EP3609885A1 - Plateforme tétrazine modulaire biocompatible - Google Patents
Plateforme tétrazine modulaire biocompatibleInfo
- Publication number
- EP3609885A1 EP3609885A1 EP18711598.5A EP18711598A EP3609885A1 EP 3609885 A1 EP3609885 A1 EP 3609885A1 EP 18711598 A EP18711598 A EP 18711598A EP 3609885 A1 EP3609885 A1 EP 3609885A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- formula
- alkyl
- groups
- spacer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- -1 folic acid Chemical class 0.000 claims description 83
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 230000000975 bioactive effect Effects 0.000 claims description 45
- 239000002254 cytotoxic agent Substances 0.000 claims description 40
- 229940127089 cytotoxic agent Drugs 0.000 claims description 40
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 40
- 239000000523 sample Substances 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000006850 spacer group Chemical group 0.000 claims description 32
- 238000005063 solubilization Methods 0.000 claims description 29
- 230000007928 solubilization Effects 0.000 claims description 29
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 235000018102 proteins Nutrition 0.000 claims description 23
- 102000004169 proteins and genes Human genes 0.000 claims description 23
- 108090000623 proteins and genes Proteins 0.000 claims description 23
- 239000002105 nanoparticle Substances 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 14
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 238000012633 nuclear imaging Methods 0.000 claims description 13
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 12
- 150000003573 thiols Chemical class 0.000 claims description 12
- 150000001336 alkenes Chemical class 0.000 claims description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 10
- 150000001345 alkine derivatives Chemical class 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 235000018417 cysteine Nutrition 0.000 claims description 8
- 238000002059 diagnostic imaging Methods 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 229960002685 biotin Drugs 0.000 claims description 7
- 235000020958 biotin Nutrition 0.000 claims description 7
- 239000011616 biotin Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000012038 nucleophile Substances 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- 150000001925 cycloalkenes Chemical class 0.000 claims description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
- 239000002502 liposome Substances 0.000 claims description 6
- 150000003384 small molecules Chemical class 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims description 5
- 229920001184 polypeptide Polymers 0.000 claims description 5
- 108090001008 Avidin Proteins 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- KDUIUFJBNGTBMD-DLMDZQPMSA-N [8]annulene Chemical compound C/1=C/C=C\C=C/C=C\1 KDUIUFJBNGTBMD-DLMDZQPMSA-N 0.000 claims description 4
- VBOOPDOMANCLLY-UHFFFAOYSA-N bicyclo[6.1.0]non-7-ene Chemical compound C1CCCCC=C2CC21 VBOOPDOMANCLLY-UHFFFAOYSA-N 0.000 claims description 4
- 239000004913 cyclooctene Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052737 gold Inorganic materials 0.000 claims description 4
- 239000010931 gold Substances 0.000 claims description 4
- 230000000269 nucleophilic effect Effects 0.000 claims description 4
- 239000000816 peptidomimetic Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 229920002643 polyglutamic acid Polymers 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 101800002638 Alpha-amanitin Proteins 0.000 claims description 3
- 108091023037 Aptamer Proteins 0.000 claims description 3
- 108010093488 His-His-His-His-His-His Proteins 0.000 claims description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 3
- 108010090804 Streptavidin Proteins 0.000 claims description 3
- CIORWBWIBBPXCG-SXZCQOKQSA-N alpha-amanitin Chemical compound O=C1N[C@@H](CC(N)=O)C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H]([C@@H](C)[C@@H](O)CO)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@H]1C[S@@](=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-SXZCQOKQSA-N 0.000 claims description 3
- 108010044540 auristatin Proteins 0.000 claims description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 3
- 229930195731 calicheamicin Natural products 0.000 claims description 3
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 claims description 3
- 229960005501 duocarmycin Drugs 0.000 claims description 3
- 229930184221 duocarmycin Natural products 0.000 claims description 3
- 229960000304 folic acid Drugs 0.000 claims description 3
- 235000019152 folic acid Nutrition 0.000 claims description 3
- 239000011724 folic acid Substances 0.000 claims description 3
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000003381 solubilizing effect Effects 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- WHBRHLKBQMWTLR-UHFFFAOYSA-N 1,2-difluorocyclooctene Chemical compound FC1=C(CCCCCC1)F WHBRHLKBQMWTLR-UHFFFAOYSA-N 0.000 claims description 2
- SHDPRTQPPWIEJG-UHFFFAOYSA-N 1-methylcyclopropene Chemical compound CC1=CC1 SHDPRTQPPWIEJG-UHFFFAOYSA-N 0.000 claims description 2
- IELMMGIVWJNLEX-UHFFFAOYSA-N 3,3-difluorocyclooctyne Chemical compound FC1(F)CCCCCC#C1 IELMMGIVWJNLEX-UHFFFAOYSA-N 0.000 claims description 2
- XXRGLCKZBCIEKO-DLMDZQPMSA-N azocine Chemical compound C/1=C/C=C\N=C/C=C\1 XXRGLCKZBCIEKO-DLMDZQPMSA-N 0.000 claims description 2
- SBTXYHVTBXDKLE-UHFFFAOYSA-N bicyclo[6.1.0]non-6-yne Chemical compound C1CCCC#CC2CC21 SBTXYHVTBXDKLE-UHFFFAOYSA-N 0.000 claims description 2
- FYECUAIUGWFPJF-UHFFFAOYSA-N bicyclo[6.1.0]nonane Chemical compound C1CCCCCC2CC21 FYECUAIUGWFPJF-UHFFFAOYSA-N 0.000 claims description 2
- UXPUKMYHKDMQLC-UHFFFAOYSA-N cyclooct-2-yn-1-ol Chemical compound OC1CCCCCC#C1 UXPUKMYHKDMQLC-UHFFFAOYSA-N 0.000 claims description 2
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004914 cyclooctane Substances 0.000 claims description 2
- FBMMEHJLWTZKOR-UHFFFAOYSA-N cycloocten-1-ol Chemical compound OC1=CCCCCCC1 FBMMEHJLWTZKOR-UHFFFAOYSA-N 0.000 claims description 2
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 claims description 2
- ZPWOOKQUDFIEIX-UHFFFAOYSA-N cyclooctyne Chemical compound C1CCCC#CCC1 ZPWOOKQUDFIEIX-UHFFFAOYSA-N 0.000 claims description 2
- VNXBKJFUJUWOCW-UHFFFAOYSA-N methylcyclopropane Chemical compound CC1CC1 VNXBKJFUJUWOCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 21
- 239000000543 intermediate Substances 0.000 abstract description 15
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 238000005698 Diels-Alder reaction Methods 0.000 abstract description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 42
- 238000003384 imaging method Methods 0.000 description 41
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 206010028980 Neoplasm Diseases 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- 125000001309 chloro group Chemical group Cl* 0.000 description 23
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical class [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 22
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 21
- 235000019253 formic acid Nutrition 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000012043 crude product Substances 0.000 description 20
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 19
- 238000011894 semi-preparative HPLC Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
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- 239000003480 eluent Substances 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 14
- 229940055742 indium-111 Drugs 0.000 description 14
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002595 magnetic resonance imaging Methods 0.000 description 12
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
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- 229960000575 trastuzumab Drugs 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical group P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 10
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 9
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- 125000004429 atom Chemical group 0.000 description 5
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- 229910021645 metal ion Inorganic materials 0.000 description 5
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- HTJMXYRLEDBSLT-UHFFFAOYSA-N 1,2,4,5-tetrazine Chemical compound C1=NN=CN=N1 HTJMXYRLEDBSLT-UHFFFAOYSA-N 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
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- 238000004458 analytical method Methods 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
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- HCZMHWVFVZAHCR-UHFFFAOYSA-N 2-[2-(2-sulfanylethoxy)ethoxy]ethanethiol Chemical compound SCCOCCOCCS HCZMHWVFVZAHCR-UHFFFAOYSA-N 0.000 description 3
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 3
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- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 3
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- 125000003636 chemical group Chemical group 0.000 description 3
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- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical compound C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 3
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
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- LJZHQOFHXBAAAE-UHFFFAOYSA-N n-ethylethanamine;2,2,2-trifluoroacetic acid Chemical compound CC[NH2+]CC.[O-]C(=O)C(F)(F)F LJZHQOFHXBAAAE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 108091008104 nucleic acid aptamers Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
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- 229930010796 primary metabolite Natural products 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 230000009257 reactivity Effects 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Definitions
- the present invention relates to the field of medical imaging agents, in particular bi-modal imaging agents and / or theriagnostic agents.
