CN102961387A - Proteasome inhibitor - Google Patents
Proteasome inhibitor Download PDFInfo
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- CN102961387A CN102961387A CN2012103987410A CN201210398741A CN102961387A CN 102961387 A CN102961387 A CN 102961387A CN 2012103987410 A CN2012103987410 A CN 2012103987410A CN 201210398741 A CN201210398741 A CN 201210398741A CN 102961387 A CN102961387 A CN 102961387A
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Abstract
The invention provides a novel compound suitable for a use as a proteasome inhibitor. The invention further provides a pharmaceutical composition containing the compound and a method of using the composition to treat various diseases.
Description
The application is that application number is 200780100142.3, and the applying date is on August 6th, 2007, and the application people is Millennium Pharm Inc., and denomination of invention is divided an application for the Chinese invention patent application of " proteasome inhibitor ".
Technical field
The invention relates to applicable boric acid and the boric acid ester compound of making proteasome inhibitor.The method that the present invention also provides the Pharmaceutical composition that contains the compounds of this invention and uses described combination treatment various diseases.
Background technology
Boric acid and boric acid ester compound represent the various biological activitys that pharmaceutically are suitable for.God flies people such as (Shenvi) at United States Patent (USP) the 4th, 499, and disclose in No. 082 (1985): peptide boric acid (peptide boronic acid) is the inhibitor of some proteolytic enzyme.Cut is received (Kettner) and god flies (Shenvi) at United States Patent (USP) the 5th, 187, No. 157 (1993), United States Patent (USP) the 5th, 242, No. 904 (1993) and United States Patent (USP) the 5th, the peptide boric acid of one class inhibition trypsin-like protease has been described in 250, No. 720 (1993).The people such as Ke Liman (Kleeman) have disclosed the end modified peptide boric acid of N-that suppresses the effect of feritin at United States Patent (USP) the 5th, 169 in No. 841 (1992).The people such as Ken Da (Kinder) have disclosed some boronic acid compounds of anticancer growth at United States Patent (USP) the 5th, 106 in No. 948 (1992).The people such as Ba Qiaofuqin (Bachovchin) have disclosed the boronic acid compounds that suppresses fibroblast activation protein in WO 07/0005991.
Boric acid and boric acid ester compound promise to be the inhibitor of proteasome (being a kind of many catalytic proteins enzyme of responsible most cells internal protein turnover) especially.The people such as Adams (Adams) have described applicable peptide boric acid ester and the boronic acid compounds of making proteasome inhibitor at United States Patent (USP) the 5th, 780 in No. 454 (1998).This document has also been described borate and boronic acid compounds reduces the muscle protein degradation rate, reduces cyclin (cyclin) degraded, the anticancer growth in the activity of NF-κ B in the cell, the degradation rate that reduces p53 albumen in the cell, the inhibition cell and suppresses the purposes that NF-κ B dependent cell adheres to.Inspire confidence in to have disclosed among WO 05/021558 that the people's such as thunder (Furet) the people's such as WO 02/096933, Cha Teji (Chatterjee) WO 05/016859 and cloth takes the people such as pasture Buddhist nun (Bernadini) and the WO 06/08660 and have according to reports proteasome and suppress active other borate and boronic acid compounds.
Nova (Ciechanover) is looked in the west, cell (Cell), 79:13-21 (1994) discloses: proteasome is the Proteolytic enzyme component of Ubiquitin-Proteasome Pathway, and protein is by being combined with a plurality of ubiquitin molecules and being degraded by targeting in this approach.The west is looked into Nova and also disclosed: Ubiquitin-Proteasome Pathway plays a crucial role in various important physiological process.The people such as Li Weite (Rivett), journal of biological chemistry (Biochem.J.) 291:1 (1993) discloses proteasome and shows trypsin, chymase and peptidyl glutamyl peptidase activity.What consist of 26S proteasome catalytic core is the 20S proteasome.The people such as Mike mark (McCormack); biochemistry (Biochemistry) 37:7792 (1998) teaching various peptide substrates decomposed by the 20S proteasome; described substrate comprises Suc-Leu-Leu-Val-Tyr-AMC, Z-Leu-Leu-Arg-AMC and Z-Leu-Leu-Glu-2NA; wherein Suc is the N-succinyl group; AMC is 7-amino-4-methylcoumarin, and 2NA is the 2-naphthylamines.
Proteasome suppresses to have embodied a kind of important New Policy for the treatment of of cancer.Gold people such as (King), science (Science) 274:1652-1659 (1996) has described the important function of Ubiquitin-Proteasome Pathway aspect cell cycle regulation, growth and metastasis of tumours.Author's teaching: many crucial regulation proteins (comprise cyclin and cell cycle protein dependent kinase p21 and p27 during cell cycle
KIP1) temporarily be degraded by Ubiquitin-Proteasome Pathway.Cell needs the orderly degraded of these protein to accelerate cell cycle and to carry out mitosis.
In addition, transcriptional control also needs Ubiquitin-Proteasome Pathway.The Paro shellfish is drawn people such as (Palombella), cell (Cell), and 78:773 (1994) teaching: the activation of transcription factor NF-KB is subject to the regulation and control of the inhibitory κBα degraded of proteasome mediation.NF-κ B plays an important role to the gene that regulation and control relate to immunoreation and inflammatory reaction again.The people such as Rui De (Read), immunity (Immunity) 2:493-506 (1995) teaching: the expression of cell adhesion molecule (for example CD62L, ICAM-1 and VCAM-1) needs Ubiquitin-Proteasome Pathway.Ze Teer (Zetter), cancer biological study literary composition volume (Seminars in Cancer Biology) 4:219-229 (1993) teaching: cell adhesion molecule by the guiding tumor cell in the body at a distance tissue site adhere to and exosmose and from vascular system to body at a distance tissue site adhere to and exosmose and be involved in (in vivo) neoplasm metastasis and angiogenesis in the body.In addition, Bei Ge (Beg) and Baltimore (Baltimore), science (Science) 274:782 (1996) teaching: NF-κ B is a kind of anti-apoptotic controlling elements, and makes cell more responsive to ambient pressure and cytotoxic agent to the inhibition of NF-kB activation.
Proteasome inhibitor
(bortezomib (bortezomib); Bortezomib) is the first proteasome inhibitor that obtains regulator's approval.The people such as Ya De, Meath (Mitsiades), contemporary drug target (Current Drug Targets), 7:1341 (2006) has summarized so that bortezomib gets permission to be used for the treatment of the clinical research of the multiple myeloma patients of having accepted at least a previous therapy.The people such as Fei Sheer (Fisher), Journal of Clinical Oncology (J.Clin.Oncol.), 30:4867 have been described and have a kind ofly been confirmed that the multicenter, international II phase of the activity of bortezomib in relapsed or stubborn lymphoma mantle cell patient studies.The people such as Shi Jing (Ishii), anticarcinogen in the pharmaceutical chemistry (Anti-CancerAgents in Medicinal Chemistry), the people such as 7:359 (2007) and Luo Kaluo (Roccaro), contemporary Pharmaceutical Biotechnology (Curr.Pharm.Biotech.), 7:1341 (2006) has discussed multiple molecular mechanism of facilitating the bortezomib anti-tumor activity.
Proved that by above list of references proteasome is the important target spot of therapeutic intervention.Therefore, constantly need novel and/or improved proteasome inhibitor.
Summary of the invention
The invention provides the chemical compound as effective proteasome inhibitor.These chemical compounds are applicable to, and interior (in vivo) proteasome enzyme inhibition of external (in vitro) and body is active, and is particularly useful for treating various cell proliferation disorders.
