Methods for treating or preventing endometriosis

Abstract

Provided herein are compounds of formula (I), as defined herein, or pharmaceutically acceptable salts thereof, and formulations containing same for use in the treatment or prevention of endometriosis.

Description

[Technical Field]

[0001] The present invention relates to the use of certain compounds or pharmaceutically acceptable salts thereof in the treatment or prevention of endometriosis, as well as pharmaceutical compositions, combinations and kits containing them. [Background technology]

[0002] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0003] Endometriosis is a disorder in which endometrial tissue grows outside the uterus, typically around the lining of the pelvis, including around the ovaries, fallopian tubes, and bladder. Rarely, such endometrial-like tissue can also be found in areas of the body away from the reproductive organs.

[0004] With each menstrual cycle, this ectopic (extrapelvic) endometrium-like tissue breaks down and becomes trapped, causing significant pain and discomfort. In the case of ovarian endometriosis, cysts called endometriomas can form. The pain experienced is often severe and unfavorable to the patient's quality of life.

[0005] Over time, the irritation caused by endometriosis can lead to the development of scar tissue and adhesions that affect organs in the pelvic region, which is often associated with symptoms such as chronic pelvic pain (cyclic and non-cyclic), painful menstruation, painful sex, and painful bowel movements and urination, generally negatively impacting fertility.

[0006] Currently, there is no cure for endometriosis, but various treatments can help manage symptoms. Lesions, scar tissue, and adhesions resulting from endometriosis can be removed by surgery, but recurrence may follow. There has also been considerable research into the use of hormonal contraceptives as preventative agents (see, for example, Zorbas, KA et al., Archives of Gynecology and Obstetrics, 292(1), 37-43(2015)).

[0007] However, there remains a need for effective means for the long-term treatment and prevention of endometriosis.

[0008] NSAIDs are among the most used and recognized drugs in the world, with billions of doses prescribed each year to treat inflammation, pain, and fever. NSAIDs include traditional forms such as ibuprofen, naproxen, indomethacin, and diclofenac, as well as selective inhibitors of COX-2, such as celecoxib (Celebrex™).

[0009] NSAIDs and COX-2 inhibitors reduce inflammation by inhibiting one or both isoforms of the COX enzyme. Cyclooxygenase (COX) enzymes exist in two forms: one constitutively expressed in many cells and tissues (COX-1) and one induced by proinflammatory stimuli such as cytokines during an inflammatory response in most cells and tissues (COX-2).

[0010] COX metabolizes arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2), which then converts it into PGE2 and PGF 2αPGE2 is further metabolized to other prostaglandins, including PGD2, prostacyclin, and thromboxane A2. These arachidonic acid metabolites are known to have significant physiological and pathophysiological activities, including proinflammatory effects. PGE2, in particular, is known to be a potent proinflammatory mediator and to induce fever, inflammation, and pain. Therefore, numerous drugs have been developed with the aim of inhibiting the formation of PGE2, primarily through the inhibition of COX-1 and / or COX-2.

[0011] In recent years, concerns about cardiovascular side effects associated with the use of these drugs have led to a series of regulatory events, including (i) the withdrawal of the groundbreaking drug Vioxx in 2004, (ii) the introduction of a "black box" warning for some NSAIDs since 2005 and for all drugs in this class since 2015, (iii) the withdrawal of Onsenal (celecoxib) for cancer prevention in 2011, and (iv) the reclassification of the over-the-counter drug diclofenac as prescription-only in the UK in 2015. Currently, the fear of NSAID-induced cardiovascular events has become a public health issue, leading to cautious prescribing of COX-2-selective drugs in favor of older-style drugs that are more toxic to the gut and a failure to realize the full clinical potential of NSAIDs in cancer prevention (Scarpignato, C. et al., BMC Med., 13, 55 (2015); Garcia Rodriguez, LA, et al., Recent Results Cancer Res., 191, 67-93 (2013)). Furthermore, inhibition of COX has the drawback of resulting in a reduction in the formation of all downstream metabolites of PGH2, some of which are known to have beneficial properties.

[0012] Inhibition of mPGES-1 is a well-developed area of ​​preclinical research, with studies showing that its genetic deletion protects against inflammation, pain, and cancer (Friesen, RW and Mancini, JA, J Med Chem., 51, 4059-4067 (2008); Howe, LR et al., Prostaglandins Other Lipid Mediat., 106, 99-105 (2013); Korotkova, M. and Jakobsson PJ, Basic Clin Pharmacol Toxicol., 114, 64-69 (2014)). However, a lack of complete understanding surrounding cardiovascular toxicity and other adverse effects means that research and translation of mPGES-1 as a therapeutic target to replace COX-2 in the treatment of a wide range of diseases and disorders has been limited.

[0013] WO2012 / 022793A1 describes the use of various mPGES-1 inhibitors in the treatment of various inflammatory disorders. WO2017 / 144909A1 describes the use of various mPGES-1 inhibitors in the treatment of diseases and disorders characterized by vasoconstriction. These disclosures do not teach or suggest the treatment or prevention of endometriosis. DETAILED DESCRIPTION OF THE INVENTION

[0014] It has now surprisingly been found that certain compounds described herein are effective agents for the treatment or prevention of endometriosis.

[0015] In a first aspect of the invention, there is provided a compound of formula I, [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of endometriosis.

[0016] In an alternative first aspect of the present invention, there is provided a method for the treatment or prevention of endometriosis, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof.

[0017] In a further alternative first aspect of the present invention there is provided the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of endometriosis.