- the invention aims in particular to allow specific labeling of biomolecules by imaging probes.
- the invention relates to a trifunctionalized platform of formula (I), as described below, which makes it possible to conjugate a bioactive vectorizing agent to at least one imaging probe, and whose third functionality can be a second probe.
- imaging application in bimodal imaging
- cytotoxic agent application in theragnostics
- affinity agent an affinity agent or a solubilizing agent.
- the invention also relates to a method for synthesizing these trifunctionalized platforms by Diels-Alder reaction with inverse electronic demand from a bifunctionalized tetrazine of formula (II) which can itself be obtained from a monofunctionalized tetrazine of formula (IV) ( Figure 1).
- the invention further relates to the mono- and bi-functionalised intermediate tetrazine platforms of formulas (IV) and (II) respectively.
- biomolecules such as for example proteins such as antibodies or peptides
- imaging probes and / or cytotoxic agents are booming and aims to provide powerful tools for chemical biology or human medicine.
- biotin-labeled proteins and fluorophores are used daily as probes to explore cell biology.
- Peptides or antibodies, conjugated to imaging probes serve as diagnostic agents in
- Rigorous control of the conjugation site on the biomolecule has been shown to be critical. Indeed, the number and location of imaging probes or cytotoxic agents attached to a biomolecule can have a strong impact on its biodistribution, image quality or therapeutic activity. In addition, random labeling of biomolecules can pose reproducibility problems, especially when switching to large-scale production, and makes it difficult for regulators to obtain marketing authorizations.
- thermoreactive potential ADC Maruani et al., Org Biomol Chem, 2016, 14, 6165-6178.
- Xu et al. have developed hetero-bivalent imaging and therapy agents that target two receptors on the surface of a specific cell to improve cell al., PNAS, 2012, 109, 21295-21300).
- FIRE I LLE OF REM PLACEM ENT (RULE 26) - Biocompatible, that can be carried out under mild conditions to preserve the integrity of sensitive constituents such as for example proteins or fluorophores;
- the present invention proposes a modular method implementing a trifunctional platform, making it possible to bind two biomolecule markers retro-vertically.
- the amino acid by which it is coupled to the trifunctional platform may be a non-natural amino acid, or a cysteine introduced by well known methods such as site-directed mutagenesis.
- the present invention provides a labeling method having excellent selectivity for the thiol functions of cysteines relative to the amine or hydroxyl functions of lysines and serines, respectively, or other potentially reactive functions present on bioactive groups such as peptides or antibodies.
- the method of the present invention is modular and allows access to the doubly labeled biomolecule in only two or three synthetic steps.
- the biomolecule can be introduced during the last stage, which makes it possible to limit its degradation during the intermediate stages if it is very sensitive or in the case of an unstable biomolecule.
- it can be introduced before the second marking, thus facilitating the optimization of double labeling and allowing pre-targeting approaches.
- the synthesis method of the invention can be carried out under extremely mild conditions and in an aqueous medium, compatible with fragile biomolecules, such as proteins or antibodies.
- the invention therefore relates to a compound of formula (I)
- R 1, R 2 and R 3 are as defined below, in particular R 1, R 2 and R 3 each independently represent a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group; with the proviso that at least one of R 1 and R 2 is a detectable group, and at least one of R 2 and R 3 is a bioactive group.
- the detectable group is selected from a fluorophore, a chromophore, a probe for nuclear imaging, an MRI probe;
- the bioactive group is chosen from an antibody, a peptide, a peptidomimetic, a protein, a small molecule such as folic acid, an aptamer, a nanoparticle or a liposome;
- the cytotoxic agent is chosen from auristatin monomethyl E, maytansinoide DM1, Duocarmycin, Calicheamicin, alpha-amanitine, a group carrying a radiometal, a silica nanoparticle or a gold nanoparticle;
- the affinity group is selected from biotin, avidin, streptavidin and a hexa-histidine peptide
- the solubilizing group is selected from linear or branched poly (ethylene glycol) chains, linear or branched poly (glutamic acid) chains and cholesterol.
- the invention further relates to a pharmaceutical composition comprising a compound of formula (I) according to the invention and a pharmaceutically acceptable carrier.
- the invention also relates to the use of the compound of formula (I) according to the invention as a medicament and / or for medical imaging.
- the invention also relates to a method for synthesizing a compound of formula (I) according to the invention, comprising bringing into contact a bifunctionalized tetrazine of formula (II):
- R 1 and R 2 are as defined below, in particular R 1 and R each independently represent a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a group solubilization; provided that at least one of R 1 and R 2 is a detectable group; with an alkyne or an alkene of formula (III)
- the synthesis method of the invention further comprises a preliminary step of forming the bifunctionalized tetrazine of formula (II) by nucleophilic substitution on a monofunctionalized tetrazine of formula (IV):
- R 1 represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group; in the presence of a thiol of formula (V)
- R 2 represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group; provided that at least one of R 1 and R 2 is a detectable group.
- the synthesis method of the invention further comprises a preliminary step of forming monofunctionalized tetrazine of formula (IV) by nucleophilic mono substitution of a tetrazine of formula (VI):
- R 1 L 1 - X 1 -H (VII) wherein X, L and R are as defined below, in particular R represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group.
- the invention further relates to an intermediate compound of formula (II)
- R 1 and R 2 are as defined below, in particular R 1 and R each independently represent a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a group solubilization; provided that at least one of R 1 and R 2 is a detectable group.
- the invention also relates to an intermediate compound of formula (IV)
- R 1 represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group.
- the invention also relates to the use of the compound of formula (IV) wherein X 1 is S, to selectively functionalize thiol functions of cysteines of a biomolecule selected from peptides, polypeptides, proteins or antibodies.
- the invention also relates to the use of the compound of formula (II) or a compound of formula (IV) as a synthetic intermediate to obtain the compound of formula (I).
- alkenyl refers to any linear or branched hydrocarbon chain carrying at least one double bond of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, such as for example ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and isomers thereof, 2-hexenyl and isomers thereof, 2,4-pentadienyl.
- alkoxy refers to a -O-alkyl group.
