Methods for treating or preventing endometriosis

Abstract

Provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and a formulation comprising the same, for use in the treatment or prevention of endometriosis.

Description

Technical Field

[0001] The present invention relates to the use of specific compounds or pharmaceutically acceptable salts thereof and pharmaceutical compositions, combinations and kits comprising the same in treating or preventing endometriosis. Background Art

[0002] The listing or discussion of an apparently prior-published document in this specification is not necessarily considered an admission that the document is prior art or part of the common general knowledge.

[0003] Endometriosis is a condition in which endometrial tissue grows outside the uterus, typically in the ovaries, in the fallopian tubes, and around the lining of the pelvis, including around the bladder. In rare cases, this endometrial-like tissue may also appear in areas of the body far from the reproductive organs.

[0004] During each menstrual cycle, this ectopic (outside the pelvic cavity) endometrial-like tissue breaks down and becomes trapped, causing considerable pain and discomfort. In the case of ovarian endometriosis, cysts called endometriomas may form. In many cases, the pain experienced is severe and detrimental to the patient's quality of life.

[0005] Over time, the irritation caused by endometriosis may lead to the formation of scar tissue and adhesions that can affect the organs in the pelvic area, which is often associated with symptoms such as chronic pelvic pain (cyclical and non-cyclical), dysmenorrhea, dyspareunia, and painful bowel movements and urination, and can often have a negative impact on fertility.

[0006] Although there is currently no cure for endometriosis, a variety of treatments can control symptoms. Lesions, scar tissue, and adhesions caused by endometriosis can be removed surgically, although recurrence may occur after surgery. There has also been a lot of research on the use of hormonal contraceptives as preventive drugs (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 commonly used and best-known 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). TM ).

[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 is constitutively expressed in many cells and tissues (COX-1), and the other is induced in most cells and tissues by proinflammatory stimuli (such as cytokines) during an inflammatory response (COX-2).

[0010] COX metabolizes arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2), which is further metabolized to other prostaglandins, including PGE2, PGF 2α , PGD2, prostacyclin and thromboxane A2. These arachidonic acid metabolites are known to have significant physiological and pathophysiological activities, including proinflammatory effects. In particular, PGE2 is known to be a strong proinflammatory mediator, and is also known to cause fever, inflammation and pain. Therefore, considering that the formation of PGE2 is mainly suppressed by inhibiting COX-1 and / or COX-2, many drugs have been developed.

[0011] More recently, 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 blockbuster drug Vioxx in 2004, (ii) the introduction of ‘black box’ warnings 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 to a prescription-only drug in 2015 (UK). Now, the fear of cardiovascular events caused by NSAIDs has become a public health issue, making the prescribing of COX-2 selective drugs cautious, turning to older drugs that are more toxic to the intestine, and failing to fully realize the 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)). In addition, the inhibition of COX has the disadvantage of causing a reduction in the formation of all metabolites downstream of PGH2, some of which are known to have beneficial properties.

[0012] Inhibition of mPGES-1 is a mature 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, the lack of a complete understanding of cardiovascular toxicity and other side effects means that the study and translation of mPGES-1 as a therapeutic target to replace COX-2 for the treatment of a variety of diseases and disorders has been limited.

[0013] WO 2012 / 022793 A1 describes the use of various mPGES-1 inhibitors in the treatment of a range of inflammatory conditions. WO 2017 / 144909 A1 describes the use of various mPGES-1 inhibitors in the treatment of diseases and conditions characterized by vasoconstriction. These disclosures do not teach or suggest the treatment or prevention of endometriosis. DETAILED DESCRIPTION

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

[0015] In the first aspect of the present invention, there is provided a compound of formula I,

[0016]

[0017] or a pharmaceutically acceptable salt thereof, for use in treating or preventing endometriosis.

[0018] In an alternative first aspect of the invention there is provided a method for treating or preventing endometriosis, the method comprising 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.

[0019] 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 preparation of a medicament for the treatment or prevention of endometriosis.

[0020] In a further alternative first 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 treatment or prevention of endometriosis.

[0021] Unless defined otherwise, 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.

[0022] Those skilled in the art will appreciate that reference to particular aspects of the invention herein will include reference to all embodiments and their specific features. In addition, all embodiments of particular aspects 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.

[0023] Compounds of the present invention

[0024] The skilled person will understand that reference to compounds of formula I will refer to the following compounds:

[0025]

[0026] The compound and its pharmaceutically acceptable salt may also be referred to herein as the compound of the present invention, etc.

[0027] The skilled person will also appreciate that the compound of formula I can 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.

[0028] 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 (e.g., in a vacuum, by freeze drying or by filtering). Salts can also be prepared by exchanging the counter ion of the compound of the present invention in salt form with another counter ion, for example, using a suitable ion exchange resin.

[0029] Specific acid addition salts that may be mentioned include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, octanoate, stearate, acrylate, hexanoate, 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 salts (e.g., salts of oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate), halide salts (e.g., chloride, bromide or iodide salts), sulfonates (e.g., benzenesulfonate, methylbenzenesulfonate, bromobenzenesulfonate or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, isethionate, 1- or 2-naphthalenesulfonate or 1,5-naphthalenedisulfonate) or sulfates (e.g., dihydrogensulfate), pyrosulfate, hydrogensulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate, etc.

[0030] Specific pharmaceutically acceptable salts that may be mentioned include dihydrogen sulfate (also called bisulfate; H2SO4) salts.

[0031] In order to avoid doubt, the technical staff will understand that the compound of the present invention can exist as solid, and therefore the scope of the present invention includes all amorphous, crystallization and partial crystalline forms thereof, and can also exist as oily matter. In the case where such compounds exist with crystallization and partial crystalline forms, such forms can include solvates, and these solvates are included in the scope of the present invention. Such compounds can also be present in solution.

