MX2008002908A - Ikk inhibitors for the treatment of endometriosis - Google Patents

Abstract

This invention relates to a method of treating and/or preventing endometriosis comprising administering an IKK inhibitor. The IKK inhibitor can also be administered combined with a hormonal suppressor. The invention further relates to the treatment of endometriosis-related infertility.

Description

INHIBITORS OF IKK FOR THE TREATMENT OF ENDOMETRIOSIS BACKGROUND OF THE INVENTION Endometriosis is one of the most frequent diseases of women in their fertile period. It is characterized by the presence of endometrial tissue outside the uterine cavity, which consists histologically of glands and stroma. The most frequently affected anatomical sites are the ovaries, uterosacral ligaments, pelvic peritoneum, rectovaginal septum, cervix, vagina, fallopian tubes and vulva. Endometriosis is considered a benign disease, but there are times when endometriotic lesions become malignant. As in other malignancies, the development of neoplasms derived from endometriosis is due to concurrent episodes that involve alterations in growth factors and / or regulation of oncogenes (Kyama et al 2003). In addition, endometriosis is considered the main cause of infertility (Giudice et al 2004). The current treatment of endometriosis consists of hormonal therapy and / or surgery. Hormone therapies include high doses of progestins, oral contraceptives (combinations of estrogen and progesterone), Dinazol (an androgen derivative of ethisterone) and, more recently, GnRH agonists. These hormonal therapies are effective for pelvic pain and may induce an objective regression of the lesions, but may be at risk. Estrogen can stimulate and cause proliferation of the endiometriotic tissue as it may be unable to respond to progesterone (Dawood et al., 1993).

Progestational can cause irregular bleeding along with depression, weight gain and fluid retention. Danazol can improve symptoms in approximately 66-100% of patients suffering from pain, but recurrence rates after 4 years are approximately 40% - 50%. Other disadvantages of Danazol therapy are weight gain and androgenic side effects. GnRH analogues are more potent and act longer than natural GnRH, which act by eliminating the estrogenic stimulus for the growth of all estrogen-sensitive tissues. The side effects of GnRH analogues are mainly secondary to profound hypoestrogenemia, such as decreased bone density, and the recurrence rate is up to 50% after 5 years (Waller et al., 1993). Surgical intervention can be conservative, if fertility is desired, or it can lead to the elimination of the uterus, tubes and ovaries in the case of serious illness. In any case, even a limited surgical treatment leads to a significant reduction in fertility. Although endometriosis is considered one of the most researched disorders of gynecology, the current understanding of the pathophysiology of the disease remains unclear. According to one of the theories that has merited favor, endometrotic lesions are developed by eutopic endometrial cells that leave their primary site, possibly by retrograde menstruation, and are implanted in distant sites, followed by invasion of host tissues and proliferation. that endometriosis is an invasive disease and metastasizing. Although endometriotic cells proliferate to a certain extent, they are not neoplastic as what is typically found in carcinomas. Apparently, the endometriotic cells become senescent, apoptotic and necrotic. Inflammatory responses that are induced or go accompanied by injury formation ultimately lead to fibrosis and scarring. It has recently been shown that the recombinant human TNFα binding protein (rh-TBP-1) is effective in reducing the size and severity of endometriotic lesions in an experimental model of endometriosis (D'Hooghe et al., 2001). These results were the first to demonstrate that an anti-inflammatory molecule (r-hTBP-1) that targeted insertion of TNFa provided an effective medical treatment pathway to patients with endometriosis that did not inhibit ovulation. IkB kinases (IKKs) are key regulatory signal molecules that coordinate the activation of NF-kB. It has been found that the activity of IkB kinase (IKK) resides in a complex of high molecular weight (> 600 kD) which contains two kinase subunits (IKK1 or a and IKK2 or ß). Both participate in a significant sequence homology and contain identical structural domains. Through its leucine zipper domains, IKK1 and IKK2 interact to form hetero-or homo-dimers in vitro, although only heterodimers are found in vivo. A third protein in the complex IKK, IKK3 or y (also called NEMO or IKKAP), which does not contain a catalytic kinase domain, is preferentially associated with IKK2 and is required for the activation of heterodimers of IKK1 -IKK2 in response to pro-inflammatory cytokines, tumor necrosis factor-a (TNF) -ae and interleukin-1 (IL-1) (Mercurio F et al., 1997) The invention described here clearly shows the unexpected result of that the inhibition of IKK by means of an inhibitor of IKK, reduces endometriosis The reduction of endometriotic lesions using IKK inhibitors can also improve the fertility rates, since the normalization of genital structure has a positive effect on the implantation rate .

SUMMARY OF THE INVENTION The present invention relates to a method of treating and / or preventing endometriosis in an individual, comprising administering a therapeutically effective amount of an IKK inhibitor. The invention further relates to a method of treating and / or preventing endometriosis by a combined treatment of a hormonal suppressant (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators). together with an IKK inhibitor. The invention also relates to a method of treating infertility related to endometriosis in a woman, comprising administering a therapeutically effective amount of an IKK inhibitor, alone or in combination with other fertilizer drugs. The invention relates, finally, to a pharmaceutical composition comprising an inhibitor of IKK, a hormonal suppressant and an excipient. pharmaceutically acceptable.

DESCRIPTION OF THE INVENTION The following paragraph gives the definitions of the various chemical fractions that constitute the compounds according to the invention and this will be applied uniformly throughout the specification and claims, unless otherwise expressly specified the definition provided. the broadest definition.

"Aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g. phenyl) or i rings or multiple fused (e.g., naphthyl). Preferred aryls include phenyl, naphthyl, phenanthrenyl and the like. "Alkylaryl" refers to an alkyl having at least one alkyl hydrogen atom replaced by an aryl moiety, such as benzyl, - (CH2) 2phenyl, - (CH2) 3phenyl, -CH (phenyl) 2 and the like. "Alkyl" refers to a saturated or unsaturated alkyl, straight or branched chain, cyclic or non-cyclic hydrocarbon having 1 to 10 carbon atoms, while "lower alkyl" or "C-Cd alkyl" has the same meaning but it only has 1 to 6 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the like; while branched saturated alkyls include isoprpyl, sec-butyl, isobutyl, tere-butyl, isopentyl, and the like. The unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (also referred to as "alkenyl" or "alkynyl", respectively) Representative straight and branched chain alkenyls include ethylene, propylene, 1-butenyl, 2-butenyl isobutenyl, 1-pentenyl, 2-pentenyl, 3-methylene-1 buten? lo, 2-? Net? L-2-butenyl, 2,3-d? Met? L-2-butenyl, and the like, while the straight-chain and branched-chain alkynyl groups 5 include acetylenyl, propynyl, 1-but ? n, 2-butyl, 1 -penteny ?, 2-pentynyl, 3-meth? -1-butynyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. and the like, while unsaturated cyclic alkyls include cyclopentyl and cyclohexyl, and the like. Cycloalkyls are also cited here as the? or "carbocyclic" rings and include bi- and tn-cyclic ring systems having from 8 to 14 carbon atoms, such as a cycloalkyl (such as cyclopentene or cyclohexene) fused to one or more aromatic carbocyclic rings (such as phenyl) or non-aromatic (such as cyclohexane) "Alkoxy" refers to -O- (alkyl) u-O-aplo, such as methoxy, ethoxy, n-propyloxy, ? So-prop? Lox ?, n-butyloxy, phenoxy and the like "C2-C6 alkenyl" refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 to 2 points of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH = CH2), n-2-propenyl (aillo, -CH2CH = CH2) and the like 0"C2-C6 alkynyl" refers to alkynyl groups preferably having 2 to 6 carbon atoms and having at least 1 -2 points of alkylamine unsaturation; Preferred alkynyl groups include ethynyl (-C = CH), propargyl (-CH2C = CH) and the like "Halogen" refers to fluorine, chlorine, bromine or iodine. "Keto" refers to a carbonyl group (ie, C = O). "Heteroaryl" refers to a 5- to 10-membered aromatic heterocycle ring and having at least one heteroatom selected from nitrogen, oxygen and sulfur and containing at least 1 carbon atom, including both mono- and bi-cyclic ring systems . Representative heteroaryls are pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. "Heteroalkylaryl" refers to an alkyl having at least one alkyl hydrogen atom replaced by a heteroaryl moiety, such as -CH2-pyridinyl, -CH2-pyrimidinyl, and the like. "Heterocycloalkyl" or "heterocycle" refers to a heterocyclic ring containing from 5 to 10 ring atoms. Specifically, a 7- to 7-membered monocyclic heterocyclic ring, or 7- to 10-membered bicyclic ring, which is saturated, unsaturated, or aromatic, and which contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, including bicyclic rings in which any of the above heterocycles is fused to a benzene ring. The heterocycle may be linked through a heteroatom or a carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the heteroails listed above, the heterocycles also include morpho nyl, pyrro dinonyl, pyrrolidinyl, pipendinyl, piperazomyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrndinyl, tetrahydro-pipmidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropipmidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like. "Alkylheterocycloalkyl" refers to an alkyl having at least one hydrogen atom of the alkyl substituted with a heterocycle, such as 2- (1-pyrrolidone) or 4-morpholine? The term "substituted", as used herein, refers to any of the above groups (ie, alkyl, alkyl, heterocyclyl and heterocycloalkyl) where at least one hydrogen atom is replaced by a substituent. In the case of a keto substituent ("C (= O)", two hydrogen atoms are replaced. entities include halogen, hydroxy, alkyl, substituted alkyl (such as haloalkyl, mono- or fully substituted amino alkyl, alkyloxyalkyl, and the like, aplo, substituted aplo, aplaxyl, substituted, substituted, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, -NRaRb, -NRaC (= O) R, - NRaC (= O) NRaRb, -NRaC (= O) ORb, -NRaSO2Rb, -ORa, -C (= O) Ra, -C (= O) ORa, -C (= O) -NRaR, -OC (= O) Ra -OC (= O) ORa -OC (= O) NRaR, NRaSO2Rb or a radical of the formula YZ-Ra where Y is alkanoyl, substituted alkanol, or a direct bond, Z is -O- -S-, S (= O) -, -S (= O) 2-, N (Rb) -, -C (= O) -, -C (= O) O, -OC ( = O) -, -N (Rb) C (= O) -, -C (= O) N (Rb) -, or a direct link, where Ra and Rb are the same or different and independently, hydrogen, amino substituted alkyl (including halogenated alkyl) aplo substituted alkyl, substituted alkyloxy, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl or substituted alkylheterocycloalkyl, or where Ra and Rb taken together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle "Haloalkyl" refers to an alkyl having one or more hydrogen atoms replaced with halogen, such as -CF3- "Hydroxyalkyl" means alkyl having one or more hydrogen atoms replaced with hydroxy, such as -CH2OH "Sulfonyl" refers to the group "-SO2R" where R is selected from H, "aplo, "heteroapyl", "C6 alkyl", "alkylod-Ce" substituted with halogens, for example, a group -SO2-CF3, "C2-C6 alkenyl", "alkan? loC2-C6", "C3-cycloalkyl" C8"," heterocycloalkyl "," aplo "," heteroaplo "," alkyld-Cβ aplo "or" alkyl (d-heteroaplo "," C2-C6 alkenyl aplo "," alken? LoC2-C6 heteroaplo "" alkenol C2-CT "cycloalkyl", "alkyl? LoC2-C6 heterocycloalkyl" "Sulfinyl" refers to groups -S (O) R where R is selected from H, "C -Cß alkyl", "alkylod-Ce "substituted with halogens, for example, a group -SO-CF3," C2-C6 alkenyl "," alk? loC2-C6"," c? cloalkyl-C3-C8", "heterocycloalkyl", "aplo", "heteroaplo", "alk? C? -C6 aplo" or "alk? (C heteroar? lo", "C2-C6 alkenyl aplo", "alken? lC2-C6heteroaplo", " C2-C6 alkynyl aplo "," alkyl? C2-C6heteroappo "alkylCrCβ cycloalkyl", "alkyl? C6-heterocycloalkyl" Sulfanyl "refers to groups -SR where R includes H," C-alkyl "," alkyl ? loC C6"substituted with halogens, for example, a -SO-CF3 group, "C2-C6 alkenyl", "alkan? loC2-C6", "C3-C8 cycloalkyl", "heterocycloalkyl", "aplo", "hetetoan" "alkyld-C? aplo" or "alk? (C heteroar? "" C2-C6 alkenyl aplo "," alkenyl C6-C6 heteroaryl "" C6-C6 alkyloyl "," alkyl? C2-C6heteroappo "alkyl C, -C6 cycloalkyl", "alkyl? CrC6 heterocycloalkyl Preferred sulfanyl include methylsulfanyl, ethylsulfanyl and the like "Carboxyl" refers to -COOH "Amino" refers to group -NRR 'wherein each R, R' are, independently, hydrogen or "alkyl d-Ce" or "aplo" or " heteroapyl "or" alk? C? -C6appa "or" alk (C? - C6) -heteroappe or "cycloalkyl" or "heterocycloalkyl" and where R and R 'taken together with the nitrogen atom to which they join, they can optionally form a 3-8 membered heterocycloalkyl ring "Ammonium" refers to a positively charged group -NRR'R ", where each R, R ', R "are, independently," C6-alkyl "or" alk-C6-C6 aplo "or" alkyldCe-hetero-pyl or "cycloalkyl" or "heterocycloalkyl" and where R and R' taken together with the nitrogen atom to which they are attached, can optionally form a 3-8 membered heterocycloalkyl ring "HCl" means hydrochloride salt of compounds represented by their chemical structure "Nitrogen-containing non-aromatic hetepcycle" refers to morpholinyl, thiomorpholinyl, pyrrolidinonyl, pipepdynyl, homopipepdynyl, piperazinyl, homopiperazinyl, hydantoinyl, tetrahydropipindinyl, tetrahydropipmidinyl, oxazolidinyl, thiazolidinyl, indo nyl, isoindo dino, tetrahydroquinolyl, tetrahydroisoquinolinyl, etc.

