CN117883585A - Medicine for targeting fibroblast activation protein and application thereof - Google Patents

Medicine for targeting fibroblast activation protein and application thereof Download PDF

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CN117883585A
CN117883585A CN202311326426.1A CN202311326426A CN117883585A CN 117883585 A CN117883585 A CN 117883585A CN 202311326426 A CN202311326426 A CN 202311326426A CN 117883585 A CN117883585 A CN 117883585A
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alkyl
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方鹏
颜成龙
虞善友
伍维思
杨思
于德峰
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Wuxi Nuoyu Pharmaceutical Technology Co ltd
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Wuxi Nuoyu Pharmaceutical Technology Co ltd
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Abstract

The invention relates to a compound of a targeted fibroblast activation protein shown in a formula (X) and application thereof, and further relates to a compound containing the compoundPharmaceutical compositions and uses; wherein the compound or pharmaceutical composition is useful for diagnosing and/or treating and/or preventing one or more tumors, cancers or cells expressing FAP.

Description

Medicine for targeting fibroblast activation protein and application thereof
PRIORITY INFORMATION
The priority and rights of the patent application number 202211260609.3 filed by the national intellectual property agency of China on day 10 and 14 of 2022 are requested for this application and are incorporated herein by reference in their entirety.
Technical Field
The invention relates to the field of biological medicine, in particular to a medicine targeting fibroblast activation protein and application thereof.
Background
Fibroblast activation proteins (FAPs, also known as fibroblast activation protein α, fapα) are highly overexpressed on cancer-associated fibroblasts (CAFs) in solid tumors, but are not generally expressed in normal tissues and benign tumors. Tumor stroma CAFs can promote the growth and infiltration of tumor cells, and have become an important target for tumor intervention. Over-expression of the tumor biomarker molecule FAP is a remarkable characteristic of CAFs, and FAP is a potential target point in the aspect of CAF targeting for tumor diagnosis and treatment.
FAP is a type II transmembrane serine protease on tumor fibroblasts, exists on the cell surface in the form of homodimers, belongs to the family of proline oligopeptidases, and its own enzymatic activity plays an important role in tumor growth and tissue remodeling. CAF surface-specific FAP can enhance tumor cell invasive capacity along fiber orientation by promoting matrix reconstruction, participating in VEGF/AKT/ERK signal transduction pathway, participating in tumor angiogenesis and the like to form tumor biological barrier and inhibit the function of effector T cells, thereby promoting tumor progression. Inducible overexpression of FAP in the tumor stroma is also dependent on malignant transformation of tumor tissue. The high expression level of FAP is positively correlated with poor prognosis of tumors.
The non-inhibitory FAP monoclonal antibody has no tumor treatment effect, and the ADC taking the antibody as a carrier is unfavorable for clinical development due to the reasons of poor permeability, long half-life, long uptake and retention time of non-target organs, larger toxic effect and the like. The small molecular FAP selective (targeting) inhibitor subjected to structural modification and optimization screening has great advantages and development value for diagnosis and treatment of cancers.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, an object of the present invention is to propose some compounds with fibroblast activation protein-alpha (FAP) binding, which have better clinical application prospects. Compared with the existing similar compounds, the compound provided by the invention has better pharmacodynamic activity, and in addition, the compound provided by the invention also has excellent physicochemical property and drug substitution property, and has lower toxic and side effects.
The following is merely a general description of some aspects of the invention and is not limited in this regard. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited document, the disclosure of the present specification controls.
Fibroblast activation protein- α is a type II transmembrane serine protease of the prolyl oligopeptidase family, characterized by its ability to cleave the Pro-AA peptide bond (wherein AA represents any amino acid). It has been shown to play a role in cancer by modifying a number of bioactive signal peptides by the enzymatic activity (Kelly et al 2005; edosada et al 2006). Expression of fibroblast activation protein-a has been detected on the surface of a plurality of fibroblasts in the matrix surrounding more than 90% of the plurality of epithelial cancers, including but not limited to: malignant breast cancer, colorectal cancer, skin cancer, prostate cancer, pancreatic cancer, and the like, and inflammation, including but not limited to: arthritis, fibrosis, etc., while there is little expression in many healthy tissues. Thus, therapies directed specifically to fibroblast activation protein- α and imaging are of clinical importance.
The invention provides a compound with fibroblast activation protein-alpha (FAP) and can be used for preparing medicines for diagnosing and/or treating and/or preventing diseases expressed as the fibroblast activation protein, such as sarcoma malignant tumors, pancreatic cancer, ovarian cancer, melanoma, esophageal cancer, breast cancer, cholangiocarcinoma, lung cancer, liver cancer, colorectal cancer, head and neck cancer and neuroendocrine tumor.
The invention also provides methods of preparing these compounds and pharmaceutical compositions comprising these compounds and methods of using these compounds or compositions in the treatment of the above-described diseases in mammals, especially humans.
The compound of the invention can be combined with fibroblast activation protein-alpha well, so that the compound has better drug effect, drug generation property and/or toxicity property, such as good bioavailability, low toxic and side effects, high safety and the like.
The compound or the pharmaceutical composition can be well combined with fibroblast activation protein-alpha, and can be used for diagnosing and/or treating and/or preventing related diseases expressed as the fibroblast activation protein.
In a first aspect of the present invention, the present invention provides a compound which is a compound represented by formula (X) or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (X),
Wherein Y is selected from ligands that bind to fibroblast activation protein- α;
l is selected from the group consisting of linkers;
at least one of X and Z is present, X, Z is each independently selected from an albumin-binding ligand, a cytotoxic drug or a chelator, and at least one of X and Z is a cytotoxic drug or a chelator.
According to an embodiment of the invention, said X and Z are different.
According to an embodiment of the present invention, Y has a structure represented by formula (I '), a stereoisomer or a pharmaceutically acceptable salt of the structure represented by formula (I'),
wherein each y is independently selected from 0, 1 or 2;
R 1x 、R 2x r is R 3x’ Each independently selected from H, -OH, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S-C 1-6 An alkyl group;
R 3x selected from H, -CN, -B (OH) 2 -C (O) alkyl, -C (O) aryl-, -c=c-C (O) aryl, -c=cs (O) 2 aryl-CO 2 H、-SO 3 H、-SO 2 NH 2 、-PO 3 H 2 Or 5-tetrazolyl;
wherein the method comprises the steps ofRepresents the point of attachment of the fibroblast activation protein-alpha binding ligand to the linker, wherein the point of attachment may be attached to the linker through any one of the 5, 6, 7 or 8 carbon atoms of the quinoline ring of the fibroblast activation protein-alpha binding ligand.
According to an embodiment of the invention, the Y structure is selected from one of the following:
according to a specific embodiment of the invention, the Y structure is selected from one of the following:
According to an embodiment of the present invention, Y has a structure represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt of the structure represented by formula (I),
wherein each y is independently selected from 0, 1 or 2;
R 1x 、R 2x r is R 3x’ Each independently selected from H, -OH, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S-C 1-6 An alkyl group;
R 3x selected from H, -CN, -B (OH) 2 -C (O) alkyl, -C (O) aryl-, -c=c-C (O) aryl, -c=cs (O) 2 aryl-CO 2 H、-SO 3 H、-SO 2 NH 2 、-PO 3 H 2 Or 5-tetrazolyl;
wherein the method comprises the steps ofRepresents the point of attachment of the fibroblast activation protein-alpha binding ligand to the linker, wherein the point of attachment may be attached to the linker through any one of the 5, 6, 7 or 8 carbon atoms of the quinoline ring of the fibroblast activation protein-alpha binding ligand.
According to an embodiment of the invention, the Y structure is selected from one of the following:
according to a specific embodiment of the invention, the Y structure is selected from one of the following:
according to an embodiment of the invention, L is selected from one or more of (a), (b) and (c),
(a)
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 1 at least one selected from-NR-, -RC (=O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -;
m 1 selected from 0, 1, 2, 3, 4, 5 or 6;
(b)
Wherein:
V 2 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 2 at least one selected from-NR-, -RC (=O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -;
m 2 m 3 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
(c)
wherein:
V 3 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 3 at least one selected from-R-, -NR-, -RC (=O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -;
m 4 m 5 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
r, R 'and R' in formula (a), (b) or (c) are each independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined herein.