[0032] The compounds of the present invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention.

[0033] As described herein, the compounds of the present invention have specific substituent orientations. For the avoidance of doubt, the compounds of the present invention have a stereochemistry as described which may be referred to as a trans orientation.

[0034] The skilled person will appreciate that the present invention can utilize not only the compounds of the present invention per se, but also compounds that can be administered to a patient (e.g., parenterally or orally) and thereafter metabolized in vivo to form the compounds of the present invention. Such compounds can be described as prodrugs of the compounds of the present invention.

[0035] Medical Uses

[0036] As described herein, the compounds of the present invention are useful for treating or preventing endometriosis in a patient in need thereof.

[0037] The skilled artisan will understand that references to specific diseases and disorders will be taken with their normal meaning as understood by those skilled in the art.

[0038] Similarly, it will be understood by the skilled person that the reference to the treatment of a particular disease (or similarly, the treatment of the disease) adopts its normal meaning in the medical field. In particular, the term can refer to the reduction of the severity of one or more clinical symptoms associated with the disease, even if the diagnosis is not yet determined when treating such symptoms. Such reduction can be measured using objective analysis (e.g., the measurement of physiological factors and / or the visualization of disease markers, such as the reduction of lesion size and / or quantity) and / or by subjective analysis (e.g., the examination of the evaluation physician, or the results of the patient's report, such as the alleviation of pain, such as using an appropriate pain scale to evaluate, and the evaluation of improving the quality of life).

[0039] The skilled person will understand that reference to the prevention of a particular disease adopts its normal meaning in the medical field. Specifically, the term can refer to achieving a reduction in the likelihood of a patient (or healthy subject) developing a disease (e.g., a reduction of at least 10%, such as a reduction of at least 20%, 30% or 40%, for example a reduction of at least 50%). The skilled person will also understand that the prevention of a particular disease can also be referred to as the prevention of the disease, and these terms can be used interchangeably.

[0040] The skilled person will appreciate that prevention can be performed in patients who do not suffer from the relevant disorder (i.e., so that the relevant disorder does occur). In particular, prevention can be performed in patients who do not suffer from the relevant disorder but are at risk of developing the relevant disorder (e.g., because they have previously suffered from the relevant disorder).

[0041] In certain embodiments, references to the treatment or prevention of endometriosis may refer to a reduction (ie, a clinically significant reduction) or a reduction in the formation of lesions, adhesions, and / or scar tissue associated with endometriosis.

[0042] A skilled artisan would be able to identify patients in need of prevention of a disease or disorder (in which case they may otherwise be healthy), such as patients at risk of developing the disorder of interest (e.g., patients who have previously been treated for the disorder but do not currently have the disorder).

[0043] The skilled person will be able to determine whether a patient suffers from a relevant disorder or is at risk of developing a relevant disorder using routine techniques in the art. For example, a patient who does not suffer from a relevant disorder can be a patient who does not experience relevant symptoms (such as pain or infertility caused by the disease) when the prevention is performed.

[0044] Without wishing to be bound by theory, it is believed that the compounds of the present invention may allow for 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). In addition, 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 compared to similar drugs prescribed for the treatment of the disease (such as those prescribed for the treatment of pain and / or hormonal drugs).

[0045] In certain embodiments, treatment or prevention (eg, therapy) as described herein requires continuous daily administration (ie, daily administration of a therapeutically effective amount as described herein) of a compound of the invention.

[0046] In more specific such embodiments, treatment or prevention is continued for an extended period of time, which can be referred to as long-term treatment (which can refer to a period of at least six weeks, such as a period of at least 12 weeks, at least 24 weeks, or at least 48 weeks).

[0047] In more specific such embodiments, continuous daily administration (including continuous daily administration for an extended period of time, i.e., long-term continuous daily administration) will include a period of time during which the patient does not (a) experience significant pain (which can be defined as greater than moderate pain) and / or (b) have menstrual cramps.

[0048] As used herein, reference to a patient will refer to a living subject receiving treatment, including a mammalian patient. In certain embodiments, reference to a patient will refer to a human patient.

[0049] Thus, in certain embodiments, the treatment or prevention as described herein is performed in a mammal, such as a human.

[0050] The skilled artisan will appreciate that endometriosis is a disease of the female reproductive system and, therefore, the intended patients are biological female patients, typically of childbearing age.

[0051] As used herein, the term therapeutically effective amount (also referred to as effective amount) will refer to the amount (i.e., dosage) of a compound that imparts a therapeutic effect to the patient being treated. 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 achieving a specific effect on the size and / or number of lesions (as assessed by imaging techniques)) or subjective (i.e., the subject gives an indication of the effect and / or feels the effect). A skilled person will be able to determine a suitable therapeutically effective dose using routine techniques in the art.

[0052] For example, specific dosages that may be mentioned include those in the range of about 10 to about 200 mg per day (non-salt free base form; if used in salt form, the dosage is adjusted), which can be administered (e.g., orally, such as in the form of tablets or capsules) as a single daily dose (once a day) or divided into two daily doses (twice a day).

[0053] The skilled person will appreciate that both the treatment and prevention of the diseases as described herein can be achieved by repeated administration of the compounds of the invention, such as by administration of a suitable dose daily (e.g. once or twice within a 24 hour period) and / or in a form that allows for extended release of the active ingredient (e.g., release over a period of at least 12 hours, such as at least 24 hours) from a suitable dosage form known to those skilled in the art.

