阅读说明：本技术 用于治疗乳腺癌和***癌的组合物 (Composition for treating breast and prostate cancer ) 是由 E·巴斯金-贝 J·艾斯内尔 E·伍德森 于 2018-12-06 设计创作，主要内容包括：本发明描述了包含赛维罗奈和/或地塞米松的药物组合物和给药方案,以及治疗疾病、障碍或其症状的方法。(Pharmaceutical compositions and dosing regimens comprising sevelamer and/or dexamethasone are described, as well as methods of treating diseases, disorders, or symptoms thereof.)

1. A pharmaceutical composition comprising a) sevelamer or a salt thereof; b) dexamethasone or a salt thereof; and c) a pharmaceutically acceptable carrier.

2. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 150mg to 750 mg.

3. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 400mg to 650 mg.

4. The composition of claim 1, wherein the amount of sevelamer in the composition is 600 mg.

5. The composition of claim 1, wherein the amount of sevelamer in the composition is 450 mg.

6. The composition of claim 1, wherein the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg.

7. The composition of claim 1, wherein the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg.

8. The composition of claim 1, wherein the amount of dexamethasone in the composition is 0.5 mg.

9. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 150mg to 750mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg.

10. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 150mg to 750mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg.

11. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg.

12. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg.

13. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg.

14. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg.

15. The composition of claim 1, wherein the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg.

16. The composition of claim 1, wherein the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg.

17. The composition of claim 1, wherein the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg.

18. The composition of claim 1, wherein the amount of sevelamer in the composition is 600mg and the amount of dexamethasone in the composition is 0.5 mg.

19. The composition of claim 1, wherein the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg.

20. The composition of claim 1, wherein the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg.

21. The composition of claim 1, wherein the amount of sevelamer in the composition is 450mg and the amount of dexamethasone in the composition is 0.5 mg.

22. A dosing regimen for treating prostate or breast cancer comprising sevelamer or a salt thereof, and dexamethasone or a salt thereof.

23. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 150mg-750 mg.

24. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 400mg-650 mg.

25. The dosing regimen of claim 22, wherein the amount of sevelamer is 600 mg.

26. The dosing regimen of claim 22, wherein the amount of sevelamer is 450 mg.

27. The dosing regimen of claim 22, wherein the amount of dexamethasone is in the range of about 0.25mg to 1000 mg.

28. The dosing regimen of claim 22, wherein the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg.

29. The dosing regimen of claim 22, wherein the amount of dexamethasone is 0.5 mg.

30. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 150mg to 750mg and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg.

31. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 150mg to 750mg and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg.

32. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 400mg-650mg and dexamethasone is 0.5 mg.

33. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 400mg-650mg and the amount of dexamethasone is in the range of about 0.25mg-1000 mg.

34. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 400mg-650mg and the amount of dexamethasone is in the range of about 0.40mg-0.60 mg.

35. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 400mg-650mg and dexamethasone is 0.5 mg.

36. The dosing regimen of claim 22, wherein the amount of sevelamer is in the range of about 400mg-650mg and dexamethasone is 0.5 mg.

37. The dosing regimen of claim 22, wherein the amount of sevelamer is 600mg and the amount of dexamethasone is in the range of about 0.25mg-1000 mg.

38. The dosing regimen of claim 22, wherein the amount of sevelamer is 600mg and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg.

39. The dosing regimen of claim 22, wherein the amount of sevelamer is 600mg and the amount of dexamethasone is 0.5 mg.

40. The dosing regimen of claim 22, wherein the amount of sevelamer is 450mg and the amount of dexamethasone is in the range of about 0.25mg-1000 mg.

41. The dosing regimen of claim 22, wherein the amount of sevelamer is 450mg and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg.

42. The dosing regimen of claim 22, wherein the amount of sevelamer is 450mg and the amount of dexamethasone is 0.5 mg.

43. The dosing regimen of claim 22, wherein sevelamer and dexamethasone are administered simultaneously.

44. The dosing regimen of claim 22, wherein the sevelamer and dexamethasone are administered sequentially.

45. A method of treating breast or prostate cancer in an individual, the method comprising administering to an individual in need thereof a pharmaceutical composition of any one of claims 1-21 or a dosing regimen of any one of claims 22-42.

46. A method of treating an individual suffering from or susceptible to breast or prostate cancer, the method comprising administering to the individual a pharmaceutical composition as claimed in any one of claims 1 to 21 or a dosing regimen as claimed in any one of claims 22 to 42.

47. A method of treating breast or prostate cancer in an individual, the method comprising administering to an individual in need thereof a pharmaceutical composition of any one of claims 1-21 or a dosage regimen of any one of claims 22-42, such that the number and/or severity of adverse events is lower than when the pharmaceutical composition or dosage regimen does not comprise dexamethasone.

48. A method of treating an individual suffering from or susceptible to breast or prostate cancer, the method comprising administering to the individual a pharmaceutical composition of any one of claims 1 to 21 or a dosage regimen of any one of claims 22 to 42, such that the number and/or severity of adverse events is lower than when the pharmaceutical composition or dosage regimen does not comprise dexamethasone.

49. A method of treating breast or prostate cancer in an individual, the method comprising administering to an individual in need thereof the pharmaceutical composition of any one of claims 1-21 or the dosage regimen of any one of claims 22-42, such that the time to progressive disease is increased relative to the time without administration of the pharmaceutical composition or dosage regimen.

50. A method of treating an individual suffering from or susceptible to breast or prostate cancer, the method comprising administering to the individual a pharmaceutical composition of any one of claims 1-21 or a dosing regimen of any one of claims 22-42, such that the time to progressive disease is increased relative to the time without administration of the pharmaceutical composition or dosing regimen.

