CN110845408A - Isotopically enriched lenvatinib - Google Patents
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- C07—ORGANIC CHEMISTRY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A61P35/00—Antineoplastic agents
Abstract
Isotopically enriched lenvatinib, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same are disclosed. In particular, the application relates to an isotopically enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1～R19Independently selected from hydrogen or deuterium; xa～XdIs independently selected from16O、17O or18O；YaAnd YbIs independently selected from12C or13C；Za～ZdIs selected from14N or15N; with the proviso that R-group (R)1～R19) X-radical (X)a～Xd) Y-group (Y)aAnd Yb) And Z-group (Z)a～Zd) Is an isotopically enriched atom or group. By the same tokenSite-directed enrichment improves pharmacokinetics, pharmacodynamics, drug metabolism, and clearance pathways, thereby improving the efficacy and/or extent of drug therapy for disease. The application further relates to compositions comprising isotopically enriched compounds and their use in the treatment of disease.
Description
Technical Field
The present invention generally relates to isotopically enriched lenvatinib, pharmaceutical compositions containing the isotopically enriched lenvatinib, and methods of treating diseases using the isotopically enriched lenvatinib.
Background
Levatinib (Levatinib), structurally shown below, is a well-known novel small molecule multi-kinase inhibitor that targets Vascular Endothelial Growth Factor (VEGF) receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor- α, and RET and KIT proto-oncogenes in the United States (US), European Union (EU), Canada, Japan and Switzerland, Levatinib is approved for the treatment of radioiodine refractory differentiated thyroid cancer, and also in the United states and European Union, Levatinib is also approved for the treatment of advanced renal cell carcinoma that had previously received C1 VEGF-targeted therapy in combination with everolimus (Pharolmus). furthermore, the use of Valvatinib for the treatment of hepatocellular carcinoma is being investigated (Hussein et al, Eur J Drug Metabalrmacokinet, 2017,42(6),903, 914).
Stable isotopes are nonradioactive forms of atoms. Although they do not produce radiation, their unique properties enable them to be used in a wide variety of applications, including water and soil management, environmental studies, nutrition assessment studies, and forensic medicine (see e.g., literaturewww.iaea.org/topics/nuclear-science/isotopes/stable-isotopes). In recent years, stable isotopes have been used in pharmaceutical research. Isotopically enriched drugs can improve pharmacokinetics, pharmacodynamics, drug metabolism, and clearance pathways, thereby improving the efficacy or scope of disease treatment. For example, deuterium enriched drug (deutetrabenzine) SD-809 has been used to treat Huntington's disease.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide isotopically enriched lenvatinib or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one isotopically enriched compound of the invention or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides kinase inhibitors that target Vascular Endothelial Growth Factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor- α, and the RET and KIT proto-oncogenes.
In another aspect, the invention provides a method for treating diseases associated with Vascular Endothelial Growth Factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor- α, and RET and KIT proto-oncogenes.
In another aspect, the invention provides a method of treating a disease selected from thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer (e.g., lung small cell lung cancer), pancreatic cancer, breast cancer, and/or colorectal cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of at least one isotopically enriched compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention.
In one embodiment, the present invention provides novel isotopically enriched lenvatinib or a pharmaceutically acceptable salt thereof for use in therapy.
In another embodiment, the present invention provides the use of a novel isotopically enriched lenvatinib or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for example, for the treatment of diseases or cancers associated with Vascular Endothelial Growth Factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor- α, and RET and KIT proto-oncogenes.
These objects and others that will become more apparent in the detailed description that follows are achieved by the use of the isotopically enriched lenvatinib as claimed herein.
Detailed Description
Any stable or pharmaceutically acceptable isotope may be used to enrich the compounds of the invention. For example, isotopically enriched compounds can each comprise D: (A), (B), (C), (2H)、13C、15N、17O and/or18O。
Isotopic enrichment is the process of producing one elemental form by altering the relative abundance of isotopes of a given element such that one particular isotopic form is enriched (i.e., increased) and the other isotopic forms are reduced or depleted. As used herein, an "isotopically enriched" compound or derivative refers to a compound in which one or more specific isotopic forms have been increased, i.e., one or more specific isotopes of one or more elements have been enriched (i.e., increased). Typically, in isotopically enriched compounds or derivatives, the specific isotopic form of an element is increased at a specific position in the compound.