[0054] The skilled artisan will appreciate that prevention of a particular disease or condition may be performed in combination with treatment of another disease or condition, or vice versa, where the disease being treated is unrelated to or is a potential (e.g., causative) factor for the disease or condition for which prevention is being provided.

[0055] In addition, the skilled artisan will appreciate that the present invention may be particularly suitable for treating chronic diseases, such as chronic manifestations of those diseases and disorders mentioned herein. As used herein, the skilled artisan will appreciate that reference to a chronic disease will refer to a disease that persists for an extended period of time (e.g., for at least three months, such as at least six months or at least one year).

[0056] Without wishing to be bound by theory, it is believed that the compounds of the invention may be particularly useful for treating endometriosis in patients who have become intolerant to, have been switched from, cannot be prescribed for, or are refractory to other therapeutic agents used to treat or prevent (e.g., treat) the same disease or condition (such as NSAIDs, hormonal drugs, paracetamol, anticonvulsants, TCAs, SSRI / SNRIs and / or opioids).

[0057] In certain embodiments, the treatment or prevention (e.g., therapy) is in a patient who is undergoing treatment or prevention (e.g., therapy) of one or more other therapeutic agents for the same disease:

[0058] (i) Intolerance;

[0059] (ii) the therapeutic agent has been switched or the dose of the therapeutic agent has been reduced;

[0060] (iii) the therapeutic agent cannot be prescribed; or

[0061] (iv) is refractory to the therapeutic agent.

[0062] The skilled artisan will understand that reference to one or more other therapeutic agents used to treat or prevent (e.g., cure) the same disease will refer to one or more (e.g., one) other therapeutic agent(s) previously prescribed (and administered) to the patient for that purpose, which may be referred to as one or more previous drugs rather than a compound of the present invention.

[0063] Other therapeutic agents for treating or preventing (e.g., treating) endometriosis as described herein (including all embodiments and specific features thereof) include NSAIDs, hormonal drugs, paracetamol, anticonvulsants, TCAs, SSRI / SNRIs and / or opioids.

[0064] In certain embodiments, the one or more additional therapeutic agents used to treat or prevent (eg, treat) endometriosis is an NSAID.

[0065] Specific NSAIDs that may be mentioned include aspirin, celecoxib, ibuprofen, naproxen and diclofenac, indomethacin and etoricoxib.

[0066] In certain embodiments, the one or more additional therapeutic agents used to treat or prevent (eg, treat) endometriosis are CNS acting agents.

[0067] Specific CNS acting agents that may be mentioned include TCAs (eg amitriptyline), anticonvulsants (eg gabapentin, pregabalin), SSRIs / SNRIs (eg duloxetine, milnacipran) and opioids (eg morphine, buprenorphine).

[0068] In certain embodiments, the one or more additional therapeutic agents used to treat or prevent (eg, treat) endometriosis are hormonal drugs.

[0069] Specific hormonal drugs that may be mentioned include hormonal contraceptives, such as combined (estrogen and progestin) contraceptives, progestins, antiprogestins, contraceptive patches, and gonadotropin-releasing hormone (GnRH) analogs (agonists and antagonists; which can be administered with low doses of estrogen), hormone synthesis or metabolism modulators (such as aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, and steroid sulfatase inhibitors).

[0070] In certain embodiments, the one or more additional therapeutic agents used to treat or prevent (eg, treat) endometriosis is acetaminophen.

[0071] In alternative embodiments, the one or more additional therapeutic agents used to treat or prevent (eg, treat) endometriosis is not acetaminophen.

[0072] For example, in certain embodiments where the one or more other therapeutic agents used to treat or prevent (e.g., treat) endometriosis is not acetaminophen, treatment or prevention with acetaminophen can be continued along with treatment or prevention with the compounds of the invention.

[0073] In certain embodiments, the treatment or prevention (eg, therapy) is in a patient who has become intolerant to one or more other therapeutic agents used to treat or prevent (eg, treat) the same disease.

[0074] The skilled artisan will understand that references to patients who have become intolerant to one or more other therapeutic agents used to treat or prevent (e.g., treat) the same disease will refer to patients for whom such treatment or prevention had previously been deemed unsuitable by a physician or appropriate medical professional based on appropriate 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.

[0075] In certain embodiments, such as where one or more other therapeutic agents used to treat or prevent (e.g., treat) the same disease are hormonal drugs, such adverse events may be selected from:

[0076] Weight gain

[0077] Decreased libido

[0078] Osteoporosis;

[0079] Suicidal ideation;

[0080] Depression and / or anxiety;

[0081] Depression; and

[0082] Symptoms of menopause (such as hot flashes / flush).

[0083] In certain embodiments, such as where the one or more other therapeutic agents used to treat or prevent (e.g., treat) the same disease is an NSAID, such adverse events may be selected from cardiovascular adverse events (including myocardial infarction (MI), stroke, heart failure (HF), increased blood pressure, atrial fibrillation, and venous thromboembolism);

[0084] Renal impairment; and

[0085] asthma;

[0086] Gastrointestinal adverse events (including dyspepsia, bleeding, ulcers, and gastric or intestinal perforation).

[0087] In certain embodiments, such as where one or more other therapeutic agents used to treat or prevent (e.g., treat) the same disease are CNS active agents, such adverse events may be selected from:

[0088] Anticholinergic effects;

[0089] Mood disorders;

[0090] drowsiness;

[0091] Blurred vision

[0092] Addiction;

[0093] Constipation; and

[0094] Development of tolerance.

[0095] In further embodiments, the treatment or prevention (eg, therapy) is in a patient who has been switched from, or has had the dosage of, one or more other therapeutic agents used to treat or prevent (eg, treat) the same disease reduced.