As "pharmaceutically acceptable cation salts or complexes" is understood those salts such as alkali metal salts (for example sodium and potassium), alkaline earth metal salts (for example calcium and magnesium), aluminum salts, ammonium salts and salts with organic amines such as with methylamine dimethylamine, t-methylamine, ethylamine, tetylamine, morpholine, N-Me-D-glucamine N N'-b? s (phen? lmet? l) -1, 2-ethanedi amine, ethanolamine diethanolamine, ethylenediamine, N-methylmorphroma, pipepdine, benzathine (N, N'-d? benc? l-et? lend? am? na), choline, ethylene diamine, meglumine (N-methyIglucamine), benetamine (N- benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-h? drox? met? l-1-3-propanod? ol), procaine, as well as amines of formula -NR, R ', R "where R, R', R" are independently, hydrogen alkyl or benzyl Especially preferred salts are the sodium and potassium salts "Pharmaceutically acceptable salts or complexes" refers to those salts or complexes of the compounds after Identified of the present invention which retain the desired biological activity Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (eg, hydrochloric acid, bromidic acid, sulfuric acid). , phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, acid pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and pogalactouronic acid These compounds can be well as salts pharmaceutically acceptable quaternaries known to those skilled in the art, and specifically include the quaternary ammonium salt of the photon -NR R 'R "Z, wherein RR' and R" are, independently hydrogen, alkyl or benzyl, d-C6 alkyl , alken? loC2-C6 alky? loC2-C6, alky? C6-arylo, alky? -6-heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counter ion, which includes chloride , bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, ghcolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamate, mandeloate, and diphenylacetate "Pharmaceutically active derivative" refers to any compound that when administered to the subject that receives it, is able to provide, directly or indirectly, the activity described herein "Aromatase inhibitors" refers to drugs that inhibit enzyme aromatase and therefore they lower the level of estradiol. The inhibitors d Preferred aromatase include, for example, anastrozole, letrozole, verozole and exemestane. "Estrogen receptor modulators (SERM)" refers to drugs that block the actions of estrogen by occupation of estrogen receptors on cells. SERMSs also include beta-antagonists. of estrogen receptor and estrogen receptor-agonists Preferred SERMs include, for example, Tamoxifen, Raloxifen "GnRH antagonists" refers to synthetic GnRH analogs, which are drugs that competitively block the pituitary GnRH receptor, which is located in the gonadotropic membrane, inducing a suppression Rapid, reversible gonadotropin secretion Preferred GnRH antagonists include for example Cetrorelix and Ganire x "GnRH agonists" refer to decapeptide modifications of the natural hormone GnRH, which are drugs that desensitize GnRH receptors of the pituitary gland, a continuous exposure, which gives rise to an initial stimulation of the pituitary-ovate axis, followed by the reduction of the concentration of circulating gonadotropin in serum and inhibition of the ovapca function. Preferred GnRH agonists include, for example, Buserelin acetate, Nafarelm , Leiprolide, Tpptolepn, Goserelin "IKK Inhibitors" refers to a compound, a peptide or a protein, which inhibits the activity of IkB kinase (IKK). When IKK is inhibited, IKK can not exert its enzymatic, biological and / or pharmacological Preferably, IKK-2 is inhibited IKK-2 is a septa-threonine kinase of 756 amino acids that has a 52% identity uctural with IKK-1 ((Mercurio et al (1997) and (Woronicz et al (1997) "Progesterone receptor modulators (SPRMs" The progesterone receptor, a member of the superfamily of nuclear receptors, is the receptor for progesterone which plays a fundamental role in female reproduction Selective progesterone receptor modulators are drugs that can have agonist, antagonist or partial agonist / antagonist (mixed) activities, depending on the site of action A preferred SPRM includes, for example, asoppsil The first aspect of the present invention is to provide a method of treatment and / or prevention of endometritis in an individual, comprising the administration of a therapeutically effective amount of an IKK inhibidoi In a preferred embodiment the individual is a female human being. In a second aspect the invention relates to a method of treatment and / or prevention of endometriosis by sequential or combined treatment of hormonal suppressor (for example GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) with an inhibitor of IKK. carrying out second or subsequent administrations of therapeutically effective amounts at a dosage that is equal to, less than or greater than the previous or initial dose administered to the individual. Second or subsequent administrations may be carried out during or before relapse into endometritis or related symptoms The terms "relapse or" recurrence "encompass the ap of one or more of the symptoms of endometritis In a third aspect, the invention relates to a method of treating infertility related to endometritis in a woman comprising administering a therapeutically effective amount of an IKK inhibitor, alone or in combination with other fertility drugs. In one embodiment , the sequential or combined treatment regimen reduces the disease by suppression of cells with endocrine dependence A fourth aspect of the present invention consists of a pharmaceutical composition comprising an inhibitor of IKK, a hormonal suppressor (for examples are GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) and a pharmaceutically acceptable excipient. A fifth aspect of the present invention consists in the use of the IKK inhibitor in the manufacture of a medicament for the treatment and / or prevention of endometriosis. The term "prevention", as used herein, shall be understood as prevention, inhibition, alleviation, or reversal, total or partial of one or more symptoms or cause (s) of endometriosis. A