- alkynyl refers to any linear or branched hydrocarbon chain bearing at least one triple bond, of 2 to 12 carbon atoms, preferably of 2 to 6 carbon atoms, such as for example ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and isomers thereof.
- chelating agent refers to a polydentate molecule capable of forming coordination bonds with a metal ion to form a metal complex, also called chelate.
- alkylaryl refers to an aryl group substituted by an alkyl group and may be: -aryl-alkyl.
- alkyl refers to any saturated linear or branched hydrocarbon chain, from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, t-butyl, pentyl and its isomers (eg n-pentyl, iso-pentyl), hexyl and its isomers (eg n-hexyl, isohexyl).
- alkylheteroaryl refers to an alkyl-substituted heteroaryl group and may be: -heteroaryl-alkyl.
- antibodies refers to gamma globulin proteins found in blood or other vertebrate body fluids, and is used by the immune system to identify and neutralize foreign bodies, such as bacteria and viruses. virus.
- the antibodies consist of two pairs of polypeptide chains, called heavy chains and light chains, which are arranged in the form of a Y.
- antibody as used herein includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, chimeric or hybrid antibodies, single domain antibodies, dimer or trimeric antibody fragment constructs or minibodies.
- arylalkyl refers to an alkyl group substituted with an aryl group and may be: -alkyl-aryl.
- aryl refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (eg phenyl) or multiple fused (eg naphthyl) or covalently linked (eg, biphenyl) aromatic rings, typically containing 5 to 15 carbon atoms. ; preferably 6 to 10, wherein at least one ring is aromatic.
- the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
- Non-limiting examples of aryl groups include phenyl, biphenylyl, biphenylenyl, 5 or 6 tetralinyl, naphthalene-1- or -2-yl, 4, 5, 6 or 7-indenyl, 1- 2-, 3-, 4 or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4 tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.
- chelate refers to a molecule comprising a metal ion. Chelation (or complexation) involves the formation or presence of two or more distinct coordination bonds between a polydentate molecule (allowing multiple bonds) and a single central metal atom. Polydentate molecules are often organic compounds, and are called chelating agents, chelating agents, ligands, or sequestering agents.
- cycled alkyne or cyclic alkene means that alkyne or alkene, present in this cycle, undergoes a stress called cycle voltage, which increases its internal energy, thus making it more reactive than its equivalent. acyclic.
- cycloalkene refers to a non-aromatic cyclic or polycyclic alkene group, optionally bridged, optionally fused with one or more aryl groups; preferably a cyclooctenyl, bicyclo [6.1.0] nonene, norbornene, 5,6-dihydrodibenzo [a, e] [8] annulenyl group.
- cycloalkyl refers to a cyclic or polycyclic alkyl group, optionally bridged, optionally fused with one or more aryl groups; preferably a cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, norbornyl, bicyclo [6.1.0] nonyl group.
- dienophiles refers to a group of atoms capable of reacting with a diene via a [4 + 2] cycloaddition reaction; preferably an alkyne or an alkene.
- spacer refers to a covalent bond or a group comprising a series of stable covalent bonds, the group having from 1 to 40 multivalent atoms selected from the group consisting of C, N, O, S and P; covalently bonding two parts of the compounds of the invention.
- the number of multivalent atoms in a spacer may be, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25 or 30.
- a spacer may be linear or not linear; some spacers have side chains or pendant functional groups (or both). Examples of such side chains are hydrophilicity modifiers, for example solubilizing groups such as, for example, sulfo (-SO 3 H or -SO 3 - ) or carboxylate (-COO).
- a spacer is composed of any combination of single, double, triple or aromatic carbon-carbon, carbon-nitrogen, nitrogen-nitrogen, carbon-oxygen, and carbon-sulfur bonds.
- the spacers may consist of a combination of groups chosen from alkyl groups, -C (O) NH-, -NHC (O) -, -C (O) Ar-, -ArC (O) -, -C (O) O-, -NH-, -S-, -O-, -C (O) -, -S (O) n - where n is 0, 1 or 2; monocyclic 5- or 6-membered rings and functional side chains (eg, sulfo, hydroxy or carboxy).
- leaving group refers to a group that brings the two electrons of the sigma bond connecting it with the aromatic carbon atom during the substitution reaction by the nucleophile.
- halogen refers to fluoro, chloro, bromo, iodo or astato groups, preferably chloro.
- heteroaryl refers to aromatic rings of 5 to 15 carbon atoms or ring systems containing from 1 to 3 rings which are fused together or covalently bound, typically containing 5 to 6 carbon atoms and at least one ring is aromatic; in which one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms; the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen atoms can optionally be quaternized.
- Such cycles can be
- FIRE I LLE OF REM PLACEM ENT fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group.
- heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo [2,1b] [1,3] thiazolyl, thieno [3,2-b] furanyl, thieno [3,2-b] thiophenyl, thien
- heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group and may be: -alkyl-heteroaryl.
- heterocycloalkene refers to a cycloalkene group as defined above, wherein one or more carbon atoms are replaced by one or more heteroatoms selected from O, S, N; preferably the heterocycloalkene group is 5,6-dihydrodibenzo [b, f] azocine.
- medical imaging refers to a set of techniques consisting of imaging different regions or different organs of the body from different physical phenomena such as X-ray absorption, fluorescence, nuclear magnetic resonance, ultrasonic wave reflection or radioactivity.
- lipid refers to hydrophobic or amphiphilic molecules, including but not limited to fats, waxes, sterols, fat-soluble vitamins, mono-, di- and triglycerides, or phospholipids.
- liposome refers to an artificial vesicle formed by concentric lipid bilayers, trapping aqueous compartments therebetween.
- FIRE I LLE OF REM PLACEM ENT (RULE 26)
- a wide variety of amphiphilic lipids can be used to form liposomes, the most commonly used being phospholipids.
- peptide refers to a linear amino acid polymer in which the amino acids are linked together by peptide bonds.
- peptidomimetic refers to a compound designed to mimic a biologically active peptide but having structural differences giving it more advantages for its function as a drug.
- protein refers to a functional entity consisting of one or more peptides and optionally non-peptide co-factors.
- nanoparticle refers to a particle having a size ranging from 1 to 100 nm; in particular, the nanoparticle may be a liposome, an iron oxide nanoparticle, a silica nanoparticle (for example, an AGuIX nanoparticle) or a gold nanoparticle.
- tetrazine refers to the reactive functional group consisting of a six-membered aromatic ring containing four nitrogen atoms and two carbon atoms. This heterocycle has three distinct isomers by the relative position of the carbon and nitrogen atoms: 1,2,3,4-tetrazine, 1,2,3,5-tetrazine and 1,2,4,5- tetrazine. In the present invention, tetrazine refers to 1,2,4,5-tetrazine.
- vehicle refers to a substance that carries the product of interest in a composition, particularly it can be a substance that dissolves it.
- the vehicle may for example be water.
- pharmaceutically acceptable carrier refers to an inert vehicle or carrier used as a solvent or diluent in which the active agent is formulated and / or administered, and which does not produce an adverse, allergic or other reaction when it is administered to an animal, preferably a human being. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption retarders and other similar ingredients.
- preparations must meet standards of sterility, general safety and purity, as required by regulatory authorities, such as the FDA or EMA.