According to an embodiment of the invention, L is selected from one or more of (a-1), (a-2), (b) and (c),
(a-1)
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 1 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 1 Selected from 0, 1, 2, 3, 4, 5 or 6;
(a-2)
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 4 selected from the group consisting of-NR-, -R-, RC (O) -, -at least one of C (O) NR-or-NR-C (O) -;
m is selected from at least one of-NR-, -O-, -OC (O) -, -C (O) NR-, -C (O) -or-RC (O) -;
m 6 m 7 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
(b)
wherein:
V 2 selected from-NR-, -O-at least one of, -C (O) -, -OC (O) -, -NRC (O) -or-NRC (S) -;
W 2 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 2 m 3 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
(c)
wherein:
V 3 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 3 selected from the group consisting of-R-, -NR-, -RC (O) -, RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 4 m 5 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
r, R 'and R' in formula (a-1), (a-2), (b) or (c) are each independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined herein.
According to an embodiment of the invention, R, R 'and R' are each independently selected from H, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl, piperazine, lactone, cyclic anhydride, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydronaphthyridinyl, substituted heterocycloalkyl, phenyl, naphthyl, substituted aryl, pyrimidine, pyridine, pyrazine, furan, thiophene, or substituted heteroaryl, the remaining variables being as defined herein.
According to an embodiment of the invention, R, R 'and R' are each independently selected from H, C 1-6 Alkyl, substitutedC of (2) 1-6 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl group,The remaining variables are as defined herein.
According to an embodiment of the present invention, the L has a structure of one of the following:
the remaining variables are as defined herein.
According to an embodiment of the present invention, the L has a structure of one of the following:
the remaining variables are as defined herein.
According to an embodiment of the invention, the albumin-binding ligand has the structure of one of the following:
The remaining variables are as defined herein.
According to an embodiment of the invention, the cytotoxic drug is selected from camptothecins or derivatives thereof, tubulin inhibitors or derivatives thereof, synthesis inhibitors of RNA or DNA or derivatives thereof. Specifically, wherein the camptothecins or derivatives thereof comprise irinotecan, SN38, DXd; the tubulin inhibitors or derivatives thereof include maytansinoids, auristatins and derivatives thereof, in particular DM1, MMAE; the RNA or DNA synthesis inhibitor or derivative thereof includes doxorubicin and its derivative, and the remaining variables are defined in the present invention.
According to a specific embodiment of the present invention, the cytotoxic drug is selected from one of the following structures and derivatives thereof:
the remaining variables are as defined herein.
According to a specific embodiment of the invention, the cytotoxic drug is derived from one of the following structures or a derivative of one of the following structures:
the remaining variables are as defined herein.
According to specific embodiments of the present invention, the derivatives include, but are not limited to, aminated derivatives, sulfided derivatives, nitrided derivatives, carbonylated derivatives, alkylated derivatives.
According to an embodiment of the present invention, the chelating agent is derived from 1,4,7, 10-tetraazacyclododecane-N, N ', -tetraacetic acid, 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid, 2- (4, 7-bis (carboxymethyl) -1,4, 7-trisazo-1-yl) glutaric acid, 2- (4, 7, 10-tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane-1-yl) glutaric acid, 1,4, 7-triazacyclononane-phosphinic acid, 1,4, 7-triazacyclononane-1- [ methyl (2-carboxyethyl) phosphinic acid ] -4, 7-bis [ methyl (2-carboxymethyl) phosphinic acid ], N' - {5- [ acetyl (hydroxy) amino ] pentyl } -N- [5- ({ 4- [ 5-aminopentyl) (hydroxy) amino ] -4-oxobutanoyl } amino) pentyl ] -N-hydroxysuccinamide, diethyltriamine pentaacetic acid, trans-cyclohexyl-diethylenetriamine pentaacetic acid, p-isocyanatobenzyl-diethylenetriamine pentaacetic acid, 1- (isocyanatobenzyl) -diethylenetriamine pentaacetic acid, 1- (3-isocyanatobenzyl) -diethylenetriamine-pentaacetic acid, 5- (2-carboxymethyl) -triethyleneacetic acid, 5- (4-hydroxybenzyl) -triethyleneamine-pentaacetic acid, 5- (2-isocyanatobenzyl) -triethyleneacetic acid, 1-oxa-4, 7, 10-triazacyclododecane-4, 7, 10-triacetic acid, 6-hydrazinonicotinic acid succinimidyl ester hydrochloride and mercaptoacetyl triglycine, the remaining variables being as defined herein.
According to an embodiment of the present invention, among the aforementioned compounds The structure is selected from one of the following (a), (b) and (c):
(a)
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 1 at least one selected from-NR-, -RC (=O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -;
m 1 selected from 0, 1, 2, 3, 4, 5 or 6;
z is a cytotoxic drug;
(b)
wherein:
V 2 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 2 at least one selected from-NR-, -RC (=O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -;
m 2 m 3 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z is a cytotoxic drug;
x is a ligand that binds albumin;
(c)
wherein:
V 3 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 3 at least one selected from-R-, -NR-, -RC (=O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -;
m 4 m 5 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z, X are each independently selected from albumin-binding ligands, cytotoxic drugs or chelators;
r, R 'and R' in formula (a), (b) or (c) are each independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined herein.
According to an embodiment of the present invention, among the aforementioned compoundsThe structure is selected from one of the following (d-1), (d-2), (d-3) and (d-4):
(d-1)
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 1 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 1 selected from 0, 1, 2, 3, 4, 5 or 6;
z is a cytotoxic drug;
x is absent;
(d-2)
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 4 selected from the group consisting of-NR-, -R-, RC (O) -, -at least one of C (O) NR-or-NR-C (O) -;
m is selected from at least one of-NR-, -O-, -OC (O) -, -C (O) NR-, -C (O) -or-RC (O) -;
m 6 m 7 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z is a cytotoxic drug;
x is absent;
(d-3)
wherein:
V 2 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 2 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 2 m 3 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z is a cytotoxic drug or chelator;
x is a ligand that binds albumin;
(d-4)
wherein:
V 3 Selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 3 selected from the group consisting of-R-, -NR-, -RC (O) -, RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; at least one of-C (O) NR-or-NR-C (O) -, andfirst, a first step;
m 4 m 5 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z, X are each independently selected from albumin-binding ligands, cytotoxic drugs or chelators;
wherein Z is selected from a cytotoxic drug or a chelator; x is selected from albumin-binding ligands;
r, R 'and R' in formula (d-1), (d-2), (d-3) or (d-4) are each independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined herein.
In a second aspect of the invention, the invention provides a compound. According to an embodiment of the present invention, the compound is a compound as described above or a stereoisomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, the structure of which is selected from one of the following:
in a third aspect of the invention, the invention relates to a complex. According to an embodiment of the present invention, the complex is formed by complexing the aforementioned compound or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof with a radionuclide or a non-radioactive element A', the structure of which is shown as formula (II),
Wherein Z is a chelator, X is an albumin-binding ligand, a cytotoxic drug or is absent, and the remaining variables are as defined herein.
In a fourth aspect of the invention, the invention relates to a complex. According to an embodiment of the present invention, the complex is formed by complexing the aforementioned compound or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof with a radionuclide or a non-radioactive element A', the structure of which is shown as formula (III),
wherein X is a chelator, Z is an albumin-binding ligand, a cytotoxic drug or is absent, and the remaining variables are as defined herein.
In a fifth aspect of the invention, the invention relates to a compound. According to an embodiment of the present invention, the compound is a compound according to the first aspect or a stereoisomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, characterized in that the structure is selected from one of the following:
in a sixth aspect of the invention, the invention relates to a complex. According to an embodiment of the invention, the complex is formed by complexation of a compound according to the fifth aspect or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof with a radionuclide or a non-radioactive element B'.
According to an embodiment of the invention, the radionuclide or non-radioactive element a 'is the same as or different from the radionuclide or non-radioactive element B'.
