HK1166795B - Use of a kinase inhibitor for the treatment of thymoma - Google Patents

Description

Use of kinase inhibitors for the treatment of thymoma

Technical Field

The present invention relates to the treatment of patients with thymoma and thymus cancer by using low molecular weight inhibitors of ATP-competitive CDK (cyclin dependent kinase) and tropomyosin-related kinase a (trka).

Background

Thymoma is a rare tumor, but is the most common tumor of the anterior mediastinal cavity. The overall incidence of malignant thymoma in the united states (1973-1998) was 0.15 per 100000 persons/year (849 cases) [ original data: "Malignant Thymoma in the United States: demographics patterns in incidences and associations with subsequentllignances "int.j. cancer, 2003; 105(4): 546-51]. Thymomas are thought to grow painlessly, but have the potential for local infiltration, pleural dissemination and distant metastasis. Patients with locally advanced or disseminated thymomas are often symptomatic of chest pain, shortness of breath, phrenic nerve paralysis, pleural effusion, and superior vena cava syndrome. Immunological disorders have been linked to thymomas, the most common being myasthenia gravis (Wright c. management of thymoma. crit. rev. oncol. hematol., 2008; 65 (2): 109-20). Thymus gland cancer is usually diagnosed in an advanced stage, with higher recurrence and poorer prognosis (survival) compared to other thymomas (NCI PDQ [ Physician Data Query)]Finally revised at 05/08/2008).

TRKA appears to play an important role in the biology of thymoma. In fact, the expression of neurotrophin (neurotrophin) receptors was unequivocally documented in a considerable series of patients (99 patients) thymic epithelial tumors (Kim DJ, Yang WI, Kim SH, Park IK, Chung KY. expression of neurotrophin receptors in therapeutically expressed thymic epithelial tumors, Eur. J. cardio. Surg., 2005; 28 (4): 611-6). In this study, the pattern of TRKA expression was analyzed according to the WHO classification for histological subtypes of thymoma. It was found that all tumor types (i.e. a, AB, B1, B2, B3, C) showed (by immunostaining) the presence of TRKA and the tumor rate indicating a strong immunoreactivity that was progressively increased from type a to type C. In contrast, any type of thymoma showed immunoreactivity with either TRKB or TRKC, suggesting that TRKA plays a specific role in this disease (yet to be further elucidated in any event).

In addition to the aforementioned WHO histological classification of thymomas, the Masaoka staging system (Masaoka staging system) is often employed to assess infiltration and as a basis for therapeutic selection, since the optimal treatment of this disease depends on its clinical stage (NCI PDQ [ Physician Data Query ]]Finally revised at 05/08/2008). Surgery (with or without radiation therapy) is the primary method of early thymus tumor treatment because in most cases the disease is localized. Radiotherapy and chemotherapy are widely used as adjuvant and palliative approaches in general (Kondo k. optimal therapy for thymoma. j. med. invest., 2008; 55 (1-2): 17-28). Advanced invasive thymomas (such as large vessel infiltration, pleural and/or pericardial spread, lymph node involvement, or distant metastatic tumors) are often not controlled by surgical resection or radiation therapy alone (Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, et al. Locally advanced or metastatic thymomas are commonly treated with a combination of therapies including radiation therapy and chemotherapy. Thymomas are generally chemically sensitive tumors. Chemotherapy actually shows significant antitumor activity against unresectable, recurrent or metastatic thymomas, producing an overall objective response in an average of two-thirds of patients (over objective responses) and complete remissions in one-third of patients (complete remissions). Combination chemotherapy based on cisplatin/doxorubicin [ PAC regimen (cisplatin, doxorubicin, cyclophosphamide) or ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide)]It appears that the best overall response rate and survival rate are produced. Other combinations of cisplatin, etoposide, ifosfamide, epirubicin, maytansine and steroids are also usedAnd/or single agent chemotherapy (Kondo k, 2008, see above). In any event, optimal treatment strategies have not been determined and other drugs are needed to improve outcomes in patients with advanced invasive tumors (Yokoi K, 2007).

