WO2023093878A1 - 激酶抑制剂的新用途 - Google Patents
激酶抑制剂的新用途 Download PDFInfo
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- WO2023093878A1 WO2023093878A1 PCT/CN2022/134614 CN2022134614W WO2023093878A1 WO 2023093878 A1 WO2023093878 A1 WO 2023093878A1 CN 2022134614 W CN2022134614 W CN 2022134614W WO 2023093878 A1 WO2023093878 A1 WO 2023093878A1
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- Prior art keywords
- prostate cancer
- castration
- compound
- heterocyclic group
- metastatic
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention belongs to the technical field of medicine, and in particular relates to a new application of a kinase inhibitor.
- PCa Prostate cancer
- ADT Androgen Deprivation Therapy
- the current therapeutic drugs for ADT include gonadotropin-releasing hormone agonists (GnRH agonists), gonadotropin-releasing hormone antagonists (GnRH antagonists), androgen secretion inhibitors, etc.
- GnRH agonists gonadotropin-releasing hormone agonists
- GnRH antagonists gonadotropin-releasing hormone antagonists
- CRPC sexual prostate cancer
- CRPC is mainly divided into two independent stages: metastatic castration resistant prostate cancer (mCRPC) with distant metastasis and non-metastatic castration resistant prostate cancer without distant metastasis.
- castration resistant prostate cancer nmCRPC
- nmCRPC castration resistant prostate cancer
- patients with nmCRPC fail new endocrine therapy (androgen receptor inhibitors, etc.) and develop distant metastasis or disease progression, they will turn into mCRPC stage, so mCRPC can be regarded as the final stage of PCa patients.
- the main therapies currently used for mCRPC include chemotherapy (docetaxel), new endocrine therapy (Abiraterone acetate, enzalutamide, etc.), immunotherapy (Sipuleucel-T) and radiation therapy for bone metastases ( Radium-223).
- Doxetaxel is the first chemotherapy drug approved by the FDA for the treatment of mCRPC, which can effectively prolong the overall survival (OS) of patients by about 19.2 months, but the drug will cause a series of side effects, such as nausea and vomiting , neurological diseases, anemia, etc.
- 17 ⁇ -hydroxylase/C17,20-lyase plays a key role in the process of androgen synthesis
- abiraterone acetate is a prodrug, which is converted into abiraterone in vivo
- abiraterone is An androgen biosynthesis inhibitor that inhibits CYP17 enzymes.
- the drug was approved by the FDA in 2011 for patients with CRPC.
- Enzalutamide is a second-generation AR (androgen receptor) antagonist. After AR is combined with enzalutamide, it cannot be normally transported into the nucleus or recruit co-activators, and the transcriptional activity of AR is reduced.
- enzalutamide Compared with the first-generation AR antagonist bicalutamide, enzalutamide has a stronger affinity for AR. Although the approval of abiraterone acetate and enzalutamide is of great significance for the treatment of mCRPC, after a period of treatment, most patients will eventually develop drug resistance.
- the compound of the general formula (I) of the present invention is a kinase inhibitor. It has been found through research that the compound of the general formula (I) has a therapeutic effect on prostate cancer; further, for castration-resistant prostate cancer and castration-sensitive prostate cancer and metastatic Castration-resistant prostate cancer has significant therapeutic potential.
- the present invention provides the following scheme:
- the present invention provides the use of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form in the preparation of drugs for treating and/or preventing prostate cancer;
- Ar is phenyl optionally substituted by 1-3 R 6 , each R 6 is independently selected from hydrogen, amino, cyano, halogen, C 1-4 alkyl and trifluoromethyl;
- Y is CR 3 ;
- P is CR4 ;
- W is N
- R 3 is hydrogen or C 1-4 alkyl
- Ar is phenyl optionally substituted with 1-3 R 6 , each R 6 independently selected from hydrogen and halogen;
- Y is CR 3 ;
- P is CR4 ;
- W is N
- R3 is hydrogen
- the ring-forming S atom in the heterocyclic group is optionally oxidized to S(O) or S(O) 2
- the ring-forming C atom is optionally oxidized to C(O)
- the heterocyclic group is optionally oxidized by one or more Substituents independently selected from C 1-3 alkyl and C 3-6 cycloalkyl are substituted.
- the (5-6) membered monoheterocyclic group is a (5-6) membered saturated monoheterocyclic group
- the (7-11) membered condensed heterocyclic group is a (7- 11) A membered saturated condensed heterocyclic group.
- the (7-11) membered saturated condensed heterocyclic group is (7-11) membered saturated heterocyclic group, (7-11) membered saturated spiroheterocyclic group or (7-11) membered saturated spiroheterocyclic group 11) A membered saturated bridged heterocyclic group.
- the compound of general formula (I) is a compound shown in Table 1 or a pharmaceutically acceptable salt, stereoisomer, or crystal form thereof.
- the compounds of the present invention may also include compounds other than compounds of general formula (I), eg, the specific compounds shown in the table below.
- the compound is or a pharmaceutically acceptable salt, stereoisomer, or crystal form thereof.
- the present invention also provides a pharmaceutical composition or a pharmaceutical combination product.
- the pharmaceutical composition or pharmaceutical combination product of the present invention comprises a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer, A crystal form and one or more pharmaceutically acceptable carriers, diluents or excipients.
- the pharmaceutical composition or pharmaceutical combination further comprises one or more other active agents.
- the definition of the compound of general formula (I) is as described above.
- the present invention also provides a method for treating prostate cancer, the method comprising administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer, crystal form or The pharmaceutical composition or pharmaceutical combination product of the present invention, wherein the definition of the compound of general formula (I) is as described above.
- the present invention also provides the use of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, crystal form or the pharmaceutical composition or pharmaceutical combination product described in the present invention in the prevention and/or treatment of prostate cancer , wherein the compound of general formula (I) is as defined above.
- the present invention also provides the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, crystal form or the pharmaceutical composition or pharmaceutical combination product described in the present invention in the preparation for preventing and/or treating prostate Use in medicine for cancer, wherein the definition of the compound of general formula (I) is as described above.
- the present invention also provides the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, crystal form or the pharmaceutical composition or pharmaceutical combination product described in the present invention for preventing and/or treating prostate cancer , wherein the compound of general formula (I) is as defined above.
- the prostate cancer is metastatic prostate cancer.
- the prostate cancer is non-metastatic prostate cancer.
- the prostate cancer is early stage prostate cancer.
- the prostate cancer is advanced prostate cancer.
