WO2024081635A2 - Colorants de quinocyanine ciblés pour la délimitation peropératoire de marges cancéreuses - Google Patents
Colorants de quinocyanine ciblés pour la délimitation peropératoire de marges cancéreuses Download PDFInfo
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- WO2024081635A2 WO2024081635A2 PCT/US2023/076452 US2023076452W WO2024081635A2 WO 2024081635 A2 WO2024081635 A2 WO 2024081635A2 US 2023076452 W US2023076452 W US 2023076452W WO 2024081635 A2 WO2024081635 A2 WO 2024081635A2
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- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- VULHYRAYXYTONQ-UHFFFAOYSA-N n-phenylmethanimine Chemical compound C=NC1=CC=CC=C1 VULHYRAYXYTONQ-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl 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
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011160 research Methods 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
- 238000013207 serial dilution Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000000107 tumor biomarker Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/083—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines five >CH- groups
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
Definitions
- the present disclosure relates to the field of dyes for visualization of certain cell types, including cells present in cancer margins.
- NSCLC non-small cell lung carcinomas
- NIR-II near-infrared II
- NIR-II fluorophores exhibit either high toxicity or lack of specificity.
- the disclosed probes can fluoresce in the near-infrared II (NIR-II) window.
- NIR-II near-infrared II
- the disclosed fluorescent molecules targeted to an enzyme overexpressed in cancers one can image tumors in vivo and delineate tumor margins to improve the rate of complete tumor resections improving clinical outcomes.
- NIR-I near-infrared I
- ICG indocyanine green
- NIR-II nearinfrared II
- the present disclosure provides a compound having the structure of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 or compound 7 :
- FIG. 1 depicts absorbance and emission spectra of compound 1, compound 2 and compound 3.
- Fig. 1A shows absorbance and emission spectra for compound 1 and compound 2.
- Fig. IB shows the maximum absorbance and maximum emission for compound 1.
- Fig. 1C shows emission intensities for 5 ⁇ M compound 1, compound 2 and compound 3.
- FIG. 2 depicts NIR-II emissions of serial dilutions of compound 1, JAS239, and ICG.
- FIG. 3 depicts NIR-II emissions of compound 1, JAS239, and ICG at varying tissue depths.
- FIG. 4 depicts a NIR-II emissions of KLN 205 cell lysates following treatment with compound 1, compound 2 and compound 3, or control.
- FIG. 5 depicts imaging of ChoKa NIR-I probe (JAS239) and ChoKa NIR-II probe (compound 1) using tissue phantom.
- Fig. 5A shows uncovered plates (left panel) or plates covered by 2 mm chicken tissue (right panel).
- Fig. 5B shows SBR for each fluorescent spot of the images.
- FIG. 6 depicts imaging of intracellular uptake and retention of ChoKa-targeted NIR- II probe (compound 1) by KLN-205 cancer cells.
- Fig. 6A shows intracellular uptake for compound 1 (top panel) and intracellular uptake for the control compound (bottom panel).
- Fig. 6B shows RFU for compound 1 and for the control compound.
- FIG. 7 depicts imaging of mice injected with compound 1.
- Fig. 7A shows a ventral image of mice at 5 mins after injection.
- Fig. 7B shows a ventral image of mice at 2 hours after injection .
- compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect.
- the term “comprising” can include the embodiments “consisting of' and “consisting essentially of.”
- the terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.
- compositions or processes as “consisting of' and “consisting essentially of the enumerated ingredients/steps, which allows the presence of only the named ingredients/steps, along with any impurities that might result therefrom, and excludes other ingredients/steps.
- the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
- an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
- approximating language can be applied to modify any quantitative representation that can vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about” and “substantially,” may not be limited to the precise value specified, in some cases. In at least some instances, the approximating language can correspond to the precision of an instrument for measuring the value.
- the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” can refer to plus or minus 10% of the indicated number.
- compositions that comprises components A and B can be a composition that includes A, B, and other components, but can also be a composition made of A and B only. Any documents cited herein are incorporated by reference in their entireties for any and all purposes.
- substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
- C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
- Co alkyl refers to a covalent bond.
- stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
- alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C 1 -C 12 ”), preferably 1 to 6 carbons atoms (“C 1 -C 6 ”), in the group.
- alkyl groups include methyl (Me, C 1 alkyl), ethyl (Et, C 2 alkyl), n-propyl (C 3 alkyl), isopropyl (C 3 alkyl), butyl (C 4 alkyl), isobutyl (C 4 alkyl), sec-butyl (C 4 alkyl), tert-butyl (C 4 alkyl), pentyl (C 5 alkyl), isopentyl (C 4 alkyl), tert-pentyl (C 4 alkyl), hexyl (C 6 alkyl), isohexyl (C 6 alkyl), and the like.
- Alkyl groups of the disclosure can be unsubstituted or substituted.
- the alkyl group can be substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
- Additional substituents include - C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O)2NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C6alkyl)2.
- alkoxide refers to he conjugate base of an alcohol and includes an organic group bonded to a negatively charged oxygen atom.
- halo or “halogen,” refers to chloro, fluoro, bromo, or iodo.
- haloalkyl refers to any alkyl radical having one or more hydrogen atoms replaced by a halogen atom.
- cycloalkyl when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C 3 - C 10 ”), preferably from 3 to 6 carbon atoms (“C 3 -C 6 ”).
- Cycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic cycloalkyl group, the cyclic groups share two common atoms.
- cycloalkyl groups include, for example, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopropylmethyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), 1 -methylcyclopropyl (C 4 ), 2-methylcyclopentyl (C 4 ), adamantanyl ( C 10 ), spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like. Cycloalkyl groups of the disclosure can be unsubstituted or substituted.
- the cycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
- Additional substituents include - C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O)2NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C6alkyl)2.
- cycloalkenyl refer to cyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C 3 -C 10 ”), preferably from 3 to 6 carbon atoms (“C 3 -C 6 ”) and containing at least one carbon-carbon double bond.
- cycloalkenyl groups include, but are not limited to cyclopropenyl, cyclobutenyl, and the like.
- heterocycloalkyl when used alone or as part of a substituent group refers to any three to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
- Heterocycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic heterocycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic heterocycloalkyl group, the cyclic groups share two common atoms.
- heterocycloalkyl refers to a heterocycloalkyl group having between three and six carbon ring atoms.
- -C 3 -C 10 heterocycloalkyl refers to a heterocycloalkyl group having between three and 10 ring atoms.
- the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
- heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2] pentanyl, oxaazaspiro[3.3]heptanyl, ox
- Heteroycloalkyl groups of the disclosure can be unsubstituted or substituted.
- the heterocycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
- Additional substituents include -C(O)NH(C 1 -C 6 alkyl), - C(O)N(C 1 -C 6 alkyl)2, -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(CI- C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
- heterocycloalkenyl when used alone or as part of a substituent group refers to any three to ten membered monocyclic or bicyclic, partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
- Heterocycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic heterocycloalkyenyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multi cyclic heterocycloalkenyl group, the cyclic groups share two common atoms.
- heterocycloalkenyl refers to a heterocycloalkenyl group having between three and six carbon atoms.
- -C 3 -C 10 heterocycloalkenyl refers to a heterocycloalkenyl group having between three and ten ring atoms.
- the heterocycloalkenyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
- Heteroycloalkenyl groups of the disclosure can be unsubstituted or substituted.
- the heterocycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, oxo, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
- Additional substituents include -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 - C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
- heteroaryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to five heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms.
- -C 5 -C 10 heteroaryl refers to a heteroaryl group containing five to ten ring atoms.
- heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like.
- Heteroaryl groups of the disclosure can be unsubstituted or substituted.
- the heteroaryl group can be substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 - C 6 haloalkoxy.
- Additional substituents include -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , - OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(CI- C 6 alkyl) 2 .
- aryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic carbon ring structure.
