CN111777621B - Novel application of quinazoline derivative tyrosine kinase inhibitor - Google Patents
Novel application of quinazoline derivative tyrosine kinase inhibitor Download PDFInfo
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- CN111777621B CN111777621B CN201910278136.1A CN201910278136A CN111777621B CN 111777621 B CN111777621 B CN 111777621B CN 201910278136 A CN201910278136 A CN 201910278136A CN 111777621 B CN111777621 B CN 111777621B
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- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
The invention relates to a novel application of a quinazoline derivative tyrosine kinase inhibitor. In particular to a new application of a compound shown as a formula (1), a pharmaceutically acceptable salt thereof or a crystal form thereof in preparing a medicament for treating squamous cell lung carcinoma.
Description
1. Field of the invention
The invention belongs to the field of medicines, and particularly relates to a quinazoline derivative tyrosine kinase inhibitor and a new application of a pharmaceutically acceptable salt or a crystal form thereof in preparation of a medicine for treating squamous cell lung carcinoma.
2. Background of the invention
Lung cancer is the most globally malignant tumor with the highest morbidity and mortality. Among them, lung cancer squamous carcinoma is one of the common pathological types. Squamous cell carcinoma of the lung (SCC), a malignant epithelial tumor derived from bronchial epithelium and may exhibit keratinizing and/or intercellular bridge characteristics. Squamous cell lung cancer is common in central lung cancer, and tends to grow in the chest cavity, and early squamous cell lung cancer often causes bronchoconstriction or obstructive pulmonary inflammation. Over 85% of lung cancers are non-small cell lung cancers, with SCC accounting for about 30-40% of non-small cell lung cancers. Globally, SCC accounts for approximately 25-35% of all types of lung cancer. Among them, most patients with SCC have a history of smoking, and the incidence of disease in men is higher than in women. Data show that about 53 thousands of Chinese non-small cell lung cancer patients are treated in 2013, and the number of the Chinese non-small cell lung cancer patients is increased to 95 thousands by 2033 years, and the increase rate reaches 80%.
The treatment method of the lung squamous carcinoma comprises operation treatment, radiotherapy, chemotherapy, medicament treatment and the like. Since lung squamous carcinoma metastasizes late and the prognosis after resection is better, surgical treatment is the first treatment. For lung squamous carcinoma which is not suitable for operation or metastasis, the treatment methods such as platinum agent and docetaxel are considered firstly, but chemotherapy brings huge side effects to patients. Therefore, various pharmaceutical companies are working on developing targeted small molecule drugs with high efficiency and low toxicity.
At present, FDA approved small molecule targeted therapeutic drugs for lung squamous carcinoma on the market are quite limited, and great drug requirements exist in the field of treatment. Although targeted therapies have achieved surprising results in the treatment of advanced lung carcinoma adenocarcinomas, such as EFGR inhibitors (gefitinib, erlotinib, and erlotinib), ALK inhibitors (crizotinib, ceritinib), and the like. However, lung carcinomas are generally less prone to driver mutations and the NCCN guidelines recommend: in patients with the pathological type of squamous cell lung carcinoma, the detection of the driver gene can be considered in only 3 cases: 1. non-smoking patients; 2. small living tissue can be obtained; 3. tumor tissue is a mixed tissue source. Even if the lung squamous carcinoma patients have the driving gene, clinical studies show that the targeted treatment effect of the advanced lung squamous carcinoma is far less than that of the lung adenocarcinoma.
WO2012027960A1 discloses a series of quinazoline derivatives tyrosine kinase inhibitors which irreversibly inhibit Pan-HER. Research shows that the Pan-HER tyrosine kinase irreversible inhibitor has an inhibiting effect on HER2/4 besides effectively inhibiting EGFR, the medicament with the irreversible inhibiting effect on HER/ErbB families improves the medicament activity and reduces the generation of medicament resistance, has a remarkable inhibiting effect on Erlotinib-resistant H1975 cell lines (non-small cell lung adenocarcinoma), and exerts good antitumor activity.
In the process of researching the patent compounds, the inventors unexpectedly found that the compound shown in the formula (1) has a good therapeutic effect on squamous cell lung carcinoma, and can obviously reduce the volume of tumors, which indicates that the compound shown in the formula (1) is expected to be a specific medicament for treating squamous cell lung carcinoma.
3. Summary of the invention
The invention relates to a novel application of a compound shown as a formula (I), a pharmaceutically acceptable salt or a crystal form of the compound in preparation of a medicament for treating squamous cell lung carcinoma.