[0018] In a further alternative first aspect of the present invention there is provided the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, in the treatment or prevention of endometriosis.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0020] Those skilled in the art will understand that reference herein to a particular aspect of the invention includes reference to all embodiments and specific features thereof. Moreover, all embodiments of a particular aspect of the invention may be combined with one or more other embodiments to form further embodiments without departing from the teachings of the present invention.

[0021] Compounds of the Invention Those skilled in the art will understand that reference to a compound of formula I refers to the following compound: [ka] This compound, together with its pharmaceutically acceptable salts, may also be referred to herein as the compound(s) of the invention.

[0022] Those skilled in the art will also understand that the compound of formula I can also be referred to by the chemical name 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (trans-4-trifluoromethylcyclohexyl)-amide.

[0023] Pharmaceutically acceptable salts include acid addition salts.Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization or filtration).Salts can also be prepared by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0024] Specific acid addition salts include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, salts, such as maleates, hydroxymaleates, hippurates, phthalates, or terephthalates), halide salts (e.g., chlorides, bromides, or iodides), sulfonates (e.g., benzenesulfonates, methyl-, bromo-, or chloro-benzenesulfonates, methyl-, bromo-, or chloro-benzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxy-ethanesulfonates, 1- or 2-naphthalenesulfonates, or 1,5-naphthalenedisulfonates), or sulfates (e.g., dihydrogen sulfates), pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, or nitrates.

[0025] Particular pharmaceutically acceptable salts that may be mentioned include dihydrogen sulfate (also called hydrogen sulfate, H2SO4) salts.

[0026] For the avoidance of doubt, those skilled in the art will understand that the compounds of the present invention may exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline, and partially crystalline forms thereof, and may also exist as oils. When such compounds exist in crystalline and partially crystalline form, such forms may include solvates, which are also included within the scope of the present invention. Such compounds may also exist in solution.

[0027] The compounds of the invention may also exhibit tautomerism, and all tautomers and mixtures thereof are included within the scope of the invention.

[0028] As described herein, the compounds of the present invention have a particular orientation of the substituents. For the avoidance of doubt, the compounds of the present invention have the stereochemistry as shown, which may be referred to as the trans orientation.

[0029] Those skilled in the art will appreciate that the present invention may utilize not only the compounds of the present invention themselves, but also compounds that may be administered to a patient (e.g., parenterally or orally) and subsequently metabolized in the body to form the compounds of the present invention. Such compounds may be described as prodrugs of the compounds of the present invention.

[0030] medical use As described herein, the compounds of the present invention are used to treat or prevent endometriosis in a patient in need thereof.

[0031] Those skilled in the art will understand that references to specific diseases and disorders have their ordinary meaning as understood by those skilled in the art.

[0032] Those skilled in the art will understand that references to "treatment" of a particular disease (or, equivalently, "treating" the disease) have their ordinary meaning in the medical arts. In particular, the term may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the disease, even if a diagnosis has not yet been determined at the time of treatment of such symptoms. Such reduction may be measured using objective analysis (e.g., measurement of physiological factors and / or visualization of disease markers, such as a reduction in the size and / or number of lesions) and / or subjective analysis (e.g., assessment by examination by a physician or patient-reported outcomes, such as reduced pain assessed using an appropriate pain scale and improved assessment of quality of life).

[0033] Those skilled in the art will understand that reference to the prevention of a particular disease has its usual meaning in the medical field. In particular, the term can refer to achieving a reduction (e.g., at least a 10% reduction, at least a 20%, 30%, or 40% reduction, etc., e.g., at least a 50% reduction) in the likelihood that a patient (or a healthy patient) will develop the disease. Those skilled in the art will also understand that the prevention of a particular disease may also be referred to as preventing the disease, and these terms may be used interchangeably.

[0034] Those skilled in the art will appreciate that prophylaxis can be practiced in patients who do not suffer from the relevant disorder (i.e., as they will develop the relevant disorder). In particular, prophylaxis can be practiced in patients who do not suffer from the relevant disorder but who are at risk of developing the relevant disorder (e.g., because they have previously suffered from it).

[0035] In certain embodiments, reference to the treatment or prevention of endometriosis may refer to a reduction (i.e., a clinically significant reduction) or reduction in the formation of lesions, adhesions and / or scar tissue associated with endometriosis.

[0036] One skilled in the art will be able to identify patients (who may otherwise be healthy) in need of disease or disorder prevention, such as patients who are at risk of developing the associated disorder (e.g., patients who have previously been treated for the disorder but do not currently have the disorder).

[0037] Those skilled in the art will be able to use routine techniques in the art to determine whether a patient has or is at risk of developing a relevant disorder. For example, a patient who does not have a relevant disorder may be one who is not experiencing the relevant symptoms (such as pain or infertility due to the disease) at the time the prevention is administered.

[0038] Without wishing to be bound by theory, it is believed that the compounds of the present invention may enable the treatment of endometriosis in a manner that provides therapeutic benefits in addition to those provided by similar drugs prescribed for the treatment of the disease, such as those prescribed for the treatment of pain (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), and paracetamol). Furthermore, it is believed that the compounds of the present invention may be administered in a continuous manner with a lower risk of adverse drug reactions than those associated with similar drugs prescribed for the treatment of the disease, such as those prescribed for the treatment of pain and / or hormonal agents.

[0039] In certain embodiments, the treatment or prevention (e.g., treatment) described herein requires continuous daily administration of a compound of the invention (i.e., daily administration of a therapeutically effective amount described herein).

[0040] In more particular such embodiments, treatment or prevention may be referred to as long-term treatment (which may refer to a period of at least 6 weeks, such as a period of at least 12 weeks, at least 24 weeks, or at least 48 weeks).