proposed model for the progression of endometriosis disease predicts that the lesions progress from benign inflammatory lesions that respond to endocrine intervention, to lesions without partial or total hormonal response that suppose regulated survival pathways in addition to inflammatory pathways. Therefore, in one embodiment, the IKK inhibitor can interfere with the pathways of survival in endometriosis. A sixth aspect of the invention relates to the use of an IKK inhibitor together with a horminal suppressor (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) and a pharmaceutically acceptable vehicle in the manufacture of a medicament for the treatment and / or prevention of endometriosis. The use of IKK inhibitor together with a hormonal suppressant (for example GnRH agonists GnRH agonists aromatase inhibitors, estrogen receptor modulators progesterone receptor modulators) can be sequential or combined IKK inhibitor and hormonal suppressor A seventh aspect of the invention relates to the use of an IKK inhibitor alone or in combination with other drugs in the manufacture of a medicament for the treatment of endometriosis. An eighth aspect of the invention relates to the use of an IKK inhibitor for the treatment of endometriosis. endometritis treatment In particular, when the infertility related to endometritis is going to be treated or cured, drugs for the treatment of infertility can be administered for example biologically active human coenic gonadotropins (hCO), luteinizing hormone (LH) or follicle-stimulating hormone. (FHS), either in the highly purified natural form or in the recombinant form These molecules and methods for their production are described in European Patent Applications EP 160 699, EP 21 1 894 and EP 322 438 The pharmaceutical compositions herein invention can be administered by a variety of routes including oral, rectal, transdermal, subcut Anemone, intravenous, intramuscular and mtranasal Compositions for oral administration may take the form of liquid solutions or suspensions, or powders, in bulk. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. "Unit dosage forms" refers to physically discrete units suitable as unit dose for human subjects and others mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled and filled ampoules or syringes of liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions In these compositions, the IKK inhibitor is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) the remainder being diverse vehicles or excipients and process aids useful for forming the desired dosage form Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffering agents, suspending and dispensing agents, dyes, sabot and similar The solid forms may include, for example, any of the following ingredients, or compounds of a similar nature, a binder such as microcpstalin cellulose, gum tragacanth or gelatin, an excipient such as starch or lactose, a disintegrating people such as alginic acid, Ppmogel, or corn starch, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetening agent such as sucrose or saccharin, or a sabotage agent such as peppermint, methyl sacrylate, or orange flavor Injectable compositions are typically based on sterile injectable saline solutions or phosphate buffered saline solutions or other Injectable vehicles known in the art As mentioned above, the IKK inhibitor in these compositions constitutes a minor component frequently in the range between 0.05 to 10% by weight with the remainder being the vehicle for injection, and the like The components described above for oral or injectable administration compositions are only representative examples. In Remington's Pharmaceutical Science, 20th edition, 2000, Marck Pubhshing Company, Easton Pennsylvania, which is incorporated herein by reference, other materials and processing techniques and the like are given. The compounds of this invention can be administered ta in sustained release forms or by sustained drug delivery drug delivery systems A description of representative sustained release materials can be found in the materials incorporated in Remington's Pharmaceutical Sciences The definition of "pharmaceutically acceptable" means Any vehicle that does not interfere with the effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered is exemplified. For example, for parenteral administration, the IKK inhibitor can be formulated into a dosage form. unit for injection, in vehicles such as saline solution, dextrose solution, serum albumin and Ringer's solution For parenteral administration (e.g., intravenous, subcutaneous, intranuscular, IKK inhibitors can be formulated as a solution, suspension, emulsion or ofilized powder in association with a parenteral vehicle. pharmaceutically acceptable (eg, water, saline, dextrose solution) and additives that maintain isotonicity (eg mannitol) or chemical stability (eg preservatives and buffering agents) The formulation is characterized by the techniques commonly used. Therapeutically effective inhibitors of an IKK inhibitor will be a function of many variables, including type of inhibitor, inhibitor affinity for IKK, any residual cytotoxic activity exhibited by the IKK inhibitor, the route of administration or the patient's clinical status. "Therapeutically effective" is that when administered, the inhibitor of IKK causes the inhibition of the biological activity of IKK. The dosage administered, as a single or multiple dose, to an individual, will vary depending on a number of factors, including pharmacokinetic properties of the IKK inhibitor, the route of administration, the condition and characteristics of the patient (sex, age, body weight, health, measures), extension of symptoms, concurrent treatments, frequency of treatment and desired effect The adjustment and management of the established dosage intervals fall within the capacity of the specialists, as well as methods in vitro and in vivo determination of inhibition of IKK in an individual IKK inhibitors can be derivatives of anilinopipmidina of Formula (I) These compounds are described in the international patent WO 02/46171 (Signal Pharmaceutical Inc.), which are described in particular for the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, infectious diseases, apoplectic seizures or cancer. In the said compounds according to formula (I), which include their isomers, prodrugs and pharmaceutically acceptable salts thereof, the substituents are defined as follows: R1 is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7; R2 is hydrogen; R3 is hydrogen or lower alkyl; R4 is optionally substituted with one to four substituents, wherein each substituent is the same or different and is independently selected from the group consisting of halogen, hydroxy, lower alkyl and lower alkoxy; R5 and R6 are the same or different and are independently selected from the group consisting of -R8, - (CH2) aC (= O) R9, - (CH2) aC (= O) OR9, (CH2) aC (= O ) NR9R10, - (CH2) aC (= O) NR9 (CH2) bC (= O) R10, - (CH2) aNR9C (= O) R10, - (CH2) aNR11C (= O) NR9R10, - (CH2) aNR9R10 , - (CH2) aOR9, - (CH2) aSOcR9), or (CH2) aSO2 NR9R10; and R5 and R6 taken together with the nitrogen atom that is attached form a heterocycle or substituted heterocycle R7 are each selected independently from the group consisting of halogen, hydroxyl, cyano carboxy nitro, alkoxy, haloalkyl, acyloxy, sulfanilalquilo, alkylsulfinyl, alkylsulfonyl, hydroxyalkyl, arito I arito substituted alquilaplo, alquilaplo substituted heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, -C (= O) OR8, -OC (= O) R8, -C (= O) NR8R9, C (= O) NR8OR9, -SOcR8, -SOcN R8NR9, -NR8SOcR9, -NR8R9, -NR8C (= O) R9, -NR8C (= O) (CH2) bOR9, -NR8C (= O) (CH2) bR9, -O (CH2) bNR8R9, and substituted or unsubstituted heterocycloalkyl Condensate to substituted or unsubstituted phenyl R8, R9, R10 and R1 are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aplo, substituted aplo, alkylamino, substituted alkylamino, heterocycloalkyl , substituted heterocycloalkyl, alkylheterocycloalkyl and alky substituted lheterocycloalkyl, or R8 and R9, taken together with the atom or atoms to which they are bound form a heterocycle or a substituted heterocycle, a and b are the same or different and are each independently selected from the group consisting of 0, 1, 2 , 3 or 4, and c is, each time, 0, 1 or 2 In one embodiment of the invention, R is a substituted or unsubstituted aplo or heterocycle When R 1 is substituted it is with one or more substituents of the defined later Preferably, when substituted, R1 is substituted with a halogen, sulfonyl or sulfonamide In another embodiment of the invention, R1 is selected from the group consisting of thiophenyl benzofui aplo fuplo anilo quinolinyl benzothiophenyl, indolyl pipolilo, oxazolyl, imidazolyl benzoxazlilo benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pirazohlo, isothiazolyl, pipdazinilo pipmidinilo, pyrazinyl, ciccolinilo thiazinyl, phthalizinyl, phthalazinyl and quinazolinyl, substituted or unsubstituted In another embodiment of the invention, R1 is a substituted or unsubstituted aplo, preferably a substituted or unsubstituted phenyl when R1 is a aplo substituted, the aplo is substituted with one or more substituents defined later. Preferably, when substituted, R1 is substituted with a halogen,? or sulfonyl or sulfonamide In another embodiment of the invention, R5 and R6, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted, nitrogen-containing, non-aromatic heterocycle, preferably substituted or unsubstituted nyl-morphine, substituted or unsubstituted thiomorpholinyl, substituted pyrrohdinonyl or without i: > replace, pyrrolidinyl substituted or unsubstituted, I pipepdinilo substituted or unsubstituted, substituted or unsubstituted homopipepdinilo, piperazinyl substituted or unsubstituted, substituted or unsubstituted hydantoinyl, substituted or unsubstituted homopiperazinyl, substituted or unsubstituted tetrahidropipndinilo, substituted or unsubstituted tetrahidropimimidinilo, oxazolidinyl substituted or unsubstituted, I tiazohdinilo substituted or unsubstituted, 0 substituted indohnilo or unsubstituted isoindolinyl, substituted or unsubstituted, tetrahydroquinolinyl substituted or unsubstituted, or substituted or unsubstituted tetrahidroisoquinohnilo When R5 and R6, taken together with the nitrogen atom to That unite they form a substituted or unsubstituted piperazinyl. substituted or unsubstituted or unsubstituted or unsubstituted, substituted or substituted piperazinyl, these are substituted with one or more of the substituents defined above. Preferably, when substituted, the substituent is alkyl, ammo, alkylamino, alkyl ester, acyl, pyrrolidinyl or pipepdinyl, embodiment of the invention, R3, R2 and R4 are hydrogen, and the compounds of this invention have the following Formula (II) In a more specific embodiment of the invention, R1 is a phenyl optionally substituted with R7, and having the following formula (III): (III) In still another embodiment of the invention, R 'is in the μ-position of the phenyl ring, as represented by the following Formula (IV): Still in another embodiment of the invention, among the anilinopyrimidine derivatives is 1- (4- {4- [4- (chloro-phenyl) -pyrimidin-2-ylamino] -benzoyl} -piperazin-1. -il) -etanone. The synthesis of compounds of Formulas (I) - (IV) is described in detail in International Patent WO 02/4617 (Signal Pharmaceutical Inc.). In another embodiment, the IKK inhibitor can be a compound represented by the following Formula (V) (Burke et al (2003)): (V) In another embodiment, the IKK inhibitor can be a compound as represented by Formula (VI) (Coghlan et al (2003)): In another embodiment, the IKK inhibitor can be a compound shown in Formula (VII) (Hideshima et al. (2002): In another embodiment, the IKK inhibitor can be a compound as shown in Formula (VIII) (WO 02/44153, Bayer): In another embodiment, the IKK inhibitor can be a compound as presented by Formula (IX) (Kishore et al (2003)): (IX) In another embodiment, the IKK inhibitor can be a compound shown in Formula (X) (Podolin et al (2005) J. Pharmacol. Exp. Ther.): In another embodiment, the IKK inhibitor can be a compound as shown in Formula (XI) (Baxter et al (2004): (XI).