- the prostate cancer is na ⁇ ve to standard treatment.
- the prostate cancer has failed standard treatment.
- the prostate cancer has failed chemotherapy.
- the prostate cancer has failed endocrine therapy.
- the prostate cancer has failed androgen deprivation therapy.
- the prostate cancer has failed treatment with an androgen synthesis inhibitor and/or an androgen receptor inhibitor.
- the prostate cancer has failed treatment with abiraterone.
- the prostate cancer is treatment refractory to enzalutamide, apalutamide, darolutamide, and/or bicalutamide.
- the prostate cancer is early and/or non-metastatic prostate cancer.
- the early stage and/or non-metastatic prostate cancer is not receiving standard treatment.
- the prostate cancer is advanced and/or metastatic prostate cancer.
- the advanced and/or metastatic prostate cancer is not receiving standard treatment.
- the advanced and/or metastatic prostate cancer has failed standard therapy.
- the prostate cancer is castration-sensitive prostate cancer.
- the prostate cancer is castration-resistant prostate cancer.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer is not receiving standard treatment.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer has failed standard treatment.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer is chemotherapy-failed.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer has failed endocrine therapy.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer is refractory to androgen deprivation therapy.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer has failed treatment with an androgen synthesis inhibitor and/or an androgen receptor inhibitor.
- the castration-sensitive prostate cancer or castration-resistant prostate cancer is refractory to abiraterone treatment.
- the castration-sensitive or castration-resistant prostate cancer is refractory to enzalutamide, apalutamide, darolutamide, and/or bicalutamide.
- the prostate cancer is metastatic castration-sensitive prostate cancer.
- the prostate cancer is non-metastatic castration-sensitive prostate cancer.
- the non-metastatic or metastatic castration-sensitive prostate cancer is not receiving standard treatment.
- the non-metastatic or metastatic castration-sensitive prostate cancer has failed standard treatment.
- the prostate cancer is metastatic castration-resistant prostate cancer.
- the prostate cancer is non-metastatic castration-resistant prostate cancer.
- the non-metastatic or metastatic castration-resistant prostate cancer is not receiving standard treatment.
- the non-metastatic or metastatic castration-resistant prostate cancer has failed standard treatment.
- the non-metastatic or metastatic castration-resistant prostate cancer has failed chemotherapy.
- the non-metastatic or metastatic castration-resistant prostate cancer has failed endocrine therapy.
- the non-metastatic or metastatic castration-resistant prostate cancer is refractory to androgen deprivation therapy.
- the non-metastatic or metastatic castration-resistant prostate cancer has failed treatment with an androgen synthesis inhibitor and/or an androgen receptor inhibitor.
- the non-metastatic or metastatic castration-resistant prostate cancer has failed treatment with abiraterone.
- the non-metastatic or metastatic castration-resistant prostate cancer has failed treatment with enzalutamide, apalutamide, darolutamide, and/or bicalutamide.
- the metastatic castrate-castrated prostate cancer is histopathologically or cytologically confirmed, previously failed prostate cancer after primary continuous androgen deprivation therapy, and has definite bone or soft tissue metastases as evidenced by imaging lesion.
- the metastatic castration-resistant prostate cancer is histopathologically or cytologically confirmed metastatic castration-resistant prostate cancer for which no standard treatment is an option.
- the present invention also provides the dosage and regimen of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form for treating prostate cancer patients, specifically as follows:
- the single administration dose of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form is 3 mg to 20 mg, for example: 3 mg, 4 mg, 5 mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg.
- the administration frequency is once a day, twice a day, or once every two days, or once every three days.
- the preferred frequency of dosing is once daily.
- the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form can also be formulated with one or more pharmaceutically acceptable carriers. Any acceptable pharmaceutical formulation.
- the pharmaceutical preparation may contain one or more pharmaceutically acceptable carriers, and may be administered orally, parenterally, rectally, or pulmonary to patients or subjects in need of such treatment.
- the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions , syrup, etc.
- suitable fillers, binders, disintegrants, lubricants and the like can be added.
- parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections and concentrated solutions for injections. When making injections, conventional methods in the existing pharmaceutical field can be used for production.
- the pharmaceutical composition When preparing injections, no additives can be added, or appropriate additives can be added according to the properties of the medicine.
- the pharmaceutical composition For rectal administration, the pharmaceutical composition can be made into suppositories and the like.
- the pharmaceutical composition When used for pulmonary administration, can be made into inhalants or sprays and the like.
- Treatment refers to administering an effective amount of a drug to a patient to slow or cure an unwanted physiological change or condition, such as a hyperproliferative condition, such as the growth, formation or spread of cancer, in order to obtain a beneficial or desired Clinical outcomes, including, but not limited to: relief of symptoms, diminishment of extent of disease, stabilization of disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of disease state, and regression (whether partial or complete), regardless of is detectable or undetectable.
- a hyperproliferative condition such as the growth, formation or spread of cancer
- the "treatment" mentioned in the present invention may include neoadjuvant therapy and adjuvant therapy.
- Neoadjuvant therapy refers to the systemic treatment performed before the planned surgical treatment or local treatment of surgery plus radiotherapy for patients with initial tumors.
- neoadjuvant therapy may be chemotherapy, endocrine, targeted direction, immunization or radiotherapy.
- the goal of neoadjuvant therapy is to provide immediate systemic therapy, potentially eradicating micrometastases that would otherwise proliferate following the standard sequence of surgery followed by systemic therapy.
- Neoadjuvant therapy can also help reduce tumor size, allowing complete resection of initially unresectable tumors or preserving parts of the organ and its functions.
- neoadjuvant therapy allows in vivo assessment of drug efficacy, which can guide the choice of subsequent therapy.
- Adjuvant therapy refers to therapy given after definitive surgery (where no evidence of residual disease can be detected) to destroy any remaining cancer cells in the body and to reduce the likelihood of tumor recurrence or spread to other sites. Treatment methods are roughly the same as neoadjuvant therapy. The goal of adjuvant therapy is to prevent cancer recurrence, and thus reduce the chance of cancer-related death. Adjuvant therapy explicitly excludes neoadjuvant therapy in this context.
- “Failure”, “treatment failure” or “chemotherapy failure” as described in the present invention refers to disease progression (PD) in the course of treatment or after the last treatment (according to tumor tissue evaluation RECIST1.1 curative effect evaluation standard is disease progression (PD) Or according to PCWG3 bone lesion evaluation criteria for prostate cancer (progressive disease (PD)), or intolerable due to toxic side effects during treatment.