[0041] In more particular such embodiments, continuous daily administration (including extended periods of continuous daily administration, i.e., extended periods of continuous daily administration) includes periods during which the patient is experiencing (a) significant pain (which may be defined as greater than moderate pain) and / or (b) no menstruation.

[0042] As used herein, reference to a patient refers to a living organism to be treated, including a mammalian patient. In certain embodiments, reference to a patient refers to a human patient.

[0043] Thus, in certain embodiments, the treatment or prevention described herein is carried out in a mammal (eg, a human).

[0044] Those skilled in the art will appreciate that because endometriosis is a disease of the female reproductive system, patients are expected to be biologically female patients, typically of reproductive age.

[0045] As used herein, the term "therapeutically effective amount" (also referred to as "effective amount") refers to the amount (i.e., dose) of a compound that provides a therapeutic effect to the treated patient. The effect may be objective (i.e., measurable by some test or marker, such as by achieving a specific level of inhibition of a target enzyme, or by achieving a specific effect on the size and / or number of lesions as assessed by imaging techniques), or may be subjective (i.e., the subject gives an indication of and / or feels an effect). Those skilled in the art will be able to determine a suitable therapeutically effective dose using techniques routinely used in the art.

[0046] For example, particular doses that may be mentioned include doses ranging from about 10 to about 200 mg per day (adjusted if used in non-salt, free base form, salt form), which may be administered as a once-daily dose (OxD) or between two doses per day (BixD).

[0047] Those skilled in the art will appreciate that both treatment and prevention of the diseases described herein may be achieved by repeated administration of the compounds of the invention, for example by administering a suitable dose and / or administration daily (e.g., once or twice per 24 hours) in a form that allows for extended release of the active ingredient (e.g., release over at least 12 hours, e.g., at least 24 hours) from suitable dosage forms known to those skilled in the art.

[0048] One of ordinary skill in the art will understand that prevention of a particular disease or disorder may be carried out in conjunction with treatment of another disease or disorder, or vice versa, where the disease being treated is either unrelated or an underlying (e.g., causative) factor for the disease or disorder for which prevention is provided.

[0049] Furthermore, those skilled in the art will appreciate that the present invention may be particularly suited to the treatment of chronic diseases, such as chronic symptoms of those diseases and disorders mentioned herein. As used herein, those skilled in the art will appreciate that reference to a chronic disease refers to a disease that persists for an extended period of time (e.g., at least 3 months, such as at least 6 months or at least 1 year).

[0050] Without wishing to be bound by theory, it is believed that the compounds of the present invention may be particularly useful for treating endometriosis in patients who are intolerant to, unable to switch to, unable to prescribe, or who are refractory to treatment with other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease or disorder (such as NSAIDs, hormones, paracetamol, anticonvulsants, TCAs, SSRIs / SNRIs, and / or opioids).

[0051] In certain embodiments, the treatment or prevention (e.g., treatment) is in combination with one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease: (i) Unbearable or (ii) have since switched or reduced their dose; (iii) it cannot be prescribed, or (iv) in patients who are refractory to it.

[0052] Those skilled in the art will understand that a reference to one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease refers to one or more (e.g., one) other therapeutic agent(s) previously prescribed (and administered) to the patient for that purpose, which may refer to one or more prior drugs other than the compound of the invention.

[0053] Other therapeutic agents for the treatment or prevention (e.g., treatment) of endometriosis described herein (including all embodiments and specific features thereof) include NSAIDs, hormones, paracetamol, anticonvulsants, TCAs, SSRIs / SNRIs and / or opioids.

[0054] In certain embodiments, the one or more other therapeutic agents for the treatment or prevention (eg, treatment) of endometriosis is an NSAID.

[0055] Specific NSAIDs that may be mentioned include aspirin, celecoxib, ibuprofen, naproxen and diclofenac, indomethacin, and etoricoxib.

[0056] In certain embodiments, the one or more other therapeutic agents for the treatment or prevention (eg, treatment) of endometriosis is a CNS acting agent.

[0057] Specific CNS acting agents that may be mentioned include TCAs (e.g., amitriptyline), anticonvulsants (e.g., gabapentin, pregabalin), SSRIs / SNRIs (e.g., duloxetine, milnacipran), and opioids (e.g., morphine, buprenorphine).

[0058] In certain embodiments, the one or more other therapeutic agents for the treatment or prevention (eg, treatment) of endometriosis is a hormonal agent.

[0059] Specific hormonal agents that may be mentioned include hormonal contraceptives such as combined (estrogen and progesterone) contraceptives, progestogens, antiprogestogens, contraceptive patches and gonadotrophin-releasing hormone (GnRH) analogues (agonists and antagonists that may be administered with low doses of estrogen), regulators of hormone synthesis or metabolism (such as aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, and steroid sulfatase inhibitors).

[0060] In certain embodiments, the one or more other therapeutic agents for the treatment or prevention (eg, treatment) of endometriosis is paracetamol.

[0061] In an alternative embodiment, the one or more other therapeutic agents for the treatment or prevention (eg, treatment) of endometriosis is other than paracetamol.

[0062] For example, in certain embodiments where one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of endometriosis are other than paracetamol, treatment or prevention with paracetamol may be continued along with treatment or prevention with a compound of the invention.

[0063] In certain embodiments, the treatment or prevention (eg, therapy) is in a patient who is intolerant to one or more other therapeutic agents for the treatment or prevention (eg, treatment) of the same disease.

[0064] Those skilled in the art will understand that reference to a patient who has failed to tolerate one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease refers to a patient for whom such treatment or prevention is determined by a physician or appropriate medical professional to be inappropriate based on suitable medical parameters, such as the level of adverse events experienced by the patient and / or the patient's lack of willingness to continue such treatment or prevention.

