Tricyclic Amino Containing Compounds for Treatment or Prevention of Symptoms Associated with Endocrine Dysfunction

Abstract

The disclosure provides methods of use of certain compounds that are useful for treating certain symptoms of endocrine disturbances, and in particular those associated with hot flashes.

Claims

1. A method of treating hot flashes comprising administering a pharmaceutical composition comprising a compound of Formula I: ##STR00205## or a pharmaceutically acceptable salt, ester or prodrug thereof to a subject in need thereof wherein each K is independently N or CH, wherein at least two K's are N; Q, T, U, and V are independently selected from H or R; W, X, Y and Z are independently selected from H, R, F, Cl, Br, I, OH, OR or CO.sub.2H; each R is independently selected from straight chain or branched alkyl groups; R.sub.1 and R.sub.2 are independently H or R; and R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from H or R.

2. The method of claim 1, wherein the subject is a menopausal or perimenopausal woman.

3. The method of claim 1, wherein the subject is menstruating or expecting to menstruate within a week.

4. The method of claim 1, wherein the subject is a woman diagnosed with vulvodynia.

5. The method of claim 1, wherein the pharmaceutical composition is administered in combination with another active agent.

6. The method of claim 1, wherein the pharmaceutical composition is administered in combination with an agonist or antagonist of an estrogen receptor.

7. The method of claim 1, wherein the pharmaceutical composition is administered in combination with tamoxifen.

8. The method of claim 1, further comprising the step of administering the pharmaceutical composition to the subject after, before, or during a surgery selected from a hysterectomy, oophorectomy, partial oophorectomy, unilateral salpingo-oophorectomy, bilaterial salpingo-oophorectomy or combination thereof.

Description

EXAMPLES

Example 1

Screening of Small Molecule Compounds With a Competitive Binding Assay Against Biotinlabeled TN14003.

[0143] A synthetic 14-mer peptide, TN14003, was previously reported to block both SDF-1/CXCR4 mediated invasion in vitro and metastasis in vivo with a high specificity by binding competitively with its ligand SDF-1. Aa competitive binding assay using biotin-labeled TN14003 and streptavidin-conjugated rhodamine was developed to determine the binding efficiency of new chemical entities to the SDF-1 binding domain of CXCR4. Cells incubated with high affinity compounds show only blue nuclear staining, whereas compounds with low affinity result in staining CXCR4 (red; rhodamine) as well as the nuclei (blue; cytox blue). Effective concentrations (EC50) for certain compounds were identified and EC50 for MSX-122 and AMD3100 were 0.6 and 26 nM, respectively.

Example 2

cAMP Assay

[0144] Because the major signaling pathway of CXCR4/SDF-1 involves the pertussis toxin-sensitive G protein Gi, compounds described herein were tested as to whether they inhibited SDF-1/CXCR4-mediated cAMP reduction. The absorption increase at 665 nm was determined by varying the concentration of SDF-1 (0-200 ng/ml) to determine EC80 to be 150 ng/ml. With pre-treatment of MSX-122 or AMD3100, the effect of SDF-1 on cAMP reduction was blocked significantly in a dose-dependent manner. While MSX-122 was effective in counteracting SDF-1 function at concentrations as low as 10 nM, AMD3100 required almost 1000 nM to significantly block SDF-1 function.

Example 3

Pharmacokinetics of MSX-122

[0145] Oral bioavailability and sustained plasma exposure was consistently observed in multiple species for certain compounds. In an initial pharmacokinetic study in mice, MSX-122 generated sustained blood levels when administered both intraperitoneally (IP) and orally. In a pharmacokinetic study in rats, the oral absorption seemed to occur very quickly with an initial Tmax of 30 min. and plasma levels remained above 100 ng/ml (342 nM) for 10 hours when it was administered at 10 mg/kg. In a pharmacokinetic/pharmacodynamic study conducted in non-nave, female cynomolgus monkeys, MSX-122 was administered orally at 1, 5 and 10 mg/kg and resulted in sustained pharmacokinetics with plasma levels that were relatively dose proportional. The 5 and 10 mg/kg doses both generated micromolar plasma concentrations with half lives that support once per day dosing.

Example 4

In Vitro Genotoxicity and Safety

[0146] MSX-122 was tested for genotoxicity in an in vitro Ames test (BioReliance Corp., Rockville, Md.) that demonstrated no evidence of mutagenicity and an in vitro chromosome aberration screening test (BioReliance Corp., Rockville, Md.) using CHO cells treated with MSX-122 which showed no statistically significant increase in structural or numerical chromosome aberrations at any dose level up to the highest dose of 2 mM. Sufficiently scorable cells in the presence of S9 were available for 4 hour treatment and in the absence of S9 for a 20 hour treatment. Finally, MSX-122 was tested for its potential to interfere with the rapid delayed rectifier current (IKr) in human ventricles through the cardiac potassium channel, hERG since inhibition of IKr has been reported to be the most common cause of cardiac action potential prolongation by non-cardiac drugs. The resulting data indicate that MSX-122 and analogs do not exert a significant inhibitory effect on hERG channel currents (1 M MSX-122 (WZ40-MS)0.2% inhibition).

Example 5

Toxicology Studies in Rats and Monkeys

[0147] In initial studies, three groups of rats (5 males and 5 females per group) were dosed with 0, 250 and 600 mg/kg of MSX-122 orally once per day for 28 days. The pharmacokinetic data show that micromolar concentrations of MSX-122 were maintained throughout the term of the study after day 1, and Cmax values were in the range of 2-4 g/ml (6.8-13.6 M). No signs or symptoms of toxicity were observed in any of the animals during the study, and no toxicity was observed upon termination from blood serum chemistry or gross necropsy. A 5-day repeat dose study was carried out in two non-nave cynomolgus monkeys (1 male and 1 female) and two nave cynomolgus monkeys (1 male and 1 female) dosed with 1,000 and 2,000 mg/kg, respectively, orally once per day for 5 days. No drug-related signs or symptoms of toxicity were observed, and there were no abnormalities in the resulting blood serum chemistry. Gross necropsy of the animals dosed at 2000 mg/kg also revealed no abnormalities or signs of toxicity. The only observations were loose and watery stool in a subset of the animals which may have been caused by the excipients in the formulation. The data showed that micromolar concentrations of MSX-122 were maintained throughout the term of the study with Cmax in the range of 5.1 M (1.5 g/ml) to 12 M (3.5 g/ml).

Example 6

Treatment of Hot Flashes

[0148] An approximately 70 kg 56-year old female with a history of aggressive high grade serous carcinomy in her right fallopian tube, a complete hysterectomy and bilateral oophorectomy after previous treatments with VEGF-Trap and docetaxel, Carboplatin and taxol and doxil was treated with MSX-122, 50mg/day oral. The woman was suffering from Graves disease and had a history of hot flashes. After her third treatment of MSX-122, she noted that her past history of hot flashes had resolved greatly since starting the trial.