MXPA01001834A - NON-PEPTIDE GnRH AGENTS, METHODS AND INTERMEDIATES FOR THEIR PREPARATION - Google Patents

Abstract

Non-peptide GnRH agents capable of inhibiting the effect of gonadotropin-releasing hormone are described. Such compounds and their pharmaceutically acceptable salts, multimers, prodrugs, and active metabolites are suitable for treating mammalian reproductive disorders and steroid hormone-dependent tumors as well as for regulating fertility, where suppression of gonadotropin release is indicated. Methods for synthesizing the compounds and intermediates useful in their preparation are also described.

Description

NON-PEPTIDE AGENTS OF THE RELEASE HORMONE GONADOTROPINE, METHODS AND INTERMEDIARIES FOR YOUR PREPARATION TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION This invention relates generally to compounds that affect the action of human gonadotropin-releasing hormone (GnRH). More particularly, it is related to non-peptidic GnRH antagonists or agonists as well as their preparation. These non-peptidic GnRH agents have advantageous physical, chemical and biological properties, and are useful drugs for diseases or conditions mediated by pituitary-gonadal axis modulation. The compounds of the invention avoid the problems of degradation and biodistribution of peptide agents.

BACKGROUND OF THE INVENTION Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LH-RH), plays a central role in the biology of reproduction. A wide variety of analogs have been used to increase the amount of clinical indications. The decapeptide of GnRH (pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 or p-EHWSYGLRPG-NH2) is produced in ReE neurons: 126388 basal hypothalamus from a larger precursor, by enzymatic processing. The decapeptide is released in a pulsatile fashion within the pituitary portal circulation system where GnRH interacts with high affinity receptors (transmembrane G protein-coupled receptors 7) in the anterior pituitary gland located at the base of the brain. In the pituitary, GnRH activates the release of two gonadotropic hormones (gonadotropins): luteinizing hormone (LH) and follicle stimulating hormone (FSH). In testes and ovaries, LH stimulates the production of testosterone and estradiol, respectively. FSH stimulates the growth of follicles in women and the formation of sperm in man. When there is correct functioning, the synchronized release and concentration levels in GnRH pulse are critical for the maintenance of gonadal steroidogenesis and for normal reproductive functions related to growth and sexual development. The response to the pituitary gland varies greatly during life. GnRH and gonadotropins appear for the first time in the fetus at approximately ten weeks of gestation. Sensitivity to GnRH decreases, after a brief increase during the first three months after birth until the onset of puberty. Before puberty, the response of FSH to GnRH is greater than that of LH. Once puberty begins, sensitivity to GnRH increases and pulsatile LH secretion occurs. Later in puberty and during all reproductive years, pulsatile release of GnRH occurs during the day, where the responsiveness of LH is greater than that of FSH. The release of pulsatile GnRH results in pulsatile release of LH and FSH and thus the release of testosterone and estradiol from the gonads. After menopause, the concentration of FSH and LH increases and the postmenopausal levels of FSH are higher than those of LH. Chronic administration of GnRH agonists and antagonists to animals or man results in decreased circulation levels of both LH and FSH. GnRH agonists are compounds that mimic endogenous GnRH to stimulate receptors in the pituitary gland, resulting in the release of LH and FSH. After a transient increase in gonadal hormone production, or "flush" response, chronic administration of GnRH agonists results in a regulation of inactivation of GnRH receptors. The regulation of GnRH receptor inactivation and loss of pituitary sensitization results in a decrease in circulating levels of LH and FSH. Despite the exacerbated hormonal flush of the symptoms that are experienced, GnRH agonists have been the treatment of choice for sex-steroid-dependent pathophysiologies. By example, GnRH agonists have been used to reduce the production of testosterone, thereby reducing the prostate volume in benign prostatic hyperplasia (BPH) and a decrease in the rate of tumor growth in prostate cancer. These compounds have also been used to treat breast and ovarian cancers. Recently, GnRH antagonists have been found available for clinical evaluation. GnRH antagonists have an immediate effect on the pituitary gland if the observed flush is associated with agonists. The use of GnRH antagonists (usually decapeptides) for the treatment of breast, ovarian and prostate cancers has been reported in the literature. Other uses of antagonists, like agonists, include endometriosis (which includes endometriosis with pain), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), prostatic hypertrophy, amenorrhea (eg secondary amenorrhea), and precocious puberty . These compounds may also be useful in the symptomatic relief of premenstrual syndrome. In addition, antagonists may be useful for regulating the secretion of gonadotropins in male mammals to suppress spermatogenesis (for example as male contraceptives) and for the treatment of male rapists. Importantly, it has been found that GnRH antagonists (as well as agonists) present utility in treatments where a reversible suppression of the hypophyseal-gonadal axis is desired. The presence of GnRH receptors in the cells of the anterior pituitary and various types of tumor cells provides the opportunity to develop drugs that act on these receptors to treat hormone-dependent and hormone-independent cancers. For more than 50 years, androgen suspension has been the most effective systematic therapy for the treatment of metastatic carcinoma of the prostate. The reasoning is simple - the prostate gland requires androgens for proper growth, maintenance and function. Although prostate cancer and benign prostatic hyperplasia are common in men and in development in an environment of continuous exposure to androgens. Therefore, the use of a GnRH antagonist to interrupt the pituitary-gonadal axis reduces androgen production and results in a modulation in tumor growth. In addition, GnRH antagonists may have a different effect on tumor growth by blocking receptors on tumor cells. For these cancers that respond to both sex hormones and GnRH directly, antagonists can be effective in slowing tumor growth by two mechanisms. Since GnRH receptors are present in many prostate and breast cancer cells, it has recently been speculated that GnRH agonists may also be effective in treating tumors that do not depend on hormones. Recent examples in the literature indicate that GnRH receptors are present in many cancer cell lines, including: Prostate cancer: GnRH agonists exert both in vitro and in vivo a direct inhibitory action on the growth of cell lines. human prostate cancer cells both androgen dependent (LNCaP) and androgen independent (DU 145). Montagnani et al, Arch. Ital. Urol. Androl. 1997, 69 (4), 257-263. The antagonists of GnRH inhibits the growth of prostate cancer PC-3 independent of androgen in athymic mice. Jungwirth et al., Prostate 1997, 32 (3), 164-172. Ovarian cancer: The demonstration of GnRH receptors in human ovarian cancers provides a rationale for the use of therapeutic solutions left in GnRH analogue in this malignant cancer. Srkalovic et al., Int. J. Oncol. 1998, 12 (3), 489-498. Breast cancer: Breast cancer is the most common type of cancer in women older than 40 years and is the leading cause of cancer-related death in women. The intervention Systematic endocrine represents a major treatment option for the management of advanced breast cancer, especially with estrogen-dependent cancers. The genes for the gonadotropin releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer. Kottler et al., In t. J. Cancer 1997, 71 (4), 595-599. The available GnRH antagonists have been mainly peptide analogs of GnRH. See, for example, international publication No. WO 93/03058. Peptide agonists peptide hormones are often very powerful. However, the use of peptide antagonists is usually associated with problems because the peptides are degraded by physiological enzymes and are often poorly distributed within the organism undergoing treatment. Therefore, they have limited effectiveness as medicines. Accordingly, there is now a need for non-peptide antagonists of the peptide hormone GnRH.

