(100 MHz，CDCl 3)：δ188.5，176.0，143.9，118.9，106.9，90.8，79.8，79.6，79.2，77.4，75.9，75.3，70.8，70.4，65.8，65.3，44.6，42.1，40.4，38.6，36.4，35.3，28.2，22.9，21.5，20.0，19.7，16.8，15.1，14.9，11.5，8.3
Step 1f: formula 1-5 compound: V=N-O-Ac, R 11=H and R 2'=Ac
In from the compound of step 1e (3g, 4.8mmol) in the solution of methylene dichloride 40ml, add acetic anhydride (1.36ml, 14.4mmol) and triethylamine (2.8ml, 20mmol).This mixture was stirred under room temperature 4 hours.Solvent removed under vacuum and with residue with flash chromatography method purifying (SiO 2, hexane: propane/1: 1) to obtain title compound (2.9g).
MS(ESI)m/z 711.50(M+H) +
13C NMR(CDCl 3)：δ184.7，176.9，174.9，170.1，141.9，122.2，99.4，81.2，79.0，77.8，77.7，76.1，73.5，71.7，68.8，65.7，63.2，43.7，40.8，39.9，38.2，36.2，35.6，31.0，25.5，23.2，21.6，21.2，19.9，19.5，17.1，15.8，14.7，11.8，7.9
The compound of step 1g: formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=Ac
In from step 1f compound (2.9g, 4.08mmol) in the solution of methylene dichloride, at room temperature add for Si Mading reagent (Dess-Martin reagent) (1.9g, 4.5mmol).This mixture was stirred under room temperature 2 hours.Should react with Sodium Hydrogen Carbonate (50ml) and Na 2S 2O 3(2g) suppress.Clean with the organic phase separation and with bittern (50ml).Solvent removed under vacuum and with residue with purification by chromatography (hexane: propane/1: 1) to obtain title compound (2.0g).
MS(ESI)m/z 709.28(M+H) +
13C NMR(CDCl 3)：205.8，184.5，177.4，170.0，168.0，141.2，124.3，100.5，79.2，78.1，77.5，76.2，74.5，73.4，72.1，71.4，69.0，65.7，63.1，50.5，45.5，40.3，38.5，30.7，25.3，23.4，21.5，21.1，20.0，19.4，17.4，15.4，13.8，13.3，12.5
Embodiment 2
The compound of formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
(2.0g, 2.82mmol) solution in methyl alcohol 40ml refluxed 5 hours with embodiment 1 compound.With solvent evaporation to obtain rough title compound.
MS(ESI)m/z 667.40(M+H) +
13C NMR(CDCl 3)：205.9，184.5，177.5，168.1，141.3，124.4，103.1，79.1，78.2，77.5，76.2，75.6，73.4，72.1，70.4，69.6，66.0，65.7，50.5，46.2，40.4，38.7，28.5，25.4，23.4，21.4，20.0，19.6，17.5，15.4，13.9，13.5，12.6
Embodiment 3
The compound of formula I: A forms C=O with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
To be cooled to-78 ℃ and in reaction whole process, feed ozone bubbles and become light blue up to solution in the solution of methyl alcohol (10ml) and methylene dichloride (30ml) from embodiment 2 crude compound.Nitrogen is fed reaction mixture removing redundant ozone, and add triphenylphosphine (5.64mmol).Spend solution was risen again to room temperature in 1 hour.Be dissolved in THF40ml with solvent evaporates and with residue.With triphenylphosphine (5.64mmol) adding and this mixture backflow is overnight.Solvent removed with vacuum and with residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia in methyl alcohol=95: 5) purifying to be to obtain title compound (1.5g).
MS(ESI)m/z 669.38(M+H) +
13C NMR(CDCl 3)：δ205.6，205.1，184.4，175.8，169.7，102.5，80.2，79.0，78.8，77.5，76.1，75.8，75.5，70.4，69.7，68.6，66.0，50.9，45.9，40.4，39.7，38.8，36.6，28.4，25.5，23.1，21.4，19.9，19.7，17.2，15.4，14.2，13.1，11.6
Embodiment 4
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-Ph, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
With the crude compound of embodiment 3 (34mg, 0.05mmol), the phenmethyl azanol (16mg, 0.1mmol) and pyridine (0.2mmol) under room temperature, stirred 1 hour in the solution of ethanol 4ml.This reaction mixture concentrated and with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia in methyl alcohol=95: 5) purifying to be to obtain title compound (35mg, cis: trans is 3: 1 mixture).
MS(ESI)m/z 774.48(M+H) +.
Embodiment 5
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-(3-pyridyl), X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Step 5a:N-phenyl-diformyl base-O-pyridin-3-yl methyl-azanol
(653mg, 4mmol) (848mg is 8mmol) in DMF-CH with yellow soda ash in N-hydroxybenzene dicarboximide 3CN-H 2In the solution of O (5ml/1ml/5ml), under room temperature by the part add 3-(brooethyl) pyridine hydrogen bromide (1.01g, 4mmol).This mixture in stirring at room 2 hours, is cleaned again with ethyl acetate (30ml) dilution, and with 5% trimethanolamine methylmethane, again with Na 2SO 4Dry.Solvent removed under vacuum and with residue with silica gel chromatography purifying (hexane: ethyl acetate/3: 2) to obtain title compound (0.8g).
The compound of step 5b: formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-(3-pyridyl), X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
N-phenyl-diformyl base-O-pyridin-3-yl methyl-azanol (81.3mg, 0.32mmol) in the solution of ethanol 5ml, under room temperature, add hydrazine hydrate (12mg, 0.24mmol).Mixture stirring under 40 ℃ was cooled to room temperature in 2 hours then.With acetate (7 μ l, 0.12mmol) add again embodiment 3 compound (27mg, 0.04mmol).This mixture was stirred 12 hours down in 60 ℃.Solvent removed under vacuum and with residue with flash chromatography method purifying (SiO 2, CH 2Cl 2: 2M ammonia is in CH 3OH=95: 5) to obtain title compound (24mg).
MS(ESI)m/z 774.48(M+H) +.
Embodiment 6
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-(2-pyridyl), X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 5 compounds and go up identical step substantially, (81.3mg is 0.32mmol) with hydrazine hydrate (12mg, 0.24mmol) reaction to make N-phenyl-diformyl base-O-pyridine-2-ylmethyl-azanol.Add Glacial acetic acid 7 μ l then and add embodiment 3 compound 27mg (0.04mmol) again.After separating, obtain the product 23mg that is desired.
MS：(ESI)m/z 774.48(M+H) +.
Embodiment 7
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-(3-quinolyl), X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 5 compounds and go up identical step substantially, (81.3mg is 0.32mmol) with hydrazine hydrate (12mg, 0.24mmol) reaction to make N-phenyl-diformyl base-O-quinoline-3-ylmethyl-azanol.Add Glacial acetic acid 7 μ l then and add embodiment 3 compound 27mg (0.04mmol) again.After separating, obtain the product 24mg that is desired.
MS(ESI)m/z 846.98(M+H) +.
Embodiment 8
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-(2-quinolyl), X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 5 compounds and go up identical step substantially, (81.3mg is 0.32mmol) with hydrazine hydrate (12mg, 0.24mmol) reaction to make N-phenyl-diformyl base-O-quinoline-2-ylmethyl-azanol.Add Glacial acetic acid 7 μ l then and add embodiment 3 compound 27mg (0.04mmol) again.After separating, obtain the product 24mg that is desired.
MS(ESI)m/z 846.96(M+H) +.
Embodiment 9
The compound of formula I: A forms C=N-O-5-pyridine-2-base thiophene-2 bases-methyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 4 compounds and go up identical step substantially, embodiment 3 compound 27mg (0.04mmol), O-(5-pyridine-2-base-thiophene-2 bases-methyl)-azanol 17mg (0.08mmol) and Glacial acetic acid 2.3 μ l (0.04mmol) are combined among the ethanol 2ml.After the separation, obtain the product 22mg that is desired.
MS(ESI)m/z 774.48(M+H) +.
Embodiment 10
The compound of formula I: A forms C=N-O-3-pyrimidine-2-base Propargyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 4 compounds and go up identical step substantially, embodiment 3 compound 30mg (0.04mmol), O-(3-pyrimidine-2-base Propargyl)-azanol 20mg (0.1mmol) and triethylamine 2.3 μ l (0.12mmol) are combined among the ethanol 5ml.After the separation, obtain the product 23mg that is desired.
MS(ESI)m/z 800.44(M+H) +.
Embodiment 11
The compound of formula I: A forms C=N-O-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 5 compounds and go up identical step substantially, with N-phenyl-diformyl base-O-phenyl-azanol 81.3mg (0.32mmol) and hydrazine hydrate (12mg, 0.24mmol) reaction.Add the compound 27mg (0.04mmol) that Glacial acetic acid 7 μ l add embodiment 3 more then.After the separation, obtain the product 24mg that is desired.