The compounds of this invention has general formula (I):
Or its pharmaceutically acceptable salt or boric anhydride, wherein:
Z
1And Z
2Be hydroxyl, alkoxyl, aryloxy group or aralkoxy independently of one another; Or Z
1And Z
2Form together the part that is derived from the boric acid chelating agent; And
Ring A is selected from the group that is comprised of following:
The boronic acid compounds of formula (I) (Z wherein
1And Z
2The hydroxyl of respectively doing for oneself) mentions with following chemical name.
Table 1. proteasome inhibitor
| ? | Chemical name |
| I-1 | [(1R)-and 1-({ [(2,3-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-2 | [(1R)-and 1-({ [(5-chloro-2-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-3 | [(1R)-and 1-({ [(3,5-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-4 | [(1R)-and 1-({ [(2,5-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-5 | [(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-6 | [(1R)-and 1-({ [(2-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-7 | [(1R)-and 1-({ [(2-chloro-5-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-8 | [(1R)-and 1-({ [(4-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-9 | [(1R)-and 1-({ [(3,4-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-10 | [(1R)-and 1-({ [(3-chlorobenzene formacyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-11 | [(1R)-and 1-({ [(2,5-dichloro-benzoyl base) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-12 | [(1R)-and 1-({ [(3,4-dichloro-benzoyl base) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-13 | [(1R)-and 1-({ [(3-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-14 | [(1R)-and 1-({ [(2-chloro-4-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-15 | [(1R)-and 1-({ [(2,3-dichloro-benzoyl base) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-16 | [(1R)-and 1-({ [(2-chlorobenzene formacyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-17 | [(1R)-and 1-({ [(2,4 difluorobenzene formoxyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-18 | [(1R)-and 1-({ [(4-chloro-2-fluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-19 | [(1R)-and 1-({ [(4-chlorobenzene formacyl) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-20 | [(1R)-and 1-({ [(2,4-dichloro-benzoyl base) amino] acetyl group } amino)-3-methyl butyl] boric acid |
| I-21 | [(1R)-and 1-({ [(3,5-dichloro-benzoyl base) amino] acetyl group } amino)-3-methyl butyl] boric acid |
Use separately or refer to have as the term " alkyl " that the part of major part is used straight or branched or the cyclic aliphatic group of 1 to 12 carbon atom.Term " alkoxyl " refers to-the O-alkyl.
Use separately or refer to contain the C of 1 to 3 ring as term " aryl " and " fragrant-" (for example " aralkyl ", " aralkoxy " or " aryloxy alkyl ") that the part of major part is used
6To C
14Aromatic hydrocarbon, described ring be optional being substituted separately.Preferably, aryl is C
6-10Aryl.Aryl includes, but is not limited to phenyl, naphthyl and anthryl." aralkyl " or " aryl alkyl " contains the aryl covalently bound with alkyl, and described alkyl or described aryl be optional being substituted independently of one another.Preferably, aralkyl is C
6-10Aryl (C
1-6) alkyl, C
6-10Aryl (C
1-4) alkyl or C
6-10Aryl (C
1-3) alkyl, include, but is not limited to benzyl, phenethyl and menaphthyl.
Term used herein " be substituted " mean specified portions the hydrogen base by the group displacement of specified substituent, prerequisite is that metalepsis causes stable or chemically feasible chemical compound.The limiting examples of suitable substituent comprises C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkyl (C
3-8) cycloalkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, cyano group, amino, C
1-6Alkyl amino, two (C
1-6) alkyl amino, benzyl are amino, benzhydryl is amino, nitro, carboxyl, carbonyl (C
1-6) alkoxyl, trifluoromethyl, halogen, C
1-6Alkoxyl, C
6-10Aryl, C
6-10Aryl (C
1-6) alkyl, C
6-10Aryl (C
1-6) alkoxyl, hydroxyl, C
1-6Alkyl sulfenyl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
6-10Artyl sulfo, C
6-10Aryl sulfonyl kia, C
6-10Aryl sulfonyl, C
6-10Aryl, C
1-6Alkyl (C
6-10) aryl and halo (C
6-10) aryl.
Phrase used herein " one or more substituent group " refers to the substituent group of some, it equals based on the possible substituent group to maximum number of the number of available one-tenth key mapping point, and prerequisite is to satisfy the condition of aforementioned stable and chemical feasibility.Except as otherwise noted, but otherwise the optional group that is substituted can have substituent group at each the position of substitution of described group, and substituent group can be identical or different.Term used herein " selected independently " means for specifying the multiple situation of code name can select identical or different value in the individualized compound.
Term " about " be used in this article expression approximate, approximately, roughly or about.When term " about " and numerical range are united when using, its by with envelope extension to more than the described numerical value and with that scope of modification of getting off.In general, term " about " is used for modifying the numerical value that is higher or lower than described value 10% in this article.
Term used herein " comprises " and means " including, but is not limited to ".
Except as otherwise noted, otherwise the structure herein is intended to comprise that difference only is to exist the chemical compound of one or more isotope enrichment atoms.For example, except with deuterium or tritium displacement hydrogen atom or with
13C or
14Has the chemical compound of structure of the present invention outside the C enrichment carbon displacement carbon atom within the scope of the present invention.
Term used herein " boric acid " refers to contain-B (OH)
2The chemical compound of part.In certain embodiments, boronic acid compounds can form the oligomerization anhydride by making the boric acid partial dehydration.For instance, the people such as Snyder (Snyder), JACS (J. Am.Chem.Soc.) 80:3611 (1958) has reported the oligomerization aryl boric acid.
Term used herein " boric anhydride " refers to by two or more boronic acid compounds molecules in conjunction with losing simultaneously the formed chemical compound of one or more hydrones.When mixing with water, the boric anhydride chemical compound is discharged free boronic acid compounds by aquation.In various embodiments, boric anhydride can contain two, three, four or more boric acid unit, and can have ring-type or linear configuration.The oligomerization boric anhydride limiting examples of boronic acid compounds of the present invention is as follows.
In formula (1) and (2), code name n is 0 to about 10 integer, is preferably 0,1,2,3 or 4.In certain embodiments, the boric anhydride chemical compound contains the cyclic trimer (" boron oxygen hydrocarbon trimer (boroxine) ") of formula (2), and wherein n is 1.Code name W has formula (3):
Its medium ring A has above about the described value of formula (I).
In certain embodiments, existing at least 80% boric acid exists with single oligomerization anhydride form in the boric anhydride chemical compound.In certain embodiments, existing at least 85%, 90%, 95% or 99% boric acid exists with single oligomerization anhydride form in the boric anhydride chemical compound.In some preferred embodiment, the boric anhydride chemical compound by or basically formed by the boron oxygen hydrocarbon trimer with formula (3).
Preferably can get off to prepare the boric anhydride chemical compound by being exposed to dehydration conditions (include, but is not limited to recrystallize, lyophilizing, be exposed to heat and/or be exposed to desiccant) by corresponding boric acid.The limiting examples of suitable recrystallize solvent comprises ethyl acetate, dichloromethane, hexane, ether, acetonitrile, ethanol and its mixture.
In certain embodiments, Z
1And Z
2Form together the part that is derived from the boric acid chelating agent.For the present invention, term " boric acid chelating agent " refers to any chemical compound with at least two functional groups, and described at least two functional groups can form covalent bond with boron separately.The limiting examples of appropriate functional group comprises amino and hydroxyl.In certain embodiments, at least one functional group is hydroxyl.Term " is derived from the part of boric acid chelating agent " and refers to remove the formed part of hydrogen atom by two functional groups from the boric acid chelating agent.
Term used herein " borate (boronate ester/boronic ester) " refers to contain-B (Z
1) (Z
2) chemical compound of part, Z wherein
1Or Z
2In at least one is alkoxyl, aralkoxy or aryloxy group; Or Z
1And Z
2Form together the part that is derived from the boric acid chelating agent with at least one hydroxyl.