BRIEF DESCRIPTION OF THE INVENTION An objec- tive of the use of small-molecule, non-peptidic GnRH antagonists that approve the mechanisms of action described above. The Non-peptidic GnRH agents have advantageous physical, chemical and biological properties compared to the peptides and will be useful drugs for diseases mediated via the pituitary-gonadal axis and by targeting the receptor directly on tumor cells. There is a need to develop drugs that act on these receptors to treat both hormone-dependent and hormone-independent cancers. Another object of the invention is to provide non-peptide compounds that are GnRH agents (agonists or antagonists) that bind to GnRH receptors and therefore model activity, especially those that are potent GnRH antagonists. Another objective of the invention is to provide effective therapies for individuals who need therapeutic regulation of GnRH and to provide methods for treating diseases and conditions mediated by GnRH regulation. Such targets have been obtained by the non-peptidic GnRH compounds of the invention, which are useful as pharmaceutical substances for indications mediated by regulation of GnRH. The compounds of the invention are pharmaceutically advantageous over the peptide compounds since they provide better biodistribution and tolerance to degradation by physiological enzymes. The invention further provides methods of synthesis of compounds as well as intermediary compounds useful for making the compounds. The invention is directed to compounds of the general formula I: where: X is selected from C = 0, C = S, S = 0, and S (O) is a 5-member heterocyclic ring that contains 1 to 4, preferably 2 or 3 heteroatoms which are selected from N, O and S, wherein the ring may be saturated, partially unsaturated or completely unsaturated and may be aromatic, - R1 and R2 are independently selected from H and lower alkyl; R3 is selected from H, halogen and from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH20R, OR and C (0) OR, wherein R is selected from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the number total carbon atoms present (not including any optional substituents) ranges from 1 to 12; R4 and R5 are independently selected from H, halogen and the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, OR and C (0) OR, where R ee as defined above , - and where the total number of carbon atoms present (do not include any optional euetituyente) varies from 1 to 12; R6 and R7 are independently selected from H, halogen and the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH, 0R, OR and C (0) OR; wherein R is as defined in the foregoing, and wherein the total number of carbon atoms present (not including any optional substituents) ranges from 1 to 12; or R6 and R7, taken together with the atoms to which they are attached, form an optionally substituted 5 or 6-membered ring having up to 4 heteroatoms which are selected from 0, N and S; R8 is a lipophilic moiety that is selected from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, OR and C (0) OR, wherein R is as defined above, and wherein the total number of carbon atoms present (and without including any optional substituent) varies from 6 to 20; and R9 is selected from H substituted and unsubstituted alkyl, preferably lower alkyl. In some embodiments, R1 or R2 may be -OH or = 0; or Rs can also be hydrogen; or both, - or R can be COR or hydrogen; or R8 can have any desired number of carbon atoms, or any of the options, - or RB and R9 can also form a ring, - or any group R, such as R5 and R6 or R3 and R4 can form a ring, such as described for R6 and R7, - or R6 may be COR; or of the group (het) may be substituted or unsubstituted. In addition, in another embodiment R8 or R9, or both, can be selected from heterocyclic groups or any compound that forms an amide bond with the nitrogen of formula I. That is, R8 and R9 can be any group starting with a carbon atom Nitrogen and general formula I. Preferred compounds of the invention are those of general formula II: where the variables of the formulas are as defined above. Especially preferred compounds have the formula III: where R8 is defined before. Preferred RB groups include: aryl, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl and - (CH2) n-0-aryl where n is an integer from 1 to 4. Preferred composition of the invention include-. which include the cis and trans isomers in the cyclohexyl substituent, - , especially the , isomer, - Y The compounds of the above formulas, the GnRH agents of the invention include such pharmaceutically acceptable multimeric forms, precursors and active metabolites of such compounds. Such non-peptidic agents are pharmaceutically advantageous over peptide agents since they provide better biodistribution and tolerance to degradation by physiological enzymes. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a GnRH agent of the invention in combination with a pharmaceutically acceptable carrier or diluent. In addition, the invention relates to a method for regulating the secretion of gonadotropins in mammals, which comprises administering therapeutically effective amounts of GnRH agents of the invention. The invention also relates to methods and intermediates useful for preparing compounds of formula I.

Other features, objects and advantages of the invention will become apparent from the following detailed description of the invention and its preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION AND MODALITIES PREFERRED Some of the compounds of the invention contain one or more centers of aeimetry and can therefore generate a variety of stereoisomerics and other forms of stereoimetry. The invention is intended to include all possible stereoisomeric as well as its racemic and optically pure forms. When the compounds described herein contain olefinic double bonds, they are intended to encompass the geometric isomers E and Z. The chemical formulas referred to herein may show the phenomenon of tautomerism. As the structure formulae shown in this specification only show one of the possible tautomeric forms, it should be understood that the invention, however, encompasses all tautomeric forms. The term "alkyl" refers to straight or branched chain alkyl groups having one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, ter-pentyl, hexyl, isohexyl and the like. The term "lower alkyl" denotes an alkyl having from 1 to 8 carbon atoms (an alkyl of 1 to 8 carbon atoms). Suitable substituted alkynes include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. The term "alkenyl" refers to straight and branched chain alkenyl groups having 2 to 12 carbon atoms. Exemplary alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like. The term "alkynyl" refers to straight and branched chain alkynyl groups having 2 to 12 carbon atoms. Exemplary alkynyl groups include prop-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl and the like. The term "carbocycle" refers to a monocyclic or polycyclic carbon ring structure (without heteroatoms) having 3 to 7 carbon atoms in each ring, which may be saturated, partially saturated or unsaturated. Exemplary carbocycles include cycloalkyls and aryls. The term "heterocycle" refers to a monocyclic or polycyclic ring structure with one or more heteroatoms that are eected from N, 0 and S and having from 3 to 7 atoms "carbon atoms plus any heteroatom" in each ring, which may be saturated, partially saturated or unsaturated. Exemplary heterocycles include tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and the like. The term "cycloalkyl" as used in the preamble refers to saturated carbocycles having 3 to 12 carbons, including bicyclic and tricyclic cycloalkyl structures. Suitable cycloalkyl es include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The terms "aryl" and "heteroaryls" refer to monocyclic and polycyclic unsaturated or aromatic ring structures with "aryl" referring to that which is carbocycle and "heteroaryl" referring to those that are heterocycle. Examples of aromatic ring structures include phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, , 2,4-oxadiazolyl, 1, 3, 4-oxadiazolyl, lH-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiopyl (tylphthalyl) and eimilar. Such portions can be optionally substituted by one or more suitable substituents, for example a substituent selected from halogen (F, Cl, Br or I); lower alkyl; OH; N02; CN; C02H; 0-lower alkyl; aril; aryl-lower alkyl; C02CH3; CONH2, - OCH2CONH2; NH2; S02NH2; OCHF2; CF3; OCF3, - and the like. Such portions can also be optionally substituted by a fused or bridged ring structure, for example OCH2-0. The term "aryl-lower alkyl" means a lower alkyl having an aryl. Examples include benzyl, phenethyl, pyridimethyl, naphthylmethyl and similaree. The aryl-lower alkyl may optionally be substituted. In general, the various portions or functional groups for variables in formula I may optionally be substituted by one or more suitable substituents. Exemplary substituents include a halogen (F, Cl, Br or I), lower alkyl, -OH, -N02, -CN, -C02H, -0-lower alkyl, -aryl, -aryl-lower alkyl, -C02CH3, - C0NH2, -OCH2CONH2, -NH ,, -S02NH2, haloalkyl (for example -CF3, -CH2CF3), -O-haloalkyl (for example -0CF3, -0CHF2) and eimilar. In addition to the compounds of formula I, the GnRH agents of the invention include pharmaceutically acceptable salts, multimeric forms, prodrugs and active metabolites of compounds of formula I. Non-peptide agents are pharmaceutically advantageous in comparison with peptide agents since they provide better biodistribution and tolerance to degradation by physiological enzymes.

Additionally, formula I is intended to cover, when applicable, solvated as well as non-solvated forms of the compounds. Therefore, formula I includes compounds having the indicated structure, which includes hydrated as well as non-hydrated forms. As indicated in the foregoing, the GnRH agent according to the invention also includes diastereomeric tautomeric active formae of the compounds of formula I which can be easily obtained using techniques known in the art. For example, optically active (R) and (S) isomers can be prepared via stereospecific synthesis for example using chiral synthons and chiral reagents, or racemic mixtures which can be prepared using conventional techniques. The GnRH agents also include multivalent or multimeric forms of active forms of the compounds of formula I. Talee "multimeric" can be made by joining or placing multiple copies of an active compound in close proximity to each other, for example using a scaffolding provided by the cutting portion. The multimeric variant dimeneions (ie, which present variant numbers of copies of an active compound) can be tested to carry a multimer of optimal size with respect to receptor binding. The provision of such multivalent forms of receptor binding compounds active with Optimal separation between the receptor binding portions can improve receptor binding (see, for example, Lee et al., Biochem., 1984, 23: 4255). The technician can control the multivalence and selection by selecting a suitable carrier portion or binding unit. Useful portions include molecular supports that contain a multiplicity of functional groups that can react with functional groups associated with the active components of the invention. Carrier portions can be used to construct highly active multimers, which include proteins such as BSA (bovine serum albumin) or HAS, peptides such as pen t ap props, c epip tics, pentadecapeptides and the like, as well as compounds non-biological that are selected for their beneficial effects or capacity for absorption, transport and resistance within the target organism. The functional groups in the carrier portion, such as amino, sulfhydryl, hydroxyl and alkylamino groups, can be selected to obtain stable linkage for the compounds of the invention, optimal separation between the immobilized compounds and optimal biological properties. Additionally, the GnRH agents of the invention include pharmaceutically acceptable salts of the compounds of formula I. The term "pharmaceutically acceptable" refers to salt forms that are pharmacologically acceptable. and eustantially non-toxic to the subject to whom the GnRH agent is administered. Pharmaceutically acceptable salts include conventional acid addition salts or base addition salts formed from non-toxic organic or inorganic or inorganic base acids. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid Ethanesulfonic acid, Ietheonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymeleic acid, glutamic acid, salicylic acid, sulphanilic acid and fumaric acid. Exemplary base addition salts include those derived from ammonium hydroxides (eg quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali metal or alkaline earth metal hydroxides (eg sodium, potassium, lithium, calcium or magnesium) and those derived from organic bases such as amines, benzylamines, piperidines and pyrrolidinae.

