CN101171257A - Pyrrolobenzodiazepines compound - Google Patents

Pyrrolobenzodiazepines compound Download PDF

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CN101171257A
CN101171257A CNA2006800157162A CN200680015716A CN101171257A CN 101171257 A CN101171257 A CN 101171257A CN A2006800157162 A CNA2006800157162 A CN A2006800157162A CN 200680015716 A CN200680015716 A CN 200680015716A CN 101171257 A CN101171257 A CN 101171257A
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CN101171257B (en
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S·J·格雷格森
P·W·霍华德
陈治治
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MedImmune Ltd
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ADC Products UK Ltd
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Abstract

Compounds of the formula: (I) or solvate thereof, wherein: R<2> is an optionally substituted C5-20 aryl group; R<6> and R<9> are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R<7> is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn and halo; R'' is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R<2>', R<6>', R<7>', R<9>', X' and M' are selected from the same groups as R<2>, R<6>, R<7>, R<9>, X and M respectively, or M and M' may together represent a divalent pharmaceutically acceptable cation.

Description

Pyrrolo-benzodiazepine derivatives compound
Technical field
The present invention relates to pyrrolo-benzodiazepine (PBDs), especially carry the pyrrolo-benzodiazepine dimer of C2 aryl substituent.
Background technology
Some pyrrolo-benzodiazepine (PBDs) has can discern DNA particular sequence and bonded performance with it; This preferred sequence is PuGPu.First PBD antitumor antibiotics Antramycin be found in 1965 (Leimgruber, etc., J.Am.Chem.Soc., 87,5793-5795 (1965); Leimgruber, etc., J.Am.Chem.Soc., 87,5791-5793 (1965)).After this, many naturally occurring PBDs are in the news, and surpass 10 kinds of synthetic routes and are developed and are applied to various analogues (Thurston, etc., Chem.Rev.1994,433-465 (1994)).This family member comprise abbeymycin (Hochlowski, etc., J.Antibiotics, 40,145-148 (1987)), (Konishi is etc., J.Antibiotics for strange Ka-7038 (chicamycin), 37,200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, etc., Chem.Brit., 26,767-772 (1990); Bose, etc., Tetrahedron, 48,751-758 (1992)), mazethramycin (Kuminoto, etc., J.Antibiotics, 33,665-667 (1980)), neothramycins A and B (Takeuchi, etc., J.Antibiotics, 29,93-96 (1976)), (Tsunakawa is etc., J.Antibiotics for porothramycin, 41,1366-1373 (1988)), prothracarcin (Shimizu, et al, J.Antibiotics, 29,2492-2503 (1982); Langley and Thurston, J.Org.Chem., 52,91-97 (1987)), sibanomicin (DC-102) (Hara, etc., J.Antibiotics, 41,702-704 (1988); Itoh, etc., J.Antibiotics, 41,1281-1284 (1988)), sibiromycin (Leber, etc., J.Am.Chem.Soc., 110,2992-2993 (1988)) and Tomamycin (Arima, etc., J.Antibiotics, 25,437-444 (1972)).The general formula of PBDs is:
Figure S2006800157162D00021
They are different because its aromatics A ring is different with substituent quantity, type and position in the pyrrolo-C ring and C ring filling degree different.Have imines (N=C), carbinolamine (NH-CH (OH)) or carbinolamine methyl ether (NH-CH (OMe)) on the N10-C11 position in the B-ring, this position is to cause the alkylating electrophilic of DNA center.All known natural products have (S)-configuration on chirality C11a position, so when they reverse to the right when C hoop A ring direction is seen.This makes them have and the identical suitable 3D shape of B-type DNA ditch spiral, thereby can mate (Kohn, In Antibiotics III.Springer-Verlag, New York, 3-11 page or leaf (1975) at binding site; Hurley and Needham-VanDevanter, Acc.Chem.Res., 19,230-237 (1986)).They can make it can disturb DNA processing in the performance that ditch forms adducts, so can be used as antitumor drug.
The present inventor once disclosed the cytotoxin compounds that has aryl on the C2 position at WO2004/043963, for example:
Figure S2006800157162D00022
The present inventor also once disclosed the dimer PBD compound that carries the C2 aryl in common unsettled PCT application PCT/GB2005/000768 (open with WO2005/085251), for example:
Figure S2006800157162D00023
Summary of the invention
The present inventor find compound for example ZC-207 have the problem of solubleness, solve these problems by adopting the dissimilar of these compounds.
The present invention includes formula I compound or its solvate:
Figure S2006800157162D00031
Wherein:
R 2Be the optional C that replaces 5-20Aromatic yl group;
R 6And R 9Independently be selected from H, R, OH, OR, SH, SR, NH 2, NHR, NRR ', nitro, Me 3Sn and halogen;
Wherein R and R ' independently are selected from the optional C that replaces 1-12Alkyl, C 3-20Heterocyclic radical and C 5-20Aromatic yl group;
R 7Be selected from H, R, OH, OR, SH, SR, NH 2, NHR, NHRR ', nitro, Me 3Sn and halogen;
R " is C 3-12Alkylidene group and/or aromatic ring (benzene or pyridine), described alkylidene chain can contain one or more heteroatoms, for example O, S, NH;
X is selected from O, S or NH;
Z is 2 or 3;
M is pharmaceutically acceptable univalent cation;
R 2', R 6', R 7', R 9', X ' and M ' be selected from respectively and R 2, R 6, R 7, R 9, group that X is identical with M, perhaps M and M ' can represent pharmaceutically acceptable divalent cation together.
Known pyrrolo-benzodiazepine with imine linkage can be converted into two-carbinolamine form in water, thereby isolated pyrrolo-benzodiazepine exists with the mixture of imines, list-carbinolamine and two-carbinolamine form usually.In addition, if the compound of separating is the solid that contains these three kinds of form mixtures, then the balance between them may time to time change.Although this can not throw into question to the administration of compound, its meeting causes difficulty to the accurate estimation of the amount of active substance in the powder of specified rate.The compounds of this invention can overcome this difficulty at least to a certain extent can also keep simultaneously active, so be applicable to the preparation of medicine.
Dimer pyrrolo-benzodiazepine has advantage than monomer pyrrolo-benzodiazepine, because they have the ability of crosslinked DNA in ditch, this makes cytotoxicity increase.
Another aspect of the present invention relates to the purposes of compound in treatment (especially treating proliferative disease) method, relates to and contains these compound compositions and their purposes in the medicine of production for treating proliferative disease.
Definition
Substituting group
Term used herein " optional replacement " is meant it can is precursor group unsubstituted or that replace.
Unless otherwise indicated, term used herein " replacement " is meant and can carries one or more substituent precursor group.Term used herein " substituting group " uses with traditional sense, is meant that the mode with covalency combines with precursor group, if perhaps suitable, condenses with precursor group.A large amount of substituting groups is well-known, and the method for its formation and introducing precursor group also is well-known.
Substituent example is described in greater detail below.
C 1-12Alkyl: term " C used herein 1-12Alkyl " be meant on the carbon atom of hydrocarbon compound and remove the monoradical that obtains behind the hydrogen atom with 1-12 carbon atom; they can be aliphatics or alicyclic, they can be saturated or unsaturated (for example part is undersaturated, undersaturated fully).So term " alkyl " comprises the subclass alkenyl discussed below, alkynyl, cycloalkyl etc.
The saturated alkyl examples of groups includes but not limited to methyl (C 1), ethyl (C 2), propyl group (C 3), butyl (C 4), amyl group (C 5), hexyl (C 6) and heptyl (C 7).
Saturated linear alkyl examples of groups includes but not limited to methyl (C 1), ethyl (C 2), n-propyl group (C 3), n-butyl (C 4), n-amyl group (C 5), n-hexyl (C 6) and n-heptyl (C 7).
The example of saturated branched alkyl group comprises different-propyl group (C 3), different-butyl (C 4), the second month in a season-butyl (C 4), tert-butyl (C 4), different-amyl group (C 5) and new-amyl group (C 5).
C 2-12Alkenyl: term " C used herein 2-12Alkenyl " be meant alkyl group with one or more carbon-to-carbon double bond.
The example of unsaturated chain alkenyl group include but not limited to vinyl (vinyl ,-CH=CH 2), 1-propenyl (CH=CH-CH 3), 2-propenyl (allyl group ,-CH-CH=CH 2), pseudoallyl (the 1-methyl ethylene ,-C (CH 3)=CH 2), butenyl (C 4), pentenyl (C 5) and hexenyl (C 6).
C 2-12Alkynyl: term " C used herein 2-12Alkynyl " be meant alkyl group with one or more carbon-to-carbon triple bond.
Unsaturated alkynyl examples of groups include but not limited to ethynyl (C ≡ CH) and 2-propynyl (propargyl ,-CH 2-C ≡ CH).
C 3-12Cycloalkyl: term " C used herein 3-12Cycloalkyl " be meant also and be the alkyl group of cyclic group group; The monoradical that obtains after removing hydrogen atom on the alicyclic annular atoms of cyclic hydrocarbon (carbocyclic ring) compound just, this group has 3-7 carbon atom, comprises 3-7 annular atoms.
The example of cycloalkyl includes but not limited to that those are derived from following group:
Saturated monocyclic hydrocarbon compound:
Cyclopropane (C 3), tetramethylene (C 4), pentamethylene (C 5), hexanaphthene (C 6), suberane (C 7), methyl cyclopropane (C 4), dimethylcyclopropane (C 5), methyl cyclobutane (C 5), dimethyl tetramethylene (C 6), methylcyclopentane (C 6), dimethylcyclopentane (C 7) and methylcyclohexane (C 7);
Undersaturated monocyclic hydrocarbon compound:
Cyclopropylene (C 3), cyclobutene (C 4), cyclopentenes (C 5), tetrahydrobenzene (C 6), methylcyclopropene (C 4), dimethyl cyclopropylene (C 5), methyl cyclobutene (C 5), dimethyl cyclobutene (C 6), methyl cyclopentene (C 6), dimethylcyclopentene (C 7) and tetrahydrotoluene (C 7); With
Saturated polycyclic hydrocarbon compounds:
Norcarane (C 7), norpinane (C 7), norbornane (C 7).
C 3-20Heterocyclic radical: term " C used herein 3-20Heterocyclic radical " be meant the monoradical that after removing hydrogen atom on the annular atoms of heterogeneous ring compound, obtains, this group has 3-20 annular atoms, and wherein 1-10 is ring hetero atom.Preferably, each ring has 3-7 annular atoms, and wherein 1-4 is ring hetero atom.
In this article, prefix (C for example 3-20, C 3-7, C 5-6Deng) represent the scope of the number or the annular atoms number of annular atoms, comprise carbon atom or heteroatoms.For example, term " C used herein 5-6Heterocyclic radical " be meant heterocyclic radical group with 5 or 6 annular atomses.
Monocyclic heterocycles base examples of groups includes but not limited to that those are derived from following group:
N 1: aziridine (C 3), azetidine (C 4), tetramethyleneimine (Pyrrolidine) (C 5), pyrroline (for example, 3-pyrroline, 2,5-pyrrolin) (C 5), 2H-pyrroles or 3H-pyrroles (different pyrroles) (C 5), piperidines (C 6), dihydropyridine (C 6), tetrahydropyridine (C 6), azepine  (C 7);
O 1: oxirane (C 3), trimethylene oxide (C 4), tetrahydrofuran (tetrahydrofuran (THF)) (C 5), oxa-cyclopentenes (dihydrofuran) (C 5),  alkane (tetrahydropyrans) (C 6), dihydropyrane (C 6), pyrans (C 6), oxa- (C 7);
S 1: thiirane (C 3), Thietane (C 4), thiacyclopentane (tetramethylene sulfide) (C 5), thia hexanaphthene (tetrahydric thiapyran) (C 6), thia  (C 7);
O 2: dioxolane (C 5), dioxane (C 6) and Dioxepane (C 7);
O 3: trioxane (C 6);
N 2: imidazolidine (C 5), diazole alkane (C 5), tetrahydroglyoxaline (C 5), pyrazoline (pyrazoline) (C 5), piperazine (C 6);
N 1O 1: tetrahydrochysene  azoles (C 5), dihydro  azoles (C 5), the different  azoles of tetrahydrochysene (C 5), the different  azoles of dihydro (C 5), morpholine (C 6), tetrahydrochysene  piperazine (C 6), dihydro  piperazine (C 6),  piperazine (C 6);
N 1S 1: thiazoline (C 5), thiazolidine (C 5), thiomorpholine (C 6);
N 2O 1:  diazine (C 6);
O 1S 1: oxygen thia cyclopentenes (C 5) and oxathiane (thiophene  alkane) (C 6); With
N 1O 1S 1:  thiazine (C 6).
The example of the monocyclic heterocycles base group that replaces comprises those groups derived from the ring-type carbohydrate, for example, and furans carbohydrate (C 5), as furans pectinose, furans lyxose, ribofuranose and furyl xylose; Pyrans carbohydrate (C 6), as pyrans allose, pyrans Ah  sugar, Glucopyranose, mannopyranose, pyrans gulose, pyrans idose, galactopyranose and pyrans talose.
C 5-20Aryl: term " C used herein 5-20Aryl " be meant the monoradical that after removing hydrogen atom on the aromatic ring atom of aromatic substance, obtains, this group has 3-20 annular atoms.Preferably, each ring has 5-7 annular atoms.
In this article, prefix (C for example 3-20, C 5-7, C 5-6Deng) represent the scope of the number or the annular atoms number of annular atoms, comprise carbon atom or heteroatoms.For example, term " C used herein 5-6Aryl " be meant aromatic yl group with 5 or 6 annular atomses.
Annular atoms can all be a carbon atom, for example in " carbon ring aromatic yl group ".
The example of carbon ring aromatic yl group includes but not limited to that those are derived from following group: benzene (being phenyl) (C 6), naphthalene (C 10), azulene (C 10), anthracene (C 14), luxuriant and rich with fragrance (C 14), naphthacene (C 18) and pyrene (C 16).
The example of aromatic yl group (comprise fused rings, wherein at least one ring is aromatic ring) includes but not limited to derived from following group: indane (as 2,3-dihydro-1H-indenes) (C 9), indenes (C 9), different indenes (C 9), tetraline (1,2,3,4-naphthane (C 10), acenaphthene (C 12), fluorenes (C 13), non-that alkene (C 13), vinegar phenanthrene (C 15) and aceanthrene (C 16).
Perhaps, annular atoms can comprise one or more heteroatoms, as in " heteroaryl groups ".The bicyclic heteroaryl examples of groups includes but not limited to that those are derived from following group:
N 1: pyrroles (C 5), pyridine (C 6);
O 1: furans (C 5);
S 1: thiophene (C 5);
N 1O 1:  azoles (C 5), different  azoles (C 5), different  piperazine (C 6);
N 2O 1:  diazole (furazan) (C 5);
N 3O 1:  triazole (C 5);
N 1S 1: thiazole (C 5), isothiazole (C 5);
N 2: imidazoles (1, the 3-diazole) (C 5),, pyrazoles (1,2-diazole) (C 5), pyridazine (1,2-diazine) (C 6), pyrimidine (1,3-diazines) (C 6) (for example cytosine(Cyt), thymus pyrimidine, uridylic), pyrazine (1,4-diazines) (C 6);
N 3: triazole (C 5), triazine (C 6); With
N 4: tetrazolium (C 5).
The example that contains the heteroaryl of fused rings includes but not limited to
C derived from following groups 9(having 2 fused rings): cumarone (O 1), isobenzofuran (O 1), indoles (N 1), isoindole (N 1), indolizine (N 1), indoline (N 1), isoindoline (N 1), purine (N 4) (for example VITAMIN B4, guanine), benzoglyoxaline (N 2), indazole (N 2), benzoxazol (N 1O 1), benzisoxa  azoles (N 1O 1), benzo dioxole (O 2), benzo furazan (N 2O 1), benzotriazole (N 3), benzo thiapyran (S 1), benzothiazole (N 1S 1), diazosulfide (N 2S);
C derived from following groups 10(having 2 fused rings): chromene (O 1), heterochromatic alkene (O 1), chroman (O 1), isochroman (O 1), benzo two  alkane (O 2), quinoline (N 1), isoquinoline 99.9 (N 1), quinolizine (N 1), benzoxazine (N 1O 1), benzodiazine (N 2), pyridopyridine (N 2), quinoxaline (N 2), quinazoline (N 2), cinnolines (N 2), phthalazines (N 2), naphthyridine (N 2), pteridine (N 4);
Derived from benzodiazepine (N 2) C 11(having 2 fused rings);
C derived from following groups 13(having 3 fused rings): carbazole (N 1), diphenylene-oxide (O 1), dibenzothiophene (S 1), carboline (N 2), perimidine (N 2), pyrido indoles (N 2); With
C derived from following groups 14(having 3 fused rings): acridine (N 1), xanthene (O 1), thioxanthene (S 1), folder dioxy anthracene (oxanthrene) (O 2), fen thiophene  (O 1S 1), azophenlyene (N 2), fen  piperazine (N 1O 1), thiodiphenylamine (N 1S 1), thianthrene (S 2), phenanthridines (N 1), phenanthroline (N 2), azophenlyene (N 2).
No matter above-mentioned group is Individual existence or exist as other substituent part, himself can choose wantonly to be selected from himself by one or more and the other substituting group listed below replaces.
Halogen :-F ,-Cl ,-Br and-I.
Hydroxyl :-OH.
Ether :-OR, wherein R is ether substituting group, for example C 1-7Alkyl group (is also referred to as C 1-7Alkoxy base will be discussed below), C 3-20The heterocyclic radical group (is also referred to as C 3-20The heterocyclic oxy group group) or C 5-20Aromatic yl group (is also referred to as C 5-20Aryloxy group), preferred C 1-7Alkyl group.
Alkoxyl group :-OR, wherein R is alkyl group, for example C 1-7Alkyl group.C 1-7The example of alkoxy base includes but not limited to-OMe (methoxyl group) ,-OEt (oxyethyl group) ,-O (nPr) (n-propoxy-) ,-O (iPr) (isopropoxy) ,-O (nBu) (n-butoxy) ,-O (sBu) (second month in a season-butoxy) ,-O (iBu) (isobutoxy) and-O (tBu) (uncle-butoxy).
Acetal :-CH (OR 1) (OR 2), R wherein 1And R 2Independent is acetal substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl, perhaps under the situation of " ring " acetal groups, R 1And R 2Form heterocyclic ring with two oxygen that they connected and the carbon that they connected with 4-8 annular atoms.The example of acetal groups includes but not limited to-CH (OMe) 2,-CH (OEt) 2With-CH (OMe) is (OEt).
Hemiacetal :-CH (OH) (OR 1), R wherein 1Be hemiacetal substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of hemiacetal group includes but not limited to-CH (OH) (OMe) and-CH (OH) (OEt).
Ketal :-CR (OR 1) (OR 2), R wherein 1And R 2Define as acetal, R is the ketal substituting group, but is not hydrogen, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of ketal includes but not limited to-C (Me) is (OMe) 2,-C (Me) (OEt) 2,-C (Me) (OMe) (OEt) ,-C (Et) (OMe) 2,-C (Et) (OEt) 2With-C (Et) (OMe) (OEt).