The technical scheme of the invention is as follows:
scheme 1: the application of the compound shown in the general formula (I), the pharmaceutically acceptable salt or the crystal form thereof in preparing the medicament for treating the lung squamous carcinoma,
wherein,
R 1 selected from unsubstituted or substituted by 1 to 2 substituents Q 1 Substituted of the following groups: 6-to 10-membered fused ring C 0-6 Alkyl, 7-10 membered spirocyclic C 0-6 Alkyl or 7-to 10-membered bridged ring C 0-6 Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be substituted by 1 to 3 same or different groups selected from O, S (O) m 、N(H) m 、NCH 3 And C (O) are replaced by hetero atoms and/or groups, but O and C (O) are not adjacent to each other in the replaced ring,
Q 1 selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, C 1-6 Alkyl carbonyl oxy, C 1-6 Alkylamido radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfinyl radical, C 1-6 Alkylsulfonamide groups and C 3-8 A cycloalkyl group;
R 2 selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q 2 Substituted C 1-6 Alkyl or C 1-6 Alkoxy radicals, substituted radicals Q 2 Substituted formyl or N (H) m ，
Q 2 Selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, C 1-6 Alkyl carbonyl oxy, C 1-6 Alkylamido radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfinyl radical, C 1-6 Alkylsulfonamido radical, C 3-8 Cycloalkyl, unsaturated C 5-7 Cycloalkyl and a saturated or unsaturated 3-to 8-membered heterocyclic group, wherein said C 3-8 Cycloalkyl, unsaturated C 5-7 The cycloalkyl group and the saturated or unsaturated 3-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q 3 The substitution is carried out by the following steps,
Q 3 selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, C 1-6 Alkyl carbonyloxy, C 1-6 Alkylamido radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfinyl radical, C 1-6 Alkylsulfonamido and halogen substituted C 1-6 An alkoxy group;
R 3 selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl or C 1-6 Alkoxy radical, C 1-6 Alkyl carbonyloxy, C 1-6 Alkylamido radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfinyl or C 1-6 An alkylsulfonamide group;
R 4 、R 5 and R 6 Each independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl or C 1-6 Alkoxy radical, C 1-6 Alkylamino or di (C) 1-6 Alkyl) amino;
l is selected from the group consisting of a covalent bond, O, S (O) m ，N(H) m ，NCH 3 Or C (O);
n is 1,2 or 3; and
m is independently selected from 0,1 or 2.
In some embodiments of the present invention, the substrate is,
R 1 selected from unsubstituted or substituted by 1 to 2 substituents Q 1 Substituted of the following groups: 6-10 membered saturated fused ring C 0-4 Alkyl, 7-10 membered saturated spirocyclic C 0-4 Alkyl or 7-to 10-membered saturated bridged ring C 0-4 Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be substituted by 1 to 3 same or different groups selected from O, S (O) m 、N(H) m 、NCH 3 And C (O) are replaced by hetero atoms and/or groups, but O and C (O) are not adjacent to each other in the replaced ring,
Q 1 selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, C 1-4 Alkyl carbonyloxy, C 1-4 Alkylamido radical, C 1-4 Alkylsulfonyl radical, C 1-4 Alkylsulfinyl radical, C 1-4 Alkylsulfonamide groups and C 3-6 A cycloalkyl group;
R 2 selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q 2 Substituted C 1-4 Alkyl or C 1-4 Alkoxy radicals, substituted radicals Q 2 Substituted formyl or N (H) m ，
Q 2 Selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, C 1-4 Alkyl carbonyloxy, C 1-4 Alkylamido radical, C 1-4 Alkylsulfonyl radical, C 1-4 Alkylsulfinyl radical, C 1-4 Alkylsulfonamido radical, C 3-6 Cycloalkyl, unsaturated C 5-7 Cycloalkyl and a saturated or unsaturated 5-to 8-membered heterocyclic group, wherein said C 3-6 Cycloalkyl, unsaturated C 5-7 The cycloalkyl group and the saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q 3 The substitution is carried out by the following steps,
Q 3 selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, C 1-4 Alkyl carbonyloxy, C 1-4 Alkylamido radical, C 1-4 Alkylsulfonyl radical, C 1-4 Alkylsulfinyl radical, C 1-4 Alkyl sulfonamide groupAnd halogen substituted C 1-4 An alkoxy group;
R 3 selected from halogen, cyano, nitro, C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl or C 1-4 Alkoxy radical, C 1-4 Alkyl carbonyloxy, C 1-4 Alkylamido radical, C 1-4 Alkylsulfonyl radical, C 1-4 Alkylsulfinyl or C 1-4 An alkylsulfonamide group;
R 4 、R 5 and R 6 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl or C 1-4 Alkoxy radical, C 1-4 Alkylamino or di (C) 1-4 Alkyl) amino;
l is selected from the group consisting of a covalent bond, O, S (O) m Or N (H) m ；
n is 1,2 or 3; and
m is independently selected from 0,1 or 2.