- intolerable toxic and side effects refers to the inability to continue treatment due to adverse reactions caused by drugs.
- the "standard treatment” described in the present invention includes androgen deprivation therapy (surgical castration and drug castration therapy including but not limited to goserelin, leuprolide, triptorelin, degarelix, etc.), Chemotherapy, whole body radiation therapy, new endocrine therapy.
- androgen deprivation therapy surgical castration and drug castration therapy including but not limited to goserelin, leuprolide, triptorelin, degarelix, etc.
- Chemotherapy whole body radiation therapy, new endocrine therapy.
- the "chemotherapy” mentioned in the present invention includes but not limited to docetaxel, combination of docetaxel and prednisone, etc.
- the "abiraterone treatment" in the present invention includes, but is not limited to, abiraterone, the combined use of abiraterone and prednisone, and the like.
- the "endocrine therapy” described in the present invention is a method for treating prostate cancer by inhibiting or reducing the activity of androgen (receptor), which includes traditional androgen deprivation therapy (ADT) and new endocrine therapy.
- ADT treatment includes surgical castration (orchiectomy, etc.) and drug castration (including but not limited to receiving goserelin, leuprolide, triptorelin, degarelix, etc.).
- New endocrine therapy includes androgen synthesis inhibitors (such as abiraterone, etc.), androgen receptor inhibitors (such as enzalutamide, apalutamide, darolutamide, bicalutamide, etc.).
- PFS Progression-free survival
- OS Overall Survival
- ORR Objective Response Rate
- Duration of response the time from the first PR or CR to the first PD or death.
- DCR Disease Control Rate
- the efficacy evaluation criteria were divided into complete remission (CR), partial remission (PR), stable (SD), and progressive (PD).
- CR Complete remission
- Partial response the sum of the diameters of target lesions is reduced by at least 30% compared with the baseline level, non-target lesions disappear or stabilize, and no new lesions appear.
- Progression of disease the relative increase of the sum of the diameters of target lesions is at least 20%, or the deterioration of non-target lesions, or the appearance of new lesions (one occurrence of the three is PD.
- Stable disease The increase/decrease of target lesions is between PR and PD, and non-target lesions are stable or disappear, and there are no new lesions.
- the "therapeutically effective amount” in the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salts, stereoisomers, and crystal forms that can at least alleviate the symptoms of the patient's disease when administered to the patient.
- the actual amount, including a “therapeutically effective amount,” will vary depending on various circumstances including, but not limited to, the particular condition being treated, the severity of the condition, the size and health of the patient, and the route of administration. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. For any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
- a “subject” or “individual” for the prevention and/or treatment of prostate cancer refers to any animal classified as a mammal, including humans, domesticated animals and farm animals, and zoo animals, sport animals or pet animals, such as dogs, horses, cats, cows, etc.
- the mammal is a human.
- a subject or individual can be a patient.
- halogen in the present invention refers to fluorine, chlorine, bromine and iodine, etc., preferably fluorine and chlorine.
- Halo in the present invention means that any hydrogen atom in the substituent can be replaced by one or more identical or different halogens. "Halogen” is as defined above.
- the "cyano group” mentioned in the present invention refers to the -CN group.
- amino group refers to the -NH 2 group.
- C 1-4 alkyl in the present invention refers to a straight-chain or branched-chain alkyl derived from a hydrocarbon part containing 1-4 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.
- C 1-3 alkyl group refers to the above-mentioned alkyl group containing 1-3 carbon atoms.
- C 3-6 cycloalkyl in the present invention refers to a monocyclic cycloalkyl, a bicyclic cycloalkyl system or a multicyclic cycloalkyl system containing 3-6 carbon atoms. These groups are saturated but not aromatic. Unless otherwise specified, single ring and condensed ring structures that can be formed are included. Examples include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, bicyclo[2.2.2]hexane, bicyclo[3.2.1]hexane.
- the "5-11 membered heterocyclic group” in the present invention refers to a non-aromatic cyclic group with 5-11 ring carbon atoms, wherein at least one ring carbon atom is selected from one of O, S, N or multiple heteroatoms, preferably 1-3 heteroatoms, and ring atoms including carbon atoms, nitrogen atoms and sulfur atoms can be oxidized.
- heterocyclic group refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group system or a polycyclic heterocyclic group system, including saturated and partially saturated heterocyclic groups, but excluding aromatic rings.
- the "5-11 membered heterocyclic group” in the present invention includes the monocyclic and condensed ring structures that can be formed unless otherwise specified.
- the single heterocyclic group can be 5-7 membered heterocyclic group, 5-6 membered heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered saturated Heterocyclyl etc.
- Examples of the 5-6 membered monoheterocyclic group in the present invention include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl , morpholino, 1,4-dioxanyl, 1,4-oxathione, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-di
- the condensed heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group, which may be saturated, partially saturated or unsaturated, but not aromatic.
- the 7- to 11-membered condensed heterocyclic group in the present invention includes the possible formation of parallel, spiro and bridge structures unless otherwise specified.
- the alkane ring group can be a 7-11 membered alkane group, preferably a 7-11 membered abheterocyclic group, examples of which include but are not limited to: 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrole And[3,4-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridine, 2,3- Dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl , 2,3 dihydr
- the spiroheterocyclyl can be a 7-11 membered spiroheterocyclyl, preferably a 7-11 membered saturated spiroheterocyclyl, examples of which include but are not limited to:
- the bridged heterocyclic group can be a 7-11 membered bridged heterocyclic group, preferably a 7-11 membered bridged heterocyclic group, examples of which include but are not limited to:
- the "pharmaceutically acceptable salt” in the present invention refers to the addition salts and solvates of pharmaceutically acceptable acids and bases.
- Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium and the like.
- a variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.
- substituents means that the number of substituents can be all chemically substituted positions of the substituted groups, preferably 1-6, more preferably 1-5, more preferably 1 - 3, more preferably 1-2.
- crystal form described in the present invention can be prepared from the compound of general formula (I) by conventional methods used in the art for preparation of crystal forms.
- the "stereoisomer" of the compound of general formula (I) described in the present invention means that when there is an asymmetric carbon atom in the compound of general formula (I), enantiomers can be produced; when the compound has a carbon-carbon double bond or When the compound has a cyclic structure, cis-trans isomers will be produced; when the compound has a ketone or oxime, tautomers will be produced. Enantiomers, diastereoisomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers and Their mixtures are included in the scope of the present invention.