- Aryl rings can include a total of 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include but are not limited to, phenyl, napthyl, and the like.
- Aryl groups of the disclosure can be unsubstituted or substituted.
- the aryl group can be substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
- Additional substituents include - C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
- alkenyl refers to C 2 -C 12 alkyl group that contains at least one carboncarbon double bond. In some embodiments, the alkenyl group is optionally substituted. In some embodiments, the alkenyl group is a C 2 -C 6 alkenyl.
- alkynyl refers to C 2 -C 12 alkyl group that contains at least one carboncarbon triple bond.
- the alkenyl group is optionally substituted.
- the alkynyl group is a C 2 -C 6 alkynyl.
- alkoxy refers to an -O-alkyl group.
- Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
- hydroxylalkyl refers to an alkyl group substituted by OH.
- C 1-3 includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 , and C 3 .
- C 1-6 Calk refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH 2 -, -CH(CH 3 )-, -CH(CH 3 )-CH 2 -, and - C(CH 3 ) 2- .
- -Coalk- refers to a bond.
- Co-C 6 alk when used alone or as part of a substituent group refers to an aliphatic linker having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
- -C 1 alk- for example, refers to a -CH 2 -.
- -Coalk- refers to a bond.
- Moieties of the disclosure for example, -C 1 -C 6 alkyl, -C1-C 10 alkyl, -C 2 -C 6 alkenyl, - C 2 -C 1 oalkenyl, -C 2 -C 6 alkynyl, -C 2 -C 1 oalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalky, are optionally substituted with 1, 2, or 3 substituents independently selected from D, -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
- Additional substituents include - C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
- the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
- Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
- Geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
- isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers, enantiomers, and atropisomers.
- the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (7 )-or fS')-stereoi somers at each asymmetric center, or as mixtures thereof.
- Compounds of the invention may also include tautomeric forms. All tautomeric forms are encompassed.
- the compounds of the present invention may exist as rotational isomers. In some embodiments, the compounds of the present invention exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds of the present invention exist as particular rotational isomers, substantially free of other rotational isomers.
- the compounds of the invention, and salts thereof are substantially isolated.
- substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which was formed or detected.
- Partial separation can include, for example, a composition enriched in the compound of the invention.
- Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
- the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
- pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
- phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
- excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
- a “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.
- Subject includes mammals, and in particular, humans.
- the terms “human,” “patient,” and “subject” are used interchangeably herein.
- Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
- Compounds of the present disclosure are meant to embrace compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 and compound 7 as described herein, as well as any stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 and compound 7 as well as the pharmaceutically acceptable salts, where the context so permits.
- stereoisomers e.g., entaniomers, diastereomers
- constitutional isomers e.g., tautomers
- isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
- an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with nonradioactive isotopes such as for example, deuterium ( 2 H or D), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
- any hydrogen may be 2 H/D
- any carbon may be 13 C
- any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
- Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- the disclosure is directed to compounds of compound 2:
- compound 2 is referred to as JAM318.
- the disclosure is directed to compounds of compound 3:
- compound 3 is referred to as JAM319.
- the disclosure is directed to compounds of compound 4:
- compound 4 is referred to as JAM320.
- the disclosure is directed to compounds of compound 5:
- the disclosure is directed to compounds of compound 7:
- the disclosure is directed to a pharmaceutical composition
- a pharmaceutical composition comprising compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 or compound 7.
- the disclosure is directed a method of imaging cancer or an inflammatory disease, the method comprising: contracting tissue with a compound of claim 1 or a pharmaceutical composition comprising the compound; illuminating the tissue with an excitation light of a wavelength absorbed by the compound; and detecting an optical signal emitted by the compound in the tissue.
- the tissue is biological tissue. In some embodiments, the tissue is in a human or an animal.
- the method comprises: illuminating the tissue comprises illuminating a surface of the tissue with the excitation light; and detecting the optical signal comprises detecting fluorescence from the compound.