In some embodiments of the present invention, the substrate is,
R 1 selected from unsubstituted or substituted by 1 to 2 substituents Q 1 Substituted of the following groups:
wherein 1 to 3 carbon atoms in the ring may be substituted by 1 to 3 same or different substituents selected from O, S (O) m 、N(H) m 、NCH 3 And C (O), but O and C (O) are not adjacent to each other in the substituted ring, p is 0,1 or 2,
Q 1 selected from the group consisting of: halogen, hydroxy, amino, carboxyl, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino and C 3-6 A cycloalkyl group;
R 2 selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q 2 Substituted C 1-4 Alkyl radicals, substituted radicals Q 2 Substituted formyl or N (H) m ，
Q 2 Selected from the group consisting of: halogen, hydroxy, amino, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, C 1-4 Alkyl carbonyloxy, C 1-4 Alkylamido radical, C 1-4 Alkylsulfonyl radical, C 1-4 Alkylsulfonamido radical, C 3-5 Cycloalkyl and saturated or unsaturated 5-8 membered heterocyclyl, wherein said C 3-5 The cycloalkyl group, saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q 3 The substitution is carried out by the following steps,
Q 3 selected from the group consisting of: halogen, hydroxy, amino, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, C 1-4 Alkyl carbonyloxy, C 1-4 Alkylamido radical, C 1-4 Alkylsulfonyl radical, C 1-4 Alkylsulfonamido and halogen substituted C 1-4 An alkoxy group;
R 3 selected from fluorine, chlorine, bromine, C 1-4 Alkyl or C 1-4 An alkoxy group;
R 4 、R 5 and R 6 Each independently selected from hydrogen, fluorine or chlorine;
l is selected from the group consisting of a covalent bond, O, S (O) m Or N (H) m ；
n is 1,2 or 3; and
m is 0,1 or 2.
In some embodiments of the present invention, the substrate is,
R 1 selected from unsubstituted or substituted by 1 to 2 substituents Q 1 Substituted of the following groups:
p is selected from 0,1 or 2,
Q 1 selected from the group consisting of: halogen, amino, C 1-4 Alkyl radical, C 1-4 Alkylamino and di (C) 1-4 Alkyl) amino;
R 2 selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q 2 Substituted methyl or ethyl radicals, by substituents Q 2 Substituted formyl or N (H) m ，
Q 2 Selected from the group consisting of:
(1) Halogen, hydroxy, amino, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, acetoxy, acetamido, methylsulfonyl and methylsulfonylamino,
(2) Cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyrazinyl and pyrimidinyl, said Q 2 The radicals may be further substituted by 1 to 2 substituents Q 3 The substitution is carried out by the following steps,
Q 3 selected from the group consisting of: halogen, hydroxy, amino, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino, halogen-substituted C 1-4 Alkoxy, acetoxy, acetamido, methylsulfonyl, and methylsulfonylamino;
R 3 selected from fluorine or chlorine;
R 4 、R 5 and R 6 Is hydrogen;
l is selected from a covalent bond or O;
n is 2; and
m is independently selected from 0,1 or 2.
In some embodiments of the present invention, the substrate is,
R 1 selected from:
R 2 selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q 2 A substituted methyl group or an ethyl group,
Q 2 selected from the group consisting of:
(1) Methoxy and di (C) 1-4 Alkyl) amino groups, in the presence of a nitrogen atom,
(2) Piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, cyclopropylalkyl, cyclopentylalkyl, pyrrolyl, pyridinyl, pyrimidinyl and thiazolyl, said Q 2 The radicals may be further substituted by 1 to 2 substituents Q 3 The substitution is carried out by the following steps,
Q 3 selected from the group consisting of: halogen, hydroxy, amino, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, di (C) 1-4 Alkyl) amino and halogen substituted C 1-4 An alkoxy group;
R 3 selected from fluorine or chlorine;
R 4 、R 5 and R 6 Is hydrogen;
l is selected from a covalent bond or O; and
n is 2.