In certain embodiments, Z
1And Z
2Form together to be derived from and have at least two by the part of the chemical compound of the hydroxyl that at least two continuous atoms separated in chain or the ring, described chain or ring contain one or more hetero atoms that carbon atom and (randomly) can be N, S or O, and the atom that wherein links to each other with boron in each situation is oxygen atom.
Term used herein " chemical compound with at least two hydroxyls " refers to any chemical compound with two or more hydroxyls.For the present invention, two hydroxyls preferably by at least two continuous atoms, preferred about 2 to about 5 continuous atoms, more preferably 2 or 3 continuous atoms separate.For convenience's sake, term " dihydroxy compounds " can be used for referring to the chemical compound with at least two hydroxyls of above-mentioned definition.Therefore, term used herein " dihydroxy compounds " is not intended to be limited to only have the chemical compound of two hydroxyls.The part that is derived from the chemical compound with at least two hydroxyls can link to each other with boron by the oxygen atom of any two hydroxyls in its hydroxyl.Preferably, boron atom, the oxygen atom that links to each other with boron form 5 or 6 yuan of rings with the atom that is connected two oxygen atoms.
For the present invention, the boric acid chelating agent is preferably pharmaceutically acceptable, namely is fit to throw with human.In some preferred embodiments, the boric acid chelating agent is sugar.Term " sugar " comprises any polyhydroxy carbohydrate part, comprises monosaccharide and disaccharide, polysaccharide, sugar alcohol and amino sugar.In certain embodiments, sugar is monosaccharide and disaccharide, sugar alcohol or amino sugar.The limiting examples of suitable sugar comprises glucose, sucrose, fructose, trehalose, mannitol, sorbitol, glycosamine and N-METHYL-ALPHA-L-GLUCOSAMINE.In certain embodiments, sugar is mannitol or sorbitol.Therefore, be among the embodiment of mannitol or sorbitol at sugar, Z
1And Z
2Form together formula C
6H
12O
6Part, wherein the oxygen atom of two deprotonated hydroxyl group may and boron form covalently bound and form boric acid ester compound.In some specific embodiment, Z
1And Z
2Form together the part that is derived from PEARLITOL 25C.
In certain embodiments, the people such as formula (I) chemical compound such as pula Meng Dong (Plamondon) are prepared into lyophilized powder described in WO 02/059131, and the full text of this case is incorporated herein by reference accordingly.In certain embodiments, lyophilized powder also comprises free dihydroxy compounds.Preferably, free dihydroxy compounds and formula (I) chemical compound are present in the mixture with the mol ratio in about 0.5: 1 to about 100: 1, more preferably about 5: 1 to about 100: 1 scopes.Be among the various embodiment of mannitol at dihydroxy compounds, lyophilized powder comprises free mannitol and the mannitol borate of mol ratio in about 10: 1 to about 100: 1, about 20: 1 to about 100: 1 or about 40: 1 to about 100: 1 scopes.
In certain embodiments, lyophilized powder comprises mannitol and formula (I) chemical compound, does not contain substantially other component.Yet compositions can further contain other material that one or more other pharmaceutically acceptable excipient, supporting agent, diluent, filler, salt, buffer agent, stabilizing agent, solubilizing agent and industry are known.The preparation that contains the pharmaceutically acceptable preparation of these materials is described in the theory and practice (Remington:The Science and Practiceof Pharmacy) of (for example) Lei Mingdengshi pharmacy, the 20th edition, Zhan Naluo (A.Gennaro) compiles, Donald Lippincott Williams Louis Wilkins (the Lippincott Williams of publishing company; Wilkins), 2000 or latest edition in.
The program preparation of preferably describing in WO 02/059131 according to people such as pula Meng Dong (Plamondon) comprises the lyophilized powder of formula (I) chemical compound.Therefore, in certain embodiments, comprise in order to the method for preparing lyophilized powder: (a) preparation comprises the aqueous mixture of peptide boric acid and dihydroxy compounds; (b) the described mixture of lyophilizing.
General synthetic method
Formula (I) chemical compound can prepare by the known method of one of ordinary skill in the art.Referring to, such as No. the 5th, 780,454, the people's such as Adams (Adams) United States Patent (USP); The open case WO 2005/097809 of the people's such as skin Gus gill (Pickersgill) international monopoly.Shown in the following surface current journey 1 of exemplary route of synthesis.
Flow process 1:
The protected glycine of compound i and N (ii) coupling is carried out subsequently N-end deprotection, thereby compound i ii is provided.The example of appropriate protection base (PG) includes, but is not limited to the acyl group protecting group, for example formoxyl, acetyl group (Ac), succinyl group (Suc) and methoxyl group succinyl group; With the carbamate protecting group, for example tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz) and fluorenylmethyloxycarbonyl (Fmoc).The peptide coupling reaction can change into by the carboxylic moiety that makes in advance compound i i Acibenzolar (for example, O-(N-hydroxy-succinamide) ester), processes to carry out with compound i subsequently.Perhaps, can be by carboxylic acid being contacted with peptide coupling reagent and producing on the spot Acibenzolar.The example of appropriate peptide coupling reagent includes, but is not limited to carbodiimides reagent, for example dicyclohexyl carbodiimide (DCC) or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimides (EDC); Phosphorus reagent, for example benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP); With urea reagent, for example, O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester (TBTU).
Subsequently, make compound i ii and the benzoic acid (ArCO that is substituted
2H) coupling provides compound i v.Above-mentioned peptide coupling condition for compound i and ii coupling also is suitable for making compound i ii and ArCO
2The H coupling.Subsequently, boric acid part deprotection is obtained chemical compound v.Preferably comprising boric acid ester compound iv, organic boronic receptor (acceptor), low-carbon (LC) alkanol, C
5-8Realize deprotection steps by ester interchange (transesterification) in the two-phase mixture of hydrocarbon solvent and aqueous inorganic acid.
Flow process 2:
Perhaps, shown in flow process 2, can put upside down the order of coupling reaction.Thereby, at first make the protected glycine of O (vi) and the benzoic acid (ArCO that is substituted
2Then ester hydrolysis reaction occurs in H) coupling, thereby forms chemical compound vii.Subsequently, describe about flow process 1 as mentioned, realize obtaining chemical compound v with compound i coupling and boric acid deprotection.
Purposes, allotment and dispensing
The invention provides the chemical compound as effective proteasome inhibitor.Can be in external or the hydrolase polypeptide of in vivoassay chemical compound proteasome enzyme inhibition mediation or the ability of protein degradation.
Therefore, in another aspect, the invention provides a kind of method that suppresses one or more peptidase activities of proteasome in the cell, it comprises makes the cell that needs proteasome to suppress contact with chemical compound as herein described or its pharmaceutically acceptable salt, borate or boric anhydride.
The present invention also provides a kind of method that suppresses cell proliferation, and it comprises the cell that makes the described inhibition of needs and contacts with Compound Phase as herein described.Phrase " inhibition cell proliferation " is used for representing comparing with the cell of not contact inhibition agent the compounds of this invention suppresses cell number or Growth of Cells in the cell that contacts ability.Can be by coming counting cells with cell counter or measuring (for example, MTT or WST measure) by cell viability and assess cell proliferation.When cell is entity growth (for example, entity tumor or organ), can assess cell proliferation with the size of the growth of exposing cell not by for example measuring growth with caliper and relatively being touched cell.
Preferably, with the growth phase ratio of exposing cell not, be delayed about at least 50% with the growth of the contacted cell of inhibitor.In various embodiments, compare with exposing cell not, be touched the cell proliferation of cell suppressed at least about 75%, at least about 90%, or at least about 95%.In certain embodiments, phrase " inhibition cell proliferation " comprises with exposing cell not and compares the decreased number that is touched cell.Therefore, the proteasome inhibitor of inhibition cell proliferation can be induced and is touched cell experience growth delay, growth retardation, programmed cell death (being apoptosis) or necrocytosis in being touched cell.