MS(ESI)m/z 760.12(M+H) +.
Embodiment 12
The compound of formula I: A=NHCH 2Ph, B=H, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
In embodiment 3 compounds (34mg, 0.05mmol), acetate (5.7 μ l, 0.1mmol) and benzene methanamine (16.4 μ l 0.15mmol) add NaCNBH under room temperature in the solution of methyl alcohol 3ml 4(6.6mg, 0.1mmol).This reaction mixture was stirred under room temperature 5 hours,, and, clean (15ml) with bittern with ethyl acetate extraction (15ml) again with 5% trimethanolamine methylmethane inhibited reaction, and with Na 2SO 4Dry.Solvent is removed under vacuum, and with residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia was in methyl alcohol=95: 5) purifying to be to obtain title compound (25mg).
MS(ESI)m/z 760.26(M+H) +.
Embodiment 13
The compound of formula I: A=NHCH 2CH 2Ph, B=H, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 12 compounds and go up identical step substantially, embodiment compound 353.5mg (0.08mmol), phenylethylamine 30 μ l (0.24mmol), Glacial acetic acid 9.2 μ l and SODIUM CYANO BOROHYDRIDE 10mg (0.16mmol) are combined in methyl alcohol.After the separation, obtain the product 40mg that is desired.
MS(ESI)m/z 774.25(M+H) +.
Embodiment 14
The compound of formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=N-O-CH with Y and affiliated carbon atom thereof 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=Ac
Step 14a:of formula 1-5 compound: V=N-O-H, R 11=HR 2'=Ac
(4.2g 4.5mmol) adds 2MHCl (10ml) in the solution of methyl alcohol 50ml in step 1b compound.This mixture was refluxed 1.5 hours, and be concentrated into 30ml, with saturated NaHCO 3(30ml) dilution is again with ethyl acetate (50ml) extraction, and with Na 2SO 4Dry.With solvent evaporates and with residue with silica gel chromatography purifying (hexane: propane/1: 1) to obtain title compound (2.5g).
MS(ESI)m/z 685(M+H) +.
13C-NMR(100 MHz，CDCl 3)：δ175.2，170.2，166.3，143.6，119.3，99.6，82.2，79.5，78.1，77.5，76.0，73.7，71.7，68.9，65.5，63.3，43.8，40.8，37.4，35.9，34.3，31.1，25.6，23.3，21.7，21.3，19.9，19.6，17.1，15.7，14.7，11.9，7.9
Step 14b: formula 1-5 compound: V=N-O-CH 2OCH 3, R 11=H and R 2'=Ac
From step 14a compound (6.85g, 10mmol) in the solution of DMF 40ml, under 0 ℃, progressively add NaH (303mg, 1.3mmol).After 10 minutes, with 15 minutes times in 0 ℃ add down MOM-Cl (900ul, 1.15mmol).With this mixture in stirring at room 16 hours and with saturated NaHCO 3(60ml) inhibited reaction.With ethyl acetate (60ml) extraction, and with Na 2SO 4Dry.(hexane: propane/1: 1) purifying is to obtain title compound (4.5g) with silica gel chromatography with solvent evaporates and with residue.
MS(ESI)m/z 729(M+H) +.
The compound of step 14c. formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=N-O-CH with Y and affiliated carbon atom thereof 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=Ac
In that (4.4g 6mmol) adds in the solution of methylene dichloride 50ml that (3.05g is 7.2mmol) in the solution of methylene dichloride 20ml for Si Mading reagent from step 14b compound.With mixture in stirring at room 2 hours.Add saturated NaHCO 3(50ml) and Na 2S2O 3(10.4g is 42mmol) with inhibited reaction.With the organic layer separation and with Na 2SO 4Dry.With solvent removal and with residue with flash chromatography method (SiO 2, hexane: purifying propane/1: 1) obtains title compound (3.0g).
MS(ESI)m/z 727.32(M+H) +
13C NMR(CDCl 3)：δ205.8，169.8，168.3，168.1，142.0，123.5，100.9，98.4，79.1，78.5，76.0，73.4，71.7，69.1，65.5，63.5，56.5，50.8，46.5，40.7，37.8，34.4，30.8，26.9，23.4，21.5，21.2，20.1，19.3，17.4，15.0，14.0，13.9，12.5.
Embodiment 15
The compound of formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=N-O-CH with Y and affiliated carbon atom thereof 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=H
(440mg, 0.6mmol) the solution backflow in methyl alcohol 5ml also concentrated to obtain the unpurified compound of being desired in 4 hours with embodiment 14 compounds.
MS(ESI)m/z 685.18(M+H) +
Embodiment 16
The compound of formula I: A forms C=O with B and affiliated carbon atom thereof, and X forms C=N-O-CH with Y and affiliated carbon atom thereof 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=H
(420mg is 0.6mmol) in methyl alcohol 7ml and CH to embodiment 15 compounds 2Cl 2The solution of 20ml feeds ozone in-78 ℃ and becomes pale blue up to solution.Squeeze into nitrogen in solution to remove redundant ozone, then add PPh 3(2 equivalent).With mixture rise again room temperature and under room temperature, stir 2 hours, concentrate, and residue is dissolved in THF 10ml, add other 2 normal PPh again 3Reflux the gained mixture overnight and concentrated.With residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia is in CH 3OH=95: 5) purifying obtains title compound (280mg).
MS(ESI)m/z 687.25(M+H) +
13C NMR(CDCl 3)：δ205.8，205.8，170.2，166.7，102.4，98.8，80.6，80.5，78.8，76.7，76.0，75.6，70.5，69.7，69.5，66.1，60.6，57.1，50.8，45.8，40.5，38.2，34.3，28.6，26.9，23.1，21.5，21.3，19.9，19.4，17.0，15.4，14.5，14.4，13.0，11.7
Embodiment 17
The compound of formula I: A forms C=NOCH with B and affiliated carbon atom thereof 2Ph, X forms C=N-O-CH with Y and affiliated carbon atom thereof 2-O-CH 3, L=CH 2CH 3, Z=H and R 2'=H
Utilize with preparation embodiment 4 compounds and go up identical step substantially, embodiment compound 16 87mg (0.13mmol), O-phenmethyl azanol 41.5mg (0.26mmol) and pyridine 21 μ l (0.26mmol) are combined in the ethanol 10ml.After separating, obtain desire product 75mg.
ESMS：774.35(M+H) +
Embodiment 18
The compound of formula I: A forms C=O with B and affiliated carbon atom thereof, and X forms C=O, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=Ac
The compound of step 18a. formula 3-1: R 11=H, R 13=H and R p=tertiary butyl dimethylsilyl
(1.26g 50mmol) adds 2-methylene-1 in the suspension of THF 40ml, (4.4g is 50mmol) in the solution of THF 30ml for ammediol in NaH.Mixture was added tertiary butyl dimethylsilyl muriate in 45 minutes again in stirring at room, and (7.54g is 50mmol) in the solution of THF 30ml.With this mixture in stirring at room 1 hour, again with saturated NaHCO 3(200ml) inhibited reaction, with extracted with diethyl ether (150ml * 2) and with the combination organic layer with MgSO 4Dry.With solvent removal and with resulting oil with flash chromatography method (SiO 2, hexane: ethyl acetate/10: 1) purifying obtains title compound (8.4g).
The compound of step 18b: formula 3-1: R 11=H, R 13=tertbutyloxycarbonyl and R p=tertiary butyl dimethylsilyl
In from the compound of step 18a (8.1g, 40mmol) in the solution of methylene dichloride 100ml, add two-tertiary butyl, two carbonic acid (13.1g, 60mmol), the hydrogen sulfate TBuA (1.2g, 3.5mmol) and 6N NaOH 30ml.Mixture was stirred under room temperature 16 hours, with methylene dichloride 100ml dilution and with saturated NaHCO 3(200ml * 3) are cleaned.With organic layer with Na 2SO 4Dry and solvent removed under vacuum.With residue with flash chromatography method (SiO 2, hexane: ethyl acetate/96: 4) purifying obtains title compound (6.8g).
The compound of step 18c. formula 3-2: R p=tertiary butyl dimethylsilyl, R 6=Ac, R 11=H, R 2'=Ac and R 4"=Ac
In erythromycin A-9 oxime 9,2 ', 4 from step 1a "-nitrilotriacetic (22g, 25mmol), from the compound of step 18b (9.1g,, 30mmol) and dppb (853mg 1mmol) in the solution of THF 250ml, adds Pd 2(dba) 3(916mg, 1mmol).It is overnight that mixture is refluxed, concentrate, and with flash chromatography method (SiO 2, propane: purifying hexane/1: 3) obtains title compound (25g).
