WO2016135495A1

WO2016135495A1 - Neurokinin b antagonist for use in inhibiting follicle development

Info

Publication number: WO2016135495A1
Application number: PCT/GB2016/050494
Authority: WO
Inventors: Richard Anderson; Karolina SKORUPSKAITE; Jyothis GEORGE
Original assignee: The University Court Of The University Of Edinburgh
Priority date: 2015-02-26
Filing date: 2016-02-25
Publication date: 2016-09-01
Also published as: GB201503207D0

Abstract

This invention relates to use of compounds in female health applications,for example as a contraceptive. In particular the invention relates to the use of compounds targeting tachykinin receptors, in particular neurokinin B receptors (NK3R). For example, the compounds are NK3R antagonists for use as a contraceptive. In particular the present application relates to uses and compositions of Compound (I):

Description

NEUROKININ B ANTAGONIST FOR USE IN INHIBITING FOLLICLE DEVELOPMENT

[0001] This invention relates to use of compounds in female health applications. In particular the invention relates to the use of compounds targeting tachykinin receptors, in particular neurokinin B receptors (NK3R). For example, the compounds are NK3R antagonists for use in female health applications, for example use as a contraceptive. The invention also relates to compositions comprising the compounds and methods of using the compounds. In particular the present application relates to uses and compositions of Compound (I):

BACKGROUND

[0002] Neurokinin B (NKB) is one of several relatively recently described neuropeptides now known to have essential functions in the control of human reproduction. For example individuals with inactivating mutations in NKB or its relevant receptor (NK3R) do not enter or progress through puberty. With appropriate stimulation they can be shown to have normal pituitary and gonadal function. This is consistent with the location of action of NKB being in the hypothalamus.

[0003] WO 2007/069977 discloses a series of compounds with affinity for neurokinin-3 receptors. The compounds are disclosed as having potential use in the treatment of a range of conditions including disorders associated with excessive gonadotrophins and/or androgens.

[0004] WO 2014/170648 discloses a related compound to the compounds of WO 2007/069977. The compound of WO 2014/170648 is disclosed as a neurokinin-3 receptor antagonist (NK3RA) and it is indicated in the treatment of polycystic ovarian syndrome (PCOS). In aspects of the invention of WO 2014/170648 the NK3RA is disclosed as treating amenorrhea, oligomenorrhea and anovulation in PCOS. WO 2014/170648 also discloses the use of the NK3RA in the restoration of fertility. [0005] Compound (I) was initially investigated for the treatment of schizophrenia, which predated any understanding that the NKB pathway might be involved in reproduction. The data presented in the present application shows that Compound (I) has a contraceptive effect.

[0006] Currently prescribed contraceptive pills contain either a combination of an estrogen (estradiol) and a progestogen (progestin) or progestogen only. Hormone based contraception is contraindicated in a number of conditions, see UK Medical Eligibility Criteria for Contraceptive Use, Faculty of Sexual and Reproductive Health Care- Royal College of Obstetricians and Gynaecologists. In addition, despite developments in improving the safety profile of current oral contraceptives adverse metabolic and vascular effects caused by the estrogen component and possible neoplastic effects of oral contraceptives remain. The inability for sufferers of certain conditions to make use of a hormonal contraceptive and the incidents of side effects results in a need to provide nonsteroidal and non-hormonal contraceptives.

[0007] The present invention is a non-hormone compound with a contraceptive effect. Without being bound by theory, it is considered that the contraceptive effect of Compound (I) is sufficient to prevent release of an egg, due to inhibition of follicle development, yet mild enough not to reduce the body's own hormones to negligible amounts. It is believed that the present compounds might potentially reduce the amount of side effects associated with hormone based contraceptive therapies whilst offering an efficacious contraceptive.

BRIEF SUMMARY OF THE DISCLOSURE

[0008] In accordance with the present inventions there is provided use of Compound (I):

(I)

in the treatment of conditions modulated by NKB, for example reproductive conditions modulated by NKB. In an aspect of the invention there is provided the use of compound (I) as a contraceptive. The use of compound (I) may be for the inhibition of follicle

development. [0009] In another aspect of the invention there is provided Compound (I) for use in the treatment of conditions modulated by NKB, for example reproductive conditions modulated by NKB. In an aspect of the invention Compound (I) may be for use as a contraceptive. Optionally, Compound (I) is a contraceptive due to inhibition of follicle development.