In some embodiments of the present invention, the substrate is,
R 1 selected from:
R 2 selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q 2 A substituted methyl group or an ethyl group,
Q 2 selected from the group consisting of: methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl and morpholinyl;
R 3 selected from fluorine or chlorine;
R 4 、R 5 and R 6 Is hydrogen;
l is selected from a covalent bond or O; and
n is 2.
In some embodiments of the present invention, the substrate is,
R 1 selected from:
preferably R 1 Selected from the group consisting of:
in some embodiments of the present invention, the substrate is,
R 2 selected from hydrogen;
R 3 independently selected from fluorine or chlorine;
l is selected from O; and
n is selected from 2.
In certain embodiments, wherein said compound of formula (I) is selected from:
in certain embodiments, the squamous cell lung carcinoma is advanced and/or metastatic squamous cell lung carcinoma.
In certain embodiments, the squamous cell lung carcinoma is one that has failed therapy with an antimetabolite antineoplastic agent, a mitotic inhibitor antineoplastic agent, a metalloplatinum antineoplastic agent, or a vascular inhibition antineoplastic agent.
In certain embodiments, the antimetabolite antineoplastic agent is selected from capecitabine, gemcitabine.
In certain embodiments, the mitotic inhibitor antineoplastic agent is selected from the group consisting of paclitaxel, vinorelbine, docetaxel, doxorubicin;
in certain embodiments, the platinum antineoplastic agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, lobaplatin;
in certain embodiments, the angiostatic antineoplastic agent is selected from recombinant human endostatin.
In certain embodiments, the lung squamous cancer patient carries one or more of an EGFR, HER2, HER3, HER4 amplification or mutation, a KRAS mutation, a PI3K mutation, a BRCA mutation, a TP53 mutation, a PIK3CB mutation, a MDM4 mutation, a SPTA1 mutation, a SF3B1 mutation, a GRM3, an ARID1B, PIK CA mutation, a BRAF mutation, a DDR2 mutation, a STK11 mutation, a CEBPA mutation, an EGFRVIII mutation, or an FGFR1 mutation. In certain embodiments, the HER3 mutation site is a182T.
In certain embodiments, the BRCA mutation site is BRCA2.
In certain embodiments, the PI3K mutation site is PIK3CA and/or PIK3CB.
In certain embodiments, the squamous cell lung carcinoma patient carries a TP53 mutation, a BRCA2 mutation, or a PIK3CB mutation.
In certain embodiments, the compound of formula (1), a pharmaceutically acceptable salt thereof, or a crystalline form thereof is administered alone or in combination with one or more other therapeutic agents.
The application of a pharmaceutical composition comprises a compound shown as a formula (1), a pharmaceutically acceptable salt thereof or a crystal form thereof and a pharmaceutically acceptable carrier, and optionally further comprises one or more other therapeutic agents.
In certain embodiments, the additional therapeutic agent is selected from the group consisting of antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metal platins, topoisomerase inhibitors, and immunosuppressive agents.
In certain embodiments, the crystalline form is selected from an isolated crystalline form of the compound of formula (I), a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), a solvate crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), or a co-crystal of the compound of formula (I).
In certain embodiments, the crystalline form is selected from a crystalline form of the free base or a crystalline form of the hydrochloride salt of the compound of formula (I).
4. Detailed description of the invention
In the present invention, "halo" means substituted by "halogen" and the term "halogen" means fluorine, chlorine, bromine or iodine.
In the present invention, the term "C 1-6 Alkyl "refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like. "C" according to the invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.
In the present inventionIn the specification, the term "C 1-6 Alkoxy "means" C 1-6 alkyl-O- "group, wherein C 1-6 Alkyl is as previously defined; examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like. "C" according to the invention 1-4 Alkoxy "means C 1-6 Specific examples of the alkoxy group having 1 to 4 carbon atoms.
In the present invention, the term "C 3-8 Cycloalkyl "refers to a monocyclic saturated carbocyclic group containing 3 to 8, e.g., 3,4, 5,6, 7, or 8 carbon atoms, preferably 3 to 6 or 3 to 5 carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
In the present invention, the term "C 1-6 Alkylamino "refers to" C 1-6 alkyl-NH- "group, wherein C 1-6 Alkyl is as previously defined; examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino, and the like.