According to an embodiment of the invention, the radionuclides a 'or B', respectively, are independently selected from: 68 Ga、 18 F、 99 mTc、 89 Zr、 111 In、 45 Ti、 59 Fe、 64 Cu、 94 mTc、 67 Ga、 71/72/74 As、 43/44 Sc、 82 mRb、 52 Mn、 86 Y、 76 Br、 177 Lu、 90 Y、 153 Sm、 67 Cu、 89 Sr、 137 Cs、 166 Ho、 177 Yb、 105 Rh、 186/188 Re、 47 Sc、 212/213 Bi、 225 Ac、 212 Pb、 149 pm and 227 at least one of Th, the remaining variables are as defined herein.
According to an embodiment of the invention, the non-radioactive elements a 'or B' are each independently selected from at least one of Ga, fe and Gd, the remaining variables being as defined herein.
According to an embodiment of the invention, the radionuclide is selected from 18 F, the remaining variables are as defined herein.
According to an embodiment of the invention, the radionuclide 18 The F complex is formed by the radioisotope aluminum fluoride, the remaining variables being as defined herein.
In a seventh aspect of the invention, the invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises a compound according to the first, second or fifth aspect, or a complex according to the third, fourth or sixth aspect, or a stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
In an eighth aspect of the invention, the invention provides the use of a compound according to the first, second or fifth aspect, or a complex according to the third, fourth or sixth aspect, or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the seventh aspect, for the manufacture of one or more agents and/or medicaments for the diagnosis and/or treatment and/or prevention of tumors, cancers or cells expressing FAP.
According to an embodiment of the present invention, the tumor or cancer expressing FAP is at least one selected from melanoma, esophageal cancer, breast cancer, cholangiocarcinoma, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, and other sarcomas, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumor.
According to a specific embodiment of the present invention, the tumor and the cancer expressing FAP are at least one of sarcoma-type malignant tumor such as fibrosarcoma and osteosarcoma, pancreatic cancer and ovarian cancer.
In a ninth aspect of the present invention, the present invention provides the use of a compound according to the first, second or fifth aspect, or a complex according to the third, fourth or sixth aspect, or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the seventh aspect, for the diagnosis and/or treatment and/or prevention of diseases associated with high expression of FAP.
In a tenth aspect of the invention, the invention provides the use of a compound according to the first, second or fifth aspect, or a complex according to the third, fourth or sixth aspect, or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the seventh aspect, for the preparation of one or more agents and/or medicaments for inhibiting FAP expression.
In an eleventh aspect of the invention, the invention provides a method of imaging tissue expressing FAP. According to an embodiment of the invention, the method comprises: applying to the tissue the complex of the third, fourth or sixth aspect or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the seventh aspect; PET imaging is used for the tissue.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The invention will apply to the following definitions unless otherwise indicated. According to the object of the invention, the chemical elements are according to the element circumferenceSchedule, CAS version and handbook of chemistry and physics, 75 th Ed., 1994. In addition, the general principles of organic chemistry are found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato, 1999, and "March's Advanced Organic Chemistry", michael b.smith and Jerry March, john Wiley&Sons, new York,2007, all of which are incorporated herein by reference.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.
Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2nd Ed.Robert E.Gawley,Jeffrey Aub e, elsevier, oxford, UK, 2012); eliel, e.l. stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); wilen, S.H.tables of Resolving Agents and Optical Resolutions p.268 (E.L.Eliel, ed., univ.of Notre Dame Press, notre Dame, IN 1972); chiral Separation Techniques: A Practical Approach (Subramannian, G.ed., wiley-VCH Verlag GmbH & Co.KGaA, weinheim, germany, 2007).
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved
. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation.
The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "substituted" generally means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Unless otherwise indicated, a substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different substituted at each substitutable position.
The term "unsubstituted" means that the specified group does not carry a substituent.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, for example, for compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may have a substituent substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=o), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-C (=o) -, alkyl-S (=o) 2 -, hydroxy-substituted alkyl-S (=o) 2 -, carboxy substituted alkoxy, and the like.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other. Taking R as an example, the specific options of R between-RC (O) -, -NRC (S) NR' -, -NRC (O) O-, -C (O) NR-, or-NR-C (O) -, are not affected by each other; meanwhile, if more than 2R are present in the same chemical formula, the specific options of R are not influenced.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH2O is equivalent to OCH2. As used herein, Representing the attachment site of the group.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
In each of the parts of the present invention, a compound of the formula (I')And +.>The same structure is represented, and the ranges of the series of compounds represented by the two structures are consistent.
The term "alkyl" means a saturated straight or branched monovalent hydrocarbon group of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein, including but not limited to deuterium, amino, hydroxyl, cyano, F, cl, br, I, mercapto, nitro, oxo (=o), and the like. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" are used herein to encompass both straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon group resulting from elimination of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene, isopropylidene, and the like.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), isopropylidene (-CH (CH) 3 )CH 2 (-), etc.
The term "alkenyl" denotes a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon sp2 double bond, which includes the positioning of "cis" and "trans", or the positioning of "E" and "Z"Bits. Wherein the alkenyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkenyl group comprises 2 to 12 carbon atoms; in another embodiment, the alkenyl group comprises 3 to 12 carbon atoms; in another embodiment, the alkenyl group comprises 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch) 2 ) Allyl (-CH) 2 CH＝CH 2 ) Etc.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 3 to 12 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) Etc.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH2CH 3 ) 2-methyl-l-propoxy(i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups; the alkyl groups have the meaning described in the present invention. Some of these are, for example, alkylamino groups of one or two C 1-6 Alkyl groups are attached to lower alkylamino groups formed on the nitrogen atom. Other embodiments are where the alkylamino group is one or two C 1-4 Is linked to an alkylamino group formed on the nitrogen atom. Suitable alkylamino groups may be mono-or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.
The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, aminomethyl, 2-aminoethyl, 3-amino-1-propyl, 4-amino-1-butyl, and the like.
The terms "haloalkyl", "haloalkenyl", "haloalkoxy" or "haloalkylamino" refer to an alkyl, alkenyl, alkoxy or alkylamino group substituted with one or more halogen atoms, wherein alkyl, alkenyl, alkoxy or alkylamino groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, 2, 3-tetrafluoropropyl, trifluoromethoxy, trifluoromethylamino and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms. In one embodiment, cycloalkyl contains 7 to 12 ring carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 8 ring carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 6 ring carbon atoms. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "carbocyclyl" or "carbocycle" means a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms. Carbobicyclo groups include spirocarbobicyclo groups and fused carbobicyclo groups. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. In one embodiment, carbocyclyl groups contain 3 to 8 ring carbon atoms; in yet another embodiment, carbocyclyl groups contain 3 to 6 ring carbon atoms. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "heteroalkyl", by itself or in combination with another term, means a stable straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, consisting of at leastOne carbon atom and at least one heteroatom selected from the group consisting of O, N, P and Si and S, and wherein the nitrogen, phosphorus and sulfur atoms can be selectively oxidized and the nitrogen heteroatom can be selectively quaternized. Heteroatoms O, N, P and S and Si may be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 25
-S(O)-CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH＝CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH＝N-OCH 3 、-CH＝CH-N(CH 3 )-CH 3 、O-CH 3 、-O-CH 2 -CH 3 -CN. Up to two or three heteroatoms may be contiguous, for example: -CH 2 -NH-OCH 3 -CH 2 -O-Si(CH 3 ) 3 。
As mentioned above, heteroalkyl groups as used in this specification include those groups linked through a heteroatom to the remainder of the molecule, for example: c (O) NR ', NR' R ', OR', SR, S (O) R and/OR-S (O) 2 ) R'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, for example: -NR 'R, etc., it should be understood that the terms heteroalkyl and-NR' R "are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to increase clarity. Thus, the term "heteroalkyl" should not be interpreted in this specification to exclude specific heteroalkyl groups, such as: -NR' R ", etc.
The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a non-aromatic ring system, an unsaturated or partially unsaturated ring system, such as a 3-to 10-membered substituted or unsubstituted cycloalkyl ring system, comprising one or more heteroatoms, which may be the same or different, and are selected from nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and may optionally comprise one or more double bonds.