Hemiketal :-CR (OH) (OR 1), R wherein 1Define as hemiacetal, R is the hemiketal substituting group, is not hydrogen, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of hemiketal includes but not limited to-C (Me) (OH) (OMe) ,-C (Et) (OH) (OMe) ,-C (Me) (OH) (OEt) and-C (Et) (OH) (OEt).
Oxo (ketone group ,-ketone) :=O.
Thioketones (thioketones) :=S.
Imino-(imines) :=NR, wherein R is the imino-substituting group, for example hydrogen, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred hydrogen or C 1-7Alkyl.The example of ester group includes but not limited to=NH ,=NMe ,=NEt and=NPh.
Formyl radical (formaldehyde) :-C (=O) H.
(=O) R, wherein R is acyl substituent, for example C to acyl group (ketone group) :-C 1-7Alkyl (is also referred to as C 1-7Alkyl acyl or C 1-7Alkyloyl), C 3-20Heterocyclic radical (is also referred to as C 3-20Heterocyclic acyl) or C 5-20Aryl (is also referred to as C 5-20Aroyl), preferred C 1-7Alkyl.The example of acyl group includes but not limited to-C (=O) CH 3(ethanoyl) ,-C (=O) CH 2CH 3(propionyl) ,-C (=O) C (CH 3) 3(t-butyryl radicals) and-C (=O) Ph (benzoyl, phenyl ketone).
Carboxyl (carboxylic acid) :-C (=O) OH.
Thiocarboxyl group (thiocarboxylic acid) :-C (=S) SH.
Thiol carboxyl :-C (=O) SH.
Thionic carboxyl :-C (=S) OH.
Imido acid :-C (=NH) OH.
Hydroximic acid :-C (=NOH) OH.
(=O) OR, wherein R is ester substituting group, for example C to ester (carboxylicesters, oxygen base carbonyl) :-C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of ester includes but not limited to-C (=O) OCH 3,-C (=O) OCH 2CH 3,-C (=O) OC (CH 3) 3With-C (=O) OPh.
(=O) R, wherein R is acyloxy substituting group, for example C to acyloxy (anti-ester (reverse ester)) :-OC 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of acyloxy includes but not limited to-OC (=O) CH 3(acetoxyl group) ,-OC (=O) CH 2CH 3,-OC (=O) C (CH 3) 3,-OC (=O) Ph and-OC (=O) CH 2Ph.
(=O) OR, wherein R is ester substituting group, for example C to oxygen base ketonic oxygen base :-OC 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of ester includes but not limited to-OC (=O) OCH 3,-OC (=O) OCH 2CH 3,-OC (=O) OC (CH 3) 3With-OC (=O) OPh.
Amino :-NR 1R 2, R wherein 1And R 2Independent is amino substituting group, for example hydrogen, C 1-7Alkyl (is also referred to as C 1-7Alkylamino or two-C 1-7Alkylamino), C 3-20Heterocyclic radical or C 5-20Aryl, preferred H or C 1-7Alkyl, perhaps, in " ring " amino situation, R 1And R 2Form heterocyclic ring with the nitrogen-atoms that they connected with 4-8 annular atoms.Amino can be uncle's ammonia (NH 2), parahelium (NHR 1) or uncle's ammonia (NHR 1R 2), and if cationic form, can be quaternary ammonium ( +NR 1R 2R 3).Amino example includes but not limited to-NH 2,-NHCH 3,-NHC (CH 3) 2,-N (CH 3) 2,-N (CH 2CH 3) 2With-NHPh.The amino example of ring includes but not limited to ethylene imine subbase (aziridino), azetidine subbase (azetidino), pyrrolidino, piperidino-(1-position only), Piperazino, morpholino and thiomorpholine generation.
Amido (formamyl, carbamyl, aminocarboxyl, methane amide) :-C (=O) NR 1R 2, R wherein 1And R 2Independent is as amino defined amino substituting group.The example of amido includes but not limited to-C (=O) NH 2,-C (=O) NHCH 3,-C (=O) N (CH 3) 2,-C (=O) NHCH 2CH 3With-C (=O) N (CH 2CH 3) 2And R wherein 1And R 2Form the amido of heterocycle structure with the nitrogen-atoms that they connected, described heterocycle structure for example piperidino-(1-position only) carbonyl, morpholino carbonyl, thiomorpholine for carbonyl and Piperazino carbonyl.
Thio acylamino (thiocarbamyl) :-C (=S) NR 1R 2, R wherein 1And R 2Independent is as amino defined amino substituting group.The example of amido includes but not limited to-C (=S) NH 2,-C (=S) NHCH 3,-C (=S) N (CH 3) 2With-C (=S) NHCH 2CH 3
Acyl group amido (acyl amino) :-NR 1C (=O) R 2, R wherein 1Be amide substituents, for example hydrogen, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred hydrogen or C 1-7Alkyl, R 2Be acyl substituent, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred hydrogen or C 1-7Alkyl.The example of acyl group acid amides includes but not limited to-NHC (=O) CH 3,-NHC (=O) CH 2CH 3With-NHC (=O) Ph.R 1And R 2Can form ring structure together, for example succinimido, dimaleoyl imino and phthalimidyl:
Figure S2006800157162D00101
Succinimido dimaleoyl imino phthalimidyl
Aminocarboxyl oxygen base :-OC (=O) NR 1R 2, R wherein 1And R 2Independent is as amino defined amino substituting group.The example of aminocarboxyl oxygen base includes but not limited to-OC (=O) NH 2,-OC (=O) NHMe ,-OC (=O) NMe 2With-OC (=O) NEt 2
Urea groups :-N (R 1) CONR 2R 3, R wherein 2And R 3Independent is as amino defined amino substituting group, R 1Be the urea groups substituting group, for example hydrogen, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred hydrogen or C 1-7Alkyl.The example of urea groups includes but not limited to-NHCONH 2,-NHCONHMe ,-NHCONHEt ,-NHCONMe 2,-NHCONEt 2,-NMeCONH 2,-NMeCONHMe ,-NMeCONHEt ,-NMeCONMe 2With-NMeCONEt 2
Guanidine radicals :-NH-C (=NH) NH 2
Tetrazyl: have five yuan of aromatic rings of 4 nitrogen-atoms and 1 carbon atom,
Figure S2006800157162D00111
Imino-:=NR, wherein R is the imino-substituting group, for example hydrogen, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred H or C 1-7Alkyl.The example of imino-includes but not limited to=NH ,=NMe and=Net.
Amidine (amidino groups) :-C (=NR) NR 2, wherein each R is the amidine substituting group, for example hydrogen, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred H or C 1-7Alkyl.The example of amidine includes but not limited to-C (=NH) NH 2,-C (=NH) NMe 2With-C (=NMe) NMe 2
Nitro :-NO 2
Nitroso-group :-NO.
Azido-:-N 3
Cyano group (nitrile) :-CN.
Isocyano-:-NC.
Cyanato-:-OCN.
Different cyanato-:-NCO.
Thiocyano (thiocyanogen) :-SCN.
Isocyanide sulfenyl (isothiocyano) :-NCS.
Sulfhedryl (mercaptan, sulfydryl) :-SH.
Thioether (sulfide) :-SR, wherein R is thioether substituting group, for example C 1-7Alkyl (is also referred to as C 1-7Alkylthio), C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.C 1-7The example of alkylthio includes but not limited to-SCH 3With-SCH 2CH 3
Disulphide :-SS-R, wherein R is disulphide substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl (is also referred to as C herein 1-7Alkyl disulfide).C 1-7The example of alkyl disulfide includes but not limited to-SSCH 3With-SSCH 2CH 3
(=O) R, wherein R is sulfonium compound substituting group, for example C to sulfonium compound (sulfinyl, sulfoxide) :-S 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of sulfonium compound includes but not limited to-S (=O) CH 3With-S (=O) CH 2CH 3
Sulfone (alkylsulfonyl) :-S (=O) 2R, wherein R is sulfone substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl comprises for example fluorizated or fluoridized C 1-7Alkyl.The example of sulfone includes but not limited to-S (=O) 2CH 3(methylsulfonyl) ,-S (=O) 2CF 3(trifyl) ,-S (=O) 2CH 2CH 3(esyl) ,-S (=O) 2C 4F 9(nonaflyl) ,-S (=O) 2CH 2CF 3(trifluoro ethylsulfonyl (tresyl)) ,-S (=O) 2CH 2CH 2NH 2(tauryl (tauryl)) ,-S (=O) 2Ph (benzenesulfonyl, besyl), 4-Methyl benzenesulfonyl base (tosyl group), 4-chlorobenzene alkylsulfonyl (to the chlorobenzene alkylsulfonyl), 4-bromobenzenesulfonyl (p-bromobenzenesulfonyl), 4-nitrophenyl (p-nitrophenyl alkylsulfonyl), 2-naphthene sulfonic acid base (napsyl) and 5-dimethylamino-naphthalene-1-base sulfonic group (dansyl).
-sulfinic acid (sulfino) :-S (=O) OH ,-SO 2H.
Sulfonic acid (sulfo group) :-S (=O) 2OH ,-SO 3H.
(=O) OR, wherein R is-sulfinic acid ester substituting group, for example C to-sulfinic acid ester :-S 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of-sulfinic acid ester includes but not limited to-S (=O) OCH 3(methoxyl group sulfinyl; The-sulfinic acid methyl esters) and-S (=O) OCH 2CH 3(oxyethyl group sulfinyl; The-sulfinic acid ethyl ester).
Sulphonate :-S (=O) 2OR, wherein R is sulphonate substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of sulphonate includes but not limited to-S (=O) 2OCH 3(methoxyl group alkylsulfonyl; Methylmesylate) and-S (=O) 2OCH 2CH 3(oxyethyl group alkylsulfonyl; The sulfonic acid ethyl ester).
(=O) R, wherein R is sulfino oxy substituents, for example C to sulfino oxygen base :-OS 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of sulfino oxygen base includes but not limited to-OS (=O) CH 3With-OS (=O) CH 2CH 3
Alkylsulfonyl oxygen base :-OS (=O) 2R, wherein R is alkylsulfonyl oxy substituents, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of alkylsulfonyl oxygen base includes but not limited to-OS (=O) 2CH 3(methanesulfonates) and-OS (=O) 2CH 2CH 3(esilate).
Sulfuric ester :-OS (=O) 2OR; Wherein R is sulfuric ester substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of sulfuric ester includes but not limited to-OS (=O) 2OCH 3With-SO (=O) 2OCH 2CH 3
Sulfamyl (-sulfinic acid acid amides) :-S (=O) NR 1R 2, R wherein 1And R 2Independent is as amino defined amino substituting group.The example of sulfamyl includes but not limited to-S (=O) NH 2,-S (=O) NH (CH 3) ,-S (=O) N (CH 3) 2,-S (=O) NH (CH 2CH 3) ,-S (=O) N (CH 2CH 3) 2With-S (=O) NHPh.
Sulfonamido (sulfonic acid amides; Sulphonamide) :-S (=O) 2NR 1R 2, R wherein 1And R 2Independent is as amino defined amino substituting group.The example of sulfonamido includes but not limited to-S (=O) 2NH 2,-S (=O) 2NH (CH 3) ,-S (=O) 2N (CH 3) 2,-S (=O) 2NH (CH 2CH 3) ,-S (=O) 2N (CH 2CH 3) 2With-S (=O) 2NHPh.
Sulfoamino-:-NR 1S (=O) 2OH, wherein R 1For as amino defined amino substituting group.The example of sulfoamino-includes but not limited to-NHS (=O) 2OH and-N (CH 3) S (=O) 2OH.
Sulfonamido (Sulfonamino) :-NR 1S (=O) 2R, wherein R 1For as amino defined amino substituting group, R is sulfonamido substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of sulfonamido includes but not limited to-NHS (=O) 2CH 3With-N (CH 3) S (=O) 2C 6H 5
Sulfonamido (Sulfinamino) :-NR 1S (=O) R, wherein R 1For as amino defined amino substituting group, R is sulfonamido substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The example of sulfonamido includes but not limited to-NHS (=O) CH 3With-N (CH 3) S (=O) C 6H 5
Phosphino-(phosphine) :-PR 2, wherein R is the phosphino-substituting group, for example-and H, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred-H, C 1-7Alkyl or C 5-20Aryl.The example of phosphino-includes but not limited to-PH 2,-P (CH 3) 2,-P (CH 2CH 3) 2,-P (t-Bu) 2With-P (Ph) 2.
Phospho :-P (=O) 2
Phosphinyl (phosphine oxide) :-P (=O) R 2, wherein R is phosphinyl substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl or C 5-20Aryl.The example of phosphinyl includes but not limited to-P (=O) (CH 3) 2,-P (=O) (CH 2CH 3) 2,-P (=O) (t-Bu) 2With-P (=O) (Ph) 2
Phosphonic acids (phosphono) :-P (=O) (OH) 2
Phosphonic acid ester :-P (=O) (OR) 2, wherein R is the phosphonate substituted base, for example-and H, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred-H, C 1-7Alkyl or C 5-20Aryl.The example of phosphonic acid ester includes but not limited to-P (=O) (OCH 3) 2,-P (=O) (OCH 2CH 3) 2,-P (=O) (uncle O--Bu) 2With-P (=O) (OPh) 2
Phosphoric acid (phosphono oxygen base) :-OP (=O) (OH) 2
Phosphoric acid ester :-OP (=O) (OR) 2, wherein R is the phosphoric acid ester substituting group, for example-and H, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred-H, C 1-7Alkyl or C 5-20Aryl.The example of phosphoric acid ester includes but not limited to-OP (=O) (OCH 3) 2,-OP (=O) (OCH 2CH 3) 2,-OP (=O) (uncle O--Bu) 2With-OP (=O) (OPh) 2
Phosphorous acid :-OP (OH) 2
Phosphorous acid ester :-OP (OR) 2, wherein R is the phosphorous acid ester substituting group, for example-and H, C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred-H, C 1-7Alkyl or C 5-20Aryl.The example of phosphorous acid ester includes but not limited to-OP (OCH 3) 2,-OP (OCH 2CH 3) 2,-OP (uncle O--Bu) 2With-OP (OPh) 2
Amino phosphorous acid ester (phosphoramidite) :-OP (OR 1)-NR 2 2, R wherein 1And R 2Be amino phosphorous acid ester substituting group, for example-H, (optional replacement) C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred-H, C 1-7Alkyl or C 5-20Aryl.The example of amino phosphorous acid ester includes but not limited to-OP (OCH 2CH 3)-N (CH 3) 2,-OP (OCH 2CH 3)-N (i-Pr) 2With-OP (OCH 2CH 2CN)-N (i-Pr) 2
Phosphoramidate :-OP (=O) (OR 1)-NR 2 2, R wherein 1And R 2Be the phosphoramidate substituting group, for example-H, (optional replacement) C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred-H, C 1-7Alkyl or C 5-20Aryl.The example of phosphoramidate includes but not limited to-OP (=O) (OCH 2CH 3)-N (CH 3) 2,-OP (=O) (OCH 2CH 3)-N (i-Pr) 2With-OP (=O) (OCH 2CH 2CN)-N (i-Pr) 2
Dioxy base alkylidene group :-O-(CH 2) n-O-, n=1-3 wherein, this group combines with adjacent atom.The example of dioxy base alkylidene group includes but not limited to-O-CH 2-O-.
Alkylidene group
C 3-12Alkylidene group: term " C used herein 3-12Alkylidene group " be meant on any one carbon atom of two identical carbon atoms of hydrocarbon compound with 3-12 carbon atom (unless otherwise indicated) or two different carbon atoms and remove the bidentate group that obtains behind two hydrogen atoms; it can be an aliphatics or alicyclic, and it can be saturated, part is undersaturated or undersaturated fully.So term " alkylidene group " comprises subclass: alkylene group, alkynylene, cycloalkylidene etc., discuss below.
Linear saturated C 3-12The example of alkylidene group includes but not limited to-(CH 2) n-, wherein n is the integer of 3-12, for example-and CH 2CH 2CH 2-(propylidene) ,-CH 2CH 2CH 2CH 2-(butylidene) ,-CH 2CH 2CH 2CH 2CH 2-(pentylidene) and-CH 2CH 2CH 2CH 2CH 2CH 2CH 2-(inferior heptyl).
The C that side chain is saturated 3-12Alkylidene group includes but not limited to-CH (CH 3) CH 2-,-CH (CH 3) CH 2CH 2-,-CH (CH 3) CH 2CH 2CH 2-,-CH 2CH (CH 3) CH 2-,-CH 2CH (CH 3) CH 2CH 2-,-CH (CH 2CH 3)-,-CH (CH 2CH 3) CH 2-and-CH 2CH (CH 2CH 3) CH 2-.
The undersaturated C of linear portion 3-12Alkylidene group (C 3-12Alkylene group and alkynylene) include but not limited to-CH=CH-CH 2-,-CH 2-CH=CH 2-,-CH=CH-CH 2-CH 2-,-CH=CH-CH 2-CH 2-CH 2-,-CH=CH-CH=CH-,-CH=CH-CH=CH-CH 2-,-CH=CH-CH=CH-CH 2-CH 2-,-CH=CH-CH 2-CH=CH-,-CH=CH-CH 2-CH 2-CH=CH-and-CH 2-C ≡ C-CH 2-.
Prop up the undersaturated C of chain portion 3-12Alkylidene group (C 3-12Alkylene group and alkynylene) include but not limited to-C (CH 3)=CH-,-C (CH 3)=CH-CH 2-,-CH=CH-CH (CH 3)-and-C ≡ C-CH (CH 3)-.
Alicyclic saturated C 3-12Alkylidene group (C 3-12Cycloalkylidene) includes but not limited to cyclopentylidene (for example, ring penta-1,3-subunit) and cyclohexylidene (for example, hexamethylene-1,4-subunit).
The undersaturated C of alicyclic part 3-12Alkylidene group (C 3-12Cycloalkylidene) includes but not limited to cyclopentenylidene (for example 4-cyclopentenes-1,3-subunit), phenylidene (2-tetrahydrobenzene-1 for example, 4-subunit; 3-tetrahydrobenzene-1, the 2-subunit; 2,5-cyclohexadiene-1,4-subunit).
Pharmaceutically acceptable positively charged ion
The example of pharmaceutically acceptable unit price and divalent cation is at J.Pharm.Sci. such as Berge, and 66,1-19 has discussion in (1977), and it is hereby incorporated by.
Pharmaceutically acceptable positively charged ion can be inorganic or organic ion.
