阅读说明：本技术 多激酶抑制剂及其在***增生和泌尿道疾病中的用途 (Multikinase inhibitors and their use in prostate hyperplasia and urinary tract disorders ) 是由 汤丹霞 刘道芬 杰拉尔德·伍德罗·德弗里斯 于 2017-12-30 设计创作，主要内容包括：一种用于预防、治疗和/或改善与上皮增生和/或纤维化相关的前列腺疾病或失调的方法,所述方法包括：向有此需要的受试者施用有效量的多激酶抑制剂,其中所述多激酶抑制剂具有一定范围的激酶抑制活性。所述多激酶抑制剂是舒尼替尼、瑞格非尼、普纳替尼、帕唑帕尼、尼达尼布和/或乐伐替尼。所述前列腺疾病或失调选自由以下项组成的组：动物和人类中的良性前列腺增生及其相关的下泌尿道症状,输尿管和肾盂的纤维化、前列腺腺瘤和前列腺上皮内瘤。(A method for preventing, treating and/or ameliorating a prostate disease or disorder associated with epithelial hyperplasia and/or fibrosis, the method comprising: administering to a subject in need thereof an effective amount of a multi-kinase inhibitor, wherein the multi-kinase inhibitor has a range of kinase inhibitory activities. The multi-kinase inhibitor is sunitinib, regorafenib, ponatinib, pazopanib, nintedanib, and/or lenvatinib. The prostate disease or disorder is selected from the group consisting of: benign prostatic hyperplasia and its associated lower urinary tract symptoms in animals and humans, fibrosis of the ureters and renal pelvis, prostatic adenomas and prostatic intraepithelial neoplasia.)

1. A method for preventing, treating and/or ameliorating a prostate disease or disorder associated with epithelial hyperplasia and/or fibrosis, the method comprising: administering to a subject in need thereof an effective amount of a multi-kinase inhibitor, wherein the multi-kinase inhibitor has a range of kinase inhibitory activities.

2. The method of claim 1, wherein the multi-kinase inhibitor is sunitinib, regorafenib, ponatinib, pazopanib, nintedanib, and/or lenvatinib.

3. The method of claim 1, wherein the multi-kinase inhibitor is sunitinib, regorafenib, nintedanib, and lenvatinib.

4. The method of claim 1, wherein the multi-kinase inhibitor is nintedanib and lenvatinib.

5. The method of claim 1, wherein the multi-kinase inhibitor is nintedanib.

6. The method of claim 1, wherein the multi-kinase inhibitor is lenvatinib.

7. The method of claim 1, wherein the prostate disease or disorder is selected from the group consisting of: benign prostatic hyperplasia and its associated lower urinary tract symptoms in animals and humans, fibrosis of the ureters and renal pelvis, prostatic adenomas and prostatic intraepithelial neoplasia.

8. The method of claim 1, wherein the prostate disease or disorder is Benign Prostatic Hyperplasia (BPH) and its associated lower urinary tract symptoms.

9. The method of any one of claims 1-8, wherein the administration of the drug is by parenteral, intramuscular, intradermal, subcutaneous, topical, intraperitoneal, intralesional, perilesional, intraprostatic, periprostaglandular, rectal, and transurethral routes.

Technical Field

The present invention relates to compounds having a range of multi-kinase inhibitory activities which act on specific growth factor and/or cytokine signal transduction pathways and/or response stages in urinary tract diseases.

Background

Benign Prostatic Hyperplasia (BPH) and its associated Lower Urinary Tract Symptoms (LUTS) are common in elderly men. Histopathologically, BPH is characterized by an increased number of epithelial and stromal cells in the periurethral part of the prostate. This is manifested by the appearance of microscopic nodules that progressively proliferate and enlarge to increase the mass of glandular and stromal prostate tissue.

Testosterone has been proposed to be involved in the progression of BPH. In the prostate, the nuclear membrane-bound enzyme 5 α -reductase converts the hormone testosterone into Dihydrotestosterone (DHT). DHT is important in causing hyperplasia, which is supported by clinical observations that inhibition of 5 α -reductase can reduce DHT levels in the prostate by as much as 85% -90%, and in turn reduce prostate volume and reduce BPH symptoms. 5 α -reductase inhibitors, such as finasteride and dutasteride, have been used globally for the treatment of BPH.

The proliferation of stromal cells in BPH is the major cause of the disease progression. Effective smooth muscle tone is regulated by the adrenergic nervous system. Stimulation of the alpha 1-adrenergic receptor mediates effective tension of the prostate smooth muscle and results in increased prostatic urethral resistance. Alpha 1-adrenoceptor antagonists, such as tamsulosin (tamsulosin) and alfuzosin (alfuzosin), can alleviate the urethral blockage associated with BPH.