[0096] The skilled artisan will understand that reference to a patient who has been switched from one or more other therapeutic agents for the treatment or prevention (e.g., treatment) of the same disease will mean that treatment or prevention with the one or more other therapeutic agents has been discontinued and that treatment or prevention with the compounds of the present invention has been switched (e.g., treatment or prevention (e.g., treatment) with the compounds of the present invention has been immediately initiated thereafter, which may mean that there has been no intervening treatment or prevention (e.g., treatment) with the same drug), which may be done as directed by a physician or appropriate medical professional.

[0097] The skilled artisan will understand that reference to a patient having a reduced dosage of one or more other therapeutic agents used to treat or prevent (e.g., cure) the same disease will refer to the patient continuing treatment or prevention with the one or more other therapeutic agents, but having had the dosage of the one or more other therapeutic agents reduced prior to initiating treatment or prevention with the compounds of the present invention, which may be done as directed by a physician or appropriate medical professional.

[0098] The skilled artisan will also understand that references to reducing the dosage of one or more other therapeutic agents will refer to the patient receiving a lower daily amount thereof, such as by reducing the dosage administered per occurrence and / or reducing the frequency of administration during a day, and / or reducing the frequency of treatment, such as by reducing the number of days that treatment is administered (e.g., during a typical 30 day period).

[0099] For the avoidance of doubt, references to reducing the dosage of one or more other therapeutic agents will indicate continuing (at reduced levels) treatment or prevention with the one or more other therapeutic agents during treatment or prevention with the compounds of the invention.

[0100] In certain embodiments, the treatment or prevention (eg, therapy) is in a patient who has been switched from one or more other therapeutic agents used to treat or prevent (eg, treat) the same disease.

[0101] In further embodiments, the treatment or prevention (eg, therapy) is in a patient in which the dosage of one or more other therapeutic agents used to treat or prevent (eg, treat) the same disease has been reduced.

[0102] In further embodiments, the treatment or prevention (eg, therapy) is in a patient for whom one or more other therapeutic agents for the treatment or prevention (eg, therapy) of the same disease cannot be prescribed.

[0103] The skilled artisan will understand that 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 will refer to a patient who cannot be prescribed the one or more other therapeutic agents, as determined by a physician or appropriate medical professional based on appropriate medical parameters (such as the patient's health, physiology, and / or medical history) or other similar factors and / or the patient's lack of willingness to receive such one or more other therapeutic agents.

[0104] In certain embodiments, the treatment or prevention is in patients who cannot be prescribed one or both of an NSAID and a hormonal drug, such as those described herein.

[0105] In certain embodiments, the treatment or prevention is in patients for whom an NSAID, such as those described herein, cannot be prescribed.

[0106] In certain embodiments, the treatment or prevention is in patients who cannot be prescribed hormonal medications, such as those described herein.

[0107] In certain embodiments, one or more other therapeutic agents cannot be prescribed to the patient based on appropriate medical parameters, such as the patient's health, physiology, and / or medical history.

[0108] In certain embodiments, the treatment or prevention as described herein is in a patient who cannot be prescribed a hormonal drug (such as those described herein) because the patient has previously experienced (i.e., has a history of) one or more conditions selected from:

[0109] Depression and / or anxiety;

[0110] Depression; and

[0111] Symptoms of menopause (such as hot flashes / flush).

[0112] In certain embodiments, the treatment or prevention as described herein is in a patient for whom one or more other therapeutic agents cannot be prescribed because the patient is trying to conceive, i.e., intending to become pregnant (including patients undergoing fertility treatments such as in vitro fertilization (IVF)).

[0113] For example, in more specific embodiments, the treatment or prevention as described herein is in a patient who cannot be prescribed an NSAID and / or hormonal medication (such as those described herein) because the patient is trying to conceive.

[0114] In certain such embodiments, when the patient is attempting pregnancy, the one or more other therapeutic agents may be other than acetaminophen (such as those described herein other than acetaminophen).

[0115] In specific embodiments, the treatment or prevention as described herein is in a patient who cannot be prescribed an NSAID (such as those described herein) because the patient has previously experienced (i.e., has a history of) one or more of the following:

[0116] adverse cardiovascular events (including myocardial infarction (MI), stroke, heart failure (HF), increased blood pressure, atrial fibrillation, and venous thromboembolism);

[0117] Gastrointestinal adverse events (including gastric ulcers).

[0118] In certain embodiments, one or more additional therapeutic agents cannot be prescribed to a patient due to the patient's lack of willingness (eg, refusal) to receive such one or more additional therapeutic agents.

[0119] In certain embodiments, the patient's lack of willingness to accept such one or more other therapeutic agents is a result of (ie, caused by) their cultural, social, religious, and / or political practices or beliefs.

[0120] For example, in certain embodiments, a hormonal medication may not be prescribed to a patient due to the patient's lack of willingness to receive such hormonal medication due to cultural, social, religious, and / or political practices or beliefs.

[0121] In further embodiments, the treatment or prevention (eg, therapy) is in a patient who is refractory to one or more other therapeutic agents used to treat or prevent (eg, treat) the same disease.

[0122] The skilled artisan will understand that reference to patients who are refractory to one or more other therapeutic agents used to treat or prevent (e.g., cure) the same disease will refer to patients who have been deemed unsuitable for such treatment or prevention, such as by a physician or appropriate medical professional based on lack of efficacy, which may mean that the disease is not responsive (or inadequately responsive) to such treatment or prevention.

[0123] In certain embodiments, the treatment or prevention (eg, therapy) is in patients who are refractory to treatment or prevention (eg, therapy) with NSAIDs and / or hormonal drugs for the same disorder.