- the compound of the general formula (I) of the present invention or its pharmaceutically acceptable salt, stereoisomer, and crystal form have a therapeutic effect on prostate cancer; further, they have a therapeutic effect on castration-resistant prostate cancer and castration-sensitive prostate cancer Significant therapeutic effect; furthermore, it also has significant therapeutic effect on metastatic castration-resistant prostate cancer, and has good clinical application potential.
- Test object compound 29 in the present invention, its structure is shown above, and the preparation method can refer to the specific embodiment part of WO2018108079A1.
- Prostate cancer cell materials DU145, PC-3, VCaP, LNCaP clone FGC.
- Test instrument use PE Envision multifunctional microplate reader.
- the data is calculated as follows:
- Inhibition rate (%) 100%-(compound signal-system positive signal)/(negative control signal-system positive signal) ⁇ 100%.
- test results are shown in Table 2, B: 0-1000nM; C: 1000-10000nM; D: >10000nM.
- the compound 29 of the present invention has good anti-tumor proliferation activity against prostate cancer cell lines, and has good clinical potential for treating prostate cancer.
- Test object compound 29 in the present invention, its structure is shown above, and the preparation method can refer to the specific embodiment part of WO2018108079A1. Abiraterone was obtained commercially.
- Human-derived prostate cancer tumor sample LD1-0034-361929 was derived from a male patient, which was resistant to abiraterone.
- Clinical diagnosis castration-resistant prostate cancer with bladder metastases; pathological diagnosis: prostate cancer-poorly differentiated adenocarcinoma;
- the tumor mass was inoculated on the right back of the mouse, and the animals were weighed before administration, and the tumor volume was measured, and grouped according to the tumor volume using a block design.
- Dose (mg/kg) number of animals Route of administration Dosing frequency Dosing cycle Vehicle control 0 5 oral gavage Qd*7 days/week 39 days Abiraterone 200 5 oral gavage Qd*7 days/week 39 days Compound 29 15 5 oral gavage Qd*7 days/week 39 days
- vehicle control 0.5% MC
- compound 29 prescription 0.5% MC
- abiraterone prescription 10% DMSO+90% vegetable oil
- TGI% relative tumor inhibition rate
- T/C% is the relative tumor proliferation rate, that is, the percentage value of the relative tumor volume between the treatment group and the control group at a certain time point.
- T and C are the relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
- T/C% T RTV /C RTV ⁇ 100%
- T RTV the average RTV of the treatment group
- C RTV the average RTV of the vehicle control group
- RTV V t /V 0
- V 0 is the average RTV of the animal at the time of grouping.
- the tumor volume of the animal, V t is the tumor volume of the animal after treatment.
- Test drug Compound 29, whose structure is shown above, and the preparation method can refer to the specific implementation part of WO2018108079A1.
- Inclusion criteria Histopathologically or cytologically confirmed metastatic castration-resistant prostate cancer patients without standard treatment options.
- Dosing regimen Compound 29 is administered orally according to the prescribed dose (such as 8 mg, 10 mg or 12 mg), once a day, and administered continuously, 28 days/cycle.
- Efficacy evaluation Among the 11 patients with efficacy evaluation data (10 patients received a single dose of 12 mg, and 1 patient received a single dose of 10 mg), 7 patients achieved partial remission (PR), 2 patients Report stable disease (SD).