- the invention relates to a trifunctionalized platform, preferably of formula (I) as described below, functionalized by at least one biomolecule (or more generally a bioactive group) and at least one imaging probe, and whose third functionality may be another imaging probe (application in bimodal imaging), a cytotoxic agent (application in theragnostics), an affinity group or a solubilization group.
- a trifunctionalized platform preferably of formula (I) as described below, functionalized by at least one biomolecule (or more generally a bioactive group) and at least one imaging probe, and whose third functionality may be another imaging probe (application in bimodal imaging), a cytotoxic agent (application in theragnostics), an affinity group or a solubilization group.
- the invention relates to a trifunctionalized lateform of formula (I):
- ring A represents a cycloalkyl, cycloalkene or heterocycloalkene group, optionally substituted with one or more groups selected from alkyl, aryl, halo, hydroxy and heteroaryl; preferably A is bicyclo [6.1.0] nonane, cyclooctane, bicyclo [6.1.0] nonene, cyclooctene, difluorocyclooctene, hydroxycyclooctene, methylcyclopropane, norbornene, 5,6-dihydrodibenzo [a, e] [8] annulene, 6-dihydrodibenzo [b, f] azocine;
- X represents S, NH or O; preferably X is S or NH;
- L 1, L 2 and L 3 each independently represent a single bond or a spacer selected from alkyl, alkoxy, aryl, arylalkyl, alkylaryl,
- FIRE I LLE OF REM PLACEM ENT (RULE 26) heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl and alkynyl, wherein the alkyl groups are optionally interrupted and / or terminated by one or more groups selected from -O-, -NH-, -S-, -C (O) -, -C (0) NH- and -
- L 1, L 2 and L 3 each independently represent an alkyl or alkylaryl spacer, optionally interrupted and / or terminated with one or more groups selected from -O-, -C (O) -, -NH- and -NHC (O ) -; even more preferably, L 1, L 2 and L 3 each independently represent a spacer selected from -CH 2 CH 2 NH-, -NHCH 2 CH 2 NH-,
- R 1, R 2 and R 3 each independently represent a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group; with the proviso that at least one of R 1 and R 2 is a detectable group, and at least one of R 2 and R 3 is a bioactive group.
- Ring A is obtained by Diels-Alder inverse electron demand reaction between a 1,2,4,5-tetrazine of formula (II) and a dienophile molecule of formula (III) as described below.
- the Diels-Alder inverse electron demand reaction between a 1,2,4,5-tetrazine and a dienophile e.g. an alkene or an alkyne
- a dienophile e.g. an alkene or an alkyne
- the dihydropyridazine product may optionally undergo an additional oxidation reaction to form the corresponding pyridazine.
- Dienophiles useful for this invention include, but are not limited to, carbonaceous dienophiles such as alkenes or alkynes, preferably a "constrained" cyclic alkyne or alkene. According to a preferred embodiment, the dienophile is preferably a bicyclononyne or a trans-cyclooctene.
- detecttable group refers to a chemical moiety that can be detected, directly or after modification, using imaging techniques known to those skilled in the art.
- the detectable group is chosen from fluorophores; chromophores; probes for nuclear imaging; MRI probes.
- the imaging techniques for detecting such a detectable group include: nuclear imaging, including positron emission tomography (PET), single photon emission computed tomography (TEMP) and Cerenkov Luminescence imaging (CLI); magnetic resonance imaging (MRI); optical imaging; fluorescence imaging.
- nuclear imaging including positron emission tomography (PET), single photon emission computed tomography (TEMP) and Cerenkov Luminescence imaging (CLI); magnetic resonance imaging (MRI); optical imaging; fluorescence imaging.
- the detectable group can be detected directly, as present on the compound of the invention by an imaging technique.
- the detectable group must be modified before being able to be detected by an imaging technique. This is the case when the detectable group is in the form of a chelating agent. In this case, a prior step of complexing with a metal ion is necessary in order to then be able to detect it by an imaging technique, preferably by nuclear imaging or by magnetic resonance imaging.
- fluorophore refers to a chemical substance capable of emitting fluorescent light after excitation.
- the fluorophores are molecules comprising several conjugated aromatic nuclei or planar and cyclic molecules having one or more ⁇ linkages.
- the fluorophores are selected from cyanine derivatives (Cyanine3, Cyanine5, Cyanine5.5, Cyanine7, sulfonated cyanines); Alexa fluorine 647; a coumarin (hydroxycoumarin, aminocoumarin, methoxycoumarin); rhodamine (X-rhodamine, rhodamine B); a fluorescein or a BODIPY.
- the fluorophore is selected from Cyanine5, a sulfonated cyanine, a rhodamine or a BODIPY.
- chromophore refers to a group of atoms having one or more double bonds, and forming with the rest of the molecule a sequence of conjugated double bonds, thereby giving color to the molecule comprising it.
- a chromophore is detectable by absorbance measurement.
- the chromophores are selected from phenolphthalein, gentian violet or Congo Red.
- probes for nuclear imaging reference is made to probes that can be detected by nuclear imaging techniques.
- the probes for nuclear imaging are selected from radioisotopes, radioisotope-labeled organic groups, chelating agents, radioisotope chelates.
- radioisotope for nuclear imaging is fluorine 18.
- the linear or cyclic chelating agents are, for example, DOTA, NOTE, deferoxamine, and their derivatives.
- Preferential derivatives of DOTA and NOTA are for example respectively DOTAGA and (R) -NODAGA.
- Radioisotopes can be obtained by complexation of these chelating agents with metal ions such as, for example: ⁇ Cu, 68 Ga, read In, 89 Zr, 177 Lu
- detecttable moiety includes both. directly detectable radioisotope chelates but also the chelating agents not yet complexing the radioisotope. In the latter case, the complexation can be carried out just before using the platform of the invention for an imaging application. This allows in particular to be able to store the platform ready to chelate and add the radioisotope, which can have a very short half-life, only at the last moment before use.
- MRI probe Magnetic Resonance Imaging
- paramagnetic e.g. comprising gadolinium
- superparamagnetic e.g. comprising iron oxide nanoparticles
- contrast agents for artificially increasing contrast and allowing visualize anatomical structures (for example, an organ) or pathological structures (for example, a tumor) naturally with little or no contrast, and that would therefore be difficult to distinguish from neighboring tissues.
- the invention relates to the use of compounds 1-1, 1-2 and / or 1-3 as described above, for targeting tumors such as, for example, mammary tumors.
- the compounds 1-1, and / or 1-3 as described above specifically target a tumor, preferably a mammary tumor.
- the MRI probes are selected from chelating agents, chelates, nanoparticles.
- the chelating agents are, for example, DOTA and DTPA.
- the corresponding chelates can be obtained by complexing these chelating agents with metal ions such as for example: Gd or Mn; or with iron oxide.
- metal ions such as for example: Gd or Mn; or with iron oxide.
- the nanoparticles are iron oxide nanoparticles or silica nanoparticles of AGuIX type.
- Bioactive group refers to any naturally occurring biological molecule or synthetically derived molecule that mimics or is an analogue of a naturally occurring biological molecule.
- Biomolecules include nucleotides, polynucleotides (eg, RNA, DNA), amino acids, peptides, polypeptides, proteins, antibodies, polysaccharides, lipids, glycans, and small molecules (eg
- FIRE I LLE OF REM PLACEM ENT example vitamins, primary and secondary metabolites, hormones, neurotransmitters.