[0124] In certain embodiments, the treatment or prevention (eg, therapy) is in patients who are refractory to treatment or prevention (eg, therapy) with an NSAID for the same disease.

[0125] In certain embodiments, the treatment or prevention (eg, therapy) is in patients who are refractory to treatment or prevention (eg, therapy) with hormonal agents for the same disease.

[0126] As described herein, treatment or prevention using the compounds of the invention may allow for treatment or prevention in certain patient populations, or may be of particular benefit to certain patient populations.

[0127] In certain embodiments, the treatment or prevention (e.g., therapy) is in a patient who is experiencing and / or has previously experienced:

[0128] Depression and / or anxiety;

[0129] Depression; and / or

[0130] Symptoms of menopause (such as hot flashes / flush).

[0131] In certain embodiments, the treatment or prevention (e.g., treatment) is in a patient who is experiencing, has an increased risk of experiencing, and / or has previously experienced:

[0132] adverse cardiovascular events (including myocardial infarction (MI), stroke, heart failure (HF), increased blood pressure, atrial fibrillation, and venous thromboembolism);

[0133] renal impairment; and / or

[0134] Gastrointestinal adverse events (including gastric ulcers).

[0135] In certain embodiments, treatment or prevention (eg, therapy) is in patients who are trying to conceive (ie, intending to become pregnant), including patients undergoing fertility treatments such as in vitro fertilization (IVF).

[0136] In certain embodiments, treatment or prevention of a related disease may further include treatment or prevention of reduced fertility (eg, infertility), which may refer to reduced fertility caused by (ie, resulting from the effects of) the disease.

[0137] In such embodiments, treatment or prevention of reduced fertility can result in a decrease in the use of IVF and an increase in the number of pregnancies (ie, live birth rate).

[0138] Thus, the compounds of the invention may also be used to prevent or treat (eg, prevent) infertility associated with endometriosis, which may result in a reduction in the use of IVF and / or an increase in the number of pregnancies (live birth rate).

[0139] 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.

[0140] In another alternative aspect of the present invention, there is provided a method for preventing or treating infertility associated with endometriosis, the method 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.

[0141] In a further alternative aspect of the 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.

[0142] The skilled artisan will appreciate that reference to infertility associated with endometriosis may refer to reduced or impaired fertility (ability to conceive) in a patient suffering from endometriosis, wherein the infertility has been determined or is expected to be caused by the effects of endometriosis (such as the formation of lesions, adhesions and / or scar tissue affecting reproductive organs (e.g., around the uterus and / or ovaries)).

[0143] In certain embodiments, treatment may be in patients who are experiencing significant (which may be defined as moderate or greater) pain, which may occur during menstruation or between menstrual cycles (eg, between menstrual cycles).

[0144] In such embodiments, treatment may result in treatment of such pain.

[0145] In certain embodiments, treatment or prevention (e.g., therapy) may be in a patient who is experiencing pain associated with:

[0146] Poor quality of life;

[0147] Impaired ability to perform activities of daily living;

[0148] Cognitive impairment;

[0149] Poor social interaction;

[0150] Decreased libido

[0151] Dyspareunia;

[0152] Symptoms of depression and anxiety; and / or

[0153] Impaired (or reduced) flow capacity.

[0154] In certain embodiments, treatment or prevention (e.g., therapy) may be in a patient experiencing chronic pain, such as chronic pain associated with:

[0155] Dysmenorrhea (before, during, or after menstruation);

[0156] low back pain;

[0157] Ovulation-related pain;

[0158] Dyspareunia;

[0159] muscle and / or joint pain;

[0160] shortness of breath, chest pain and / or cough, and / or in some cases a collapsed lung;

[0161] Painful bowel movements;

[0162] Chronic pelvic pain;

[0163] Cyclic pelvic pain;

[0164] Difficulty urinating; and / or

[0165] Vaginal burning pain.

[0166] In certain embodiments, treatment or prevention (eg, therapy) can be in a patient who is experiencing chronic pelvic pain.

[0167] In such embodiments, treatment may result in treatment of such associated factors.

[0168] In certain embodiments, treatment may be in patients who are experiencing irregular, reduced or suppressed menstrual cycles.

[0169] In such embodiments, treatment may cause the patient to achieve regular menstrual cycles.

[0170] In certain embodiments, treatment or prevention (eg, therapy) is in patients who are not suitable for surgical treatment to treat the relevant disease, as determined by a physician or appropriate medical professional based on appropriate medical parameters.

[0171] In certain embodiments, treatment or prevention (eg, therapy) is in a patient who has previously undergone surgery to treat the disease in question, which may be referred to as post-operative treatment or prevention.

[0172] In certain embodiments, postoperative treatment is in patients who are experiencing significant pain (which may be defined as greater than moderate pain).

[0173] As described herein, treatment or prevention (e.g., treatment) using the compounds of the invention can be associated with effects other than the treatment or prevention of pain. For example, treatment or prevention (e.g., treatment) using the compounds of the invention can be associated with (e.g., cause / induce) a reduction in the size and / or number of endometrioid lesions (which may also be referred to as lesions and / or cysts), such as endometriosis.

[0174] Pharmaceutical preparations, combinations and kits

[0175] The skilled artisan will appreciate that the compounds of the present invention may be administered in the form of pharmaceutical formulations.

[0176] In a second aspect of the present invention, there is provided a pharmaceutical preparation for treating or preventing endometriosis, comprising a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0177] In an alternative second aspect of the present invention, there is provided a method for treating or preventing endometriosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of 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.

[0178] The skilled artisan will appreciate that the compounds of the invention and pharmaceutical formulations containing the same may be administered systemically and / or locally (eg topically).