The cycloheteroalkyl ring may be optionally fused or otherwise linked to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. The plurality of heterocycles includes those having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the nitrogen and sulfur heteroatoms may be selectively oxidized and the nitrogen heteroatoms may be selectively quaternized. In certain embodiments, the term heterocycle refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including but not limited to: a bicyclic or tricyclic group comprising a plurality of fused six-membered rings having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be selectively oxidized, (iii) the nitrogen heteroatoms may be selectively quaternized, and (iv) the ring of any of the above-described heterocycles may be fused with an aryl or heteroaryl ring. Systems of multiple representative cycloheteroalkyl rings include, but are not limited to: pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrothiopyranyl, and the like.
The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, denote the cyclic forms of "alkyl" and "heteroalkyl", respectively. In addition, for heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl groups include, but are not limited to: cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl groups include, but are not limited to: 1- (1, 2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "cycloalkenyl" and "heterocycloalkenyl" refer to divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
An unsaturated alkyl group is a group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to: vinyl, 2-propenyl, crotyl (crotyl), 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl and higher homologs and isomers. Alkyl groups limited to hydrocarbyl groups are referred to as "homoalkyl (homoalkyl).
The term "aryl" refers to aromatic hydrocarbon substituents which may be monocyclic or fused together or covalently linked monocyclic or polycyclic (e.g., 1 to 3 rings). The term "heteroaryl" refers to a plurality of aryl groups (or rings) comprising one to four heteroatoms (in each single ring in the case of multiple rings) selected from N, O and S, wherein the nitrogen and the sulfur atoms are optionally oxidized and the nitrogen atom (S) are optionally quaternized. Heteroaryl groups may be attached to the remainder of the molecule through a carbon atom or heteroatom. A number of non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. The substituents of each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.
For brevity, when the term "aryl" is used in combination with other terms (e.g., aryloxy, arylthio, arylalkyl), the term "aryl" includes aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl" and "heteroarylalkyl" are intended to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like), including those in which a carbon atom (e.g., methylene) has been substituted with, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like). However, the term "haloaryl" as used in this specification is intended to encompass aryl groups substituted with one or more halogens only.
The term "heteroaryl" may be used alone or as part of a "heteroarylalkyl" or "heteroarylalkoxy" group, meaning mono-, bi-and tricyclic ring systems containing a total of 5-14 membered rings, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning described herein, wherein each ring system contains a 3-7 membered ring and has one or more attachment points attached to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "aromatic heterocycle" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) 2 -, hydroxy-substituted alkyl-S (=o) 2 -, carboxy substituted alkoxy, and the like.
Other embodiments are those wherein the aromatic heterocycle includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiodiazolyl, 1,3, 4-thiodiazolyl, 1,2, 5-thiodiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al, J.pharmaceutical Sciences,66,1-19,1977. Pharmaceutically acceptable non-toxic acid-forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid Salts, bisulfate, borate, butyrate, camphoric acid, camphorsulfonic acid, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodic acid, 2-hydroxy-ethanesulfonate, lactoaldehyde, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium/quaternary ammonium salts and amine cations resistant to counter ion formation, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 Sulfonate and aromatic sulfonate.
A number of pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art and include salts of a number of active compounds prepared with a number of relatively non-toxic acids or bases according to the number of specific substituents present on the number of compounds described in this specification. When the compounds of the present disclosure contain multiple relatively acidic functional groups, the neutral form of the compounds can be contacted with a sufficient amount of the desired base to obtain multiple base addition salts, either in solvent-free (heat) conditions or in a suitable inert solvent or by ion exchange whereby one basic counterion (base) in one ion complex is replaced by another. Examples of the plurality of pharmaceutically acceptable base addition salts include: sodium, potassium, calcium, ammonium, organic amino or magnesium salts or the like.
When the compounds of the present disclosure contain multiple relatively basic functional groups, the neutral form of the compounds can be contacted with a sufficient amount of the desired acid to obtain multiple acid addition salts, either directly under solventless conditions or in a suitable inert solvent or by ion exchange (whereby one acidic counterion (acid) in an ionic complex is replaced by another). Examples of the plurality of pharmaceutically acceptable acid addition salts include: a plurality of acid addition salts derived from a plurality of inorganic acids, for example: salts of hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogen, dihydrogen, sulfuric, monohydrogen, hydrofluoric or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids, such as: salts of acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and also salts of amino acids such as: arginine salts and the like, and salts of organic acids such as: glucuronic acid or galacturonic acid, and the like (see, e.g., berge et al, "pharmaceutically acceptable salts", journal of pharmaceutical sciences, 1977, 66, 1-19). Certain specific compounds of the present disclosure include both basic and acidic functionalities that allow the plurality of compounds to be converted into a base addition salt or an acid addition salt.
Thus, a number of pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, citrate, edetate, ethanedisulfonate, propionate dodecasulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl para-aminophenylarsenate (glycolylarsanilate), hexylresorcinol salt (hexylesporinate), hydramine (hydrobromide), hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucinate, naphthalenesulfonate, nitrate, pamoate (enbenzoate), pantothenate, phosphate/diphosphate, polygalactoate, salicylate, stearate, sub-acetate, succinate, sulfate, tanninate, tartrate or 8-chlorotheophyllinate. Other pharmaceutically acceptable salts can be found, for example, in lepton pharmaceutical science and practice (20 th edition) leptoside, williams and wilkins publishers (2000).
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (X). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1 -C 24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al, prodrug: design and Clinical Applications, nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al, prodrugs of Phosphates and Phosphonates, journal of Medicinal Chemistry,2008,51,2328-2345.
"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in other embodiments, one of the present compound molecules may be associated with more than one water molecule, such as a dihydrate, and in still other embodiments, one of the present compound molecules may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.
In therapeutic and/or diagnostic applications, the plurality of compounds of the present disclosure may be formulated for a variety of modes of administration, including systemic or local administration. Techniques and formulations are generally found in lepton pharmaceutical science and practice (20 th edition) leptoside, williams and wilkins press (2000).
Depending on the particular conditions being treated, these agents may be formulated in liquid or solid dosage forms and administered systemically or locally. The plurality of agents may be delivered in a timed or sustained slow release form, as known to those skilled in the art. Can be found in "Leimton: several techniques for formulation and administration are found in pharmaceutical science and practice (20 th edition) LiPing Kot, williams and Wills Press (2000). A number of suitable approaches may include: by inhalation spray, transdermal, or transmucosal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal (intrathecal), direct intraventricular, intravenous, intra-articular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections, or other modes of delivery.
For injection, the various agents of the present disclosure may be formulated and diluted in various aqueous solutions, for example in a physiologically compatible buffer such as hank's solution, ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, such penetrants generally known in the art.
Pharmaceutical compositions suitable for use in the present disclosure include: a plurality of compositions containing an effective amount of the active ingredient to achieve its intended purpose. Determination of such effective amounts is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein. Typically, the plurality of compounds according to the invention are effective over a wide dosage range. For example: in the treatment of adults, multiple doses of 0.01 to 1000 milligrams (mg), 0.5 to 100 milligrams, 1 to 50 milligrams and 5 to 40 milligrams per day are several examples of doses that may be used. One non-limiting dose is 10 to 30 milligrams per day. The exact dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the body weight of the subject to be treated, the bioavailability, adsorption, distribution, metabolism and excretion (ADME) toxicity of the compound(s), and the preferences and experience of the attending physician.
In addition to the plurality of active ingredients, the plurality of pharmaceutical compositions may also contain a plurality of suitable pharmaceutically acceptable carriers comprising a plurality of excipients and auxiliaries which facilitate processing of the plurality of active compounds into preparations which can be used pharmaceutically.