In another aspect, the invention provides a kind of Pharmaceutical composition, it comprises formula (I) chemical compound or its pharmaceutically acceptable salt or boric anhydride, and pharmaceutically acceptable supporting agent.
If use the pharmaceutically acceptable salt of the compounds of this invention in these compositionss, then described salt preferred source is from inorganic or organic acid or alkali.About the summary of acceptable acid addition salts can referring to (such as) people such as Burger (Berge), the theory and practice of pharmaceutical science magazine (J.Pharm.Sci.) 66:1-19 (1977) and Lei Mingdengshi pharmacy (Remington:The Scienceand Practice of Pharmacy), the 20th edition, Zhan Naluo (A.Gennaro) compiles, Donald Lippincott Williams Louis Wilkins (the Lippincott Williams of publishing company; Wilkins), 2000.
The limiting examples of appropriate acid addition salts comprises following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, fumarate, gluceptate (lucoheptanoate), glycerophosphate, Hemisulphate, enanthate, caproate, hydrochlorate, hydrobromate, hydriodate, 2-hydroxyethanesulfonic acid salt, lactate, maleate, methane sulfonates, the 2-naphthalene sulfonate, nicotinate, oxalates, embonate, pectate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, rhodanate, toluene fulfonate and undecylate.
The appropriate base addition salts includes, but is not limited to: ammonium salt; Alkali metal salt, for example lithium salts, sodium salt and potassium salt; Slaine on the alkali, for example calcium salt and magnesium salt; Other multivalent metal salt, for example zinc salt; With the salt that organic base forms, described organic base for example has hexanamine, N-methyl D-glycosamine, tert-butylamine, ethylenediamine, ethanolamine and gallbladder alkali; And with amino acids formed salt, described aminoacid for example has arginine, lysine and like that.In certain embodiments, pharmaceutically acceptable salt is the base addition salts of formula (I) boronic acid compounds, wherein Z
1And Z
2Be hydroxyl.
Term " pharmaceutically acceptable supporting agent " is used in reference in this article with to accept individuality (be preferably mammal, more preferably human) compatible and be suitable for the material that agent of activity is stopped to the target location delivering active agents.For reaching the desired use of activating agent, the toxicity relevant with supporting agent or ill effect (if existence) are preferably with rational risk/benefit ratio quite.
Term " supporting agent ", " adjuvant " or " mediator " be used interchangeably in this article and comprise be suitable for the particular dosage form of wanting arbitrarily and all solvents, diluent and other liquid mediator, dispersion or suspension aids, surfactant, pH adjusting agent, isotonic agent, thickening agent or emulsifying agent, antiseptic, solid binder, lubricant and like that.The theory and practice of Lei Mingdengshi pharmacy (Remington:The Science and Practice of Pharmacy), the 20th edition, Zhan Naluo (A.Gennaro) compiles, Donald Lippincott Williams Louis Wilkins (the Lippincott Williams of publishing company; Wilkins), 2000 disclosed various supporting agents and its known technology of preparing that is used for allocating pharmaceutically acceptable compositions.Unless any conventional supporting agent medium incompatible with the compounds of this invention (for example owing to produce any bad biological effect or not so interact with any other component of harmful mode and pharmaceutically acceptable compositions), otherwise its use is all contained within the scope of the invention.Some examples that can serve as the material of pharmaceutically acceptable supporting agent include, but is not limited to ion-exchanger, aluminium oxide, aluminium stearate, lecithin, serum albumin (for example human serum albumin); Buffer substance, for example phosphate, carbonate, magnesium hydroxide and aluminium hydroxide, glycine, sorbic acid or potassium sorbate; The partial glyceride mixture of saturated vegetable fatty acid; Water, apyrogeneity matter water, salt or electrolyte, for example protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salt; Silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, lanoline; Sugar, for example lactose, glucose, sucrose and mannitol; Starch, for example corn starch and potato starch; Cellulose and its derivant, for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth gum powder, Fructus Hordei Germinatus, gelatin, Talcum, excipient, for example cocoa butter and suppository wax; Oils, for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; Glycols, for example propylene glycol and Polyethylene Glycol; Esters, for example ethyl oleate and ethyl laurate; Agar, alginic acid, isotonic saline solution, Ringer's mixture (Ringer ' s solution); Alcohols, for example ethanol, isopropyl alcohol, hexadecanol and glycerol; Cyclodextrin, for example hydroxypropylβ-cyclodextrin and sulfobutyl ether beta-schardinger dextrin-; Lubricant, for example sodium lauryl sulfate and magnesium stearate; Petroleum hydrocarbon, for example mineral oil and vaseline (petrolatum).According to allotment person's judgement, coloring agent, releasing agent, coating materials, sweeting agent, flavoring agent and aromatizing agent, antiseptic and antioxidant also can be present in the compositions.
The method manufacturing that Pharmaceutical composition of the present invention can be known by industry, such as routine granulation, mixing, dissolving, encapsulation, lyophilizing or emulsifying process etc.Compositions can be made as various forms, comprises granule, precipitate or microgranule, powder (comprising lyophilization powder, Rotary drying powder or spray-dried powders, amorphous powder), tablet, capsule, syrup, suppository, injection, emulsion, elixir, suspension or solution.
According to a preferred embodiment, for to mammal (preferred human) dispensing compositions of the present invention being allocated.These Pharmaceutical compositions of the present invention can be oral, with without the intestinal mode, by nebulizer, with part, per rectum, per nasal, through cheek, transvaginal mode or via the implanted reservoir throw and.That term used herein " without intestinal " comprises is subcutaneous, in the intravenous, intramuscular, intraarticular, synovial membrane, in the breastbone, in the sheath, in the liver, intralesional and intracranial injection or infusion techniques.Preferably, composition oral, intravenous or subcutaneous throwing with.Preparation of the present invention can be designed to fugitive, rapid release or long-acting.Further, chemical compound can the part but not the general mode throw with, for example at the tumor sites place (for example by injection) throw with.
Be used for oral liquid dosage form and include, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except reactive compound, liquid dosage form also can contain the normally used inert diluent of industry, for example water or other solvent, solubilizing agent and emulsifying agent, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, cyclodextrin, dimethyl formamide, oils (especially being Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol and sorbitan carboxylic esters, with and composition thereof.Except inert diluent, Orally administered composition also can comprise adjuvant, for example, and wetting agent, emulsifying agent and suspending agent, sweeting agent, flavoring agent and aromatizing agent.
Can use suitable dispersant or wetting agent and suspending agent to allocate injectable formulation according to known technology, for example the aqueous of sterile injectable or oleagenous suspension.Sterile injectable preparation also can be in sterile injectable solution, suspension or emulsion nontoxic, without intestinal in acceptable diluent or the solvent, for example solution in 1,3 butylene glycol.In acceptable mediator and solvent, spendable have water, Ringer's mixture, U.S.P. and an isotonic sodium chlorrde solution.In addition, conventionally use aseptic expressed oi as solvent or suspension media.For this reason, the expressed oi of any gentleness be can use, synthetic monoglyceride and two glyceride comprised.In addition, in the preparation of injection, use fatty acid, for example oleic acid.Can sterilize to injectable formulation, for example, by filtering via bacteria filter, or by incorporate antibacterial in the aseptic solid composite form, described compositions can be dissolved in before use or be scattered in sterilized water or other sterile injectable medium.Being used for through allotment can be by annotating or by regularly injecting to inject without the compositions of intestinal dispensing, maybe can by continuous infusion throw with.