Compound (I) may be for use in inhibiting follicle development.

[0010] In another aspect of the invention there is provided a pharmaceutical composition comprising Compound (I), wherein the composition is for use as a contraceptive. The pharmaceutical composition may alternatively or additionally be for use in the inhibition of follicle development.

[0011] The pharmaceutical composition may comprise Compound (I) in association with at least one pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical composition may comprise:

Compound (I);

mannitol and microcrystalline cellulose;

croscarmellose sodium,

hydroxypropyl cellulose,

sodium lauryl sulphate, and

magnesium stearate.

[0012] In an aspect of the invention there is provided a method of preventing conception, wherein the method comprises administering to a subject in need thereof a

pharmaceutically effective amount of Compound (I) or a pharmaceutically acceptable salt or solvate thereof. Optionally, conception is prevented by inhibition of follicle development. In an aspect there is provided a method of inhibiting follicle development, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of Compound (I) or a pharmaceutically acceptable salt or solvate thereof.

Compound (I) may be administered alone or Compound (I) may be administered in a pharmaceutical composition. Therefore, in an embodiment any method of the invention may comprise administering a pharmaceutical composition comprising Compound (I).

[0013] In any of the aspects or embodiments of the current invention Compound (I) may be for use in or for administration to a subject or patient who wishes to prevent conception. In any of the aspects or embodiments of the current invention Compound (I) may be for use in or for administration to a subject or patient for whom a hormone-based

contraceptive is contraindicated. For example, a hormone based contraceptive may be contraindicated in patients or subjects who have suffered from, been diagnosed with or are at risk of suffering from cardiovascular disease (including cardiovascular disease risk factors for example patients who are older or smoke), valvular heart disease, congenital heart disease, hypertension, diabetes, obesity, a venous thrombosis (e.g. a blood clot), a known thrombogenic mutation (e.g. Factor V Leiden, Prothrombin mutation, Protein S, Protein C, and Antithrombin deficiencies), ischemic heart disease, stroke, gall bladder disease, cholestasis, viral hepatitis, cirrhosis, systemic lupus erythematosus, focal migraines (e.g. migraines associated with sensory disturbance, sensory loss, visual disturbance or visual loss), migraines with aura, liver tumours, or hormone sensitive cancers (e.g. breast cancer, including carriers of known gene mutations associated with breast cancer for example BRCA1). In addition or alternatively the subject or patient may have experienced side effects with a hormone-based contraceptive, optionally wherein the side effects led to cessation of use of hormone-based contraceptives.

[0014] Therefore, any of the aspects or embodiments of the current invention may be used in or administered to a subject or patient who have suffered from, been diagnosed with or are at risk of suffering a venous thrombosis (e.g. a blood clot), focal migraines (e.g. migraines associated with sensory disturbance, sensory loss, visual disturbance or visual loss) or hormone sensitive cancers (e.g. breast cancer).

[0015] In an aspect of the invention there is provided a use of Compound (I) in the manufacture of a medicament for use as a contraceptive. There is also provided a use of Compound (I) in the manufacture of a medicament for use in inhibiting follicle

development.

[0016] The inhibition of follicle development, discussed herein, may be sufficient to prevent maturation of any follicles, thereby preventing release of an oocyte (also referred to as an egg) from an ovary. Inhibiting follicle development can have a contraceptive effect. Thus in embodiments Compound (I) is efficacious as a contraceptive due to inhibition of follicle development. Follicle development may be inhibited such that a diameter of a largest follicle is less than 1 1.0 mm, optionally less than 10.5 mm. The diameter of the largest follicle may be less than 10.0 mm, less than 9.8 mm, less than 9.5 mm, less than 9.3 mm, or less than 9.0 mm. The largest follicle may be in a size range selected from: 7.0 to 10.0 mm, 7.5 to 10.0 mm, 7.0 to 9.5 mm, 7.5 mm to 9.5 mm, 7.5 to 9.0 mm.