In another embodiment, the IKK inhibitor can be a compound as represented in Formula (XII) (WO 04/022553, Aventia Pharma): The present invention is illustrated below with examples, which are not limiting thereof in any way.

EXAMPLES Example 1: Models of endometriosis The effect of inhibitors of IKK in endometriosis models in vitro and in vivo was evaluated.

Example 1 .1 Cytokine secretion For in vivo studies, human endometriotic cells (12Z) were used (Zeitvogel et al, 2001). These cells secrete cytokines in response to TNFα, which have been described above, to increase in the peritoneal fluid of endometriosis patients. 12Z endometriotic cells were stimulated with TNFa for 24 hours and the culture supernatant was measured for the presence of GMCSF, IL-6 and IL-8. These cytokines were quantitatively determined by Meso Scale Discovery technology. This is a multiplex assay platform, which employs sandwich ELISA assay. , at the touch of the 96 wells, antibodies for IL-6, IL-8 and GMCSF to measure the three atocins in the same well The three atocins increase in response to different concentrations of TNFa in 12Z cells Five different IKK inhibitors were used for inhibit the expression of atocines N- (6-chloro-9H-beta-carbol? n-8-? l) -n? cot? nam? da (an inhibitor of formula VII) was tested. { 4- [4- (4-chloro-phen? L) -p? Pm? D? N-2-? Lam? No] -fen? L} -p? peraz? n-1 -? l-methanone,. { 4- [4- (4-chloro-phen? L) -p? Pm? D? N-2-? Lam? No] -fen? L} - [4- (2-h? Drox? -et? L) -p? Peraz? N-1 -? L] -metanone,. { 4-. { 4- (4-chloro-phen? L) -p? Pm? D? N-2-? Lam? No] -benzo? L} - [p? peraz? n-1 -? l] -metanone, and 1 - (4- { 4 - [- (4-chloro-phen? l) -p? pm? d? n-2-? lam? no] -fen? l.}. - { 4- (2-etox? -et? l) -p? peraz? n-1 -? l] -ethanone, (all inhibitors of formula I) presence of a fixed concentration of TNFa (15 ng / ml), all inhibitors of IKK, depending on the dose, blocked the secretion of atocin The inhibitors, by themselves, do not give rise to any significant effect on the atocins According to this, IKK inhibitors are able to block the secretion of atocin by human endometropoietic cells induced by TNFa By blocking the pathway of IKK, inflammatory atocins associated with endometriosis can be specifically inhibited and therefore these IKK inhibitors be useful for the treatment of endometriosis Example 1 2 Nude mouse model Human endometrium tissue was injected into naked ovapoectomized patients to establish the disease (Brunei-Fran et al 2002). In short, the endometrial biopsies obtained from normal voluntapas or from endometrial patients were cut in small pieces and cultured in the presence of estradiol during 24 hours Treated tissues were injected subcutaneously or intrapeptoneally in nude mice ovapoectomized with estradiol implant 2-4 days after injection, ectopic endometrial lesions were developed in the animals. Treatment with progesterone or? nh? b? dor-5 of IKK 1 - (4- [4-. {4- (4-chloro-phen? l) -p was started. ? r? m? d? n-2-? lam? no] -? or benzo? l.]. - [p? peraz? n-1 -? l] -ethanone 10 days after the injection of tissue The compound was administered at a dose of 10 mg / kg and 30 mg / kg / animal for 15 days. Previous studies using this model had established that treatment with progesterone prevents the progression of the disease, so it was used as a control Once the treatment was completed, the animals were sacrificed, ID were measured (both size and number) lesions developed from the transplanted tissue found in both subcutaneous sites as intrapeptoneales Table 1 below shows the results of studies carried out in nude mice The IKK inhibitor, a dose of 10 mg / kg 0 and 30 mg / kg is effective for regression of established disease by 125% and 100% respectively compared to progesterone treatment the average lesion size was also reduced by 90% and 75% respectively by the treatment These results are significant, since the model measures the growth / regression of human endometropus tissue and therefore has a direct relevance to the disease in humans The treatment with inhibitor of IKK had no effect on the weight and size of the uterus of the animals Table 1 Effect of IKK inhibitor-5 on regression of endometrial lesions in xenograft model in nude mice List of references Burke et al (2003) J Biol Chem, 278, 1450-1456 Coghlanycol (2003) Inflam Res 52.2-5 D'Hooheycol ASRM (2001) Dawoodycol (1993) Int J Gynaecol Obstet 40 (Supplement), 29-42 Giudiceycol (2004) Lancet 364, 1789-1799 Hideshima et al (2002) J Biol Chem 19, 16639-47 Kishore et al (2003) J Biol Chem Kyamaycol 35.32861-71 (2003) Biol Reprod Endocpnol 1 123 Mercury and al (1997) Science 278, 860,866) Podohn et al (2005) J Pharmacol Exp Ther Wallerycol (1993) Fertil Stepl 59.511-515 Woronicz et al (1997) Science 278, 866-869 Zeitvogel et al (2001) Am J Pathol 1591839 -52 Patent EP 160699 Patent EP211894 Patent EP 322438 International Patent WO 02/44153 Patent WO 02/46171 Patent WO 04/022553