Be used for oral solid dosage forms and comprise capsule, tablet, pill, powder and granule.In these solid dosage formss, with reactive compound and at least a inertia, pharmaceutically acceptable excipient or supporting agent (for example sodium citrate or dicalcium phosphate) and/or a) filler or extender (starch for example, lactose, sucrose, glucose, mannitol and silicic acid), b) binding agent (carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum), c) wetting agent (for example glycerol), d) disintegrating agent (agar-agar for example, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate), e) resistance solvent (for example paraffin), f) absorption enhancer (for example quaternary ammonium compound), g) wetting agent (for example spermol and glyceryl monostearate), h) absorbent (for example Kaolin and bentonite) and i) lubricant (Talcum for example, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and its mixture mix.In the situation of capsule, tablet and pill, described dosage form also can comprise buffer agent, for example phosphate or carbonate.
Also can use excipient (for example, lactose or toffee and high molecular weight polyethylene glycol and like that) with the solid composite of similar type as the implant in soft filling and the hard-filled gelatin capsule.The solid dosage forms of tablet, dragee, capsule, pill and granule can be prepared as has coating and shell, other coating of for example knowing in enteric coating and the modification of drug technology.It optionally contains opacifier, and only can be or preferentially at the intestinal specific part randomly with the compositions of delayed mode release of active ingredients.The example of spendable embedding composition comprises polymeric material and wax.Also can use excipient (for example, lactose or toffee and high molecular weight polyethylene glycol and like that) with the solid composite of similar type as the implant in soft filling and the hard-filled gelatin capsule.
Reactive compound also can be microencapsulation form with one or more above-mentioned excipient.The solid dosage forms of tablet, dragee, capsule, pill and granule can be prepared as has coating and shell, other coating of for example knowing in enteric coating, controlled release coat and the modification of drug technology.In these solid dosage formss, reactive compound can be mixed with at least a inert diluent (for example sucrose, lactose or starch).As in normal operation, these dosage forms also can comprise other material except inert diluent, for example tabletting lubricant and other compression aids, for example magnesium stearate and microcrystalline Cellulose.In the situation of capsule, tablet and pill, described dosage form also can comprise buffer agent.It optionally contains opacifier, and only can be or preferentially at the intestinal specific part randomly with the compositions of delayed mode release of active ingredients.The example of spendable embedding composition comprises polymeric material and wax.
The dosage form that is used for the throwing of part or percutaneous and the compounds of this invention comprises ointment, paste, emulsifiable paste, lotion, gel, powder, solution, spray, inhalant or paster.Under aseptic condition, active component and pharmaceutically acceptable supporting agent and any required antiseptic or buffer agent are mixed on request.Ophthalmic preparation, ear drop and eye drop also are covered by within the scope of the present invention.In addition, the use transdermal patch is also contained in the present invention, and it has the additional benefit that chemical compound controlled delivery in health is provided.These dosage forms can make by making compound dissolution or being scattered in the suitable media.Also can increase the flux that chemical compound passes skin with absorption enhancer.Can be by rate controlling membranes being provided or coming speed control by chemical compound is scattered in polymeric matrix or the gel.
In certain embodiments, formula (I) chemical compound intravenous throw with.In these embodiments, formula (I) chemical compound (Z wherein
1And Z
2Form together the part be derived from the boric acid chelating agent) can be prepared into the form of above-mentioned lyophilized powder.Preferably be suitable for by interpolation that medicine is thrown and aqueous solvent come composite lyophilized powder.The example of suitable complex solvent includes, but is not limited to water, saline and phosphate buffered saline (PBS) (PBS).Preferably, Application standard (0.9%) saline comes composite lyophilized powder.After composite, equilibrium establishment between boric acid ester compound and corresponding free boronic acid compounds.In certain embodiments, after adding aqueous medium, reach very soon balance, for example within 10-15 minute.The relative concentration of existing borate and boric acid depends on all multiparameters during balance, the boric acid chelating agent that for example exists in the character of pH, temperature, boric acid chelating agent and the lyophilized powder and the ratio of boric acid ester compound.
Pharmaceutical composition of the present invention is preferably in order to throw and to suffer from proteasome mediation sexually transmitted disease (STD) disease or be in the patient among the risk of suffering from proteasome mediation sexually transmitted disease (STD) disease or the recurrence of experience proteasome mediation sexually transmitted disease (STD) disease and allocate.Term used herein " patient " means animal, is preferably mammal, and is more preferably human.Preferred Pharmaceutical composition of the present invention is those compositionss that are used for oral administration medicine supplying, intravenous dispensing or subcutaneous administration through allotment.Yet above-mentioned any dosage form that contains the compounds of this invention for the treatment of effective dose is all complete within the scope of routine test, and therefore, fully within the scope of the present invention.In certain embodiments, Pharmaceutical composition of the present invention can further contain another therapeutic agent.In certain embodiments, described another therapeutic agent be usually treat to suffering from disease or condition of illness patient's throwing and therapeutic agent.
The amount of the reduction that " treatment effective dose " means to be enough to cause that proteasome activity or the proteasome mediation sexually transmitted disease (STD) disease order of severity can detect.The amount of desirable proteins enzyme body inhibitor should depend on inhibitor to the effectiveness of given cell category and treat the required time span of described disease.Should also be clear that, for any particular patient, concrete dosage and therapeutic scheme should depend on various factors, comprise the activity of the particular compound of using, patient's age, body weight, general health situation, sex and diet, dispensing time, excretion rate, drug regimen, treatment doctor's judgement and the order of severity of the specified disease for the treatment of.In the present composition amount of existing other therapeutic agent usually should be no more than with regard to contain this therapeutic agent as usually will throw with regard to the compositions of unique activating agent and amount.Preferably, the scope of the amount of other therapeutic agent can be and contains this therapeutic agent as about 50% to about 100% of common existing amount in the compositions of unique therapeutic activity agent.
In another aspect, the invention provides the method that a kind for the treatment of suffers from proteasome mediation sexually transmitted disease (STD) disease or is in the patient among the risk of suffering from proteasome mediation sexually transmitted disease (STD) disease or the recurrence of experience proteasome mediation sexually transmitted disease (STD) disease.Term used herein " proteasome mediation sexually transmitted disease (STD) disease " comprises by proteasome expresses or active increase is caused or is characterised in that proteasome is expressed or the increase of activity or need any disease, disease or the condition of illness of proteasome activity.Term " proteasome mediation sexually transmitted disease (STD) disease " also comprises any disease, disease or the condition of illness helpful to the inhibition of proteasome activity.
For instance, the compounds of this invention and Pharmaceutical composition are applicable to treat protein (for example, NF κ B, the p27 via being subjected to the proteasome activity regulation and control
Kip, p21
WAF/CIP1, p53) disease that mediates.Associated conditions comprises that inflammatory disease (for example, rheumatoid arthritis, inflammatory bowel, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, dermatosis (for example, atoipc dermatitis, psoriasis)), vascular proliferation sexually transmitted disease (STD) disease (for example, atherosclerosis, restenosis), the eye proliferative disorders (for example, diabetic retinopathy), optimum proliferative disorders (for example, hemangioma), autoimmune disease (for example, multiple sclerosis, tissue and organ rejection response), and the inflammation relevant with infection (for example, immunoreation), the nervus retrogression disease (for example, Alzheimer (Alzheimer ' s disease), parkinson (Parkinson ' s disease), motor neuron disease, neuropathic pain, triplet repeats disease (tripletrepeat disorder), astrocytoma and the nerve degeneration that is caused by alcoholic liver disease), ischemia injury (for example, apoplexy) and cachexia (for example, follow acceleration muscle protein degraded (for example, the nerve injury of various physiological and pathological states, go on a hunger strike, fever, acidosis, HIV infects, cancer and some endocrinopathy)).