[0017] In any of the aspects or embodiments discussed herein Compound (I) may be for use in or for administration to a subject or patient who does not have polycystic ovary syndrome, for example a patient or subject who has not been diagnosed with polycystic ovary syndrome. Patients or subjects who do not have polycystic ovary syndrome (PCOS) may also fall within a patient or subject class discussed above. For example Compound (I) may be for use in or for administration to a patient or subject who does not have PCOS and for whom a hormone based contraceptive is contraindicated.

[0018] Preferably Compound (I) is the S enantiomer. Alternatively, Compound (I) is the R enantiomer. Preferably, Compound (I) is a compound according to Formula (II):

(N)

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

Figure 1 is a bar chart showing follicle diameter (mm) in women administered with Compound (I) compared to a control group of women.

Figure 2 is a bar chart showing estradiol concentration (pmol/L) in women administered with Compound (I) compared to a control group of women.

Figure 3 is a bar chart showing endometrial thickness (mm) in women

administered with Compound (I) compared to a control group of women.

Figure 4 is a bar chart showing LH concentration (International Units per liter—

"IU/L") in women administered with Compound (I) compared to a control group of women.

Figure 5 is a bar chart showing FSH concentration (IU/L) in women administered with Compound (I) compared to a control group of women.

Figures 6 shows the study protocol and assessment intervals for the study of Example 3.

Figure 7 is a bar chart showing follicle diameter (mm) in women administered with Compound (I) compared to a control group of women.

Figure 8 is a bar chart showing estradiol concentration (pmol/L) in women administered with Compound (I) compared to a control group of women. Figure 9 is a bar chart showing endometrial thickness (mm) in women

administered with Compound (I) compared to a control group of women.

Figure 10 is a bar chart showing LH concentration (IU/L) in women administered with Compound (I) compared to a control group of women.

Figure 11 shows that Compound (I) delays progesterone rise (centred on day of

LH surge in control cycle)

Figure 12 is a bar charting showing the postponed peak in progesterone and the postponed next menstrual cycle in subjects administered with Compound (I) compared to a control group.

DETAILED DESCRIPTION

[0020] The invention contemplates Compound (I) as a pharmaceutically acceptable salt or prodrug. These may include the acid addition and base salts of Compound (I). In addition the invention contemplates solvates of Compound (I). These may be hydrates or other solvated forms of the compound.

[0021] Suitable acid addition salts are formed from acids which form non-toxic salts.

Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,

hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[0022] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0023] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

by reacting the compound of the invention with the desired acid or base; by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0024] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[0025] Compound (I) may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

[0026] Included within the scope of the invention are complexes such as clathrates, drug- host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non- ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0027] Hereinafter all references to Compound (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0028] Compound (I) may include all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.

[0029] The present invention also includes all pharmaceutically acceptable isotopically- labelled versions of Compound (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0030] Examples of isotopes suitable for inclusion in Compound (I) include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S. [0031] Certain isotopically-labelled versions of Compound (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0032] Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0033] Before purification, Compound (I) may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.

[0034] Throughout the description the disclosure of Compound (I) encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. Both (R) and (S) stereoisomers of Compound (I) are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are contemplated by the present application.

Compound (I) may be present as a single stereoisomer or may be a mixture of

stereoisomers, for example racemic mixtures and other enantiomeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) of 100% but could have an e.e. or d.e. of about at least 85%

[0035] Compound (I) and the pharmaceutical compositions of the invention may be administered topically (e.g. to the skin) in the form, e.g. , of creams, gels, lotions, solutions suspensions or on a patch, or administered systemically, e.g. by an implantation; by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; vaginal administration in the form of a intrauterine coil, vaginal ring, gel, lotion, wax, pessary; or by inhalation in the form of an aerosol. Preferably, pharmaceutical compositions of the invention may be administered topically in the form of a patch, a tablet, a intrauterine coil, vaginal rings, by injection or as a pessary.

[0036] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0037] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[0038] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[0039] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0040] Compound (I) may be synthesised by any route known to a person skilled in the art. An exemplary synthesis of Compound (I) is described in WO 2007/069977 and WO 2014/170648, the disclosure of which is incorporated herein by reference.