MS(ESI)m/z 1059.65(M+H) +
13C NMR(CDCl 3)：δ181.2，179.3，175.9，175.5，173.5，148.5，116.5，104.8，102.0，85.2，84.3，83.9，83.6，82.8，82.2，79.7，78.1，77.6，75.6，72.4，70.4，69.0，68.6，54.6，49.9，46.2，43.2，40.8，36.5，33.6，31.4，27.1，27.0，26.6，26.3，25.2，25.1，24.0，23.7，22.0，20.4，16.0，15.2，0.5，0.0
Step 18d: the compound of formula (3-2), Rp=tertiary butyl dimethylsilyl, R 6=H, R 11=H, R 2'=H, R 4"=Ac
(3.18g, 3mmol) solution in methyl alcohol 80ml refluxed 8 hours with step 18c compound.With this solution concentration and with flash chromatography method (SiO 2, 2M ammonia is in methyl alcohol: purifying methylene dichloride/3: 97), and to obtain title compound (2.6g, 89%).
MS(ESI)m/z 975.47(M+H) +
13C NMR(CDCl 3)：δ179.5，178.9，175.7，150.6，121.5，106.8，101.4，85.3，83.9，83.7，82.4，82.0，79.3，77.8，76.7，76.5，72.7，70.4，70.1，69.3，68.3，54.6，49.8，45.5，43.0，42.9，40.6，38.1，34.0，31.1，30.5，27.1，26.3，26.1，26.0，24.3，23.7，23.5，21.5，19.9，15.7，14.8，0.5，0.0
The compound of:R of step 18e. formula 3-4 p=H, R 11=H, R 2'=H and R 4"=Ac
To the compound of step 18d (2.44g, 2.5mmol) emulsification in Virahol 25ml and water 30ml add formic acid (380 μ l, 10mmol) and Na 2S 2O 4(1.39,8mmol).Reaction mixture is heated to 90 ℃ and stirred 8 hours.With this solution with ethyl acetate (60ml) dilution and with saturated NaHCO 3(60ml * 3) are cleaned.With the organic layer separation and with anhydrous Na 2SO 4(～5g) is dry, concentrated, and with flash chromatography method (SiO 2, 2M ammonia is in methyl alcohol: methylene dichloride/3: 97) purifying is to obtain title compound (1.7g).
MS(ESI)m/z 846.54(M+H) +
13C NMR(CDCl 3)：δ221.3，175.3，170.6，147.0，114.1，101.8，96.6，79.9，79.2，78.8，78.7，77.4，75.0，72.8，71.4，68.8，67.8，65.4，65.3，63.7，63.4，60.6，49.6，45.5，44.8，40.4，38.2，38.0，35.6，22.0，21.2，21.1，19.6，18.6，16.5，14.4，12.2，10.6，9.8
Step 18f. formula 3-4 compound: R p=H, R 11=H, R 2'=Ac and R 4"=Ac
(94ul, (338.4mg is 0.4mmol) in the solution of methylene dichloride (5ml) 1mmol) to add step 18e compound with acetic anhydride.Mixture was stirred under room temperature 16 hours.Solvent removed under vacuum and with product with flash chromatography method (SiO 2, propane: hexane/4: 6vl) purifying obtains title compound (330mg).
MS(ESI)m/z 888.58(M+H) +
13C NMR(CDCl 3)：δ221.3，175.1，170.6，170.3，146.8，114.2，99.6，96.5，79.9，79.1，78.5，78.4，77.1，74.9，72.8，72.1，68.9，67.1，65.1，63.7，63.5，63.1，49.3，45.5，44.8，40.6，38.0，37.7，37.6，35.5，29.4，21.8，21.3，21.1，21.0，19.4，18.6，16.6，12.2，10.6，9.6
The compound of step 18g. formula 3-4: R p=tertbutyloxycarbonyl, R 11=H, R 2'=Ac and R 4"=Ac
With di-t-butyl two carbonic acid (69 l, 0.3mmol) under room temperature, add step 18f compound (178mg, 0.2mmol) and triethylamine (56 μ l are 0.4mmol) in the solution of methylene dichloride (8ml).After 10 minutes, and adding DMAP (12.2mg, 0.1mmol).Resulting solution was stirred under room temperature 2 hours.Solvent removed under vacuum and with product with flash chromatography method (SiO 2, propane: hexane/1: 3vl) purifying obtains title compound (180mg).
MS(ESI)m/z 988.41(M+H) +
13C NMR(CDCl 3)：δ219.6，174.6，170.6，170.3，153.8，141.3，116.8，99.6，96.5，82.0，80.2，79.4，78.7，78.6，76.8，74.9，72.9，72.4，69.1，67.9，67.2，64.8，63.6，63.4，49.4，45.2，44.8，41.0，37.9，37.7，37.6，35.6，31.8，31.3，31.2，28.2，28.1，22.9，21.8，21.5，21.4，21.1，19.4，18.7，16.7，16.6，14.4，12.5，10.7，9.7
Step 18h. formula 3-6 compound: R 11=H, R 2'=Ac and R 4"=Ac
With 1, and two (biphenyl phosphino-) butane of 4-(8.5mg, 0.02mmol) and Pd 2(dba) 3 (9.2mg, (98.8mg is 0.1mmol) in the solution of anhydrous solution THF 2ml 0.01mmol) to be added into step 18g compound under room temperature.Resulting mixture was refluxed 30 minutes.Solvent is removed under vacuum, obtain title compound (85mg).
MS(ESI)m/z 870.49(M+H) +
Step 18i. compound of formula 1-5:V=O, R 11=H and R 2'=Ac
(700mg 0.8mmol) adds 1M HCl 25ml in the solution of ethanol 10ml in step 18h compound.With the mixture 2 hours cool to room temperature then that reflux.To add 2MNaOH the pH of mixture is adjusted into 10, then with ethyl acetate extraction.With extract with Na 2SO 4Drying concentrates, and with residue with flash chromatography method (SiO 2, hexane: purifying propane/1: 1) obtains title compound (480mg).
MS(ESI)m/z 670.23(M+H) +
13C NMR(CDCl 3)∶δ216.3，175.0，170.1，141.8，122.1，99.4，81.1，79.0，77.7，77.5，76.2，75.6，72.1，71.7，68.8，65.6，63.2，60.5，46.5，43.7，40.8，39.1，38.6，35.9，31.1，23.0，21.6，21.3，21.2，19.8，18.5，17.3，14.8，14.3，13.0，11.7，7.9
The compound of step 18i. formula I: A forms C=O with B and affiliated carbon atom thereof, and X forms C=O, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=Ac
Step 18i compound (480mg, 0.7mmol) in the solution of methylene dichloride 10ml, under room temperature, add for Si Mading reagent (385mg, 0.9mmol).Reaction mixture was stirred under room temperature 2 hours, again with saturated NaHCO 3(15ml) and Sulfothiorine (0.4g) inhibited reaction.Organic layer is separated, clean with bittern (15ml), with Na 2SO 4Dry and concentrated.With residue with flash chromatography method (SiO 2, hexane s: purifying propane/2: 1) obtains title compound (400mg).
MS(ESI)m/z 668.02(M+H) +
13C NMR(CDCl 3)：δ218.2，205.8，170.0，168.1，140.9，125.1，101.0，78.9，78.3，76.5，75.0，72.7，70.4，69.3，65.7，63.6，50.8，46.6，46.3，40.9，39.3，39.1，30.8，23.4，21.6，21.3，19.9，18.5，17.8，14.2，14.0，12.5，12.4
Embodiment 19
The compound of formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=O, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
(300mg, 0.45mmol) solution in methyl alcohol 10ml refluxed 8 hours with the compound of embodiment 18.Solvent removed under vacuum and with residue with silica gel chromatography (CH 2Cl 2: 2M ammonia is in methyl alcohol/97: 3vl) purifying is to obtain title compound (270mg).
MS(ESI)m/z 626.10(M+H) +.
13C NMR(CDCl 3)：δ218.4，205.9，168.1，141.0，125.2，103.5，78.7，78.3，76.6，76.1，72.6，70.6，70.3，69.8，66.1，65.7，50.9，47.3，46.4，40.5，39.4，39.3，28.5，23.4，21.5，20.0，18.5，17.9，14.6，14.1，12.5，12.4
Embodiment 20
The compound of formula I: A forms C=O with B and affiliated carbon atom thereof, and X forms C=O, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
(94mg is 0.15mmol) in methyl alcohol 2ml and CH with embodiment 19 compounds 2Cl 2Solution in the 4ml feeds ozone in-78 ℃ and becomes pale blue up to solution.Nitrogen is squeezed into solution to remove unnecessary ozone, add PPh then 3(2 equivalent).With rise again room temperature and under room temperature, stirring 2 hours of mixture.Mixture is concentrated and residue is dissolved in THF 5ml, add other 2 normal PPh again 3Reflux the mixture of gained overnight and concentrated.With residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia was in methyl alcohol/95: 5) purifying to be to obtain title compound (80mg).