The use of 5 α -reductase inhibitors is slow acting and associated with sexual side effects. Alpha 1-adrenoceptor antagonists are more potent and rapid acting, but can produce vasodilator side effects. In addition, these drug therapies are effective primarily in the mild to moderate stages of the disease. There is clearly a need for improved drug therapy for benign prostatic hyperplasia and lower urinary tract symptoms.

Prostate cancer is mostly a very slowly progressing disease and starts in glandular cells. Prostate cancer begins with small changes in the shape and size of prostate gland cells-Prostatic Intraepithelial Neoplasia (PIN). Nearly 50% of all 50-year-old men have PIN. Any patient found to have a high grade of PIN after prostate tissue biopsy is at significantly greater risk of having cancer cells in their prostate.

Many growth factors and cytokines are involved in the progression of BPH and/or PIN. It is believed that members of the FGF, IGF and TGF families contribute particularly to the progression of BPH. Staining of VEGF, VEGFR-1, VEGFR-2, and CD 105 positive microvessels in human BPH tissues was reported. This suggests a powerful role for VEGF in the pathological process of BPH.

These data indicate that modulation of growth factor and cytokine signal transduction pathways through the use of multi-kinase receptor inhibitors would be a novel strategy for preventing and/or treating proliferative and fibrotic disorders of the prostate and urinary tract and their associated symptoms.

Summary of The Invention

Some embodiments of the invention provide agents having a range (spectrum) of multi-kinase inhibitor activity and useful for treating a prostate disease or disorder associated with epithelial hyperplasia and/or fibrosis, comprising: administering an effective amount of a multi-kinase inhibitor to an animal or human. Some embodiments of the invention also relate to the therapeutic or prophylactic use of such compounds and compositions, and methods for treating prostate diseases or disorders associated with epithelial hyperplasia and/or fibrosis.

In one aspect, the invention provides agents having a range of multi-kinase inhibitor activities and accordingly useful in methods of treating disease states and/or disorders associated with benign prostatic hyperplasia or lower urinary tract symptoms in humans. More particularly, the invention also relates to the therapeutic or prophylactic use of such compounds and compositions, as well as methods of treating disease states and/or disorders associated with benign prostatic hyperplasia and its associated lower urinary tract symptoms, fibrosis of the ureters and renal pelvis, prostatic adenoma, and prostatic intraepithelial neoplasia.

In one aspect, the present invention provides a method of treating/preventing benign prostatic hyperplasia and its associated lower urinary tract symptoms by administering to a human subject in need of such treatment or prevention a therapeutically effective amount of a multi-kinase inhibitor, wherein the multi-kinase inhibitor may include, but is not limited to, sunitinib (sunitinib), regorafenib (regorafenib), ponatinib (ponatinib), pazopanib (pazopanib), nintedanib (nintedanib), and lenvatinib (lenvatinib). The prostate disease or disorder is selected from the group consisting of: benign prostatic hyperplasia and its associated lower urinary tract symptoms in animals and humans, fibrosis of the ureters and renal pelvis, prostatic adenomas and prostatic intraepithelial neoplasia.

Drawings

Figure 1 shows a microscopic image of glandular hyperplasia in the dorsolateral prostate of a rat at 100-fold magnification. Panel (a) is a vehicle-treated sample showing normal (score ═ 0) gland contours. Panel (B) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with vehicle, showing significant (score of 4) epithelial hyperplasia. Panel (C) is TE and PE induced and nintedanib treated samples showing moderate (score of 3) epithelial hyperplasia. Panel (D) is TE and PE induced and sunitinib treated samples showing moderate (score of 3) epithelial hyperplasia. Panel (E) is TE and PE induced and lenvatinib treated samples showing slight (score of 2) epithelial hyperplasia. Panel (F) is TE and PE induced and doxazosin (doxazosin) treated sample showing moderate (score of 3) epithelial hyperplasia.

Figure 2 shows a representative image from the ventral prostate at 100 x magnification. Panel (a) is a vehicle-treated sample showing normal (score ═ 0) gland contours. Panel (B) is TE) and PE induced and vehicle treated samples showing significant (score 4) epithelial hyperplasia. Panel (C) is TE and PE induced and nintedanib treated samples showing moderate (score of 3) epithelial hyperplasia. Panel (D) is TE and PE induced and sunitinib treated samples showing moderate (score of 3) epithelial hyperplasia. Panel (E) is TE and PE induced and lenvatinib treated samples showing slight (score of 3) epithelial hyperplasia. Panel (F) is TE and PE induced and doxazosin treated samples showing moderate (score of 3) epithelial hyperplasia.

