阅读说明：本技术 西奥罗尼用于小细胞肺癌的治疗 (Seoroni for treatment of small cell lung cancer ) 是由 鲁先平 山松 潘德思 宁志强 于 2020-03-24 设计创作，主要内容包括：本发明涉及利用西奥罗尼治疗小细胞肺癌的方法。本发明还涉及西奥罗尼在制备用于治疗小细胞肺癌的药物中的应用。(The present invention relates to methods of treating small cell lung cancer using seorony. The invention also relates to the application of the seolonib in preparing the medicine for treating the small cell lung cancer.)

1. Application of seolonib compound in formula (I) in preparation of medicine for treating small cell lung cancer

2. Use of the compound of formula (I) according to claim 1 in combination with another active pharmaceutical compound for the preparation of a medicament for the treatment of small cell lung cancer.

3. A method of treating small cell lung cancer comprising administering to a subject in need thereof seolony, a compound of formula (I) as described in claim 1.

4. The therapeutic method of claim 3, further comprising administering to the subject an additional therapeutic agent.

Technical Field

The invention relates to the technical field of medicines, in particular to application of a compound seolonide in treatment of small cell lung cancer.

Background

The incidence and mortality of lung cancer are high in the first place of malignant tumors, Small Cell Lung Cancer (SCLC) accounts for 10% -15% of the total lung cancer, the clinical characteristics and biological behavior of the lung cancer are different from those of other types of lung cancer, the multiplication time is short, early metastasis easily occurs, and the malignancy degree is extremely high. Patients who do not receive treatment often die within 2-4 months, although the initially treated patients are sensitive to chemotherapy, the patients are easy to generate drug resistance and relapse, and the patients are relatively insensitive to second-line chemotherapy drugs, so that the prognosis is poor. 30% -40% of patients are diagnosed in the limited phase and 60% -70% are in the extensive phase. The limited-term long-term survival rate is 20%, and the wide-term survival rate is only 2%.

The etoposide/cisplatin regimen (EP regimen) is currently the primary chemotherapeutic regimen for SCLC. Phase III clinical study results show that in limited phase SCLC patients, the 2-and 5-year survival rates of the EP regimen are superior to the cyclophosphamide/epirubicin/vincristine regimen (25% to 10%, 8% to 3%); for patients with SCLC in the extended period, EP protocols may also provide survival benefits. A subsequent series of studies also confirmed the effectiveness of the EP regimen, which became the standard first-line chemotherapeutic regimen for SCLC.

Irinotecan/cisplatin (CPT-11/DDP) (IP regimen) is another conventional chemotherapeutic regimen for the treatment of SCLC. In a control study, both IP and EP regimen groups were established and showed Objective Remission Rates (ORR) of 84.4% and 67.5%, respectively (P ═ 0.02), and median survival of 12.8 and 9.4 months, respectively (P ═ 0.002).

In addition to the conventional EP and IP regimens described above, there are a few second-line treatment regimens, such as combination therapy with topotecan or paclitaxel. Research shows that the overall survival period, the life quality and the symptom of the topotecan combined best support treatment group are obviously better than those of the topotecan combined best support treatment group which is singly used, so that the topotecan becomes a second-line chemotherapeutic drug of SCLC.

Despite the existence of such treatment regimens, SCLC in general lacks effective therapeutic means, with few second-line alternatives (e.g., topotecan, paclitaxel, etc.) following failure of conventional EP or IP regimens, and with failure of second-line therapy, NCCN et al guidelines recommend only supportive therapy or clinical studies, at which time there is a lack of available treatment regimens. In addition, cisplatin toxicity tends to inhibit its efficacy, either in EP or IP regimens, resulting in patient compliance with the treatment. Thus, for small cell lung cancer, there is a need to find treatment regimens with better efficacy and/or fewer adverse effects.

Disclosure of Invention

In view of the above, the present invention aims to provide a therapeutic regimen for small cell lung cancer with better therapeutic effect and/or less adverse reactions. The inventor unexpectedly discovers in research that the compound shown in the formula (I), of which the chemical name is N- (2-aminophenyl) -6- (7-methoxyquinoline-4-oxy) -1-naphthamide and the common Chinese name is Seaorony, can effectively treat small cell lung cancer, has a satisfactory clinical benefit rate for the small cell lung cancer, and has relatively obviously better tumor inhibition activity than other types of tumors such as non-small cell lung cancer, colon cancer and the like.

Accordingly, in one aspect of the invention there is provided the use of seoroni in the manufacture of a medicament for the treatment of small cell lung cancer.