The example of pharmaceutically acceptable unit price inorganic cation includes but not limited to alkalimetal ion, for example Na +And K +The example of pharmaceutically acceptable divalence inorganic cation includes but not limited to alkaline earth metal cation, for example Ca 2+And Mg 2+Pharmaceutically acceptable organic cation includes but not limited to that ammonium ion (is NH 4 +) and the ammonium ion that replaces (NH for example 3R +, NH 2R 2 +, NHR 3 +, NR 4 +).The ammonium ion of the replacement that some is suitable is those derived from following ammonium ion: ethylamine, diethylamide, dicyclohexylamine, triethylamine, butylamine, quadrol, thanomin, diethanolamine, piperazine, benzyl amine, phenylbenzyl amine, choline, meglumine and Trometamol, also comprise amino acid, for example Methionin and arginine.The example of ammonium ion commonly used is N (CH 3) 4 +
Proliferative disease
Those of ordinary skills can determine more easily whether candidate compound can treat the proliferative disease of any particular cell types.For example, described among the embodiment below and gone for estimating the active analytical procedure of specific compound.
Term " proliferative disease " is meant excessive cell or paracytic cell proliferation unwanted or out of control, and no matter it all is unwanted still in vivo external, for example tumorigenesis growth or hyperplasia growth.
The example of proliferative disease includes but not limited to optimum, before cancerating, the malignant cell hyperplasia, include but not limited to: vegetation and tumour are (for example, histiocytoma, neurospongioma, astrocytoma, osteoma), cancer (for example, lung cancer, small cell lung cancer, gastrointestinal cancer, intestinal cancer, colorectal carcinoma, mammary cancer, ovarian cancer, prostate cancer, carcinoma of testis, liver cancer, kidney, bladder cancer, carcinoma of the pancreas, the cancer of the brain, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemia, psoriatic, osteopathy, fibroproliferative disease (for example fibroproliferative disease of reticular tissue) and arteriosclerosis.
The cell of any kind all can be treated, and includes but not limited to lung, stomach and intestine (comprising, for example intestines, colon), mammary gland (breast), ovary, prostate gland, liver, kidney, bladder, pancreas, brain and skin.
Methods of treatment
As mentioned above, the invention provides the purposes of formula I compound in methods of treatment.Methods of treatment also is provided, has comprised the formula I compound of the patient treatment significant quantity that needs treatment, the form of preferred pharmaceutical compositions.Term " treatment significant quantity " is for being enough to the patient is produced the amount of beneficial effect.This type of beneficial effect is for improving at least a symptom at least.The actual amount of administration and the frequency of administration and time cycle are depended on the character and the severity of disease to be treated.Common medical practitioner and other doctor have a responsibility for drafting treatment prescription (for example dosage)
Compound can be individually dosed or with other treatment combined utilization, administration simultaneously or sequential administration depend on disease to be treated.The example of treatment includes but not limited to chemotherapy (give activeconstituents, comprise for example medicine), surgical operation and radiotherapy.
Except activeconstituents is formula I compound, pharmaceutical composition of the present invention and can comprise pharmaceutically acceptable vehicle, carrier, buffer reagent, stablizer or other material well-known to those skilled in the art according to application of the present invention.This type of material should be effect nontoxic and can the interferon activity composition.The definite performance of carrier or other material depends on route of administration, can be oral administration, perhaps by drug administration by injection, for example skin, subcutaneous or intravenous administration.
Being used for pharmaceutical composition for oral administration can be tablet, capsule, powder or liquid form.Tablet can contain solid carrier or auxiliary material.Composition of liquid medicine contains liquid vehicle usually, for example water, oil, animal or plant oil, mineral oil or synthetic oil.Can comprise normal saline solution, glucose or other saccharide solution or glycols, as ethylene glycol, propylene glycol or polyoxyethylene glycol.Capsule can contain solid carrier, for example gelatin.
For intravenously, skin or subcutaneous injection or in the injection at ailing position, activeconstituents can be the form of the acceptable aqueous solution of parenteral admin, pyrogen-free has suitable pH, osmotic pressure and stability.This area person skilled can adopt for example wait ooze carrier such as sodium chloride for injection, ringer's inj, lactated ringer's inj prepares suitable solution.If desired, can add sanitas, stablizer, buffer reagent, oxidation inhibitor and/or other additive.
Other form that comprises
Unless otherwise indicated, also comprise these substituent known ions, salt, solvate and protection form above.For example, mention that carboxylic acid (COOH) also comprises its negatively charged ion (carboxylate radical) form (COO-), salt or solvate forms and conventional protection form.Equally, mention the amino protonated form (N that also comprises amino group +HR 1R 2), salt or solvate forms, for example hydrochloride, and amino conventional protected form.Equally, mention that hydroxyl also comprises its anionic form (O -), salt or solvate forms, and conventional protected form.
Particularly, mention group (SO zM) also comprise its anionic form (SO z -) or solvate forms and conventional protected form.
Isomer and solvate
Some compound may exist that one or more special how much, optics, enantiomerism, non-mapping are different, epimerization, resistance change isomery, stereoisomerism, tautomerism, conformation or end group isomeric form, include but not limited to, and cis-and trans; E-and Z-type; C-, t-and r-type; In-and outer-type; R-, S-and meso-form; D-and l-configuration; (+) and (-) configuration; Ketone-form, enol-and enolate-form; Suitable-and anti--configuration; To tiltedly-and by tiltedly-configuration; α-and beta configuration; Axial and calm form; Boat form, chair form, encapsulated type and half-chair; And combination, be collectively referred to as " isomer " (or isomeric forms) hereinafter.
In certain embodiments, The compounds of this invention has following three-dimensional chemical configuration in the C11 position:
Figure S2006800157162D00181
Attention: except the following tautomeric form of discussing, especially should get rid of structure in the term used herein " isomer " (or formation) isomer (that is, the connection between the atom is different and be not only to be the different isomer in the position of atom in the space).For example mention methoxyl group-OCH 3Do not comprise its constitutional isomer methylol-CH 2OH.Equally, mention that neighbour-chloro-phenyl-does not comprise between its constitutional isomer-chloro-phenyl-.Yet, should comprise constitutional isomer form (for example, the C in this class formation when mentioning a class formation 1-7Alkyl comprises n-propyl group and different-propyl group; Butyl comprise n-, different-, secondary-and tert-butyl; P-methoxy-phenyl comprise the neighbour-,-and right-p-methoxy-phenyl).
Above-mentioned eliminating is not meant tautomeric form, for example, the ketone type-, enol-and enolate-form, for example, following tautomerism is right: ketone type/enol (the following describes), imines/enamine, acid amides/imino-alcohol, amidine/amidine, nitroso-group/oxime, thioketones/alkene mercaptan, N-nitroso-group/hydroxyl azo-group and nitro/acid-nitro.
Figure S2006800157162D00182
Ketone type enol enolate
Attention: in term " isomer ", comprise especially for having the substituent compound of one or more isotropic substances.For example, H can be any isotropic substance form, comprises 1H, 2H (D) and 3H (T); C can be any isotropic substance form, comprises 12C, 13C and 14C; O can be any isotropic substance form, comprises 16O and 18O or the like.
Unless stated otherwise, this type of all isomeric forms be should comprise when mentioning specific compound, (wholly or in part) racemoid and other mixture thereof comprised.Preparation method of this type of isomeric forms (for example asymmetric synthesis) and separation method (for example fractional crystallization and chromatographic process) are well known in the art, or by adopting this paper method or currently known methods to be easy to obtain.
The corresponding solvent thing of preparation, purifying and/or processing active compound is convenient and needs.The conventional meaning of term used herein " solvate " is meant the mixture of solute (as the salt of active compound, active compound) and solvent.If solvent is a water, then solvate is meant hydrate, for example list-hydrate, two-hydrate, three-hydrate etc.
General synthetic route
Deep discussion has been carried out in synthesizing of PBD compound in WO00/12508, this discussion is hereby incorporated by.
According to the discussion in the patent application, the committed step in the PBD preferred routes is that cyclisation encircles to produce B-, is included in 11 and goes up generation aldehyde (or its suitable functional group), and attacked by Pro-N10-nitrogen in this position:
Figure S2006800157162D00191
Wherein substituting group as defined above, R 8Representative and other PBD partly be connected base (X-R "-X-), R 10Be nitrogen-protecting group group, R 12Be R 2Or its precursor." masked aldehyde "-CPQ can be acetal or thioacetal, and cyclisation comprises and sheltering in the case.Perhaps, it can be alcohol-CHOH, and in the case, reaction comprises oxidation, for example, and by TPAP, TEMPO or DMSO (Swern oxidation).
Masked aldehyde cpd can be corresponding 2 by making, and tetramethyleneimine that 4-replaces and 2-nitrobenzoic acid carry out condensation and obtain:
Figure S2006800157162D00201
Then, can be-NH with nitroreduction 2And by protecting with suitable reagent react (for example carbonochloridic acid ester), this reagent provides removable nitrogen-protecting group group in formula IV compound.
The method that comprises oxidation-cyclization process is described (cyclisation of another kind of type is described in the flow process 2 in the back) in flow process 1.
Flow process 1
Tetrapropyl ammonium perruthenate (TPAP)/N-methylmorpholine N-oxide compound (NMO) that alcohol (B) (wherein Pro-N10-nitrogen usually protected be carbamate) is exposed to by the A4 sieve thus the oxidizing reaction of generation and to be accompanied by spontaneous B-ring closed obtains the product IV that needs.Have been found that the TPAP/NMO oxidising process is specially adapted to reaction on a small scale, and adopt method for oxidation (particularly Swern oxidation) to prove that it (for example＞1g) is better than fairly large operation based on DMSO.Particularly preferred oxidising agent (diacetoxy iodine) benzene (1.1eq) and TEMPO (0.1eq) are dissolved in CH 2Cl 2In.
The alcohol of cyclisation (B) can not be prepared as follows: usually in solution; usually at alkali for example in the presence of the pyridine (preferred 2 equivalents); under moderate temperature (for example 0 ℃), make nitrogen protection reagent (preferred carbonochloridic acid ester or acyl chlorides) and the solution of amino alcohol C of formula D react.Under these conditions, almost do not have usually or do not observe the O-acylation reaction.
Crucial amino alcohol C can be prepared by the reduction of corresponding nitro-compound E, and selection can make the method that the molecule other parts are kept perfectly.In appropriate solvent (for example in the methyl alcohol of Hui Liuing), adopt tin chloride (II) to handle E, remove pink salt then, can obtain the product of needs usually with high yield.
E is exposed to hydrazine/Raney nickel avoids the generation of pink salt, and can access the C of higher yields, conflict although this method has with the scope of possible C and A-ring substituents.For example, if C-ring is that undersaturated (C ring itself is unsaturated, perhaps R 2Or R 3Unsaturated), then this technology is inapplicable.Another kind of suitable method of reducing is to adopt the palladium charcoal to make the catalytic hydrogenation of catalyzer.
At for example K 2CO 3Exist down, in-25 ℃, in nitrogen environment, carry out coupling by making suitable neighbour-nitrobenzoyl chloride and formula F compound, nitro-compound that can preparation formula E.Formula F compound can be for example easily be prepared by the olefination derived from the ketone of L-trans-hydroxy proline(Pro).The ketone intermediate also can be converted into the enol triflate, is used for palladium mediated coupled reaction.
Neighbour-nitrobenzoyl chloride can be synthetic from neighbour-nitrobenzoic acid (the perhaps alkyl ester after the hydrolysis) of formula G, and the latter self can vanillic acid (or alkyl ester) derivative H preparation.Manyly in them can derive from commerce, have some to be disclosed in Althuis, T.H. and Hess, H.J., J.Medicinal Chem., 20 (1), 146-266 (1977).
Another kind of selectable cyclization (flow process 2)
Figure S2006800157162D00221
Flow process 2
In flow process 1, final step or penultimate stride are the oxidative cyclization reactions.The method that has shown the coupling of a kind of selectable employing thioacetal in the flow process 2.The going to shelter of mercury mediation makes that cyclisation is protected PBD compound IV.
Thioacetal compound can prepare as shown in Scheme 2: adopt literature method, make the C-ring of thioacetal protection [prepare according to literature method: Langley, D.R.﹠amp; Thurston, D.E., J.Organic Chemistry, 52,91-97 (1987)] and (G) coupling of neighbour-nitrobenzoic acid (or the alkyl ester after the hydrolysis).Because the existence of thioacetal group, the nitro-compound that obtains can not reduce by hydrogenation, so, can adopt tin chloride (II) method to obtain amine.Then, by for example with the reaction of carbonochloridic acid ester or acyl chlorides (for example 2,2,2-three chloro ethyl chloride subtituted acid esters), carry out N-protected.
The C-that contains acetal encircles to comprise in other method de-protected reaction scheme of (comprise and adopt acidic conditions) at this type of and is used as quid pro quo.
Dimer synthesizes (flow process 3)
Figure S2006800157162D00231
Flow process 3
The PBD dimer can adopt and be used for the synthetic monomeric strategy of protected PBD and synthesize among the present invention.The synthetic route of describing in the flow process 3 has shown that wherein dimer connects basic formula-O-(CH that is 2) nThe compound of-O-, this connection base can easily be modified as other dimer and connect base.Generally include in the step that dimer forms and form two (nitroacid) G '.Then, this compound as above in surface current journey 1 or the flow process 2 compound G handle.
Described two (nitroacid) G ' can obtain by nitrated (for example adopting 70% nitric acid) two (carboxylic acid).This can be under alkaline condition synthesizes by the alkylated reaction that makes two normal corresponding phenylformic acid and suitable diiodo-alkane.Multiple phenylformic acid can derive from commerce, other can be synthetic by ordinary method.Perhaps, corresponding benzoic ether can carry out Mitsunobu etherificate, nitrated and then hydrolysis subsequently combine (no longer describing in detail) by adopting suitable alkane glycol.
The another kind of synthetic method of two (nitroacids) comprises the oxidation of two (nitroaldehydes), for example adopts the oxidation of potassium permanganate.This can be by adopting for example 70%HNO 3Direct nitrated acquisition to two (aldehyde).At last, two (aldehyde) can obtain by the Mitsunobu etherification reaction of two normal phenyl aldehydes and suitable alkane glycol.
But the another kind selection schemer of PBD
The method of the PBD of another kind of synthetic N10 protection is disclosed in WO2005/023814, is incorporated herein the document, and it has described the application of isocyanic ester intermediate.
The introducing of C2 aryl substituent: on C2, introduce leavings group
Figure S2006800157162D00241
By adopting suitable raw material, can be with the corresponding position of C2 aryl substituent drawing-in system IV compound, N10 can remove to protect the compound (face as follows) that needs to obtain in the case.Perhaps, can adopt following method, wherein R12 is a protected hydroxyl.Form the B-ring after the cyclisation, preferably C11-alcohol IV is protected once more by ordinary method then to obtain IIIb.For example, if R 11Be TBS, then described protection can be by making IV and TBSOTf and 2, and the 6-lutidine reacts and carries out.Remove the C2-blocking group from the IIIb cracking then and obtain C2 alcohol.For example, as C2 blocking group (R 14) when being acyl group, this protective reaction can be by adding K 2CO 3The aqueous solution carry out.
Protection once more on the described C11 position and C2 alcohol go protection to make selectively to react on the C2 alcohol, make that simultaneously the C11 position is unaffected.Then, C2-alcohol is oxidized to ketone IIIb.Preferred this oxidation is carried out under the Swern condition, obtains good yield.Yet, comprise that other method for oxidation of TPAP or Dess Martin reagent also can obtain described ketone with good yield.
R in the formula II compound " 12Can be-OSO 2CH 3,-OSO 2(C nF 2n+1), n=0,1 or 4 wherein perhaps can be-OSO 2R S, the conversion of IIIb can be finished by adopting suitable acid anhydrides to handle in the case.For example, if R " 12Be triflate, then this reaction adopts trifluoromethanesulfanhydride anhydride in DCM, carry out in the presence of pyridine.
R in the formula II compound " 12Also can be-I or-Br, in the case, the conversion of IIIb can be finished with the reaction of iodine or bromine respectively by adopting hydrazine.
R in the formula II compound " 12Also can be-Cl, then the conversion of IIIb can by with phosphoryl chloride (POCl for example 3) reaction and finish.
The introducing of C2 aryl substituent: the displacement of leavings group
Figure S2006800157162D00251
This formula II compound can react the PBD precursor molecule that has the pendent group (pendant group) of coupling on the C2 position of Ic to obtain under the multiple condition.
Especially preferably adopt the palladium catalyzed coupling, for example Suzuki, Stille and Heck coupling.This palladium catalyst can be any suitable catalyzer, for example Pd (PPh 3) 4, Pd (OCOCH 3) 2, PdCl 2, Pd (dba) 3The compound that carries out coupling can be any suitable reagent, for example, for the Heck coupling, adopts to have sp 2The alkene of H; For the Stille coupling, adopt organic stannane (organostannanes); For the Suzuki coupling, adopt organic boron derivative.
The present invention preferred aspect, coupling can be carried out under microwave condition.Usually, palladium catalyst, for example Pd (PPh 3) 4, for solid supported, for example on polystyrene, so that handle and the recycle of catalyzer.Unreacted boric acid can adopt PS-DEAM to separate after the triflate completely consumed, adopts the post (phase separator cartridge) that is separated to separate coupling product simultaneously.This method is can be in the identical time synthetic simultaneously more than a kind of (for example at the most 10,20 or 30 kind) compound.
Imine linkage in the formula Ic compound can go protection to obtain de-protected compounds ib (it can be that its carbinolamine form or methyl alcohol amidogen ether form, and this depends on used solvent) by standard method.For example, if R 10Be Alloc, then go protection to adopt palladium to carry out to remove N10 blocking group, subsequent dewatering.If R 10Be Troc, then go protection to adopt the Cd/Pb coupling reagent to carry out to obtain formula Ib compound.
Also can be with reference to synthetic discussion and the embodiment among WO2004/043963 and the WO 2005/085251, they all are hereby incorporated by.
Be converted into the sulfur-bearing form
Formula Ib compound can be by adding suitable hydrosulphite or-sulfinate and being undertaken by suitable purification step subsequently to the conversion of The compounds of this invention.Other method is described in GB2053894, is hereby incorporated by.
Other preferred embodiment
Preferred X is O.
Preferred R " represent the saturated C of linearity 3-12Alkylidene group more preferably has the alkylidene group of 3,5,7,8,9,10,11 or 12 carbon atoms.Wherein, preferred C 3And C 5Linear saturated alkylidene group.
R 9Be preferably H.
R 6Be preferably selected from H, OH, OR, SH, NH 2, nitro and halogen, more preferably H or halogen most preferably are H.
R 7Be preferably selected from H, OH, OR, SH, SR, NH 2, NHR, NRR ' and halogen, more preferably independently be selected from H, OH and OR, wherein R is preferably selected from the optional C that replaces 1-7Alkyl, C 3-10Heterocyclic radical and C 5-10Aryl.Particularly preferred substituting group is OMe and OCH on the 7-position 2Ph.
R 2Be preferably the optional C that replaces 5-7Aryl most preferably is the optional phenyl that replaces.
In certain embodiments, R 2Be C 9-12Aryl, for example naphthalene-1-base or naphthalene-2-base.C 9-12Other example of aryl comprises quinolyl, for example quinoline-2-base, quinoline-3-base and quinoline-6-base.
In another embodiment, R 2Be C 5-7Heteroaryl, for example furyl, thienyl and pyridyl.Wherein, preferred thienyl, for example thiophene-2-base and thiene-3-yl-.