In the present invention, the term "di (C) 1-6 Alkyl) amino "means" (C) 1-6 Alkyl radical) 2 -N- "group, two of which are C 1-6 The alkyl groups may be the same or different and are each as defined above; examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, dibutylamino and the like.
In the present invention, the term "C 1-6 Alkylcarbonyloxy group and C 1-6 Alkylamide group "," C 1-6 Alkylsulfonyl group "," C 1-6 Alkylsulfonamido "or" C 1-6 Alkylsulfinyl "means respectively" C 1-6 alkyl-C (O) O- "," C 1-6 alkyl-C (O) NH- "," C 1-6 alkyl-SO 2 -”、“C 1-6 alkyl-SO 2 NH- "and" C 1-6 alkyl-SO- "group, wherein C 1-6 Alkyl is as defined above.
In the present invention, the following procedures are performedThe term "6-to 10-membered fused ring" refers to a saturated or unsaturated fused ring system containing 6 to 10 carbon atoms, wherein the ring carbon atoms may be substituted by 1 to 3 identical or different atoms selected from O, S (O), formed by at least two ring structures sharing two adjacent atoms m 、N(H) m 、NCH 3 And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, 5,6-dihydroimidazole [1.2-a ]]Pyrazin-7 (8H) -yl, 5,6-dihydro-1,7-naphthyridin-7 (8H) -yl, 5H-pyrrole [3.4-b ]]Pyridin-6 (7H) -yl, 7,8-dihydropyridine [4.3-d]Pyrimidin-6 (5H) -yl, 2,3,6,7-tetrahydro-1H-pyrazolo [4.3-c]Pyridin-5 (4H) -yl, 6,7-dihydrothiazole [5.4-c ]]Pyridin-5 (4H) -yl, 3-methyl-6,7-dihydro-3H-pyrazolo [4.5-c]Pyridin-5 (4H) -yl, 2-methylhexahydropenta [ c ]]Pyrrol-5-yl and the like.
In the present invention, the term "7-to 10-membered spirocyclic ring" refers to a saturated or unsaturated fused ring system containing 7 to 10 carbon atoms, wherein the ring carbon atoms may be substituted by 1 to 3 identical or different ring members selected from O, S (O), formed by at least two rings sharing one atom with each other m 、N(H) m 、NCH 3 And C (O), wherein O and C (O) are not adjacent to each other in the substituted ring. Examples include, but are not limited to, 6-azaspiro [2.5 ]]Octane-6-yl, 7-azaspiro [3.5]]Nonan-7-yl, 8-azaspiro [4.5 ]]Decan-8-yl, 1-methyl-1,7-diazaspiro [4.4 ]]Nonan-7-yl, 2-methyl-2,6-diazaspiro [3.4 ]]Octane-6-yl, 6-azaspiro [3.4 ]]Octane-6-yl, 2-oxa-7-azaspiro [4.5 ]]Decan-7-yl, 2-oxa-8-azaspiro [4.5 ]]Decan-8-yl, 2-methyl-2,7-diazaspiro [4.5 ]]Decane, etc.
In the present invention, the term "7-to 10-membered bridged ring" refers to a fused ring system containing 7 to 10 carbon atoms, saturated or unsaturated, wherein any two rings share two atoms not directly connected, and wherein the ring carbon atoms may be substituted by 1 to 3 same or different atoms selected from the group consisting of O, S (O) m 、N(H) m 、NCH 3 And C (O), wherein O and C (O) are not adjacent to each other in the substituted ring. Examples include, but are not limited to, (1S, 4S) -2-methyl-2-azabicyclo [2.2.1]Hexane, 2-azabicyclo [2.2.1 ]]Heptane, 8-methylbicyclo [3.2.1 ]]Octane, 3-oxa-8-azabicyclo [3.2.1]Octane, 2-Azabicyclo [2.2.2]Octane, 7-azabicyclo [2.2.1]Heptane, 3-azabicyclo [3.2.1]Octane, 3-azabicyclo [3.3.2 ]]Decane, 7-oxabicyclo [2.2.1]Heptane, 8-oxabicyclo [3.2.1 ]]Octane, and the like.
In the present invention, the term "unsaturated C 5-7 Cycloalkyl "refers to a monocyclic unsaturated carbocyclic group containing 5 to 7, e.g., 5,6, or 7, carbon atoms, examples of which include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like.