[0041] Compound (I) and/or a composition comprising compound (I) may be

administered by any route known to the person skilled in the art. For example, Compound (I) and/or a composition comprising Compound (I) can be administered orally, parenterally, buccally, vaginally, rectally, by inhalation, by insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

[0042] Preferably, Compound (I) or a composition comprising Compound (I) will be administration orally, optionally by ingestion. [0043] The quantity of the Compound (I) to be administered will vary for the patient being treated. Any dose of Compound (I) that provides a contraceptive effect or an inhibitory effect for follicle development without causing toxicity may be administered to a patient or subject. For example the dose may vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day. Dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, the skilled artisan can readily determine the amount of Compound (I) to be administered and in addition the amount of optional additives, vehicles, and/or carriers in compositions comprising Compound (I).

[0044] The quantity of Compound (I) to be administered will vary from about 5 mg to 100 mg per day. Optionally, Compound (I) may be administered in a dose of: from 5 mg to 80 mg, from 10 mg to 80 mg, from 10 mg to 60 mg, from 20 mg to 80 mg, from 20 mg to 60 mg, from 30 mg to 60 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 35 mg to 100 mg, from 35 mg to 90 mg, from 35 mg to 80 mg, from 30 mg to 100 mg, from 30 mg to 90 mg, or from 30 mg to 80 mg. Preferably, Compound (I) will be administered in a dose of from 20 mg to 60 mg; from 20 mg to 50 mg; or 30 mg to 50 mg. Doses indicated may be the amount of a single administration. A dose may be administered more than once in a day. Therefore, daily administration may be a multiple of the doses indicated, for example administration twice daily will give a total dose two times the doses indicated. Optionally, the dose of Compound (I) discussed in this paragraph may be administered twice per day. Therefore, the daily dosage may be from 40 mg to 120 mg; from 40 mg to 100 mg; or 60 mg to 100 mg

[0045] Compound (I) may be administered following any dosage regimen known to one skilled in the art. For example, Compound (I) may be administered once a day, twice a day, three times a day or four times a day. Optionally, the dose of Compound (I) may be administered twice a day. There may be a period of at least 2 hours between 2 doses taken in the same day. There may be a period of at least 4 hours between the 2 doses taken in the same day. There may be a period of at least 6 hours between the 2 doses taken in the same day. There may be a period of at least 8 hours between the 2 doses taken in the same day. There may be a period of at least 10 hours between the 2 doses taken in the same day. The total daily dosage may be in the range 20mg to 180mg. The total daily dosage may be in the range 40mg to 80mg. The total daily dosage is in the range 70mg to 90mg. The total daily dosage is about 80mg of NK3R. The total daily dosage may be about 80mg administered as a 40mg dose twice a day.

[0046] Exampie 1

[0047] 3-(Methanesulfonamido)-2-phenyl-N-[(1S)-1-phenylpropyl1quinoline- 4-carboxamide (Compound (I)) may be prepared as follows: [0048] To 3-[(methylsulfonyl)amino ]-2-phenylquinoline-4-carboxylic acid (lc) (20.00g, 58.4 mmol) in ethyl acetate (180mi) 1 , 1 '<carbonyldiimidazole (13.26g_: 81.8mmoi) is added. The resulting slurry is heated to 50 °C and the reaction mixture stirred at 50 °C for 6h. (S)- (-)-l-phenylpropylamine (11.85g, 87.6 mmol) in ethyl acetate (15m1) is then added and the reaction mixture further heated to 70°C and stirred for 8 h. The solution is then cooled to room temperature and the residue partitioned between ethyl acetate and aqueous hydrochloric acid. The organic phase is then co-distilled with isopropanol to result in an isopropanol solution. This is then seeded and cooled. The solid is collected by filtration, washed with isopropanol and dried to yield the title compound (19.74g, 74%) as a solid.

[0049] ¹ HNMR (300MHz, CDCb,) δ 0.94 (t, 3H) 1.97 (m, 2H), 3.44 (s, 3H), 5.17 (q, 1 H), 5,47 (m, 2H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1 H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m,

[0050] 1 H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z ~ 460 (M+1).