The term "precursor" refers to a metabolic precursor of a compound of formula I (or a salt thereof) that is pharmaceutically acceptable. A precursor can be inactive when administered to a subject but can be converted in vivo into an active compound of formula I. The term "active metabolite" refers to a metabolic product of a compound of formula I which is pharmaceutically acceptable and cash. The precursors and active metabolites of the compounds of the formula I can be determined using techniques known in the art. A wide variety of eneayoe and known techniques can be used to determine the level of activity of the divereae forms of the compounds in the GnRH systems. Ligand-binding enzymes are used to determine the interaction with the receptor of interest. When the binding is of interest, a labeled receptor can be used, where the tag is a fluoreactive, enzyme, radio-ottope or similar, which registers a quantifiable change before the binding of the receptor. Alternatively, those skilled in the art can provide an antibody to the receptor, when the antibody is labeled, which allows amplification of the signal. The binding by competitive displacement of the ligand bound to the receptor can also be determined, wherein the ligand is labeled with a detectable label. When the activity of the agonist or antagonist is of interest, it can an intact organism or cell is studied, and the change in an organic or cellular function can be measured in response to the binding of the compound of interest. Various devices are available to detect the cellular response, such as an available microfromiometer from Molecular-Devices, Redwood City, California. The eneayoe in vi tro and in vivo useful to measure the antagonist activity of GnRH are known in the art. See, for example, Bowers et al., "LH suppression in cultured rat pituitary celle treated with 2 ng of LHRH," Endocrinology, 1980, 106: 675-683 (in vi tro) and Corbin et al., "Antiovulatory activity ( AOA) in rats, "Endocr. Res. Commun. 1975, 2: 1-23 (in vivo). The particular test protocols that can be used are described below. For example, the GnRH receptor antagonist can be functionally determined by measuring the change in extracellular acidification rates as follows. The ability of the compote to block the extracellular rate of GnRH-mediated acidification in HEK 293 cells expressing human GnRH receptors is determined as a measure of the antagonistic activity of the in vitro compounds. Approximately 100,000 cells / chamber are immobilized in suspension or agarose medium (Molecular Devices) and perfused with MEM medium without buffer using the CytosensorM Microphysiometer (Molecular Devices). The cells are allowed to reach the equilibrium haeta that the speed of basal acidification remains stable (approximately 1 hour). Dose-response control curves for GnRH are elaborated (10"1XM to 10" 7M). The compounds are allowed to incubate 15 minutes before stimulation with GnRH, and are determined to determine the antagonist activity. After incubation with the test compounds, repeated dose-repeat curves for GnRH in preemption or absence of various concentrations of the test compounds are obtained. The Schild regression analysis is performed on the compounds to determine if the compounds antagonize GnRH-mediated increases in extracellular acidification rates through competitive interaction with the GnRH receptor. In another test the accumulation of total inositol foefatoe can be measured by extraction of formic acid from cells, followed by separation of the phosphates in Dowex columns. The cells are divided using trypsin in two 12-well plates and pre-labeled with 3 H-myoinositol (0.5 Ci-2 mCi per ml) for 16-18 hours in inositol-free medium. The medium is then aspirated and the cells are rinsed either with IX HBSS, 20 mM HEPES (pH 7.5) or serum free DMEM, IX HBSS, 20 mM HEPES (pH 7.5) containing agonite and 20 mM LiCl, and then add and the cells are incubated for the desired time. The medium is aspirated and the reaction is stopped by the addition of ice-cold 10 mM formic acid, which It also serves to extract cellular lipids. The inositol foefatoe are separated by ion exchange chromatography on Dowex columns, which are then washed with 5 ml of 10 mM myoinositol and 10 mM formic acid. The columns are then washed with 10 ml of 60 mM sodium formate and 5 mM borax, and the total inositol phosphates are eluted with 4.5 ml of 1M ammonium formate, and 0.1M formic acid. Preferred GnRH agents of the invention include those having a K value of about 10 μM or less. Especially preferred GnRH agents are those that have a value of Kx in the nanomolar range. The compuets of the inventions are shown in the following table: COMPOSITE NO. STRUCTURAL FORMULA weight in moles 492. 704 ,492,704 11 627,869 12 465.63 13 431,577 14 429.6 ,475,625 16 446,631 17 443,627 18 443,627 19 443,584 461,599 The pharmaceutical compositions according to the invention comprise an amount effective to eradicate GnRH from at least one GnRH agent according to the invention and an inert or pharmaceutically acceptable carrier or diluent. Compositions can be prepared in an appropriate unit dosage form for the desired mode of administration, for example parenteral or oral. To treat diseases or conditions mediated by GnRH agonism or antagonism, a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (ie, a GnRH modulating amount effective to obtain the therapeutic efficacy) of at least one GnRH agent of the invention (as an active ingredient) with one or more pharmaceutically suitable carriers or diluents. Such formulations can be prepared according to conventional procedure, for example by mixing, granulating and compressing and appropriately dissolving the ingredients in ways known. Optionally, one or more different active ingredients such as antagonists other than GnRH, can be used in a pharmaceutical composition. The pharmaceutical carrier can be solid or liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Illustrative of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include materials for time delay or time release known in the art, such as glyceryl monostearate or distearate alone or in combination with a wax, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate or the like . Various pharmaceutical forms can be used. For example, if a solid carrier is used, the separation may be in the form of a tablet, hard gelatin capsule, powder, granule, trocizco or dragee. The amount of solid carrier can vary widely with an exemplary amount ranging from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution, suspension in a vial or bottle or a non-aqueous liquid suspension.

To obtain a stable and water soluble dosage form, a pharmaceutically acceptable salt of the compound of formula I can be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of succinic acid, or more preferably , citric acid. If a soluble salt form is not available, the agent can be dissolved in one or more suitable co-solvent. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0% to 60% of the total volume. In an exemplary embodiment, a compound of formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of a compound of the formula I in an appropriate aqueous vehicle, such as water or isotonic saline or dextrose solutions. The pharmaceutical compositions of the present invention can be manufactured using conventional techniques, for example mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients or auxiliaries that are selected to facilitate the processing of active compounds in pharmaceutical preparations. One is selected appropriate formulation in view of the route of administration that is chosen. To prepare injectable preparations, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution, or physiological saline buffer. For transmucosal administration, appropriate penetrants are used for the barrier in the formulation and can be selected from those known in the art. For oral administration, the agents can be easily formulated by combining the active ingredient or ingredients with pharmaceutically acceptable carriers known in the art. Porting carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suepensions and the like for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining one or more agents with a solid excipient, optionally ground from the resulting mixture into granules and processing the mixture of the granules after adding suitable auxiliaries, as desired, to obtain tablets or tablets. dragee cores. Suitable excipients include fillers such as sugars (for example lactose, sucrose, mannitol or sorbitol) and preparations of cellulose (e.g. corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP) or any of the foregoing). If desired, disintegrating talee agents can be added as cross-linked PVP, agar or alginic acid or a salt of the moiety such as eodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which optionally contain gum arabic, PVP, Carbopol ™ gel, polyethylene glycol, titanium dioxide, lacquer solutions or one or more suitable organic solvents. Dyes or pigments can be added to the tablets or coated with dragees for identification or to characterize the different combinations of active compound dosies. Pharmaceutical forms which are suitable for oral administration include push-filled capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Lae capeulae that are placed by thrust may contain the active ingredient or ingredients in admixture with one or more filler materials such as lactoea, binder such as starch or tamale lubricants such as talc or magnesium stearate and, optionally stabilizing.