In the present invention, the term "3-8 membered heterocyclic group" means a cyclic system composed of 3 to 8, for example, 3,4, 5,6, 7 or 8, preferably 5 to 8 carbon atoms and 1 to 4 (preferably 1 to 3, more preferably 1 to 2) heteroatoms selected from nitrogen, oxygen and sulfur, examples of which include, but are not limited to, the following ring-forming groups: aziridine, 2H-aziridine, diazirine, 3H-diazirine, azetidine, 1,2-diazetidine, azetidine, 1,2-diazetidine, pyrrole, dihydropyrrole, pyrrolidine, imidazole, 4,5-dihydroimidazole, imidazolidine, pyrazole, 4,5-dihydropyrazole, pyrazolidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, 2-pyridone, 4-pyridone, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepane, 1,2-diazacyclotriene, 1,3-diazacyclotriene, 1,4-diazacyclo-4235-cyclooctacyclo-e 1,4-dihydro-1,4-diazacyclooctatriene, ethylene oxide, dioxirane, thietane, oxetane, 1,2-dioxetane, thietane, 1,2-dithiocyclobutene, furan, tetrahydrofuran, thiophene, 1,2-dihydrothiophene, tetrahydrothiophene, 1,2-dioxolane, 1,2-dioxol-2-one 1,2-dithiole, 1,2-dithiolane, 2H-pyran-2-one, 1,2-dihydro-2H-pyran, 4H-pyran, tetrahydropyran, 4H-pyran-4-one, 1,2-dioxane, 1,2-dithiine, 1,2-oxathihexadiene, 1,2-dioxane, 2H-pyran-2-one, 1,2-dihydropyran, 1,3-oxathiane, oxacycloheptatriene, thiacycloheptatriene, 1,4-dioxacyclooctatriene, oxaziridine, oxazole, 4,5-dihydrooxazole, isoxazole, 4,5-dihydroisoxazole, 2,3-dihydroisoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4,5-dihydrothiazole, isothiazole, 1,2,3-thiadiazole, 3567-thiadiazole, 1,3,4-thiadiazole, 2H-1,2-oxazine, 4H-4235 zxft 6235-oxazine, 6H-1,2-oxazine, 2H-5252-oxazine, 4H-zft-58 zzft 6262626262626262626262626262626262626258, 2H-4258 zxft 6258-dihydrooxazine, 2H-4258 zxft H-4258-zzft H-58-H-7-zzft-H-58-H-zzft-57-dihydrooxazine, 2H-58-H-zzft-6258-zzft-H-zzft-6258-H-zzft-2-7-zthiazine, and the like.
"C" according to the invention 0-6 Alkyl "refers to a straight or branched chain alkyl group containing 0 to 6 carbon atoms, when the alkyl group contains 0 carbon atoms it means that the alkyl group is absent, when the alkyl group contains 1 to 6 carbon atoms it is as previously defined for" C 1-6 Alkyl groups "as described.
The "halo C" of the present invention 1-6 Alkyl "means one or more halogen atoms substituted for C 1-6 Radicals derived from one or more hydrogen atoms of the alkyl radical, the said "halogens" and "C 1-6 Alkyl "is as defined above.
The "halo C" of the present invention 1-6 Alkoxy "means one or more halogen atoms substituted for C 1 -6 radicals derived from one or more hydrogen atoms of the alkoxy radical, said "halogen" and "C 1-6 Alkoxy "is as defined above.
The stereoisomers of the compounds of formula (I) according to the invention include all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds. Optical isomers are meant when the compounds of the present invention contain one or more asymmetric centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
The compounds of formula (I) of the present invention contain olefinic double bonds, and unless otherwise specified, the stereoisomers of the present invention include cis-and trans-isomers thereof.
The compounds of formula (I) of the present invention may exist in tautomeric forms, and each tautomer and mixtures thereof are included within the scope of the present invention.