The compounds of this invention and Pharmaceutical composition are specially adapted to treat cancer.Term used herein " cancer " refers to a kind of cell disease, it is characterized by the cell differentiation of cell proliferation, the reduction of uncontrolled or imbalance, attacks the ability of surrounding tissue and/or form the ability of new growth in the dystopy site inadequately.Term " cancer " includes, but is not limited to entity tumor and neoplastic hematologic disorder.The disease of skin, tissue, organ, bone, cartilage, blood and blood vessel contained in term " cancer ".Term " cancer " also comprises primary carcinoma and metastatic carcinoma.
The limiting examples of the entity tumor of the available proteasome inhibitor treatment that discloses comprises cancer of pancreas; Bladder cancer; Colorectal carcinoma; Breast carcinoma comprises metastatic breast cancer; Carcinoma of prostate comprises androgen-dependent carcinoma of prostate and Androgen Independent Prostate Cancer; Renal carcinoma comprises (for example) metastatic renal cell cancer; Hepatocarcinoma; Pulmonary carcinoma comprises (for example) nonsmall-cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC) and adenocarcinoma of lung; Ovarian cancer comprises (for example) carrying out property epithelial cancer or Primary peritoneal carcinoma; Cervical cancer; Gastric cancer; Esophageal carcinoma; The incidence cancer comprises (for example) squamous cell carcinoma of the head and neck; Melanoma; Neuroendocrine carcinoma comprises the transitivity neuroendocrine tumor; Brain tumor comprises (for example) glioma, a glioma that tails off, becomes variable shape glucagonoma between Human glioblastoma and adult; Osteocarcinoma; And soft tissue sarcoma.
The limiting examples of the hematologic malignancies of the available proteasome inhibitor treatment that discloses comprises acute myeloid leukemia (AML); Chronic lymphocytic leukemia (CML) comprises accelerated period CML and acute transformation phase CML (CML-BP); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin (Hodgkin ' sdisease, HD); Non-Hodgkin lymphoma (NHL) comprises follicular lymphoma and lymphoma mantle cell; B cell lymphoma; T cell lymphoma; Multiple myeloma (MM); Macroglobulinemia Waldenstron (Waldenstrom ' smacroglobulinemia); Myelodysplastic syndromes (MDS), comprise refractory anemia (RA), refractory anemia with annular sideroblast (RARS), refractory anemia with the too much RAEB (RAEB-T) in (RAEB) and the transformation of germinal cell; With the bone marrow proliferative syndrome.
In certain embodiments, the compounds of this invention or compositions be used for the treatment of suffer from cancer or be in suffer from cancer or the experience cancer return risk among the patient, described cancer is selected from the group that is comprised of multiple myeloma and lymphoma mantle cell.
In certain embodiments, proteasome inhibitor of the present invention and another therapeutic agent unite throw with.But described another therapeutic agent is proteasome enzyme inhibition also, or can work by different mechanisms.In certain embodiments, described another therapeutic agent be usually treat to suffering from disease or condition of illness patient's throwing and therapeutic agent.Proteasome inhibitor of the present invention can with another therapeutic agent with single dosage form or with separate dosage forms throw with.When throw with separate dosage forms and the time, described another therapeutic agent can throw with proteasome inhibitor of the present invention before, simultaneously or afterwards throw with.
In certain embodiments, the proteasome inhibitor of formula (I) and anticarcinogen unite throw with.Term used herein " anticarcinogen " refer to for the purpose for the treatment of cancer to cancered individual throw and any medicament.
The limiting examples of DNA damage chemotherapeutics comprises topoisomerase I inhibitor (for example, irinotecan (irinotecan), topotecan (topotecan), camptothecine (camptothecin) and its analog or metabolite and amycin (doxorubicin)); Topoisomerase II inhibitors (for example, etoposide (etoposide), teniposide (teniposide) and daunorubicin (daunorubicin)); Alkylating agent (for example, melphalan (melphalan), chlorambucil (chlorambucil), busulfan (busulfan), thiophene is for sending (thiotepa), ifosfamide (ifosfamide), carmustine (carmustine), lomustine (lomustine), semustine (semustine), streptozotocin (streptozocin), dacarbazine (decarbazine), methotrexate (methotrexate), ametycin (mitomycinC) and cyclophosphamide (cyclophosphamide)); DNA intercalator (for example, cisplatin (cisplatin), oxaliplatin (oxaliplatin) and carboplatin (carboplatin)); DNA intercalator and free-radical generating agent, for example bleomycin (bleomycin); And nucleoside analogies (for example, 5-fluorouracil (5-fluorouracil), capecitabine (capecitibine), gemcitabine (gemcitabine), fludarabine (fludarabine), cytosine arabinoside (cytarabine), purinethol (mercaptopurine), thioguanine (thioguanine), Pentostatin (pentostatin) and hydroxyurea (hydroxyurea)).
The chemotherapeutics that destroys cellular replication comprises: paclitaxel (paclitaxel), Docetaxel (docetaxel) and related analogs; Vincristine (vincristine), vinblastine (vinblastin) and related analogs; Thalidomide (thalidomide), lenalidomide (lenalidomide) and related analogs (for example, CC-5013 and CC-4047); Protein tyrosine kinase inhibitor (for example imatinib mesylate (imatinib mesylate) and gefitinib (gefitinib)); Proteasome inhibitor (for example, bortezomib); The NF-kB inhibitor comprises I kappa b kinase inhibitor; With cross the protein bound be expressed in the cancer and and then the antibody (for example, Herceptin (trastuzumab), Rituximab (rituximab), Cetuximab (cetuximab) and bevacizumab (bevacizumab)) of downward modulation cellular replication; Raised in cancer, cross and express or the protein of activation or other inhibitor of enzyme with known, described inhibition can be reduced cellular replication.
In order to understand more fully the present invention, statement following preparation example and test case.How these embodiment explanations prepare or test specific compound, but should not be considered as limiting the scope of the invention by any way.
Description of drawings
The specific embodiment
Example
Abbreviation
The DCM dichloromethane
The DIEA diisopropylethylamine
EDCI N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride
The EtOAc ethyl acetate
H hour
The HPLC high performance liquid chromatography
TBTU o-benzotriazole-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester
HOBt I-hydroxybenzotriazole hydrate
The LCMS liquid chromatography mass
Min minute
The holdup time of tr diode array spectrum
Analytical type LC-MS method
Use following gradient to carry out spectral measurement at Symmetry C18-3.5 μ m-4.6 * 50mm post:
Solvent orange 2 A: 2% isopropyl alcohol, 98% water, 10mM NH
4OAc
Solvent B:75% acetonitrile, 25% methanol, 10mM NH
4OAc
| Time [min] | Flow velocity [mL/min] | The percentage ratio of solvent B |
| 0.0 | 1.0 | 5.0 |
| 3.5 | 1.0 | 100.0 |
| 4.9 | 1.0 | 100.0 |
| 5.0 | 1.0 | 5.0 |
Example 1:[(1R)-and 1-({ [(2,3-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid 20D-mannitol (I-1) synthetic
Step 1:[(2, the 3-difluoro benzoyl) amino] methyl acetate
To 2,3-difluoro-benzoic acid (0.190g, 1.2mmol) oxolane (5mL) solution in add glycine methyl ester hydrochloride (0.150g, 1.2mmol), HOBt (0.162g, 1.2mmol), DIEA (0.209mL, 1.2mmol) and EDCI (0.252g, 1.3mmol).Reactant mixture is stirred to spend the night.With saturated sodium bicarbonate solution stopped reaction mixture reaction, and product is allocated among the DCM.Separate organic layer, then remove solvent, obtain [(2,3-difluoro benzoyl) amino] methyl acetate, its not purified next step that namely is used for.