51. A method of treating an individual suffering from or susceptible to breast or prostate cancer, the method comprising administering to the individual the pharmaceutical composition of any one of claims 1-21 or the dosage regimen of any one of claims 22-42, such that ACTH drive is reduced, adrenal androgen is reduced, and/or upstream steroid is reduced, relative to the pharmaceutical composition or dosage regimen without dexamethasone.

52. A method of treating breast or prostate cancer in an individual, the method comprising administering the pharmaceutical composition of any one of claims 1-21 or the dosage regimen of any one of claims 22-42 to an individual in need thereof such that ACTH drive is reduced, adrenal androgen is reduced, and/or upstream steroid is reduced relative to the pharmaceutical composition or dosage regimen without dexamethasone.

Summary of The Invention

The present invention relates to compounds (e.g., any of those described herein) and methods of treating diseases, disorders, or symptoms thereof. The methods may include the compounds herein.

In one aspect, the present invention provides a pharmaceutical composition comprising a) sevieronel or a salt thereof; b) dexamethasone or a salt thereof; and c) a pharmaceutically acceptable carrier. In another aspect, the amount of sevelamer in the composition is in the range of about 150mg to 750 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650 mg. In another aspect, the amount of sevelamer in the composition is 600 mg. In another aspect, the amount of sevelamer in the composition is 450 mg. In another aspect, the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 150mg to 750mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 150mg to 750mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is 0.5 mg.

In one aspect, the present invention provides a dosing regimen comprising sevelamer or a salt thereof; and dexamethasone or a salt thereof. In another aspect, the amount of sevelamer is in the range of about 150mg to 750 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650 mg. In another aspect, the amount of sevelamer is 600 mg. In another aspect, the amount of sevelamer is 450 mg. In another aspect, the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is in the range of about 150mg to 750mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is in the range of about 150mg to 750mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is 600mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is 600mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is 600mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is 450mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is 450mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is 450mg, and the amount of dexamethasone is 0.5 mg. In another aspect, sevelamer and dexamethasone are administered simultaneously. In another aspect, sevelamer and dexamethasone are administered sequentially.

In one aspect, the invention provides a method of treating an individual suffering from or susceptible to a condition or disease described herein, comprising administering to the individual an effective amount of a compound or pharmaceutical composition described herein.

The methods herein include those wherein the disease or disorder is prostate cancer, breast cancer, endometriosis, uterine leiomyoma, inflammatory bowel disease, psoriasis, systemic fungal infection, onychomycosis, or cardiovascular disease.

The methods described herein include those in which an individual is identified as being in need of a particular described treatment. Identifying an individual in need of such treatment can be within the judgment of the individual or a healthcare professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

Brief Description of Drawings

The invention is further described with reference to the following non-limiting examples and with reference to the following drawings, in which:

figure 1 depicts the results of a prostate cancer study on: 1) patients treated with sevelamer without dexamethasone at any time during the study (referred to as "without dexamethasone" in figure 1); 2) patients treated with sevelamer and greater than 30 days of dexamethasone (referred to as "plus dexamethasone" in figure 1); and 3) patients treated with sevelamer and dexamethasone within 3 days of the study on day 1 of cycle 1 (referred to as "new subjects of dexamethasone" in figure 1).

Figure 2 depicts the results of a prostate cancer study, which is a plot of the Swim of patients who failed treatment with enzalutamide or abiraterone (i.e., single failure) prior to sevelamer or sevelamer and dexamethasone administration.

Figure 3 depicts a plot of Swim for patients who failed treatment with enzalutamide and abiraterone (i.e., double failure) prior to administration of sevelamer or sevelamer and dexamethasone.

FIG. 4 depicts the Kaplan-Meier evaluation (radiographic progression and PSA progression) of single failure patients treated with SEVI (i.e., sevelarin) and SEVI-D (i.e., sevelafin and dexamethasone).

FIG. 5 depicts the Kaplan-Meier evaluation (radiographic progression and PSA progression) of double failure patients treated with SEVI (i.e., sevelarin) and SEVI-D (i.e., sevelafin and dexamethasone).

Figure 6 depicts median time to progression (radiographic progression and PSA progression) for double-failure patients treated with: 1) treatment with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 6); and 2) treatment with sevelamer and ≧ 30 days of dexamethasone (referred to as "plus dexamethasone" in FIG. 6).

Fig. 7 depicts endocrine status of prostate cancer patients treated with SEVI.

FIG. 8 depicts endocrine status of prostate cancer patients treated with SEVI-D.

Figure 9 depicts Treatment Emergency Adverse Events (TEAE) for double failure patients: 1) treatment with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 9); 2) treatment with sevelamer and greater than or equal to 30 days of dexamethasone (referred to as "plus dexamethasone" in FIG. 9); and 3) treatment with sevelamer and dexamethasone over 3 days of the study on day 1 of cycle 1 (referred to as "new subject for dexamethasone" in figure 9).

Figure 10 depicts adverse event grade level classification for double failure patients: 1) treatment with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 10); and 2) treatment with sevelamer and dexamethasone within 3 days of the study on day 1 of cycle 1 (referred to as "new subjects of dexamethasone" in figure 10).

Figure 11 depicts the improved relative risk of patients treated with sevelamer and dexamethasone (referred to as "new subjects of dexamethasone" in figure 11) within 3 days of the study on day 1 of cycle 1 relative to patients treated with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 11).