[0065] In certain embodiments, where the one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease are hormonal agents, such adverse events may be Weight gain, decreased libido, osteoporosis, suicidal thoughts, depression and / or anxiety, Depression, and Symptoms of menopause (hot flashes, hot flushes, etc.) may be selected.

[0066] In certain embodiments, in which the one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease are NSAIDs, such adverse events include cardiovascular adverse events (including myocardial infarction (MI), stroke, heart failure (HF), elevated blood pressure, atrial fibrillation, and venous thromboembolism), Renal dysfunction, and asthma, Gastrointestinal adverse events (including dyspepsia, bleeding, ulceration, gastric or intestinal perforation) may be selected from:

[0067] In certain embodiments, where one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease are CNS-active agents, such adverse events may be anticholinergic effects, mood disorders, drowsiness, Blurred vision, addiction, constipation, and The development of resistance may be selected against.

[0068] In a further embodiment, the treatment or prevention (e.g., treatment) is in a patient who has switched or reduced the dose of one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease.

[0069] Those skilled in the art will understand that reference to a patient who has switched from one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease refers to a patient who has discontinued treatment or prevention with one or more other therapeutic agents and switched to treatment or prevention with a compound of the present invention (e.g., initiating treatment or prevention immediately after, which may refer to the absence of intervening treatment or prevention (e.g., treatment) of the same disease). This may be done under the direction of a physician or appropriate medical professional.

[0070] Those skilled in the art will understand that a reference to a patient who has reduced the dose of one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease refers to a patient who continues treatment or prevention with the one or more other therapeutic agents, but who has reduced the dose of the one or more other therapeutic agents as directed by a physician or appropriate medical professional before initiating treatment or prevention with a compound of the invention.

[0071] Those skilled in the art will also understand that reference to reducing the dose of one or more other therapeutic agents refers to a patient receiving a lower daily dose thereof by reducing the frequency of treatment, such as by reducing the dose administered at each occurrence and / or by reducing the frequency of administration throughout the day and / or by reducing the number of days that treatment is administered (e.g., during a typical 30 day period).

[0072] For the avoidance of doubt, reference to reducing the dose of one or more other therapeutic agents will indicate that treatment or prophylaxis with the one or more other therapeutic agents is continued (at reduced levels) during treatment or prophylaxis with a compound of the invention.

[0073] In certain embodiments, the treatment or prevention (eg, therapy) is in a patient who has switched from one or more other therapeutic agents for the treatment or prevention (eg, treatment) of the same disease.

[0074] In a further embodiment, the treatment or prevention (eg, treatment) is in a patient who has reduced doses of one or more other therapeutic agents for the treatment or prevention (eg, treatment) of the same disease.

[0075] In further embodiments, the treatment or prevention (e.g., treatment) is in a patient who cannot be prescribed one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease.

[0076] Those skilled in the art will understand that a reference to a patient who cannot be prescribed one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease refers to a patient who cannot be prescribed one or more other therapeutic agents, as determined by a physician or appropriate medical professional based on pertinent medical parameters, such as the patient's health, physiology, and / or medical history, or other similar factors, and / or the patient's unwillingness to accept such one or more other therapeutic agents.

[0077] In certain embodiments, treatment or prevention is in patients who cannot be prescribed one or both of an NSAID and a hormonal agent, such as those described herein.

[0078] In certain embodiments, the treatment or prevention is in patients who cannot be prescribed an NSAID such as those described herein.

[0079] In certain embodiments, the treatment or prevention is in patients who cannot be prescribed hormonal agents such as those described herein.

[0080] In certain embodiments, the patient may not be prescribed one or more other therapeutic agents based on suitable medical parameters, such as the patient's health, physiology, and / or medical history.

[0081] In certain embodiments, the treatment or prevention described herein is in a patient in whom a hormonal agent (such as those described herein) cannot be prescribed because the patient has previously experienced (i.e., has a history of) one or more conditions selected from the following: depression and / or anxiety, Depression, and Symptoms of menopause (such as hot flashes / flushes).

[0082] In certain embodiments, the treatment or prevention described herein is in patients who cannot be prescribed one or more other therapeutic agents because the patient is attempting to conceive, i.e., intending to become pregnant (including patients undergoing infertility treatments such as in vitro fertilization (IVF)).

[0083] For example, in more specific embodiments, the treatment or prevention described herein is in patients in whom NSAIDs and / or hormones (such as those described herein) cannot be prescribed because the patient is attempting to conceive.

[0084] In certain such embodiments, if the patient is attempting to conceive, the one or more other therapeutic agents may be other than paracetamol (e.g., such as those described herein other than paracetamol).

[0085] In certain embodiments, the treatment or prevention described herein is in a patient in whom an NSAID (such as those described herein) cannot be prescribed because the patient has previously experienced (i.e., has a history of) one or more of the following: adverse cardiovascular events (including myocardial infarction (MI), stroke, heart failure (HF), elevated blood pressure, atrial fibrillation, and venous thromboembolism); Gastrointestinal adverse events (including gastric ulcers).

[0086] In certain embodiments, the patient cannot be prescribed one or more other therapeutic agents due to a lack of willingness (eg, refusal) to accept such one or more other therapeutic agents.

[0087] In certain embodiments, the unwillingness to accept such one or more other therapeutic agents is a result of (i.e., caused by) the patient's cultural, social, religious and / or political practices or beliefs.

[0088] For example, in certain embodiments, a patient cannot be prescribed hormonal medication due to a lack of willingness to accept such treatment due to cultural, social, religious and / or political practices or beliefs.

[0089] In a further embodiment, the treatment or prevention (eg, treatment) is in a patient who is refractory to one or more other therapeutic agents for the treatment or prevention (eg, treatment) of the same disease.