Under normal conditions, deuterium (D or2H) (stable isotope of hydrogen, with a mass of about twice that of its common isotope), nitrogen-15 (15N), carbon-13 (13C) Oxygen-18 (18O) and oxygen-17 (17O) was found to be 0.016%, 0.37%, 1.11%, 0.204% and 0.037%, respectively. As used herein, an "isotopically enriched" compound or derivative has an isotopic level above its natural abundance. The level of isotopic enrichment will vary depending upon the natural abundance of the particular isotope itself. In some embodiments, the isotopic enrichment level of the compound or the isotopic enrichment level of an element in the compound can be from about 2 to about 100 mole percent (%) on a molar (or molar) percentage basis, for example, about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100%.
Achieving 100% isotopic enrichment in the laboratory for any element at any site in laboratory scale amounts of compounds (e.g., milligrams or greater) can be very difficult. When described as isotopic enrichment of 100%, it is believed that a small amount of the element in its native form is still present. Isotopic enrichment can be achieved by exchanging a particular naturally abundant form of an element for other isotopic forms of the element or by synthesizing the molecule from isotopically enriched starting materials.
However, it is understood that the isotopic form of two or more elements in the compound can be increased.
Further, the isotopically enriched compounds can be a mixture of more than one specific isotopically enriched form, more than one elemental enriched isotopically enriched form, or a mixture of more than one specific isotopically enriched forms of more than one element.
In a first main aspect, the present invention provides isotopically enriched lenvatinib of formula I or a pharmaceutically acceptable salt or ester thereof:
wherein R is1～R19Independently selected from hydrogen or deuterium; xa～XdIs independently selected from16O、17O or18O；YaAnd YbIs independently selected from12C or13C; and Za～ZdIs selected from14N or15N; with the proviso that R-group (R)1～R19) X-radical (X)a～Xd) Y-group (Y)a～Yb) And Z-group (Z)a～Zd) Atoms or groups that are not both naturally abundant (i.e., at least one of them is an isotopically enriched atom or group).
The present invention does not encompass compounds in which all atoms or elements in the structure are in their natural abundance (non-isotopically enriched compounds).
In one embodiment, the present invention provides an isolated novel isotopically enriched compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the unnatural isotopic abundance of any single element can be from 5% to 100%.
In another embodiment, the invention provides isotopically enriched compounds of formula I, or pharmaceutically acceptable salts or esters thereof, wherein the isotopic abundance of any single element can be about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% as a molar (or molar) percentage.
In another embodiment, the invention provides a multi-isotopically enriched compound of formula I, wherein each isotopically enriched element is independently about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% as a molar (or molar) percentage.
In another embodiment, the invention provides a single-element isotopically-enriched compound of formula I, wherein the isotopic enrichment of an element at each position is independently about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% as a molar (or molar) percentage.
In another embodiment, the invention provides multi-isotopically enriched compounds and pharmaceutically acceptable salts of formula I, wherein each element independently has a molar (or molar) percentage of isotopically enriched elements at a particular position of about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99% or 100%.
In a second main aspect, the present invention provides deuterium enriched lenvatinib of formula II or a pharmaceutically acceptable salt or ester thereof:
wherein R is1～R19Independently selected from hydrogen (H) or deuterium (D or2H) (ii) a And at least one of the R-groups is deuterium enriched or has no natural abundance.
In one embodiment, the present invention provides a novel isolated deuterium enriched compound of formula II or a pharmaceutically acceptable salt thereof wherein the deuterium abundance may be between 5% and 100%.
In other embodiments, the present invention provides a novel isolated deuterium enriched compound of formula II or a pharmaceutically acceptable salt thereof wherein the deuterium abundance at any particular position may be between 1% and 100%.
In another embodiment, the present invention provides a novel isolated deuterium enriched compound of formula II or a pharmaceutically acceptable salt thereof wherein the deuterium abundance at one or any selected position may be between 5% and 100%.
In another embodiment, the present invention provides a novel isolated deuterium-enriched compound of formula II, or a pharmaceutically acceptable salt thereof, wherein the deuterium abundance at one or any selected position(s) may be about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99% or 100% as a molar (or molar) percentage.
In yet another embodiment, the present invention provides a novel isolated deuterium-enriched compound of formula II or a pharmaceutically acceptable salt thereof, wherein the deuterium enrichment is independently selected from R4、R5、R13And R14Or is R4、R5、R13And R14Enrichment of all positions.