Thus, there is an unmet medical need for new effective agents for the treatment of thymoma and, in particular, thymus cancer. The present invention solves this problem.

Disclosure of Invention

The present invention provides a low molecular weight compound which is capable of inhibiting CDKs (particularly CDK2/cyclin a complex) and TRKA signalling channels and which is effective in inhibiting the proliferation of thymoma and particularly thymoma.

The compound of the invention that exhibits the desired activity is a pyrazoloquinazoline designed to target the ATP pocket (pocket) of the protein kinase. The compounds have been shown to be potent ATP-competitive inhibitors of CDKs. It has been found that the compounds also show significant inhibitory potency against TRKA.

In terms of their biological activity, the compounds of the invention open a new avenue for the therapeutic development of patient populations suffering from thymoma and thymus cancer.

In fact, in the phase I study, two thymus cancer patients reported objective tumor responses.

Detailed description of the invention

In a first aspect, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating thymoma.

As used herein, the term "thymoma" includes the 6 histological classifications (types A, AB, B1, B2, B3, C) identified by the 1999 WHO classification (Rosa J, sonic L.structural typing of tumors of the thymus. world Health Organization. International pathological typing of tumors. Heidelberg. Springer-Verlag, 1999), and thus also includes the "thymoma" and the "thymoma" histological classification according to the latest WHO classification (2004) in which the subtype of thymoma B3 is also classified as a differentiated type of thymus cancer and the thymoma C is classified as a thymus cancer (Travis W et al, eds. Pathology and genetics of tumors of the thymus, world Health, and Organization).

In a preferred embodiment, the compounds of formula (I) above are used in a method of treating thymus cancer.

The compound of formula (I) is chemically 8- [4- (4-methyl-piperazin-1-yl) -phenylamino ] -1, 4, 4-trimethyl-4, 5-dihydro-1H-pyrazolo [4, 3-H ] quinazoline-3-carboxylic acid carboxamide. It can be prepared as described in WO2004104007, has protein kinase inhibitory activity and is therefore suitable in therapy as an antitumor agent. In particular, a preferred process for the preparation of the compound of formula (I) is described in example 58 of the above mentioned international patent application.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic or organic acids such as nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, isethionic and salicylic acid and the like.

Within the scope of the invention claimed are the use of all possible isomers of the compounds of formula (I) and their mixtures, as well as the use of metabolites and pharmaceutically acceptable biological precursors (otherwise known as prodrugs) of the compounds of formula (I). A prodrug is any covalently bonded compound that releases the active parent drug according to formula (I) in vivo.

Once it is determined that the disease or undesirable condition from which the subject is suffering will benefit from treatment with the compound, a therapeutically effective amount of the compound of formula (I) may be administered to the subject. As part of the diagnosis of a disease or condition in a subject, a medical or clinical person may make this determination. The compounds may also be used in the prevention of such conditions, which may be considered as reducing the likelihood of a subject suffering from one or more conditions.

As used herein, a "therapeutically effective amount" of a compound means an amount sufficient to achieve its intended purpose. Determination of an effective amount is well within the ability of those skilled in the art to achieve the desired effect. An effective amount will depend on factors including, but not limited to, the size of the subject and/or the extent of progression of the disease or undesirable condition from which the subject is suffering. The effective amount will also depend on whether the compound is administered to the subject in a single dose or periodically over time.

The compounds of formula (I) according to the invention are intended for use in the treatment of a subject. As used herein, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian species: human, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like.

The term "treating" as used herein includes achieving a therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the associated disorder being treated. For example, in a cancer patient, therapeutic benefit includes eradication or amelioration of the associated cancer. In addition, therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient despite the fact that the patient may still be suffering from the underlying disorder.

Another object of the present invention is a therapeutic composition for use in a method of treating thymoma comprising (a) a compound of formula (I) as defined above and (b) one or more cytotoxic or cytostatic chemical agents. Preferably, the thymoma is thymus carcinoma.