The crystal form of the pharmaceutically acceptable salt of the compound shown in the formula (I) is selected from a hydrochloride crystal form, a phosphate crystal form, a methanesulfonate crystal form, a trifluoromethanesulfonate crystal form, a malate crystal form, a fumarate crystal form, a succinate crystal form, a tartrate crystal form, a benzoate crystal form or a maleate crystal form of the compound shown in the formula (I), and preferably a hydrochloride crystal form, a maleate crystal form, a succinate crystal form or a benzoate crystal form;
the solvate crystal form of the compound shown as the formula (I) is selected from a hydrate crystal form, a methoxide crystal form, an ethoxide crystal form, an ether crystal form and an acetonide crystal form, and preferably a hydrate crystal form;
the solvate of the pharmaceutically acceptable salt of the compound shown as the formula (I) is selected from a hydrochloride hydrate crystal form, a hydrochloride methylate crystal form, a hydrochloride ethylate crystal form, a benzoate hydrate crystal form, a benzoate methylate crystal form, a benzoate ethylate crystal form, a maleate hydrate crystal form, a maleate methylate crystal form or a maleate ethylate crystal form, preferably a hydrochloride hydrate crystal form, and more preferably a dihydrochloride monohydrate crystal form;
the cocrystal of the compound of formula (I) in the invention is selected from cocrystals of the compound of formula (I) and one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid and saccharin, preferably cocrystals with proline, tartaric acid or saccharin.
In the "pharmaceutically acceptable salt of the compound of formula (I)" and "solvate crystal form of the pharmaceutically acceptable salt of the compound of formula (I)" described in the present invention, the molecular ratio of the compound of formula (I) to the corresponding alkali metal, other metal, organic base, inorganic acid, organic acid may be any value, preferably 10.
The pharmaceutical composition is any pharmaceutically acceptable dosage form, and is applied to a patient in need of the pharmaceutical composition in a mode of oral administration, parenteral administration, rectal administration or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
The pharmaceutically acceptable carrier includes, but is not limited to: fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, and solubilizers.
The tumor, cancer or carcinoma of the present invention also includes metastases in the primary organ, tissue and/or any other location, regardless of the location of the tumor metastasis.
The term "patient" as used herein refers to a mammal, preferably a human. In some embodiments, the patient is a patient lacking or failing standard therapy.
The present invention also provides a method of treating a patient with squamous cell lung carcinoma, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (1), a pharmaceutically acceptable salt thereof or a crystalline form thereof, which may be administered by any conventional and acceptable means known in the art, the therapeutically effective amount being adjusted according to the race, sex, age, body weight, medical condition, type of disease, severity of disease, route of administration and associated health condition of the patient and other factors known to those skilled in the art.
By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human for the treatment of a disease, is sufficient to effect treatment for the disease.
The invention also provides a combination of a compound of formula (1) and one or more other therapeutic agents which may be administered simultaneously or sequentially with a compound of formula (1) for the treatment of patients with squamous cell lung carcinoma.
5. Attached drawing of the specification
FIG. 1 CT/MRI radiographic image before administration of Compound 18
FIG. 2 CT/MRI radiographic image seven weeks after administration of Compound 18
FIG. 3 CT/MRI radiographic image after confirmation of efficacy for 4 weeks
Detailed Description
The above-mentioned contents of the present invention will be described in further detail with reference to experimental examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following experimental examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The following abbreviations represent the following definitions:
HP-beta-CD: hydroxypropyl betacyclodextrin
Experimental example 1 therapeutic effect of Compound of formula (1) on transplantation tumor of Lung squamous carcinoma 10023 in nude mouse
And (3) testing the sample: the compound 18 crystal form I is self-prepared by referring to a preparation method in WO2017107985A 1.
The experimental method comprises the following steps:
fresh tumor tissue from tumor-bearing mice was cut into 3 × 3mm 3 The small pieces were inoculated subcutaneously into female BALB/c nude mice when tumors grew to 150mm 3 The treatment group was orally administered with a dose of 20mg/kg of the compound of formula (1) once a day for 21 days, and the other group was orally administered with 10% HP- β -CD once a day for 21 days.
And (3) data analysis:
the volume (V) is calculated as:
V＝1/2×a×b2
wherein a and b represent length and width, respectively.
TGI: (1- (Td-T0)/(Cd-C0)). 100; td refers to the tumor volume after administration of the treatment group, T0 refers to the tumor volume on the day of treatment of the treatment group; cd refers to the tumor volume after dosing in the vehicle group (10% HP- β -CD) and C0 refers to the tumor volume on the day of vehicle group.