MS(ESI)m/z 628.10(M+H) +
13C-NMR(CDCl 3)：δ215.2，205.6，205.3，169.9，102.5，80.5，79.4，78.6，77.5，76.3，76.1，75.3，70.5，69.8，68.5，66.1，51.0，46.3，46.2，40.5，39.8，39.0，28.5，22.9，21.5，19.8，18.3，17.3，14.4，13.6，12.4，11.6
Embodiment 21
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2Ph, X forms C=O, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Use with the compound for preparing embodiment 4 and go up identical step substantially, compound 19mg (0.03mmol), O-phenmethyl azanol 10mg (0.06mmol) and the pyridine 5 μ l (6mmol) of embodiment 20 are combined in ethanol 5ml.After separating, obtain desire product 20mg.
MS(ESI)m/z 733.24(M+H) +
Embodiment 22
The compound of formula I: A forms C=CH with B and affiliated carbon atom thereof 2, X forms C=NH, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Salt of wormwood (50mg) is added embodiment 2 compounds in the solution of methyl alcohol (6ml).Mixture was stirred under room temperature 3 days.Solvent removed under vacuum and with residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia was in methyl alcohol/95: 5) purifying, obtain title compound (70mg).
MS(ESI)m/z：625.36(M+H) +
Embodiment 23
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-p-NO 2Ph, X forms C=N-AcL=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
With embodiment 3 compounds (53.5mg, 0.08mmol), the phenmethyl hydroxylamine hydrochloride (33mg, 0.16mmol) and pyridine (0.16mmol) under room temperature, stirred 1 hour in the solution of ethanol 4ml.Solvent removed under vacuum and with residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M ammonia was in methyl alcohol/95: 5) purifying, obtaining cis and trans ratios is 3: 1 blended title compounds (52mg).
MS(ESI)m/z：819.22(M+H) +
Embodiment 24
The compound of formula I: A forms C=N-O-(CH with B and affiliated carbon atom thereof 2) 2-Ph, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Use with the compound of preparation embodiment 5 and go up identical step substantially, with compound 50mg (0.074mmol) and N-phenyl-diformyl base-O-styroyl-azanol 100mg (0.37mmol) reaction of embodiment 3, to obtain title compound.
MS(ESI)m/z：788(M+H) +
Embodiment 25
The compound of formula I: A forms C=N-O-(CH with B and affiliated carbon atom thereof 2) 3-Ph, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Use with the compound of preparation embodiment 5 and go up identical step substantially, with compound 50mg (0.074mmol) and N-phenyl-diformyl base-O-1-(3-phenyl) propyl group-azanol 105mg (0.37mmol) reaction of embodiment 3, to obtain title compound.
MS(ESI)m/z：802(M+H) +
Embodiment 26
The compound of formula I: A forms C=N-O-CH with B and affiliated carbon atom thereof 2-CH=CH-Ph, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Use with the compound of preparation embodiment 5 and go up identical step substantially, compound 50mg (0.074mmol) and N-phenyl-diformyl base-O-1-(3-phenyl) propyl group-2-thiazolinyl-azanol 105mg (0.37mmol) reaction with embodiment 3 obtain title compound.
MS(ESI)m/z：800(M+H) +
Embodiment 27
The compound of formula I: A is NH-(CH 2) 3-Ph, B are H, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Use with the compound of preparation embodiment 12 and go up identical step substantially, compound 33.5mg (0.05mmol) and the 3-phenylpropylamine 21.8 μ l (0.1mmol) of embodiment 3 are reacted to obtain title compound 18mg.
MS(ESI)m/z：788(M+H) +
Embodiment 28
The compound of formula I: A is NH-(CH 2) 4-Ph, B are H, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Use with the compound of preparation embodiment 12 and go up identical step substantially, compound 24mg (0.05mmol) and the 4-phenyl butylamine 33.5 μ L (0.15mmol) of embodiment 3 are reacted to obtain title compound 12mg.
MS(ESI)m/z：802(M+H) +
Embodiment 29
The compound of formula I: A is CH 2-CH=CH 2, B is OH, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
(0.23g, 0.34mmol) solution in anhydrous THF 20mL is cooled to-78 ℃ with the compound of embodiment 3.With syringe be incorporated in bromination allyl group magnesium in the THF (1.0M, 1.5mL, 1.5mmol).This reaction mixture was stirred 1 hour down in-78 ℃, then with NaHCO 3Aqueous solution inhibited reaction.With the mixture room temperature of slowly rising again, then with CH 2Cl 2(3 * 30mL) extractions.With the combination organic layer with anhydrous Na 2SO 4Dry.Make solvent evaporates and with residue with flash chromatography method (SiO 2, CH 2Cl 2Containing the 5%2M ammonia solution in methyl alcohol) purifying to be to provide title compound (0.21g, 86%).
MS(ESI)m/z 711(M+H) +
13C-NMR(100MHz，CDCl 3)：δ205.5，186.1，179.9，169.7，132.9，118.3，102.3，80.0，79.4，76.1，73.7，72.7，70.4，70.4，69.7，66.2，50.8，44.9，41.2，40.5，39.8，39.4，37.1，28.6，25.5，23.6，21.5，20.2，20.0，17.3，15.9，14.3，12.6，12.0
Embodiment 30
The compound of formula I: A=CH 2-Ph, B are OH, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
(70mg, 0.1mmol) with person as described in embodiment 29, (0.85M is in THF, and 0.6mL 0.5mmol) handles with benzyl bromide magnesium with the compound of embodiment 3.After same work finishes, with this crude mixture with flash chromatography method (SiO 2, CH 2Cl 2Containing the 5%2M ammonia solution in methyl alcohol) purifying to be to provide title compound (12mg, 18%).
MS(ESI)m/z 761(M+H) +
13C-NMR(100MHz，CDCl 3)：δ205.7，186.3，179.5，169.8，136.3，131.0，128.1，126.5，101.8，80.1，79.3，76.0，73.5，73.1，70.6，70.1，69.2，66.6，50.9，44.8，42.4，40.5，39.8，39.3，37.1，29.9，25.6，23.6，21.3，20.2，20.1，17.3，15.9，14.4，12.7，12.0
Embodiment 31
The compound of formula I: A=(CH 2) 2-Ph, B=OH, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
With the compound of embodiment 3 (70mg, 0.1mmol) as described in the embodiment 29 with bromination styroyl magnesium handle (1.0M in THF, 0.5mL, 0.5mmol).After same program, with crude mixture with flash chromatography method (SiO 2, CH 2Cl 2Containing the 5%2M ammonia solution in methyl alcohol) purifying to be to provide title compound (12mg, 16%).
MS(ESI)m/z 775(M+H) +
Embodiment 32
The compound of formula I: A=Ph, B=OH, X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
With the compound of embodiment 3 (70mg, 0.1mmol) as described in the embodiment 29 with bromination styroyl magnesium handle (1.0M in THF, 0.5mL, 0.5mmol).After same program, with crude mixture with flash chromatography method (SiO 2, CH 2Cl 2Containing the 5%2M ammonia solution in methyl alcohol) purifying implements semipreparative HPLC again so that title compound (5mg) to be provided.
MS(ESI)m/z 747(M+H) +
Embodiment 33
The compound of formula I: A is CH 2-CH=CH-Ph, B are OH, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Will from the compound of embodiment 29 (50mg, 0.07mmol), iodobenzene (32mg, 0.15mmol), Pd (OAc) 2(2.5mg), (o-tolyl) 3P (10mg) and triethylamine (0.1mL, surplus) are dissolved in CH 3CN 3ml, and with the degassing under-40 ℃ of this solution.With this reaction mixture room temperature of under nitrogen, rising again, in 50 ℃ of heating 1 hour down, and maintain 80 ℃ following 12 hours.With reaction mixture with ethyl acetate dilution, with saturated NaHCO 3Clean, and with anhydrous Na 2SO 4Dry.With solvent evaporates and with residue with flash chromatography method (SiO 2, CH 2Cl 2Containing the 5%2M ammonia solution in methyl alcohol) purifying to be to provide title compound (40mg, 76%).