In many embodiments of the methods of the present disclosure, the subject treated by the methods of the present disclosure is desirably a human subject, although it should be understood that the multiple methods described herein are effective for all vertebrate species, which are intended to be included in the term "subject. Thus, a "subject" may include a human subject for a number of medical purposes, such as: an animal (non-human) subject for the treatment of an existing condition or disease or for a prophylactic treatment to prevent the onset of a condition or disease, or for medical, veterinary or developmental purposes. The plurality of suitable animal subjects includes: mammals, including, but not limited to: primates, for example: humans, monkeys, apes, etc.; bovine animals, for example: cattle (cattle), cattle (oxen), etc.; ovine animals, for example: sheep (sheep), etc.; goats, for example: goats (goats), and the like; porcine animals, for example: pigs (pigs), hogs), and the like; equine animals, for example: horses, donkeys, zebras, etc.; a feline comprising: wild cats and domestic cats; a canine comprising: a dog; a lagomorpha animal comprising: rabbits, hares, etc.; and rodents, comprising: mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the object is a human, including but not limited to: fetal, neonatal, infant, adolescent, and adult subjects. Further, "subject" may include a patient suffering from or suspected of suffering from a disorder or disease. Thus, the terms "subject" and "patient" are used interchangeably herein. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human.
As used herein, the term "treating" may include reversing, alleviating, inhibiting the progression of, preventing or reducing the disease or the condition to which the term applies or one or more symptoms or manifestations of the disease or disorder.
"preventing" means not causing a deterioration in a disease, disorder, symptom or performance or severity. Thus, the plurality of compounds of the present disclosure may be administered prophylactically to prevent or reduce the occurrence or recurrence of the disease or disorder.
The term "treating" any disease or disorder as used herein refers to all slowing, interrupting, arresting, controlling or stopping the progression of the disease or disorder, but does not necessarily mean that the symptoms of all diseases or disorders are all absent, and includes prophylactic treatment of such symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to an individual, is effective for: (1) At least partially alleviating, inhibiting, preventing and/or ameliorating a disorder or disease that is (i) mediated by FAP, or (ii) associated with FAP activity, or (iii) characterized by aberrant activity of FAP; or (2) reduce or inhibit FAP activity; or (3) reduce or inhibit expression of FAP. In another embodiment, the term "therapeutically effective amount" means an amount that, when administered to a cell, or organ, or non-cellular biological substance, or medium, at least partially reduces or inhibits FAP activity; or an amount of a compound of the invention effective to at least partially reduce or inhibit FAP expression.
The terms "administration" and "administering" of a compound as used herein should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. It will be appreciated that one skilled in the art will now be able to treat diseases currently suffering from FAP-expressing diseases, such as fibrosarcoma, osteosarcoma, pancreatic cancer ovarian cancer, etc., by using an effective amount of a compound of the present invention.
The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any products that result directly or indirectly from mixing, compounding or aggregation of any two or more ingredients, or from decomposition of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a nuclear magnetic resonance spectrum of NYM030 in accordance with an embodiment of the invention;
FIG. 2 is an LC-MS diagram of NYM030, according to an embodiment of the invention;
FIG. 3 is an HPLC chromatogram of NYM030 according to an embodiment of the invention;
FIG. 4 is a nuclear magnetic resonance spectrum of NYM031 according to an embodiment of the present invention;
Fig. 5 is an LC-MS diagram of NYM031 according to an embodiment of the present invention;
FIG. 6 is an HPLC chromatogram of NYM031 according to an embodiment of the present invention;
FIG. 7 is a graph showing the results of an in vitro antitumor activity test of NYM030 according to an embodiment of the invention;
FIG. 8 is a plot of tumor volume size trend on an HT1080 tumor-bearing murine model according to an embodiment of the present invention;
FIG. 9 is a graph showing the body weight trend of HT1080 tumor-bearing mice according to an embodiment of the invention;
FIG. 10 is a graph showing the change in tumor volume of SJSA-1 tumor-bearing mice according to embodiments of the invention;
FIG. 11 is a graph showing weight change of SJSA-1 tumor-bearing mice according to embodiments of the present invention;
FIG. 12 is an ICR mouse weight change profile according to an embodiment of the invention;
FIG. 13 is a graph of body weight trend of ICR mice according to an embodiment of the invention.
Detailed Description
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not limiting in any way.
Preparation of the Compounds of example 1
1. Process for the preparation of the Compound NYM030 molecule
NYM030 molecular structure (nuclear magnetic resonance spectrum thereof is shown in figure 1, LC-MS spectrum is shown in figure 2)
The synthetic route is as follows:
step one:
compound (1) (6.00 g,24.0mmol,1.00 eq) was dissolved in 50.0mL of HF solvent, NMM (3.23 g,31.9mmol,3.51mL,1.30 eq) and methylsulfonyl methanesulfonate (5.56 g,31.9mmol,1.30 eq) were added and stirred at 20℃for 2 hours. H for reaction solution 2 O (50.0 mL) was diluted, extracted 3 times with ethyl acetate, each time with 50mL (50.0 mL x 3). The extracted organic layer was washed with 50.0mL of brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give compound (2) (7.50 g,23.2 mmol) as a yellow oil.
Step two:
compound (2) (7.50 g,23.2mmol,1.00 eq) was reacted with MeNH 2 The mixture of (52.2 g,504mmol,50.0mL, purity 30.0%,21.7 eq) was stirred in a sealed tube at 70℃for 12 hours. The reaction mixture was then quenched with 1.00M HCl and the pH was adjusted to 7, followed by suction filtrationCompound (3) (6.2 g) was obtained as a colorless oil.
Step three:
compound (4-1) (10.0 g,39.6mmol,1.00 eq) was dissolved in 100mL MeCN solvent, cs was added to this solution 2 CO 3 (19.4 g,59.5mmol,1.50 eq) and BnBr (6.79 g,39.6mmol,4.71mL,1.00 eq). The reaction mixture was stirred at 20 ℃ for 12 hours, then diluted with 150mL of water, extracted 3 times with ethyl acetate, each with 50mL (50.0 mL 3). The extracted organic layer was washed with 100mL of brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a residue. The residue was separated and purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1-5/1) (petroleum ether: ethyl acetate=3:1, rf.about.0.60) to give compound (4) (12.0 g,35.0 mmol) as a yellow oil.
Step four:
to this solution were added Pd, by dissolving compound (3) (5.60 g,21.7mmol,1.00 eq) and compound (4) (7.45 g,21.7mmol,1.00 eq) in 50.0mL dioxane 2 (dba) 3 (1.99 g, 2.18mmol,0.10 eq), xphos (1.04 g, 2.18mmol,0.10 eq) and Cs 2 CO 3 (14.2 g, 43.5mmol,2.00 eq). The mixture was stirred at 100℃for 12 hours. The reaction product was diluted with 100mL of water, extracted with ethyl acetate (50.0 mL of x 3), 3 times with 50mL each time. The extracted organic layer was washed with 100mL of brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA reagent) to give compound (5) (4.24 g,8.18 mmol) as a yellow oil.
Step five:
compound (5) (7.00 g,13.5mmol,1.00 eq) was dissolved in 70.0mL of HF in N 2 Pd/C (700 mg, purity 10%) was added to this solution under purging. The resulting suspension was degassed under vacuum and purged several times with hydrogen. At H 2 (15 psi) the mixture was stirred at 20 ℃ for 12 hours, filtered and the filtrate was freed from solvent under vacuum to give a residue. Purification by prep-HPLC (TFA reagent) gave compound (6) (4.70 g,10.9mmol, 81.2%) as a red solid.
Step six:
compound (6) (650 mg, 1.52mmol, 1.02mmol, 1.00 eq) and compound (7) (1.03 g, 1.52mmol,53% purity,1.00eq, tsOH) were dissolved in 5.00ml of LDMF solvent, and HATU (864 mg,2.27mmol,1.50 eq) and DIEA (390 mg,3.02mmol,2.00 eq) were added to this solution. The mixture was stirred at 20 ℃ for 1 hour and then the solvent was removed under vacuum. Purification of the mixture by prep-HPLC (TFA reagent) gave compound (8) (624 mg,1.04 mmol) as a yellow solid.
Step seven:
compound (8) (600 mg,1.00mmol,1.00 eq) was dissolved in 6.00 mM LMeCN solvent, to which TsOH.H was added 2 O (390 mg,2.05mmol,2.05 eq). The mixture was stirred at 20 ℃ for 12 hours and then the solvent was removed under vacuum. Compound (9) (712 mg, tsoh) was obtained as a red solid.