Experimental results and conclusions:
TABLE 1 curative effect of compound of formula (1) on transplanted tumor of lung squamous carcinoma 10023 nude mouse
The compound shown in the formula (1) can obviously inhibit the growth of transplanted tumor of lung squamous carcinoma 10023 nude mouse, and the average tumor volume of the solvent control group reaches 1709.13mm after 21 days of administration 3 And the average tumor volume of the compound of formula (1) (20 mg/kg) treated group was 673.73mm, respectively 3 The tumor inhibition rate is 62.8%, which indicates that the compound shown in the formula (1) can obviously inhibit the growth of the transplantation tumor of the lung squamous carcinoma 10023 nude mouse.
Experimental example 2 therapeutic Effect of Compound of formula (1) on squamous cell lung carcinoma
And (3) testing the sample: tablets of compound 18, compound 18 prepared according to the preparation method in WO2012/027960A1, compound 18 prepared with the addition of suitable excipients to form tablets of compound 18, format 30mg, twice daily.
The medical history:
in males, age 63, left upper lobe lesions, central lung cancer with obstructive pulmonary inflammation, multiple lymph node metastases in the 4L mediastinal and left phylum. The pathology is squamous cell carcinoma.
The treatment process comprises the following steps:
in the prior art, gemcitabine, lobaplatin and enidine chemotherapy are carried out for 2 cycles, synchronous radiotherapy and chemotherapy (chemotherapy for taxanes and enidine) are carried out, chest radiotherapy is finished for 12 times, pulmonary inflammation is aggravated due to hyperpyrexia, bronchoscopy is used for removing alveolar lavage fluid to find the echinococcus carinii, the infection resistance is relieved, and the radiotherapy is not continued;
then docetaxel + enidegree 2 cycle treatment is carried out, and PD is rechecked for 1 month and 8 days;
when gemcitabine is replaced by single-dose therapy, patients do not take gemcitabine for the second time due to the reduction of white blood cells and blood platelets at 2 degrees after gemcitabine is used, abandon the therapy and take home-use traditional Chinese medicine prescriptions, and stop taking the gemcitabine 1 month before entering the group.
The curative effect is as follows:
PR was judged as 7 weeks of treatment with compound 18. And confirmed by 4 weeks of therapeutic effect.
Claims (11)
1. The use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient with squamous cell lung carcinoma,
wherein,
the compound of formula (1) is selected from: n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide.
2. The use according to claim 1, wherein the squamous cell lung carcinoma is advanced and/or metastatic squamous cell lung carcinoma.
3. The use according to claim 1, wherein the squamous cell lung carcinoma is a squamous cell lung carcinoma which fails to be treated by an antimetabolite antineoplastic agent, a mitosis inhibitor antineoplastic agent, a metal platinum antineoplastic agent or a blood vessel inhibition antineoplastic agent.
4. The use of claim 1, wherein said antimetabolite antineoplastic agent is selected from the group consisting of capecitabine, gemcitabine; the mitotic inhibitor antitumor drug is selected from paclitaxel, vinorelbine, docetaxel and doxorubicin; the metal platinum antineoplastic agent is selected from carboplatin, cisplatin, oxaliplatin and lobaplatin; the vascular inhibition antineoplastic agent is selected from recombinant human vascular endostatin.
5. The use of claim 1, wherein the lung squamous cancer patient carries one or more of an EGFR, HER2, HER3, HER4 amplification or mutation, a KRAS mutation, a PI3K mutation, a BRCA mutation, a TP53 mutation, an MDM4 mutation, an SPTA1 mutation, an SF3B1 mutation, a GRM3, an ARID1B, BRAF mutation, a DDR2 mutation, an STK11 mutation, a CEBPA mutation, an EGFRVIII mutation, or an FGFR1 mutation.
6. The use according to claim 5, wherein the mutation site of HER3 is A182T; the BRCA mutation site is BRCA2; the PIK3 mutation site is PIK3CA and/or PIK3CB.
7. The use according to claim 1, wherein the squamous cell lung carcinoma patient carries a TP53 mutation, a BRCA2 mutation or a PIK3CB mutation.
8. The use of claim 1, wherein the compound of formula (1) or a pharmaceutically acceptable salt thereof is administered alone or in combination with one or more other therapeutic agents.
9. The use according to claim 8, wherein the other therapeutic agent is selected from the group consisting of antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metalloplatins, topoisomerase inhibitors and immunosuppressives.
10. Use of a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, optionally together with one or more other therapeutic agents,
the compound of formula (1) is selected from: n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide.
11. The pharmaceutical composition for use according to claim 10, wherein the other therapeutic agent is selected from the group consisting of antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metalloplatins, topoisomerase inhibitors, and immunosuppressive agents.
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