In other embodiments, the present invention provides a novel isolated deuterium enriched compound of formula II or a pharmaceutically acceptable salt thereof, wherein the deuterium enrichment is independently selected from R1～R3、R6～R12And R15～R19Is enriched at one or more positions of, or is R1～R3、R6～R12And R15～R19Enrichment of all positions.
In a third main aspect, the present invention provides a compound of formula III18Enriched in O or17O-enriched lenvatinib or a pharmaceutically acceptable salt or ester thereof:
wherein, Xa～XdIs independently selected from16O、17O or18O, and at least one of the X-groups has no natural abundance.
In another broad aspect, the invention provides a compound of formula IV13C-enriched lenvatinib or a pharmaceutically acceptable salt or ester thereof:
wherein, YaAnd YbIs independently selected from12C or13C; and at least one of the Y-groups is not naturally abundant.
In another broad aspect, the invention provides isotopically enriched lenvatinib of formula V:
wherein Z isa～ZdIs independently selected from14N or15N; and at least one of the Z-groups is not naturally abundant.
In another broad aspect, the invention provides a multi-isotopically enriched lenvatinib, wherein the isotopically enriched elements are present in the same compound of two or more elements and are independently selected from D, a,17O、18O、13C and15N。
in one embodiment, the present invention provides novel isotopically enriched compounds or pharmaceutically acceptable salts of formula I to formula V.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I to formula V or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a novel method of treating diseases associated with Vascular Endothelial Growth Factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor- α, and the RET and KIT proto-oncogenes, said method comprising administering to a patient in need thereof a therapeutically effective amount of an isotopically enriched compound of the present invention or a pharmaceutical composition of the present invention.
In another aspect, the invention provides a method of treating a disease selected from thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer (e.g., lung small cell lung cancer), pancreatic cancer, breast cancer, and/or colorectal cancer, the method comprising: administering a therapeutically effective amount of an isotopically enriched compound of the invention or a pharmaceutical composition of the invention to a patient in need thereof.
In other embodiments, the invention provides the use of an isotopically enriched compound of the invention in the manufacture of a medicament (e.g. for the treatment of cancer).
In another embodiment, the invention provides an isotopically enriched compound of the invention as described above for use in therapy.
The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention encompasses all combinations of the preferred aspects of the invention mentioned herein. It is to be understood that any and all embodiments of the present invention may be combined with any other embodiment to describe yet further preferred embodiments. It is also to be understood that each separate element of the preferred embodiments is intended individually as its own independent preferred embodiment. Moreover, any element of an embodiment is intended to describe a further embodiment in combination with any and all other elements of any embodiment.
Definition of terms
Unless otherwise indicated, the examples provided in the definitions herein are non-exclusive. They include but are not limited to the enumerated examples.
The "host" preferably refers to a human. Hosts also include other mammals, including equine, porcine, bovine, feline, and canine.
"treatment" encompasses treatment of a disease state in a mammal and includes: (a) preventing the occurrence of a disease state in a mammal, particularly when such mammal is susceptible to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease state, e.g., arresting its development; and/or (c) relieving the disease state, e.g., causing regression of disease symptoms until a desired endpoint is reached. Treatment also includes amelioration of disease symptoms (e.g., reduction of pain or discomfort), where such amelioration may or may not directly affect the disease (e.g., cause, spread, expression, etc.).
By "therapeutically effective amount" is meant an amount of a compound of the present invention that is effective, when administered alone or in combination, to treat the targeted symptom or condition. "therapeutically effective amount" refers to an amount of a combination of claimed compounds effective to treat the symptoms or conditions of interest. The combination of compounds is preferably a synergistic combination. Synergistic effects occur when the effect of the compounds when administered in combination is superior to the additive effect of the compounds when administered alone as a single agent, as described, for example, by Chou and Talalay in adv.EnzymeRegul.1984,22: 27-55. In general, the synergistic effect is most clearly demonstrated in sub-optimal concentrations of the compounds. The synergistic effect may be lower cytotoxicity, increased antiviral effect, or some other combination of beneficial effects as compared to the individual components.
"pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic moieties. Pharmaceutically acceptable salts include, for example, the conventional quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from the following inorganic and organic acids: 1, 2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylaspartic acid, hexylresorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleate, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, peracetic acid (subacetic), succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.
The compounds of the invention may have asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, for example by resolution of racemic forms or by synthesis from optically active starting materials. It is to be understood that all processes used to prepare the compounds of the present invention, and intermediates prepared therein, are part of the present invention. All tautomers of the compounds shown or described are likewise to be considered as part of the present invention.