MS(ESI)m/z 787(M+H) +
Select 13C-NMR (100MHz, CDCl 3): δ 205.5,186.3, and 179.7,169.9,137.7,133.2,128.6,127.2,126.5,124.8,101.9,80.0,79.4,76.1,73.9,73.2,70.5,70.1,69.3,66.3,50.9,46.5,44.8,40.7,40.2,39.8,39.4,37.0,29.4,25.6,23.6,21.3,20.2,20.1,17.3,16.0,14.5,12.6,11.9,8.9
Embodiment 34
The compound of formula I: A is (CH 2) 3-Ph, B are OH, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Will (15mg 0.02mmol) carries out hydrogenation 24 hours in room temperature with the Pd-C in ethanol under 1 normal atmosphere hydrogen from the compound of embodiment 24.Solvent is volatilized under vacuum.With flash chromatography method (SiO 2, CH 2Cl 2Contain the 5%2M ammonia solution in methyl alcohol) obtain title compound (13.2mg, 88%).
MS(ESI)m/z 789(M+H) +
Embodiment 35
The compound of formula I: A forms C=CH-CH=CH-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H, and R 2'=H
Step 35a: the compound of formula (1-5): V is N-Ac, R 11Be CH-CH-Ph, R 2'=Ac
To the compound of formula (1-5) (0.5g, 0.7mmol) in dry DMF 8ml, wherein V=N-Ac, R 11=H and R 2'=Ac, under room temperature, add β-bromstyrol (0.15ml, 1.2mmol) and K 2CO 3(200mg, 1.5mmol).Dihydro dichloro (two-tertiary butyl phosphorus-κ P) palladate (II) (POPd is from the Kang Bifosi catalyst Co.) with the simple degassing of mixture and adding catalytic amount.With reaction mixture in airtight in vitro be heated to 100 ℃ 48 hours.Add ethyl acetate (50mL) and with solution with NaHCO 3The aqueous solution cleans 3 times.With organic layer with anhydrous Na 2SO 4Dry.Solvent volatilized under vacuum and with residue with flash chromatography method (SiO 2, propane: hexane s/1: 1 purifying), so that title compound to be provided.
MS(ESI)m/z 813(M+H) +
The compound of step 35b: formula I: A forms C=CH-CH=CH-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=Ac
Will be from the compound dissolution of step 35a in CH 2Cl 2And add for Si Mading cross iodine alkane (1,1,1-triacetyl Oxy-1,1-dihydro-1,2-benzo iodine is disliked-3 (1H)-ketone) (0.3g, 0.7mmol).The mixture stirring was added NaHCO in 1 hour then 3The aqueous solution.With mixture with CH 2Cl 2Extract 3 times and with anhydrous Na 2SO 4The organic layer of dry combination.Solvent is volatilized under vacuum, and with residue with flash chromatography method (SiO 2, propane: hexane/2: 3) purifying is to provide title compound (0.24g, 42%).
MS(ESI)m/z 811(M+H) +
The compound of step 35c: formula I: A forms C=CH-CH=CH-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Will (0.16g, 0.05mmol) solution in methyl alcohol 10mL stirs under room temperature 48 hours from the compound of step 35b.Solvent is volatilized under vacuum.With flash chromatography method (SiO 2, CH 2Cl 2Containing the 3%2M ammonia solution in methyl alcohol) purifying to be to obtain title compound (0.12g, 79%).
MS(ESI)m/z 769(M+H) +
13C-NMR(100MHz，CDCl 3)：δ206.4，184.7，177.9，167.8，137.6，136.4，136.2，134.2，128.7，128.0，127.0，124.0，103.4，79.8，76.4，72.5，70.5，69.7，66.8，66.6，66.2，51.1，47.2，40.5，38.8，28.6，25.4，23.9，21.5，20.0，17.7，15.2，14.1，13.1
Embodiment 36
The compound of formula I: A is (CH 2) 3-Ph, B are H, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Compound (15mg, 0.02mmol) H under hydrogen with embodiment 35 2(30psi) with the hydrogenation 12 hours under room temperature of the Pd-C in the ethanol.Solvent is volatilized under vacuum.With flash chromatography method (SiO 2, CH 2Cl 2Containing the 5%2M ammonia solution in methyl alcohol) purifying to be to obtain title compound (7.0mg, 50%).
MS(ESI)m/z 773(M+H) +
Embodiment 37
The compound of formula I: A forms the C=CH-CH=CH-3-pyridyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 190mg (0.2mmol) of embodiment 1 and 1-bromo-2-(3-pyridyl) ethene 35mg (0.2mmol) are reacted to obtain title compound.
MS(ESI)m/z 770(M+H) +
Embodiment 38
The compound of formula I: A forms the C=CH-CH=CH-3-quinolyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 240mg (0.35mmol) of embodiment 1 and 1-bromo-2-(3-quinolyl) ethene 100mg (0.43mmol) are reacted to obtain title compound.
MS(ESI)m/z 794(M+H) +
Embodiment 39
The compound of formula I: A forms the C=CH-2-quinolyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 500mg (0.7mmol) of embodiment 1 and 3-bromoquinoline 25mg (1.2mmol) are reacted to obtain title compound.
MS(ESI)m/z 820(M+H) +
Embodiment 40
The compound of formula I: A forms the C=CH-2-quinolyl with B and affiliated carbon atom thereof, and X forms C=N-H, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 63mg (0.1mmol) of embodiment 22 and 3-bromoquinoline 42mg (0.2mmol) are reacted to obtain title compound 7.5mg.
MS(ESI)m/z 742(M+H) +
Embodiment 41
The compound of formula I: A forms C=CH-4-biphenyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 213mg (0.3mmol) of embodiment 1 and 4-bromo biphenyl 142mg (0.6mmol) are reacted to obtain title compound.
MS(ESI)m/z 819(M+H) +
Embodiment 42
The compound of formula I: A forms C=CH-3-biphenyl with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 213mg (0.3mmol) of embodiment 1 and 3-bromo biphenyl 103 μ L (0.6mmol) are reacted to obtain title compound.
MS(ESI)m/z 819(M+H) +
Embodiment 43
The compound of formula I: A forms C=CH-4-phenoxy group benzene with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Utilize with the compound of preparation embodiment 35 and go up identical step substantially, the compound 142mg (0.2mmol) of embodiment 1 and 4-bromo biphenyl ether 71 μ L (0.4mmol) are reacted to obtain title compound.
MS(ESI)m/z 835(M+H) +
Embodiment 44
The compound of formula I: A forms C=CH-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Step 44a:3-acetone-1,3-two-tertiary butyl two carbonic acid
In 1,3-dihydroxypropane dimer (36.03g, 0.20mol) and DMAP (1.22g, 10.0mmol) at methylene dichloride (80mL) and pyridine (97.0mL, 1.20mol) solution in, (200.0g is 0.92mol) in the solution of methylene dichloride (40mL) to spend 3 hours interpolation two-tertiary butyl two carbonic acid via the funnel that drips under room temperature.After stirring 15 hours under the room temperature, reaction mixture is concentrated under vacuum.With 1: 1 mixture diluted of residue, with CuSO with hexane and ether 4The aqueous solution and bittern clean.With organic layer with Na 2SO 4Dry and solvent removed in vacuum.With residue with flash chromatography method (SiO 2, hexane: the ethyl acetate gradient was by 95: 5 to 85: 15) and purifying, obtain title compound (45.0g, 39%).
13C-NMR(125MHz，CDCl 3)：δ198.5，152.6，83.5，68.5，27.6.
The compound of step 44b. formula 1-3: R 11=Ph and R 13=t-Bu
(520mg, (1.6M is in hexane, and 0.81mL 1.30mmol) handles 1.20mmol) in the suspension of THF (5.0mL) in-78 ℃ of n-Butyl Lithiums under nitrogen with phenmethyl triphenyl phosphonium bromide.In that (290mg 1.0mmol) spent mixture on 1 hour in the solution of THF (2.5mL) and rises again-15 ℃ before being added under-70 ℃ from step 44a compound.Reaction mixture spent 1 hour and rise again room temperature and stirred under room temperature restir 14 hours.Reaction mixture is diluted with ethyl acetate, organic layer is cleaned with water and bittern, and with Na 2SO 4Dry.Make solvent evaporates and with residue with flash chromatography method (SiO 2, hexane: CH 2Cl 2/ 1: 1) purifying is to obtain title compound (253mg, 70% yield).
13C-NMR(125MHz，CDCl 3)：δ153.1，153.0，135.1，134.6，130.4，128.6，128.2，127.6，82.0，81.9，68.4，62.7，27.6，27.5
The compound of step 44c: formula 1-4: R 6=Ac, R 11=Ph, R 2'=Ac, R 4"=Ac
With erythromycin A-9 oxime nitrilotriacetic (525mg, 0.60mmol), from the compound (250mg of step 44b, 0.69mmol), 1, two (biphenyl phosphino-) butane (51.2mg of 4-, 0.12mmol) and three (diphenylmethylene propane), two palladiums (54.9mg, 0.06mmol) in the degassing of the mixture of THF (5.0mL) and be heated to 75 ℃ 15 hours.Solvent is removed under vacuum, and with the residue that obtains with flash chromatography method (SiO 2, hexane: propane/4: 1～1.5: 1) purifying is to obtain the title compound that the double-bond isomerism thing is 2.6: 1 mixtures (330mg, 55% yield).