Step eight:
compound (10) (500 mg,1.27mmol,1.00 eq) was dissolved in 5mL of THF solvent; to this solution were added DIEA (247 mg,1.91mmol,1.50 eq) and compound (11) (308 mg,1.53mmol,1.20 eq), the mixture was stirred at 25 ℃ for 12 hours to give a reaction mixture, after removal of the solvent under vacuum, the resulting product was triturated in 10mL of solvent of MTBE to give compound (12) (512 mg, 178 umol) as a yellow solid.
Step nine:
compound (9) (350 mg, 521. Mu. Mol,1.00 eq) and compound (12) (29 mg, 521. Mu. Mol,1.00 eq) obtained in the above step were dissolved in 3.00ml of an LDMF solvent, and triethylamine TEA (158 mg,1.56mmol,3.00 eq) was added to the solution. The mixture was stirred at 20℃for 2 hours. The mixture was purified by prep-HPLC (TFA reagent) to give compound (NYM 030) (60.0 mg,65.1umol, purity 99.6%) as an orange solid, with the HPLC profile of NYM030 shown in FIG. 3.
2. Process for the preparation of the Compound NYM031 molecule
NYM031 molecular structure (its nuclear magnetic resonance spectrum is shown in FIG. 4, and LC-MS spectrum is shown in FIG. 5)
The synthetic route is as follows:
step one:
compound (10) (2.00 g,5.10mmol,1.00 eq) was dissolved in 20mL of DCM solvent, tert-butyldimethylsilyl chloride TBSCl (1.92 g,12.7mmol,2.50 eq) and N, N-diisopropylethylamine DIEA (1.98 g,15.3mmol,3.01 eq) were added to the solution, and the mixture was stirred at 20℃for 2 hours. After removal of the solvent in vacuo, prep-HPLC (TFA reagent) was used to give compound (13) (2.45 g,4.84 mmol) as a white solid.
Step two:
the compound (13) obtained in the above step was dissolved in 5mL of DCM solvent, DMAP (390 mg,3.26mmol,3.30 eq) and sodium sulfate (281mg, 1.97mmol,2.00 eq) were added to the solution, and the mixture was stirred at 25℃for 1 hour. Compound (11) (239 mg,1.18mmol,1.20 eq) was dissolved in 2.0mL DCM solvent at 0deg.C and this solution was then added to the aforementioned mixture. The mixed solution was stirred at 25℃for 11 hours. After removal of the solvent under vacuum, compound (14) (720 mg) was obtained as a yellow solid.
Step three:
compound (9) (350 mg, 521. Mu. Mol, 1.00 eq) and compound (14) (350 mg, 521. Mu. Mol, 1.00eq, tsOH) were dissolved in 3.00mL of DCM solvent, and TEA (158 mg, 1.56mmol, 3.00 eq) was added to this solution. The mixture was stirred at 20 ℃ for 1 hour and then the solvent was removed under vacuum. The mixture was purified by prep-HPLC (TFA condition) to give compound (NYM 031) (61 mg,65.7umol, purity 98.9%) as an orange solid, with the HPLC profile of NYM031 shown in FIG. 6.
EXAMPLE 2 SPR affinity test of NYM030 pharmaceutical Compounds
Affinity of NYM030 compounds for FAP was determined using Biacore 8K protein interaction system. BR102910 served as a positive control, which had a strong affinity for FAP.
FAP (purchased from ACROBiosystems Inc) was coupled to the CM5 chip surface, running buffer consisting of 50mM Tris,150mM NaCl,0.05% P20 (Tween 20), and 5% DMSO, pH 7.2-7.4, a series of samples BR102910 (a selective Fibroblast Activation Protein (FAP) inhibitor, purchased from MedChemExpress LLC), NYM030 molecules were prepared at different concentrations, a series of samples solutions (highest concentration: 70nM, dilution ratio: 2,5 different concentrations) were diluted in equal proportions, and the affinities of the samples BR102910, NYM030 and FAP were measured. The affinities of the samples BR102910 and NYM030 and FAP are represented by equilibrium dissociation constant KD (Kd/Ka), wherein Kd is the dissociation constant, ka is the binding constant, and the smaller the KD value, the higher the affinity of the compound to the protein.
The test results are shown in table 1 below, where NYM030 shows a low nanomolar affinity for FAP, which is higher than BR 102910.
TABLE 1SPR affinity assay results
EXAMPLE 3 inhibition Activity of NYM030 drugs on tumor cell proliferation
ES-2 (ovarian cancer), HS746T (gastric cancer), SJSA-1 (osteosarcoma), 5637 (bladder cancer), SHP-77 (lung cancer) cells in the exponential growth phase were collected and viable Cell count was performed using a Vi-Cell XR cytometer, the Cell suspension was adjusted to the appropriate concentration, and the medium used to culture the different cells and the Cell number information added per well were shown in Table 2. Mu.l of cell suspension was added to each well in 96-well cell culture plates at 37℃with 5% CO 2 And 95% humidity for 24 hours;
a series of gradient dilutions were prepared with a sample stock solution (DMSO solution of NYM030 at a concentration of 6 mg/ml) and DMSO at a 1:3 equal ratio. Then diluted 100-fold with each medium. Finally, 10 mu l of corresponding 100-fold diluent is respectively added into each cell, 3 compound holes are respectively arranged at the concentration of each drug, and the cells are placed at 37 ℃ and 5% CO 2 Culturing in incubator for 72 hr;
after 72 hours of drug treatment, 50. Mu.l of CTG solution previously thawed and equilibrated to room temperature was added to each well according to the cell viability assay (CELL TITER-GLO) luminescence protocol, mixed with a microplate shaker for 2 minutes, and after 10 minutes at room temperature, the fluorescent signal value was measured using an Envision2104 plate reader.
The results of the in vitro antitumor activity test and the cell viability of the NYM030 are shown in Table 3 and FIG. 7 respectively, and the results show that the NYM030 has a strong in vitro antitumor effect on ES-2, SJSA-1 and 5637 cells, can remarkably inhibit proliferation of ES-2, SJSA-1 and 5637 cells, has the highest inhibition activity on ES-2 and has low antitumor activity on HS746T, SHP-77 cells, and the specific antitumor activity of the NYM030 is shown.
TABLE 2 cell line culture information
Cell lines Culture medium Cell number per well
ES-2 McCoy's 5a+10％FBS 2000
HS746T DMEM+10％FBS 3000
SJSA-1 RPMI1640+10％FBS 2000
5637 RPMI1640+10％FBS 2500
SHP-77 RPMI1640+10％FBS 3500
TABLE 3NYM030 in vitro anti-tumor Activity IC 50 Value and maximum inhibition rate
Cell lines IC 50 (μM) Max inh.(％)
ES-2 1.977 89.13％
HS746T >6 5.04％
SJSA-1 5.339 56.43％
5637 2.949 67.10％
SHP-77 >6 8.15％
EXAMPLE 4 efficacy test of NYM030 drug in HT1080 tumor model
The experimental animal HT1080 model is provided by Suzhou Hengjia biotechnology Co., ltd, and is a HT1080 subcutaneous xenograft tumor model established based on BALB/c nude mice, and the model is a mouse model established by human fibrosarcoma cells. 20 female HT1080 ectopic human fibrosarcoma model mice were randomly selected for the experiment. Tumor size is measured before the experiment, and according to the tumor size, the tumor sizes are sequentially arranged, 16 tumor mice with proper tumor volumes are selected and input into groups, and the groups are divided into three groups: the numbers are G1, G2 and G3 respectively. Six tumor mice in group G1 (treatment group) were injected with NYM030 physiological saline solution via tail vein at an amount of about 10mg/kg, and the amount of the drug injected was calculated according to the body weight of each tumor-bearing mouse. Six tumor mice in group G2 (positive control group) were each injected with irinotecan in physiological saline solution via tail vein at an amount of about 5mg/kg (the same molar amounts of NYM030 and irinotecan, i.e., the same amount of cytotoxic drug). Group G3 (control) four tumor mice, each animal was injected with physiological saline solution via the tail vein in an amount similar to the volume of groups G1 and G2, and the injection time of each group was recorded. The tumor volume (long diameter and short diameter) and the body weight were measured before the administration, 2 days after the administration, 4, 6, 8, 10, 12, and 14 days in the G1 group, the G2 group, and the G3 group, and the state of the mice was observed and accurately recorded. The tumor long diameter and short diameter measured during tumor efficacy evaluation are used for calculating the tumor volume size, and the calculation formula is as follows: tumor Volume (TV) =a×b 2 And/2 (a is a long diameter and b is a short diameter). The trend of the tumor volume and the trend of the body weight of the mice are shown in fig. 8 and 9, and the speed of inhibiting the tumor growth of NYM030 is more obvious compared with irinotecan and normal saline, and the body weight of the mice is not obviously changed, so that the NYM030 has good anti-tumor effect and better safety.