[0090] Those skilled in the art will understand that reference to a patient who is refractory to one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease refers to a patient for whom such treatment or prevention has been determined by a physician or appropriate medical professional to be inappropriate based on lack of efficacy of such treatment or prevention, which may refer to a disease that does not respond (or does not respond adequately) to such treatment or prevention.

[0091] In certain embodiments, the treatment or prevention (eg, treatment) is in patients who are refractory to treatment or prevention (eg, treatment) of the same disease with an NSAID and / or a hormonal agent.

[0092] In certain embodiments, the treatment or prevention (eg, treatment) is in a patient who is refractory to treatment or prevention (eg, treatment) of the same disease with an NSAID.

[0093] In certain embodiments, the treatment or prevention (eg, treatment) is in a patient who is refractory to treatment or prevention (eg, treatment) of the same disease with a hormonal agent.

[0094] As described herein, treatment or prevention with the compounds of the present invention may enable treatment or prevention in, or may be particularly beneficial for, particular patient groups.

[0095] In certain embodiments, treatment or prophylaxis (e.g., treatment) is in a patient experiencing and / or previously experiencing: depression and / or anxiety, Depression and / or Symptoms of menopause (such as hot flashes / flushes).

[0096] In certain embodiments, treatment or prevention (e.g., treatment) is in a patient experiencing, at risk of experiencing, and / or previously experiencing: adverse cardiovascular events (including myocardial infarction (MI), stroke, heart failure (HF), elevated blood pressure, atrial fibrillation, and venous thromboembolism), renal dysfunction, and / or Gastrointestinal adverse events (including gastric ulcers).

[0097] In certain embodiments, treatment or prevention (e.g., treatment) is in patients who are attempting to conceive, i.e., intending to become pregnant (including patients undergoing infertility treatments such as in vitro fertilization (IVF)).

[0098] In certain embodiments, treatment or prevention of the associated disease may further include treatment or prevention of reduced fertility (e.g., infertility), which may refer to reduced fertility resulting from the disease (i.e., caused by the effects of the disease).

[0099] In such embodiments, treating or preventing reduced fertility may result in a reduction in the use of IVF and an increase in the number of pregnancies (ie, the rate of bringing babies home).

[0100] Thus, the compounds of the invention may also be useful in preventing or treating (e.g., preventing) infertility associated with endometriosis, which may result in a reduction in the use of IVF and / or an increase in the number of pregnancies (rates of bringing babies home).

[0101] Thus, in an alternative aspect of the present invention there is provided a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of infertility associated with endometriosis.

[0102] In a further alternative aspect of the present invention, there is provided a method for the prevention or treatment of infertility associated with endometriosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof.

[0103] In a further alternative aspect of the present invention there is provided the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of infertility associated with endometriosis.

[0104] Those skilled in the art will understand that reference to infertility associated with endometriosis may refer to reduced or impaired fertility (ability to conceive) in patients with endometriosis, where the infertility has been determined to be or is expected to be due to the effects of endometriosis (e.g., the formation of lesions, adhesions and / or scar tissue affecting the reproductive organs around the uterus and / or ovaries).

[0105] In certain embodiments, treatment may be for a patient experiencing significant pain (which may be defined as moderate or greater), which pain may occur during menstruation or during the menstrual cycle (e.g., between menstrual cycles).

[0106] In such embodiments, the treatment may result in treatment of such pain.

[0107] In certain embodiments, treatment or prophylaxis (e.g., treatment) can be in a patient experiencing pain associated with: reduced quality of life, Decreased ability to perform activities of daily living, cognitive impairment, reduced social interaction, decreased libido, dyspareunia, Symptoms of depression and anxiety, and / or Impaired (or reduced) mobility.

[0108] In certain embodiments, treatment or prophylaxis (e.g., treatment) may be in a patient experiencing chronic pain, such as chronic pain associated with: Dysmenorrhea (premenstrual, menstrual, postmenstrual), lower back pain, Pain associated with ovulation, dyspareunia, muscle and / or joint pain, shortness of breath, chest pain and / or cough, and / or in certain cases, collapsed lungs; Painful defecation, chronic pelvic pain, cyclic pelvic pain, urinary problems, and / or Burning sensation in the vagina.

[0109] In certain embodiments, treatment or prophylaxis (e.g., treatment) can be in a patient experiencing chronic pelvic pain:

[0110] In such embodiments, treatment may result in treatment of such associated factors.

[0111] In certain embodiments, treatment may be in patients experiencing irregular, reduced, or disrupted menstrual cycles.

[0112] In such embodiments, treatment may result in the patient achieving regular menstrual cycles.

[0113] In certain embodiments, the treatment or prophylaxis (e.g., treatment) is in patients who are unsuitable for surgical treatment for the treatment of the associated disease, as determined by a physician or suitable medical professional based on suitable medical parameters.

[0114] In certain embodiments, the treatment or prophylaxis (eg, treatment) is in patients who have previously undergone surgical treatment for the treatment of the relevant disease, which may be referred to as post-operative treatment or prophylaxis.

[0115] In certain embodiments, the post-operative treatment is in patients experiencing significant pain, which may be defined as more than moderate pain.

[0116] As described herein, treatment or prevention (e.g., treatment) with a compound of the invention may be associated with an effect other than the treatment or prevention of pain. For example, treatment or prevention (e.g., treatment) with a compound of the invention may be associated with a reduction in the size and / or number of (e.g., resulting in / inducing) endometrial lesions (which may also be called lesions and / or cysts), such as endometriomas.