- Amino acids can include fragments other than those found in the 20 naturally occurring amino acids.
- the amino acids may also include nonproteinogenic functional groups (eg CF 3 , N 3 , F, NO 2 ).
- the polypeptides and proteins may contain such amino acids.
- Polysaccharides include mono-, di- and oligosaccharides comprising O- and N-glycosyl linkages. Polysaccharides may include functional groups that are not commonly found in a cellular environment (eg, cyclopropene, halogens, and nitriles).
- Lipids include amphipathic, phospho- and glycolic lipids and sterols such as cholesterol.
- An "amphipathic lipid” refers to a lipid having hydrophilic and hydrophobic characteristics.
- Phospholipid refers to a lipid bound to a phosphate group and carries a charge. Examples of phospholipids include phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine and phosphatidylinositol.
- a “glycolipid” refers to a lipid bound to a poly- or oligosaccharide.
- glycolipids examples include galactolipids, sulfolipids, glycosphingolipids and glycosylphosphatidylinositol. Lipids may include substituents seldom found in the cellular environment (eg, cyclopropene, halogens, and nitriles).
- a "small molecule” as used herein refers to any small molecule naturally produced in a biological environment and may contain non-naturally occurring fragments or linkages that are not typically found in a cell but tolerated during treatment within a cell (eg cyclopropene, halogens, nitriles).
- the bioactive group is preferably selected from an antibody, a peptide, a peptidomimetic, a protein, a small molecule such as folic acid, an aptamer, preferably a nucleic acid aptamer, a nanoparticle or a liposome; more preferentially, the bioactive group is chosen from antibodies (such as, for example, Trastuzumab) or peptides.
- the bioactive group is bovine serum albumin ("Bovine Serum Albumin", BSA).
- cytotoxic agent refers to a substance capable of killing cells, including cancer cells. These agents can prevent cells from dividing and in the case of cancer cells can induce a reduction in tumor size.
- the cytotoxic agent is selected from auristatin monomethyl E, maytansinoid DM1, Duocarmycin, Calicheamicin, alpha-amanitine or a group carrying a radiometal (for example a 131 I-labeled group, a radiometal chelate such as 90 Y, 223 Ra, 225 Ac, 177 Lu).
- a radiometal for example a 131 I-labeled group, a radiometal chelate such as 90 Y, 223 Ra, 225 Ac, 177 Lu.
- the cytotoxic agent is a nanoparticle, preferably a silica nanoparticle or a gold nanoparticle.
- the nanoparticle can serve as a radio-sensitizer.
- cytotoxic agents examples include cytotoxic agents and their biological targets and / or mechanism of action.
- affinity group refers to a chemical group, sometimes called a label, which can be selectively and non-covalently linked to another partner chemical group, using techniques known to those skilled in the art.
- the affinity group is selected from biotin (partner: streptavidin or avidin), avidin (partner: biotin), steptavidin (partner: biotin) or a hexa-histidine peptide (partner: nickel).
- solubilization group refers to a chemical group, synthetic or natural, for modifying the physicochemical properties of the trifunctional platform, in particular its hydrophilic / lipophilic nature, its molecular volume or its overall electrical charge in a buffered medium.
- solubilization group can affect the biodistribution of the platform (I), its pharmacokinetics or its bioavailability in animals.
- the solubilization group is selected from linear or branched poly (ethylene glycol) chains, linear or branched poly (glutamic acid) chains, or cholesterol.
- R 1 represents a detectable group
- R 2 represents a bioactive group and R represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group, preferably R represents a detectable group.
- R 2 represents a detectable group
- R 3 represents a bioactive group
- R 1 represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group, preferably R 1. represents a detectable group.
- R 1 represents a detectable group
- R 3 represents a bioactive group and R represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group, preferably R represents a detectable group.
- X 1 represents S, NH or O, preferably X 1 represents S or NH. According to a particular embodiment, X 1 represents S. According to another particular embodiment, X 1 represents NH.
- L 1 represents an alkyl or alkylaryl spacer, optionally interrupted and / or terminated with one or more groups selected from -O-, -C (O) -, -NH- and -NHC (O) -; preferably L 1 represents a spacer selected from -CH 2 CH 2 NH-, -NHCH 2 CH 2 NH-, -CH 2 OCONHCH 2 CH 2 NHCO-CH 2 CH 2 -, -CH 2 OCO-, -COCH 2 CH 2 NH-, -CH 2 CH 2 NHCOCH 2 CH 2 - and - CH 2 CH 2 NHCO - / - - Ph-.
- L represents an alkyl or alkylaryl spacer, optionally interrupted and / or terminated with one or more groups selected from -O-, -C (O) -, -NH- and -NHC (O) -; preferably L represents a spacer selected from -CH 2 CH 2 NH-, -NHCH 2 CH 2 NH-, -CH 2 OCONHCH 2 CH 2 NHCOCH 2 CH 2 -,
- FIRE I LLE OF REM PLACEM ENT (RULE 26) -CH 2 OCO-, -COCH 2 CH 2 NH-, -CH 2 CH 2 NHCOCH 2 CH 2 - and -CH 2 CH 2 NHCO - /? - Ph-; more preferably, L represents -CH 2 CH 2 NH-.
- L represents an alkyl or alkylaryl spacer, optionally interrupted and / or terminated with one or more groups selected from -O-, -C (O) -, -NH- and -NHC (O) -; preferably L represents a spacer selected from -CH 2 CH 2 NH-, -NHCH 2 CH 2 NH-, -CH 2 OCONHCH 2 CH 2 NHCO-CH 2 CH 2 -, -CH 2 OCO-, -COCH 2 CH 2 NH-, -CH 2 CH 2 NHCOCH 2 CH 2 - and
- the trifunctionalized platforms of formulas (I) are of formula (Ia):
- the trifunctionalized platforms of formulas (I) are of formula (Ib):
- R 4 , R 4 , R 5 and R 5 each independently represent H, hydroxy, halo.
- R 4 , R 4 , R 5 and R 5 are all H. According to another embodiment, R 4 and R 4 represent H and R 5 and R 5 represent halo, preferably F. According to one embodiment, In another embodiment, R 5 and R 5 are H and R 4 and R 4 are halo, preferably F. In another embodiment, R 4 , R 4 and R 5 are H and R 5 is hydroxy.
- the trifunctionalized platforms of formulas (I) are of formula (le):
- the trifunctionalized platforms of formulas (I) are of formula (Id):
- the trifunctionalized platforms of formulas (I) are of formula (le):
- the trifunctionalized platforms of formulas (I) are of formula (If):
- the trifunctionalized platforms of formulas (I) are of formula (Ig):
- the trifunctionalized platforms of formulas (I) are of formula (Hi):
- the trifunctionalized platform of formula (I) is selected from:
- the invention also relates to the use of trifunctionalized platforms of formula (I) as a medicament and / or for medical imaging.
- the invention relates to the use of trifunctionalized platforms of the invention in medical imaging.
- the following detection methods can be used to detect the compounds of the invention: nuclear imaging, including positron emission tomography (PET), single photon emission computed tomography (TEMP) and Cerenkov Luminescence imaging (CLI) ); magnetic resonance imaging (MRI); optical imaging; fluorescence imaging.
- the invention relates to the use of compounds 1-1 and / or 1-3 as described above, in medical imaging.