Figure 12 depicts the results of a breast cancer study for the following cases: 1) patients treated with sevelamer, but not dexamethasone at any time during the study (referred to as "without dexamethasone" in figure 12); 2) patients treated with sevelamer and greater than 30 days of dexamethasone (referred to as "plus dexamethasone" in FIG. 12); and 3) patients treated with sevelamer and dexamethasone within 3 days of the study on day 1 of cycle 1 (referred to as "new subjects of dexamethasone" in figure 12).

Figure 13 depicts a Swim plot of the results of a triple negative breast cancer study in patients treated with SEVI or SEVI-D.

FIG. 14 depicts Swim plots of the results of triple negative breast cancer studies in patients treated with SEVI or SEVI-D and having ≧ 2 prior therapies for advanced disease or < 2 prior therapies for advanced disease.

Figure 15 depicts a Swim plot of the results of a triple negative breast cancer study in patients with visceral disease or without visceral disease treated with SEVI or SEVI-D.

Figure 16 depicts the results of a triple negative breast cancer study in women treated with sevelamer and dexamethasone within 3 days of the cycle 1 day 1 study (referred to as "new subjects of dexamethasone" in figure 16).

Figure 17 depicts the results of a breast cancer study for the following cases: 1) males treated with sevelamer without dexamethasone at any time during the study; and 2) men treated with sevelamer and greater than or equal to 30 days of dexamethasone.

FIG. 18 depicts a waterfall plot of the percent change determined for breast cancer tumors in female patients treated with SEVI and SEV-D.

Fig. 19 depicts the response of progesterone in female breast cancer subjects: 1) treatment with sevelamer without dexamethasone at any time during the study (referred to as "sevelamer (without dexamethasone)" in figure 19); and 2) treatment with sevelamer and ≧ 30 days of dexamethasone (referred to as "sevelamer (dexamethasone)" in FIG. 19).

FIG. 20 depicts ER treated with SEVI or SEVI-D⁺Breast cancer patients had no clinically relevant increase in progesterone relative to patients treated with abiraterone and prednisone (referred to as "abiraterone/prednisone" in figure 20).

Figure 21 depicts adverse events (TEAE) occurring during treatment of female breast cancer patients: 1) treatment with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 21); 2) treatment with sevelamer and ≧ 30 days of dexamethasone (referred to as "plus dexamethasone" in FIG. 21); and 3) treatment with sevelamer and dexamethasone over 3 days of the study on day 1 of cycle 1 (referred to as "new subject for dexamethasone" in figure 21).

Figure 22 depicts the adverse event rank level classification for female breast cancer patients: 1) treatment with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 22); and 2) treatment with sevelamer and dexamethasone over 3 days of the study on day 1 of cycle 1 (referred to as "new subject for dexamethasone" in figure 22).

Figure 23 depicts the improved relative risk of breast cancer patients treated with sevelamer and dexamethasone (referred to as "new dexamethasone" in figure 23) over 3 days of the study on day 1 of cycle 1 relative to patients treated with sevelamer without dexamethasone at any time during the study (referred to as "no dexamethasone" in figure 23).

Detailed Description

Definition of

In order that the present invention may be more readily understood, certain terms are first defined herein for convenience.

As used herein, the term "treating" a disorder includes preventing, ameliorating, alleviating and/or controlling the disorder and/or the condition that causes the disorder. The term "treatment" refers to a method of alleviating or reducing the disease and/or its attendant symptoms. According to the present invention, "treating" includes preventing, blocking, inhibiting, alleviating, protecting, modulating, reversing the effects of, and reducing the appearance of, for example, adverse effects of the condition.

As used herein, "inhibit" includes preventing, reducing and halting progression. Note that "enzyme inhibition" (e.g., metalloenzyme inhibition) is distinguished therefrom and described below.

The term "modulate" refers to an increase or decrease in the activity of an enzyme in response to exposure to a compound of the invention.

The terms "isolated," "purified," or "biologically pure" refer to a substance that is substantially or essentially free of components that normally accompany it as found in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. Specifically, in embodiments the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

The term "administering" or "administering" includes the route by which the compounds are introduced into an individual to perform their intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal.

The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. The effective amount of the compound may vary depending on factors such as: the disease state, age, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. The dosage regimen may be adjusted to provide the optimal therapeutic response. An effective amount is also an amount at which the therapeutically beneficial effect of the inhibitor compound outweighs any toxic or detrimental effects (e.g., side effects).

The phrases "systemic administration," "administered systemically," "administered peripherally" and "administered peripherally" as used herein refer to the administration of a compound, drug or other material to enter a patient's body and thereby undergo metabolism and other similar processes.

The term "therapeutically effective amount" refers to an amount of a compound administered sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated.

A therapeutically effective amount (i.e., effective dose) of the compound may be in the range of about 0.005 μ g/kg to about 200mg/kg body weight, preferably about 0.01mg/kg to about 200mg/kg body weight, more preferably about 0.015mg/kg to about 30mg/kg body weight. In other embodiments, the therapeutically effective amount may range from about 1.0pM to about 10 μ M. The skilled artisan will appreciate that certain factors may affect the dosage required to effectively treat an individual, including, but not limited to, the severity of the disease or disorder, prior treatments, the general health and/or age of the individual, and other diseases present. Furthermore, treatment of an individual with a therapeutically effective amount of a compound may comprise a monotherapy, or preferably may comprise a series of therapies. In one embodiment, an individual is treated with about 0.005 μ g/kg to about 200mg/kg of body weight of the compound 1 time per day for about 1 to 10 weeks, preferably for 2 to 8 weeks, more preferably for about 3 to 7 weeks, and more preferably for about 4, 5, or 6 weeks. In another example, an individual may be treated daily for years in the case of a chronic condition or disease. It is also understood that the effective dose of the compound for treatment may be increased or decreased over the course of a particular treatment.