Claims (2)

1. CLAIMS 1. A method of treating and / or preventing endometriosis in a patient comprising administering a therapeutically effective amount of an IKK inhibitor.
2. 2. The method according to claim 1, wherein said inhibitor of IKK is administered in combination of a hormonal suppressant.

   3. The method according to claim 1 or 2, wherein said suppressor? or hormonal is selected from the group consisting of GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor modulator and an estrogen receptor modulator.

   4. The method according to any of claims 1 to 3, wherein said IKK inhibitor is administered alone or in combination with drugs for the treatment of infertility related to endometriosis.

   5. The method according to any of claims 1 to 4, wherein said IKK inhibitor is a compound according to formula (I)

   (i)

   as well as its isomers, prodrugs and pharmaceutically acceptable salts and pharmaceutically acceptable derivatives thereof, wherein R1 is aplo or heteroaphole opaquely substituted with one to four substituents independently selected from R7, R2 is hydrogen, R3 is hydrogen or lower alkyl R4 is opaquely substituted with one to four substituents, the same or different, and are independently selected from the group consisting of halogen, hydroxy, lower alkyl and lower alkoxy; R5 and R6 are the same or different and are independently selected from the group consisting of -R8, - (CH2) aC (= O) R9, - (CH2) aC (= O) OR9, (CH2) aC (= O) NR9R10, - (CH2) aC (= O) NR9 (CH2) bC (= O) R10 , - (CH2) aNR9C (= O) R10, - (CH2) aNR11C (= O) NR9R10, - (CH2) aNR R10, - (CH2) aOR9, - (CH2) aSOcR9, or (CH2) aSO2 NR9R10, and R5 and R6 taken together with the nitrogen atom to which they are bound form a heteroazo or substituted heteroaclo, R7 is each independently selected from the group consisting of halogen no, hydroxy, aano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, sulfanylalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aplo, substituted ary, alkylamp, substituted alkylap, heteroacloalkyl, substituted heteroacloalkyl, alkylheteroacloalkyl, substituted alkylheteroacloalkyl,, -C ( = O) OR8, -

   OC (= 0) R8 -C (= 0) NR8R9, C (= O) NROR9, -SOr R8 -SOcN R8NR9, -NR8SOcR9, -NR8R9, -NR8C (-0) R9 -NR8C (= 0) (CH2 ) bOR9 --NR8C (= 0) (CH2) bOR9

   0 (CH2) bNR8R9 and heteroacloalkyl fused to phenyl R8, R9 R? u and R "are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aplo, substituted aplo, alkylamino, substituted alkylamino, heterocycloalkyl, substituted heteroacloalkyl, alkylheteroacloalkyl, and alkyl-heteroacloalkyl. substituted, or R8 and R9, taken together with the atom or atoms to which they are attached form an opaquely substituted heterocycle, a and b are the same or different and are each independently selected from the group consisting of 0, 1, 2, 3 and 4 , and c is, each, 0, 1 or 2

   The method according to claim 5, wherein R5 and R6, taken together with the nitrogen atom to which they are bound, form a non-aromatic heteroach containing opaquely substituted nitrogen