[0051] The starting acid, 3-[(methylsulfon y1)amino] -2-phenylquinoline-4-carboxylic acid (1 c), may be prepared in the following manner:

[0052] N-(2-oxo-2-phenylethyl)methanesuifonamide (I b)

[0053] A solution of 2-amino-i-phenylethanonehydrochloride (200g, 1.165mol) in NMP (800 rnl.) is formed and after cooling, methyl sulfonyl chloride (1 17.3ml_, 1.515mol) is added slowly. This is followed by the slow addition of N-methylmorpholine

(450.1 m1 ,4.078mol), the reaction mixture is then stirred at 0 C for 1 h. The mixture is warmed, with brine and seed then being added. The result slurry is cooled and solid collected by filtration, washed with water and dried to yield the title compound (209.9g, 85%) MS APCI m/z = 214 (M+l).

[0054] 3-[(methylsulfonyl)amino1-2-phenylquinoline-4-carboxylic acid (1 c)

[0055] A slurry of N-(2-oxo-2-phenylethyl)methanesulfonamide (lb) (100g, 0.469mol) and isatin (69g, 0.469mol) in isopropanol (700ml) is heated to 50°C. Aqueous sodium hydroxide (133ml, 2.334rnol) is added. The reaction mixture is heated to 75°0 and stirred for 1 h. The resulting solution is cooled and acidified with hydrochloric acid to pH4. The solution is seeded and further hydrochloric acid added to achieve pH2-3. The resulting solid is coiiected by filtration, washed with isopropanol and water and dried to yield the title compound (112.1g, 65%). ¹ H NMR (300MHz, CDCb) δ 3. 1 (s, 3H), 7005 (d, 1 H), 7.39 (d, 2H), 7.64 (m, 2H), 7.78 (m, 1 H), 8.06 (m, 1 H), 8.19 (m, 1 H), 8.47 (m, 1 H), 10.03 (b, 2H). MS APCI, m/z = 343 (M+ 1). [0056] Example 2

[0057] Below we discuss a study into the effect of Compound (I) on eight healthy women. The eight women had regular menstrual cycles and were administered with Compound (I), 40mg po twice daily for 5 days from menstrual cycle day 4-5. A transvaginal ultrasound scan was performed at the end of drug administration to measure follicle diameter and endometrium thickness, and serum gonadotrophins (luteinising hormone (LH) and follicle- stimulating hormone (FSH)) and estradiol were measured. The LH, FSH and estradiol levels were measured using the commercially available assay system - ARCHITECT Chemiluminescent Micro particle Immunoassays (CIMA's) from Abbott. Each sample was prepared and tested as follows:

• Sample and anti-hormone coated paramagnetic micro particles were combined;

• Hormone present in the sample was bound to the coated microparticles;

• Anti-hormone acridinium-labeled conjugate was added;

• Activating solutions were added;

· Resulting chemiluminescent reaction was measured as relative light units (RLUs); and

• Amount of hormone present in sample was correlated with RLUs detected by

analyser.

[0058] The results observed in the eight women administered with Compound (I) were cycle day matched to 9 control women receiving no treatment and the results were compared.

[0059] The results of the study are shown in Figures 1-5. Figure 1 shows the diameter of the largest follicle in women treated with Compound (I) was 8.3 ± 0.4 mm, significantly smaller than 11.8 ± 0.7 mm in control women (p=0.0006). Figure 2 shows serum estradiol concentrations were also significantly reduced in women treated with Compound (I) (122.3 ± 22.1 pmol/L vs 281.8 ± 43.8 pmol/L, p=0.007). In keeping with a reduction in the estradiol concentrations endometrial thickness was also reduced (3.7 ± 0.3 vs 6.5 ± 0.9 mm, p=0.05), as shown in Figure 3. LH concentration was however not significantly altered following 5 days of administration with Compound (I) (pretreatment LH 4.9 ± 0.6 IU/L vs posttreatment 6.2 ± 1.5 IU/L, p=0.4) or when compared to control women (LH 4.4 ± 0.6 IU/L, p=0.2). FSH concentration was higher in women treated with Compound 1 (4.6±0.4 IU/L vs 2.6±0.3 in controls, p=0.0007). One woman had minimal vaginal bleeding; there were no adverse events. [0060] We have shown for the first time that an NK3R antagonist, Compound (I), is a potent suppressor of follicle development. These data clearly show evidence of suppression of ovarian activity. This shows that Compound (I) is efficacious as a contraceptive and as an agent for inhibiting follicle development.