Exemplary cytostatic or cytotoxic chemical agents include alkylating agents (nitrogen mustards such as cyclophosphamide and ifosfamide), alkylating-like agents (i.e., platinum derivatives such as cisplatin or carboplatin), topoisomerase II inhibitors [ e.g., anthracyclines (such as doxorubicin and epirubicin) and podophyllotoxins (such as etoposide) ], antimicrotubule agents (such as taxanes, vincristine and maytansine), steroids, hormonal agents, immunological agents, interferon-type agents (interferon-type agents), cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors (telomeasarinhibitors), tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (e.g., anti-angiogenic inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cyclin-dependent kinase inhibitors (cdks inhibitors), tubulin binding agents, topoisomerase I inhibitors, and the like.

The invention also relates to a pharmaceutical composition for use in a method of treating thymoma, preferably thymus cancer, comprising a compound of formula (I) as defined above, in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

In another embodiment, the pharmaceutical composition according to the invention further comprises one or more cytotoxic or cytostatic chemical agents.

Pharmaceutical compositions comprising the compounds of the invention are generally prepared by conventional methods and administered in suitable pharmaceutical forms.

For example, a solid oral form may comprise, together with the active compound: diluents, such as lactose, glucose, sucrose (saccharose), sucrose (sucrose), cellulose, corn starch or potato starch; lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycol; binders, such as starch slurry, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrants, for example starch, alginic acid, alginates or sodium carboxymethyl starch; an effervescent mixture; a colorant; a sweetener; wetting agents such as lecithin, polysorbates, lauryl sulfate; and non-toxic and pharmacologically inactive substances commonly used in pharmaceutical preparations. Such pharmaceutical preparations may be manufactured by known methods, e.g. by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.

Liquid dispersions for oral administration may be, for example, syrups, emulsions or suspensions.

For example, the syrup may contain a carrier which is sucrose, or sucrose containing glycerol, or mannitol and/or sorbitol containing glycerol.

The suspension and the emulsion may contain natural gums, agar, sodium alginate, pectin, methylcellulose, hydroxymethylcellulose or polyvinyl alcohol as examples of the carrier.

In therapeutic use, the compound of formula (I) is administered at about 10mg/m per day²To about 400mg/m²The body surface area dose level is administered to the subject. About 20mg/m²To 200mg/m²The dosage level of (a) constitutes a particularly suitable range. A dose of about 20mg to about 800mg per dose, more preferably about 40mg to about 400mg per dose, for 1 to 28 consecutive days may be used as a non-limiting example of an adult human subject. A preferred treatment schedule comprises: in a 4-week cycle, treatment was continued for 3 weeks at a dose of 150 mg/day for 4 days followed by rest for 3 days. Alternatively, the following treatment schedules are also suitable: treatment at a dose of 150 mg/day for 7 days, followed by rest for 7 days, in a 2-week cycle; or in a 3 week period at 48-72mg/m²Day (corresponding to about 8)0-120 mg/day) for 14 days, followed by rest for 7 days. The above treatment schedule is intended to be repeated periodically until medically indicated.

Lower or higher doses than those disclosed herein may be used as desired. However, such dosages may be varied depending upon a number of variables, not limited to the activity of the compound employed, the condition being treated, the mode of administration, the treatment regimen, the individual subject's needs, the severity of the condition being treated, and the judgment of the practitioner. The foregoing ranges are indicative only, the numbers as variables are enormous for individual treatment regimens, and significant deviations from these recommended values are not uncommon.

In order to better illustrate the invention without imposing any limitation, the following examples are now given.

Examples

Example 1 Scintillation Proximity Assay (SPA) format for kinases

This test enables the measurement of the inhibition of the kinase activity of specific enzymes obtained with the test compounds. Different kinases can be tested in parallel.