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Abstract
一种激酶抑制剂的新用途。通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型在制备治疗和/或预防前列腺癌的药物中的用途,所述通式中的各个变量如说明书中所定义。研究表明,通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型对前列腺癌具有治疗作用;进一步地,对于去势抵抗性前列腺癌和去势敏感性前列腺癌以及转移性去势抵抗性前列腺癌具有显著的治疗作用。
Description
本发明属于医药技术领域,具体涉及激酶抑制剂的新用途。
前列腺癌(prostate cancer,PCa)是男性中最常见的恶性肿瘤之一,在世界范围内,PCa的发生率在男性肿瘤中位居第2位,在美国男性恶性肿瘤中发生率排名第1位,病死率仅次于肺癌。
根据前列腺癌的分期及危险程度不同,治疗方案也不尽相同。对于早期低危前列腺癌患者,以主动监控为主。由于早期前列腺癌无明显症状或受检测手段的限制等原因,大部分前列腺癌确诊时已处于晚期,其中半数以上已发生远处转移,远处转移者5年相对生存率仅为30%。对于晚期、转移性前列腺癌患者,以药物去势或手术去势为主要治疗手段,即雄激素剥夺治疗(Androgen Deprivation therapy,ADT)。由于正常前列腺细胞和前列腺癌细胞的生长均依赖于雄激素,通过手术去势或药物去势可以最大程度降低患者体内雄激素的浓度,从而抑制雄激素信号通路,最终抑制肿瘤细胞的生长。目前用于ADT的治疗药物包括促性激素释放激素激动剂(GnRH激动剂)、促性激素释放激素拮抗剂(GnRH拮抗剂)、雄激素分泌抑制剂等。大部分患者在开始时治疗对ADT治疗敏感,为去势敏感性前列腺癌(castration sensitive prostate cancer,CSPC),但因遗传或药物诱导等原因,2年后几乎所有患者都将进展为去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC),形成耐药。一旦进展为CRPC,患者的中位生存时间仅为9-12个月。
CRPC主要分为两个独立阶段:发生远处转移的转移性去势抵抗性前列腺癌(metastatic castration resistant prostate cancer,mCRPC)和未发生远处转移的非转移性去势抵抗性前列腺癌(non metastatic castration resistant prostate cancer,nmCRPC)。当nmCRPC患者经新型内分泌治疗(雄激素受体抑制剂等)治疗失败后发生远处转移或疾病进展时将转为mCRPC阶段,因此mCRPC可被看作是PCa患者的最终阶段。目前用于mCRPC的主要疗法包括化疗(多西他赛),新型内 分泌治疗(醋酸阿比特龙(Abiraterone acetate)、恩杂鲁胺等),免疫疗法(Sipuleucel-T)及骨转移的放射治疗(镭-223)。多西他赛(Doxetaxel)是最早通过FDA批准的治疗mCRPC的化疗药物,能够有效的延长患者总生存期(overall survival,OS)约19.2月,但该药物会引发一系列副作用,如恶心、呕吐、神经疾病、贫血等。17α-羟化酶/C17,20-裂解酶(CPY17酶)在雄激素合成过程中起到关键作用,醋酸阿比特龙是一种前体药,在体内转化成阿比特龙,阿比特龙是一种雄激素生物合成抑制剂,可抑制CYP17酶。该药已于2011年被FDA批准用于CRPC患者。恩杂鲁胺(Enzalutamide)是第二代AR(雄激素受体)拮抗剂,AR与恩杂鲁胺结合后不能正常被转运至细胞核内或募集共激活因子,AR转录活性降低。与第一代AR拮抗剂比卡鲁胺(Bicalutamide)相比,恩杂鲁胺与AR的亲和力更强。虽然醋酸阿比特龙和恩杂鲁胺等的获批对治疗mCRPC有重要意义,但经过一段时间的治疗后,多数患者最终会产生耐药。
由于治疗药物的耐药性和安全性问题,前列腺癌的治疗仍是临床上的一个难题,探索有效的治疗方式是非常迫切需要的。
发明内容
本发明通式(I)化合物为激酶抑制剂,通过研究发现,通式(I)化合物对前列腺癌具有治疗作用;进一步地,对于去势抵抗性前列腺癌和去势敏感性前列腺癌以及转移性去势抵抗性前列腺癌具有显著的治疗作用。
为实现上述目的,本发明提供了下述方案:
本发明提供通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型在制备治疗和/或预防前列腺癌的药物中的用途;
其中,Ar为任选被1-3个R
6取代的苯基,每个R
6独立地选自氢、氨基、氰基、卤素、C
1-4烷基和三氟甲基;
Y为CR
3;
P为CR
4;
W为N;
R
3为氢或C
1-4烷基;
R
4为-(CH
2)
n-(5-11)元杂环基,其中,n=0-6,所述杂环基中的成环S原子任选被氧化为S(O)或S(O)
2,成环C原子任选被氧化为C(O),所述杂环基任选被一至多个独立地选自C
1-3烷基和C
3-6环烷基的取代基取代。
在一些实施方案中,Ar任选被1-3个R
6取代的苯基,每个R
6独立地选自氢和卤素;
Y为CR
3;
P为CR
4;
W为N;
R
3为氢;
R
4选自-(CH
2)
n-(5-6)元单杂环基和-(CH
2)
n-(7-11)元稠杂环基,其中,n=0-6,所述杂环基中的成环S原子任选被氧化为S(O)或S(O)
2,成环C原子任选被氧化为C(O),所述杂环基任选被一至多个独立地选自C
1-3烷基和C
3-6环烷基的取代基取代。
在进一步的实施方案中,所述的(5-6)元单杂环基为(5-6)元饱和单杂环基,所述的(7-11)元稠杂环基为(7-11)元饱和稠杂环基。在一个优选的实施方式中,所述的(7-11)元饱和稠杂环基为(7-11)元饱和并杂环基、(7-11)元饱和螺杂环基或(7-11)元饱和桥杂环基。
在一个实施方案中,通式(I)的化合物为表1所示的化合物或其药学上可接受的盐、立体异构体、晶型。
表1 本发明的化合物
在一些实施方案中,本发明的化合物还可以包括除通式(I)的化合物之外的化合物,例如,下表中所示的具体化合物。
本发明还提供药物组合物或药物组合产品,本发明所述的药物组合物或药物组合产品包含治疗有效量的通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型以及一种或多种药学上可接受的载体、稀释剂或赋形剂。任选地,所述药物组合物或药物组合产品还包含一种或多种其它活性剂。其中对通式(I)化合物的定义如前文所述。
本发明还提供治疗前列腺癌的方法,所述方法包括向有需要的前列腺癌症患者施用治疗有效量的通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型或本发明所述的药物组合物或药物组合产品,其中对通式(I)化合物的定义如前文所述。
本发明还提供通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型或本发明所述的药物组合物或药物组合产品在预防和/或治疗前列腺癌的用途,其中对通式(I)化合物的定义如前文所述。
本发明还提供通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型或本发明所述的药物组合物或药物组合产品在制备用于预防和/或治疗前列腺癌的药物中的用途,其中对通式(I)化合物的定义如前文所述。
本发明还提供用于预防和/或治疗前列腺癌的通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型或本发明所述的药物组合物或药物组合产品,其中对通式(I)化合物的定义如前文所述。
在一些实施方案中,所述前列腺癌为转移性前列腺癌。
在一些实施方案中,所述前列腺癌为非转移性前列腺癌。
在一些实施方案中,所述前列腺癌为早期前列腺癌。
在一些实施方案中,所述前列腺癌为晚期前列腺癌。
在一些实施方案中,所述前列腺癌是未接受标准治疗的。
在一些实施方案中,所述前列腺癌是接受标准治疗失败的。
在一些实施方案中,所述前列腺癌是接受化疗失败的。
在一些实施方案中,所述前列腺癌是接受内分泌治疗失败的。
在一些实施方案中,所述前列腺癌是接受雄激素剥夺治疗失败的。
在一些实施方案中,所述前列腺癌是接受雄激素合成抑制剂和/或雄激素受体抑制剂治疗失败的。