- the method comprises: filtering the light detected by a fluorescence detector to separate out fluorescent components; and forming an image of the tissue surface.
- the excitation light is continuous wave (CW) in nature.
- the method is used to assist in detection, diagnosis, surgery, staging, treatment, monitoring of treatment, monitoring of disease progression or monitoring therapy.
- the method is used to assist in detection of a disease or disorder.
- the method is used to assist in diagnosis of a disease or disorder.
- the method is used to assist in surgery.
- the method is used to assist in staging.
- the method is used to assist in treatment of a disease or disorder.
- the method is used to assist in monitoring of treatment.
- the method is used to assist in monitoring of disease progression.
- the method is used to assist in monitoring therapy.
- the method is used to assist in detection, diagnosis, surgery, staging, treatment, monitoring of treatment, monitoring of disease progression or monitoring therapy of cancer or of a precancerous condition.
- the method is used to assist in detection of cancer or of a precancerous condition.
- the method is used to assist in diagnosis of cancer or of a precancerous condition.
- the method is used to assist in surgery.
- the method is used to assist in staging.
- the method is used to assist in treatment of cancer or of a precancerous condition.
- the method is used to assist in monitoring of cancer treatment.
- the method is used to assist in monitoring of cancer progression.
- the method is used to assist in monitoring cancer therapy.
- the cancer is colorectal cancer, esophageal cancer, breast cancer, prostate cancer, head cancer, neck cancer, ovarian cancer, rectal cancer, pancreatic cancer, thyroid cancer, gastric cancer or a sarcoma.
- the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In other embodiments, the cancer is head cancer. In other embodiments, the cancer is neck cancer. In other embodiments, the cancer is ovarian cancer. In yet other embodiments, the cancer is rectal cancer. In yet other embodiments, the cancer is pancreatic cancer. In yet other embodiments, the cancer is thyroid cancer. In yet other embodiments, the cancer is gastric cancer. In yet other embodiments, the cancer is a sarcoma.
- the compound used in the methods described herein is compound 1 or JAM317.
- the compound used in the methods described herein is compound 2 or JAM318.
- the compound used in the methods described herein is compound 3 or JAM319.
- the compound used in the methods described herein is compound 4 or JAM320.
- the compound used in the methods described herein is compound 5.
- the compound used in the methods described herein is compound 6.
- the compound used in the methods described herein is compound 7.
- the compounds described herein absorb and emit in the NIR-II window, which has improved resolution and increased light penetration through tissue in vivo compared to currently available fluorophores in the NIR-I window (700-900 nm). Decreased tissue scattering, absorption, and autofluorescence in the NIR-II range improves resolution in vivo.
- the compounds described herein Compared to known NIR-II fluorophores, the compounds described herein have a low molecular weight, which eases their translation into the clinical space.
- the core structure of the compounds described herein is easily modifiable at the nitrogen in the head group and at the chlorine-substituted carbon in the polymethine linker region.
- Targeting groups can be introduced to these locations to target the fluorophores to different disease states or for imaging specific biology in vivo. Further decreased tissue scattering, absorption, and autofluorescence in the NIR-II range improves resolution in vivo.
- the compounds described herein are able to penetrate deeper into tissue, with strong emission observed up to 3mm deep as compared to existing NIR probes JAS239 and ICG.
- the solution was cooled to -20°C in a methanol-liquid nitrogen bath. 17 mL of 12.1 M HCI were added slowly by pipet while stirring. The resulting solution was a viscous orange liquid.
- the reaction mixture was warmed to 0°C in an ice water bath. 6.3 mL (69. 14 mmol) of aniline w'ere added by pipet with slow stirring for 30 min.
- the solution turned to a dark violet and was poured onto ice to precipitate.
- the metallic purple solid was isolated by vacuum filtration and rinsed with ice-cold H O before drying overnight by lyophilization.
- Example 1 4-((E)-2((E)-2-chloro-3-(2-((Z)- J-ethylquinolin-4(JH)-ylidene)-ethylidene) cyclohex-l-en-l-yl)vinyl)-J-ethylquinolin-l-ium iodide (compound 1/JAM317)
- Precipitation was facilitated by placing the reaction mixture in a -20°C freezer overnight.