The term "adverse event" or "AE" refers to any adverse medical event in the individual to whom the pharmaceutical product is administered or in the individual under clinical study, and which does not necessarily have a causal relationship to the treatment. Thus, an Adverse Event (AE) can be any adverse and unexpected sign (including, for example, abnormal laboratory findings), symptom, or disease that is temporarily associated with the use of a pharmaceutical product, whether or not considered to be associated with a pharmaceutical product.

The term "adverse drug reactions" or "ADRs" refers to all adverse and unexpected responses to a drug product associated with any dose. The phrase "response to a pharmaceutical product" refers to the likelihood that a causal relationship between a pharmaceutical product and an adverse event is at least reasonable, i.e., the relationship cannot be ruled out.

The term "unexpected adverse drug reaction" refers to an AE, wherein the nature or severity of the AE is inconsistent with applicable product information (e.g., survey manuals, research protocols, or Informed Consent (ICF)).

The term "severe adverse event" or "SAE" refers to any adverse medical event at any dose: a) leading to death; b) are life-threatening (events in which the individual is at risk of death at the time of the event; it does not refer to an event that is assumed to have caused death if more serious); c) requiring hospitalization of hospitalized patients or extending existing hospitalization times; d) resulting in persistent or significant disability/disability; e) is a congenital anomaly or congenital defect; f) other important medical events that may not be immediately life threatening or result in death or hospitalization, but may harm the individual or may require intervention to prevent one of the other outcomes listed above. Examples of such events are intensive treatment of allergic bronchospasm in the emergency room; blood cachexia or convulsions that do not result in hospitalization; or the development of drug dependence or drug abuse. The term "acute" is generally used to describe the intensity (severity) of an event; the event itself may have relatively minor medical significance (e.g., severe headache). This is in contrast to "serious" based on individual/event outcomes or action criteria, which are typically associated with events that threaten the life or function of an individual.

An AE can be classified as "unrelated" to a study drug if the event is not temporally related to study drug administration (too early or too late or not taking the study drug), or there is a reasonable causal relationship between the AE and another drug, a concurrent disease or condition.

An AE can be classified as "related" to a study drug if the event has a temporal relationship with drug administration, which makes the causal relationship unlikely to be true, and where other drugs, chemicals, or potential diseases provide a plausible explanation.

An AE may be classified as "likely to be associated with a study drug" if the events follow a reasonable temporal sequence from administration of the study drug and the events follow a known response pattern to the study drug, but the events may have resulted from a concurrent medical condition that is unlikely to be associated with use of the study drug, based on the pathophysiology of the condition and the pharmacology of the study drug, or the events may be the effect of a concomitant drug.

An AE may be classified as "likely to be related to a study drug" if the events follow a reasonable temporal sequence from administration of the study drug, the events follow a known response pattern to the study drug, and the events cannot be reasonably interpreted by a concurrent medical condition or the events cannot be the effect of a concomitant drug.

An AE can be classified as "specifically related" to a study drug if the events follow a reasonable temporal sequence from administration of the study drug, the events follow a known response pattern to the study drug, and the events are clearly correlated with the effect of the study drug based on the known pharmacology of the study drug.

The term "chiral" refers to a molecule having properties that do not coincide with its mirror partner, while the term "achiral" refers to a molecule that does coincide with its mirror partner.

The term "diastereomer" refers to a stereoisomer that has two or more asymmetric centers and whose molecules are not mirror images of each other.

The term "enantiomer" refers to two stereoisomers of a compound that are not mirror images of each other. An equimolar mixture of two corresponding isomers is called a "racemic mixture" or "racemate".

The term "isomer" or "stereoisomer" refers to compounds that are identical in chemical composition but differ in the arrangement of atoms or groups in space.

The term "prodrug" includes compounds having moieties that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, e.g., Berge et al (1977) "Pharmaceutical Salts", J.pharm.Sci.66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by reacting the purified compound in its free acid form or the hydroxy group alone with a suitable esterifying agent. The hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionates), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen, or methoxy substituents) aryl and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionates and acyl esters. Prodrugs that are converted to the active form in vivo by other mechanisms are also included. In some aspects, the compounds of the invention are prodrugs of any of the formulae herein.

The term "subject" refers to an animal, such as a mammal, including, but not limited to, a primate (e.g., human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, and the like. In certain embodiments, the subject is a human.

The singular forms "a", "an" and "the" are intended to mean "one or more" when used in this application, including the claims. Thus, for example, reference to "a sample" includes a plurality of samples, unless the context clearly dictates otherwise (e.g., a plurality of samples), and so forth.

Throughout this specification and the claims, the words "comprise", "comprising" and "contain" are used in a non-exclusive sense unless the context requires otherwise.

The term "about" as used herein when referring to a numerical value is intended to encompass the following differences from the stated amount: in some embodiments, 20% difference from the specified amount, in some embodiments, 10% difference from the specified amount, in some embodiments, 5% difference from the specified amount, in some embodiments, 1% difference from the specified amount, in some embodiments, 0.5% difference from the specified amount, and in some embodiments, 0.1% difference from the specified amount, whereby these differences are suitable for practicing the disclosed methods or using the disclosed compositions.

The word "inhibitor" is used herein to mean a molecule that exhibits activity to inhibit metalloenzymes. By "inhibiting" herein is meant that the activity of the metalloenzyme is reduced compared to the activity of the metalloenzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" refers to a decrease in metalloenzyme activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibition refers to a decrease in metalloenzyme activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition refers to a decrease in metalloenzyme activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such a reduction can be measured using a variety of techniques recognized by those skilled in the art. Specific assays for measuring the respective activities are described below.

