Claims for Patent: 9,056,141
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Summary for Patent: 9,056,141
Title: | Thiol-ene click chemistry for drug conjugates |
Abstract: | The present invention relates to linker molecules that readily conjugate cellular recognition ligand at one end and drug payload at the other, and are useful in treating or preventing cancer, an autoimmune disease, an inflammatory condition, a central nervous system disorder or an infection. The linker inker molecules of the invention are represented by Formula I, II and III; Linker-Drug compounds represented by Formula IV, V and VI; and Ligand-Linker-Drug conjugates represented by Formula VII, VIII and IX: ##STR00001## |
Inventor(s): | Xu; Ze-Qi (Woodridge, IL), Wang; Qianli (Chicago, IL), Joseph; Augustine Rudolph (Des Plaines, IL), Fang; Zhiqiang (Hawthorn Woods, IL) |
Assignee: | SynChem, Inc. (Elk Grove Village, IL) |
Application Number: | 13/907,427 |
Patent Claims: | 1. A method of preparing a Ligand-Linker-Drug conjugate compound, the method comprising (a) coupling a linker (LK) compound selected from Formula I, II or III ##STR00076##
wherein R.sub.1, R.sub.2 and R.sub.3 are independently selected from H, deuterium, halogen, CN, NO.sub.2, HC(O), CO.sub.2H, C(O)NH.sub.2, S(O).sub.2OH, S(O).sub.2NH.sub.2, a straight or branched C.sub.1-8 alkyl, aryl-C.sub.1-8 alkyl,
heterocycle-C.sub.1-8 alkyl, cyclo(C.sub.3-9)alkyl, aryl, heterocycle, R.sub.4C(O), R.sub.4O, R.sub.4S, R.sub.4S(O), R.sub.4S(O).sub.2, R.sub.4NH, R.sub.4R.sub.5N, C(Y)OR.sub.4, C(Y)SR.sub.4, C(Y)NHR.sub.4, C(Y)NR.sub.4R.sub.5, R.sub.4OC(Y),
R.sub.4SC(Y), R.sub.4NHC(Y), R.sub.4R.sub.5NC(Y), R.sub.4OS(O).sub.2, H--Y--(CH.sub.2CH.sub.2O).sub.m, R.sub.4--Y--(CH.sub.2CH.sub.2O).sub.m, R.sub.4C(Y)--O--(CH.sub.2CH.sub.2O).sub.m, R.sub.4C(Y)--S--(CH.sub.2CH.sub.2O).sub.m,
R.sub.4C(Y)--NH--(CH.sub.2CH.sub.2O).sub.m, R.sub.4C(Y)--N(R.sub.5)--(CH.sub.2CH.sub.2O).sub.m, or --X--Z, wherein the aryl comprises phenyl or naphthyl; the heterocyle comprises a 5 or 6 membered aromatic heterocycle selected from the group consisting
of pyridyl, diazinyl, pyrimidinyl, 5-methoxy pyrimidinyl, (1,2,4)triazine-3,5-dione-6-yl, 6-mercaptopyrimidine-4-yl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, and thienyl a 3 to 9 membered non-aromatic
heterocycle selected from the group consisting of piperazinyl, 4-methyl piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, thiazolidinyl, thiazolinyl, isothiazolidinyl, isothiazolinyl, pyranyl, and morpholinyl; or a polycyclic heterocycle selected
from the group consisting of indolyl, benzthienyl, benzofuranyl, isoindolyl, isobenzothienyl, and isobenzofuranyl; wherein each alkyl, cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups (e.g., 1, 2, or 3 group)
which are each independently halogen, CN, N.sub.3, NO.sub.2, OH, SH, NH.sub.2, HONH, HON.dbd., CO.sub.2H, C(O)NH.sub.2, S(O).sub.2OH, S(O).sub.2NH.sub.2, C.sub.1-8 alkyl, R.sub.4O, R.sub.4S, R.sub.4S(O), R.sub.4S(O).sub.2, R.sub.4NH, R.sub.4R.sub.5N,
R.sub.4ONH, R.sub.4ON.dbd., R.sub.4C(O), R.sub.4C(Y)O, R.sub.4C(Y)S, R.sub.4C(Y)NH, R.sub.4C(Y)N(R.sub.5), C(Y)OR.sub.4, C(Y)SR.sub.4, C(Y)NHR.sub.4, C(Y)NR.sub.4R.sub.5, R.sub.4OC(Y)O, R.sub.4OC(Y)S, R.sub.4OC(Y)NH, R.sub.4OC(Y)NR.sub.5, R.sub.4SC(Y)O,
R.sub.4SC(Y)S, R.sub.4SC(Y)NH, R.sub.4SC(Y)NR.sub.5, R.sub.4NHC(Y)O, R.sub.4NHC(Y)S, R.sub.4NHC(Y)NH, R.sub.4NHC(Y)NR.sub.5, R.sub.4R.sub.5NC(Y)O, R.sub.4R.sub.5NC(Y)S, R.sub.4R.sub.5NC(Y)NH, R.sub.4R.sub.5NC(Y)NR.sub.4, S(O).sub.2OR.sub.4,
S(O).sub.2SR.sub.4, S(O).sub.2NHR.sub.4, S(O).sub.2NR.sub.4R.sub.5, H--Y--(CH.sub.2CH.sub.2O).sub.m, R.sub.4--Y--(CH.sub.2CH.sub.2O).sub.m, R.sub.4C(Y)--O--(CH.sub.2CH.sub.2O).sub.m, R.sub.4C(Y)--S--(CH.sub.2CH.sub.2O).sub.m,
R.sub.4C(Y)--NH--(CH.sub.2CH.sub.2O).sub.m, R.sub.4C(Y)--N(R.sub.5)--(CH.sub.2CH.sub.2O).sub.m, X--(CH.sub.2CH.sub.2O).sub.m, --X--Z, or R.sub.1 and R.sub.2, R.sub.1 and R.sub.3 taken together with the carbon atoms to which they are attached form a
cyclo(C.sub.3-9)alkyl, aryl, or heterocycle, wherein each alkyl, cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups as previously defined; R.sub.4 and R.sub.5 above are independently selected from a straight or