[0061] These results very clearly show a suppression of follicle development and estradiol secretion in women taking Compound (I). This is evidenced in both the smaller follicle, the reduced estradiol concentrations, and the thinner endometrium. We

hypothesised that we would see a suppression of LH and FSH secretion in women taking this drug, but this is not evident. Wthout being bound by theory, in the case of LH that this is likely to be because of the pulsatile nature of secretion of this hormone and the single time point analysis as we have performed may be insufficient to show this. The mildly elevated FSH concentrations are, however, consistent with a slight suppression of gonadotrophin-releasing hormone (GnRH), perhaps paradoxically, because serum FSH is primarily controlled by estradiol negative feedback, and thus reduced estradiol negative feedback will increase FSH even in the presence of reduced GnRH secretion. Estrogen production from the ovary is driven by LH and FSH thus the lower estradiol concentrations indicate that there may well be an overall suppression of LH secretion that we have not identified with the current sampling methodology.

[0062] Example 3

[0063] The data given in Example 2 was validated by a further study conducted on six healthy women administered with Compound (I). The six healthy women recruited into the study had regular menstrual cycle and were taking no hormonal contraceptives. The study was over two menstrual cycles, which did not have to be consecutive. Volunteers were randomised to start with either the control (i.e. no treatment) or the treatment (Compound (I)) cycle. Each volunteer returned in the subsequent menstrual cycle for an alternate treatment allocation (i.e. control cycle, if the volunteer started with the treatment cycle, and a treatment cycle, if the first cycle was a control one). Compound (I) was administered orally at 40mg twice a day for 7 days in the early follicular phase of the menstrual cycle (starting from cycle day 5). Serum hormones (LH, FSH and estradiol) were measured and transvaginal ultrasonography performed to assess the size of the leading follicle and endometrial thickness through the follicular phase of the cycle until ovulation (see Fig. 6 for the study protocol and assessment intervals). Ovulation was confirmed either by the disappearance of the dominant follicle or the appearance of corpus luteum. Urine was collected daily until next menses for progesterone analysis. Volunteers were followed up by telephone consultation to ascertain the next menstrual period. Data were compared by ANOVA with Bonferroni multiple comparison post hoc analysis and by paired t-test as appropriate. Ethical approvals and informed consent were obtained.

[0064] The data generated from this study is shown in Figure 7 to 12. Figure 7 shows the statistically significant reduction in the size of the largest follicle in subjects

administered with Compound (I) (referred to as NK3Ra in Figures 7 to 12). Similarly Figure 8 shows a reduction in estradiol levels in subjects administered with Compound (I) when compared to the control. Figures 9 to 12 also confirm the beneficial contraceptive effect of Compound (I).

[0065] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0066] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0067] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Claims

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1. Use of Compound (I) or a pharmaceutically acceptable salt or solvate thereof:

(I)

in the treatment of conditions modulated by NKB.

2. Use of Compound (I) or a pharmaceutically acceptable salt or solvate thereof:

(I)

a contraceptive.

A compound for use as a contraceptive, wherein the compound is Compound (I):

(I)

or a pharmaceutically acceptable salt or solvate thereof. P222898W01

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4. The compound of claim 3, wherein the compound is for use as a contraceptive in a subject or patient for whom a hormone-based contraceptive is contraindicated

5. A compound for use in inhibiting follicle development, wherein the compound is Compound (I):

a pharmaceutically acceptable salt or solvate thereof.

A pharmaceutical composition comprising Compound (I):

(I)

wherein the composition is for use as a contraceptive

7. A method of preventing conception comprising administering to a subject in need thereof a pharmaceutically effective amount of Compound (I):

(I) P222898W01

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8. The method of claim 6, wherein conception is prevented by inhibiting follicle development.

9. The method of claim 6 or claim 7, wherein a hormone-based contraceptive is contraindicated for the subject in need thereof.

10. A method of inhibiting follicle development comprising administering to a subject ^' need thereof a pharmaceutically effective amount of Compound (I):

(I)

or a pharmaceutically acceptable salt or solvate thereof.

The method of claim 9, wherein a hormone-based contraceptive is contraindicated for the subject in need thereof.