Step 2:[(2, the 3-difluoro benzoyl) amino] acetic acid
In methanol (7mL) solution of [(2,3-difluoro benzoyl) amino] methyl acetate (0.250g, 1.1mmol), add Lithium hydrate (0.053g, 2.2mmol) and water (3mL).Reactant mixture is stirred to spend the night.Mixture water (20mL) dilution and with 1N HCl (5mL) acidify.Product is distributed in DCM/ methanol (4: 1).Use the dried over sodium sulfate organic layer, and remove solvent, obtain [(2,3-difluoro benzoyl) amino] acetic acid, its not purified next step that namely is used for.
Step 3:2,3-two fluoro-N-[2-((1R)-and 3-methyl isophthalic acid-[(3aR, 4R, 6R, 7aS)-3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] Benzoylamide
In dimethyl formamide (10mL) solution of [(2,3-difluoro benzoyl) amino] acetic acid (0.205g, 0.95mmol), add TBTU (0.337g; 1.0mmol) and (1R)-3-methyl isophthalic acid-[(3aS; 4S, 6S, 7aR)-3a; 5; 5-trimethyl six hydrogen-4,6-methylene-1,3; 2-benzo dioxy borine-2-yl] trifluoroacetate (0.362g, 0.95mmol) of fourth-1-amine.Make mixture be cooled to 0 ℃, and drip DIEA (0.498mL, 2.9mmol).Making reactant mixture be warmed up to room temperature and stir spends the night.With 100mL water stopped reaction, and product is allocated among the DCM.Use the dried over sodium sulfate organic layer, and the removal solvent, obtain 2,3-, two fluoro-N-[2-((1R)-3-methyl isophthalic acid-[(3aR, 4R, 6R, 7aS)-3a, 5,5-trimethyl six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] Benzoylamide.
Step 4:[(1R)-and 1-({ [(2,3-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid
To 2,3-two fluoro-N-[2-((1R)-3-methyl isophthalic acid-[(3aR, 4R, 6R, 7aS)-3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] methanol/1N HCl (1: 1) of Benzoylamide (0.536g, 1.2mmol) (1.5mL) adds enanthol (1mL) and boric acid isobutyl ester (0.207g, 2.0mmol) in the solution.Reactant mixture is stirred to spend the night.The enanthol layer separated and concentrate methanol/HCl layer.By reversed-phase HPLC purification of crude product, obtain [(1R)-and 1-({ [(2,3-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid.
Step 5:[(1R)-and 1-({ [(2,3-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid 20D-mannitol (I-1)
To [(1R)-1-({ [(2; the 3-difluoro benzoyl) amino] acetyl group } amino)-the 3-methyl butyl] boric acid (0.085g; 0.26mmol) add PEARLITOL 25C (0.943g, 5.2mmol) in the solution in the tert-butyl alcohol (2mL) and water (5mL).Warm soloution also makes it to stir until all dissolvings.Then solution is freezing and remove solvent by lyophilization, obtain [(1R)-and 1-({ [(2,3-difluoro benzoyl) amino] acetyl group } amino)-3-methyl butyl] boric acid 20D-mannitol (I-1) (0.98g, 97%).
Example 2:[(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid 20D-mannitol (I-5) synthetic
Step 1:[2-((1R)-and 3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] t-butyl carbamate
Through 15 minutes clockwise (1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] trifluoroacetate (4.9g, 10.8mmol), N-α-(tertbutyloxycarbonyl) glycine (1.98g, 11.3mmol) and the TBTU (3.81g of fourth-1-amine, 11.9mmol) drip DCM (25mL) solution of DIEA (5.64mL, 32.4mmol) in the mixture in DCM (100mL).Reactant mixture is stirred spend the night and concentrated.By column chromatography purification of crude product, obtain [2-((1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] t-butyl carbamate (2.5g, 55%).
Step 2:2-amino-N-{ (1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } acetamide
To [2-((1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-and 3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] add the 4M HCl in the diox (5.9mL) in DCM (15mL) solution of t-butyl carbamate (2.5g, 5.9mmol).Reactant mixture is stirred also concentrated in 2 hours, obtain 2-amino-N-{ (1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-and 3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } acetamide, its not purified next step that namely is used for.
Step 3:2-bromo-N-[2-((1R)-and 3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] Benzoylamide
In DCM (2.25mL) solution of 2-bromobenzoic acid (0.124g, 0.62mmol), add EDCI (0.119g, 0.62mmol), HOBt (0.084g, 0.62mmol), N-methylmorpholine (0.185mL, 1.68mmol) and 2-amino-N-{ (1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-and 3a, 5,5-trimethyl, six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } acetamide (0.2g, 0.56mmol).Reactant mixture is stirred also to be concentrated in 2 hours.Extract with residue diluted with water and with EtOAc.Organic solution is merged, use the salt water washing, through MgSO
4Drying is filtered and is concentrated.By column chromatography purification of crude product, obtain 2-bromo-N-[2-((1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] Benzoylamide (0.22g, 78%).
Step 4:[(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid
To 2-bromo-N-[2-((1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethyl six hydrogen-4,6-methylene-1,3,2-benzo dioxy borine-2-yl] butyl } amino)-the 2-oxoethyl] Benzoylamide (0.220g, 0.44mmol) in the solution of methanol/hexane (1: 1) in (2.2mL), add 1N HCl (1mL, 1.0mmol) and boric acid isobutyl ester (0.078g, 0.76mmol).The reactant mixture stirring is spent the night.Concentrated reaction mixture also passes through the reversed-phase HPLC purification, obtain [(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid (0.119g, 73%).
Step 5:[(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid 20D-mannitol (I-5)
To [(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid (0.103g; 0.28mmol) add PEARLITOL 25C (1.01g, 5.5mmol) in the solution in the tert-butyl alcohol (9mL) and water (15mL).Warm soloution also makes it to stir until all dissolvings.Then solution is freezing and remove solvent by lyophilization, obtain [(1R)-and 1-({ [(2-benzoyl bromide) amino] acetyl group } amino)-3-methyl butyl] boric acid 20D-mannitol (I-5) (0.92g, 84%).
To prepare chemical compound in the following table with example 1 or 2 similar methods by suitable initial substance.
Example 2:20S proteasome is analyzed
In 37 ℃ of 1 μ L test compounds that are dissolved in DMSO in the 384 hole black microtitration plates, add 25 μ L and contain human PA28 activator (Boston Biochem, final concentration 12nM) with the mensuration buffer of Ac-WLA-AMC (β 5 selective substrates) (final concentration 15 μ M), add again the mensuration buffer that 25 μ L contain human 20S proteasome (Boston Biochem, final concentration 0.25nM) at 37 ℃ subsequently.Measure buffer and be comprised of 20mM HEPES, 0.5mMEDTA and 0.01%BSA, pH value is 7.4.Read plate device (37 ℃, 380nm excites, 460nm emission, 20 gains) with BMG Galaxy and follow the tracks of reaction.Suppress (DMSO) and 100% with respect to 0% and suppress (10 μ M bortezomib) matched group calculating inhibition percentage ratio.
When measuring when test with this, Compound I-1 all represents the IC50 value less than 50nM to I-21.
Example 3: antiproliferative is measured
100 μ L are supplemented with the suitable cell culture medium (McCoy ' s5A for HCT-116 of 10% hyclone (hero company (Invitrogen)), hero company) HCT-116 in (1000) or other tumor cell inoculation and spend the night 37 ℃ of cultivations in the hole of 96 porocyte culture plates.Test compounds is joined in the hole and plate was cultivated 96 hours at 37 ℃.In each hole, add MTT or WST reagent (10 μ L, Roche Holding Ag (Roche)), and cultivated 4 hours at 37 ℃ by manufacturer is described.For MTT, according to manufacturer specification (Roche Holding Ag) dye solubilization of institute's metabolism is spent the night.Use spectrophotometer (molecular device company (Molecular Devices)) under 595nm (dominant wavelength) and 690nm (reference wavelength), to read the optical density in each hole for MTT, then under 450nm, read the optical density in each hole for WST.For MTT, deduct the reference optical density value from the optical density value of dominant wavelength.Calculate inhibition percentage ratio with the value that is made as 100% DMSO matched group.