C 5-20Aryl can carry any substituting group.Preferred its carries 1-3 substituting group, more preferably carries 1 and 2 substituting group, optimum menu substituted radical.
Preferred C 5-20The substituting group of aryl (particularly phenyl) comprises halogen (for example F, Cl, Br); C 1-7Alkoxyl group (for example methoxyl group, oxyethyl group); C 1-7Alkyl (for example methyl, trifluoromethyl, ethyl, propyl group, tert-butyl); Two-oxygen base-alkylidene group (for example two-oxygen base-methylene radical ,-O-CH 2-O-).The C of particularly preferred replacement 5-20Aryl includes but not limited to 4-methyl-phenyl, 4-methoxyl group-phenyl, 3-p-methoxy-phenyl, 4-fluoro-phenyl, 3,4-dioxy methylene-phenyl, 4-trifluoromethyl, 4-methylthio group phenyl (methylthiophenyl), 4-cyano-phenyl and 4-Phenoxyphenyl.
Particularly preferred unsubstituted C 5-20Aryl includes but not limited to thiophene-2-base, naphthalene-2-base, quinoline-3-base and quinoline-6-base.
If R is the optional C that replaces 1-12Alkyl is preferably the optional C that replaces 1-7Alkyl.
Preferred two PBD monomers all are substituted equally.
Preferred M and M ' are pharmaceutically acceptable univalent cation, and more preferably it is Na +
Z is preferably 3.
Preferred compound comprises:
Figure S2006800157162D00271
Figure S2006800157162D00281
Preferred compound comprises:
Figure S2006800157162D00291
Most preferred is:
Figure S2006800157162D00292
Above-mentioned preferred compound also can have C 5The alkylidene group connection chain.
Embodiment
Embodiment 1
(a) (2S, 4R)-N-(benzyl oxygen base carbonyl)-2-tert-butyl dimetylsilyl oxygen ylmethyl-4-hydroxyl pyrrolidine (1)
Figure S2006800157162D00301
According to four-step method as known in the art, begin from trans-4-hydroxyl-L-proline(Pro), with high yield obtain compound 1 (S.J.Gregson etc., J.Med.Chem., 2004,1161-1174).
(b) (2S, 4R)-N-(benzyl oxygen base carbonyl-2-literary composition-butyl dimetylsilyl oxygen ylmethyl-4-oxygen base acetyl-pyrrolidine (2)
Figure S2006800157162D00302
With pyridine (18.3g, 18.7mL, 232mmol, 1.1eq), diacetyl oxide (23.6g, 21.8mL, 232mmol, 1.1eq) and DMAP (5.14g, 42.1mmol, 0.2eq) add to stirring 1 (76.9g is in anhydrous THF (1L) solution 211mmol).After reaction mixture stirred 16 hours, thin-layer chromatography (95: 5v/v CHCl 3/ MeOH) show that raw material consumption is complete.Remove excessive solvent by rotary evaporation, residue be dissolved in EtOAc (1L), with 1N HCl (2 * 1L), H 2O (1L), salt solution (1L) washing, dry (MgSO 4).Filtration and evaporating solvent obtain the acetate 2 (80.7g, 94%) into colorless oil: 1H NMR (400MHz, CDCl 3) (rotational isomer) δ 7.36-7.12 (m, 5H), 5.30-5.10 (m, 3H), 4.09-3.97 (m, 2H), 3.74-3.55 (m, 3H), 2.36-2.29 (m, IH), 2.11-2.06 (m, 1H), 2.02 (s, 3H), 0.87 (s, 6H), 0.86 (s, 3H), 0.03 and 0.00 (s * 2,6H); MS (ES), m/z (relative intensity) 430 ([M+Na] +., 95), 408 ([M+H] +., 100).
(c) (2S, 4R)-2-tert-butyl dimetylsilyl oxygen ylmethyl-4-oxygen base acetyl-pyrrolidine (3)
Figure S2006800157162D00311
With silyl ether 2 (1.95g, 4.80mmol) and the soup compound of 10%Pd/C (0.17g) in dehydrated alcohol (10mL) in 45Psi through Parr hydrogenation 16 hours, this moment thin-layer chromatography (95: 5v/vCHCl 3/ MeOH) show that raw material consumption is complete.With reaction mixture by diatomite filtration to remove Pd/C, filter bed ethanol repetitive scrubbing.Decompression is removed excessive solvent through rotary evaporation down, obtains the amine 3 (1.28g, 98%) into light orange wax shape oil: IR (CHCl 3) 3315,2930,2858,1739,1652,1472,1435,1375,1251,1088,838,779,667cm -1
(d) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(2S, 4R)-(5-methoxyl group-2-nitro-1,4-phenylene) carbonyl]] two [2-(tert-butyl dimetylsilyl oxygen ylmethyl)-4-oxygen base acetyl-pyrrolidine] (5)
Figure S2006800157162D00312
With the DMF (2) of catalytic amount add to nitro-acid 4 (8.12g, 17.4mmol) 1And oxalyl chloride (43.5mmol is in anhydrous THF (250mL) stirred solution 2.5eq) for 3.80mL, 5.52g.Initial throw out dissolves gradually, and reaction mixture was stirred under room temperature 16 hours.In nitrogen environment, in 0 ℃ (ice/acetone) with the solution of acid chloride that obtains drop to stirring amine 3 (11.9g, 43.5mmol, 2.5eq), TEA (9.71mL, 7.05g, 69.7mmol, 4.0eq) and H 2In THF (100mL) solution of O (2.26mL).Reaction mixture is warmed to room temperature, restir 2.5 hours.Remove excessive THF by rotary evaporation, with the residue that obtains at H 2Distribute between O (400mL) and the EtOAc (400mL).Separate each layer, (3 * 200mL) extract water layer with EtOAc.Then with the organic layer that merges with saturated NH 4Cl (200mL), saturated NaHCO 3(200mL), salt solution (200mL) washs dry (MgSO 4).Filtration and evaporating solvent obtain the crude product product into dark oily matter.Through purification by flash chromatography (99.7: 0.3v/v CHCl 3/ MeOH) separation obtains pure acid amides 5, be light yellow glass thing (13.3g, 78%): 1H NMR (400MHz, CDCl 3) δ 7.60 (s, 2H), 6.60 (s, 2H), 5.06 (br s, 2H), 4.44 (br s, 2H), 4.25-4.20 (m, 4H), 4.10-4.08 (m, 2H), 3.80 (s, 6H), 3.64-3.62 (m, 2H), and 3.36-3.32 (m, 2H), 3.11-3.08 (m, 2H), 2.36-2.26 (m, 4H), 2.13-2.08 (m, 2H), 1.92 (s, 6H), 0.80 (s, 18H), 0.00 (s * 2,12H); 13C NMR (100.6MHz, CDCl 3) δ 171.0,166.3,154.5,148.2,137.4,128.0,127.2,109.2,108.5,72.9,65.6,62.6,57.4,56.5,54.8,33.0,28.6,25.8,21.0,18.1; MS (ES), m/z (relative intensity) 1000 ([M+Na] +., 39), 978 ([M+H] +., 63), 977 (M +., 100), 812 (13).
(e) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(2S, 4R)-(5-methoxyl group-2-amino-1,4-phenylene) carbonyl]] two [2-(tert-butyl dimetylsilyl oxygen ylmethyl)-4-oxygen base acetyl-pyrrolidine] (6)
Figure S2006800157162D00321
(16.59g, 95.27mmol 5eq) add to acid amides 5 (18.6g, H 19.1mmol) with V-Brite B 2In the stirred solution of O (200mL) and THF (400mL).After 36 hours, rotary evaporation is removed excessive THF with the reaction mixture stirring, with residue EtOAc (3 * 250mL) extractions that obtain.Then with the organic layer H that merges 2O (300mL), salt solution (300mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, it obtained product 6 through purification by flash chromatography (80: 20v/v hexane/EtOAc, gradient is to pure EtOAc then), be yellow foam thing (9.53g, 55%): 1H NMR (400MHz, CDCl 3) (rotational isomer) δ 6.70 and 6.67 (s * 2,2H), 6.25 and 6.23 (s * 2,2H), 5.20 (br s, 2H), 4.49 (br s, 4H), 4.16-4.05 (m, 6H), 3.70 (s, 6H), 3.68-3.57 (m, 4H), 2.36-2.27 (m, 4H), 2.12-2.04 (m, 2H), 1.96 (s, 6H), 0.85 (s, 18H), 0.01 and 0.00 (s * 2,12H); 13C NMR (100.6MHz, CDCl 3) δ 170.6,170.0,141.1,116.3,113.1,102.3,102.1,102.0,66.2,65.3,65.2,57.0,28.9,18.2; MS (ES), m/z (relative intensity) 946 (M +.+29,43), 933 ([M+16] +., 61), 932 ([M+15] +., 100), 918 ([M+H] +., 72).
(f) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(2S; 4R)-[5-methoxyl group-1; 4-phenylene-2-(2,2,2-three chloro ethoxy carbonyl amino)] carbonyl]] two [2-(tert-butyl dimetylsilyl oxygen ylmethyl)-4-oxygen base acetyl-pyrrolidine] (7)
Figure S2006800157162D00331
In-10 ℃ (liquid nitrogen/ethylene glycol), with 2,2,2-three chloro ethyl chloride subtituted acid ester (3.58mL, 5.50g, 26.0mmol, 2.2eq) anhydrous DCM (60mL) drop to anhydrous pyridine (3.82mL, 3.80g, 47.2mmol, 4.0eq) and p-diaminodiphenyl (bis-aniline) 6 (10.8g is in anhydrous DCM (150mL) solution 11.8mmol).In under the room temperature after 16, with reaction mixture with saturated NH 4Cl (2 * 150mL), saturated CuSO 4(150mL), H 2O (150mL), salt solution (150mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains yellow heavy-gravity oily matter, with its through purification by flash chromatography (70: 30v/v hexane/EtOAc), obtain 7 (13.8g, 92%) into white glass shape thing: 1H NMR (400MHz, CDCl 3) δ 9.42 (br s, 1H), 7.83 (s, 2H), 6.76 and 6.74 (s * 2,2H), 5.21 (br s, 2H), 4.79 and 4.73 (dx 2,4H, J=12.0Hz), 4.56 (br s, 2H), and 4.26-4.23 (m, 4H), 4.09-4.04 (m, 2H), 3.74 (s, 6H), 3.72-3.68 (m, 2H), 3.60 (br s, 4H), 2.40-2.32 (m, 4H), 2.23-2.08 (m, 2H), 1.95 (s, 6H), 0.85 (s, 18H), 0.01 and 0.00 (s * 2,12H); 13C NMR (100.6MHz, CDCl 3) δ 170.4,169.2,151.9,151.5,150.8,143.4,132.6,114.4,111.7,95.3,74.4,65.5,65.4,57.3,56.4,32.5,28.8,25.8,21.1,18.1,14.9; MS (ES), m/z (relative intensity) 1306 ([M+38] +., 92), 1304 ([M+36] +., 100), 1282 ([M+14] +., 97), 1280 ([M+12] +., 55).
(g) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(2S, 4R)-[5-methoxyl group-1,4-phenylene-2-(2,2,2-three chloro ethoxy carbonyl amino)] carbonyl]] two (2-hydroxymethyl-4-oxygen base acetyl-pyrrolidine) (8)
Figure S2006800157162D00332
With glacial acetic acid (310mL) and H 2The mixture of O (100mL) drops to 7, and (13.8g in THF 10.9mmol) (250mL) solution, stirred 16 hours under room temperature.Reaction mixture is diluted with DCM (750mL), with saturated NaHCO 3(5L) neutralization.(3 * 500mL) extractions merge organic layer to water layer, wash with salt solution (1L), dry (MgSO with DCM 4).Thin-layer chromatography (60: 40v/v hexane/EtOAc) demonstration raw material completely dissolve.Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.7: 0.3v/v CHCl 3/ MeOH gradient to 96: 4v/vCHCl 3/ MeOH), obtain product 8 (11.6g,＞100%) into white glass shape thing: 1HNMR (500 MHz, CDCl 3) δ 8.92 (br s, 2H), 7.55 (s, 1H), 6.71 (s, 1H), 5.18 (br s, 2H), 4.78 (d, 2H, J=12.0Hz), 4.72 (d, 2H, J=12.0 z), 4.50 (br s, 2H), 4.22-4.19 (m, 4H), 4.00 (br s, 2H), 3.78 (s, 6H), 3.76-3.52 (m, 6H)), 2.32-2.30 (m, 2H), 2.21-2.17 (m, 2H), 2.09-2.04 (m, and 2H) 1.94 (s, 6H); 13CNMR (125.8 MHz, CDCl 3) δ 170.4,152.2,149.8,145.0,111.3,106.5,95.6,74.4,72.5,65.4,64.1,58.7,56.5,56.3,33.6,29.l, 21.1.
(h) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS, 2R)-10-(2; 2,2-three chloro ethoxy carbonyls)-11-hydroxyl-7-methoxyl group-2-oxygen base ethanoyl-1,2,3,10; 11,11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (9)
Figure S2006800157162D00341
With TEMPO (0.69g, 4.42mmol, 0.4eq) and BAIB ((11.5g is in the solution of the stirring of DCM 11.1mmol) (150mL) 4.4eq) to add to glycol 8 for 15.7g, 48.7mmol.Reaction mixture was stirred 2 hours, with DCM (400mL) dilution, with saturated NaHSO 3(500mL), saturated NaHCO 3(500mL), salt solution (200mL) washs dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.9: 0.1v/vCHCl 3/ MeOH, gradient to 99.7 then: 0.3v/v CHCl 3/ MeOH) obtain product 9, be light yellow glassy mass (4.43g, 39%): 1H NMR (400MHz, CDCl 3) δ 7.28 (s, 2H, H6), 6.84 (s, 2H, H9), 5.68 (d, 2H, J=9.1Hz, H11), 5.37-5.35 (m, 2H, H2), 5.18 (d, 2H, J=12.0Hz, Troc CH 2), 4.32-4.21 (m, 6H, OCH 2CH 2CH 2O, Troc CH 2), 4.03 (dd, 2H, J=13.2,2.6Hz, H3), 3.92 (s, 6H, OCH 3* 2), 3.39-3.69 (m, 4H, H3 and H11a), 2.39-2.35 (m, 6H, OCH 2CH 2CH 2O and H1), 2.03 (s, 6H, CH 3CO 2* 2); 13C NMR (100.6MHz, CDCl 3) δ 170.4 (CH 3CO 2), 167.4 (C Quat), 154.3 (C Quat), 150.5 (C Quat), 149.1 (C Quat), 127.4 (C Quat), 124.9 (C Quat), 114.1 (C9), 110.9 (C6), 95.0 (Troc CCl 3), 87.5 (C11), 75.0 (Troc CH 2), 71.4 (C2), 65.5 (OCH 2CH 2CH 2O), 58.4 (C11a), 56.1 (OCH 3), 51.1 (C3), 35.8 (C1), 29.1 (OCH 2CH 2CH 2O), 21.0 (CH 3CO 2); MS (ES), m/z (relative intensity) 1058 ([M+Na] +., 100).
(i) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S; 11aS, 2R)-10-(2,2; 2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-oxygen base ethanoyl-1; 2,3,10; 11; 11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (10)
Figure S2006800157162D00351
With TBSOTf (2.70mL, 3.10g, 11.7mmol, (4.05g, 3.91mmol) and 2, (15.6mmol is in the solution of the stirring of DCM 4.0eq) (50mL) for 1.82mL, 1.68g for the 6-lutidine 3.0eq) to add to di-alcohol 9.Reaction mixture was stirred 2.5 hours, with DCM (150mL) dilution, with saturated CuSO 4(2 * 100mL), saturated NaHCO 3(100mL), salt solution (200mL) washs dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.9: 0.1v/v CHCl 3/ MeOH), obtain product 10 (5.05g,＞100%) into white glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.05 (s, 2H, H6), 6.52 (s, 2H, H9), 5.53 (d, 2H, J=9.0Hz, H11), 5.14 (br s, 2H, H2), 4.99 (d, 2H, J=12.0Hz, Troc CH 2), 4.06-3.87 (m, 8H, OCH 2CH 2CH 2O, Troc CH 2And H11a), 3.71 (s, 6H, OCH 3* 2), and 3.48-3.43 (m, 4H, H3), 2.21-2.11 (m, 4H, OCH 2CH 2CH 2O and H1), and 2.03-1.96 (m, 2H, H1), 1.81 (s, 6H, CH 3CO 2* 2), 0.63 (s, 18H, TBS CH 3* 6), 0.00 (s * 2,12H, TBS CH 3* 4); 13C NMR (100.6MHz, CDCl 3) δ 170.3 (CH 3CO 2), 167.9 (C Quat), 153.6 (C Quat), 150.4 (C Quat), 149.2 (C Quat), 127.9 (C Quat), 125.5 (C Quat), 113.9 (C9), 110.7 (C6), 95.2 (TrocCCl 3), 88.2 (C11), 74.7 (Troc CH 2), 71.7 (C2), 65.0 (OCH 2CH 2CH 2O), 60.5 (C11a), 56.1 (OCH 3), 51.2 (C3), 36.2 (C1), 28.8 (OCH 2CH 2CH 2O), 25.6 (TBS CH 3), 21.0 (CH 3CO 2), 17.8 (TBS C Quat), 14.2 and 14.1 (TBS CH 3); MS (ES), m/z (relative intensity) 1285 ([M+21] +., 100), 1265 ([M+H] +., 75).
(j) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS, 2R)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-hydroxyl-1,2,3,10,11,11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (11)
Figure S2006800157162D00361
With K 2CO 3(93mg, 0.67mmol, H 5.0eq) 2O (2mL) drips of solution adds to acetic ester 10, and (170mg is in the solution of the stirring of MeOH 0.13mmol) (3mL).Initial colourless solution finally becomes yellow, observes the formation white depositions.Reaction mixture was stirred 16 hours, at this moment thin-layer chromatography (95: 5v/v CHCl 3/ MeOH) show that raw material consumption is complete.Rotary evaporation is removed excessive solvent, and mixture is neutralized to pH7 carefully with 1N HCl.(3 * 25mL) extractions are then with organic layer salt solution (40mL) washing that merges, dry (MgSO with EtOAc with the mixture that obtains 4).Filter and remove to desolvate and obtain product 11 (151mg, 95%) into white glass shape thing: 1H NMR (400 MHz, CDCl 3) δ 6.94 (s, 2H, H6), 6.52 (s, 2H, H9), 5.53 (d, 2H, J=9.0Hz, H11), 5.00 (d, 2H, J=12.0Hz, Troc CH 2), 4.36-4.35 (m, 2H, H2), 4.06-3.82 (m, 8H, OCH 2CH 2CH 2O, Troc CH 2And H3), 3.61 (s, 6H, OCH 3* 2), and 3.54-3.48 (m, 2H, H11a), 3.39-3.34 (m, 2H, H3), 2.96 and 2.95 (br s * 2,2H, OH * 2), 2.21-2.20 (m, 2H, OCH 2CH 2CH 2O), and 2.19-2.08 (m, 2H, H1), 1.90-1.74 (m, 2H, H1), 0.64 (s, 18H, TBS CH 3* 6), 0.00 (s, 12H, TBS CH 3* 4); 13CNMR (100.6MHz, CDCl 3) δ 168.5 (C Quat), 153.6 (C Quat), 150.3 (C Quat), 149.1 (C Quat), 127.9 (C Quat), 125.4 (C Quat), 113.9 (C9), 110.7 (C6), 95.2 (TrocCCl 3), 88.3 (C11), 74.7 (Troc CH 2), 69.4 (C2), 65.0 (OCH 2CH 2CH 2O), 60.9 (C11a), 55.9 (OCH 3), 54.1 (C3), 38.8 (C1), 28.9 (OCH 2CH 2CH 2O), 25.6 (TBS CH 3), 17.8 (TBS C Quat); MS (ES), m/z (relative intensity) 1196 ([M+16] +., 100), 1181 ([M+H] +., 82).