- the following detection methods can be used to detect compounds 1-1 and / or 1-3 as previously described: nuclear imaging, including positron emission tomography (PET), emission tomography single-photon (TEMP) and Cerenkov Luminescence (CLI) imaging; magnetic resonance imaging (MRI); optical imaging; fluorescence imaging; preferably, single photon emission computed tomography (TEMP); optical imaging and / or fluorescence imaging.
- nuclear imaging including positron emission tomography (PET), emission tomography single-photon (TEMP) and Cerenkov Luminescence (CLI) imaging
- MRI magnetic resonance imaging
- fluorescence imaging preferably, single photon emission computed tomography (TEMP); optical imaging and / or fluorescence imaging.
- Bimodal imaging includes, for example, PET / MRI imaging, TEMP / MRI imaging, PET / optics imaging, TEMP / optic imaging or MRI / optic imaging.
- the invention relates to the use of the trifunctionalized platforms of the invention as a medicament. This is particularly the case when the platform is functionalized by a cytotoxic agent.
- the trifunctionalized platforms of the invention comprise a detectable group and a cytotoxic agent, then applications as a medicine and in theragnostics can be performed.
- theragnostics reference is made to the use of medical imaging techniques to detect and / or quantify the presence of the cytotoxic agent in the body or on biopsies.
- the trifunctionalized platforms of the invention can also be used as a tool for assisting surgery in the case of imaging-assisted surgery.
- the trifunctionalized platforms of the invention can also be used as a tool for decision-making. In particular, they can be used as companion tools for the selection of patients likely to respond to a targeted therapy.
- the trifunctionalized platforms of the invention may furthermore be used to identify new biological targets or to monitor biomarkers.
- an optical probe, a bioactive group and an affinity group such as a biotin can make it possible to locate (by microscopy) and to isolate (by chromatography). affinity) the different targets of a bioactive group.
- the trifunctionalized platforms of the invention can also be used as a tool to aid the development of new therapeutic agents.
- the modular nature of the platform makes it easy to detect in vivo a complex therapeutic agent, which combines a bioactive agent with a cytotoxic or a solubilization group. Due to its modular nature, the platform allows partners to be rapidly varied in order to identify a therapeutic agent with optimal pharmacological properties in vivo.
- the trifunctionalized platforms of the invention can also be used as a preclinical tool for pharmacological studies. This may include the use of imaging technique to identify tissue, cell or subcellular the fate of therapeutic agents such as ADC (antibody drug conjugates).
- ADC antibody drug conjugates
- the invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) according to the invention and a pharmaceutically acceptable carrier.
- the trifunctionalized platforms of the invention preferably compounds 1-1 and / or 1-3 as described above, can be used as multimodal imaging agent ex vivo or in vivo.
- the compounds 1-1 and / or 1-3 as described above are accumulated preferentially in the tumor relative to other organs such as the liver, kidneys, muscles, blood, spleen and / or bladder.
- the invention also relates to the method of synthesis of trifunctionalized platforms of formula (I) of the invention.
- the synthesis method of the invention implements a Diels-Alder reaction with inverse electronic demand from a bifunctionalized tetrazine of formula (II) which can itself be obtained from a monofunctionalized tetrazine of formula (IV ) ( Figure 1).
- the synthesis method of the invention comprises a preliminary step of forming a monofunctionalized tetrazine of formula
- X, L and R are as defined in formula (I) above; and Y represents a halogen or a leaving group selected from mesylate, tosylate, triflate and 3,5-dimethyl-1H-pyrazolyl groups; preferably Y represents a halogen, more preferably chlorine;
- Y 1 and Y 2 each independently represent a halogen or a leaving group selected from mesylate, tosylate, triflate and 3,5-dimethyl-1H-pyrazolyl groups; preferably Y 1 and Y 2 represent a halogen, more preferably chlorine; by a nucleophile of formula (VII):
- the formation of the monofunctionalized tetrazine of formula (IV) takes place in an aprotic polar solvent, preferably anhydrous acetonitrile or N, N-dimethylformamide (DMF).
- an aprotic polar solvent preferably anhydrous acetonitrile or N, N-dimethylformamide (DMF).
- the formation of the monofunctionalized tetrazine of formula (IV) takes place in the presence of a buffer, preferably a buffer setting the pH to a value ranging from 5 to 9, preferably a pH of about 8. ; preferably the buffer is a borate buffer (2.5 mol / L, pH 8).
- the formation of the monofunctionalized tetrazine of formula (IV) takes place in the presence of a base, preferably N, N-diisopropylethylamine (DIPEA).
- a base preferably N, N-diisopropylethylamine (DIPEA).
- DIPEA N, N-diisopropylethylamine
- the formation of monofunctionalized tetrazine of formula (IV) is carried out at a temperature ranging from 0 ° C to 37 ° C, preferably at room temperature.
- the step of forming the monofunctionalized tetrazine of formula (IV) is conducted for a period ranging from 1 min to 5 hours, preferably from 5 min to 1 hour.
- the intermediate (IV), when X 1 is S, has an excellent selectivity, in particular in buffered aqueous solution at a pH of between 3.5 and 8, for the thiol functions of the cysteines with respect to the amine or hydroxyl functions of the cysteines.
- the synthesis method of the invention comprises an intermediate step of forming a bifunctionalized tetrazine of formula (II):
- X 1 , L 1 and R 1 are as defined in formula (I) above; and Y represents a halogen or a leaving group selected from mesylate, tosylate, triflate and 3,5-dimethyl-1H-pyrazolyl groups; preferably Y 2 represents a halogen, more preferably chlorine;
- the formation of the bifunctionalized tetrazine of formula (II) takes place in a polar solvent, preferably anhydrous N, N-dimethylformamide (DMF) or distilled water.
- a polar solvent preferably anhydrous N, N-dimethylformamide (DMF) or distilled water.
- the formation of the bifunctionalized tetrazine of formula (II) takes place in the presence of a buffer, preferably a buffer fixing the pH at a value ranging from 3.5 to 8, preferably a pH of about 7; preferentially, the buffer is a phosphate buffer.
- a buffer preferably a buffer fixing the pH at a value ranging from 3.5 to 8, preferably a pH of about 7; preferentially, the buffer is a phosphate buffer.
- the formation of the bifunctionalized tetrazine of formula (II) takes place in the presence of a base, preferably N, N-diisopropylethylamine (DIPEA).
- DIPEA N, N-diisopropylethylamine
- the formation of the bifunctionalized tetrazine of formula (II), preferentially when X 1 is S, is carried out at a temperature ranging from 4 ° C. to 37 ° C., preferably at room temperature of 25 ° C.
- the formation of the bifunctionalized tetrazine of formula (II), preferably when X 1 is NH, is carried out at a temperature ranging from 50 ° C. to 90 ° C., preferentially at a temperature ranging from 70 ° C. at 80 ° C, more preferably at a temperature of 75 ° C.
- the step of forming the bifunctionalized tetrazine of formula (II) is carried out for a duration ranging from 10 seconds to 5 hours, preferably from 3.5 minutes to 0.5 hour.