Example 5 efficacy experiment of NYM030 drug SJSA-1 tumor model
The experimental animal SJSA-1 model is provided by the Zhongmeiguanke biotechnology (Taicang) limited company and is a female BALB/c nude mouse animal model for subcutaneous xenograft of a human SJSA-1 cell strainType (2). BALB/c nude mice were inoculated subcutaneously 2X 10 on the right dorsal side 6 SJSA-1 cells, tumors grew to an average volume of about 100mm 3 。
The experiment was divided into individual single drug groups of 3 doses (10 mg/kg,3mg/kg and 1mg/kg, with 5% dextrose solution formulated as dosing solution) of negative control and NYM030, 8 each, with a dosing volume of 10. Mu.L/g for two weeks, and the experiment ended on day 28. The specific administration information is shown in Table 4. All animals were weighed before dosing began and tumor volumes were measured with vernier calipers. Tumor volume (major and minor diameters) and body weight were measured before and after administration, while observing the effect of tumor growth and treatment on normal behavior of animals, including activity, feeding and drinking, weight gain or loss, and other abnormalities in experimental animals. Efficacy was evaluated based on tumor volume inhibition (TGI) and safety was evaluated based on animal weight changes (fig. 11) and mortality. Tumor inhibition rate, TGI (%), was calculated as follows: TGI% = (1-T/C) ×100%, T and C being average tumor volumes of the treatment group and the control group, respectively, at a certain time point; tumor Volume (TV) =a×b 2 And/2 (a is a long diameter and b is a short diameter).
As shown in FIG. 10, on day 24, the negative control group had a tumor volume of more than 3000mm in mice 3 Is euthanized. On day 24, the average tumor volume of the negative control group was 2997.74mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Tumor growth can be obviously inhibited by each dosage group of NYM030 (10 mg/kg,3mg/kg and 1 mg/kg), and TGI is 60.69%,46.59% and 44.46%, wherein the tumor inhibition effect of the high dosage group is better, no obvious weight loss exists in each dosage group of the negative control group and the NYM030, and no abnormal situation occurs in mice, so that the safety of the NYM030 is good.
Table 4 dosing information
Group of Number of animals Administration group Single administration agent (mg/kg) Time of administration (Tian)
01 8 5% glucose solution - Day 1.2.3.4.8.9.10.11
02 8 NYM030 1 Day 1.2.3.4.8.9.10.11
03 8 NYM030 3 Day 1.2.3.4.8.9.10.11
04 8 NYM030 10 Day 1.2.3.4.8.9.10.11
EXAMPLE 6 toxicity test with continuous administration
The mouse model was a 6-8 week old female ICR mouse purchased from sozhou constant biotechnology limited. Randomly selecting 6 ICR mice, administering NYM030 medicine, 10mg/kg once, continuously administering for 7 days, observing animal general indexes (animal hair, activity, diet, etc.), animal death condition (death time, etc.), weighing animal weight change (before administration, observation period, death at test end), and killing at the last day of the experiment, and anatomically observing tissue change of main organs such as heart, liver, spleen, lung, kidney, etc. The weight change in fig. 12 was used to evaluate the change in weight at a certain time point from the weight before the start of the experiment, and the calculation formula was: body weight change = body weight at weighing/initial body weight 100%.
As shown in fig. 12, after 7 days of continuous administration, all mice did not die, did not have abnormal reactions, were anatomically observed for visceral organs, and did not significantly change body weight during the experiment. Thus, the NYM030 molecule was found to be excellent in safety.
EXAMPLE 7ICR murine acute toxicity test
The mouse model was a 6-8 week old female ICR mouse purchased from sozhou constant biotechnology limited. Randomly selecting 9 ICR mice, dividing into three groups, 3 mice in each group, administering 100mg/kg NYM031 in the experimental group, administering 50mg/kg irinotecan in the positive control group, administering physiological saline in the control group, observing the general index conditions (animal hair, activity, diet, etc.), animal death conditions (death time, etc.) and weighing animal body weight of animals before, 2, 4, 6 and 8 days after administration, and anatomically observing the presence or absence of abnormality of each main organ at the last day of the experiment. As shown in fig. 13, in the 8-day observation, all mice were not dead, were not abnormal in response, were not abnormal in anatomy, and were all increased in body weight after the completion of the experiment; on the premise of consistent amounts of the effective drugs (cytotoxic drugs), the weight of the mice in the experimental group is reduced less than that of the mice in the positive control group. At the end of the experiment, the mice in the experimental group had increased body weight compared to the mice before administration, while the positive control group did not. Thus, the NYM031 molecule has good safety.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (25)

1. A compound which is a compound represented by the formula (X) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound represented by the formula (X),
Wherein Y is selected from ligands that bind to fibroblast activation protein- α;
l is selected from the group consisting of linkers;
at least one of X and Z is present, X, Z is each independently selected from an albumin-binding ligand, a cytotoxic drug or a chelator, and at least one of X and Z is a cytotoxic drug or a chelator.
2. The compound of claim 1, wherein Y has a structure represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt of the structure represented by formula (I),
wherein each y is independently selected from 0, 1 or 2;
R 1x 、R 2x r is R 3x’ Each independently selected from H, -OH, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S-C 1-6 An alkyl group;
R 3x selected from H, -CN, -B (OH) 2 -C (O) alkyl, -C (O) aryl-, -c=c-C (O) aryl, -c=cs (O) 2 Aryl, -CO 2 H、-SO 3 H、-SO 2 NH 2 、-PO 3 H 2 Or 5-tetrazolyl;
wherein the method comprises the steps ofRepresents the point of attachment of the fibroblast activation protein-alpha binding ligand to the linker, wherein the point of attachment may be attached to the linker through any one of the 5, 6, 7 or 8 carbon atoms of the quinoline ring of the fibroblast activation protein-alpha binding ligand.
3. The compound of claim 2, wherein the Y structure is selected from one of:
4. a compound according to claim 3, wherein the Y structure is selected from one of:
5. A compound according to any one of claims 1 to 4, wherein L is selected from one or more of (a-1), (a-2), (b) and (c),
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 1 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 1 selected from 0, 1, 2, 3, 4, 5 or 6;
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 4 selected from the group consisting of-NR-, -R-, RC (O) -, -at least one of C (O) NR-or-NR-C (O) -;
m is selected from at least one of-NR-, -O-, -OC (O) -, -C (O) NR-, -C (O) -or-RC (O) -;
m 6 m 7 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
wherein:
V 2 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 2 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, NRC (O) O-, -C (O) NR-, or-NR-)At least one of C (O) -;
m 2 m 3 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
wherein:
V 3 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 3 selected from the group consisting of-R-, -NR-, -RC (O) -, RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 4 M 5 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
r, R 'and R' in formula (a-1), (a-2), (b) or (c) are each independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.
6. The compound of claim 5, wherein R, R' and R "are each independently selected from H, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl, piperazine, lactone, cyclic anhydride, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrochysene, substituted heterocycloalkyl, phenyl, naphthyl, substituted aryl, pyrimidine, pyridine, pyrazine, furan, thiophene, or substituted heteroaryl.