   The method according to claim 5 or 6, wherein the nitrogen-containing non-aromatic heteroample is selected from the group consisting of morphonyl, thiomorphonyl, pyrrolidinonyl, pyrrolidinyl, pipepdinyl, homopipepdinyl, piperazinyl, homopiperazinyl, hydantoinyl, tetrahydropipindinyl, tetrahydropipmidinyl, oxazolidinyl , thiazolidinyl, indolinyl, isomdolinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl

   The method according to any of claims 5 to 7, wherein R is aplo or hetei oaplo

   The method according to any of claims 5 to 8, wherein R 'is selected from the group consisting of aplo, furry, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrroyl, indole, oxazole, benzoxazole, imidazole, benzoimidazolyl, thiazolyl, benzothiazole, isoxazolyl, pyrazole, 25-isothiazolyl, pipdazinyl, pipmidinyl, pyrazinyl, tpazinyl, cinnolinyl, phthalazinyl and quinazolinyl

   The method according to any of claims 5 to 9, wherein R1 is phenyl

   The method according to any of claims 7 to 10, wherein the nitrogen-containing heteroample is piperazinyl I The method according to any of claims 7 to 10, wherein the nitrogen-containing heteroach is piperazinyl.

   The method according to any of claims 7 to 10, wherein the heteroatom containing nitrogen is morfohnyl

   The method according to any of claims 1 to 4, wherein said inhibitor of IKK is a compound according to Formula (II)

   as well as their isomers, prodrugs and pharmaceutically acceptable salts and pharmaceutically acceptable derivatives thereof wherein R1 is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7: R5 and R6 are the same or different and are independently selected from the group consists of -R8, - (CH2) aC (= O) R9, - (CH2) aC (= O) OR9, (CH2) aC (= O) NR9R10, - (CH2) aC (= O) NR9 (CH2) bC (= O) R10, - (CH2) aNR9C (= O) R10, - (CH2) aNR11C (= O) NR9R10, - (CH2) aNR9R10, - (CH2) aOR9, - (CH2) aSOcR9, and (CH2 ) aSO2 NR9R10; or R5 and R6 taken together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle; R7 is each independently selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, sulfanylalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl,, -C (= O) OR8,

   OC (= O) R8, -C (= 0) NR8R9, C (= O) NR8OR9, -SOcR8, -SOcN R8NR9, -NR8SOcR9, -NR8R9, -NR8C (= 0) R9. -NR8C (= 0) (CH2) bOR \ -NR8C (= 0) (CH2) bOR9, 0 (CH2) bNR8R9, and fused heterocycloalkyl to phenyl; R8, R9, R10 and R "are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, hetero-cycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl and substituted alkyl-heterocycloalkyl, or R8 and R9, taken together with the atom or atoms to which they are attached form a heterocycle or a substituted heterocycle, and a and b are the same or different and are each independently selected from the group consisting of 0, 1, 2, 3 or 4, and c is, each time, 0, 1 or 2.

   15. The method according to claim 14, wherein R5 and R6, taken together with the nitrogen atoms to which they are attached form an optionally substituted non-aromatic heterocycle containing nitrogen.

   16. The method according to claim 14 or 15, wherein the nitrogen-containing non-aromatic heterocycle is selected from the group consisting of morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, hydantoinyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, oxazolidinyl, thiazolidinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

   The method according to any of claims 14 to 16, wherein R 1 is either aplo or heterolane

   The method according to any of claims 14 to 17, wherein R1 is selected from the group consisting of aplo, fuplo, benzofuranyl, thiophenyl, benzothiophenyl, quinoyl, pyrrole, indolyl, oxazolyl, benzoxazole, imidazole, benzoimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazole 25, isothiazolyl, pipdazinyl, pipmidinyl, pyrazinyl, tpazinyl, annolinyl, phthalazinyl and quinazolinyl

   The method according to any of claims 14 to 18, wherein R1 is phenyl

   The method according to any of claims 15 to 19, wherein the heteroach containing nitrogen is piperazinyl

   The method according to any of claims 15 to 19, wherein the nitrogen-containing heterocycle is pipepdmyl

   The method according to any of claims 15 to 19, wherein the nitrogen-containing heteroach is morpholinyl

   The method according to any of claims 1 to 4, wherein said

   IKK inhibitor is a compound according to Formula (III):

   where R5, R6, R7, R8, R9, R10 and R11 are defined as in claims 14 to 22.

   24. The method according to any of claims 1 to 4, wherein said IKK inhibitor is a compound according to Formula (IV)

   where R5, R6, R7, R8, R9, R10 and R11 are defined as in claims 14 to 22.

   25. The method according to any of claims 1 to 4, wherein said IKK inhibitor is 1- (4- {4- [4- (4-chloro-phenyl) -pyrimidin-2-ylamino] -benzoyl}. -piperazin-

   1 - . 1 -? L) -etanone

   A pharmaceutical composition comprising an inhibitor of IKK, a hormonal supplement and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 26, wherein said hormonal suppressant is selected from the group consisting of a GnRH antagonist, a GnRH agonist, Aromatase inhibitor, progesterone receptor modulator and a estrogen receptor modulator? or 28 The pharmaceutical composition according to claim 26 or 27 wherein said IKK inhibitor is a compound as defined in any of claims 5 to 25.

   ID 29 The pharmaceutical composition according to any of claims 25 to 28, wherein said IKK inhibitor is 1 - (4-. {4- [4- (4-chloro-phen? L) -p? Pm? D? n-2-? lam? no] -benzo? l.}. -p? peraz? n-1 -? l) -etanone