branched C.sub.1-8 alkyl, aryl-C.sub.1-8 alkyl, heterocycle-C.sub.1-8 alkyl, cyclo(C.sub.3-9)alkyl, aryl, heterocycle, or R.sub.4 and R.sub.5 taken together with the nitrogen atom to which they are attached form a cyclo(C.sub.3-9)alkyl, aryl, or
heterocycle, wherein each alkyl, cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups as previously defined; each Y is independently selected from O, S, NH, NR.sub.4, wherein R.sub.4 is defined as above; each Z is
selected from OH, SH, NCS, NCO, NHR.sub.6, CONR.sub.4R.sub.5, CONHR.sub.6, CO.sub.2R.sub.6, C(O)SR.sub.6, C(O)R.sub.6, where R.sub.4 and R.sub.5 are defined as above; R.sub.6 is H, C.sub.1-8 alkyl, cyclo(C.sub.3-9)alkyl, aryl, or heterocycle, wherein
each alkyl, cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups as previously defined; R.sub.7, R.sub.8 are independently selected from H, deuterium, and F; or R.sub.7 and R.sub.8 can be taken together to form
.dbd.O and .dbd.S; Y.sub.2 is independently selected from CH.sub.2, O, S, NH, and NR.sub.4; wherein R.sub.4 is defined as above; each X is a spacer independently selected from: [C(O)].sub.n--W.sub.o--[C(O)].sub.p--{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub-
.s--[C(O)].sub.q-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]- .sub.u--W.sub.r--[C(O)].sub.q-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]-
.sub.u--[C(O)].sub.q--W.sub.r-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]- .sub.u--C(O)--Y.sub.1--W.sub.r-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]-
.sub.u--W.sub.r--C(O)--Y.sub.1--W.sub.r-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]- .sub.u--W.sub.r--Y.sub.1--[C(O)].sub.q--W.sub.r-(AA).sub.t-,
[C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]- .sub.u--W.sub.r--Y.sub.1--C(O)--Y.sub.1--W.sub.r-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m]-
.sub.u-(AA).sub.t-[Y.sub.1--(CH.sub.2CH.sub.2O).sub.m].sub.u--W.sub.r--, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub- .s-(AA)-{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub.s--[Y.sub.1--(CH.sub.2CH.sub.-
2O).sub.m].sub.u--[C(O)].sub.q--W.sub.r-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub- .s-(AA)-C(O)--{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub.s--[Y.sub.1--(CH.sub.2C-
H.sub.2O).sub.m].sub.u--[C(O)].sub.q--W.sub.r-(AA).sub.t-, [C(O)].sub.n--W.sub.o--[C(O)].sub.p--{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub- .s-(AA)-{Y.sub.1--[C(O)].sub.q--W.sub.r}.sub.s--C(O)--[Y.sub.1--(CH.sub.2C-
H.sub.2O).sub.m].sub.u--[C(O)].sub.q--W.sub.r-(AA).sub.t-, wherein each W is selected from a straight or branched C.sub.1-8 alkyl, aryl-C.sub.1-8 alkyl, heterocycle-C.sub.1-8 alkyl, cyclo(C.sub.3-9)alkyl, aryl, or heterocycle, wherein each alkyl,
cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups as previously defined; each AA is an amino acid residue sequence independently selected from the group, consisting of alanine, glycine, isoleucine, leucine,
methionine, phenylalanine, proline, tryptophan, valine, lysine, lysine protected with acetyl or formyl, arginine, arginine protected with tosyl or nitro groups, histidine, ornithine, ornithine protected with acetyl or formyl, citrulline, and combinations
thereof; each m is an integer independently selected from 1 to 20; each n, o, p, q, r and t is an integer independently selected from 0 and 1; when o is 0, n and p cannot be 1; each s is an integer independently selected from 0 to 8; each u is an
integer independently selected from 1 to 8; X.sub.1 and X.sub.2 are independently selected from H, deuterium, --X--Z, wherein X and Z are defined as above, or X.sub.1 and X.sub.2 taken together can form a cyclic ring; each Y.sub.1 is selected from O,
S, NH, NR.sub.4, N--[C(O)].sub.q--W.sub.r--X--Z, wherein R.sub.4, W, X, Z, r and q are defined as above; with a proviso that, when R.sub.1 and R.sub.3 are both H and s is 0, R.sub.7 and R.sub.8 together cannot be .dbd.O in Formula II; with a drug (D)