(k) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-oxo-1,2,3,10,11,11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (12)
Figure S2006800157162D00371
In nitrogen environment, in-60 ℃ of (liquid nitrogen/CHCl 3), with anhydrous DMSO (0.82mL, 0.90g, 11.5mmol, anhydrous DCM (20mL) drips of solution 6.0eq) adds to oxalyl chloride, and (the DCM solution of 2.88mL 2M, 5.76mmol is in stirred solution 3.0eq).In-55 ℃ stir 1.5 hours after, with substrate 11 (2.26g, anhydrous DCM (30mL) drips of solution 1.92mmol) adds in the reaction mixture, then with it in-45 ℃ of restir 2 hours.With TEA (10.8mL, 7.82g; 71.7mmol anhydrous DCM (90mL) drips of solution 4.2eq) adds in the mixture restir 30 minutes.Reaction mixture is warmed to 0 ℃, with cold 1N HCl (2 * 50mL), H 2O (50mL), salt solution (50mL) washing, dry (MgSO 4).Filter and vacuum evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (70: 30v/v hexane/EtOAc, gradient to 40 then: 60v/v hexane/EtOAc), obtain carbinolamine 12 (1.62g, 72%) into white glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.02 (s, 2H, H6), 6.54 (s, 2H, H9), 5.59 (d, 2H, J=9.2Hz, H11), 4.98 (d, 2H, J=12.0Hz, Troc CH 2), 4.09-3.86 (m, 8H, OCH 2CH 2CH 2O, Troc CH 2And H3), 3.75-3.66 (m, 10H, OCH 3* 2, H11a, and H3), 2.72 (dd, 2H, J=10.2,19.6Hz, H1), 2.82 (dd, 2H, J=2.6,19.6Hz, H1), 2.22-2.19 (m, 2H, OCH 2CH 2CH 2O), 0.63 (s, 18H, TBS CH 3* 6), 0.00 (s * 2,12H, TBS CH 3* 4); 13C NMR (100.6MHz, CDCl 3) δ 207.7 (C2), 168.0 (C Quat), 153.7 (C Quat), 150.7 (C Quat), 149.4 (C Quat), 127.8 (C Quat), 124.6 (C Quat), 114.0 (C9), 110.6 (C6), 95.1 (TrocCCl 3), 87.4 (C11), 74.8 (Troc CH 2), 65.0 (OCH 2CH 2CH 2O), 58.9 (C11a), 56.1 (OCH 3), 53.0 (C3), 40.3 (C1), 28.8 (OCH 2CH 2CH 2O), 25.6 (TBS CH 3), 17.8 (TBS C Quat); MS (ES), m/z (relative intensity) 1224 ([M+48] +., 100), 1210 ([M+34] +., 60), 1199 ([M+Na] +., 35), 1192 ([M+16] +., 40), 1176 (M +., 18).
(l) 1; 1 '-[[(propane-1; 3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2; 2-three chloro ethoxy carbonyls)-and 11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-[[(trifluoromethyl) alkylsulfonyl] the oxygen base]-1; 10,11,11a-tetrahydrochysene-5H-pyrrolo-[2; 1-c] [1,4] benzodiazepine-5-ketone]] (13)
Figure S2006800157162D00381
Under room temperature, in the nitrogen environment, anhydrous trifluoromethanesulfanhydride anhydride (the 3.09mL that will in the ampoule of just having opened, take out, 5.19g, 18.4mmol, 22eq) the fast disposable ketone 12 that adds to vigorous stirring (0.98g, 0.84mmol) and anhydrous pyridine (1.49mL, 1.46g, 18.4mmol, in anhydrous DCM (50mL) solution 22eq).The initial throw out that forms dissolves gradually, and solution finally changes scarlet into.Reaction mixture was stirred 4.5 hours, and this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Pour mixture into cold saturated NaHCO 3(60mL), with DCM (3 * 80mL) extractions.Then with the organic layer that merges with saturated CuSO 4(2 * 125mL), salt solution (125mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc), obtain being light yellow glassy mass triflate 13 (0.74mg, 61%): [α] 25D=+46.0 ° of (c=0.33, CHCl 3); 1HNMR (400MHz, CDCl 3) δ 7.23 (s, 2H, H6), 7.19 (s, 2H, H3), 6.77 (s, 2H, H9), 5.94 (d, 2H, J=8.9Hz, H11), 5.23 (d, 2H, J=12.0Hz, Troc CH 2), 4.31-4.28 (m, 2H, OCH 2CH 2CH 2O), 4.18 (d, 2H, J=12.2Hz, Troc CH 2), 4.15-4.13 (m, 2H, OCH 2CH 2CH 2O), 3.95-3.91 (m, 8H, OCH 3* 2, H11a), 3.35 (dd, 2H, J=11.0,16.6Hz, H1), 2.84 (d, 2H, J=16.6Hz, H1), 2.46-2.44 (m, 2H, OCH 2CH 2CH 2O), 0.89 (s, 18H, TBS CH 3* 6), 0.29 and 0.26 (s * 2,12H, TBS CH 3* 4); 13C NMR (100.6MHz, CDCl 3) δ 164.9 (C Quat), 153.6 (C Quat), 151.0 (C Quat), 149.5 (C Quat), 136.0 (C Quat), 127.7 (C Quat), 123.9 (C Quat), 121.0 (C3), 114.0 (C9), 110.9 (C6), 95.1 (Troc CCl 3), 86.3 (C11), 74.8 (TrocCH 2), 65.0 (OCH 2CH 2CH 2O), 60.6 (C11a), 56.2 (OCH 3), 34.4 (C1), 28.8 (OCH 2CH 2CH 2O), 25.6 (TBS CH 3), 17.8 (TBS C Quat); IR (CHCl 3) 3020,2957,2860,1725,1674,1651,1604,1516,1466,1454,1431,1409,1329,1312,1274,1216,1138,1113,1083,1042,1006,900,840,757,668,646,610cm -1MS (ES), m/z (relative intensity) 1461 ([M+21] +., 100), 1440 (M +., 55).
(m) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(right-anisole)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (14)
Figure S2006800157162D00391
Under room temperature, with TEA (0.20mL, 148mg, 1.46mmol, H 6.0eq) 2O (1.5mL) and EtOH (10mL) solution add to triflate 13, and (350mg is in toluene 0.24mmol) (10mL) solution.In this mixture, add the 4-methoxyphenylboronic acid (96mg, 0.63mmol, 2.6eq) and Pd (PPh 3) 4(11mg, 9 μ mol, 0.04eq).Reaction mixture was stirred 15 minutes, and this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved in EtOAc (25mL), use H 2O (15mL), salt solution (15mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc, gradient to 50 then: 50v/v hexane/EtOAc), obtain 14 (286mg, 87%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.38 (s, 2H, H3), 7.32-7.28 (m, 6H, H6 and H13), 6.92 (d, 4H, J=8.7Hz, H14), 6.81 (s, 2H, H9), 5.93 (d, 2H, J=8.8Hz, H11), 5.24 (d, 2H, J=12.0Hz, Troc CH 2), 4.34-4.29 (m, 2H, OCH 2CH 2CH 2O), 4.20-4.11 (m, 4H, Troc CH 2And OCH 2CH 2CH 2O), 4.00-3.96 (m, 8H, H11a and OCH 3* 2), 3.84 (s, 6H, OCH 3* 2), 3.36 (dd, 2H, J=10.8,16.6Hz, H1), 2.85 (d, 2H, J=16.5Hz, H1), 2.48-2.45 (m, 2H, OCH 2CH 2CH 2O), 0.93 (s, 18H, TBS CH 3* 6), 0.30 and 0.27 (s * 2,12H, TBSCH 3* 4); 13C NMR (100.6MHz, CDCl 3) δ 162.5 (C Quat), 161.3 (C Quat), 159.2 (C Quat), 151.1 (C Quat), 148.1 (C Quat), 140.3 (C Quat), 126.2 (C13), 126.0 (C Quat), 123.2 (C Quat), 121.9 (C3), 119.3 (C Quat), 114.3 (C6), 111.9 (C14), 111.2 (C9), 95.2 (Troc CCl 3), 87.3 (C11), 74.8 (Troc CH 2), 65.0 (OCH 2CH 2CH 2O), 61.5 (C11a), 56.1 and 55.3 (OCH 3), 35.3 (C1), 28.8 (OCH 2CH 2CH 2O), 25.7 (TBSCH 3), 17.9 (TBS C Quat); MS (ES), m/z (relative intensity) 1357 (M +., 63), 1114 (48), 955 (59), 919 (78).
(n) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(right-anisole)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (ZC-207)
Figure S2006800157162D00401
With 10%Cd/Pd (461mg, 3.73mmol, 20eq) add to quick stirring 14 (253mg, 0.19mmol), THF (5mL) and 1N NH 4In the mixture of OAc (5mL).Reaction mixture was stirred 1.5 hours, and this moment, thin-layer chromatography showed that raw material consumption is complete.With solid filtering and use H 2O and DCM washing.(3 * 30mL), the merging organic extract liquid is used salt water washing (50mL) to water layer, dry (MgSO with extraction DCM 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.9: 0.1v/v CHCl 3/ MeOH, gradient to 95 then: 5v/v CHCl 3/ MeOH), obtain ZC-207 (132mg, 96%): [α] into yellow glass shape thing 20D=+880.0 ° of (c=0.22, CHCl 3); 1H NMR (400MHz, CDCl 3) δ 7.79 (d, 2H, J=3.9Hz, H11), 7.44 (s, 2H, H6), 7.30 (s, 2H, H3), 7.24 (d, 4H, J=8.7Hz, H13), 6.81 (d, 4H, J=8.7Hz, H14), 6.79 (s, 2H, H9), 4.30-4.18 (m, 6H, OCH 2CH 2CH 2O and H11a), 3.86 (s, 6H, OCH 3* 2), 3.74 (s, 6H, OCH 3* 2), 3.48 (dd, 2H, J=11.8,16.2Hz, H1), 2.85 (d, 2H, J=16.2Hz, H1), 2.38-2.32 (m, 2H, OCH 2CH 2CH 2O); 13CNMR (62.9MHz, CDCl 3) δ 162.5 (C11), 161.3 (C Quat), 159.2 (C Quat), 151.1 (C Quat), 148.1 (C Quat), 140.3 (C Quat), 126.2 (C13), 126.0 (C Quat), 123.2 (C Quat), 121.9 (C3), 114.3 (C14), 111.9 (C9), 111.2 (C6), 65.4 (OCH 2CH 2CH 2O), 56.2 and 55.3 (OCH 3), 53.8 (C11a), 35.6 (C1), 28.9 (OCH 2CH 2CH 2O); MS (ES), m/z (relative intensity) 741 (M +., 43), 660 (71).
(o) 1,1 ' [[(propane-1,5-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(4-p-methoxy-phenyl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (ZC-423)
Figure S2006800157162D00402
Water (1.5mL) solution of sodium bisulfite (6.74mg, 65 μ mol) is added in the stirred solution of methylene dichloride (1.5mL) of ZC-207 (24.01mg, 32 μ mol).With reaction mixture vigorous stirring 2 hours, separate organic layer and water layer then.(eluent-EtOAc) show that aqueous phase does not have ZC-207 to exist has the baseline material that strong uv absorbs but have to exist to thin layer chromatography analysis.The water layer freeze-drying is obtained sulphite adducts ZC-423 (17mg, 55%) into white solid: 1H NMR (400MHz, d 6-DMSO) δ 7.42 (s, 2H, H-3), 7.38 (d, 4H, J=8.72Hz, 2 '-H), 7.05 (s, 2H, H-6), 6.92 (d, 4H, J=8.92Hz, 3 '-H), 6.52 (s, 2H, H-9), 5.27 (s, 2H, NH), 4.35-4.25 (m, 2H, H11a), 4.15-4.05 (m, 4H, OCH 2CH 2CH 2O), 3.95 (d, 2H, J=10.4Hz, H11), 3.77 (s, 6H, OMe), 3.72 (s, 6H, OMe), 3.55-3.45 (m, 2H, H1), 3.30-3.15 (m, 2H, H1), 2.25-2.15 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 2
(a) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(naphthalene-2-yl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (17)
Figure S2006800157162D00411
Under room temperature, with TEA (0.15mL, 1.05mmol, H 6.0eq) 2O (1mL) and EtOH (10mL) solution add to 13, and (251mg is in toluene 0.17mmol) (6mL) solution.In this mixture, add the 2-naphthalene boronic acids (77.9mg, 0.45mmol, 2.6eq) and Pd (PPh 3) 4(8.0mg, 7 μ mol, 0.04eq).With reaction mixture in microwave irradiation in 100 ℃ of heating 20 minutes, this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved among the EtOAc (20mL), use H 2O (15mL), salt solution (15mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc, gradient to 50 then: 50v/v hexane/EtOAc), obtain 17 (191mg, 81%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.32-7.29 (m, 6H, H Arom), 7.61-7.58 (m, 6H, H Arom), 7.52-7.42 (m, 4H, H3 and H Arom), 7.30 (s, 2H, H6), 6.81 (s, 2H, H9), 5.98 (d, 2H, J=8.8Hz, H11), 5.24 (d, 2H, J=12.0Hz, Troc CH 2), 4.35-4.30 (m, 2H, OCH 2CH 2CH 2O), 4.20-4.13 (m, 4H, Troc CH 2And OCH 2CH 2CH 2O), and 4.08-4.00 (m, 2H, H11a), 3.97 (s, 6H, OCH 3* 2), 3.50 (dd, 2H, J=10.8,16.6Hz, H1), 2.98 (d, 2H, J=16.5Hz, H1), 2.50-2.48 (m, 2H, OCH 2CH 2CH 2O), 0.94 (s, 18H, TBS CH 3X6), 0.30 and 0.28 (s * 2,12H, TBSCH 3* 4).
(b) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(naphthalene-2-yl)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (18)
Figure S2006800157162D00421
With 10%Cd/Pb (455mg, 3.71mmol, 26eq) add to quick stirring 17 (190mg, 0.14mmol), THF (3.2mL) and 1N NH 4In the mixture of OAc (3.2mL).Reaction mixture was stirred 6.5 hours, and thin-layer chromatography showed that raw material consumption is complete and formed by product this moment.With solid filtering and use H 2O and MeOH washing.Remove excessive solvent, with residue H 2O (25mL) and DCM (25mL) dilution.(3 * 25mL) extractions merge organic extract liquid to water layer, use salt water washing (50mL), dry (MgSO with DCM 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99: 1v/v CHCl 3/ MeOH, gradient to 98 then: 2v/vCHCl 3/ MeOH), obtain 18 (38mg, 36%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.85 (d, 2H, J=3.9Hz, H11), 7.77-7.65 (m, 6H, H Arom), 7.59-7.50 (m, 6H, H3 and H Arom), 7.47 (s, 2H, H6), 7.44-7.33 (m, 4H, H Arom), 6.82 (s, 2H, H9), 4.42-4.32 (m, 2H, H11a), 4.31-4.14 (m, 4H, OCH 2CH 2CH 2O), 3.89 (s, 6H, OCH 3* 2), and 3.69-3.56 (m, 2H, H1), 3.50-3.37 (m, 2H, H1), 2.45-2.29 (m, 2H, OCH 2CH 2CH 2O).
(c) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(naphthalene-2-yl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (19)
Figure S2006800157162D00422
With sodium bisulfite (6.67mg, 0.064mmol, H 2.0equiv.) 2O (1.5mL) solution adds to compound 18, and (25mg is in anhydrous DCM (1.5mL) solution 0.032mmol).Reaction mixture was stirred 5 hours.Reaction mixture dilutes with DCM (5mL) and H2O (5mL).Separate water layer (not jolting separating funnel) and the dry white solid 19 (7mg, 22%) that obtains to light specific gravity in lyophilizer: 1H NMR (400MHz, DMSO) δ 7.78-7.72 (m, 8H, H Arom), 7.68 (s, 2H, H3), 7.59-7.27 (m, 6H, H Arom), 6.92 (s, 2H, H6), 6.41 (s, 2H, H9), 5.21 (d, 2H, J=5.2Hz, NH), 4.38-4.31 (m, 2H, H11a), 4.12-3.96 (m, 4H, OCH 2CH 2CH 2O), 3.87 (d, 2H, J=10.4Hz, H11), 3.70 (s, 3H, OCH 3), 3.61 (s, 3H, OCH 3), 3.40-3.12 (m, 4H, H1), 2.28-2.22 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 3
(a) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(thiophene-2-yl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (20)
Figure S2006800157162D00431
With TEA (0.11mL, 0.82mmol, H 6.0eq) 2O (0.8mL) and EtOH (5mL) solution add to 13, and (197mg is in toluene 0.14mmol) (5mL) solution.In this mixture, add thiophene-2-boric acid (45.5mg, 0.36mmol, 2.6eq) and Pd (PPh 3) 4(6.3mg, 5 μ mol, 0.04eq).Reaction mixture was stirred under room temperature 3 hours, and this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved in EtOAc (20mL), use H 2O (15mL), salt solution (15mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc), obtain 20 (168mg, 94%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.32 (s, 2H, H3), 7.26 (s, 2H, H6), 7.24-7.19 (m, 2H, H Arom), 7.04-6.79 (m, 2H, H Arom), 6.94-6.88 (m, 2H, H Arom), 6.78 (s, 2H, H9), 5.92 (d, 2H, J=8.9Hz, H11), 5.24 (d, 2H, J=12.0Hz, Troc CH 2), 4.36-4.25 (m, 2H, OCH 2CH 2CH 2O), 4.19-4.08 (m, 4H, Troc CH 2And OCH 2CH 2CH 2O), 4.02-3.87 (m, 8H, H11a and OCH 3* 2), 3.37 (dd, 2H, J=10.8,16.6Hz, H1), 2.85 (d, 2H, J=16.5Hz, H1), 2.52-2.37 (m, 2H, OCH 2CH 2CH 2O), 0.91 (s, 18H, TBS CH 3X6), 0.28 and 0.25 (s * 2,12H, TBS CH 3* 4).