MS(ESI)m/z：1003(M+H) +
The compound of step 44d: formula 1-4: R 6=Ac, R 11=Ph, R 2'=H, R 4"=Ac
The preparation system of title compound will reflux from the compound of step 44c in methyl alcohol according to the described step of embodiment 1 step 1.
MS(ESI)m/z：919(M+H) +
The compound of step 44e: formula 2-2: R 11=Ph, R 2'=H
To under room temperature, handle that (20% at 3%HCl, 0.77mL) 2 hours, handles 1 hour down at 50 ℃ then from the compound (0.30mmol) of step 44d with titanous chloride in the solution of methyl alcohol (5.0mL).This mixture then can be at CH 2Cl 2And saturated NaHCO 3Layering between the aqueous solution.With this aqueous solution with CH 2Cl 2Extraction also will be made up extract with the bittern cleaning and with Na 2SO 4Dry.After the volatilization, with residue with flash chromatography method (SiO 2, CH 2Cl 2: 2M NH 3At MeOH/98: 2～93: 7) purifying obtains the title compound that the double-bond isomerism thing is 4: 1 mixtures (105mg, 50% yield).
MS(ESI)m/z：703(M+H) +
The compound of step 44f: formula 1-5: V=N-Ac, R 11=Ph, R 2'=Ac
Will (105mg be 0.15mmol) in CH from the compound of step 44e 2Cl 2Solution (3.0mL) with triethylamine (104 μ L, 0.74mmol) and acetic anhydride (42 μ L 0.45mmol) handled under room temperature 19 hours before volatilization, and in vacuum-drying, to obtain title compound.
MS(ESI)m/z 787(M+H) +
The compound of step 44g: formula I: A forms C=CH-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=Ac
Will be from the compound (0.15mmol at most) of step 44f in CH 2Cl 2(108mg 0.25mL) handled 4.5 hours under room temperature solution (3.0mL) to cross iodine alkane (Dess-Martin periodinane) for Si Mading.Resulting mixture can be at ethyl acetate and saturated NaHCO 3: Na 2S 2O 3Layering between/3: 1 aqueous solution.Organic layer is cleaned with water and bittern.At warp (Na 2SO 4) after the dry and volatilization, with residue with flash chromatography method (SiO 2, hexane: purifying propane/4: 1～1.5: 1), to obtain the title compound that the double-bond isomerism thing is 5: 1 mixtures (62.7mg, 54% yield).
MS(ESI)m/z 785(M+H) +
The compound of step 44h: formula I: A forms C=CH-Ph with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3,, Z=H and R 2'=H
(62.7mg, 0.08mmol) solution in methyl alcohol (3.0mL) stirred 5 days under room temperature before volatilization the compound of step 44g in the future.With flash chromatography method (SiO 2, CH 2Cl 2: 2M NH 3In MeOH/99: 1～96: 4) [purifying is 5: 1 mixture title compounds (49.6mg, 84%) to obtain the double-bond isomerism thing.
MS(ESI)m/z 743(M+H) +
Embodiment 45
The compound of formula I: A forms C=CH-2-(2 pyridyl)-thiophene-5-base with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
The compound of step 45a: formula 6-3: V is N-Ac, X A=OH, X B=H, R 2'=Ac
To from the compound of embodiment 1 step 1f (8.70g, 12.25mmol) in the solution of the trimethyl carbinol (18mL) add 4 methylmorpholine N-oxide compounds (2.07g, 14.7mmol) and OsO 4(4% in water, 0.78ml).Mixture was stirred under room temperature 1 hour, then in CH 2Cl 2And saturated NaHCO 3Layering between the aqueous solution.With water layer with CH 2Cl 2The extraction and with the combination organic extract with NaSO 4Dry and concentrated under vacuum.With flash chromatography method (SiO 2, hexane: propane/1: 1～1: 3) purifying is to obtain the title compound that diastereoisomer is 1: 1 mixture (6.90g, 76% yield).
MS(ESI)m/z 745(M+H) +
The compound of step 45b: formula 6-2: V is N-Ac, X A=OH, X B=H, R 2'=Ac
Will (2.00g, 2.69mmol) (1: 1, (1.15g 5.37mmol) handles solution 20.0mL) with sodium periodate in propane and water from step 45a compound.Mixture was stirred under room temperature 3.5 hours, then in CH 2Cl 2And saturated NaHCO 3Layering between the aqueous solution.With water layer with CH 2Cl 2The extraction and with the combination organic extract with NaSO 4Dry and concentrated under vacuum.With flash chromatography method (SiO 2, hexane: propane/1: 1) purifying is to obtain title compound (1.50g, 78% yield).
MS(ESI)m/z 713(M+H) +
13C NMR(CDCl 3)：δ205.4，184.4，175.8，175.4，169.9，99.2，81.8，80.6，79.4，78.2，77.4，76.5，75.7，71.4，69.0，68.8，63.0，43.8，50.6，39.1，38.3，36.1，36.0，30.8，25.3，22.6，21.4，21.0，19.6，19.2，16.7，15.5，14.6，11.1，7.6
The compound of step 45c: formula 8-1: V is N-Ac, X A=OH, X B=H, X H=Br, R 2'=Ac
(443mg, 1.01mmol) (1.0M is at THF, and 1.00mL 1.00mmol) handles under nitrogen in-78 ℃ with two (TMS) acid amides sodium in the suspension of THF (4.0mL) with brooethyl San Ben Phosphonium bromide.(127mg 0.18mmol) before the solution of THF (5.0mL), stirs mixture down in-70～-60 ℃ and to spend 1 hour in 1 hour and make rise again room temperature and stirred 5 hours with this temperature of reaction mixture from step 45b compound in adding.Mixture can layering between ethyl acetate and water.Organic extract is cleaned with water and bittern, with Na 2SO 4Drying, and under vacuum, concentrate.With flash chromatography method (SiO 2, hexane: propane/9: 1～1.5: 1) purifying is the title compound (87mg, 62% yield) of 2.5～4: 1 mixture to obtain two mirror isomers.
MS(ESI)m/z 789/791(M+H) +
Step 45d:2-(2-pyridine) thienyl-5-bromide
(3.00g is 18.6mmol) in CH with 2-(2-thienyl) pyridine 2Cl 2Solution (90mL) dropwise adds bromine water (0.95mL) at CH under 0 ℃ 2Cl 2Solution (5mL).With mixture with CH 2Cl 2(200mL) before the dilution, make its rise again room temperature and high degree of agitation 1.5 hours.With mixture with saturated NaHCO 3, Na 2SO 3, bittern cleans, and with Na 2SO 4Dry.Solvent flashing is to obtain title compound (4.40g, 100%).
MS(ESI)m/z 240，242(M+H) +
13C NMR(CDCl 3)：δ152.0，149.8，146.5，136.9，131.1，124.6，122.4，118.3，115.3
Step 45e:2-(2-pyridine) thienyl-5-tributyltin
Adding three (normal-butyl) tin chloride (0.80mL, 2.95mmol) preceding, earlier will from the compound of step 45d (600mg, 2.50mmol) (1.6M is in hexane with n-Butyl Lithium in the solution of THF (8.0mL), 1.56mL, 2.50mL) under-78 ℃, handled 30 minutes in stirring down.Mixture is spent 1.5 hours room temperatures of rising again, then at ethyl acetate and saturated NaHCO 3Between layering.Organic layer is cleaned with water and bittern, with Na 2SO 4Clean, and under vacuum, concentrate.With flash chromatography method (SiO 2, hexane: ethyl acetate/98: 2) purifying obtains title compound (998mg, 89% yield).
MS(ESI)m/z 448/449/450/451/452(M+H) +
13C NMR(CDCl 3)：δ152.7，150.1，149.6，140.4，136.6，136.3，125.6，121.5，118.8，28.9，27.2，13.6，10.8
The compound of step 45f: formula 9-2: V is N-Ac, X A=OH, X B=H, R 11=2-(2 pyridyl)-thiophene-5-base, R 2'=Ac
Will be from the compound (210mg of step 42c, 0.26mmol), from the compound (150mg of step 45e, 0.33mmol) and four (triphenyl phosphine) palladium (61mg, the 0.05mmol) solution of (8.0mL) degassing in toluene, and then under nitrogen, stirred 14 hours in 100 ℃.With resulting material with flash chromatography method (SiO 2, hexane: propane/9: 1～1: 1.5), obtain the title compound that the double-bond isomerism thing is 1: 3.8 mixture (140mg, 61% yield).