Example 4: in-vivo tumour efficacy models
Use No. 263/8 pin of 1mL (Ref#309625 of Bi Di company (Becton Dickinson)) with HCT-116 (2-5 * 10 of the fresh separated in the 100 μ LRPMI-1640 culture medium (Sigma-aldrich (Sigma-Aldrich))
6Individual) or other tumor cell aseptic injection to the subcutaneous space of the right dorsal part of female CD-1 nude mouse (5-8 week age, Charles River company (CharlesRiver)).Perhaps, some heteroplastic transplantation models need the continuous passage of tumor fragment.In these situations, via No. 13 trocar (Bo Puer ﹠amp; (the Popper of Sen Si company; Sons) 7927) with small fragment (about 1mm of tumor tissues
3) be implanted subcutaneously the right dorsal part through anesthesia (3-5% isoflurane/oxygen mixture) C.B-17/SCID mice (5-8 week age, Charles River company).From after the inoculation the 7th day, use slide gauge to measure tumor 2 times weekly.Application standard program (0.5 * (length x width
2)) the calculating gross tumor volume.When gross tumor volume reaches about 200mm
3The time, mice is divided at random some treatment groups and begins to accept Drug therapy.Determine dosage and the time-histories of each experiment based on the result who before from pharmacokinetics/pharmacodynamics and maximum tolerated dose research, obtains.Matched group will accept not contain the mediator of any medicine.Usually, with various dose and time-histories with test compounds (100-200 μ L) via vein (No. 27 pins), oral (No. 20 tube feed pins) or subcutaneous (No. 27 pins) approach throw with.Measure weekly tumor size and body weight for twice, and reach about 2000mm when control tumor
3In time, stop studying.
Although preamble has described in detail the present invention for the purpose of clarity and understanding, these specific embodiments should be regarded as illustrative but not tool is restricted.One of ordinary skill in the art should be appreciated that after reading this disclosure, can do various changes to form and details in the situation that does not break away from true scope of the present invention, and true scope of the present invention should be defined by enclose claims but not specific embodiment.
Patent mentioned herein and scientific and technical literature provide available knowledge for one of ordinary skill in the art.Unless otherwise defined, otherwise all scientific and technical terminologies used herein have with those skilled in the art of the invention and usually understand identical implication.Granted patent, application case and the list of references quoted herein are incorporated herein by reference, and it quotes degree just as specifically and individually indicating each granted patent, application case and list of references have been incorporated into by reference.In the situation of contradiction, should be as the criterion with this disclosure (comprising definition).
Claims (10)
1. formula (I) chemical compound or its boric anhydride be for the preparation of the purposes of medicine for the treatment of cancer,
Wherein:
Z
1And Z
2Be hydroxyl independently of one another; Or
Z
1And Z
2Form together the part that is derived from the boric acid chelating agent.
2. purposes according to claim 1, wherein said medicine and the second therapeutic agent are united to throw and are given.
3. purposes according to claim 2, wherein said the second therapeutic agent are selected from by the DNA damage chemotherapeutics and destroy the group that the chemotherapeutics of cellular replication forms.
4. purposes according to claim 2, wherein said the second therapeutic agent is selected from the group that is comprised of following material: the topoisomerase I inhibitor; Topoisomerase II inhibitors; Alkylating agent; The DNA intercalator; DNA intercalator and free-radical generating agent; The nucleoside analogies; Paclitaxel, the pure and mild related analogs of Taxotere; Vincristine, vinblastine and related analogs; Thalidomide, lenalidomide and related analogs; Proteasome inhibitor; The NF-kB inhibitor; In the cancer that will treat, raised, crossed protein or the enzymeinhibition agent expressing or activate; And with cross the antibody be expressed in the protein bound in the cancer that will treat.
5. purposes according to claim 1, wherein said cancer is multiple myeloma.
6. according to claim 2,3 or 4 described purposes, wherein said cancer is multiple myeloma.
7. purposes according to claim 3, wherein said the second therapeutic agent is Thalidomide, lenalidomide or related analogs.
8. purposes according to claim 1, wherein said cancer is hematologic malignancies, it is selected from myeloid leukemia (AML); Chronic lymphocytic leukemia (CML) comprises accelerated period CML and acute transformation phase CML (CML-BP); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin (HD); Non-Hodgkin lymphoma (NHL) comprises follicular lymphoma and lymphoma mantle cell; B cell lymphoma; T cell lymphoma; Multiple myeloma (MM); Macroglobulinemia Waldenstron; Myelodysplastic syndromes (MDS), comprise refractory anemia (RA), refractory anemia with annular sideroblast (RARS), refractory anemia with the too much RAEB (RAEB-T) in (RAEB) and the transformation of germinal cell; And bone marrow proliferative syndrome.
9. according to claim 2,3 or 4 described purposes, wherein said cancer is hematologic malignancies, it is selected from myeloid leukemia (AML); Chronic lymphocytic leukemia (CML) comprises accelerated period CML and acute transformation phase CML (CML-BP); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin (HD); Non-Hodgkin lymphoma (NHL) comprises follicular lymphoma and lymphoma mantle cell; B cell lymphoma; T cell lymphoma; Multiple myeloma (MM); Macroglobulinemia Waldenstron; Myelodysplastic syndromes (MDS), comprise refractory anemia (RA), refractory anemia with annular sideroblast (RARS), refractory anemia with the too much RAEB (RAEB-T) in (RAEB) and the transformation of germinal cell; And bone marrow proliferative syndrome.
10. purposes according to claim 9, wherein said the second therapeutic agent is Thalidomide, lenalidomide or related analogs.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146542A (en) * | 2015-04-23 | 2016-11-23 | 北京大学 | Curcumin boronic acid derivatives, its preparation method and application |
| CN107249635A (en) * | 2015-02-17 | 2017-10-13 | 千年药物公司 | Combination treatment for treatment of cancer |
| WO2017198194A1 (en) * | 2016-05-19 | 2017-11-23 | 成都奥璟生物科技有限公司 | Boronic acid and borate ester compound and applications thereof |
| CN110357787A (en) * | 2019-08-02 | 2019-10-22 | 苏州艾和医药科技有限公司 | Yi Shazuo meter synthesising process research |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI345465B (en) * | 2003-08-14 | 2011-07-21 | Cephalon Inc | Proteasome inhibitors and methods of using the same |
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2007
- 2007-08-06 CN CN201210398741.0A patent/CN102961387B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107249635A (en) * | 2015-02-17 | 2017-10-13 | 千年药物公司 | Combination treatment for treatment of cancer |
| CN106146542A (en) * | 2015-04-23 | 2016-11-23 | 北京大学 | Curcumin boronic acid derivatives, its preparation method and application |
| WO2017198194A1 (en) * | 2016-05-19 | 2017-11-23 | 成都奥璟生物科技有限公司 | Boronic acid and borate ester compound and applications thereof |
| CN107400142A (en) * | 2016-05-19 | 2017-11-28 | 成都奥璟生物科技有限公司 | A kind of boric acid and boric acid ester compound and its application |
| CN107400142B (en) * | 2016-05-19 | 2019-11-19 | 成都奥璟生物科技有限公司 | A kind of boric acid and boric acid ester compound and its application |
| CN110357787A (en) * | 2019-08-02 | 2019-10-22 | 苏州艾和医药科技有限公司 | Yi Shazuo meter synthesising process research |
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