- the synthetic method of the invention comprises a step of forming the trifunctionalized platform of formula (I):
- ring A represents a cycloalkene, cycloalkany or heterocycloalkyne group, optionally substituted by one or more groups selected from alkyl, aryl, halo, hydroxy and heteroaryl; preferably A represents a trans group
- SUBSTITUTE SHEET (RULE 26) bicyclo [6.1.0] nonene, iraws-cyclooctene, bicyclo [6.1.0] nonyne, cyclooctyne, difluorocyclooctyne, hydroxycyclooctyne, methylcyclopropene, norbornene, 5,6-didehydro-1, 12-dihydrodibenzo [a, e] [8] Annulene, 1 l, 12-didehydro-5,6-dihydrodibenzo [b, f] azocine.
- the dihydropyridazine product obtained when (III) is an alkene may optionally undergo an additional oxidation reaction to form the corresponding pyridazine.
- the compounds of formulas (III) are those of formula ma), (IIIb-1), (IIIb-2), (IIIb-3), (IIIc), (Illd), (IIle), (Illf), (Illg), (Illh):
- the formation of the trifunctionalized platform of formula (I) takes place in an aprotic polar solvent, preferably dimethylsulfoxide (DMSO).
- a aprotic polar solvent preferably dimethylsulfoxide (DMSO).
- the formation of the trifunctionalized platform of formula (I) takes place in the presence of a buffer, preferably a buffer fixing the pH at a value ranging from 4 to 9, preferably a pH of about 7. , 4; preferably the buffer is a phosphate buffered saline (PBS).
- PBS phosphate buffered saline
- the formation of the trifunctionalized platform of formula (I) is carried out at temperatures ranging from 20 ° C. to 50 ° C., preferably from room temperature to a physiological temperature of approximately 37 ° C. vs.
- the step of forming the trifunctionalized platform of formula (I) is conducted for a period ranging from 30 minutes to 20 hours, preferably from 50 minutes to 16 hours.
- the invention also relates to a bifunctionalized tetrazine platform of formula (II), as described below, functionalized by at least one detectable group by imaging.
- a bifunctionalized tetrazine platform can be used to obtain the trifunctionalized platform of formula (I) according to the invention.
- the invention therefore relates to a bifunctionalized tetrazine of formula (II):
- X 1 represents S, NH or O
- L 1 and L 2 each independently represent a single bond or spacer selected from alkyl, alkoxy, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl and alkynyl, wherein the alkyl groups are optionally interrupted and / or terminated by one or more groups selected from -O-, -NH-, -S-, -C (O) -, -C (O) NH- and -NHC (O) -; preferably L 1 and L 2 each independently represent an alkyl or alkylaryl spacer, optionally interrupted and / or terminated by one or more groups selected from -O-, -C (O) -, -NH- and -NHC (O) - ; even more preferably, L 1 and L 2 each independently represent a spacer selected from -CH 2 CH 2 NH-, -NHCH 2 CH 2 NH-, -CH 2 OCON
- R 1 and R 2 each independently represent a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group; provided that at least one of R 1 and R 2 is a detectable group.
- the bifunctionalized platform of formula (II) is selected armi:
- the invention also relates to a monofunctionalized tetrazine platform of formula (IV), as described below.
- a monofunctionalized tetrazine platform can be used to obtain the bifunctionalized tetrazine platform of formula (II) described above and thus to have access to the trifunctionalized platform of formula (I) according to the invention.
- the invention thus relates to a monofunctionalized tetrazine of formula (IV):
- Y represents a halogen or a leaving group selected from mesylate, tosylate, triflate and 3,5-dimethyl-1H-pyrazolyl groups; preferably Y 2 represents a halogen, more preferably chlorine;
- X 1 represents S, NH or O
- L 1 represents a single bond or a spacer selected from alkyl, alkoxy, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl and alkynyl, wherein the alkyl groups are optionally interrupted and / or terminated by one or more groups selected from -O-, -NH-, -S-, -C (O) -, -C (O) NH- and -NHC (O) -; preferably L 1 represents an alkyl or alkylaryl spacer, optionally interrupted and / or terminated with one or more groups selected from -O-, -C (O) -, -NH- and -NHC (O) -; still more preferably L 1 represents a spacer selected from -CH 2 CH 2 NH-, -NHCH 2 CH 2 NH-, -CH 2
- R 1 represents a detectable group, a bioactive group, a cytotoxic agent, an affinity group or a solubilization group.
- the monofunctionalized tetrazine of formula (IV) is selected armi:
- FIG. 1 represents a synthesis scheme of trifunctionalized platforms (I) of the invention involving mono- and bi-functionalised (IV) and (II) tetrazine intermediates.
- FIG. 2 shows the multimodal TEMP / CT image of a mouse xenografted by BT-474 cells (mammary tumor) treated with radiolabelled indium-111 compound 1-1 (FIG. 2A), and radiolabeled compound 1-1 indium co-injected with an excess of unlabeled trastuzumab ( Figure 2B).
- FIG. 3 represents a histogram showing the average percentage of dose injected per gram of organ determined by gamma counting in various organs of mice treated with indium-radiolabelled compound 1-1 (lot A - light gray) or mice treated with radiolabeled indium compound 1-1 with excess trastuzumab (lot B - dark gray).
- Figure 4 shows the photograph with (b) or without (a) fluorescence, of a mouse treated with compound 1-1 radiolabelled with indium 111.
- Figure 5 shows the ex vivo fluorescence photograph of the tumor and various organs of a mouse treated with radiolabeled 1-1 indium compound 111.
- Figure 6 is a histogram showing the average biodistribution of indium-111 radiolabeled compound 1-1 in the tumor and various organs for Lot A mice (light gray) or Lot B mice (dark gray).
- Figure 7 shows the in vivo fluorescence photography of a mouse treated with compound 1-3 after 1 h, 4 h or 24 h post-injection.
- Figure 8 shows the photograph with ex vivo fluorescence of the tumor and various organs of a mouse treated with compound 1-3 after 24 hours post-injection.
- Figure 9 is a histogram showing the average biodistribution of compound 1-3 in the tumor and various organs for batch C mice.
- DIPEA diisopropylethylamine
- DOTAGA 2- (4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-1-yl) pentanedioic acid
- Fab ' Fab' fragment of pertuzumab (anti-HER2)
- HATU 1- [Bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
- NODAGA 2- (4,7-bis (carboxymethyl) -1,4,7-triazonan-1-yl) pentanedioic acid
- PBS "phosphate buffered saline", i.e. phosphate buffered saline
- TIS triisopropylsilane
- Flash chromatography purifications were carried out on a puriFlash® 430 (Interchim) system using pre-packaged Interchim columns in normal phase or reverse phase (particle size 15 ⁇ or 25 ⁇ ).
- the LC-MS analyzes were performed on an UltiMate 3000 liquid chromatography system equipped with a DAD detector and coupled to an MSQ Plus mass detector (Thermo Scientific), in ESI mode.
- the chromatographies were carried out on a Kinetex TM C 18 column, 2.6 ⁇ , 100 A, 50 ⁇ 2.1 mm (Phenomenex) with eluents HPLC grade (Eluent A: H 2 O 0, 1% formic acid (FA eluent B: acetonitrile 0.1% FA) with a gradient of 5% to 100% of B in 5 min, a plateau at 100% for 1.5 min. Purity of the compounds was determined from LC-MS chromatograms at 214 nm wavelength.
- the high-resolution mass spectra (HRMS ESI) of the final compounds were made by the PACSMUB platform (DIJON, France) on an LTQ Orbitrap XL mass spectrometer, equipped with an ESI source (Thermo Scientific).