Further, the compounds of the present invention include olefins having any of the following geometries: "Z" refers to a geometry referred to as the "cis" (same side) configuration and "E" refers to a geometry referred to as the "trans" (opposite side) configuration. For nomenclature of chiral centers, the terms "d" and "l" (or + and-) configurations are defined by IUPAC nomenclature (IUPAC Recommendation). For the use of the terms below, diastereomers, racemates, epimers and enantiomers will be used in their usual context to describe the stereochemistry of the formulations.

The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon group containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to C1-C6 alkyl chains. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl and n-pentyl. Alkyl groups may be optionally substituted with one or more substituents.

The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may be optionally substituted with one or more substituents.

The term "alkynyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

Sp of alkenyl and alkynyl²Or the sp carbon may each optionally be the point of attachment of an alkenyl or alkynyl group.

The term "alkoxy" refers to-O-alkyl.

The term "haloalkoxy" refers to an-O-alkyl group substituted with one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2, 2-trifluoroethoxy.

The term "halogen" or "halo" as used herein refers to-F, -Cl, -Br, or-I.

The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2,3, or 4 atoms in each ring of the cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2,3, 4, 5, or 6 atoms in each ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remaining ring atoms being carbon (with appropriate hydrogen atoms unless otherwise specified). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2,3, or 4 atoms in each ring of the heteroaryl group can be substituted with a substituent. Examples of heteroaryl groups include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

The term "nitrogen-containing heteroaryl" refers to heteroaryl groups having 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogen heteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system that includes 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2,3, or 4 atoms in each ring of the heterocycloalkyl group can be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1, 3-dioxolanyl, tetrahydrofuranyl, tetrahydrothienyl, thienyl, and the like.

The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl moiety in alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. The acid catalyst is any acidic chemical, which may be inorganic (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic in nature (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). The acid is used in catalytic or stoichiometric amounts to promote the chemical reaction. The base is any basic chemical, which may be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic in nature (e.g., triethylamine, pyridine). The base is used in a catalytic or stoichiometric amount to promote the chemical reaction.

An alkylating agent is any agent capable of alkylating the functional group in question (e.g. an oxygen atom of an alcohol, a nitrogen atom of an amino group). Alkylating agents are known in the artIncluding references cited herein, are known and include alkyl halides (e.g., methyl iodide, benzyl bromide, or chloride), alkyl sulfates (e.g., methyl sulfate), or other combinations of alkyl leaving groups known in the art. Leaving groups are any stable species capable of being detached from a molecule during a reaction (e.g., elimination, replacement) and are known in the art, including the references cited herein, and include halides (e.g., I-, C1-, Br-, F-), hydroxyls, alkoxys (e.g., -OMe, -O-t-Bu), acyloxyanions (e.g., -OAc, -OC (O) CF₃) Sulfonates (e.g., methylsulfonyl, tosyl), acetamides (-NHC (O) Me), carbamates (e.g., N (Me) C (O) Ot-Bu), phosphonates (e.g., -OP (O) (OEt))₂) Water or alcohol (proton state), etc.

In some embodiments, the substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be on any atom of that group, wherein any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted with one or more substituents (which can be the same or different), each substituted for a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, cyano, nitro, alkoxy, haloalkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxy, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, acylamino, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, ureido, carbamoyl, thioureido, thiocyanato, sulfonamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidino, or N' -aryl, N "-hydroxyamidino.

The compounds of the invention may be prepared by means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary to minimize competing by-products, are known in the art. Reaction Optimization And amplification may advantageously utilize high speed parallel synthesis apparatus And computer controlled microreactors (e.g., Design And Optimization in organic synthesis, second edition, Carlson R, Ed, 2005; Elsevier Science Ltd.;k et al, Angew43406; and references therein). The skilled person can do this by using commercially available database software with a queryable structure, e.g.

(CAS division of the American chemical society) and Cross fire

(Elsevier MDL) or by performing a suitable keyword search using a web search engine such as or a keyword database such as the us patent and trademark office text database.

The compounds herein may also contain linkages (e.g., carbon-carbon bonds) where bond rotation is limited with respect to that particular linkage, e.g., due to the presence of a ring or double bond. Thus, all cis/trans and E/Z isomers are expressly included in the present invention. The compounds herein may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be present. All such isomeric forms of these compounds herein are expressly included in the present invention. All crystal forms and polymorphs of the compounds described herein are expressly included in the present invention. Extracts and fractions comprising the compounds of the invention are also practiced. The term isomer is intended to include diastereomers, enantiomers, regioisomers, structural isomers, rotamers, tautomers and the like. For compounds containing one or more stereocenters, such as chiral compounds, the methods of the invention can be practiced using enantiomerically enriched compounds, racemates, or diastereomeric mixtures.

Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more, more preferably the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In a preferred embodiment, only one enantiomer or diastereomer of a chiral compound of the invention is administered to a cell or individual.