Figure 3 shows mean scores for glandular hyperplasia of the dorsolateral prostate for the experiment described in figure 1.

Figure 4 shows mean scores for glandular hyperplasia of the ventral prostate for the experiment described in figure 2.

Fig. 5 shows the prostate weight/100 g body weight for each treatment group.

Figure 6 shows a representative image from the dorsolateral prostate at 100 x magnification. Panel (1) is an image of group 5 (vehicle) rats showing normal (score ═ 0) gland contours. Panel (2) is an image of group 1 (TE + PE-induced and vehicle-treated) rats showing slight (score-2) epithelial hyperplasia. Panel (3) is an image of group 3 (TE + PE-induced and 1% sorafenib-treated) rats showing slight (score ═ 2) epithelial hyperplasia. Panel (4) is an image of group 4 (TE + PE-induced and 2.5% pirfenidone (pirfenidone)) rats, showing minimal (score ═ 1) epithelial hyperplasia. Panel (5) is an image of group 6 (TE-induced) rats showing slight (score 2) epithelial hyperplasia. Panel (6) group 7 (TE-induced and 1% riociguat (riociguat) treated) rats showed minimal (score ═ 1) epithelial hyperplasia.

Figure 7 shows the mean epithelial proliferation score in the rat BPH model for the experiment described in figure 6.

Figure 8 shows the histological findings in the corneal suture fibrosis model described in example 4.

Figure 9 shows the reduction of neovascularisation in the rat choroidal angiogenesis model described in example 5.

Detailed Description

Some embodiments of the invention relate to the prevention and/or treatment of diseases or disorders associated with benign prostatic hyperplasia and its associated lower urinary tract symptoms, fibrosis of the ureters and renal pelvis, prostatic adenomas and prostatic intraepithelial neoplasia in animals and humans. According to some embodiments of the invention, a method for treating benign prostatic hyperplasia or its associated lower urinary tract symptoms may involve: administering to a subject in need of such treatment a composition comprising a multi-kinase inhibitor having a selected range of activity inhibiting a selected kinase (e.g., VEGF and TGF β).

The compositions of the invention may comprise a multi-kinase inhibitor or a pharmaceutically acceptable salt thereof. As used herein, the term "multi-kinase inhibitor" refers to an inhibitor that inhibits multiple kinases. As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali metal or organic salts of acidic residues (e.g., carboxylic acids); and so on. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound/molecule formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts may include those derived from inorganic acids (e.g., hydrochloric acid).

According to some embodiments, the invention also includes pharmaceutical compositions containing one or more of the compounds/molecules of the invention herein as an active ingredient, together with at least one pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, the compounds/molecules of the present invention may be administered by parenteral, intramuscular, intradermal, subcutaneous, topical (topical), intraperitoneal, intralesional, perilesional, intraprostatic, periprostatic, rectal and transurethral routes.

The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician in determining the individual regimen and dosage level best suited for a particular patient. That is, a therapeutically effective amount will be based on the patient (age, weight, etc.), disease condition, route of administration, and the like. One skilled in the art will be able to determine a therapeutically effective amount without the need for inventive work.

According to some embodiments of the invention, the administration protocol may be administered before (induction) surgery, after surgery (trauma/acute inflammation, proliferation, remodeling, to maturity or before).

According to some embodiments of the invention, for the preparation of pharmaceutical compositions from the compounds/molecules of the invention, the inert pharmaceutically acceptable carrier may be a solid or a liquid.

The term composition is intended to include a formulation of the active ingredient or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. For example, the present invention may be formulated by means known in the art into forms such as aqueous or oily solutions, suspensions, emulsions, creams (creams), ointments (ointments), gels, and sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral use.

Liquid form compositions include solutions, suspensions, and emulsions. Sterile aqueous or water-propylene glycol solutions of the active compounds/molecules may be mentioned as examples of liquid preparations suitable for parenteral administration. Liquid compositions may also be formulated as solutions in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration may be prepared by: the active ingredient is dissolved in water and suitable colorants, flavors, stabilizers, and thickeners are added as desired. Aqueous suspensions for oral use may be prepared by: the finely divided active ingredient is dispersed in water together with viscous materials such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical formulation art.

The pharmaceutical composition may be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation.

The compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for rectal, topical or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

For solid compositions, conventional non-toxic solid carriers can be used including, for example, pharmaceutical grades of mannitol, lactose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can be prepared, for example, by: the active compounds/molecules and optional pharmaceutical adjuvants, as defined above, are dissolved, dispersed, etc. in a carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form a solution or suspension. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like. The actual methods of making such dosage forms are known or will be apparent to those skilled in the art.