[0117] Pharmaceutical Formulations, Combinations and Kits Those skilled in the art will appreciate that the compounds of the present invention can be administered in the form of pharmaceutical formulations.

[0118] In a second aspect of the present invention, there is provided a pharmaceutical formulation comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, for use in the treatment or prevention of endometriosis.

[0119] In an alternative second aspect of the present invention, there is provided a method for the treatment or prevention of endometriosis, comprising administering to a patient in need thereof a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0120] Those skilled in the art will appreciate that the compounds of the present invention, and pharmaceutical formulations containing same, can be administered systemically and / or locally (eg, topically).

[0121] Those skilled in the art will appreciate that the compounds of the present invention, and pharmaceutical formulations containing same, are typically administered in a pharmaceutically acceptable dosage form, orally, intravenously, subcutaneously, buccally, rectally, vaginally, intradermally, intranasally, bronchially, sublingually, intranasally, topically, intrauterinely, intraperitoneally, by any other parenteral route, or via inhalation.

[0122] In particular, compounds that are mPGES-1 inhibitors can be administered in known pharmaceutical formulations (i.e., compositions suitable for use in medicine), including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, pessaries for vaginal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

[0123] As used herein, those skilled in the art will understand that reference to a pharmaceutically acceptable excipient includes reference to a pharmaceutically acceptable adjuvant, diluent, and / or carrier, as known to those skilled in the art. For example, suitable pharmaceutically acceptable excipients and methods of formulation may include those described in "Handbook of Pharmaceutical Excipients" by P.J. Sheskey, B.C. Hancock, G.P. Moss and D.J. Goldfarb, Ninth edition, Pergamon Press, 1995.

[0124] Those skilled in the art will appreciate that the mPGES-1 inhibitors described herein, and pharmaceutical formulations containing same, can act systemically and / or locally (i.e., at a specific site).

[0125] Thus, the pharmaceutical preparations described herein can be administered orally, intravenously, subcutaneously, buccally, rectally, intradermally, intranasally, bronchially, by any other parenteral route, or via inhalation in a pharmaceutically acceptable dosage form. Alternatively, particularly mPGES-1 inhibitors are intended to act locally, and the compounds of the present invention can be administered locally (in which case the pharmaceutical preparation can be a formulation for topical administration).

[0126] For example, depending on the potency and physical properties of the compounds of the present invention, pharmaceutical formulations that may be mentioned include those in which the compound is present in at least 1% by weight (or at least 10% by weight, at least 30% by weight, or at least 50% by weight), i.e., the ratio of active ingredient to other components of the pharmaceutical formulation (i.e., excipients) is at least 1:99 (or at least 10:90, at least 30:70, or at least 50:50) by weight.

[0127] In certain embodiments, the treatment or prevention using the compounds of the invention described herein may be combined with one or more other (i.e., different) therapeutic agents useful in the treatment or prevention of the same disease (i.e., endometriosis).

[0128] Thus, in certain embodiments, the pharmaceutical formulation further comprises one or more additional therapeutic agents (i.e., other than a compound of Formula I or a pharmaceutically acceptable salt thereof) for the treatment or prevention of endometriosis.

[0129] Those skilled in the art will understand that pharmaceutical formulations comprising additional therapeutic agents may be presented in the form of a single formulation (i.e., a formulation containing all of the relevant therapeutic agents) or as a combination product for administration of a compound of the invention in conjunction with one or more additional therapeutic agents as separate formulations (i.e., separate formulations in which at least one of the formulations contains a compound of the invention and at least one contains the other (additional) therapeutic agent).

[0130] In a third aspect of the present invention, (I) a compound of formula I as defined in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof; (II) one or more other therapeutic agents useful in the treatment or prevention of endometriosis, Combination products are provided in which each of components (I) and (II) is formulated, optionally in admixture with one or more pharmaceutically acceptable excipients.

[0131] In a fourth aspect of the present invention, (a) a pharmaceutical formulation as defined in the second aspect of the present invention; (b) a pharmaceutical formulation comprising one or more other therapeutic agents useful for the treatment or prevention of endometriosis, optionally in admixture with one or more pharmaceutically acceptable excipients, A kit of parts is provided in which components (a) and (b) are each provided in a form suitable for administration in conjunction with the other.

[0132] Those skilled in the art will be able to identify compounds suitable for treating or preventing endometriosis that are known in the art. For example, compounds for treating or preventing endometriosis may include paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxysteroid dehydrogenase inhibitors, androgen agonists (e.g., danazol), prolactin antagonists, dopamine agonists, P2X2 / P2X3 / P2X4 antagonists, gonadotropin-releasing hormone (GnRH) modulators, hormonal contraceptives, and hormone synthesis or metabolism modulators (such as aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, and steroid sulfatase inhibitors).

[0133] Particular compounds for the treatment or prevention of endometriosis would include paracetamol.

[0134] Those skilled in the art will also understand that the treatment or prevention with the compounds of the invention described herein may be combined with a medical procedure performed to treat or prevent the same disease, such as a surgical procedure. For example, the use of the compounds of the invention may be used post-operatively (i.e., after surgical treatment for a disease described herein).

[0135] Preparation of compounds The compounds of the present invention are known in the literature and may be commercially available. Such compounds can be prepared by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions according to standard techniques. In this regard, those skilled in the art may refer to standard reference materials such as: "Comprehensive Organic Synthesis" by B.M. Trost and I. Fleming, Pergamon Press, 1991; "Heterocyclic Chemistry" by J.A. Joule, K. Mills and G.F. Smith, 3rd edition, published by Chapman & Hall; and "Comprehensive Heterocyclic Chemistry II" by A.R. Katritzky, C.W. Rees and E.F.V. Scriven, Pergamon Press, 1996.