在一些实施方案中,所述前列腺癌是接受阿比特龙治疗失败的。
在一些实施方案中,所述前列腺癌是接受恩杂鲁胺、阿帕鲁胺、达洛鲁胺和/或比卡鲁胺治疗失败的。
在一些实施方案中,所述前列腺癌为早期和/或非转移性前列腺癌。
在一些实施方案中,所述早期和/或非转移性前列腺癌是未接受标准治疗的。
在一些实施方案中,所述前列腺癌为晚期和/或转移性前列腺癌。
在一些实施方案中,所述晚期和/或转移性前列腺癌是未接受标准治疗的。
在一些实施方案中,所述晚期和/或转移性前列腺癌是接受标准治疗失败的。
在一些实施方案中,所述前列腺癌为去势敏感性前列腺癌。
在一些实施方案中,所述前列腺癌为去势抵抗性前列腺癌。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是未接受标准治疗的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受标准治疗失败的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受化疗失败的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受内分泌治疗失败的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受雄激素剥夺治疗治疗失败的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受雄激素合成抑制剂和/或雄激素受体抑制剂治疗失败的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受阿比特龙治疗失败的。
在一些实施方案中,所述去势敏感性前列腺癌或去势抵抗性前列腺癌是接受恩杂鲁胺、阿帕鲁胺、达洛鲁胺和/或比卡鲁胺治疗失败的。
在一些实施方案中,所述前列腺癌为转移性去势敏感性前列腺癌。
在一些实施方案中,所述前列腺癌为非转移性去势敏感性前列腺癌。
在一些实施方案中,所述非转移性或转移性去势敏感性前列腺癌是未接受标准治疗的。
在一些实施方案中,所述非转移性或转移性去势敏感性前列腺癌是接受标准治疗失败的。
在一些实施方案中,所述前列腺癌为转移性去势抵抗性前列腺癌。
在一些实施方案中,所述前列腺癌是非转移性去势抵抗性前列腺癌。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是未接受标准治疗的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受标准治疗失败的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受化疗失败的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受内分泌治疗失败的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受雄激素剥夺治疗治疗失败的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受雄激素合成抑制剂和/或雄激素受体抑制剂治疗失败的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受阿比特龙治疗失败的。
在一些实施方案中,所述非转移性或转移性去势抵抗性前列腺癌是接受恩杂鲁胺、阿帕鲁胺、达洛鲁胺和/或比卡鲁胺治疗失败的。
在一些实施方案中,所述转移性去势前列腺癌是经组织病理或细胞学证实的,既往经初次持续性雄激素剥夺治疗后失败的前列腺癌,且影像学证实具有明确的骨或软组织转移病灶。
在一些实施方案中,所述转移性去势前列腺癌是经组织病理学或细胞学证实的,无标准治疗可选择的转移性去势抵抗性前列腺癌。
在一些实施方案中,本发明还提供通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型治疗前列腺癌患者的给药剂量和给药方案,具体如下:
在一些实施方案中,所述通式(I)的化合物或其药学上可接受的 盐、立体异构体、晶型的单次给药剂量为3mg~20mg,例如:3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg。给药频次为每日一次、每天两次、或每两日一次、每三日一次。优选给药频次为每日一次。
在一些实施方案中,所述通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型,还可以与一种或多种药学上可接受的载体制成药学上可接受的任意药物制剂。
在一些实施方案中,所述药物制剂可以包含一种或多种药学上可接受的载体,可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时,所述药物组合物可制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,所述药物组合物可制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中的常规方法生产,配置注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。用于直肠给药时,所述药物组合物可制成栓剂等。用于经肺给药时,所述药物组合物可制成吸入剂或喷雾剂等。
本发明所述的“治疗”是指给予患者有效量的药物,减缓或者治愈患者不想要的生理学变化或病症,诸如过度增殖性状况,诸如癌症的生长、形成或扩散,以获得有利或期望的临床结果,包括但不限于:缓解症状、削弱疾病的程度、疾病状态稳定(即不恶化)、延迟或减缓疾病进展、改善或减轻疾病状态、及消退(无论是部分的还是完全的),无论是可检测的还是不可检测的。
本发明所述的“治疗”可以包括新辅助治疗和辅助治疗。
“新辅助治疗”是指对于初始肿瘤患者,在计划中的手术治疗或者手术加放疗的局部治疗前进行的全身系统性治疗,根据不同的肿瘤类型,新辅助治疗手段可能是化疗、内分泌、靶向、免疫或者放疗。新辅助治疗的目的是提供即刻系统性治疗,从而潜在根治微转移,所述微转移在其它情况中在遵循手术,继之以系统性疗法的标准顺序时会增殖。新辅助治疗也可以帮助缩小肿瘤大小,从而容许最初不能切除的肿瘤的完全切除或者保留器官及其功能的部分。此外,新辅助治 疗允许药物效力的体内评估,其可以指导随后治疗的选择。
“辅助治疗”是指在确定性手术(其中不能检出残余疾病的证据)之后给予的疗法,以消灭体内任何残留的癌细胞,用于降低肿瘤复发或者向其他部位散播的可能性。治疗手段与新辅助治疗大致相同。辅助疗法的目标是预防癌症复发,及因此降低癌症相关死亡的机会。辅助疗法在本文中明确排除新辅助治疗。
本发明所述的“失败的”、“治疗失败的”或“化疗失败的”是指治疗过程中或末次治疗后出现疾病进展(根据肿瘤组织评估RECIST1.1疗效评定标准为疾病进展(PD)或根据前列腺癌的骨病灶评价标准PCWG3为疾病进展(PD))、或治疗过程中因为毒副作用不可耐受。
本发明所述的“毒副作用不可耐受”是指因药物引起的不良反应不能继续接受治疗。
本发明所述的“标准治疗”包括雄激素剥夺治疗(手术去势以及包括但不限于戈舍瑞林、亮丙瑞林、曲普瑞林、地加瑞克的药物去势治疗等)、化疗、全身放射性治疗、新型内分泌治疗。
本发明所述的“化疗”包括但不限于多西他赛、多西他赛与泼尼松联用等。
本发明所述的“阿比特龙治疗”包括但不限于阿比特龙、阿比特龙与泼尼松联用等。
本发明所述的“内分泌治疗”是通过抑制或减少雄激素(受体)活性从而达到治疗前列腺癌的方法,它包含传统的雄激素剥夺治疗(ADT)和新型内分泌治疗。其中,ADT治疗包括手术去势治疗(睾丸切除等)和药物去势治疗(包括但不限于接受戈舍瑞林、亮丙瑞林、曲普瑞林、地加瑞克等)。新型内分泌治疗包括雄激素合成抑制剂(如阿比特龙等等),雄激素受体抑制剂(如恩杂鲁胺,阿帕鲁胺,达洛鲁胺,比卡鲁胺等等)。
无进展生存期(PFS):在有效性分析集中从第一次使用研究药物的时间到出现疾病进展或因任何原因死亡的时间。
总生存期(OS):从开始研究药物治疗的时间到因任何原因死亡的时间。对于在分析时尚未死亡的患者,将使用最后一次获知其生存的日期进行审查。
客观缓解率(ORR):每例患者停用试验药物时,最佳响应为CR或 PR的患者所占的比例。
缓解持续时间(DOR):首次PR或者CR至首次PD或者死亡的时间。