(b) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(thiophene-2-yl)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (21)
Figure S2006800157162D00441
With 10%Cd/Pb (288mg, 2.35mmol, 20eq) add to quick stirring 20 (154mg, 0.12mmol), THF (3mL) and 1N NH 4In the mixture of OAc (3mL).Reaction mixture was stirred 3 hours, and this moment, thin-layer chromatography showed that raw material consumption is complete.Cross filter solid and use H 2O and DCM washing.(3 * 15mL) extractions merge organic extract liquid to water layer, use salt water washing (40mL), dry (MgSO with DCM 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99: 1v/v CHCl 3/ MeOH, gradient to 98 then: 2v/v CHCl 3/ MeOH), obtain 21 (59mg, 72%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.90 (d, 2H, J=4.0Hz, H11), 7.51 (s, 2H, H6), 7.36 (s, 2H, H3), 7.22 (d, 2H, J=5.2Hz, H Arom), 7.02 (dd, 2H, J=3.6,5.0Hz, H Arom), 6.98 (d, 2H, J=3.4Hz, H Arom), 6.88 (s, 2H, H9), 4.43-4.23 (m, 6H, H11a and OCH 2CH 2CH 2O), 3.94 (s, 6H, OCH 3* 2), 3.59 (ddd, 2H, J=2.0,11.5,16.0Hz, H1), 2.85 (ddd, 2H, J=1.5,5.2,16.0Hz, H1), 2.49-2.40 (m, 2H, OCH 2CH 2CH 2O).
(c) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(thiophene-2-yl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (22)
With sodium bisulfite (16.5mg, 0.159mmol, H 2.0equiv.) 2O (3.5mL) solution adds to compound 21, and (55.0mg is in DCM 0.079mmol) (3.5mL) solution.Reaction mixture was stirred 4 hours.Thin-layer chromatography (EtOAc) shows that raw material consumption is complete, and the product spot is positioned at the baseline place.With reaction mixture DCM and H 2The O dilution.Separate water layer (not jolting separating funnel), the dry yellow solid 22 (53.9mg, 75%) that obtains to light specific gravity in lyophilizer: 1HNMR (400MHz, DMSO) δ 7.42 (dd, 2H, J=1.5,4.7Hz, H Arom), 7.33-7.30 (m, 6H, H Arom), 6.53 (s, 2H, H9), 5.30 (d, 2H, J=3.8Hz, NH), 4.35-4.29 (m, 2H, H11a), 4.12-4.06 (m, 4H, OCH 2CH 2CH 2O), 3.95 (d, 2H, J=10.3Hz, H11), 3.72 (s, 6H, OCH 3* 2), and 3.53-3.19 (m, 4H, H1), 2.23-2.21 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 4
(a) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(quinoline-6-yl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (23)
Figure S2006800157162D00451
Under room temperature, with TEA (0.12mL, 0.84mmol, H 6.0eq) 2O (0.8mL) and EtOH (5mL) solution add to triflate 13, and (202mg is in toluene 0.14mmo1) (5mL) solution.In this mixture, add 6-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) quinoline (93.0mg, 0.36mmol, 2.6eq) and Pd (PPh 3) 4(6.5mg, 6 μ mol, 0.04eq).With reaction mixture in microwave irradiation in 100 ℃ of heating 15 minutes, this moment, thin-layer chromatography (80: the 20v/vEtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved in EtOAc (20mL), use H 2O (15mL), salt solution (15mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc, gradient to 50 then: 50v/v hexane/EtOAc), obtain 23 (126mg, 64%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 8.88 (dd, 2H, J=1.6,4.2Hz, H Arom), 8.14 (d, 2H, J=7.6Hz, H Arom), 8.07 (d, 2H, J=9.0Hz, H Arom), 7.85 (dd, 2H, J=1.8,8.9Hz, H Arom), 7.66 (s, 2H, H3), 7.55 (d, 2H, J=1.8Hz, H Arom), 7.41 (dd, 2H, J=4.3,8.3Hz, H Arom), 7.31 (s, 2H, H6), 6.82 (s, 2H, H9), 5.98 (d, 2H, J=8.8Hz, H11), 5.25 (d, 2H, J=12.1Hz, Troc CH 2), 4.34-4.31 (m, 2H, OCH 2CH 2CH 2O), 4.21-4.15 (m, 4H, Troe CH 2And OCH 2CH 2CH 2O), and 4.09-4.03 (m, 2H, H11a), 3.97 (s, 6H, OCH 3* 2), 3.48 (ddd, 2H, J=1.6,10.4,16.1Hz, H1), 2.98 (dd, 2H, J=2.4,16.1Hz, H1), 2.50-2.47 (m, 2H, OCH 2CH 2CH 2O), 0.95 (s, 18H, TBS CH 3* 6), 0.32 and 0.28 (s * 2,12H, TBSCH 3* 4).
(b) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(quinoline-6-yl)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (24)
Figure S2006800157162D00461
With 10%Cd/Pb (516mg, 4.21mmol, 25eq) drop to quick stirring 23 (234mg, 0.17mmol), THF (5mL) and 1N NH 4In the mixture of OAc (5mL).Reaction mixture was stirred 5 hours, and thin-layer chromatography showed that raw material consumption is complete and formed a spot of by product this moment.Cross filter solid and use H 2O and a large amount of MeOH washings.Remove excessive solvent, with residue H 2O (35mL) and CHCl 3(35mL) dilution.Water layer CHCl 3(3 * 30mL) extractions merge organic extract liquid, with salt water washing (100mL), and dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.5: 0.5v/v CHCl 3/ MeOH, gradient to 96 then: 4v/v CHCl 3/ MeOH), obtain 24 (44mg, 33%) into yellow glass shape thing: 1HNMR (400MHz, CDCl 3) δ 8.85 (dd, 2H, J=1.6,4.2Hz, H Arom), 8.09 (d, 2H, J=7.6Hz, H Arom), 8.03 (d, 2H, J=9.0Hz, H Arom), 7.88 (d, 2H, J=3.9Hz, H11), 7.82 (dd, 2H, J=1.8,8.9Hz, H Arom), 7.24 (s, 2H, H3), 7.59 (s, 2H, H Arom), 7.52 (s, 2H, H6), 7.48 (dd, 2H, J=4.3,8.3Hz, H Arom), 6.88 (s, 2H, H9), 4.48-4.42 (m, 2H, H11a), 4.39-4.28 (m, 4H, OCH 2CH 2CH 2O), 3.94 (s, 6H, OCH 3* 2), and 3.76-3.63 (m, 2H, H1), 3.09-2.98 (m, 2H, H1), 2.46-2.43 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 5
(a) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(3-anisole)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (25)
Figure S2006800157162D00462
Under room temperature, with TEA (0.071mL, 0.51mmol, H 6.0eq) 2O (0.6mL) and EtOH (3.5mL) solution add to triflate 13, and (122mg is in toluene 0.085mmol) (3.5mL) solution.In this mixture, add 3-methoxyphenol boric acid (33.5mg, 0.22mmol, 2.6eq) and Pd (PPh 3) 4(3.9mg, 3.4 μ mol, 0.04eq).With reaction mixture in microwave irradiation in 100 ℃ of heating 5 minutes, this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved in EtOAc (10mL), use H 2O (10mL), salt solution (10mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc, gradient to 60 then: 40v/v hexane/EtOAc), obtain 25 (66mg, 57%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.23 (s, 2H, H3), 7.05-7.00 (m, 4H, H6 and H Arom), 6.70 (d, 2H, J=8.7Hz, H Arom), 6.64 (s, 2H, H Arom), 6.67-6.64 (m, 4H, H AromAnd H9), 5.67 (d, 2H, J=8.8Hz, H11), 4.98 (d, 2H, J=12.0Hz, Troc CH 2), 4.08-4.02 (m, 2H, OCH 2CH 2CH 2O), 3.92-3.84 (m, 4H, Troc CH 2And OCH 2CH 2CH 2O), 3.74-3.66 (m, 8H, H11a and OCH 3* 2), 3.68 (s, 6H, OCH 3* 2), 3.10 (dd, 2H, J=10.8,16.6Hz, H1), 2.60 (d, 2H, J=16.5Hz, H1), 2.22-2.19 (m, 2H, OCH 2CH 2CH 2O), 0.68 (s, 18H, TBS CH 3* 6), 0.02 and 0.00 (s * 2,12H, TBSCH 3* 4).
(b) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(3-anisole)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (26)
With 10%Cd/Pb (269mg, 2.20mmol, 25eq) add to quick stirring 25 (119mg, 0.088mmol), THF (3mL) and 1N NH 4In the mixture of OAc (3mL).Reaction mixture was stirred 3.5 hours, and this moment, thin-layer chromatography showed that raw material consumption is complete.Cross filter solid and use H 2O and MeOH washing.Remove excessive solvent, with residue H 2O (20mL) and DCM (20mL) dilution.(3 * 20mL) extractions merge organic extract liquid to water layer, use H with DCM 2O (50mL) and salt solution (50mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.9: 0.1v/v CHCl 3/ MeOH, gradient to 98 then: 2v/vCHCl 3/ MeOH), obtain 26 (35mg, 54%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.79 (d, 2H, J=3.9Hz, H11), 7.44 (s, 2H, H3), 7.42 (s, 2H, H6), 7.21-7.16 (m, 2H, H Arom), 6.90 (d, 2H, J=8.7Hz, H Arom), 6.84-6.83 (m, 2H, H Arom), 6.80 (s, 2H, H9), 4.33-4.17 (m, 6H, OCH 2CH 2CH 2O and H11a), 3.86 (s, 6H, OCH 3* 2), 3.75 (s, 6H, OCH 3* 2), 3.44 (dd, 2H, J=11.8,16.2Hz, H1), 3.30 (d, 2H, J=16.2Hz, H1), 2.39-2.33 (m, 2H, OCH 2CH 2CH 2O).
(c) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(3-anisole)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (27)
Figure S2006800157162D00481
With sodium bisulfite (7.6mg, 0.073mmol, H 2.0equiv.) 2O (1.7mL) solution adds to compound 26, and (27.0mg is in DCM 0.036mmol) (1.7mL) solution.Reaction mixture was stirred 2 hours.Thin-layer chromatography (EtOAc) shows that raw material consumption is complete, and the product spot is positioned at the baseline place.With reaction mixture DCM (5mL) and H 2O (5mL) dilution.Separate water layer and lyophilize and obtain 27, be the white solid (12.1mg, 35%) of light specific gravity: 1H NMR (400MHz, DMSO) δ 7.61 (s, 2H, H3), 7.27-7.23 (m, 2H, H Arom), 7.08-6.99 (m, 6H, H Arom andH6), 6.81-6.78 (m, 2H, H Arom), 6.54 (s, 2H, H9), 5.30 (s, 2H, NH), 4.37-4.30 (m, 2H, H11a), 4.17-4.08 (m, 4H, OCH 2CH 2CH 2O), 3.84 (d, 2H, J=10.4Hz, H11), 3.78 (s, 6H, OCH 3* 2), 3.62 (s, 6H, OCH 3* 2), and 3.52-3.20 (m, 4H, H1), 2.26-2.20 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 6
(a) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(3,4-methylenedioxyphenyl base)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (28)
Figure S2006800157162D00482
Under room temperature, with TEA (0.066mL, 0.47mmol, H 6.0eq) 2O (0.6mL) and EtOH (3.5mL) solution add to triflate 13, and (122mg is in toluene 0.085mmol) (3.5mL) solution.In this mixture, add 3, and 4-methylenedioxyphenyl ylboronic acid (34.2mg, 0.21mmol, 2.6eq) and Pd (PPh 3) 4(3.6mg, 3.2 μ mol, 0.04eq).With reaction mixture 100 ℃ of heating 5 minutes in microwave irradiation, this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved among the EtOAc (10mL), use H 2O (10mL), salt solution (10mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc, gradient to 65 then: 35v/v hexane/EtOAc), obtain 28 (84mg, 77%) into yellow glass shape thing: 1H NMR (400 MHz, CDCl 3) δ 7.34 (s, 2H, H6), 7.26 (s, 2H, H3), 6.89 (s, 2H, H9), 6.78-6.76 (m, 4H, H Arom), 5.98 (s, 2H, OCH 2O), 5.89 (d, 2H, J=8.8Hz, H11), 5.23 (d, 2H, J=12.0Hz, Troc CH 2), 4.32-4.27 (m, 2H, OCH 2CH 2CH 2O), 4.18-4.09 (m, 4H, Troc CH 2And OCH 2CH 2CH 2O), 3.97-3.91 (m, 8H, H11a and OCH 3* 2), 3.30 (dd, 2H, J=10.8,16.6Hz, H1), 2.76 (d, 2H, J=16.6Hz, H1), 2.46-2.44 (m, 2H, OCH 2CH 2CH 2O), 0.88 (s, 18H, TBS CH 3* 6), 0.28 and 0.25 (s * 2,12H, TBSCH 3* 4).
(b) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(3,4-methylenedioxyphenyl base)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (29)
Figure S2006800157162D00491
With 10%Cd/Pb (307mg, 2.51mmol, 25eq) add to quick stirring 28 (139mg, 0.101mmol), THF (3.5mL) and 1N NH 4In the mixture of OAc (3.5mL).Reaction mixture was stirred 5 hours, and thin-layer chromatography showed that raw material consumption is complete and formed a spot of by product this moment.Cross filter solid and use H 2O and MeOH washing.Remove excessive solvent, with residue H 2O (25mL) and DCM (25mL) dilution.(3 * 40mL) extractions merge organic extract liquid to water layer, use H with DCM 2O (80mL) and salt solution (80mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (99.9: 0.1v/v CHCl 3/ MeOH, gradient to 98 then: 2v/v CHCl 3/ MeOH), obtain 26 (30mg, 39%) into yellow glass shape thing: 1HNMR (400MHz, CDCl 3) δ 7.86 (d, 2H, J=3.9Hz, H11), 7.60 (s, 2H, H6), 7.36 (s, 2H, H3), 6.91 (d, 2H, J=0.9Hz, H Arom), 6.86 (s, 2H), 6.82-6.78 (m, 4H, H9 and H Arom), 5.97 (s, 2H, OCH 2O), 4.36-4.25 (m, 6H, H11a and OCH 2CH 2CH 2O), 3.93 (s, 6H, OCH 3* 2), 3.52 (dd, 2H, J=10.8,16.6Hz, H1), 3.33 (d, 2H, J=16.6Hz, H1), 2.46-2.40 (m, 2H, OCH 2CH 2CH 2O).
(c) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(3,4-methylenedioxyphenyl base)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (30)
Figure S2006800157162D00501
With sodium bisulfite (2.2mg, 0.021mmol, H 2.0equiv.) 2O (0.5mL) solution adds to compound 29, and (8.1mg is in DCM 0.0105mmol) (0.5mL) solution.Reaction mixture was stirred 5 hours.Thin-layer chromatography (EtOAc) shows that raw material consumption is complete, and the product spot is positioned at the baseline place.With reaction mixture DCM (1.5mL) and H 2O (1.5mL) dilution.Separate water layer and lyophilize and obtain 30, be the white solid (3.5mg, 34%) of light specific gravity: 1H NMR (400MHz, DMSO) δ 7.47 (s, 2H, H3), 6.98 (s * 2,2H, H6), 7.06-6.78 (m, 6H, H Arom), 6.51 (s * 2,2H, H9), 5.27 (s, 2H, NH), 4.32-4.26 (m, 2H, H11a), 4.17-4.07 (m, 4H, OCH 2CH 2CH 2O), 3.93 (d, 2H, J=10.4Hz, H11), 3.72 (s, 6H, OCH 3* 2), and 3.50-3.20 (m, 4H, H1), 2.27-2.20 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 7
(a) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(4-fluorobenzene)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (31)
Under room temperature, with TEA (0.072mL, 0.52mmol, H 6.0eq) 2O (0.6mL) and EtOH (3.5mL) solution add to triflate 13, and (125mg is in toluene 0.086mmol) (3.5mL) solution.In this mixture, add the 4-fluorobenzoic boric acid (31.6 0.22mmol, 2.6eq) and Pd (PPh 3) 4(4.0,3.4 μ mol, 0.04eq).With reaction mixture in microwave irradiation in 100 ℃ of heating 5 minutes, this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Remove excessive solvent, residue is dissolved in EtOAc (10mL), use H 2O (10mL), salt solution (10mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc, gradient to 65 then: 35v/v hexane/EtOAc), obtain 31 (82mg, 71%) into yellow glass shape thing: 1H NMR (400 MHz, CDCl 3) δ 7.40 (s, 2H, H3), 7.42 (dd, 4H, J=5.2,8.7Hz, H Arom), 7.28 (s, 2H, H6), 7.06 (dd, 4H, J=8.7Hz, H Arom), 6.70 (s, 2H, H9), 5.92 (d, 2H, J=8.8Hz, H11), 5.22 (d, 2H, J=12.0Hz, Troc CH 2), 4.32-4.29 (m, 2H, OCH 2CH 2CH 2O), 4.19-4.10 (m, 4H, Troc CH 2And OCH 2CH 2CH 2O), 4.00-3.92 (m, 8H, H11a and OCH 3* 2), 3.33 (dd, 2H, J=10.8,16.5Hz, H1), 2.84 (d, 2H, J=16.5Hz, H1), 2.49-2.44 (m, 2H, OCH 2CH 2CH 2O), 0.92 (s, 18H, TBS CH 3* 6), 0.30 and 0.27 (s * 2,12H, TBSCH 3* 4).
(b) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(4-fluorobenzene)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (32)
Figure S2006800157162D00511
With 10%Cd/Pb (342mg, 2.80mmol, 25eq) add to quick stirring 31 (149mg, 0.112mmol), THF (4.5mL) and 1N NH 4In the mixture of OAc (4.5mL).Reaction mixture was stirred 5 hours, and this moment, thin-layer chromatography showed that raw material consumption is complete.Cross filter solid and use H 2O and MeOH washing.Remove excessive solvent, with residue H 2O (30mL) and DCM (30mL) dilution.(3 * 30mL) extractions merge organic extract liquid to water layer, use H with DCM 2O (80mL) and salt solution (80mL) washing, dry (MgSO 4).Filter and evaporating solvent obtain the crude product product with it through flash column chromatography chromatography purification (99.9: 0.1v/v CHCl 3/ MeOH, gradient to 98 then: 2v/vCHCl 3/ MeOH), obtain 32 (60mg, 75%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) 7.88 (d, 2H, J=3.9Hz, H11), δ 7.51 (s, 2H, H6), 7.43 (s, 2H, H3), 7.34 (dd, 4H, J=5.3,8.6Hz, H Arom), 7.06 (dd, 4H, J=8.7Hz, H Arom), 6.87 (s, 2H, H9), 4.41-4.25 (m, 6H, H11a and OCH 2CH 2CH 2O), 3.93 (s, 3H, OCH 3* 2), 3.55 (dd, 2H, J=10.8,16.5Hz, H1), 3.37 (d, 2H, J=16.5Hz, H1), 2.46-2.42 (m, 2H, OCH 2CH 2CH 2O).