[0179] The skilled artisan will appreciate that the compounds of the invention and pharmaceutical formulations containing the same will typically be administered orally, intravenously, subcutaneously, buccally, rectally, intravaginally, dermally, nasally, bronchially, sublingually, intranasally, topically, intrauterinely, intraperitoneally, by any other parenteral route or via inhalation in a pharmaceutically acceptable dosage form.

[0180] Specifically, compounds that are mPGES-1 inhibitors can be administered in the form of 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 intravaginal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

[0181] As used herein, the skilled artisan will appreciate that reference to a pharmaceutically acceptable excipient will include 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 formulations may include those described in "Handbook of Pharmaceutical Excipients", 9th edition, Pergamon Press, 1995 by PJ Sheskey, BC Hancock, GP Moss and DJ Goldfarb.

[0182] The skilled artisan will appreciate that the mPGES-1 inhibitors as described herein and pharmaceutical formulations comprising the same may act systemically and / or locally (ie at a specific site).

[0183] Thus, the pharmaceutical formulations as described herein can be administered orally, intravenously, subcutaneously, orally, rectally, dermally, nasally, bronchially, by any other parenteral route or via inhalation in a pharmaceutically acceptable dosage form. Alternatively, particularly where mPGES-1 inhibitors are intended to act locally, the compounds of the invention can be administered topically (in which case the pharmaceutical formulation can be a formulation for topical administration).

[0184] Depending on, for example, the potency and physical properties of the compound of the invention, pharmaceutical preparations that may be mentioned include those in which the compound is present at least 1% by weight (or at least 10%, at least 30% or at least 50%); that is, in which the ratio of active ingredient to other components (i.e. excipients) of the pharmaceutical preparation is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

[0185] In certain embodiments, treatment or prevention using the compounds of the invention as described herein may also be combined with one or more other (ie, different) therapeutic agents useful for treating or preventing the same disease (ie, endometriosis).

[0186] Thus, in certain embodiments, the pharmaceutical formulation further comprises one or more additional therapeutic agents useful for treating or preventing endometriosis (ie, in addition to the compound of Formula I or a pharmaceutically acceptable salt thereof).

[0187] The skilled person will appreciate that pharmaceutical formulations comprising additional therapeutic agents may be present in the form of a single formulation (i.e. a formulation comprising all relevant therapeutic agents) or as a combination product providing for administration of a compound of the invention in combination with one or more additional therapeutic agents as separate formulations (i.e. different formulations, wherein at least one of those formulations comprises a compound of the invention and at least one comprises the other (additional) therapeutic agent).

[0188] In a third aspect of the present invention, there is provided a combination product comprising:

[0189] (I) a compound of formula I as defined in the first aspect of the present invention or a pharmaceutically acceptable salt thereof; and

[0190] (II) one or more other therapeutic agents useful for treating or preventing endometriosis,

[0191] Each of components (I) and (II) is optionally mixed with one or more pharmaceutically acceptable excipients.

[0192] In a fourth aspect of the present invention, there is provided a kit of parts comprising:

[0193] (a) a pharmaceutical preparation as defined in the second aspect of the present invention; and

[0194] (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,

[0195] Components (a) and (b) are each provided in a form suitable for administration in combination with the other component.

[0196] The skilled person will be able to identify suitable compounds known in the art for the treatment or prevention of endometriosis. For example, compounds for the treatment or prevention of 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 modulators of hormone synthesis or metabolism (such as aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, and steroid sulfatase inhibitors).

[0197] Specific compounds used to treat or prevent endometriosis will include paracetamol.

[0198] The skilled artisan will also appreciate that treatment or prevention utilizing the compounds of the invention as described herein may also be combined with a medical procedure (such as surgery) performed to treat or prevent the same disease. For example, the use of the compounds of the invention may be used post-operatively (i.e., after surgical treatment of a disease as described herein).

[0199] Preparation of compounds

[0200] The compounds of the present invention are known in the literature and may be commercially available. Such compounds can be prepared by conventional synthesis procedures using appropriate reagents and reaction conditions from available starting materials according to standard techniques. In this regard, technicians can refer to standard reference materials, such as "Comprehensive Organic Synthesis" by BMTrost and I.Fleming, Pergamon Press, 1991; "Heterocyclic Chemistry" by JA Joule, K. Mills and GF Smith, 3rd edition, published by Chapman & Hall; and "Comprehensive Heterocyclic Chemistry II" by AR Katritzky, CW Rees and EF V Scriven, Pergamon Press, 1996.

[0201] In particular, the skilled person may refer to the synthesis methods mentioned in WO 2012 / 022793 A1 (in particular the examples provided therein, such as Example 1, and the relevant data), the content of which is incorporated herein by reference.

[0202] Stereoisomers can be obtained by separation using conventional techniques (e.g., chromatography or fractional crystallization). Various stereoisomers can be separated by separating racemic mixtures or other mixtures of compounds using conventional (e.g., fractional crystallization or HPLC) techniques. Alternatively, the desired stereoisomer can be prepared by reacting the starting material with the appropriate stereochemistry under conditions that will not cause racemization or epimerization, or by reacting with an appropriate chiral reagent or chiral catalyst, all of which are carried out under conditions known to those skilled in the art.

[0203] As described herein, the present invention is based on the unexpected discovery that the compounds of the present invention are surprisingly effective in the treatment and prevention of endometriosis.

[0204] Therefore, the compounds of the present invention may have the following advantages: whether used for the above indications or others, they may be more effective, less toxic, longer acting, more potent, produce fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical or chemical properties than the compounds known in the prior art. Specifically, the compounds of the present invention may have the following advantages: they are more effective and / or exhibit favorable properties in vivo.