疾病控制率(DCR):为最佳响应为CR、PR或SD的患者所占的比例。
疗效评定标准根据RECIST1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
完全缓解(CR):所有靶病灶消失(全部病理淋巴结短直径必须减少至<10mm),非靶病灶均消失,无新病灶出现。
部分缓解(PR):靶病灶直径之和比基线水平减少至少30%,非靶病灶消失或稳定,无新病灶出现。
疾病进展(PD):靶病灶直径之和相对增加至少20%,或非靶病灶恶化,或新病灶出现(三者发生一项即PD。
疾病稳定(SD):靶病灶增加/减少介于PR和PD之间,且非靶病灶稳定或消失,无新病灶。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物或其药学上可接受的盐、立体异构体、晶型的量。包含“治疗有效量”的实际量会根据多种情况而变化,多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。例如,可给药单次推注,可随时间给药数个分剂量,或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意,剂量值可随要减轻的病况的类型及严重性而变化,且可包括单次或多次剂量。对于任何特定个体,具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
用于预防和/或治疗前列腺癌的“对象”或“个体”指分类为哺乳动物的任意动物,包括人类,驯养动物和农场动物,及动物园动物、运动动物或宠物动物,如狗、马、猫、牛等。优选地,该哺乳动物是人。对象或个体可以是患者。
定义
本发明所述的“卤素”是指氟、氯、溴和碘等,优选氟和氯。
本发明所述的“卤代”是指取代基中的任一氢原子可被一个或多个 相同或不同的卤素替代。“卤素”如前文所定义。
本发明所述的“氰基”是指-CN基团。
本发明所述的“氨基”是指-NH
2基团。
本发明所述“C
1-4烷基”指含有1-4个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。所述“C
1-3烷基”指含有1-3个碳原子的上述烷基。
本发明所述的“C
3-6环烷基”,是指含有3-6个碳原子的单环环烷基,双环环烷基系统或者多环环烷基系统。这些基团是饱和的、但不是芳族的。在不特别指明的情况下,包括所能够形成的单环和稠环结构。其实例包括但不限于:环丙烷基、环丁烷基、环戊烷基、环己烷基、双环[2.2.2]己烷、双环[3.2.1]己烷。
本发明所述的“5-11元杂环基”是指具有5-11个环碳原子的非芳香性的环状基团,其中至少一个环碳原子被选自O、S、N的一个或多个杂原子替代,优选1-3个杂原子,同时包括碳原子、氮原子和硫原子在内的成环原子可以被氧化。
所述的“杂环基”,是指单环杂环基、双环杂环基系统或多环杂环基系统,包括饱和、部分饱和的杂环基,但不包括芳环。本发明所述的“5-11元杂环基”在不特别指明的情况下,包括所能够形成的单环和稠环结构。
所述的单杂环基可以为5-7元杂环基、5-6元杂环基、5-6元含氧杂环基、5-6元含氮杂环基、5-6元饱和杂环基等。本发明所述的5-6元单杂环基的实例包括但不限于四氢呋喃基、四氢吡咯基、四氢噻吩基、咪唑烷基、吡唑烷基、1,2-噁唑烷基、1,3-噁唑烷基、1,2-噻唑烷基、1,3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌嗪基、吗啉基、1,4-二氧杂环己烷基、1,4-氧硫杂环己烷基、4,5-二氢异噁唑基、4,5-二氢噁唑基、2,5-二氢噁唑基、2,3-二氢噁唑基、3,4-二氢-2H-吡咯基、2,3-二氢-1H-吡咯基、2,5-二氢-1H-咪唑基、4,5-二氢-1H-咪唑基、4,5-二氢-1H-吡唑基、4,5-二氢-3H-吡唑基、4,5-二氢噻唑基、2,5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、2,3,4,5-四氢吡啶基、1,2-异噁嗪基、1,4-异噁嗪基或6H-1,3-噁嗪基等。
所述的稠杂环包括并杂环基、螺杂环基、桥杂环基,可以是饱和 的、部分饱和的或不饱和的,但不是芳香性的。本发明所述的7-11元稠杂环基,在不特别指明的情况下,包括所能够形成的并、螺、桥结构。
所述的并杂环基可以为7-11元并环基,优选7-11元饱和并环基,其实例包括但不限于:3,6-二氮杂双环[3.2.0]庚烷、3,8-二氮杂双环[4.2.0]辛烷基、3,7-二氮杂双环[4.2.0]辛烷基、八氢吡咯并[3,4-c]吡咯、八氢吡咯并[3,4-b]吡咯、八氢吡咯并[3,4-b][1,4]噁嗪基、八氢-1H-吡咯并[3,4-c]吡啶、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃基-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2,3二氢苯并噻吩-2基、八氢-1H-吲哚基、八氢苯并呋喃基。
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐和溶剂化物。这样的可药用盐包括诸如以下的酸的盐:盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH
2)n-COOH(其中n=0~4))等。这样的可药用盐还包括诸如以下的碱的盐:钠、钾、钙、铵等。本领域技术人员知晓多种无毒的可药用加成盐。
本发明所述的所有数值范围,均表示包括该范围的两个端点、该范围之内的所有整数以及由这些整数形成的子范围。例如“5-11元”包括5、6、7、8、9、10、11元,“5-6元”包括5、6元,“7-11元”包括7、8、9、10、11元等等。
本发明关于取代基所述的“一至多个”是指取代基的数量可以为所取代基团所有化学上可以被取代的位置,优选1-6个,更优选1-5个,更优选1-3个,更优选1-2个。
本发明所述的“晶型”可以通过本领域用于制备晶型的常规方法由通式(I)的化合物制备。
本发明所述的通式(I)化合物的“立体异构体”是指当通式(I)化合物存在不对称碳原子时,会产生对映异构体;当化合物存在碳碳双键或环状结构时,会产生顺反异构体;当化合物存在酮或肟时,会产生互变异构体。所有通式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物,均包括在本发明范围中。
本发明所述的通式(I)化合物的制备可参见WO2018108079A1具体实施方式部分。
本发明的有益效果
本发明通式(I)的化合物或其药学上可接受的盐、立体异构体、晶型对前列腺癌具有治疗作用;进一步地,对于去势抵抗性前列腺癌和去势敏感性前列腺癌具有显著的治疗作用;更进一步地,对于转移性去势抵抗性前列腺癌也具有显著的治疗作用,具有良好的临床应用潜力。
为使本发明的目的、技术方案、及优点更加清楚明白,以下对本发明进一步详细说明。显然,所描述的实施方案仅仅是本发明一部分实施方案,而不是全部的实施方案。基于本发明中的实施方案,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施方案,都属于本发明保护的范围。
在本发明中所使用的缩写和英文表述具有以下含义:
缩写/英文 | 含义 |
DMSO | 二甲基亚砜 |
MC | 甲基纤维素 |
Qd | 每日一次 |
mCRPC | 转移性去势抵抗性前列腺癌 |
实验例1本发明化合物的细胞活性测试
测试物:本发明中的化合物29,其结构见前文所示,制备方法可参WO2018108079A1具体实施方式部分。
前列腺癌细胞材料:DU145、PC-3、VCaP、LNCaP clone FGC。
测试仪器:使用PE Envision多功能酶标仪。
试验方法:
各株细胞接种于384孔板中贴壁培养过夜后,加入不同浓度的化合物(10个剂量组,4倍DMSO系列稀释)使最高终浓度为10000nM,其中DMSO终含量均为0.33%,使用终浓度为10uM的星胞菌素作为系统阳对(100%抑制)。阴性对照孔为等含量DMSO的培养基(0%抑制)。37℃,5%CO2,95%湿度孵育72h后待测。每孔加入30μL Cell titer-Glo试剂,室温孵育30min后,使用酶标仪读取终数据。
数据计算如下:
抑制率(%)=100%-(化合物信号-系统阳对信号)/(阴性对照信号-系统阳对信号)×100%.