payload via group Z of the LK and a functional group of D to form a Linker-Drug conjugate compound selected from the formulae ##STR00077## wherein LK is a linker moiety selected from Formula I, II or III; D is a drug moiety independently selected from
the group selected from doxorubicin, vincristine, monomethyl auristatin E, monomethyl auristatin F, monomethyl dolastatin 10, maytansinoids, and calicheamicin; M is a radioisotope selected from .sup.211At, .sup.225Ac, .sup.213Bi, .sup.60Co, .sup.125I,
.sup.131I, .sup.111In, .sup.177Lu, .sup.32P, .sup.223Ra, .sup.186Re, .sup.188Re, .sup.153Sm, .sup.227Th and .sup.90Y; SI is a tethering group or self-immolative moiety that, upon a single activation event when internalized by the target cell or on the
target cell surface, leads to a spontaneous and rapid release of the fully active drug; CL is a metal chelating moiety that is able to chelate and hold the radioisotope and prevent it from premature release and off-target cell destruction; a is an
integer selected from 1 to 10; v and w are integers independently selected from 1 to 10; x is an integer selected from 0 to 9; provided that the sum of w and x does not exceed 10; and (b) reacting a sulfhydryl or thiol group (--SH) on the ligand (LG)
moiety with the double bond on the Linker-Drug conjugate compound selected from Formula IV, V or VI to form a Ligand-Linker-Drug conjugate compound selected from the formulae ##STR00078## wherein D, SI, CL M, a, v, w and x are defined above; LK is a
linker moiety selected from Formula I, II or III and covalently attached to a ligand (LG) through a thioether bond formed between a sulfhydryl or thiol group (--SH) on the LG with the double bond of the LK; and LG is selected from abciximab, adalimumab,
alemtuzumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, certolizumab, cetuximab, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ipilimumab, ibritumomab, infliximab, motavizumab, muronomab-CD3, natalizumab,
ofatumumab, omalizumab, palivizumab, panitumumab, raxibacumab, ranibizumab, rituximab, tocilizumab, tositumomab, trastuzumab, ustekinumab, anti-CD30 antibody cAC10, RGD-peptide homing ligands, 2-[3(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA)
targeting prostate specific membrane antigen (PSMA), epidermal growth factor, vascular endothelial growth factor, steroidal estrogens, somatostatin, bombesin, polyunsaturated fatty acids, lectins, folate, biotin, riboflavin, hyaluronic acid, and
transferrin.
2. A method of claim 1, wherein each X is a spacer. 3. A method of claim 1, wherein each X is non-cleavable spacer when the conjugates contains radioisotopes. 4. A method of claim 1, step (a), wherein the said Linker-Drug conjugate compound of Formula IV, V or VI is formed between the functional group Z present in a linker compound of Formula I, II or III and a functional group, either natively present or chemically introduced, in the drug moiety selected from primary or secondary amine, hydroxyl, sulfhydryl, carboxyl, aldehyde or ketone via a covalent bond by esterification, amidation, reductive amination or aldol reaction. 5. A method of claim 1, wherein step (b) proceeds either under UV irradiation at wavelength of 254 or 365 nm, or via thermal reaction, in the presence of initiator selected from the group consisting of diphenyl 2,4,6-trimethylbenzoyl phosphine oxide, 2,2-dimethoxy-2-phenylacetophenone, benzophenone, DL-Camphorquinone, dimethyl phenyl phosphine, ##STR00079## |
Details for Patent 9,056,141
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Janssen Biotech, Inc. | REOPRO | abciximab | Injection | 103575 | 12/22/1994 | ⤷ Try a Trial | 2032-05-31 |
Genentech, Inc. | RITUXAN | rituximab | Injection | 103705 | 11/26/1997 | ⤷ Try a Trial | 2032-05-31 |
Idec Pharmaceuticals Corp. | RITUXAN | rituximab | Injection | 103737 | 02/19/2002 | ⤷ Try a Trial | 2032-05-31 |
Hoffmann-la Roche Inc. | ZENAPAX | daclizumab | Injection | 103749 | 12/10/1997 | ⤷ Try a Trial | 2032-05-31 |
Novartis Pharmaceuticals Corporation | SIMULECT | basiliximab | For Injection | 103764 | 05/12/1998 | ⤷ Try a Trial | 2032-05-31 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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