7. The compound of claim 5, wherein R, R' and R "are each independently selected from H, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl radicals、
8. A compound according to any one of claims 1 to 7, wherein L has the structure of one of:
9. The compound of claim 1, wherein the albumin-binding ligand has a structure of one of:
10. the compound of claim 1, wherein the cytotoxic drug is selected from camptothecins or derivatives thereof, tubulin inhibitors or derivatives thereof, inhibitors of synthesis of RNA or DNA or derivatives thereof;
preferably, the cytotoxic drug is derived from one of the following structures:
11. the compound of claim 1, wherein the chelator is derived from 1,4,7, 10-tetraazacyclododecane-N, N ' -tetraacetic acid, 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid, 2- (4, 7-bis (carboxymethyl) -1,4, 7-trisazononan-1-yl) pentanedioic acid, 2- (4, 7, 10-tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane-1-yl) pentanedioic acid, 1,4, 7-triazacyclononane-1- [ methyl (2-carboxyethyl) phosphinic acid ] -4, 7-bis [ methyl (2-carboxymethyl) phosphinic acid ], N ' - {5- [ acetyl (hydroxy) amino ] pentyl } -N- [5 {4- [ 5-aminopentyl) (hydroxy) amino ] -4-oxo-4-succinyl ] -N- (4, 7, 10-tetraazacyclononane-1-yl) penta-diphosphonic acid, 1,4, 7-triazacyclononane-1- [ methyl (2-carboxyethyl) phosphinic acid ] -4, 7-bis [ methyl (2-carboxyethyl) phosphinic acid ], N ' - {5- [ acetyl (hydroxy) amino ] -5-pentyl) amino ] -4- (hydroxy) butanamide, penta-2- (2-iminodiacetic acid, penta-5-amino) butanamide, penta-ethyl-2- (2-isocyanide) penta-ethyl) amine, penta-isocyanide, penta-ethyl-2-isocyanide, penta-ethyl-acetic acid 1-oxa-4, 7, 10-triazacyclododecane-4, 7, 10-triacetic acid, 6-hydrazinonicotinic acid succinimidyl ester hydrochloride and mercaptoacetyl triglycine.
12. A compound according to any one of claims 1 to 11,the structure is selected from one of the following (d-1), (d-2), (d-3) and (d-4):
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 1 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 1 selected from 0, 1, 2, 3, 4, 5 or 6;
z is a cytotoxic drug;
x is absent;
wherein:
V 1 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -NRC (O) -, or-NRC (S) -At least one of (2);
W 4 selected from the group consisting of-NR-, -R-, RC (O) -, -at least one of C (O) NR-or-NR-C (O) -;
m is selected from at least one of-NR-, -O-, -OC (O) -, -C (O) NR-, -C (O) -or-RC (O) -;
m 6 m 7 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z is a cytotoxic drug;
x is absent;
wherein:
V 2 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 2 selected from the group consisting of-NR-, -RC (O) -, -RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 2 m 3 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z is a cytotoxic drug or chelator;
x is a ligand that binds albumin;
Wherein:
V 3 selected from the group consisting of-NR-, -O-, -C (O) -, -OC (O) -, -at least one of NRC (O) -or-NRC (S) -;
W 3 selected from the group consisting of-R-, -NR-, -RC (O) -, RCH 2 C (O) -, -NRC (S) NR' -, -NRC (O) O-; -at least one of C (O) NR-or-NR-C (O) -;
m 4 m 5 Each independently selected from 0, 1, 2, 3, 4, 5, or 6;
z is a cytotoxic drug or chelator;
x is a ligand that binds albumin;
r, R 'and R' in the formula (d-1), (d-2), (d-3) or (d-4) are each independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.
13. A compound consisting of a compound according to any one of claims 1 to 12 or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, characterized in that the structure is selected from one of the following:
14. a complex, characterized in that the complex is formed by complexing a compound according to any one of claims 1-12 or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof with a radionuclide or a non-radioactive element A', the structure of the complex is shown as a formula (II),
Wherein Z is a chelator and X is an albumin-binding ligand, a cytotoxic drug or is absent.
15. A complex, characterized in that the complex is formed by complexing a compound according to any one of claims 1-12 or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof with a radionuclide or a non-radioactive element A', the structure of the complex is shown as a formula (III),
wherein X is a chelator and Z is an albumin-binding ligand, a cytotoxic drug or is absent.
16. A compound consisting of a compound according to any one of claims 1 to 12 or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, characterized in that the structure is selected from one of the following:
17. a complex formed by complexation of a compound according to claim 16 or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof with a radionuclide or a non-radioactive element B'.
18. The complex of any one of claims 14 to 15, 17, wherein the radionuclides a 'or B', respectively, are independently selected from the group consisting of: 68 Ga、 18 F、 99 mTc、 89 Zr、 111 In、 45 Ti、 59 Fe、 64 Cu、 94 mTc、 67 Ga、 71/72/74 As、 43/ 44 Sc、 82 mRb、 52 Mn、 86 Y、 76 Br、 177 Lu、 90 Y、 153 Sm、 67 Cu、 89 Sr、 137 Cs、 166 Ho、 177 Yb、 105 Rh、 186/188 Re、 47 Sc、 212/213 Bi、 225 Ac、 212 Pb、 149 Pm and 227 at least one of Th;
optionally, the non-radioactive elements a 'or B' are each independently selected from at least one of Ga, fe, and Gd;
optionally, the radionuclide is selected from 18 F；
Optionally, the radionuclide 18 The F complex is formed by the radioisotope aluminum fluoride.
19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, 16, or a complex according to any one of claims 14 to 15, 17 to 18, or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition of claim 19, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
21. Use of a compound according to any one of claims 1 to 13, 16 or a complex according to any one of claims 14 to 15, 17 to 18, or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition according to any one of claims 19 to 20, for the preparation of one or more agents and/or medicaments for the diagnosis and/or treatment and/or prevention of tumors, cancers or cells expressing FAP.
22. The use according to claim 21, wherein the tumor, cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, cholangiocarcinoma, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, head and neck cancer, neuroendocrine tumor;
preferably, the tumor or cancer expressing FAP is at least one selected from fibrosarcoma, osteosarcoma, pancreatic cancer and ovarian cancer.
23. Use of a compound according to any one of claims 1 to 13, 16 or a complex according to any one of claims 14 to 15, 17 to 18, or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition according to any one of claims 19 to 20, for the diagnosis and/or treatment and/or prevention of a disease associated with high expression of FAP.
24. Use of a compound according to any one of claims 1 to 13, 16 or a complex according to any one of claims 14 to 15, 17 to 18, or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition according to any one of claims 19 to 20, for the preparation of one or more agents and/or medicaments for inhibiting FAP expression.
25. A method of imaging tissue expressing FAP, the method comprising:
applying the complex of any one of claims 14-15, 17-18, or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of any one of claims 19-20, to the tissue;
PET imaging is used for the tissue.
CN202311326426.1A 2022-10-14 2023-10-12 Medicine for targeting fibroblast activation protein and application thereof Pending CN117883585A (en)

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CN116617420A (en) * 2017-10-23 2023-08-22 约翰霍普金斯大学 Compound targeting fibroblast activation protein alpha, pharmaceutical composition and application
CN111699181A (en) * 2018-02-06 2020-09-22 海德堡大学 FAP inhibitors
HUE058835T2 (en) * 2020-02-12 2022-09-28 Philochem Ag Fibroblast activation protein ligands for targeted delivery applications
CN114790194B (en) * 2020-12-21 2024-03-26 苏州药明博锐生物科技有限公司 Fibroblast activation protein inhibitor
CN114790195B (en) * 2020-12-21 2024-05-17 苏州药明博锐生物科技有限公司 Fibroblast activation protein inhibitor
CN114790193B (en) * 2020-12-21 2024-05-10 苏州药明博锐生物科技有限公司 Fibroblast activation protein inhibitor
KR20230165818A (en) * 2021-04-02 2023-12-05 더 존스 홉킨스 유니버시티 Heterobivalent and homobivalent agents targeting fibroblast activation protein alpha and/or prostate-specific membrane antigen
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