Examples
Deuterium enriched lenvatinib
In one embodiment, deuterium enriched lenvatinib is provided having 19 hydrogen atoms in the molecule, including 4 protic hydrogens (hydrogen atoms on nitrogen) and 15 aprotic hydrogens. Through with D2Simple deuterium exchange of O can easily perform deuterium substitution of hydrogen for protic hydrogen. Under normal conditions, hydrogen atoms at other positions in the molecule have different capacities of exchanging with deuterium; and enrichment of deuterium at these positions can be achieved by synthesizing the molecule from deuterium enriched starting materials or intermediates.
The present invention is based on increasing the amount of deuterium present in lenvatinib above its natural abundance. This increase is referred to as enrichment or deuterium enrichment. If not otherwise specified, the enrichment percentage refers to the percentage of deuterium present in the compound, mixture of compounds, or composition. Examples of enrichment amounts include about 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 12 mol%, 16 mol%, 21 mol%, 25 mol%, 29 mol%, 33 mol%, 37 mol%, 42 mol%, 46 mol%, 50 mol%, 54 mol%, 58 mol%, 63 mol%, 67 mol%, 71 mol%, 75 mol%, 79 mol%, 84 mol%, 88 mol%, 92 mol%, 96 mol%, to about 100 mol%. Replacement of a single hydrogen atom with deuterium will result in a molecule with deuterium enrichment of about 5% due to the presence of 19 hydrogens in the compound. To achieve enrichment of less than about 5%, but above natural abundance, only one site needs to be partially deuterated. Thus, enrichment of less than about 5% still refers to deuterium enriched lenvatinib.
In view of the natural abundance of deuterium enriched lenvatinib, the present invention also relates to isolated or purified deuterium enriched lenvatinib. Isolated or purified deuterium enriched lenvatinib is a class of molecules with deuterium levels (e.g., 5%) higher than naturally occurring levels. Isolated or purified deuterium enriched lenvatinib may be obtained by techniques known to those skilled in the art (see, e.g., the syntheses described below). Specific synthetic examples of deuterium enriched lenvatinib are shown below:
preparation of compound 1:
intermediate-1 (Int-1):
the method comprises the following steps:
the method 2 comprises the following steps:
the method 3 comprises the following steps:
preparation of compound 2:
intermediate-2 (Int-2):
other similar deuterium enriched starting materials can be obtained following procedures described in the literature, for example, see j.laboratory comp.and rad.2010, 53(11-12), 668-673. Compound 2 was synthesized by any of the 3 methods described above, starting from deuterium-enriched Int-2.
Preparation of compound 3:
other examples of deuterium enriched lenvatinib can be synthesized following the above or similar procedures starting from suitable deuterium enriched chemicals or starting materials. Examples of some specific compounds are given in table 1.
18O/17O-enriched lenvatinib
In another embodiment, provided is18O/17O-enriched lenvatinib having 4 oxygen atoms in the molecule. All oxygen atoms in lenvatinib can be made independently and individually18O/17Enriched in O, or made simultaneously with any combination of 2 oxygen atoms and/or 3 oxygen atoms18O/17Enriched in O, or made entirely of18O/17And (4) enriching O. The synthesis of compound 38 is schematically shown below; and is provided in table 218O/17Examples of O-enriched lenvatinib.
Preparation of compound 38:
intermediate-3 (Int-3):
compound 38:
13c-enriched lenvatinib
In yet another embodiment, there is provided13C-enriched lenvatinib. The carbon atoms in the molecule may be made individually or together13C-enrichment. Examples include, but are not limited to13C-methoxy derivatives and13c-cyclohexyl derivatives. The synthesis of these examples 53 and 54 is shown below; and shown in Table 313Other examples of C-enriched lenvatinib.
Preparation of compound 53:
preparation of compound 54:
15n-enriched lenvatinib
In yet another embodiment, there is provided15N-enriched lenvatinib having 4 nitrogen atoms in the molecule. All nitrogen atoms in lenvatinib can be independently and individually made15N-enriched or made simultaneously in any combination of 2 and/or 3 nitrogen atoms15Enriched in N, or made entirely of15And (4) enriching N. The synthesis of compound 57 is schematically shown below; and is provided in table 415Examples of N-enriched lenvatinib.