(c) 1,1 '-[[(propane-1,3-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(4-fluorobenzene)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (33)
Figure S2006800157162D00521
With sodium bisulfite (13.9mg, 0.134mmol, H 2.0equiv.) 2O (3mL) solution adds to compound 32, and (48.0mg is in DCM 0.067mmol) (3mL) solution.Reaction mixture was stirred 2 hours.Thin-layer chromatography (EtOAc) shows that raw material consumption is complete, and the product spot is positioned at the baseline place.With reaction mixture DCM (8mL) and H 2O (8mL) dilution.Separate water layer and lyophilize and obtain 33, be the white solid (35.5mg, 58%) of light specific gravity: 1H NMR (400MHz, DMSO) δ 7.56 (s, 2H, H3), 7.49 (dd, 4H, J=5.3,8.6Hz, H Arom), 7.17 (dd, 4H, J=8.7Hz, H Arom), 7.07 (s, 2H, H6), 6.53 (s, 2H, H9), 5.28 (s, 2H, NH), 4.36-4.30 (m, 2H, H11a), 4.17-4.09 (m, 4H, OCH 2CH 2CH 2O), 3.95 (d, 2H, J=10.4Hz, H11), 3.73 (s, 6H, OCH 3* 2), and 3.53-3.22 (m, 4H, H1), 2.27-2.19 (m, 2H, OCH 2CH 2CH 2O).
Embodiment 8
(a) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(2S, 4R)-(5-methoxyl group-2-nitro-1,4-phenylene) carbonyl]] two [2-(tert-butyl dimetylsilyl oxygen ylmethyl)-4-hydroxyacetyl tetramethyleneimine] (36)
Figure S2006800157162D00531
With the DMF (2) of catalytic amount add to stirring nitro-acid 34 (15.0g, 30.4mmol) and oxalyl chloride (13.5mL, 19.3g is in anhydrous THF (300mL) solution 152mmol).Reaction mixture was stirred 16 hours solvent removed in vacuo under room temperature.The residue that obtains is dissolved among the anhydrous THF (225mL) again, in 0 ℃ (ice/acetone), nitrogen environment, with this solution of acid chloride drop to stirring amine 35 (20.7g, 76.0mmol) and TEA (84mL, 61.52g is in THF 608mmol) (150mL) solution.Reaction mixture is warmed to room temperature, restir 16 hours.Rotary evaporation is removed excessive THF, with the residue that obtains at H 2Distribute between O (400mL) and the EtOAc (400mL).Separate each layer, (3 * 130mL) extract water layer with EtOAc.Then with the organic layer that merges with saturated NH 4Cl (200mL), saturated NaHCO 3(200mL), salt solution (200mL) washs dry (MgSO 4).Filtration and evaporating solvent obtain the crude product product, are dark oily matter.Through purification by flash chromatography (gradient moving phase: 60: 40v/v hexane/EtOAc to 40: 60v/v hexane/EtOAc) separates and obtains pure acid amides 36, is light yellow glassy mass (23.56g, 77%): 1H NMR (400MHz, CDCl 3) (rotational isomer) δ 7.66 (s, 2H), 6.71 (s, 2H), 5.21-5.17 (m, 2H), 4.57-4.53 (m, 2H), 4.21-4.08 (m, 6H), 3.91 (s, 6H), 3.76-3.72 (m, 2H), 3.46 (dd, 2H, J=11.8,4.6Hz), 3.21 (d, 2H, J=11.9Hz), 2.44-2.37 (m, 2H), 2.24-2.18 (m, 2H), 2.03-1.94 (m, 10H), 1.75-1.67 (m, 2H), and 0.91-0.84 (m, 18H), 0.11--0.05 (m, 12H); 13C NMR (100MHz, CDCl 3) δ 171.0,166.4,154.4,148.5,137.5,127.7,109.2,108.3,72.9,69.3,62.6,57.4,56.5,54.8,33.0,28.5,25.8,22.5,21.0,18.2 ,-5.4 and-5.5; 2.93 minutes (ES+) m/z (relative intensity) of LC/MS, 1006 ([M+H] +., 100).
(b) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(2S, 4R)-(5-methoxyl group-2-amino-1,4-phenylene) carbonyl]] two [2-(tert-butyl dimetylsilyl oxygen ylmethyl)-4-hydroxyacetyl tetramethyleneimine] (37)
EtOAc (20mL) soup compound of 10%Pd-C (550mg) is added to nitro-compound 36, and (5.5g is in EtOAc 5.47mmol) (73mL) solution.Adopt Parr equipment in 30psi hydrogenation 24 hours in mixture.With the mixture degassing and through thin layer chromatography analysis (EtOAc), it is complete to observe raw material consumption.Remove catalyzer by the vacuum filtration of Whatman GF/F filter paper, filtrate evaporation obtained aniline 37 (5.17g, 100%) into the grey foam: 1H NMR (400MHz, CDCl 3) δ 6.71 (s, 2H), 6.22 (s, 2H), 5.25-5.23 (m, 2H), 4.58-4.30 (m, 6H), 4.14-4.05 (m, 2H), 3.99 (t, J=6.6Hz, 4H), 3.79-3.73 (m, 8H), 3.69-3.54 (m, 4H), and 2.40-2.33 (m, 2H), 2.16-2.08 (m, 2H), 2.00 (s, 6H), 1.94-1.87 (m, 4H), 1.68-1.60 (m, 2H), 0.89 (s, 18H), 0.05 and 0.04 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 170.6,170.0,151.5,141.7,141.2,113.1,111.0,102.0,73.5,68.5,62.6,57.0,56.2,32.9,28.7,25.6,22.6,21.1,18.1 ,-5.1 and-5.4; 2.78 minutes (ES+) m/z (relative intensity) of LC/MS, 946 ([M+H] +., 52), 672 (30), 399 (20), 274 (65), 166 (20).
(c) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(2S; 4R)-[5-methoxyl group-1; 4-phenylene-2-(2,2,2-three chloro ethoxy carbonyl amino)] carbonyl]] two [2-(tert-butyl dimetylsilyl oxygen ylmethyl)-4-hydroxyacetyl tetramethyleneimine] (38)
Figure S2006800157162D00542
In-10 ℃ (liquid nitrogen/ethylene glycol), with 2,2,2-three chloro ethyl chloride subtituted acid ester (2.63mL, 4.05g, anhydrous DCM (45mL) drips of solution 19.1mmol) add to stirring amine 37 (8.21g, 8.70mmol) and anhydrous pyridine (2.81mL, 2.75g, in anhydrous DCM (120mL) solution 34.8mmol).After stirring 16 hours under the room temperature, thin-layer chromatography (50: 50v/v hexane/EtOAc) show that raw material consumption is complete.With reaction mixture with saturated NH 4Cl (2 * 70mL), saturated CuSO 4(70mL), H 2O (70mL), salt solution (70mL) washing, dry (MgSO 4).Filtration and evaporating solvent obtain Troc-carbamate 38, are yellow foam (11.25g, 99%): 1H NMR (400MHz, CDCl 3) δ 9.48 (br s, 1H), 7.85 (s, 2H), 6.79 (s, 2H), 5.28-5.24 (m, 2H), 4.86-4.76 (m, 4H), 4.70-4.53 (m, 2H), 4.12 (t, J=6.4Hz, 4H), 4.14-4.10 (m, 2H), 3.80 (s, 6H), 3.76 (dd, 2H, J=12.2,3.8Hz), 3.69-3.62 (m, 4H), and 2.44-2.37 (m, 2H), 2.16 (dd, 2H, J=14.1,8.1Hz), 2.10-1.92 (m, 10H), and 1.72-1.65 (m, 2H), 0.90 (s, 18H), 0.06 and 0.04 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 170.5,169.3,152.0,151.1,144.2,132.4,114.4,111.8,105.2,95.3,74.4,73.4,68.7,62.3,57.3,57.2,56.5,32.6,28.7,25.8,22.6,21.1,18.1 ,-5.4 and-5.5; 3.23 minutes (ES+/ES-) m/z of LC/MS (M +, do not observe), 472 (30), 416 (15), 302 (85), 274 (60), 198 (20), 170 (100), 142 (50), 110 (80).
(d) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(2S, 4R)-[5-methoxyl group-1,4-phenylene-2-(2,2,2-three chloro ethoxy carbonyl amino)] carbonyl]] two (2-hydroxymethyl-4-hydroxyacetyl tetramethyleneimine) (39)
Figure S2006800157162D00551
Glacial acetic acid (90mL) is added to 38 (5.06g, H 3.91mmol) of stirring 2In O (30mL) and THF (30mL) solution.Reaction mixture was stirred under room temperature 16 hours, at this moment thin-layer chromatography (95: 5v/v CHCl 3/ MeOH) demonstration reacts completely.In 0 ℃ (ice/acetone), this acidic solution is dropped to the NaHCO of stirring 3H (132g) 2In O (1.3L) solution.(3 * 200mL) extractions merge organic layer to water layer, use H with EtOAc 2O (200mL), salt solution (200mL) washing, dry (MgSO 4).Filter and vacuum evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (98: 2v/vCHCl 3/ MeOH), obtain di-alcohol 39 (4.04g, 97%) into white glass shape thing: 1HNMR (400MHz, CDCl 3) δ 9.01 (br s, 2H), 7.66 (s, 2H), 6.79 (s, 2H), and 5.23-5.20 (m, 2H), 4.84 (d, 2H, J=12.0Hz), 4.77 (d, 2H, J=12.0Hz), and 4.63-4.55 (m, 2H), 4.10 (t, J=6.4Hz, 4H), 4.08-4.01 (m, 2H), 3.82 (s, 6H), 3.75 (dd, 2H, J=12.6,3.7Hz), 3.70-3.58 (m, 4H), 2.26 (dd, 2H, J=14.1,7.6Hz), 2.15-2.06 (m, 2H), 2.01 (s, 6H), 1.98-1.92 (m, 4H), 1.74-1.65 (m, 2H); 13CNMR (100MHz, CDCl 3) δ 170.6,170.4,152.1,150.9,144.8,131.0,115.6,111.3,105.7,95.3,74.3,72.5,68.7,64.3,58.8,56.6,56.5,33.6,28.5,22.6.21.1.
(e) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11S, 11aS, 2R)-10-(2; 2,2-three chloro ethoxy carbonyls)-11-hydroxyl-7-methoxyl group-2-hydroxyacetyl-1,2,3,10; 11,11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (40)
Figure S2006800157162D00561
With TEMPO (234mg, 1.50mmol) and BAIB (5.31g, (4.0g is in DCM 3.75mmol) (140mL) solution 16.5mmol) to drop to the di-alcohol 39 of stirring.Reaction mixture was stirred in nitrogen environment 24 hours, at this moment thin-layer chromatography (95: 5v/v CHCl 3/ MeOH) show that feedstock conversion is a product.Mixture is diluted with DCM (30mL), with saturated NaHSO 3(2 * 30mL) aqueous solution, saturated NaHCO 3(2 * 30mL) aqueous solution, salt solution (30mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (gradient elution: CHCl 3To 99.5: 0.5v/v CHCl 3/ MeOH), obtain product 40 (1.99g, 50%) into the cyclisation of light yellow glassy mass: 1H NMR (400MHz, CDCl 3) δ 7.27 (s, 2H), 6.78 (s, 2H), 5.68 (d, 2H, J=9.7Hz), 5.41-5.35 (m, 2H), 5.24 (d, 2H, J=12.0Hz), 4.23 (d, 2H, J=12.0Hz), 4.14-3.97 (m, 6H), 3.93 (s, 6H), 3.77-3.69 (m, 4H), 2.46-2.33 (m, 4H), 2.05 (s, 6H), 2.03-1.87 (m, 4H), 1.70-1.62 (m, 2H); 13CNMR (100 MHz, CDCl 3) δ 170.4,167.5,154.4,150.6,149.0,127.3,124.5,113.7,110.8,95.0,87.5,75.0,71.4,68.8,58.3,56.2,51.1,35.8,28.5,22.4,21.0.
(f) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11S; 11aS, 2R)-10-(2,2; 2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-hydroxyacetyl-1; 2,3,10; 11; 11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (41)
Figure S2006800157162D00562
((1.96g, 1.85mmol) and 2, (0.86mL, 0.79g is in anhydrous DCM (40mL) solution 7.39mmol) for the 6-lutidine 5.54mmol) to drop to the di-alcohol 40 of stirring for 1.27mL, 1.47g with TBSOTf.Reaction mixture was stirred in nitrogen environment 5 hours, and thin-layer chromatography this moment (EtOAc) shows that raw material consumption is complete.Use DCM (50mL) dilution then, organic mixture is with saturated CuSO 4(30mL), saturated NaHCO 3(30mL), salt solution (50mL) washs dry (MgSO 4).Filter and vacuum evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (40: 60v/v hexane/EtOAc) obtain product 41 is (1.31g, 55%) of white glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.27 (s, 2H), 6.72 (s, 2H), 5.76 (d, 2H, J=9.0Hz), 5.37 (br s, 2H), 5.24 (d, 2H, J=12.1Hz), 4.17 (d, 2H, J=12.1Hz), 4.14-3.96 (m, 6H), 3.93 (s, 6H), and 3.75-3.66 (m, 4H), 2.40-2.33 (m, 2H), 2.28-2.18 (m, 2H), 2.04 (s, 6H), 1.98-1.90 (m, 4H), 1.69-1.62 (m, 2H), 0.86 (s, 18H), 0.23 and 0.22 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 170.4,168.0,153.6,150.5,149.1,127.9,125.3,113.9,110.7,95.2,88.2,74.7,71.7,68.7,60.5,56.2,51.2,36.3,28.7,25.6,22.7,21.1,17.8 ,-4.2 and-5.2.
(g) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11S, 11aS, 2R)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-hydroxyl-1,2,3,10,11,11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (42)
Figure S2006800157162D00571
With K 2CO 3(685mg, H 4.96mmol) 2O (15mL) drips of solution adds to the acetate compound 41 of stirring, and (1.28g is in MeOH 0.99mmol) (15mL) solution.Initial colourless solution finally changes yellow into, observes the formation white depositions.In the heating down 5 hours that refluxes, thin-layer chromatography this moment (EtOAc) shows that raw material is converted into product fully with reaction mixture.Rotary evaporation is removed excessive solvent, and mixture is neutralized to pH7 with 1N HCl carefully.With the mixture that obtains with DCM (5 * 20mL) extractions, then with the organic layer that merges with salt water washing (50mL), dry (MgSO 4).Filter, vacuum-evaporation subsequently removes and desolvates, and obtains the product 42 (982mg, 82%) into white solid: 1H NMR (400MHz, CDCl 3) δ 7.19 (s, 2H), 6.72 (s, 2H), 5.75 (d, 2H, J=9.0Hz), 5.22 (d, 2H, J=12.0Hz), 4.58-4.56 (m, 2H), 4.18 (d, 2H, J=12.0Hz), 4.11-3.95 (m, 6H), 3.85 (s, 6H), 3.75-3.69 (m, 2H), 3.59 (dd, 2H, J=12.7,4.2Hz), 2.55 (br s, 2H), 2.38-2.25 (m, 2H), and 2.14-2.03 (m, 2H), 1.97-1.85 (m, 4H), and 1.74-1.62 (m, 2H), 0.86 (s, 18H), 0.22 and 0.21 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 168.5,153.6,150.6,149.1,127.9,125.3,114.0,110.8,95.3,88.3,74.7,69.5,68.8,60.8,56.0,54.0,38.8,28.8,25.6,22.7,17.8 ,-4.2 and-5.2.
(h) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-oxo-1,2,3,10,11,11a-six hydrogen-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (43)
Figure S2006800157162D00581
In 5 minutes, under nitrogen atmosphere ,-60 ℃ of (liquid N 2/ CHCl 3), with anhydrous DMSO (0.34mL, 0.37g, anhydrous DCM (4mL) drips of solution 4.78mmol) add to stirring oxalyl chloride (the DCM solution of the 2M of 1.20mL, 2.39mmol).After 15 minutes, (962mg, anhydrous DCM (8mL) solution 0.80mmol) dropped in the reaction mixture in 10 minutes with substrate 42 in-55 ℃ of stirrings.In-55 ℃ of restir after 1 hour, with TEA (1.56mL, 1.13g; 11.2mmol) anhydrous DCM (4mL) solution in 5 minutes, drop in the reaction mixture.Reaction mixture is warmed to 0 ℃, uses DCM (50mL) dilution then.With organic solution with cold 1N HCl (20mL), H 2O (20mL), salt solution (30mL) washing, dry (MgSO 4).Filter and vacuum evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (50: 50v/v hexane/EtOAc), obtain di-ketone 43 (550mg, 57%) into foam: 1H NMR (400MHz, CDCl 3) δ 7.25 (s, 2H), 6.76 (s, 2H), 5.82 (d, 2H, J=9.3Hz), 5.22 (d, 2H, J=12.0Hz), 4.32 (d, 2H, J=20.4Hz), 4.22 (d, 2H, J=12.0Hz), 4.17-4.08 (m, 4H), 4.03-3.89 (m, 10H), 2.96 (dd, 2H, J=19.6,10.2Hz), 2.56 (dd, 2H, J=19.6,2.8Hz), 1.99-1.92 (m, 4H), 1.72-1.64 (m, 2H), 0.86 (s, 18H), 0.24 and 0.23 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 207.7,168.0,153.8,151.0,149.5,127.9,124.4,114.1,110.8,95.2,87.5,74.8,68.8,58.9,56.2,52.9,40.4,28.7,25.6,22.8 17.8 ,-4.12 and-5.31.
(i) 1; 1 '-[[(pentane-1; 5-two bases) dioxy base] two [(11S, 11aS)-10-(2,2; 2-three chloro ethoxy carbonyls)-and 11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-[[(trifluoromethyl) alkylsulfonyl] the oxygen base]-1; 10,11,11a-tetrahydrochysene-5H-pyrrolo-[2; 1-c] [1,4] benzodiazepine-5-ketone]] (44)
In 0-5 ℃ (ice), nitrogen environment, anhydrous trifluoromethanesulfanhydride anhydride (the 1.61mL that will in the ampoule of just having opened, take out, 2.71g, 9.60mmol) the disposable ketone 43 (525mg that add to vigorous stirring fast, 0.44mmol) and anhydrous pyridine (0.78mL, 759mg is in anhydrous DCM (25mL) solution 9.60mmol).Reaction mixture is warmed to room temperature immediately, finally changes scarlet into.Reaction mixture was stirred 28 hours totally, and this moment, thin-layer chromatography (80: 20v/v EtOAc/ hexane) show that raw material consumption is complete.Pour mixture into cold saturated NaHCO 3(50mL), with DCM (3 * 20mL) extractions.Then with the organic layer that merges with saturated CuSO 4(30mL), salt solution (30mL) washs dry (MgSO 4).Filter and vacuum evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (80: 20v/v hexane/EtOAc) obtain triflate 44 is yellow foam (249mg, 39%): 1H NMR (400MHz, CDCl 3) δ 7.23 (s, 2H), 7.17 (s, 2H), 6.73 (s, 2H), 5.93 (d, 2H, J=8.9Hz), 5.22 (d, 2H, J=12.1Hz), 4.21 (d, 2H, J=12.0Hz), 4.15-4.07 (m, 2H), 4.02-3.86 (m, 8H), 3.33 (ddd, 2H, J=16.6,10.7,2.3Hz), 2.82 (dd, 2H, J=16.7,2.6Hz), 1.98-1.91 (m, 4H), 1.71-1.63 (m, 2H), 0.88 (s, 18H), 0.28 and 0.25 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 164.9,153.6,151.3,149.6,136.0,127.8,123.7,121.0,118.6 (q, J=321.5Hz), 114.2,111.0,95.1,86.4,74.9,68.8,60.6,56.2,34.4,28.7,25.6,22.8,17.8 ,-4.2 and-5.4.