[0136] In particular, those skilled in the art may refer to the synthetic methods mentioned in WO2012 / 022793A1 (in particular the examples provided therein, such as Example 1, and related data), the contents of which are incorporated herein by reference.

[0137] Stereoisomers may be obtained by separation using conventional techniques, such as chromatography or fractional crystallization. The various stereoisomers can be isolated by separating a racemic or other mixture of compounds using conventional, for example, fractional crystallization or HPLC techniques. Alternatively, the desired stereoisomer may be prepared by reaction of the starting material with the appropriate stereochemistry under conditions that will not cause racemization or epimerization, or by reaction with an appropriate chiral reagent or chiral catalyst, all under conditions known to those skilled in the art.

[0138] As described herein, the present invention is based on the unexpected discovery that the compounds of the present invention are surprisingly effective in treating and preventing endometriosis.

[0139] As such, the compounds described herein, whether for use in the above indications or otherwise, may have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more readily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or possess other useful pharmacological, physical, or chemical properties than compounds known in the prior art. In particular, the compounds of the present invention may have the advantage that they are more effective and / or exhibit advantageous properties in vivo.

[0140] Without wishing to be bound by theory, it is believed that the compounds of the present invention can provide an effective means for the treatment or prevention of endometriosis by reducing the size and / or number of endometriotic lesions, thereby reducing the pain, inflammation, fibrosis, and / or adhesion associated with the disease, and thus improving, among other things, the patient's behavior and well-being. Lesion load can mechanically cause pain depending on the number, size, and location. For example, lesions, adhesions, and scar tissue in the uterine / ovarian ligaments can contribute to dyspareunia, and therefore reducing lesion load has a beneficial effect in addressing these symptoms. Such effects are achieved in addition to the direct effects on pain and inflammation, which are believed to further contribute to therapeutic benefits. These unexpected properties enable more effective treatments, making the compounds suitable for use as prophylactic agents, enabling treatment and prevention in certain patient groups. The use of the compounds of the present invention can also enable the prevention or treatment of infertility associated with endometriosis, which may result in a reduction in the use of IVF and an increase in the number of pregnancies (rate of bringing babies home). [Brief explanation of the drawings]

[0141] [Figure 1] The design of the study as reported in the Examples is shown. [Figure 2] 1 shows the changes in blood flow observed during the testing process described in the Examples. [Figure 3] 1 shows the change in the number of individual lesions observed over the course of the study described in the Examples. [Figure 4] 1 shows the change in the number of abnormal endometrial lesions over the course of the study described in the Examples. [Figure 5] The behavioral changes of feeding trees over the course of the study are shown. [Figure 6] Shows changes in WGTA behavior during the research process. [Figure 7] Changes in grooming behavior over the course of the study are shown. [Example]

[0142] The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

[0143] material compound The substances shown below (prepared according to the procedure in WO2012 / 022793A1) were orally administered to common marmoset monkeys for 6 weeks at a dose of 6.67 mg / kg (calculated based on the free base; actual weight of compound administered was calculated as appropriate for the hydrogen sulfate salt). [ka] [Table 1]

[0144] The marmosets ranged in age from 3 to 16 years. All animals were female and had long-standing established endometriosis. Induction of endometriosis was performed as described by Einspanier et al., Mol Human Reprod., 12(5), 291-9 (2006). In some animals, endometriosis had been induced several years previously, while in others, it was newly induced.

[0145] Preparation of dosing solutions: Compounds were formulated weekly according to this protocol. Compounds were administered as suspensions made in 0.2% Natrosol® 250HX (hydroxyethylcellulose) in demineralized water, with a dosing volume of 200 μl / kg. The suspension was kept tightly covered, protected from light, and refrigerated (2-8°C) until administration.

[0146] Animal husbandry housing The animals were housed in cages with male marmoset monkeys under standard conditions with a 12-hour light / dark cycle. Room temperature (24°C) and humidity (50%) were kept constant. Room cleaning was performed as described in the standard animal facility procedures.

[0147] food Animals were fed twice daily. Morning pap was given between 7 and 8 a.m. and contained baby fruit pap, banana, and a vitamin and mineral mixture. Lunch food was provided around noon and contained fruit, high protein, carbohydrates, and vegetables. Marmoset pellets (Sniff) were available throughout the day.

[0148] water Animals had free access to tap water, and water in Makrolon bottles was changed daily.

[0149] ethics The study protocol was approved by the local ethical committee for animal experiments.

[0150] Experimental design The study design is shown in Figure 1.

[0151] general health All animals were weighed before and weekly during treatment. Health examinations, including clinical signs and blood chemistry analysis, were performed regularly by a responsible veterinarian.

[0152] Urine and blood sampling for progesterone analysis Urine samples for each animal were collected before and once during treatment for analysis of prostaglandin profiles. Urine samples were stored at -80°C until transport. Blood samples were collected from each animal before and during treatment for measurement of plasma concentrations.

[0153] Blood was collected before and weekly during treatment for analysis of serum progesterone concentrations to monitor the reproductive cycle. Serum was separated from the blood samples by centrifugation (2600 rpm for 10 minutes, Eppendorf centrifuge 5810R) within 2 hours of sample collection and stored at -80°C.

[0154] Color Doppler Ultrasound Scan Color Doppler ultrasound scans were performed before and three times during the treatment period to track blood flow. Color Doppler scans were performed as described by Einspanier (ibid.).

[0155] laparotomy Laparotomy was performed twice, once 7 weeks before the start of treatment and once immediately after the end of treatment, with at least 3 months between each laparotomy.