Method of treatment

In another embodiment, the present invention provides a method of treating breast cancer or prostate cancer in an individual, comprising administering to the individual in need thereof any of the pharmaceutical compositions or dosing regimens described herein. In another embodiment, the invention provides a method of treating breast or prostate cancer in an individual, comprising administering to the individual in need thereof any of the pharmaceutical compositions or dosing regimens described herein, such that the number and/or severity of adverse events is lower than when the pharmaceutical composition or dosing regimen does not comprise dexamethasone. In another embodiment, the invention provides a method of treating breast or prostate cancer in an individual, the method comprising administering to an individual in need thereof any of the pharmaceutical compositions or dosing regimens described herein, such that the time to progressive disease (e.g., radiographic progression, PSA progression, tumor growth, etc.) is increased relative to the time without administration of the pharmaceutical composition or dosing regimen. In another embodiment, the invention provides a method of treating breast or prostate cancer in an individual, the method comprising administering to the individual in need thereof any of the pharmaceutical compositions or dosing regimens described herein, such that ACTH driver (ACTH drive) is decreased, adrenal androgen is decreased, and/or upstream steroid is decreased, relative to the pharmaceutical composition or dosing regimen without dexamethasone.

In another embodiment, the invention provides a method of treating an individual suffering from or susceptible to breast or prostate cancer, comprising administering to the individual any of the pharmaceutical compositions or dosing regimens described herein. In another embodiment, the invention provides a method of treating an individual suffering from or susceptible to breast or prostate cancer, comprising administering to the individual any of the pharmaceutical compositions or dosing regimens described herein, such that the number and/or severity of adverse events is lower than when the pharmaceutical composition or dosing regimen does not comprise dexamethasone. In another embodiment, the invention provides a method of treating an individual suffering from or susceptible to breast or prostate cancer, the method comprising administering to the individual any of the pharmaceutical compositions or dosing regimens described herein, such that the time to progressive disease (e.g., radiographic progression, PSA progression, tumor growth, etc.) is increased relative to the time without administration of the pharmaceutical composition or dosing regimen. In another embodiment, the invention provides a method of treating an individual suffering from or susceptible to breast or prostate cancer, comprising administering to the individual any of the pharmaceutical compositions or dosing regimens described herein, such that ACTH driver is reduced, adrenal androgen is reduced, and/or upstream steroid is reduced, relative to the pharmaceutical composition or dosing regimen without dexamethasone.

In certain embodiments, the invention provides methods of treating a disease, disorder, or symptom thereof, wherein the disorder is prostate cancer, breast cancer, androgen-dependent cancer, estrogen-dependent cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, onychomycosis, adrenal hyperplasia, prostatic hypertrophy, virilization, hirsutism, male pattern baldness, precocious puberty, endometriosis, uterine fibroids, uterine cancer, uterine leiomyoma, mastopathy, polycystic ovary syndrome, infertility, acne, functional ovarian hyperandrogenism, hyperandrogenism with chronic anovulatory disease, hyperandrogenism, early adrenal function, adrenal or androgen excess.

In certain embodiments, the invention provides methods of treating a disease, disorder, or symptom thereof, wherein the disorder is prostate cancer, breast cancer, androgen-dependent cancer, estrogen-dependent cancer, adrenal hyperplasia, prostatic hypertrophy, virilization, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterine fibroids, uterine cancer, uterine leiomyoma, mastopathy, polycystic ovary syndrome, infertility, acne, functional ovarian hyperandrogenism, hyperandrogenism with chronic anovulatory hyperandrogenism, adrenal function presenility, adrenal gland or hyperandrogenism.

In certain embodiments, the subject is a mammal, preferably a primate or human.

In another embodiment, the present invention provides a method as described above, wherein the effective amount of the compound or composition is as described herein.

In another embodiment, the present invention provides a method as described above, wherein any of the compounds or compositions described herein is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically.

As used herein, a "CYP 17-related disorder" is a physiological or pathological condition that is dependent on CYP17 activity. Non-limiting examples of CYP 17-related disorders include prostate cancer, breast cancer, adrenal hyperplasia, prostatic hypertrophy, virilization, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterine fibroids, uterine cancer, mastopathy, polycystic ovary syndrome, infertility, acne, functional ovarian hyperandrogenism, hyperandrogenism with chronic anovulosis, hyperandrogenism, early adrenal function, adrenal and androgen excess.

Another object of the invention is the use of a compound described herein (e.g., of any formula herein) in the manufacture of a medicament for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the invention is the use of a compound described herein (e.g., of any formula herein) in the treatment of a metalloenzyme-mediated disorder or disease. Another object of the invention is the use of a compound described herein (e.g., of any formula herein) in the preparation of an agricultural composition for the treatment or prevention of a metalloenzyme-mediated disorder or disease in an agricultural or agro-farming setting.

Pharmaceutical composition

In one aspect, the present invention provides a pharmaceutical composition comprising: a) sevelamer or a salt thereof; b) dexamethasone or a salt thereof; and c) a pharmaceutically acceptable carrier. In another aspect, the amount of sevelamer in the composition is in the range of about 150mg to 750 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650 mg. In another aspect, the amount of sevelamer in the composition is 600 mg. In another aspect, the amount of sevelamer in the composition is 450 mg. In another aspect, the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 150mg to 750mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 150mg to 750mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is in the range of about 400mg to 650mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is 600mg, and the amount of dexamethasone in the composition is 0.5 mg. In another aspect, the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer in the composition is 450mg, and the amount of dexamethasone in the composition is 0.5 mg.

In one aspect, the present invention provides a dosing regimen comprising sevelamer or a salt thereof; and dexamethasone or a salt thereof. In another aspect, the amount of sevelamer is in the range of about 150mg to 750 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650 mg. In another aspect, the amount of sevelamer is 600 mg. In another aspect, the amount of sevelamer is 450 mg. In another aspect, the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is in the range of about 150mg to 750mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is in the range of about 150mg to 750mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is in the range of about 400mg to 650mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is 600mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is 600mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is 600mg, and the amount of dexamethasone is 0.5 mg. In another aspect, the amount of sevelamer is 450mg, and the amount of dexamethasone is in the range of about 0.25mg to 1000 mg. In another aspect, the amount of sevelamer is 450mg, and the amount of dexamethasone is in the range of about 0.40mg to 0.60 mg. In another aspect, the amount of sevelamer is 450mg, and the amount of dexamethasone is 0.5 mg. In another aspect, sevelamer and dexamethasone are administered simultaneously. In another aspect, sevelamer and dexamethasone are administered sequentially.