[0205] Without wishing to be bound by theory, it is believed that the compounds of the present invention allow for an effective means of treating or preventing endometriosis by reducing the size and / or number of endometriotic lesions, which in turn allows for an improved effect in alleviating pain, inflammation, fibrosis and / or adhesions associated with the disease, and thus, in particular, improving the patient's behavior and health. Lesion load may physically cause pain by number, size and positioning, for example, lesions, adhesions and scar tissue in the uterine / ovarian ligaments may contribute to dyspareunia, and thus reducing lesion load has a beneficial effect on addressing these symptoms. It is believed that such effects are achieved together with direct effects on pain and inflammation, further contributing to the therapeutic advantage. These unexpected properties allow for more effective treatment, making the compounds suitable for use as preventive agents, and allowing for treatment and prevention of specific patient populations. The use of the compounds of the present invention may also allow for 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 (live birth rates). BRIEF DESCRIPTION OF THE DRAWINGS

[0206] Figure 1 The study design reported in the example is shown.

[0207] Figure 2 Shown are changes in blood flow observed during the studies described in the Examples.

[0208] Figure 3 Shown are the changes in the number of individual lesions observed during the course of the studies described in the examples.

[0209] Figure 4 Shown are changes in the number of endometriotic lesions during the course of the studies described in the Examples.

[0210] Figure 5 Shown are changes in feeding tree behavior over the course of the study.

[0211] Figure 6 Shown are changes in WGTA behavior during the study.

[0212] Figure 7 Shows changes in grooming behavior over the course of the study.

[0213] Examples

[0214] The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

[0215] Material

[0216] Compound

[0217] The material depicted below (prepared according to the procedure in WO 2012 / 022793 A1) was orally administered to common marmosets at a dose of 6.67 mg / kg twice / day (calculated on a free base basis, with the actual weight of compound administered calculated based on the need for the bisulfate salt) for 6 weeks.

[0218]

[0219] Characterization of test animals

[0220]

[0221] The age range of the marmosets was between 3 and 16 years. All animals were female and had established endometriosis for many years. Endometriosis was induced as described in Einspanier et al., Mol Human Reprod., 12(5), 291-9 (2006). Some animals had endometriosis induced several years ago and some had it newly induced.

[0222] Preparation of dosing solution

[0223] Compounds were prepared weekly according to this regimen. The compounds were dosed at 0.2% The suspension was administered as a suspension made in 250HX (hydroxyethylcellulose) in demineralized water and the administration volume was 200 μl / kg. The suspension was kept securely covered until administration, protected from light and refrigerated (2 to 8° C.).

[0224] Animal Care

[0225] case

[0226] Animals were paired-housed with male marmosets under standard conditions using a 12-hour light and dark cycle. Room temperature (24°C) and humidity (50%) were kept constant. Cleaning of the room was performed as described in the standard procedures of the animal facility.

[0227] food

[0228] Animals were fed twice daily. Morning soft food was given between 7:00 and 8:00 a.m. The morning soft food contained baby fruit soft food, banana, vitamin and mineral mix. Lunch food was provided around noon and contained fruit, high protein, carbohydrates and vegetables. Marmoset pellets (sniff) were available throughout the day.

[0229] water

[0230] The animals had ad libitum access to tap water. The water in the macrolon bottles was changed daily.

[0231] ethics

[0232] The study protocol was approved by the local animal experiment ethics committee.

[0233] Experimental design

[0234] Study design Figure 1 shown.

[0235] General health

[0236] All animals were weighed before and weekly during treatment. Health examinations, including clinical signs as well as blood chemistry analysis, were performed regularly by the responsible veterinarian.

[0237] Urine and blood sampling for progesterone analysis

[0238] For each animal, a urine sample for analyzing the prostaglandin profile was collected before treatment and a urine sample for analyzing the prostaglandin profile was collected once during treatment. The urine samples were stored at -80°C until transportation. For each animal, a blood sample was collected once before treatment and a blood sample was collected once during treatment for measuring plasma concentrations.

[0239] To analyze serum progesterone concentrations to monitor the reproductive cycle, blood was collected before and weekly during treatment. Serum was separated from blood samples by centrifugation (2600 rpm, 10 minutes, Eppendorf centrifuge 5810R) within two hours of sampling and stored at -80°C.

[0240] Color Doppler ultrasound scan

[0241] Color Doppler ultrasound scans were performed before the treatment period and 3 times during the treatment period to track blood flow. Color Doppler scans were performed as described by Einspanier (supra).

[0242] Laparotomy

[0243] Laparotomy was performed twice, seven weeks before the start of treatment and immediately after the end of treatment, with a minimum of 3 months between each laparotomy.

[0244] use After premedication with Mischung MII (a mixture of ketamine, xylazine and atropine), isoflurane inhalation anesthesia was performed for an average of 60 minutes. A 1 cm range of the abdomen was opened next to the white line to observe the reproductive tract and bladder. Endometriotic lesions were characterized and recorded in pictures. During the second laparotomy, samples from the lesions were collected. Postoperative care of the animals was performed in accordance with the requirements of local laws. The collected tissue samples were fixed in paraformaldehyde and embedded in paraffin or stored at -80°C. All organs were put back in place before the abdomen was sutured. For medical reasons, all females were separated from their males for a few hours and given antibiotics for a few days.

[0245] Behavioral analysis

[0246] Different behavioral test systems were used to study pain and discomfort and to establish social comfort, memory, learning, and activity. All primates used in the study were familiarized with the test system (over a period of more than 6 months) to confirm that the results obtained were drug-related and not a learning effect over time.