- Rhodamine B 200 mg, 418 ⁇
- the HATU HATU
- the disulfonated cyanine 3.0 (24.5 mg, 38.8 ⁇ ), the TSTU (16.1 mg, 53.5 ⁇ , 1.4 eq) and the DIPEA (10.0 ⁇ , 57.3 ⁇ , 1.5 eq) are dissolved in 1 mL of anhydrous DMF.
- the solution is stirred at room temperature for 15 minutes, and then the 2-aminoethanethiol hydrochloride (10 mg, 96.8 ⁇ , 2.5 eq) and the DIPEA (13.6 ⁇ ,, 77.7 ⁇ , 2.0 eq) are added. After 25 min at room temperature the reaction is complete.
- NODAGA-NH-Tz-Cl is obtained in the form of an orange powder (43.8 mg, 36%).
- BODIPY-SH (29.1 mg, 60.2 ⁇ ) and s-dichlorotetrazine (10.6 mg, 70.2 ⁇ , 1.2 eq) are dissolved in 1.5 mL of DMF / ACN 0.6 / 0.4 (v / v) and DIPEA ( 12.5 ⁇ , 72.2 ⁇ , 1.2 eq) is added to the reaction medium. After 1 h stirring at room temperature, the solvents are removed under reduced pressure. The purification of the crude product was carried out by reverse phase semi-preparative HPLC (eluants: H 2 0.1% formic acid, ACN 0.1% formic acid).
- BODIPY-S-Tz-Cl is obtained in the form of a red powder (24.1 mg, purity: 90%, product reduced to dihydrotetrazine: 10%).
- Rhodamine B-SH 200 mg, 399 ⁇
- s-dichlorotetrazine 60.3 mg, 399 ⁇ , 1.0 eq
- DIPEA 69.5 ⁇ M, 399 ⁇ , 1.0 eq
- Rhodamine BS-Tz-Cl was obtained as a pink powder (47.8 mg, 19%).
- Rhodamine B-SH 39.7 mg, 79.0 ⁇
- DOTAGA-NH-Tz-Cl 50.0 mg, 79.0 ⁇ , 1.0 eq
- the solution was stirred at 75 ° C for 3h and then the solvent was removed under reduced pressure.
- the purification of the crude product was carried out by reverse phase semi-preparative HPLC (eluants: H 2 0.1% formic acid, ACN 0.1% formic acid).
- DOTAGA-NH-Tz-S-Rhodamine B was obtained as a red oil (37.0 mg, 43%) 1H NMR (500 MHz, D 2 O) d: 1.13 (m, 12H, CH 3 ) 2.01 (m, 2H, CH 2 ), 2.56 (m, 2H, CH 2 ), 2.96 (m, 2H, CH 2 ), 3.00 to 3.48 (m, 12H, CH 2 ), 3.48 to 3.63 (m, 8H). CH 2 ), 3.69 (m, 10H;
- Cyanine 5.0-SH (14.9 mg, 26.8 ⁇ ) and DOTAGA-NH-Tz-Cl (19.5 mg, 30.8 ⁇ , 1.1 eq) were dissolved in 1 mL of anhydrous DMF and DIPEA (28.0 ⁇ M, 149.5 ⁇ , 5.6 eq) was introduced into the reaction medium. The solution was stirred at 75 ° C for 1 h and then the solvent was removed under reduced pressure. The purification of the crude product was carried out by reverse phase semi-preparative HPLC (eluants: H 2 0.1% formic acid, ACN 0.1% formic acid). DOTAGA-NH-Tz-S-cyanine 5.0 was obtained as a blue powder (15.1 mg, 49%).
- FIRE I LLE OF REM PLACEM ENT (RULE 26) and tyrosine (phenol). They differ in the presence of a cysteine (thiol) in one, which is substituted by one methionine (thioether) in the other.
- the conversion rate to product resulting from the substitution of (R) -NODAGA-S-Tz-Cl chlorine by the peptides is determined by LC-MS at 214 nm. The results are shown in the table below.
- the product is concentrated and the bicarbonate buffer is exchanged with a PBS buffer (0.01 M, pH 7.4).
- Trastuzumab-BCN is isolated in solution in 51 of PBS at a concentration of 35.5 mg / ml (1.81 mg, 12.1 nmol, labeling yield: 91%).
- the BCN / antibody ratio is 3.3 (determined by MALDI / TOF mass spectrometry).
- FIRE I LLE OF REM PLACEM ENT (RULE 26) (final concentration of trastuzumab-BCN: 10 mg / mL).
- the solution is stirred in a thermomixer (800 rpm, 37 ° C) for 16 h.
- Excess probe is removed by FPLC purification (Akta Pure Healthcare, GE) on a desalting column (Hitrap desalting, 5 mL, pre-packaged with Sephadex G-25 Superfine) with AcONH 4 buffer (0.1 M, pH 5.8, Trace Select) as eluent.
- the probe / antibody ratio is 1.7 (determined spectrophotometrically).
- the denaturing electrophoresis gel analysis shows a fluorescent signal for the molecular weight corresponding to compound 1-1, indicating a covalent linkage between the probe and the trastuzumab antibody. The stability of the compound 1-1 is verified by incubation at 37 ° C.
- the compound 1-1 after indium 111 radiolabelling was studied for multimodal imaging by single photon emission tomography (TEMP / CT) and for optical imaging (fluorescence).
- Compound 1-3 has been studied by optical imaging.
- the in vivo experiment was conducted on a mouse model carrying a xenografted mammary tumor (model BT-474).
- the purpose of this experiment is to demonstrate the specificity of the indium 111 radiolabeled compound 1-1 used as an imaging agent.
- mice treated with compound 1-1 radiolabelled with indium 111 and an excess of unlabeled trastuzumab (n 3). 24 hours after injection, images of the A and B batches of mice were recorded by single photon emission computed tomography (TEMP / CT) and optical imaging. The injection of a large excess of unlabeled trastuzumab (which saturates the HER2 receptors) makes it possible to demonstrate the specificity of the imaging agent.
- TEMP / CT Single Photon Emission Tomography
- FIG. 4 shows the in vivo photograph of a radiolabeled 1-1 compound treated mouse at indium 111 ( Figure 4 (a)) on which the location of the tumor is clearly visible (protuberance at the top, left of the back of the animal).
- Figures 5 and 6 show the results obtained on isolated organs (ex vivo).
- the fluorescence intensity emanating from the tumor is much more intense than that from other isolated organs.
- Figure 6 confirms that indium-111 radiolabeled compound 1-1 acts as a tumor-specific imaging agent. Indeed, a clear difference in biodistribution is observed between lots A and B for the tumor compared to other organs for which the signals are comparable.
- the fluorescence results confirm the results obtained in nuclear imaging.
- the interest of the double trastuzumab site-specific labeling is thus demonstrated for multimodal TEMP / CT / optic imaging applications.
- Figure 7 shows the evolution of the fluorescence signal in vivo in a mouse from the group of batch C. It shows that after injection of compound 1-3 fluorescence signals are intense (light areas) in the tumor region even after 24 hours. , compared to the rest of the body.
- Figure 8 illustrates the results obtained on isolated organs and tumor (ex vivo) for a mouse of batch C. A fluorescence signal more intense in the tumor compared to other organs, is observed.
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