In one aspect, the invention provides a pharmaceutical composition comprising any of the compounds described herein.

In one aspect, the invention provides a kit comprising an effective amount of any of the compounds described herein, or a combination thereof, in unit dosage form, and instructions for administering the compound to an individual suffering from or susceptible to prostate cancer, breast cancer, androgen-dependent cancer, estrogen-dependent cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, onychomycosis, adrenal hyperplasia, prostatic hypertrophy, virilization, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterine fibroids, uterine cancer, uterine leiomyoma, mastopathy, polycystic ovary syndrome, infertility, acne, functional ovarian hyperandrogenism, hyperandrogenism with chronic anovulemia, hyperandrogenism, early adrenal function, adrenal or hyperandrogenism.

In one aspect, the invention provides a kit comprising an effective amount of any of the compounds described herein, or a combination thereof, in unit dosage form, and instructions for administering the compound to an individual suffering from or susceptible to prostate cancer, breast cancer, androgen-dependent cancer, estrogen-dependent cancer, adrenal hyperplasia, prostatic hypertrophy, virilization, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterine fibroids, uterine cancer, uterine leiomyoma, mastopathy, polycystic ovary syndrome, infertility, acne, functional ovarian hyperandrogenism, hyperandrogenism with chronic unorganization, hyperandrogenism, early adrenal function, adrenal or hyperandrogenism.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonate, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present invention.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are the same as the parent form of the compound for purposes of the present invention.

In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent.

Certain compounds of the invention may exist in unsolvated (unsolvated) forms as well as solvated (solvated) forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

The invention also provides pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the compound is administered to the subject using a pharmaceutically acceptable formulation, e.g., the pharmaceutically acceptable formulation provides sustained delivery of the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after administration of the pharmaceutically acceptable formulation to the subject.

The actual dosage level and time course of administration of the active ingredient in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without toxicity (or unacceptable toxicity) to the patient.

In use, at least one compound of the present invention is administered in a pharmaceutically effective amount in a pharmaceutical carrier to an individual in need thereof by intravenous, intramuscular, subcutaneous, or intracerebroventricular injection, or by oral or topical administration. According to the present invention, the compounds of the present invention may be administered alone or in combination with a second, different therapeutic agent. "in combination with …" means co-administration substantially simultaneously or sequentially. In one embodiment, the compounds of the invention are administered acutely. Thus, the compounds of the invention may be administered for short term treatment, e.g., from about 1 day to about 1 week. In another embodiment, the compounds of the invention may be administered over a longer period of time to ameliorate a chronic condition, for example for about 1 week to several months depending on the condition to be treated.

As used herein, a "pharmaceutically effective amount" refers to an amount of a compound of the present invention that is high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The pharmaceutically effective amount of the compounds of the invention will vary depending upon the particular objective to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of the treatment, the nature of concurrent therapy, and the particular compound employed. For example, a therapeutically effective amount of a compound of the invention administered to a child or newborn infant will be proportionally reduced according to sound medical judgment. An effective amount of a compound of the invention is therefore the lowest amount that provides the desired effect.

A definite practical advantage of the present invention is that the compounds can be administered in a convenient manner, for example by intravenous, intramuscular, subcutaneous, oral or intracerebroventricular injection routes, or by topical administration, for example as an ointment or gel. Depending on the route of administration, the active ingredients comprising the compounds of the present invention may need to be encapsulated within a material to protect the compound from the action of enzymes, acids and other natural conditions that may inactivate the compound. To administer the compounds of the present invention by means other than parenteral administration, the compounds may be coated with or administered with a material to prevent inactivation.

The compounds may be administered parenterally or intraperitoneally. Dispersants may also be prepared, for example, in glycerol, liquid polyethylene glycols and mixtures thereof, and oils.

Some examples of substances that can act as drug carriers are: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc powder; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and a phosphate buffer solution; skimmed milk powder; and other non-toxic compatible substances used in pharmaceutical preparations, such as vitamin C, estrogens and echinacea (echinacea). Wetting and lubricating agents such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Solubilizers including, for example, castor oil polyoxyethylene ether (cremaphore) and beta-cyclodextrin may also be used in the pharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds (or prodrugs thereof) of the presently disclosed subject matter can be prepared by conventional mixing, dissolving, granulating, dragee-making, milling, emulsifying, encapsulating, entrapping or lyophilizing processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.

The pharmaceutical compositions of the presently disclosed subject matter can take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal administration, and the like, or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound or prodrug may be formulated as a solution, gel, ointment, cream, suspension, or the like.

Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compounds in aqueous or oily vehicles. The composition may also contain formulating agents (formulating agents), such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers), and may contain an added preservative.

Alternatively, the injectable formulations may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen-free water, buffer, dextrose solution, and the like, prior to use. To this end, the active compounds may be dried by any technique known in the art, such as freeze-drying, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated, for example with sugar or enteric coatings, by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens or sorbic acid). The formulations may also optionally contain buffer salts, preservatives, flavouring agents, colouring agents and sweetening agents.

It is well known that formulations for oral administration may be suitably formulated to provide controlled release of the active compound or prodrug.