Preparation of compound 57:
multi-element isotopically enriched lenvatinib
In another embodiment, there is provided a multielement isotopically enriched lenvatinib. Isotopic enrichment is selected from D,18O (or17O)、13C and/or15A combination of two or more elements of N. These combinations offer a large number of options, e.g.2H、18Enrichment of O (i.e., simultaneous enrichment of deuterium and oxygen-18 isotopes in the molecule);2H、13c is enriched;2H、15enriching N;13C、18enrichment of O, and the like.
The following example Compound 73(2H、13C-isotopically enriched lenvatinib) is an example of the above-mentioned multielement isotopic enrichment. Further examples of such compounds are given in table 5.
Preparation of compound 73:
TABLE 1 examples of deuterium enriched lenvatinib
Table 2.18O/17Examples of O-enriched lenvatinib
Table 3.13Examples of C-enriched lenvatinib
TABLE 4. richness in15Examples of N Levatinib
TABLE 5 examples of multielement isotopically enriched lenvatinib
Many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Claims (20)
1. An isotopically enriched compound of formula I:
wherein R is1～R19Independently selected from hydrogen or deuterium;
Xa～Xdis independently selected from16O、17O or18O；
YaAnd YbIs independently selected from12C or13C；
Za～ZdIs selected from14N or15N；
With the proviso that R-group (R)1～R19) X-radical (X)a～Xd) Y-group (Y)aAnd Yb) And Z-group (Z)a～Zd) Is an isotopically enriched atom or group.
2. The isotopically enriched compound of claim 1, wherein the compound is a compound of formula II:
wherein R is1～R19Independently selected from hydrogen (H) or deuterium (D or2H) (ii) a And at least one of the R-groups is deuterium enriched or has no natural abundance.
3. The isotopically enriched compound of claim 1, wherein the compound is a compound of formula III:
wherein, Xa～XdIs independently selected from16O、17O or18O, and at least one of the X-groups has no natural abundance.
4. The isotopically enriched compound of claim 1, wherein the compound is a compound of formula IV:
wherein, YaAnd YbIs independently selected from12C or13C; and at least one of the Y-groups is not naturally abundant.
5. The isotopically enriched compound of claim 1, wherein the compound is a compound of formula V:
wherein Za～ZdIs independently selected from14N or15N; and at least one of the Z-groups is not naturally abundant.
6. The isotopically enriched compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein isotopic enrichment of two or more elements is present in the same compound; and the isotopically enriched elements are independently selected from D, B, C,17O、18O、13C and15N。
7. the isotopically enriched compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the unnatural isotopic abundance of any single element is from 5% to 100%.
8. The isotopically enriched compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein the abundance of an isotope of any single element is about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% in mole percent.
9. The multi-isotopically enriched compound of claim 6, wherein each isotopically enriched element is independently about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% by mole percentage.
10. The isotopically enriched compound of claim 1, wherein the isotopic enrichment of a single element at each position is independently about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% by mole percentage.
11. The multi-isotopically enriched compound of claim 9, wherein the isotopically enriched elements for each element at a particular position are independently about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% in mole percent.
12. The isotopically enriched compound of any one of claims 2 to 5, wherein the isotopic enrichment of a corresponding element at a particular position of the element is independently about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% as a mole percentage.
13. An isotopically enriched compound of any one of claims 1 to 6, wherein the compound is selected from compound 1 to compound 79 of tables 1 to 5, or a pharmaceutically acceptable salt thereof.
14. The isotopically enriched compound of claim 13, wherein the isotopic abundance of a single element at each position is 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, greater than about 98%, about 99%, or 100% in mole percent.
15. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier, and a therapeutically effective amount of a compound according to claims 1-14 or a pharmaceutically acceptable salt form thereof.
16. A method of treating diseases associated with Vascular Endothelial Growth Factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor- α, and RET and KIT proto-oncogenes, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claims 1-14 or a pharmaceutically acceptable salt form thereof, or a pharmaceutical composition of claim 15.
17. A method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claims 1-14 or a pharmaceutically acceptable salt form thereof, or a pharmaceutical composition of claim 15.
18. A method of using the isotopically enriched compounds of the invention for the preparation of a medicament.
19. The method of claim 18, wherein the medicament is for treating cancer.
20. The method of claim 18, wherein the medicament is for treating diseases and cancers associated with Vascular Endothelial Growth Factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor- α, and RET and KIT proto-oncogenes.
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| CN114213404A (en) * | 2021-12-27 | 2022-03-22 | 武汉九州钰民医药科技有限公司 | Synthesis process of VEGFR inhibitor tivozanib |
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