In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. For buccal administration, the compositions can take the form of tablets or dragees formulated in a conventional manner. For administration by inhalation, the compounds for use in accordance with the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packets or a nebulizer, with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane , dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to supply a measured or dosed amount. Lae capsules and cartridges of, for example, gelatin for use in an inhaler or ineffective can be formulated to contain a powder mixture of the agent and a suitable powder base such as lactose or starch. The agents can be formulated for parenteral administration by injection, for example by bolus injection or continuous infuence. Formulations for injection can be prepared in unit dosage form, for example in ampoules, or in multi-dose containers, with a conservative added. The compositions may take such forms as suspensionee, solutions or emulsion in vehicle oil or water and may contain formulating agents such as agents that improve suspension, stability or dispersion. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspeneionee of the active compounds can be prepared as appropriate oil injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or ester oils of ethoxylates such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated as rectal compositions, such as suppositories or enemas of retention, for example containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange regions, or as poorly soluble derivatives, for example as a sparingly soluble salt. An exemplary pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, an organic polymer visible in water and an aqueous base. The co-solvent system can be a VPD coefficient seventh (VPD is a 3% w / v benzyl alcohol solution, 8% w / v non-polar surfactant.) Polysorbate 80 and 65% w / v polyethylene glycol 300, constituted up to a volume in absolute ethanol). The VPD cosolvent system (VPD: 5W) consists of VPD diluted 1: 1 with a 5% solution of dextrose in water. This cosolvent system dissolves well hydrophobic compounds, and the resulting formulation produces low toxicity before systemic administration. As will be evident, The proportions of a suitable cosolvent system may vary based on the solubility and toxicity characteristics. In addition, the identity of the cosolvent components can vary: for example, other non-polar surfactants of low toxicity can be used instead of polyeorbate 80; the polyethylene glycol portion size may vary; one or more additional biocompatible polymers (eg PVP) can be added or substituted for polyethylene glycol; and dextrose can replace other sugars or polysaccharides. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic medicaments and can be used to formulate suitable preparations. Certain organic solvents such as dimethyl sulfoxide may be used, although this may cause an increase in toxicity. Additionally, supply can be obtained using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Several sustained release materials are available and are known to those skilled in the art. Sustained release capsules may, depending on their chemical nature, release the compounds for a period lasting from several weeks to more than 100 days. In baee in the chemical nature and biological stability of the therapeutic agent, additional techniques for protein stabilization can easily be used. Pharmaceutical compositions also comprise carriers or excipients in a suitable solid or gel phase. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycose. Some of the compounds of the invention can be provided as salts with pharmaceutically compatible counterions. The pharmaceutically acceptable salts can be formed with many acids including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic and similar acids. The saltse tend to be more soluble in aqueous solvents and other protonic solvents as compared to the corresponding free base forms. It will be appreciated that the actual doses of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, the host and the disease in question. . Optimal dosages for a given set of conditions can be determined by those skilled in the art using dosage determination tests conventional in view of the experimental data for a given compound. For oral administration, an exemplary daily dose used will generally be from about 0.001 to about 1000 mg / kg body weight with courses of treatment repeated at appropriate intervals. The administration of prodrugs can be dosed at pee levels that are chemically equivalent to the weight levels of the fully active compounds. Examples of specific pharmaceutical preparations according to the invention are given below. Parenteral composition: To prepare a pharmaceutical composition of this invention suitable for administration for injection, 100 mg of pharmaceutically acceptable water-soluble salt of a compound of formula I are dissolved in DMF or then mixed with 10 ml of sterile 0.9% saline. The resulting mixture is incorporated in a unit dosage form suitable for administration by injection. Oral composition: To prepare an orally administrable pharmaceutical composition, 100 mg of a compound of formula I are mixed with 750 mg of lactose. The resulting mixture is incorporated in a unit dosage form suitable for oral administration, such as a hard gelatin capsule.

SYNTHESIS OF GnRH REAGENTS AND COMPOUNDS TO . Example of building block: Construction block based on naf taleno: A useful acylating agent is prepared by sequential alkylation of Friedel-Craf ts: A1C13 CH2C1S Compound 2 can be prepared as follows: 2,5-Dimethyl-2,5-hexanediol (200 grams, 1.37 moles) is added as a solid in portions to 3 liters of concentrated hydrochloric acid in a large Erlenmeyer flask. The diol dissolves rapidly in hydrochloric acid and the desired product 2,5-dichloro-2,5-dimethylhexane is formed and prepared Precipitated from the solution. The reaction is stirred at room temperature for 4 hours. One liter of 50% ethyl acetate in hexanes is added and the organic layer is separated and washed several times with water (until neutral pH determined with strip). The organic solvents are removed in vacuo at room temperature. The crude 2, 5-dichloro-2,5-dimethylhexane is dissolved in hexanes and passed through a pad of silica gel (ratio 10: 1) and eluted with hexanes. This final filtration step provides a white solid after removal of the organic solvent in vacuo. The recovery of pure 2,5-dichloro-2,5-dimethylhexane is 230 grams 92% yield. H NMR (CDC13, delta): 1.96 (4H, S); 1.61 (12H, s). Using a similar procedure, 2,4-dimethyl-pentanediol is converted to 2,4-dichloro-2,4-dimethylpentane. ÍH NMR (CDC13, delta): 2.42 (2H, s); 1.73 (12H, s). 1,1,4,4,6-pentame-l, 2,3,4-tetrahydronaphthalene 4: To a solution of 2,5-dichloro-2,5-dimethylhexane 2 (10 g, 54.7 mmoles) in toluene ( 270 ml, 0.2 M) aluminum trichloride (5.47 g, 41 mmol) is slowly added as a solid over a period of 15 minutes. The reaction is complete after 10 minutes as ene enea by CCD in hexanes. Unreacted aluminum trichloride is slowly suspended with water for 10 minutes. An additional 250 ml of toluene is added to extract the product from the layer watery The organic layer is passed through 40 g of a pad of silica gel and eluted with toluene. The organic layer is evaporated in vacuo to dryness to provide 1, 1, 4, 4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 4 (11 g, 97% yield). NMR 1.29 (s, 6H), 1.28 (s, 6H), 1.69 (s, 4H), 2.32 (s, 3H), 7.22 (d, ÍH), 7.12 (s, ÍH), 6.97 (dd, ÍH). 5 - [(3,5,5,8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl) methyl] -2-methyl furoate 6: To a solution containing (20 g, 99 mmolee) and methyl 5- (chloromethyl) -2-furoate (17.28 g, 99 mmol) in methylene chloride (500 ml, 0.2 M), aluminum trichloride (16.46 g) is added slowly, 124 mmole) as a solid, at the reflux temperature of methylene chloride. The solution is refluxed for an additional 2 hours. The reaction is monitored by CCD in a solution of 10% ethyl acetate / hexanes. The reaction is cooled to room temperature and unreacted aluminum trichloride is suspended with water for 15 minutes. The crude product is extracted with methylene chloride and passed through 80 g of silica gel and eluted with methylene chloride. The solvent is evaporated in vacuo to a syrup.

The crude product is purified with 300 g of silica gel by means of a plug in a filtration column. 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl) methyl] -2-methyl furoate eluted 6. with 2% ethyl acetate / hexanes to provide 15.4 g (46% yield). NMR 1.25 (s, 6H), 1. 28 (s, 6H), 1.67 (s, 4H), 2.23 (s, 3H), 3.89 (s, 3H), 3.97 (e, 2H), 5.95 (d, ÍH), 7.09 (m, 3H). 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthaleniDmethyl] -2-furoic acid 7: To a solution containing 5- [(3,5, 5.8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthaleniDmethyl] -2-methyl furoate 6 (15.1 g, 44 mmolee) in 175 ml of MeOH and 175 ml of water, add one NaOH solution (3.53 g, 88.3 mmolee) in 29 ml of water The reaction mixture is stirred overnight After the reaction is considered to be completed by CCD, the solution is acidified with 1M HCl to pH 2 The crude product is extracted into an organic layer using ethyl acetate and concentrated to provide 5 - [(3, 5, 5, 8, 8 -pentamet-il-5, 6, 7, 8-tet rahydro-2-acid. NaphthaleniDmethyl] -2-furoic acid 7 (15.0 g, 99% yield). NMR 1.26 (s, 6H), 1.28 (s, 6H), 1.68 (e, 4H), 2.24 (s, 3H), 4.00 (e, 2H), 6.01 (d, ÍH), 7.10 (e, 2H), 7.23 (d, ÍH) Chloride of 5 - [(3, 5, 5, 8, 8 - pent ame t il - 5, 6, 7 , 8 -tetrahydro-2-naph taleniDmetil] -2-furoi 8: To a solution containing 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naph talenidomethyl] -2-furoic acid 7 (20.15 g, 61.77 mmole) in 310 ml methylene chloride, thionyl chloride (45 ml, 617 mmoles) is added. The reaction is refluxed for 5 hours and another batch of thionyl chloride (45 ml, 617 mmol) is added. The solution is stirred overnight at room temperature. The solution is concentrated to a syrup and It is passed through 50 g of a pad of silica gel, washed with 3% hexanes and concentrated in vacuo to give 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthaleniDmethyl] -2-furoyl 8 (17 g, 80% yield). NMR 1.26 (s, 6H), 1.28 (s, 6H), 1.68 (s, 4H), 2.25 (e, 3H), 4.00 (s, 2H), 6.11 (d, ÍH), 7.10 (s, ÍH), 7.11 (s, ÍH), 7.41 (d, ÍH). Additional building blocks can be prepared under these reaction conditions lae which contain divereoe functional groups contained in the general formula shown above.