测试结果如表2所示,B:0-1000nM;C:1000-10000nM;D:>10000nM。
表2 本发明的化合物29对前列腺癌细胞增殖的抑制活性
细胞 | 化合物IC 50/nM |
DU145 | B |
PC-3 | B |
VCaP | B |
LNCaP clone FGC | C |
由表2实验结果可见,本发明的化合物29对前列腺癌细胞系显示良好的抗肿瘤增殖活性,具有良好的临床上治疗前列腺癌的潜力。
实验例2本发明化合物对人源去势抵抗性前列腺癌PDX皮下异种移植肿瘤模型的体内药效学研究
测试物:本发明中的化合物29,其结构见前文所示,制备方法可参WO2018108079A1具体实施方式部分。阿比特龙来源于市售。
动物、瘤块来源患者信息等材料:人源前列腺癌肿瘤样本LD1-0034-361929来源于一名男性患者,对阿比特龙耐药。临床诊断:去势抵抗性前列腺癌,伴有膀胱转移灶;病理诊断:前列腺癌-低分化腺癌;
雄性Nu/Nu裸小鼠,6-8周。
试验方法:
1,荷瘤小鼠构建与分组
瘤块接种于小鼠右后背,给药前称重动物,测量瘤体积,根据瘤体积采用区组设计分组。
2,给药方案
按照如下表格进行给药。
组别 | 剂量(mg/kg) | 动物只数 | 给药途径 | 给药频率 | 给药周期 |
溶媒对照 | 0 | 5 | 口服灌胃 | Qd*7天/周 | 39天 |
阿比特龙 | 200 | 5 | 口服灌胃 | Qd*7天/周 | 39天 |
化合物29 | 15 | 5 | 口服灌胃 | Qd*7天/周 | 39天 |
注:溶媒对照:0.5%MC;化合物29处方:0.5%MC;阿比特龙处方:10%DMSO+90%植物油
3,实验观察指标
每天监测动物的健康状况及死亡情况,每周测量两次体重以及瘤体积,末次给药后收集样本。肿瘤体积大小的疗效用TGI%评价,相对肿瘤抑制率TGI(%):TGI=1-T/C(%)。T/C%为相对肿瘤增值率,即在某一时间点,治疗组和对照组相对肿瘤体积的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)。计算公式为:T/C%=T
RTV/C
RTV×100%(T
RTV:治疗组平均RTV;C
RTV:溶媒对照组平均RTV;RTV=V
t/V
0,V
0为分组时该动物的瘤体 积,V
t为治疗后该动物的瘤体积。
结果如表3所示:
表3本发明的化合物29对人前列腺癌LD1-0034-361929皮下异种移植肿瘤模型肿瘤生长的影响
由表3实验结果可见,化合物29对阿比特龙耐药的人源去势抵抗性前列腺癌PDX皮下异种移植肿瘤模型LD1-0034-361929具有显著的抑制作用。说明本发明化合物29治疗对阿比特龙耐药的mCRPC肿瘤具有较好的临床应用潜力。
实验例3本发明化合物治疗转移性去势抵抗性前列腺癌患者的临床研究
受试药物:化合物29,其结构见前文所示,制备方法可参WO2018108079A1具体实施方式部分。
入组标准:经组织病理学或细胞学证实的,无标准治疗可选择的转移性去势抵抗性前列腺癌患者。
给药方案:化合物29按照规定剂量(如8mg、10mg或12mg)口服,每日1次,连续给药,28天/周期。
疗效评估:在11例有疗效评估数据的患者中(10例患者单次给药剂量为12mg,1例患者单次给药剂量为10mg),7例患者达到部分缓解(PR),2例患者报告病情稳定(SD)。
该研究表明,化合物29在临床上对于转移性去势抵抗性前列腺癌具有非常好的治疗效果。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明保护的范围之内。
Claims (12)
- 如权利要求1所述的用途,其中,Ar任选被1-3个R 6取代的苯基,每个R 6独立地选自氢和卤素;Y为CR 3;P为CR 4;W为N;R 3为氢;R 4选自-(CH 2) n-(5-6)元单杂环基和-(CH 2) n-(7-11)元稠杂环基,其中,n=0-6,所述杂环基中的成环S原子任选被氧化为S(O)或S(O) 2,成环C原子任选被氧化为C(O),所述杂环基任选被一至多个独立地选自C 1-3烷基和C 3-6环烷基的取代基取代。
- 包含如权利要求1~5中任一项所述的化合物或其药学上可接受的盐、立体异构体、晶型的组合物或组合产品在制备治疗和/或预防前列腺癌的药物中的用途。
- 如权利要求1~6任一项所述的用途,其中所述前列腺癌为早期或晚期前列腺癌。
- 如权利要求1~6任一项所述的用途,其中所述前列腺癌为转移性或非转移性前列腺癌。
- 如权利要求1~6任一项所述的用途,其中所述前列腺癌为去势敏感性前列腺癌或去势抵抗性前列腺癌。
- 如权利要求1~6任一项所述的用途,其中所述前列腺癌为非转移性去势抵抗性前列腺癌或转移性去势抵抗性前列腺癌。
- 如权利要求1~6任一项所述的用途,其中所述前列腺癌是接受标准治疗失败的或未接受标准治疗的前列腺癌。
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CN113620949A (zh) * | 2020-05-08 | 2021-11-09 | 南京药捷安康生物科技有限公司 | 抗肿瘤化合物的合成方法及其中间体 |
CN115120598A (zh) * | 2021-03-29 | 2022-09-30 | 药捷安康(南京)科技股份有限公司 | 多激酶抑制剂的联合应用 |
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CN113620949A (zh) * | 2020-05-08 | 2021-11-09 | 南京药捷安康生物科技有限公司 | 抗肿瘤化合物的合成方法及其中间体 |
CN115120598A (zh) * | 2021-03-29 | 2022-09-30 | 药捷安康(南京)科技股份有限公司 | 多激酶抑制剂的联合应用 |
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