- the precipitate was isolated by vacuum filtration and dried by lyophilization.
- Purification was performed by precipitation of 1.44 g product dissolved in 25 mL of DMSO before pouring into 1 L of ice-cold H 2 O. The mixture was left to settle for 1 hour before isolating the precipitate by vacuum filtration and drying overnight by lyophilization.
- Example 2 4-((E)-2((E)-2-chloro-3-(2-((Z)-l-hydroxyethylquinolin-4(JH)- ylidene)- ethylidene)cyclohex-l-en-l-yl)vinyl)-l-hydroxyethylquinolin-l-ium chloride (compound 2/JAM318)
- Example 3 l-(2-hydroxyethyl)-4-((JE,3E,5E)-7-((Z)-J-(2-hydroxyethyl)- quinoline- 4(JH)-ylidene)hepta-l,3,5-trien-l-yl)quinoline-l-ium chloride (compound 3/JAM319) [00119] 1.273 g (4.47 mmol) of (1E,2E,5E) ⁇ N 7,N 5 -diphenylpent-2-ene-l,5-diimiine were mixed with 2.0 g (8.94 mmol) of Intermediate 1 in 37 mL of anhydrous pyridine.
- Compound 1, JAS239, and ICG were dissolved in DMSO and added to a 96- well black- well clear- bottom plate at concentrations from 1 ⁇ M to 100 ⁇ M. The plate was then imaged using the PhotonEtc IR Vi vo using the NIR-II emission filter (1000- 1250 nm) with excitation at 760 nm, 808 nm, 890 nm, or 940 nm.
- C ompound 1 , JAS239, and ICG were diluted in DMSO and placed in a 96-well black-well clear-bottom plate at concentrations from O.l ⁇ M to 100 ⁇ M. The plate was then imaged using the PhotonEtc IR Vivo using the NIR-II emission filter with excitation at 760, 808, 890, or 940 nm. Wells were then covered with thinly sliced raw chicken breast tissue from 1 mm to 3 mm thick. Imaging was then repeated for each tissue thickness.
- KLN 205 cells were seeded into an 8 chamber slide at 15,000 cells/well. Cells were incubated overnight at 37 C 'C and 5% CO2. Cells were then treated in 500 pL with 10 ⁇ M of compound 1, compound 2 or compound 3, or with vehicle (DMSO). The slide was incubated for 2 hours with treatment at 37°C and 5% CO 2 . [00126] Following treatment, the solution was aspirated, and cells were rinsed twice with 500 ⁇ L of ice-cold DPBS. Triton X-100 was diluted to be 0.5% Triton, and 500 pL of this solution were added to each chamber for 10 min at 37°C and 5% CO2 to lyse the cells.
- compound 1 and compound 2 have similar absorbance and emission spectra, with a maximum absorbances at 970 nm and maximum emissions at 1010 and 1007 nm, respectively.
- Compound 3 has a maximum absorbance at 942 nm and maximum emission at 979 nm. The emission intensities were determined with excitation at 900 nm.
- NIR-II emission for compound 1 was compared to the well-characterized indocarbocyanines, JAS239 and ICG, as shown in FIG. 2. Dyes were excited with excitation lasers at 760, 808, 890, and 940 nm and emissions were measured between 1,000 and 1,250 nm. All dyes exhibited NIR-II fluorescence. However, only compound 1 had measurable fluorescence in the NIR-II window with 890 and 940 nm excitation lasers. With shorter wavelength excitation lasers (760 and 808 nm) JAS239 and ICG exhibited the strongest NIR-II emissions. When excited by the longer wavelength 890 and 940 nm lasers, JAS239 and ICG NIR-II emissions disappeared, and compound 1 demonstrated a strong NIR-II signal.