MS(ESI)m/z 870(M+H) +
The compound of step 45g: formula I: A forms C=CH-2-(2 pyridyl)-thiophene-5-base with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=Ac
Will (140mg be 0.16mmol) in CH from the compound of step 45f 2Cl 2(122mg 0.29mmol) handled 1 hour under room temperature solution (5.0mL), then at ethyl acetate and saturated NaHCO to cross iodine alkane for Si Mading 3: Na 2S 2O 3Layering between/3: 1 aqueous solution.Organic layer is cleaned with water and bittern.With Na 2SO 4After drying and the volatilization, resulting rough title compound is 1: 3.8 mixture (140mg, 100% yield) for the double-bond isomerism thing.
MS(ESI)m/z 868(M+H) +
The compound of step 45h: formula I: A forms C=CH-2-(2 pyridyl)-thiophene-5-base with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=H and R 2'=H
Will from the compound of step 45g (140mg, 0.16mmol) in the solution of methyl alcohol (4.0mL) in stirring 64 hours under the room temperature and in vacuum, concentrating.With flash chromatography method (SiO 2, CH 2Cl 2: 2M NH 3In MeOH/99: 1～96: 4) purifying obtains the title compound that the double-bond isomerism thing is 1: 3 mixture (97mg, 73%).
MS(ESI)m/z 826(M+H) +
Embodiment 46
The compound of formula I: A forms C=O with B and affiliated carbon atom thereof, and X forms C=N-Ac, L=CH with Y and affiliated carbon atom thereof 2CH 3, Z=F and R 2'=Ac
Figure A20038011099701421
Step 46a: the fluoridizing of the 3rd position
To the 3-keto compounds of embodiment 1 (12.04g, 17.0mmol) in dry DMF (70mL) in 0 ℃ solution, add a part sodium hydride (60% in mineral oil, 1.50g, 37.5mmol).Then, ice bath is removed after adding sodium hydride again.Reaction mixture was stirred under room temperature 30 minutes, and reaction mixture can transfer green to and then becomes yellowish during this period.When being cooled to 0 ℃ once more, (5.90g 18.7mmol) and in 0 ℃ stirred 2 hours to add solid N-fluorobenzene sulfimide.Then, with isopropyl acetate (600mL) dilution, clean (200mLX2) with water, with anhydrous Na 2SO 4, drying, and with solvent evaporates.Residue obtains the white solid title compound of 7.77g (63%) with flash chromatography method purifying (silica gel, propane/hexane, 40: 60).
13C-NMR(125MHz，CDCl 3)：δ205.1，204.9，184.1，177.1，170.0，165.1，164.9，141.9，125.3，101.6，99.8，98.2，79.8，79.3，78.5，76.1，71.9，71.0，69.4，65.5，63.4，41.2，40.8，38.8，31.1，30.8，25.3，24.4，24.3，23.0，21.6，21.3，20.9，17.3，14.5，12.5
MS(ESI)m/z＝727(M+H) +.
Step 46b:2 '-hydroxyl go the protection
To in methyl alcohol, reflux from the fluorinated compound of step 46a step, to produce 2 ' oxy-compound according to embodiment 2.
Step 46c: ozone decomposes
The prepared series of compounds of step 46b is decomposed into title compound via embodiment 3 illustrated steps through ozone.
The embodiment compound 47-114 of formula A:
Ar wherein 1, Ar 2, M, each embodiment describes in Q and Z such as the Table A.
Embodiment compound 47-114, wherein Z=H is by the title compound of embodiment 3 and suitable formula Ar 2-M-Ar 1-O-NH 2Azanol via the described methods preparation of embodiment 4.
Embodiment compound 47-114, wherein Z=F is by the title compound of embodiment 46 and suitable formula Ar 2-M-Ar 1-O-NH 2Azanol via the described methods preparation of embodiment 4.
There is the mixture of E and Z isomer in embodiment below all, and it can utilize HPLC separately.
The employed azanol of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via this field known synthetic method person of preparation.
Table A
Figure A20038011099701432
Figure A20038011099701441
Figure A20038011099701451
Figure A20038011099701461
Figure A20038011099701481
Figure A20038011099701511
The embodiment compound 115-263 of formula A1:
Figure A20038011099701512
Ar wherein 1, Ar 2, M, each embodiment describes in Q and Z such as the Table A 1.
Embodiment compound 115-262, wherein Z=H is compound and the formula Ar with embodiment 3 2-M-Ar 1-O-NH 2Suitable azanol by the described methods preparation of embodiment 4.
Embodiment compound 115-262, wherein Z=F is compound and the formula Ar with embodiment 46 2-M-Ar 1-O-NH 2Suitable azanol by the described methods preparation of embodiment 4.
The embodiment that Table A 1 is narrated is the isomer of single E type, and it can be separated through silica gel chromatography or HPLC by the E/Z mixture.
The employed azanol of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via this field known synthetic method person of preparation.
Table A 1.
Figure A20038011099701521
Figure A20038011099701561
Figure A20038011099701571
Figure A20038011099701591
Figure A20038011099701601
Figure A20038011099701611
Figure A20038011099701631
Figure A20038011099701641
Figure A20038011099701651
Figure A20038011099701661
Figure A20038011099701711
Figure A20038011099701731
Figure A20038011099701741
Figure A20038011099701761
Figure A20038011099701791
Figure A20038011099701821
Figure A20038011099701841
Figure A20038011099701881
Figure A20038011099701891
Figure A20038011099701901
Figure A20038011099701931
Figure A20038011099701951
Figure A20038011099701971
Figure A20038011099701981
The embodiment compound 263-337 of formula A2:
Ar wherein 1, Ar 2, M, each embodiment describes in Q and Z such as the Table A 2.
Embodiment compound 263-337, wherein Z=H is title compound and the formula Ar with embodiment 3 2-M-Ar 1-O-NH 2Suitable azanol by the described methods preparation of embodiment 4.
Embodiment compound 263-337, wherein Z=F is title compound and the formula Ar with embodiment 46 2-M-Ar 1-O-NH 2Suitable azanol by the described methods preparation of embodiment 4.
The embodiment that Table A 2 is narrated is the isomer of single E type, and it can be separated through silica gel chromatography or HPLC by the E/Z mixture.
The employed azanol of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via the general known synthetic method person of preparation in this field.
Table A 2.
Embodiment Q -Ar 1-M-Ar 2 Z MS(ESI)： m/z (M+H) + 13C NMR(125 MHz，CDCl 3)： δ
Figure A20038011099702001
Figure A20038011099702011
Figure A20038011099702031
Figure A20038011099702041
Figure A20038011099702061
Figure A20038011099702071
Figure A20038011099702081
Figure A20038011099702101
Figure A20038011099702131
Figure A20038011099702141
Figure A20038011099702151
Figure A20038011099702171
Figure A20038011099702181
Figure A20038011099702191
Figure A20038011099702201
Figure A20038011099702211
Figure A20038011099702221
Figure A20038011099702231
Figure A20038011099702241
Figure A20038011099702261
Figure A20038011099702291
Figure A20038011099702311
Figure A20038011099702321
Figure A20038011099702331
Figure A20038011099702341
Figure A20038011099702351
Figure A20038011099702371
The embodiment compound 338-352 of formula B:
R wherein 11, Q and Z describe as each embodiment among the table B.
Embodiment compound 338-352, Z=H wherein, be by formula ( 1-5) title compound, V=N-Ac wherein, R 11=H and R 2'=H is with formula Br-R 11Suitable bromine compounds, via with the described identical in fact route of synthesis preparation of embodiment 35.
Embodiment compound 338-352, wherein Z=F is with embodiment 46, the compound of step 46a prepares by embodiment 35 described methods with suitable precursor.
The table embodiment that B narrated comprises the mixture of E and Z isomer, and it can be separated by silica gel chromatography or HPLC.
The employed bromine compounds of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via the general known synthetic method person of preparation in this field.
Table B
Figure A20038011099702391
Figure A20038011099702401
The embodiment compound 353-374 of formula B1:
R wherein 11, Q and Z describe as each embodiment among the table B1.
Embodiment compound 353-374, Z=H wherein, be by formula ( 1-5) title compound, V=N-Ac wherein, R 11=H and R 2'=H is with formula Br-R 11Suitable bromine compounds, R wherein 11As previously mentioned, via preparing with embodiment 35 described identical in fact route of synthesis.
Embodiment compound 353-374, wherein Z=F is with embodiment 46, the compound of step 46a prepares by embodiment 35 described methods with suitable precursor.
The table embodiment that B1 narrated is the isomer of single E type, and it can be separated through silica gel chromatography or HPLC by the E/Z mixture.
The employed bromine compounds of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via the general known synthetic method person of preparation in this field.