[0247] Two test systems were used in the study as described in Arnold et al., J Med Primatol., 40, 317-326 (2011).

[0248] 1. Feed the Tree

[0249] 2. Wisconsin General Testing Instruments (WGTA)

[0250] Social interactions, such as grooming, were recorded before and during the study.

[0251] Statistical methods

[0252] As the data were not normally distributed, all analyses were performed using the Wilcoxon signed-rank test. result Clinical signs, vitality, and observations of animals

[0253] There were no changes in clinical signs, general health behavior of the study animals during the study period. All blood laboratory parameters were within physiological ranges before and after treatment.

[0254] weight

[0255] During the treatment period, the treated marmosets showed no significant changes in body weight.

[0256] Reproductive cycle

[0257] Before treatment, 2 animals showed ovarian cycle activity, 5 animals showed irregular cycles, and 1 animal showed no activity. After treatment, 6 of 8 animals showed ovarian cycle activity, and 2 showed irregular cycles.

[0258] Color Doppler scan

[0259] Color Doppler ultrasound scans were performed to measure blood flow in the reproductive tract (uterus and ovaries) and bladder regions. Reduced blood flow was found in all animals in both regions.

[0260] Individual blood flow measurements are provided in Table 1, 0 = no visible blood flow, 1 = weak blood flow, 2 = moderate blood flow, and 3 = heavy blood flow. When the median blood flow reduction for all animals was compared before and at the end of treatment, both the bladder and reproductive tract reached statistical significance (p < 0.05), see Table 2.

[0261] Table 1

[0262]

[0263] Table 2

[0264] Research Week -2(BL) <![CDATA[6 (EoT) ]]> bladder 2(1.75；3) <![CDATA[1(1; 1)* ]]> Reproductive tract 2(1.75；2.25) <![CDATA[1(0.75; 2)* ]]>

[0265] Values ​​are medians (25% N quantile; 75% N quantile); *p<0.05 compared with baseline (Wilcoxon signed-rank test)

[0266] The changes in blood flow observed were as follows Figure 2 shown.

[0267] Laparotomy

[0268] Laparotomy analysis was performed to assess endometriotic lesions. Endometrial lesions were significantly reduced in all animals, and all sizes of lesions were affected by treatment.

[0269] Changes in the number of endometriotic lesions Figure 3 shown.

[0270] Individual data for endometriotic lesions before and after treatment are shown in Table 3. When comparing the reduction in the total number of endometriotic lesions in all animals combined before and at the end of treatment, both the bladder and the reproductive tract reached statistical significance (p<0.01), see Table 4.

[0271] Table 3: Individual data on the number and size of endometriotic lesions in the bladder and genital tract

[0272] | Individual data on the number and size of bladder endometriotic lesions

[0273]

[0274] Individual data on the number and size of genital endometriotic lesions

[0275]

[0276] IQR: interquartile range (25% ; 75% quartile)

[0277] *sp=visible but not measurable

[0278] Table 4

[0279]

[0280] Values ​​are medians (25% quartile; 75% quartile; **p<0.01 compared with baseline (Wilcoxon signed-rank test)

[0281] Changes in the number of endometriosis lesions Figure 4 shown.

[0282] Feeding the Tree

[0283] The feeding tree was designed to test motor activity associated with pain, discomfort, and / or distress. The feeding tree provided food at different reaching locations, which required different levels of movement. If the animal was experiencing discomfort, distress, or abdominal pain, it would not seek food in the upper area or at all. Additionally, if memory was impaired, thorough searching would be reduced. In the setting, each primate had to clear each rewarded hiding place within 5 minutes to be fully successful. The responses of the eight animals before, during, and after treatment were rated on a scale of 0-4, representing the number of hiding places cleared within 5 minutes.

[0284] All animals had improved success in the feeding tree during treatment

[0285] Changes in feeding tree behavior during the study Figure 5 Shown are median values.

[0286] Wisconsin General Test Instruments

[0287] The primates were tested for memory and learning. All animals received a WGTA training reward. The animals, sitting in a transport box, were trained to look for a special figure or place where a reward was hidden. An observer could watch the animal's behavior, but the animal could not see the observer.

[0288] The memory of eight animals was tested in the WGTA by testing the ability to remember the figure or the location of a hidden reward. The fitness of primates is associated with the willingness to find food, which was also included in this test system. The animals had to find the reward under three different figures three times within 5 minutes. Each animal was trained on the location of the figure or the figure itself.

[0289] During the treatment period, all females showed an increased success rate in placing the correct figure or location of the reward within the time frame.

[0290] During the study, the behavior of WGTA changed as follows: Figure 6 Shown are median values.

[0291] Social Interaction

[0292] Grooming was recorded by daytime observation. These behavioral observations provide information about health, while grooming is a sign of active social activity. Social grooming was recorded by observing couples for 10 minutes each time, 1 hour after breakfast and 1 hour after lunch. For each animal, the number of grooming interactions during the observation period was recorded.

[0293] All animals increased grooming during treatment compared to before treatment.

[0294] During the study, the changes in combing behavior such as Figure 7 Shown are median values.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, for use in treating or preventing endometriosis.

2. A method for treating or preventing endometriosis, which comprises 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. Use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing endometriosis.

4. A pharmaceutical preparation for treating or preventing endometriosis, comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

5. A combination product comprising: (I) a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof; and (II) one or more other therapeutic agents useful for treating or preventing endometriosis, Each of components (I) and (II) is optionally mixed with one or more pharmaceutically acceptable excipients.

6. A kit of parts comprising: (a) a pharmaceutical preparation as defined in claim 4; as well as (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, Components (a) and (b) are each provided in a form suitable for administration in combination with the other component.

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