B. Examples of acylation The following diagram shows several examples which can be used for the general synthesis procedure for acylations that are provided below.

Examples of reagents that are coupled to Y Hydrazines and hydrazides The amines are either dissolved or suspended in dichloromethane, dichloroethane, ethyl acetate, acetonitrile or the like (concentration 0.2M), followed by the addition of an acid chloride reagent (1.00 mmoles equivalent). To the mixture is added triethylamine (5.00 mole equivalents) and the reaction is stirred at room temperature for 12-48 hours. The solvents they are removed in vacuo. The product is purified by column chromatography on silica gel and eluted with an appropriate eluting solvent. For example 3: 1 hexanes: ethyl acetate). The solvents are removed in vacuo to provide the acylated product. As an alternative, the reaction mixture is diluted with dichloromethane (five times the amount of dichloromethane used) and washed with saturated sodium bicarbonate. The organic layer is dried on magnesium eulfate and filtered. The product is purified by column chromatography on silica gel and eluted with an appropriate eluting solvent (for example 3: 1 hexane: ethyl acetate). The solvents are removed in vacuo to provide the acylated product. Using the general reaction protocol, large amounts of compounds can easily be prepared and tests can be conducted to determine their activities and even as pure or impure materials. The reaction protocols work well in anilinae, aminae, benzylamines, hydrazines, hydrazides, alcoholee and similaree. Specific examples show various structures acylated according to a general procedure and are shown below.

COMPOSITE NO. STRUCTURE weight in moles 492. 704 ,492,704 n 627,869 12 465.63 13 431,577 14 429.6 ,475,625 16 446,631 17 443,627 18 443,627 19 443,584 461. 599 Synthesis and acylation of compounds containing guanidine: Step 1 - Preparation of the compound protected by 1- (NN '-diBoc) -cyanidinomethylation: Alternative steps 1 (A) and 1 (B) below provide two general procedures of 1- (N, N' -diBoc) -guanidinomethylation .

Step 1 (A): To a solution of diamine (2.00 mmol equivalents) in THF (0.7 M) is added a solution of 1-H-pyrazole-1- (N, N-bis (tert-butoxycarbonyl) carboxamidine) ( 1.00 mmol equiv). The solution is stirred at room temperature for 3 hours (h), or until no further transformation is observed by CCD (thin layer chromatography). The solvent is removed under reduced pressure to provide a residue in the form of syrup, which is taken up in ethyl acetate (~ 1.5 times the volume amount of THF used in the volume reaction or solvent necessary to dissolve the amount of residue obtained) and washed with water until neutral pH. The organic layer is washed with brine, dried over MgSO 4 and concentrated. The product is purified by column chromatography on silica gel and eluted with an appropriate elution solvent (which is easily determined, for example, using 5% MeOH in dichloromethane as the starting point). The solvents are removed in vacuo to provide the bound 1- (N, N * -diBoc) -guanidinomethylamine. In addition to the other reagents they can be used to place a protected N, N'-diBoc guanidine unit or in diamines, such as 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudorea (CAS No. 107819- 90- 0). Alternatively, 1-H-pyrazole-1- (N, N-tert-butoxycarbonyl) carboxamidine) can be added directly as a solid, instead of a solution as described above.

Step 1 (B): To a solution of diamine (1.00 mmoles equivalent) in 0.07M THF is added to portions as a solid (over a period of 10 minutes) l-H-pyrazole-1- (N, N-bie (tert-butoxy-carbonyl) carboxamidine) (1.00 mmoles equivalent). The solution is stirred at room temperature for 0.5 h. The solvent is removed under reduced pressure to provide a liquid in the form of syrup which is taken up in ethyl acetate (0.5 times the volume amount of THF used in the reaction, or the volume of solvent needed to dissolve the amount of residue obtained) and washed twice with water. The layers are separated and the product is purified by column chromatography on silica gel and eluted with 100% ethyl acetate to remove any non-polar impurities and then 100% isopropyl alcohol to provide the pure product. The solvents are removed in vacuo to provide the desired product. Typical CCD conditions are 15: 85: 0.1 methanol / chloroform / acetic acid. Typical yield ranges are from 40% to 44% of the desired protected compound.

Stage 2 - Reductive amination (optional): The reductive amination can be carried out in an appropriate way. For reductive amination of aldehydes and ketones with sodium triacetoxyborohydride, see generally: Abdel-Magid et al., J. "Org. Chem., 1996, 61: 3849. Alternative reductive aminations are described below.

Step 2 (A): 3,5,5,8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphth-aldehyde (1.00 mmoles equivalent) and 1- (N, N'-diBoc) - bound guanidinomethylamine (1.00 mmole equivalents) are dissolved in methanol (0.09M). Then, 1% glacial acetic acid in methanol solution (10% of the volume of methanol used) is added followed by NaCNBH3 (1.00 mmoles equivalent) and the reaction content is stirred overnight. The reaction is tested by CCD to show three components (aldehyde, the desired product and the initial guanidine derivative). The reaction is completed by adding water (50% of the volume of methanol used, it is extracted with dichloromethane (10 times the volume of methanol used) and washed with saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated. The product is purified by column chromatography on silica gel and eluted with an appropriate eluting solvent (for example ethyl acetate 3: 1 in hexanes to remove the unreacted aldehyde, followed by elution with ethyl acetate in hexanoe 1: 1), obtaining the desired reductive amination product. In some cases, heating under reflux for 2 hours will facilitate the imine formation reaction, see also Abdel-Magid et al., J. Org. Chem. , 1996, 61: 3849, which It describes the reductive amination of aldehyde and ketones with sodium triacetoxyborohydride.

Stage 2 (B): 3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphth-aldehyde (1.00 mmoles equivalent) and 1- (N, N'-diBoc) are dissolved. ) -guanidinomet bound ilamine (1.00 mmol equivalents) in 0.09M methanol. After NaBH4 is added (1.00 mmol equivalents) (in ethanol via the procedure at a small additional level provided below, or carefully as a solid) and the reaction content is stirred overnight. A reaction assay is performed by CCD to reveal three components (aldehyde, the desired product and initial guanidino derivative). The reaction is terminated by the addition of water (50% of the volume of methanol used), extracted with dichloromethane (10 times the volume of methanol used), and washed with saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated. The product is purified by column chromatography on silica gel and eluted with an appropriate eluting solvent (as can be easily determined by one skilled in the art or, for example, with 3: 1 ethyl acetate in hexanes to remove the aldehyde that has not reacted, followed by elution 1: 1 in ethyl acetate in hexane) to obtain the reductive amination product deeeado. In some cases, heating to reflux for 2 hours facilitates the imine formation reaction.

Stage 3 - Acylation: The products of reductive amination (1.00 mmoles equivalents) are dissolved in dichloromethane ("0.2 to 0.05M, based on the solubilities of the substrates), followed by the addition of triethylamine (2.00 mmoles equivalent) and reagent of 2-furoyl chloride 8 (1.00 mmol equivalents) The reaction content is stirred overnight at room temperature (RT) The reaction mixture is diluted with dichloromethane (5 times the amount of dichloromethane used) and washed with saturated sodium bicarbonate The organic layer is dried over magnesium sulfate and filtered The product is purified by column chromatography on silica gel and eluted with an appropriate elution solvent (for example 3: 1 hexanoe: ethyl acetate). ethyl ether) are removed in vacuo to provide the acylated product.