In the presence of ATP containing a gamma 33-ATP tracer, biotinylated substrates are transphosphorylated by specific kinases. The reaction was terminated and the phosphorylated substrate was then collected using Streptavidin-coated SPA beads (Streptavidin-coated SPA beads). A concentrated solution of 5M CsCl was added and the mixture was incubated for 4 hours. This floated the SPA particles on top of the CsCl solution containing unbound radiolabeled ATP.

The degree of phosphorylation was determined using a beta counter. In these tests, the compounds of formula (I) showed potent inhibitory activity on the CDK2/Cyclin A complex (IC)₅₀45nM), also showed a strong correlation to the closely related CDKs, CDK1. Activity of CDK4 and CDK5 (IC, respectively)₅₀398, 160 and 265nM) and also exhibits activity (IC) against the tropomyosin-related kinase a (trka)₅₀＝53nM)。

Example 2 Objective tumor response in Thymus gland cancer patients

Objective tumor responses were obtained in one 24 year old female patient who was first diagnosed with thymus cancer at 5 months 2002 and had third disease progression to metastasis to the lung at 7 months 2007, entering phase I clinical trial at 9 months 2007. Treatment with a compound of formula (I) is administered at a daily dose of 150mg following a treatment schedule comprising: in a 4-week cycle, 3 weeks of treatment followed by 3 days of rest. After 10 weeks of treatment, patients showed partial tumor responses (PR) as a 31.2% reduction in the total number of target lesions (target lesions) from baseline, according to the solid tumor RECIST criteria (therase P, arc S, Eisenhauer EA, wandersJ, Kaplan RS, Rubinstein L, et al, New peptides to viral therapy to treatment in solid tumors.J.Natl.cancer Instrument, 2000; 92 (3): 205-); the PR was confirmed after 1 month and recorded to 13 cycles, which is a 37.6% reduction in the total number of target lesions from baseline. Prior to treatment in the clinical trial, the patient received additional treatment for his thymus cancer as follows: from month 1 2005 to month 6 2005: doxorubicin(Adriamycin) Cyclophosphamide, cyclophosphamide(Cytoxan) Cisplatin; from 2 months 2006 to 5 months 2006: ifosfamide; from month 10 2006 to month 6 2007:tibet extract(Taxol) Carboplatin; from 6 months 2007 to 7 months 2007: doxorubicinCyclophosphamideVincristine. The patient was also surgically operated in 5 months 2002 and radiation treated in 7 months 2002 and 7 months 2006.

Example 3 Objective tumor response in a second thymus cancer patient

Another objective tumor response was obtained in a 62 year old male patient who was first diagnosed with thymus cancer at 2006-5 months and became metastatic to the lungs, bones and peritoneum at 2007-10 months. The patient was treated in the phase I clinical trial beginning at 12 months 2008. Treatment with a compound of formula (I) is administered at a daily dose of 150mg following a treatment schedule comprising: in a 4-week cycle, 3 weeks of treatment followed by 3 days of rest. After 6 cycles of treatment, patients showed a partial tumor response (PR) of 30% reduction in the total number of target lesions compared to baseline and stable non-target lesions, according to RECIST criteria; the PR was confirmed after 1 month as a 40% reduction in the total number of target lesions over baseline and stable non-target lesions. Prior to clinical trial treatment, the patient received first-line chemotherapy (cisplatin/gemcitabine) between 11 months 2007 and 3 months 2008; he had performed surgery at 5 months 2006 and radiation treatment at 9 months 2006.

Claims (7)

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of thymoma

2. The use of claim 1, wherein the thymoma is thymus carcinoma.

3. Use of a therapeutic combination comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more cytotoxic or cytostatic chemical agents in the manufacture of a medicament for the treatment of thymoma

4. The use of claim 3, wherein the thymoma is thymus carcinoma.

5. Use of a pharmaceutical composition comprising a compound of formula (I) in admixture with a pharmaceutically acceptable carrier, diluent or excipient for the manufacture of a medicament for the treatment of thymoma

6. The use of claim 5, wherein the medicament further comprises one or more cytotoxic or cytostatic chemical agents.

7. The use of any one of claims 5 or 6, wherein the thymoma is a thymus carcinoma.