[0156] After premedication with Goettinger Mischung M II (a mixture of ketamine, xylazine, and atropine), animals were anesthetized with isoflurane by inhalation, lasting an average of 60 minutes. The abdomen was opened 1 cm laterally to the skeletal line to visualize the reproductive system and bladder. Endometrial abnormalities were characterized and photographically documented. During a second laparoscopic surgery, specimens were collected from the lesions. Postoperative care of the animals was performed as required by local legislation. Collected tissue samples were fixed in paraformaldehyde, embedded in paraffin, or stored at -80°C. All organs were replaced before abdominal closure. All females were separated from males for several hours for medical reasons and received antibiotics for several days.

[0157] behavior analysis Different behavioral test systems were used to test pain and discomfort, social comfort, memory, learning, and activity. All primates used in the studies were familiarized with the test systems (for a period of 6 months or more) to ensure that the results obtained were drug-related and not a learning effect over time.

[0158] Two test systems were used in the study as described in Arnold et al., J Med Primatol., 40, 317-326 (2011). 1. Feeding Tree 2. Wisconsin General Testing Apparatus (WGTA)

[0159] Documentation of social interactions, such as grooming, was performed before and during the study.

[0160] statistical methods Because the data were not normally distributed, all analyses were performed by the Wilcoxon signed-rank test.

[0161] Clinical signs, survival and observations of animals There were no changes in clinical signs or general health behavior of the test animals during the study period. All blood test parameters were within physiological ranges before and after treatment.

[0162] body weight There was no significant change in the body weight of the treated marmosets during the treatment period.

[0163] Reproductive cycle Before therapy, two animals showed ovarian cycling activity, five showed irregular cycles, and one showed no activity. After treatment, six of eight animals showed ovarian cycling activity and two showed irregular cycles.

[0164] Color Doppler Scan Color Doppler ultrasound scans were performed to measure blood flow in the reproductive system (uterus and ovaries) and bladder regions. Decreased blood flow was observed in all animals in both regions.

[0165] Individual blood flow measurements are provided in Table 1, with 0 indicating no blood flow, 1 indicating weak blood flow, 2 indicating moderate blood flow, and 3 indicating heavy blood flow. Comparing the median reduction in blood flow in all animals before and at the end of treatment achieved statistical significance (p<0.05) for both the bladder and reproductive systems (see Table 2). [Table 2] [Table 3]

[0166] The observed changes in blood flow are shown in Figure 2.

[0167] laparotomy Laparotomy analysis was performed to assess endometrial abnormal lesions. All animals showed a significant reduction in endometrial lesions, with lesions of all sizes affected by treatment.

[0168] The changes in the number of individual abnormal endometrial lesions are shown in FIG.

[0169] Individual data for abnormal endometrial lesions before and after treatment are shown in Table 3. Comparison of the reduction in the total number of abnormal endometrial lesions in all animals treated with the combination before and at the end of treatment achieved statistical significance (p<0.01) for both the bladder and reproductive system (see Table 4). [Table 4] [Table 5]

[0170] The changes in the number of abnormal endometrial lesions are shown in Figure 4.

[0171] Feeding Tree The feeding tree was used to test motor activity related to pain, discomfort, and / or distress. The feeding tree offered food at different locations for reaching, which required different levels of movement. If an animal experienced discomfort, pain, or abdominal pain, it would search for food in the upper area or not at all. Furthermore, impaired memory reduced systematic searching. In the setup, each primate was required to empty all hideouts containing rewards within 5 minutes for complete success. The responses of eight animals were graded on a scale of 0 to 4, indicating the number of hideouts emptied within 5 minutes, before, during, and after treatment.

[0172] All animals improved their success on the feeding tree during treatment. Changes in feeding tree behavior over the course of the study are shown in Figure 5 , presented as median values.

[0173] Wisconsin General Testing Equipment Primate memory and learning were tested. All animals received training rewards for the WGTA. The animals were seated in a transport box, trained for a specific person or place, and the reward was hidden. The observer could see the animal's behavior, but the animal could not see the observer.

[0174] Eight animals were tested for memory in the WGTA by memorizing either the figure or the location of a hidden reward. Primate well-being is related to their willingness to search for food, which is also included in this test system. Animals had to find the reward under three different figures three times within five minutes. Each animal was trained for either the location of the figure or the figure itself.

[0175] During treatment, all females showed an increased success rate in finding the correct shape or location where the reward was placed in time.

[0176] Changes in WGTA behavior over the course of the study are shown as median values ​​in Figure 6 .

[0177] social interaction Grooming was recorded during daytime observations. These behavioral observations provide information about well-being, as grooming is a marker of positive social activity. Social grooming was recorded one hour after breakfast and one hour after lunch by observing couples for 10 minutes each time. For each animal, the number of grooming interactions during the observation period was recorded.

[0178] Grooming increased in all animals during treatment compared to before treatment.

[0179] The median changes in grooming behavior over the course of the study are shown in Figure 7 .

Claims

1. A compound of formula I, 【Chemical 1】 A compound, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of endometriosis.

2. A method for the treatment or prevention of endometriosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof.

3. 10. Use of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of endometriosis.

4. 10. A pharmaceutical formulation comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, for use in the treatment or prevention of endometriosis.

5. below: (I) a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof; (II) one or more other therapeutic agents useful in the treatment or prevention of endometriosis, A combination product in which each of components (I) and (II) is formulated, optionally in admixture with one or more pharmaceutically acceptable excipients.

6. (a) the pharmaceutical formulation of claim 4; (b) a pharmaceutical formulation comprising one or more other therapeutic agents useful for the treatment or prevention of endometriosis, optionally in admixture with one or more pharmaceutically acceptable excipients, A kit of parts in which components (a) and (b) are each provided in a form suitable for administration in conjunction with the other.