Step 4 - Deprotection of the basic group: The product of the acylation step (1.00 mmole equivalent) is dissolved in a solution of 25-50% TFA in 0.02M dichloromethane, and the reaction content is stirred at room temperature (15). -20 minutes, the solution turns a red-orange color). The reaction content is stirred for 1 hour and 20 minutes additional or until the deprotection of BOC is completed. The reaction is terminated by concentration in vacuo, followed by the addition of 0.006M water / acetonitrile and lyophilization overnight. The final compound is purified by high-performance liquid chromatography (HPLC) methodology. The solvents are removed in vacuo (yields provide 30% to 50%) to provide the product. An alternative procedure for removing N, N'-bis-BOC guanidines using tin tetrachloride, which could provide the corresponding salts of guanidinium chloride, is described in Miel et al., Tetrahedron Letters, 1997, 38: 7865-7866. Compound 9 can be prepared according to the steps shown earlier with the excision of step # 2, as shown in the following scheme: 21 23 Reagent Preparation: Reagents useful for synthesizing compounds can be obtained or prepared according to techniques known in the art. For example, the preparation of free amines from common salt forms in concentrated reagent solutions can be useful for small scale reactions. See also Abdel-Magid et al., "Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride," J. Org. Chem. , 1996, 61: 3849. The methanol solutions of the free bases can be prepared from hydrochloride, dihydrochloride, hydrobromide or other salts when the free base is soluble in methanol. In this procedure, once sodium methoxide is added, care must be taken to avoid exposure to air, since the bases free of amine, particularly primary amines, absorb carbon dioxide from the air to form salts. An amount of 10 ml of a 0.1M solution of the free base in methanol can be prepared as follows. The weight of 1.0 mmol of an eal of monohydrochloride in a tared Erlenmeyer flask containing a stir bar, and 7 ml of methanol are added. To the stirred suspension is added 229 ml (1.0 mmol, 1 equivalent) of sodium methoxide in methanol (25% by weight, 4.37M), the flask is closed and the mixture is stirred vigorously for 2 hours. The suspension will sometimes change in appearance to a finer, milder, precipitate of eodium chloride that forms. The euepeneion is filtered through a glass funnel with a crypt of 15 ml of medium, the filter cover is washed with 1-2 ml of methanol, the filtrate is transferred to a 20 ml fraeco and diluted to 10 ml. with methanol. The theoretical yield of eodium chloride is almost 59 mg, but recovery is usually not quantitative due to its methanol solubility.

For a dihydrochloride salt, 458 ml of a second equivalent of sodium methoxide is required. A 0.5M solution of sodium borohydride in ethanol can be prepared as follows. Eodium borohydride (520 mg, 13.8 mmolee) is stirred in anhydrous pure (undenatured) ethanol (25 ml) for 2-3 minutes.The suspension is filtered through a glass funnel with medium frit to remove an amount. small of undissolved eolid (typically about 5% of the total borohydride mass, or 25 mg) The filtrate appears as a colorless eolith that produces only a little hydrogen This solution must be used immediately as it decomposes significantly over a period of a few hours, which results in the formation of a gelatinous precipitate.Sodium borohydride is hygroecic, so it should avoid exposure to the air when processing the solution at the moment after weighing the solid. Sodium borohydride has a solubility of about 4% in ethanol at room temperature.This corresponds to a little more than 0.8M.However, sometimes a small percentage of the solid remains without dissolve no matter what concentration is prepared, even after shaking for = 5 minutes. In order to carry out a sample at a small scale of the components of formula I, the reactions described below must be carried out to prepare various useful reagents in the reaction scheme described above. As with the rest of the specification all temperatures in the description that follows are in degrees Celsius and all parts and percentages are in weight, unless otherwise indicated. Diverse initial materials and other reagents may be purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesie Ltd., and are used in additional purification, unless otherwise indicated. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) are purchased from Aldrich in SureSeal ™ flask and used as received. All of the eolventee are purified using standard methods in the art, unless otherwise indicated. The reactions set forth below are carried out under a nitrogen pressure or with a drying tube, at room temperature (unless otherwise indicated), in anhydrous solvents, and the reaction flasks are placed with rubber stopper for the introduction of substrates and reagents by means of a syringe. All glassware is kiln-dried or heat-dried. Analytical thin-layer chromatography is carried out on silica gel in glass support in plates of 254 to 15 ° C (60 ° F) (Analtech (0.25 mm)) and eluted with the appropriate relations of eolventee (v / v). The reactions are carried out in tests by CCD and are considered finalized by the consumption of the initial material. The tip plates are visualized with a p-anisaldehyde spray reagent or a foefomolybdic acid reagent (Aldrich Chemical, 20 wt.% In ethanol) and activated with heat. The treatments are typically carried out by doubling the reaction volume with the reaction solvent or the extraction solvent and then washing with the indicated aqueous solutions using 25 volume% of the extraction volume (unless otherwise indicated). The product solutions are dried over anhydrous Na2SO4 before filtration and the evaporation of the solvents is low under reduced pressure in a rotary evaporator and indicated as solvent removed in vacuo. Flash column chromatography (Still et al., AJ Org. Chem., 1978, 43: 2923) is carried out using Baker grade flash silica gel (47-61 mm) and a silica gel: raw material ratio from about 20: 1 to 50: 1, unless it is established otherwise. The hydrogenation is carried out at the indicated pressure or at room temperature. The 'H-NMR spectra are recorded on a Bruker instrument operating at 300 MHz and the "C-NMR spectra are recorded operating at 75 MHz. The NMR spectra are obtained as CDC13 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD3OD (3.4 and 4.8 ppm as well as 49.3 ppm), or an internal standard of tetramethylsilane (0.00 ppm) when appropriate. Other solvents for NMR are used as needed. When peak multiplicities are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = extended, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when provided, are reported in Hertz. The infrared spectra are recorded in a Perkin-Elmer FT-IR spectrometer as pure oils or as KBr granules, or as solutions of CDC13, and when reported are in wave numbers (cm "1). using LSIMS or electroasperation All the fusion points are uncorrected.

Preparation of the l-H-pyrazole-1-carboxamidine building block: 1-H-pyrazole-l-carboxamidine is prepared according to Bernatowicz et al., J. Org. Chem., 1992, 57: 2497-2502 (and references therein), and is protected with diterbutyl dicarbonate to provide 1-H-pyrazole-1 - (N, N-bis (tert-butoxycarbonyl) carboxamidine) agreement with Drake et al., Synth., 1994, 579-582.

Preparation of 1- (N'N'-diBoc) -guanidinomethyl-4- to inomethylcyclohexane: 22 To a solution of 1,4-bis-aminomethyl-cyclohexane 22 (20 g, 0.14 mole) in 200 ml of THF, a solution of 1-H-pyrazole-1- (N, N-bie (terbutoxycarbonyl) carboxamidine) 21 (22.0 g, 0.07 mol) in 100 ml of THF. (Note that 1-H-pyrazole-1- (N, N-bis (tert-butoxycarbonyl) carboxamidine) does not it needs to dissolve in THF; instead of this you can add pure as a solid to the process. The solution is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure to provide a residue in the form of syrup which is taken up in 500 ml of ethyl acetate and washed with water until neutral pH. The organic layer is washed with brine, dried over MgSO4 and concentrated. The product is purified by column chromatography on silica gel and eluted with 5% MeOH in dichloromethane. The solvents are removed in vacuo to provide 11.6 g (43% yield) of 1- (N, N '-diBoc) -guanidinomethyl-4-aminomethyl cyclohexane (Compound 23). 'H NMR (CDC13) 5 11.5 (s broad, ÍH), 8.35 (broad e, ÍH), 3.26 (dt, 2H), 2.52 (dd, 2H), 1.82-0.-97 (m, 28H, with a singlet to 1.5). An alternative preparation of 1- (N, N '-diBoc) -guanidinomethyl-3-aminomethylcyclohexane is as follows. To a solution of cis / trans 1,4-bie-aminomethyl-cyclohexane (9.0 g, 63.3 mmol) in THF 903 mL, 0.07 M) is added to portion as a solid (over a period of 10 minutes) 1-H- pyrazole-1- (N, N-bi e (tert-butyloxycarbonyl) carboxamidine) (19.6 g, 63.3 mmol). The solution is stirred at room temperature for 0.5 hours. The solvent is removed under reduced pressure to provide a residue in the form of syrup, which is taken up in 500 ml of ethyl acetate and washed twice with water. The layers are separated and the product is purified by column chromatography on silica gel and elute with 100% ethyl acetate to remove any non-polar impurities, followed by elution with 100% isopropyl alcohol, to provide the pure product. The solvents are removed in vacuo to provide 10.2 g (42% yield) of 1- (N, N '-diBoc) -guanidinomethyl-4-aminomethylcyclohexane. XH NMR (CDC13) d 11.5 (broad s, ÍH), 8.35 (broad e, ÍH), 3.26 (dt, 2H), 2.52 (dd, 2H), 1.82-0.97 (m, 28H, with an eingulete to 1.5) .