Table B1
Figure A20038011099702431
Figure A20038011099702451
Figure A20038011099702461
Figure A20038011099702471
Figure A20038011099702491
The embodiment compound 376-384 of formula B2:
Figure A20038011099702502
R wherein 11, Q and Z describe as each embodiment among the table B2.
Embodiment compound 375-383, Z=H wherein, be by formula ( 1-5) title compound, V=N-Ac wherein, R 11=H and R 2'=H is with formula Br-R 11Suitable bromine compounds, R wherein 11As previously mentioned, via preparing with embodiment 35 described identical in fact route of synthesis.
Embodiment compound 375-383, wherein Z=F is with embodiment 46, the compound of step 46a prepares by embodiment 35 described methods with suitable precursor.
The table embodiment that B2 narrated is the isomer of single E type, and it can be separated through silica gel chromatography or HPLC by the E/Z mixture.
The employed bromine compounds of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via the general known synthetic method person of preparation in this field.
Table B2
Figure A20038011099702511
Figure A20038011099702521
Figure A20038011099702541
Figure A20038011099702551
The embodiment compound 384-390 of formula C:
Figure A20038011099702552
R wherein 11, Q and Z describe as each embodiment among the table B2.
Embodiment compound 384-390, Z=H wherein, be by formula ( 1-5) title compound, V=N-Ac wherein, R 11=H and R 2'=H is with suitable NH 2-R 11, NH 2NH 2-SO 2-R 11, NH 2NH 2-R 11, NH 2NH 2-N=CH-R 11, NH 2NH 2-C (O)-R 11Compound, R wherein 11As previously mentioned, via preparing with embodiment 4 described identical in fact route of synthesis.
Embodiment compound 375-383, Z=F wherein is by embodiment 4 described methods preparations with the title compound of embodiment 46 and suitable precursor.
The table embodiment that C narrated is the isomer mixture that comprises E and Z type, and it can separate through silica gel chromatography or HPLC.
The employed aminocompound of following examples is that commercially available getting maybe can utilize the initial substance that is easy to obtain via the general known synthetic method person of preparation in this field.
Table C
Though the present invention has been not to be intended to limit with the explanation of various preferred embodiment, be familiar with this art person and should be appreciated that in spirit of the present invention and appended claim scope, can do various variations and modification.

Claims (1)

1. one kind with following formula:
Compound or its pharmacologically acceptable salts, ester or the prodrug of representative, wherein
A is selected from
a)-OH；
B)-OR p, R wherein pBe hydroxyl protecting group;
C)-R 1, R wherein 1Be independently selected from:
(1) aryl;
(2) substituted aryl;
(3) heteroaryl; And
(4) substituted heteroaryl;
D)-OR 1, R wherein 1As definition before;
E)-R 2, R wherein 2Be selected from:
(1) hydrogen;
(2) halogen;
(3) C 1-C 12Alkyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S or N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(4) C 2-C 12Alkenyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; And
(5) C 2-C 12Alkynyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
F)-OR 2, R wherein 2Independently as definition before;
G)-S (O) nR 11, wherein n=0,1 or 2, and R 11Be hydrogen, R independently 1Or R 2, R wherein 1And R 2As definition before;
H)-NHC (O) R 11, R wherein 11As definition before;
I)-NHC (O) NHR 11, R wherein 11As definition before;
J)-NHS (O) 2R 11, R wherein 11As definition before;
K)-NR 14R 15, R wherein 14And R 15Independent separately is R 11, R wherein 11As definition before; And
L)-NHR 3, R wherein 3Be amino protecting group;
B is selected from:
A) hydrogen;
B) deuterium;
C) halogen;
d)-OH；
E) R 1, R wherein 1As definition before;
F) R 2, R wherein 2As definition before; And
G)-OR p, R wherein pAs definition before,
H) condition be when B be halogen ,-OH or-OR pThe time, A is R 1Or R 2
Perhaps, A is connected carbon atom on it with B with them, be selected from:
a)C＝O；
B) C (OR 2) 2, R wherein 2As definition before;
C) C (SR 2) 2, R wherein 2As definition before;
D) C[-O (CH 2) m] 2, m=2 or 3 wherein;
E) C[-S (CH 2) m] 2, wherein m is as before definition;
F) C=CHR 11, R wherein 11As definition before;
G) C=N-O-R 11, R wherein 11As definition before;
H) C=N-O-Ar 1-M-Ar 2, wherein
(1)-Ar 1-be R 31, R wherein 31Be independently selected from:
(a) R 1, R wherein 1As definition before;
(b) C 1-C 12Alkyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S or N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(c) C 2-C 12Alkenyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; Perhaps
(d) C 2-C 12Alkynyl, it comprises that randomly 0,1,2 or 3 is selected from the heteroatoms of O, S and N, randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(2)-M-do not exist or is selected from:
(a)-C 1-C 12Alkyl, it randomly comprises:
0-3 heteroatoms that is selected from O, S or N; And
0-3 is selected from-C=N-,-N=N ,-C (O)-group;
(b)-C 2-C 12Alkenyl, it randomly comprises:
0-3 heteroatoms that is selected from O, S or N; And
0-3 is selected from-C=N-,-N=N ,-C (O)-group;
(c)-C 2-C 12Alkynyl, it randomly comprises:
0-3 heteroatoms that is selected from O, S or N; And
0-3 is selected from-C=N-,-N=N ,-C (O)-group;
(d) substituted aryl;
(e) substituted heteroaryl; Perhaps
(f) substituted heterocycle alkyl; And
(3)-Ar 2Be selected from:
(a) aryl;
(b) substituted aryl;
(c) heteroaryl; Perhaps
(d) substituted heteroaryl;
I) C=NNHR 11, R wherein 11As definition before;
J) C=NNHC (O) R 11, R wherein 11As definition before;
K) C=NNHC (O) NHR 11, R wherein 11As definition before;
L) C=NNHS (O) 2R 11, R wherein 11As definition before;
M) C=NNHR 3, R wherein 3As definition before;
N) C=NR 11, R wherein 11As definition before; Or
O) C=N-N=CHR 11, R wherein 11As definition before;
One of them is selected from X and Y for another person of hydrogen:
A) hydrogen;
B) deuterium;
c)-OH；
D)-OR p, R wherein pAs definition before;
E)-NR 4R 5, R wherein 4With R 5Be selected from independently of one another:
(1) hydrogen;
(2) C 1-C 12Alkyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; Or
(3) R 4With R 5The nitrogen-atoms that is connected on it with them forms the assorted alkyl ring of 3-10 person together, and it comprises 0-2 extra heteroatoms that is selected from O, S and N;
Perhaps, X is connected carbon atom on it with Y with them, be selected from:
a)C＝O；
B) C=N-Q, wherein Q is selected from:
(1)-R 11, R wherein 11As definition before;
(2) amino protecting group;
(3)-C (O) R 11, R wherein 11As definition before;
(4)-OR 6, R wherein 6Be independently selected from:
(a) hydrogen;
(b)-CH 2O(CH 2) 2OCH 3
(c)-CH 2O (CH 2O) nCH 3, wherein n is as before definition;
(d)-C 1-C 12Alkyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(e)-C 3-C 12Cycloalkyl;
(f)-C (O)-C 1-C 12Alkyl;
(g)-C (O)-C 3-C 12Cycloalkyl;
(h)-C (O)-R 1, R wherein 1As definition before; Or
(i)-Si (R a) (R b) (R c), R wherein a, R bAnd R cBe selected from C independently of one another 1-C 12Alkyl, aryl and substituted aryl; Or
(5) O-C (R 7) (R 8)-O-R 6, R wherein 6As definition before, condition is R 6Non-C (O)-C 1-C 12Alkyl, C (O)-C 3-C 12Cycloalkyl or C (O)-R 1, and R 7With R 8The carbon atom that connects on it with them forms C 3-C 12Cycloalkyl perhaps is selected from independently of one another:
(1) hydrogen; Or
(2) C 1-C 12Alkyl;
L is selected from:
a)-CH 3；
b)-CH 2CH 3；
c)-CH(OH)CH 3；
D) C 1-C 6Alkyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
E) C 2-C 6Alkenyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; Or
F) C 2-C 6Alkynyl randomly replaces with one or more substituting group that is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
W is-NR 20R 21, R wherein 20And R 21Be selected from independently of one another:
A) hydrogen;
B) C 1-C 12Alkyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
C) C 2-C 12Alkenyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
D) C 2-C 12Alkynyl randomly replaces with one or more substituting group that is selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; Perhaps
E) R 20And R 21The nitrogen-atoms that connects on it with them forms Heterocyclylalkyl; Or Z is selected from:
A) hydrogen;
B) methyl; Or
C) halogen; And
R 2' be hydrogen or R p, R wherein pAs definition before.
CNA2003801109976A 2003-11-20 2003-11-20 6-11 bicyclic ketolide drivatives Pending CN1914221A (en)

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