- C ell uptake of compound 1, compound 2 and compound 3 was evaluated by incubating KLN 205 cells in 10 ⁇ M of compound 1, compound 2 and compound 3, or with DMSO for 2 hrs. Following incubation, cells were rinsed twice with ice-cold DPBS before lysing by treatment with Triton. The lysates w ere then transferred to a 96-well black-well clear-bottom plate and imaged for NIR-II fluorescence in the IR Vivo, as shown in FIG. 4. Lysates from cells treated with compound 1 and compound 2 had measurable emissions, but no fluorescence was observed in lysates for cells treated with compound 3 or DMSO.
- FIG. 5A Imaging of ChoKa NIR-I probe (JAS239) and ChoKa NIR-II probe (compound 1) using tissue phantom is shown in FIG. 5.
- FIG. 5A the plate was uncovered (left panel) or covered by 2 mm chicken tissue (right panel). Imaging of the probes dilution with and without plate covering by the tissue.
- FIG. 5B SBR was shown for each fluorescent spot of the images.
- Compound 1, compound 2 and compound 3 were designed to be modifiable with an extended electron-conjugated region compared to the indocarbocyanines.
- the central chlorine attached to the polymethine linker was designed to allow for the substitution of targeting moi eties for bi omarkers of NSCLC.
- the absorbance and emission spectra of compound 1, compound 2 and compound 3 demonstrated measurable NIR-II fluorescence making them promising candidates for further investigation into targeting for NSCLC imaging.
- Compound 1 exhibited the highest fluorescence with an emission maximum in the NIR-II window making it the lead fluorophore for future studies.
- NIR-II fluorescence of the probe Vivo confirmed NIR-II fluorescence of the probe and showed comparable NIR-II emissions to ICG when excited near its absorbance maximum.
- the primary goal of developi ng the NIR-H fluorophores was to improve on the in vivo resolution observed for NIR-I fluorophores.
- ICG and JAS239 have measurable emissions in the NIR-II window, but both probes require excitation with a NIR-Ilaser.
- compound 1 was tested forNIR-II fluorescence emission intensity and resolution at increasing tissue depths compared to ICG and JAS239 with excitation from 760 to 940 nm using four different lasers.
- C hicken breast tissue was layered over wells containing varying concentrations of each fluorophore in 1 mm sections. Fluorescence in the NIR-II window was measured following excitation at 760, 808, 890, and 940 nm. At 3 mm tissue depth, none of the probes exhibited resolvable fluorescence when excited with a NIR-1 laser. However, wells containing compound 1 were easily resolved at 3 mm when using longer wavelength excitation lasers. Tissue scattering, absorption, and autofluorescence decreases at i ncreasing wavelengths of light. 'Thus, the improved resoluti on of compound 1 with increasing wavelength of excitation laser likely resulted from improved tissue penetration of the excitation laser. Compound 1 has a maximum absorption at 970 nm resulting in strong excitation of the probe and fluorescence conversion.
- Compound 1, compound 2 and compound 3 represent a new family of NIR-II fluorophores with low molecular weights.
- Compound 1 exhibited improved fluorescence resolution compared to well-established fluorophores when imaged through chicken breast tissue making them promising candidates in development for in vivo imaging.
- the easily modifiable synthetic scheme promotes the introduction of targeting moieties to various diseases including NSCLC.
- Athymic Nu/Nu mice were injected with 40 nmol compound 1 through the tail vein in Normal Saline and filtered through a 0.22 pm filter. The results are shown in FIG. 7.
- a ventral image of mice at 5 mins after injection shows compound lin the liver, as shown in FIG. 7A.
- a ventral image of mice at 2 hours after injection shows compound 1 in the throat, liver and intestines, as shown in FIG. 7B.
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Abstract
La divulgation concerne le composé 1, le composé 2, le composé 3, le composé 4, le composé 5, le composé 6 et le composé 7 ; des compositions pharmaceutiques contenant le composé 1, le composé 2, le composé 3, le composé 4, le composé 5, le composé 6 et le composé 7, ainsi que leurs méthodes d'utilisation et de préparation.
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