Accordingly, the present invention also provides a method of treating small cell lung cancer comprising administering to a subject in need thereof seoroni.

In the above pharmaceutical uses and methods of treatment of the present invention, seoronit may also be combined with additional active pharmaceutical ingredients.

In some preferred embodiments of the invention, the small cell lung cancer is relapsed or refractory small cell lung cancer.

By relapsed or refractory small cell lung cancer is meant the progression or recurrence of small cell lung cancer disease that occurs after receiving 1 or 2 or more different treatments, particularly systemic chemotherapy regimens (e.g., platinum-containing chemotherapy regimens).

The sevoroni is a small-molecule anti-tumor targeted drug taking multi-protein kinase as a target. However, there is no report on the application of seoroni to small cell lung cancer.

We performed phase I clinical trials of Seaoronir in patients with advanced solid tumors, and included 18 patients with 8 indications including colorectal, non-small cell lung, gastric, ovarian, papillary thyroid, diffuse large B-cell lymphoma, fibrosarcoma, renal hypo-differentiated carcinoma, etc., and the results indicated that no objective remission of the clinically major therapeutic indices, including all remission (CR) and Partial Remission (PR) cases, was observed.

We also performed a phase Ib clinical trial of seoronide on relapsing refractory small cell lung cancer, involving 25 patients with small cell lung cancer, of which 20 patients with efficacy assessments. The results showed that the best efficacy was evaluated as PR and the Objective Remission Rate (ORR) was 20% in 4 patients. Considering the difficulty of treatment of small cell lung cancer, the outcome of this treatment is quite encouraging.

The test results show that objective remission of the patient is not observed in clinical main curative effect indexes of the seofuloney in clinical tests aiming at 8 tumors such as non-small cell lung cancer, colon cancer and the like. However, seoroni showed good efficacy in clinical trials of small cell lung cancer with an Objective Remission Rate (ORR) of 20%. Indicating that the small cell lung cancer is an effective tumor indication of the seoroni. The efficacy of seoroni for small cell lung cancer is unexpected compared to the efficacy for other types of tumors.

Based on the above findings, the present invention proposes the use of seoroni in patients with small cell lung cancer, including but not limited to treatment with seoroni alone, and in combination with other drugs or auxiliary drugs or therapeutic agents, and also in combination with other therapeutic means (e.g., surgery, radiotherapy, etc.).

Drawings

Figure 1 shows a cascade of efficacy profiles of seorony on various tumors in a phase I clinical study;

figure 2 shows a cascade of efficacy of seolonide on small cell lung cancer in a phase Ib clinical study.

Detailed Description

The invention discloses application of seolonide in treatment of small cell lung cancer, and can be realized by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that the techniques of the invention can be implemented and practiced with modification, or with appropriate modification, and combination of parts and features without departing from the spirit and scope of the invention.

In the present invention, seoronit can be used in the form of its prototype compound or salt (pharmaceutically acceptable salt) or in the application. The pharmaceutically acceptable salts can be prepared by using, for example, the following inorganic or organic acids: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic or toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an aqueous solution of an organic acid or an inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and separating the precipitated salt.

The seocaline or a pharmaceutically acceptable salt thereof according to the invention may comprise a solvate form, preferably the solvate is a hydrate.

In the treatment of seoroni in combination with an additional therapeutic agent, the additional therapeutic agent is intended to mean any compound or ingredient that has an effect on the treatment or prevention of cancer, including that can reduce, modulate, ameliorate or eliminate its cause, or improve its symptoms or contribute to the overall therapeutic effect of the patient.

In the therapeutic use of the invention, the amount of cioroni administered may be from 1mg to 500mg per day, for example from 1mg to 100mg per day, preferably from 5mg to 80mg per day, from 5mg to 70mg per day, from 5mg to 60mg per day or from 5mg to 50mg per day, more preferably the daily amount may be, for example, 1mg, 2mg, 3mg, 4mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg or 50mg per day. The specific application dosage can be adjusted according to the actual condition of a patient, a treatment scheme and the condition of combination with other medicaments.

In the therapeutic applications of the present invention, seironi may be administered to a subject in the form of any suitable pharmaceutical composition. The pharmaceutical composition may be in a dosage form such as oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes), for example capsules, tablets, granules, powders, syrups, emulsions, microemulsions, solutions or suspensions.

In the combination therapeutic application of the present invention, seironi may be administered separately, simultaneously or sequentially with an additional therapeutic agent to the subject to be treated; the seironi may be present in the same pharmaceutical composition as the additional therapeutic agent or administered separately in the form of a different pharmaceutical composition (or kit). The use of the seolony provided by the present invention is further explained below.