Reductive amination: 23 25 3, 5, 5, 8, 8 -pentamet il-5, 6, 7, 8 -tetrahydro-2-naft-aldehyde (0.2021 g, 0.88 mmolee) and 1- (N, N'-diBoc) - guanidinomethyl-4-aminomethylcyclohexane (Compound 23, 0.337 g, 0.88 mmolee) in 10 ml of methanol. After, it is added 1% glacial acetic acid in 100 μl of a methanol solution followed by NaCNBH 3 (55.4 mg, 0.88 mmol, 1.0 equivalents), and the reaction content is stirred overnight. The reaction is tested by CCD to show three components (aldehyde, the desired product and an initial guanidine derivative). The reaction is terminated by addition of water ("5 ml), extracted with dichloromethane (" 100 ml), and washed with saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered, concentrated and subjected to column chromatography eluting with 3: 1 ethyl acetate in hexane to remove the unreacted aldehyde, followed by elution with ethyl acetate in the reaction mixture. hexanoe, 1: 1, which provides the desired product (compoteto 25., cyclohexyl, cis / trane mixture). The solvents are removed in va cuo (typical yields vary from 50 to 80%).

Preparation of the acylated derivative followed by deprotection of guanidine: The product of reductive amination 25 (1.0 equivalents) is dissolved in 10-15 ml of dichloromethane, followed or the addition of 2 equivalents of triethylamine and one equivalent of 2-furoyl chloride reagent. The content of the reaction is stirred overnight at room temperature. The reaction is diluted with 50 ml of dichloromethane and washed with saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and purified by column chromatography and eluted using 3: 1 hexanes in ethyl acetate. The solvents are removed in vacuo to provide compound 26. The product of the acylation reaction is dissolved 26 (1.0 equivalents) in a 50% TFA solution in dichloromethane (20-25 ml) and the reaction content is stirred at room temperature (15-20 minutes, - the solution ee turns slightly reddish-orange in color. ). The content of the reaction is stirred for 1 hour and 20 minutes added until the protection is complete. The reaction is terminated by in vacuo concentration, followed by the addition of water / acetonitrile ("50 ml) and lyophilization overnight." The final compound is purified by HPLC methods, the solvents are stirred in vacuo to provide the Compound. 27. The following discussion relates to the preparation of exemplary compounds (e) - (k) Compounds (e) - (k) can be used as described above to produce the corresponding deprotected compounds (free guanidinyl) through hydrolysis under acidic conditions.

Preparation of 1- (N, N '-diBoc) -guanidinomethyl-3-aminomethylcyanohexane: To a solution of cis / traus-1, 3-bis-aminomethylcyclohexane (7.5 g, 52.8 mmolee) and 30 ml of THF is added a solution of 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea (7.65 g, 26.3 mmoles) in 40 ml of THF in the next 0.5 hour. The solution is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure and the product is purified by column chromatography on silica gel using a methylene chloride / methanol mixture as eluent, to provide 2.2 g (22% yield) of l- (N, NT-diBoc) -guanidinomethyl-3- aminomethylcyclohexane (Compound (e)). ? E NMR (CDC13) 6 11.53 (broad s, ÍH), 8.40 (broad e, ÍH), 3.28-3.30 (m, 2H), 2.54-2.61 (m, 2H), 1.81 (broad e, 2H), 1.27 -1.58 (m, 26H), 0.89 (m, ÍH), 0.65 (m, ÍH). Alternatively, compound (e) can be prepared as follows. To a solution of cis / trans 1,3-bis-aminomethylcyclohexane (10.0 g, 70.3 mmol) in THF (1000 mL, 0.07M) is added portionwise as a solid (over a period of 10 minutes) lH-pyrazole-1 - (N, N-bis (tert-butoxycarbonyl) carboxamidine) (21.8 g, 70.3 mmol). The solution is stirred at room temperature for 0.5 hours. The solvent is removed under reduced pressure to provide a residue in the form of syrup, which is taken up in 500 ml of ethyl acetate and washed twice with water. The layers are separated and the product is purified by column chromatography on silica gel and eluted with 100% ethyl acetate to remove any non-polar impurities, followed by elution with 100% isopropyl alcohol to provide the pure product. The solvents are removed in vacuo to provide 11.4 g (41% yield) of 1- (N, N'-diBoc) -guanidinomethyl-3-aminomethylcyclohexane. lE NMR (CDC13) d 11.53 (broad s, ÍH), 8. 40 (s broad, ÍH), 3.28-3.30 (m, 2H), 2.54-2.61 (m, 2H), 1.81 (8 broad, 2H), 1.27-1.58 (m, 26H), 0.89 (m, ÍH), 0.65 (m, ÍH).

Preparation of 1- (N'N'-diBoc) -guanidinomethyl-4-aminomethylbenzene: To a solution of -xi 1 -enodi amine (6.44 g, 47.4 mmol) in 30 ml of THF is added to a solution of 1,3-bie (tert-butoxycarbonyl) -2-methyl-2-thiopeeudourea (6.63 g, 22.9 mmoles) in 40 ml of THF, in the following 0.5 hours. The solution is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, and the product purify by silica gel column chromatography using a mixture of methylene chloride / methanol as the eluent, to provide 8.0 g (92% yield) of 1- (N, N '-diBoc) -guanidinomethyl-4-aminomethylbenzene ( Compound (f)). XH NMR (CDC13) d 11.54 (broad s, ÍH), 8.56 (broad e, ÍH), 7.29 (e, 4H), 4.60 (d, 2H), 3.86 (s, 2H), 1.64 (broad e, 2H) , 1.52 (s, 9H), 1.48 (e, 9H).

Preparation of 1- (N, N '-diBoc) -guanidinomethyl-3-aminomethylbenzene: To a solution of m-xylylenediamine (7.14 g, 52.5 mmoles) in 30 ml of THF is added a solution of 1,3-bie (tert-butoxycarbonyl) -2-methyl-2-thiopeeudourea (7.57 g, 26.1 mmoles) in 40 ml of THF in the next 0.5 hour. The solution is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure and the product is purified by column chromatography on silica gel using a methylene chloride / methanol mixture as the eluent, to give 7.9 g (80% yield) of 1- (N, N '-diBoc) -guanidinomethyl-3-aminomethylbenzene (Compound (g)). H NMR (CDC13) d 11.54 (s broad, ÍH), 8.58 (s broad, ÍH), 7.19-7.34 (m, 4H), 4.62 (d, 2H), 3.86 (s, 2H), 1.83 (s broad, 2H), 1.52 (e, 9H), 1.48 (s, 9H).

Preparation of 1 - (N. N '-diBoc) -guanidine-4-aminobutane (h) To a solution of 1,4-diaminobutane (4.15 g, 47.1 mmoles) in 50 ml of THF is added a solution of 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopeeudourea (6.83 g, 23.6 mmolee ) in 40 ml of THF in the next 0.5 hour. The solution is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure and the product is purified by column chromatography on silica gel using a methylene chloride / methanol mixture as the eluent, to give 3.0 g (40% yield) of 1- (N, N '-diBoc) -guanidino-4-aminobutane (Compound (h)). 'H NMR (CDC13) d 11.49 (s broad, ÍH), 8.35 (s broad, ÍH), 3.42-3.47 (m, 2H), 2.72-2.76 (t, 2H), 0.86-1.65 (m, 24H). An alternative procedure for preparing the Compotete (h) is as follows. To a solution of 1,4-diaminobutane (6.0 g, 68.1 mmol) in THF (972 mL, 0.07M) is added in portions as a solid (over a period of 10 minutes) 1H-pyrazole-1 - (N , N-bis (tert-butoxycarbonyl) carboxamidine) (21.5 g, 68.1 mmol). The solution is stirred at room temperature for 0.5 hour. The solvent is removed under reduced pressure to provide a liquid in the form of syrup, which is taken up in 500 ml of ethyl acetate and washed twice with water. The layers are separated and the product is purified by column chromatography on silica gel and eluted with 100% ethyl acetate to remove any non-polar impurities, and followed by 100% isopropyl alcohol to provide the pure product. The solvents are removed in vacuo to provide 10.0 g (44% yield) of 1- (N, N '-diBoc) -guanidino-4-aminobutane. XH NMR (CDC13) d 11.49 (s broad, ÍH), 8.35 (broad s, ÍH), 3.42-3.47 (m, 2H), 2.72-2.76 (t, 2H), 0.86-1.65 (m, 24H).