(j) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11S, 11aS)-10-(2,2,2-three chloro ethoxy carbonyls)-11-(tert-butyl dimetylsilyl oxygen base)-7-methoxyl group-2-(right-p-methoxy-phenyl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (45)
Figure S2006800157162D00592
Under room temperature, with Pd (PPh 3) 4(7.43mg, 6.43 μ mol) drop to triflate 44 (236mg, 0.16mmol), 4-anisole ylboronic acid (63mg, 0.42mmol), TEA (0.13mL, 98mg, H 0.97mmol) 2In O (0.8mL), EtOH (5mL) and toluene (5mL) solution.With reaction mixture in microwave in 100 ℃ of heating 30 minutes, this moment, thin-layer chromatography (80: the 20v/vEtOAc/ hexane) show that raw material consumption is complete.Excessive solvent is removed in vacuum-evaporation, and the residue that obtains is dissolved among the EtOAc (50mL), uses H 2O (20mL), salt solution (20mL) washing, dry (MgSO 4).Filter and evaporating solvent obtains the crude product product, with its through the flash column chromatography chromatography purification (gradient elution: 80: 20v/v hexane/EtOAc to 50: 50 v/v hexanes/EtOAc), obtain C2-aryl product 45 (117mg, 52%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.35 (s, 2H), 7.31 (s, 2H), 7.31-7.27 (m, 6H), 6.90 (d, 4H, J=8.8Hz), 6.76 (s, 2H), 5.92 (d, 2H, J=8.8Hz), 5.23 (d, 2H, J=12.0Hz), 4.20 (d, 2H, J=12.1Hz), and 4.14-4.05 (m, 4H), 4.04-3.95 (m, 2H), 3.93 (s, 6H), 3.83 (s, 6H), 3.34 (ddd, 2H, J=16.3,10.4,2.0Hz), and 2.86-2.75 (m, 2H), 2.02-1.94 (m, 4H), 1.72-1.66 (m, 2H), 0.93 and 0.86 (s * 2,18H), 0.28 and 0.25 (s * 2,12H); 13C NMR (100MHz, CDCl 3) δ 163.7,159.1,153.7,150.8,149.3,127.8,126.3,126.1,125.4,122.3,122.2,114.3,114.2,110.9,95.3,87.3,74.8,68.8,61.5,56.2,55.4,35.3,28.8,25.7,22.8,17.9 ,-4.0 and-5.1.
(k) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11aS)-and 7-methoxyl group-2-(right-p-methoxy-phenyl)-1,11a-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] (46)
(192mg 1.55mmol) adds to 45 (107mg, 77.3 μ mol), THF (2.5mL) and the 1N NH of quick stirring with 10%Cd/Pb 4In the mixture of OAc (2.5mL).Reaction mixture was stirred 3 hours, at this moment thin-layer chromatography (95: 5 v/v CHCl 3/ MeOH) show the PBD that formation needs, with production of by-products.Solid collected by filtration is used H 2O and DCM washing.(3 * 10mL) extractions merge organic extract liquid to water layer, wash with salt solution (50mL), dry (MgSO with DCM 4).Filter and evaporating solvent obtains the crude product product, with it through flash column chromatography chromatography purification (gradient elution: CHCl 3To 99: 1v/v CHCl 3/ MeOH), obtain imines 46 (32.5mg, 55%) into yellow glass shape thing: 1H NMR (400MHz, CDCl 3) δ 7.89 (d, 2H, J=3.9Hz), 7.53 (s, 2H), 7.39 (s, 2H), 7.34 (d, 4H, J=8.8Hz), 6.90 (d, 4H, J=8.8Hz), 6.82 (s, 2H), 4.43-4.38 (m, 2H), 4.18-4.05 (m, 4H), 3.95 (s, 6H), 3.83 (s, 6H), 3.58 (ddd, 2H, J=16.2,11.5,1.9Hz), 3.38 (ddd, 2H, J=16.3,5.1,1.6Hz), and 2.01-1.94 (m, 4H), 1.73-1.66 (m, 2H); 13C NMR (100MHz, CDCl 3) δ 162.6,161.3,159.2,151.3,148.1,140.3,126.2,126.0 (x2), 123.2,122.0,119.1,114.3,111.9,110.9,68.8,56.2,55.4,53.9,35.6,28.7,22.6.
(j) 1,1 '-[[(pentane-1,5-two bases) dioxy base] two [(11aS)-and 11-sulfo group-7-methoxyl group-2-(right-p-methoxy-phenyl)-1,10,11,11a-tetrahydrochysene-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine-5-ketone]] sodium salt (47)
Figure S2006800157162D00611
Water (3mL) drips of solution of sodium bisulfite (4.90mg, 47.2 μ mol) is added in methylene dichloride (1.5mL) solution of 46 (18.11mg, 23.6 μ mol) of stirring.With reaction mixture vigorous stirring 24 hours, separate organic and inorganic layer then.The thin-layer chromatographic analysis of water (95: 5v/vCHCl 3/ MeOH) show 46 (R f～0.3) do not exist, have the baseline material that strong UV-absorbs but exist.Water layer obtains sulphite adducts 47 through lyophilize, is the solid (10mg, 43%) of light specific gravity:
1H NMR(400MHz，DMSO-d 6)δ7.41(s，2H)，7.37(d，4H，J＝8.7Hz)，7.04(s，2H)，6.91(d，4H，J＝8.9Hz)，6.47(s，2H)，5.24(s，2H)，4.31-4.21(m，2H)，4.06-3.86(m，6H)，3.76(s，6H)，3.71(s，6H)，3.51-3.21(m，4H)，1.90-1.70(m，4H)，1.62-1.51(m，2H)。
Embodiment 9: vitro cytotoxicity is measured
K562 clone (MTT analysis)
Exposed in 1 hour
In 37 ℃, containing 5%CO 2Damp atmosphere in, the human chronic bone marrow leukemia cells of K562 is stored in RPM1 1640 media that are supplemented with 10% foetal calf serum and 2mM glutamine, its medicine one with given dose was arised from 37 ℃ of dark cultivation 1 hour.By centrifugal termination cultivate (5min, 300g), with the medium washed cell that does not contain medicine once.After the suitable drug treating, with cell transfer (every hole 10 in the micro plate of 96-hole 4Individual cell, each sample 8 hole).Then plate is placed 37 ℃, the dark moist 5%CO that contains 2Environment in.With yellow solubility tetrazolium salts 3-(4,5-dimethylthiazole-2-yl)-2, (MTT Aldrich-Sigma) is reduced to the sedimentary ability of insoluble purple first Za and analyzes 5-phenylbenzene-2H-tetrazolium bromide according to survivaling cell.The plate cultivation after 4 days (making control cells quantitatively increase about 10 times), is added the MTT solution (phosphate buffered saline buffer of 5mg/mL) of 20 μ L in each hole, plate was cultivated 5 hours again.Then with plate centrifugal 5 minutes in 300g, sucking-off medium in cell precipitation, making every hole resid vol is 10-20 μ L.Add DMSO (200 μ L) in each hole, the jolting sample mixes with assurance.Read to read optical density(OD) in 550nm on the plate instrument at TitertekMultiscan ELISA then, and draw dose-response curve.For each bar curve, the 50% needed drug dose that final optical density(OD) is reduced to control value is IC 50Value.
Exposed in 96 hours
In the amending method of aforesaid method, with 5 * 10 4Individual K562 cell (as mentioned above) is kept in the RPMI1640 medium (Sigma) that is supplemented with 10% foetal calf serum (Sigma) and 20mM L-glutaminate (Sigma), with the above-mentioned solution of 190 μ L and the medicine of given dose (10 μ L) in 37 ℃ at 5%CO 2The middle cultivation 96 hours.In each hole, add 250 μ g/ml (final concentration) MTT, plate was cultivated 4 hours again.Adopt Envision to read plate instrument (Applied Biosystems) and read optical density in the 450nm place.Then, by Graphpad PRISM analytical data, obtain IC 50(be defined as and make cell quantity reduce half needed compound concentrations).
The result
Compound IC 50(μM)
ZC-207 0.0053 a
ZC-423 0.0015 b
aCultivated in 1 hour
bCultivated in 96 hours
K562 clone (Alamar Blue analysis)
To treat that experimental compound is dissolved among the DMSO of 100%Biotech grade (Sigma), dilution is the storage concentration of 2 μ M or 200nM in 2%DMSO then.The storage concentration of 100 μ l is arrived in middle (intermediate) polystyrene 96 porocyte culture plates (Nunc) with 1: 3 serial dilution in 2%DMSO.Place outer row to be used as blank 2%DMSO, and place the 2nd or the 11st row (what depend on employing is the top or the bottom of analysis plates) with comparing.Then with in the whole row of intermediate plate each hole with the B row-D row that transfers to fluorescence consistency polystyrene 96 porocyte culture plates (GreinerBioOne) in triplicate or E row-G row, every hole 10 μ l. do not contain to prepare among the phenol red RPMI1640 (Sigma) and contain 5 * 10 being supplemented with 10% foetal calf serum (Sigma) and 20mM L-glutaminate (Sigma) 4The cell solution of individual cell/ml.190 μ l cell solutions are added in each hole of analysis plates, be listed as to the 11st row from the 2nd.190 μ l developing mediums are added to the 1st row and the 12nd row.With plate in 37 ℃ at 5%CO 2The middle cultivation 96 hours.The rezasurin (cell transformation of being survived is fluorescence resofurin) of 1 μ M (final concentration) is dropped in each hole, plate was cultivated 4 hours again.Adopt Envision to read plate instrument (Applied Biosystems) and read fluorescence in 530-570nm exciting light and 580-620nm emission light.Then, by Graphpad PRISM analytical data, obtain IC 50(be defined as and make cell quantity reduce half needed compound concentrations).
The result
Compound IC 50(nM)
19 ＜1
22 ＜1
26 ＜1
27 ＜1
29 ＜1
30 ＜1
32 ＜1
33 ＜1
LOXIMVI and OVCAR-5 clone
Do not contain among the phenol red RPMI1640 (Sigma) preparation to contain concentration be 5 * 10 being supplemented with 10% foetal calf serum (Sigma) and 20mM L-glutaminate (Sigma) 4The cell solution of human melanoma cells of the LOXIMVI of individual cell/ml or OVCAR-5 human ovarian tumour cell.The cell solution of 190 μ l is added in each hole of fluorescence consistency polystyrene 96 porocyte culture plates (Greiner BioOne), be listed as to the 11st row from the 2nd.190 μ l developing mediums are added to the 1st row and the 12nd row.With plate in 37 ℃ at 5%CO 2Middle overnight incubation.Compound is dissolved among the DMSO (Sigma) of 100%Biotech grade, in 2%DMSO, is diluted to storage concentration subsequently.With the storage concentration of 100 μ l in 2%DMSO with 1: 3 serial dilution in the middle polystyrene 96 porocyte culture plates (Nunc).Place outer row to be used as blank 2%DMSO, and place the 2nd or the 11st row (what depend on employing is the top or the bottom of analysis plates) with comparing.Then with the whole row of intermediate plate with in the B row-D row that transfers to Tissue Culture Plate in triplicate or each hole that E row-G arranges, every hole 10 μ l.With plate in 37 ℃ at 5%CO 2The middle cultivation 96 hours.The rezasurin (cell transformation of being survived is fluorescence resofurin) of 1 μ M (final concentration) is added in each hole, plate was cultivated 4 hours again.Adopt Envision to read plate instrument (Applied Biosystems) and read fluorescence in 530-570nm exciting light and 580-620nm emission light.Then, by Graphpad PRISM analytical data, obtain IC 50(be defined as and make cell quantity reduce half needed compound concentrations).
The result
Clone ZC-423IC 50(nM)
LOXIMVI 4.83
OVCAR-5 5.2
Embodiment 10: anti-tumor activity
Following experiment is by Home Office, and London carries out under the project approval of UK approval, and fully according to UK CCCR governing principle (Workman, P., etc., British Journal ofCancer, 77,1-10 (1998)) carry out.
LOX IMVI (human melanoma) is at nude mice (B﹠amp; K Universal, Hull, UK) subcutaneous growth.By trochar tumour is transplanted to veutro with the form of single tumor fragment.With the (iv) predefined maximum tolerated dose of single intravenous injection (MTD) 3mgkg -1Adopt ZC423 that 8 mouse groups of carrying tumour are treated, adopt 5%DMA/ salt solution as solvent.Control mice (n=8) adopts solvent to treat separately.
When tumour can be definitely during with kind of calliper (average area 4 * 4mm) begin treatments, result of treatment by every day kind of calliper tumour size and mouse body weight estimate.Gross tumor volume is by formula a 2* b/2 calculates, wherein a be tumour than minor diameter, b be tumour than major diameter.The results are shown in Figure 1, it is figure (the ■ ZC423 of relative tumour volume and time; ◆ contrast-solvent).By Mann-Whitney analyze (for example, as described in document: Essential Statistics second edition (1989), D.G.Rees, ISBN0412320304, Chapman and Hall, London) activity that shows ZC423 has the remarkable meaning on the statistics.
Fig. 2 shown identical experiment the result (● ZC423; ◆ contrast-solvent), but prolong experimental period, and the scale degree of average RTV amplifies.Control group stopped in the time of 16 days, and compare with the treatment group this moment, and the whole mouse of control group all have tumour to exist, and all animals did not still have tumour to exist in the time of the 68th day in the treatment group.
Under above-mentioned identical condition, adopt OVCAR-5 (human ovarian's tumour) to study.The results are shown in Figure 3 (● ZC423; ◆ contrast-solvent).In this research, control group stopped in the time of 32 days.
Embodiment 11: crosslinked and solubleness
DNA is crosslinked
Closed loop puc18 DNA adopts the HindIII linearizing, and dephosphorylation finally adopts polynucleotide kinase to use [γ 32P]-ATP at 5 ' end mark then.Comprise 10ng DNA and medicine to react on 37 ℃ be that (25mM trolamine, 1mM EDTA pH7.2) carry out in the aqueous buffer solution for 1 * TEOA of 50 μ L in final volume.By adding isopyknic stop bath (0.6M NaOAc, 20mMEDTA, 100 μ g/mL tRNA) termination reaction, use ethanol sedimentation subsequently.After sample is centrifugal, the reject supernatant will precipitate lyophilize.In 10 μ L alkalescence sex change damping fluid (4mg tetrabromophenol sulfonphthalein, 600mg sucrose and 40mg NaOH), vortex is 3 minutes under room temperature with the sample resuspending.The contrast resuspending that will not have a sex change is on 10 μ L standard sucrose in the sample dyestuff (2.5mg tetrabromophenol sulfonphthalein, the blue and 4g sucrose of 2.5mg dimethylbenzene nitrile).Sample and contrast all directly are splined on the sepharose.
Electrophoresis carried out 16 hours on the horizontal sepharose of 0.8% immersion of 20cm length, 38-40V, 1 * TAE electrophoretic buffer (2.42g Tris alkali, 0.372g EDTA, 0.571ml glacial acetic acid).Gel places Savant SG210D SpeedGel gel drying device one deck Whatman3MM to go up in 80 ℃ of dryings 80 minutes, and one deck DE81 filter paper is arranged below.After being exposed to FujiRX x-radiographic film and spending the night, obtain the radio-autograph phasor.Adopt BioRad GS-670 imaging laser light densometer quantitative assay film colour band.Calculate crosslinked percentage by the ratio of measuring in each bar swimming lane total DNA (double-stranded colour band and strand colour band density and) and the amount of double-stranded colour band density.With drug level the percentage level mapping of the crosslinked DNA that measures is obtained dose response curve, can obtain making DNA crosslinked 50% needed amount (XL by it 50).
Solubleness
By the experimental compound dissolving is determined solubleness to obtain the required least quantity of saturated solution.
The result
DNA is crosslinked
Compound IC 50(μM)
18 0.2
19 2
21 0.5
22 0.3
Solubleness
Compound The amount of compound (g) in the 1L water
ZC-207 Insoluble
ZC-423 11
27 9
30 4
33 3
。

Claims (17)

1. formula I compound or its solvate:
Wherein:
R 2Be the optional C that replaces 5-20Aryl;
R 6And R 9Independently be selected from H, R, OH, OR, SH, SR, NH 2, NHR, NRR ', nitro, Me 3Sn and halogen;
Wherein R and R ' independently are selected from the optional C that replaces 1-12Alkyl, C 3-20Heterocyclic radical and C 5-20Aryl;
R 7Be selected from H, R, OH, OR, SH, SR, NH 2, NHR, NHRR ', nitro, Me 3Sn and halogen;
R " is C 3-12Alkylidene group and/or aromatic ring, wherein alkylidene chain can contain one or more heteroatoms;
X is selected from O, S or NH;
Z is 2 or 3;
M is pharmaceutically acceptable univalent cation;
R 2', R 6', R 7', R 9', X ' and M ' be selected from respectively and R 2, R 6, R 7, R 9, group that X is identical with M, perhaps M and M ' can represent pharmaceutically acceptable divalent cation together.
2. the compound of claim 1, wherein X is O.
3. the compound of claim 1 or claim 2, wherein R " represent linear saturated C 3-12Alkylidene group.
4. each compound, wherein R among the claim 1-3 9Be H.
5. each compound, wherein R among the claim 1-4 6Be H.
6. each compound, wherein R among the claim 1-5 7Be selected from H, OH and OR, wherein R is selected from the optional C that replaces 1-7Alkyl, C 3-10Heterocyclic radical and C 5-10Aryl.
7. the compound of claim 6, wherein R 7Be OMe or OCH 2Ph.
8. each compound, wherein R among the claim 1-7 2Be the optional C that replaces 5-7Aryl.
9. the compound of claim 8, wherein R 2Be the optional phenyl that replaces.
10. each compound among the claim 1-9, wherein two PBD monomers are replaced equally.
11. each compound among the claim 1-10, wherein M and M ' are pharmaceutically acceptable univalent cation.
12. the compound of claim 11, wherein M and M ' are Na +
13. each compound among the claim 1-12, wherein z is 3.
14. each compound is used for the treatment of in the method among the claim 1-13.
15. pharmaceutical composition, this pharmaceutical composition contain among the claim 1-13 each compound and pharmaceutical excipient.
16. each compound is used for the treatment of purposes in the medicine of proliferative disease in production among the claim 1-13.
17. each compound is used for the treatment of proliferative disease among the claim 1-13.
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