Embodiments of the present invention will be illustrated by the following examples. It will be understood by those skilled in the art that these examples are for illustration only and that other modifications and variations may be made without departing from the scope of the invention.

Example 1

Despite morphological and anatomical differences between human and rodent prostates, there are many similarities in their pharmacology and histochemistry, making the study of BPH in rats a useful study. The prostate in both humans and rats is innervated by a fine network of surrounding glandular elements. Most of these neural structures are catecholaminergic and contain different subtypes of adrenergic receptors.

The effect of phenylephrine administration on rat prostate has been examined due to the potential effect of adrenergic innervation on prostate cell growth. Phenylephrine induces irregular tracts with intraluminal projections (intraluminal projections) at a dose of 1mg/kg per day. The epithelium becomes thicker and even has a focal "pile-up" of cells. The matrix in turn exhibits hypertrophy and hyperplasia of fibroblasts and smooth muscle cells. These changes correspond to the presence of benign prostatic hyperplasia in humans. Furthermore, phenylephrine has a dual role in the progression of PIN lesions, affecting both epithelial and stromal components of the prostate in rats.

BPH is a real proliferative process. Histological studies demonstrated an increase in cell number. Therefore, studies were conducted to determine the effect of test compounds and vehicles on Testosterone (TE) and Phenylephrine (PE) induced benign prostatic hyperplasia in rats. Male Wistar rats were induced on days 5 to 32 by daily administration of testosterone (2mg/kg) plus phenylephrine (5mg/kg) by subcutaneous injection. Vehicle or test compounds (both 1% w/w) nintedanib, sunitinib, lenvatinib and 0.5% doxazosin mesylate were administered by intraprostatic injection (0.4ml) on day 1 and day 18 in the dorsolateral and ventral lobes. Animals were euthanized on day 32. Body weight was measured and prostate was harvested. The experimental design is listed in Table 1

Table 1: summary of research design

^*All animals received Testosterone (TE) and Phenylephrine (PE) except group 1.

At necropsy, the ventral and dorsolateral lobes of the prostate were separated and then cut in half. The left half was fixed in 10% neutral buffered formalin, sectioned, and stained with hematoxylin and eosin (H & E). Histological changes in these sections were scored. Epithelial hyperplasia is believed to be an increase in epithelial cells within the normally occurring glandular contour, reflected primarily by the stratification of epithelial cells and the increased presence of epithelial clustering and papillae. A severity grade of 0 (absent) to 5 (severe) was assigned to each sample. Representative images are presented in fig. 1 and 2. The mean scores (+/-SD) are shown in fig. 3 and 4.

Figure 1 shows a representative image from the dorsolateral prostate at 100 x magnification. Panel (a) is a vehicle-treated sample showing normal (score ═ 0) gland contours. Panel (B) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with vehicle, showing significant (score of 4) epithelial hyperplasia. Panel (C) is a Testosterone (TE) and Phenylephrine (PE) induced and nintedanib treated sample showing moderate (score of 3) epithelial hyperplasia. Panel (D) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with sunitinib, showing moderate (score of 3) epithelial hyperplasia. Panel (E) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with lenvatinib, showing slight (score of 2) epithelial hyperplasia. Panel (F) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with doxazosin, showing moderate (score of 3) epithelial hyperplasia.

Figure 2 shows a representative image from the ventral prostate at 100 x magnification. Panel (a) is a vehicle-treated sample showing normal (score ═ 0) gland contours. Panel (B) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with vehicle, showing significant (score of 4) epithelial hyperplasia. Panel (C) is a Testosterone (TE) and Phenylephrine (PE) induced and nintedanib treated sample showing moderate (score of 3) epithelial hyperplasia. Panel (D) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with sunitinib, showing moderate (score of 3) epithelial hyperplasia. Panel (E) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with lenvatinib, showing slight (score of 3) epithelial hyperplasia. Panel (F) is a sample induced with Testosterone (TE) and Phenylephrine (PE) and treated with doxazosin, showing moderate (score of 3) epithelial hyperplasia.

The results of the study indicated histological changes in TE and PE induced hyperplasia of glands in rats, which was observed in human prostate hyperplasia and adenoma, i.e. hyperplasia of glands forming papillary structures towards the lumen. The test compounds nintedanib, sunitinib, lenvatinib and doxazosin were shown to reduce glandular hyperplasia compared to untreated TE/PE-induced prostate (fig. 1B and fig. 2B). Nintedanib, sunitinib, lenvatinib and doxazosin inhibit benign prostatic hyperplasia in this model, suggesting that these compounds are effective in treating Benign Prostatic Hyperplasia (BPH) and proliferative and fibrotic disorders of the urogenital tract.