For oral administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For rectal and vaginal administration, the active compounds may be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound or prodrug may conveniently be delivered in the form of a spray, from pressurized packs or a nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by setting a valve to deliver a metered amount. Capsules and cartridges (e.g., of gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following: active compound or prodrug (0.5-20 mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (80; 0.5-5 mg/ml); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg/ml); phenyl ethanol (1-4 mg/ml); and dextrose (20-50 mg/ml). The pH of the final suspension may be adjusted to a range of about pH5 to pH 7, typically about pH 5.5.

For ophthalmic administration, the active compounds or prodrugs can be formulated as solutions, emulsions, suspensions, and the like, suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are disclosed in us patent 6,261,547; us patent 6,197,934; us patent 6,056,950; us patent 5,800,807; U.S. Pat. nos. 5,776,445; us patent 5,698,219; us patent 5,521,222; us patent 5,403,841; us patent 5,077,033; us patent 4,882,150; and U.S. patent No. 4,738,851, each of which is incorporated herein by reference in its entirety.

For prolonged delivery, the active compound or prodrug may be formulated as a depot formulation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems may be used which are prepared as adhesive sheets or patches which slowly release the active compound for transdermal absorption. To this end, penetration enhancers may be used to promote transdermal penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Pat. nos. 5,407,713; us patent 5,352,456; us patent 5,332,213; U.S. Pat. nos. 5,336,168; us patent 5,290,561; us patent 5,254,346; us patent 5,164,189; us patent 5,163,899; us patent 5,088,977; us patent 5,087,240; us patent 5,008,110; and U.S. patent No. 4,921,475, each of which is incorporated herein by reference in its entirety.

Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are examples of delivery vehicles known to be useful for delivering active compounds or prodrugs. Certain organic solvents such as dimethyl sulfoxide (DMSO) may also be employed.

If desired, the pharmaceutical composition may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound. The package may for example comprise a metal or plastic foil, such as a blister pack. The packaging or dispensing device may be accompanied by instructions for administration.

The active compounds or prodrugs of the presently disclosed subject matter, or compositions thereof, will generally be employed in an amount effective to achieve the desired result, e.g., in an amount effective to treat or prevent the particular disease being treated. The compound may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. Therapeutic benefit refers to the elimination or amelioration of the underlying disorder being treated and/or the elimination or amelioration of one or more symptoms associated with the underlying disorder such that the patient reports a sensation or improvement in the disorder, although the patient may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides a therapeutic benefit not only when the underlying allergy is eliminated or ameliorated, but also when the severity or duration of symptoms associated with the allergy is reported to be reduced after the patient is exposed to the allergen. As another example, therapeutic benefits in the context of asthma include improved breathing or reduced frequency or severity of asthma attacks following an asthma attack. Therapeutic benefits also include halting or slowing the progression of the disease, whether or not improvement is achieved.

For prophylactic administration, the compound may be administered to a patient at risk of developing one of the previously described diseases. As defined by an appropriate medical professional or panel, a patient at risk of developing a disease may be a patient with characteristics that cause the patient to be assigned to a designated panel of at-risk patients. The patient at risk may also be a patient who is generally or often in a situation where the development of an underlying disease that can be treated by administration of a metalloenzyme inhibitor of the invention is likely to occur. In other words, a patient at risk is a person who is generally or commonly exposed to a disease or condition causing condition or who may be severely exposed for a limited time. Alternatively, prophylactic administration may be applied to avoid the onset of symptoms in patients diagnosed with an underlying condition.

The amount of the compound administered will depend on a variety of factors including, for example, the particular indication being treated, the mode of administration, whether prophylactic or therapeutic benefit is desired, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, and the like. Determination of an effective dose is within the ability of those skilled in the art.

The effective dose can be estimated initially from in vitro assays. For example, an initial dose used in an animal can be formulated to achieve a circulating blood or serum concentration of the active compound that is at or above the IC50 for the particular compound measured in an in vitro assay, e.g., in an in vitro CHMC or BMMC and other in vitro assays described in the examples section. It is within the ability of the skilled person to calculate the dosage to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound. For guidance, see Fingl & Woodbury, "General Principles," in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1-46, latest edition, Pagamonon Press, and references cited therein, which are incorporated herein by reference.

Initial doses can also be estimated from in vivo data, such as animal models. Animal models for testing the efficacy of compounds to treat or prevent the various diseases described above are well known in the art.

Dosage amounts typically range from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, mode of administration, and the various factors discussed above. The amount and spacing of the doses can be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. In the case of topical administration or selective uptake, for example topical application, the effective local concentration of the active compound is independent of the plasma concentration. The skilled artisan is able to optimize effective topical dosages without undue experimentation.

The compound may be administered once, several or several times per day, or even multiple times per day, depending on, among other things, the condition being treated and the judgment of the prescribing physician.

Preferably, the compounds will provide therapeutic or prophylactic benefit without causing substantial toxicity. Standard pharmaceutical procedures can be used to determine the toxicity of the compounds. The dose ratio of toxic to therapeutic (or prophylactic) effect is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred.

Recitation of a chemical group as recited in any definition of a variable herein includes definitions of that variable as any individual group or combination of groups listed. Recitation of embodiments of variables herein includes embodiments taken as any individual embodiment or in combination with any other embodiment or portion thereof.

Examples

The invention will now be illustrated using specific embodiments which should not be construed as limiting.

General experimental method

The definitions of the variables in the structures of the schemes herein match the definitions of the variables at the corresponding positions in the formulae described herein.

Sevelamer (aka VT-464 and INO-464; 1- (6, 7-bis (difluoromethoxy) naphthalen-2-yl) -2-methyl-1- Synthesis of (1H-1,2, 3-triazol-4-yl) propan-1-ol)