Preparation of i-N.N-dimethylaminomethyl-4-aminomethylbenzene: (i) To a solution of 1-N, N-dimethylaminomethyl-4-carbonbonitrile benzene (4.8 g, 30 mmol) in THF is added a 90 ml solution of tetrahydrofuran and 1 M borane complex. The mixture is stirred at room temperature. reflux for 16 hours under nitrogen. After cooling to room temperature, 100 ml of a 1 M solution of HCl in methanol are added. The reaction mixture is heated to reflux for 3 h. The product, which precipitates, is collected by filtration, washed with diethyl ether and dried in vacuo to give 5.9 g (83% yield) of the product as a hydrochloride salt (compound (i)): * H NMR (DMSO) -d6) d 8.65 (broad e, 3H), 7.55 (dd, 4H), 4.25 (s, 2H), 3.98 (s, 2H), 2.62 (s, 6H).

Preparation of 1- (N.N '-diBoc) -guanidinomethyl-2-aminomethylbenzene: (j) To a solution of o-xyl-ilenodiamine (7.14 g, 52.5 mmoles) in 30 ml of THF is added a solution of 1,3-bie (tert-butoxycarbonyl) -2-methyl-2-thiopeeudourea (7.57 g, 26.1 mmolee) in 40 ml of THF in the next 0.5 hour. The solution is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure and the product is purified by column chromatography on silica gel using a methylene chloride / methanol mixture as the eluent to provide 1- (N, N '-diBoc) -guanidinomethyl-3-aminomethyl. -benzene (Compound (j)).

Alternatively, compound (j) can be prepared in a manner analogous to the alternative preparation described above for Compound (e).

Preparation of 1- (N, N '-diBoc) -guanidinomethyl-2-aminomethyl-cyclohexane: () To a solution of cis / traps- 1,2-bis-aminomethylcyclohexane (7.5 g, 52.8 mmol) in 30 ml of THF, a solution of 1,3-bie (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea is added. (7.65 g, 26.3 mmoles) in 40 ml of THF in the next 0.5 hour. The solution is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure and the product is purified by column chromatography on silica gel using a methylene chloride / methanol mixture as the eluent to provide 1- (N, N'-diBoc) -guanidinomethyl-2-aminomethylcyclohexane. (Compound (k)). Alternatively, Compound (k) can be prepared in a manner analogous to the alternative preparation described above for Compound (e).

D. Pyrimidine compounds Pyrimidines can be used according to the following procedures: 29 30 A general procedure for the preparation of pyrimidine-containing compounds is as follows. To a solution of 1,3-diamine 2 -9 in THF is added 28 and the contents are refluxed for 12 hours. The solvents are removed in vacuo and the added adduct is purified by column chromatography. The pure compound 31 is acylated according to the general procedure given above to provide 11. As will be appreciated by those skilled in the art, various compounds can be prepared according to the invention, based on the above teachings. The chemical reactions described above have general applicability to the preparation of the GnRH agents of the invention. Therefore, other GnRH agents can be prepared in an appropriate manner by appropriate modification, as will be readily appreciated by those skilled in the art, for example, by protection of interfering groups, or by adaptation for use with other conventional reagents, or either by systematic modifications or habitualee of reaction conditions.

IN VITRO PHARMACOLOGY OF RADIOLOGICAL UNION Cells of membranes prepared from cells 293 of human embryonic kidney transfected stably with cDNA for the human GnRH receptor are suspended in buffer of binding assay containing: 50 mM HEPES, 1 mM EDTA, MgCl, 2.5 mM and 0.1% bovine serum albumin. Membranes (5-50 μg) of total protein are incubated per well containing approximately 10-100 flee of the GnRH receptor) in duplicate in 96-well plate in a total volume of 200 μl with 125 I-GnRH-A (approximately 0.05) nM) and the test compounds, for one hour at room temperature. All the compounds are diluted in 1% DMSO (final assay concentration) in binding assay buffer. The non-specific binding is determined in the presence of 100 n GnRH. The reactions are terminated by rapid filtration in 96-well Packard GF / C filters wetted with 0.1% polyethyleneimine. The filters are washed three times with PBS buffer, dried and counted in a Packard Topcount by liquid scintillation counting. The test conditions are identical to determine compound activities in other species. A similar number of GnRH receptors were used for each species assay. For rat GnRH receptor binding, membranes are prepared from the rat pituitary and approximately 25-30 μg / well of total membrane protein is used. For binding of bovine GnRH receptor, membranes are prepared from bovine hypophysis and used at 40-50 μg / well. For binding of mouse GnRH receptor, membranes are prepared from 293 cells that express stably Mouse GnRH receptors are used at approximately 25-30 μg / well. IC50 values for control and test peptides are calculated using GraphPad PriemR software. In Figure 1 the result of a radioligand binding experiment is shown. Table 1 shows the average values for multiple experiments of the affinities of divereoe peptidic and non-peptidic compounds at four species GnRH receptors.

Figure 1. Effects of the bonding compounds of 125I-GnRH-A to hGnRH receptors expressed in HEK-293 cells. The ability of GnRH (frames) and 9 (triangles) to displace 125I-GnRH-A (approximately 0.05 nM) binding to hGnRH receptors was examined. The values shown are from a representative experiment performed in duplicate. Several compounds of Formula I are synthesized according to the general reaction scheme described generally above. The crude compounds are tested using the competing radioligand binding assay described above. The results of the competitive binding assay of GnRH are shown in the table (each compound is tested at 1 or 10 μM).

Table 1 The values are mean ± SE (standard error) of at least three experiments performed in duplicate. ND = not determined.

MEASUREMENT OF TOTAL INOSITOL PHOSPHATES To determine the activity of the compounds as agonists or antagonists, an assay that measures total inositol phosphate accumulation is used. They are seeded in 293 cellsplates containing the hGnRH receptor in 24-well plate (approximately 200,000 cells / well) using half DME. The next day, the cells were loaded with [3 H] myo-inositol (0.5 Ci / ml) for 16-18 hours in inositol-free medium. The medium is aspirated and the cells are rinsed with serum-free DMEM. The medium is watered and the cells are then treated with the test compounds or with the vehicle for 30 minutes at 37 ° C. A half-maximal GnRH (1 nM) or vehicle concentration is then added to the cells and allowed to equilibrate at 37 ° C for 45 minutes. The medium is mixed with ice-cooled 10 mM formic acid, which defines the reaction and also erases the cellular fluid. Inositol foefatoe is eeparated by ion exchange chromatography on Dowex columns, which are washed with 2.5 ml of 10 mM myoinositol and 10 mM formic acid. The columns are then washed with 5 ml of 60 mM sodium formate and 5 mM borax, and the total inositol phosphate is eluted with 5 ml of 1M ammonium formate, 0.1M formic acid. The column elutoe is added to the fraecoe of liquid scintillation containing 15 ml of scintillation mixture and are counted by counting liquid scintillation. Figure 2 shows the results of a typical experiment.

Figure 2. Effect of the compounds of the accumulation of total inositol phosphate stimulated by GnRH in HEK-293 cells expressing the hGnRH receptor. The ability of the peptide antagonist, Antide, a non-peptide compound 9 to block stimulated increases by GnRH in [3 H] inositol foefate, was examined. None of the compounds only stimulated an increase in the total [3 H] inositol phosphates (not shown) but both compounds were able to inhibit the stimulation mediated by the maximum concentration of the GnRH peptide. GnRH only increases the accumulation of [3 H] inoeitol foefate with an EC50 of approximately 0.8 n in a dose-dependent manner. In the experiment shown, the Kb values of Antide and compound 9 were determined by the Cheng and Prusoff method (Biochem Pharmacol 22: 3099-3108, 1973). The values are from an experiment performed in duplicate.

IN VIVO PHARMACOLOGY OF ANIMAL EFFECTIVENESS STUDIES Experimental protocol: Male Sprague-Dawley rats (225-250 g) are hunted and allowed to undergo post-operative recovery for 10 days. Ten days after the fall, the animals are instrumented with catheters buried in the venous and femoral arteries to facilitate remote blood loss and sampling. On the day of the experiment, the animals are allowed to acclimate to the procedure room while they are in their own cage. Samples of blood are extracted baeal de todoe loe animalee. After basal sampling, the vehicle is administered intravenously (10% DMSO, cremophor / 10% saline solution), Antide (1.0 μg) or compound 11 (10 mg / kg). Blood samples are drawn at 10, 60, 90, 120, 180 and 240 minutes after the injections. The blood is subjected to centrifugation, collected by serum and stored in a freezer at -70 ° until the eneayoe are made. Samples of serum are analyzed using a DSL-4600 ACTIVE LH immunoradiometric test kit from Diagnostic Systems Laboratories, Inc.

The results and discussion: The removal of lae gonadae eliminates the negative feedback of testosterone in the hypothalamus, resulting in increased GnRH and consequently elevated LH. Figure 3 illustrates the concentration in plasma of both LH and testosterone in control and castrated rats 10 days after surgery. In these rats, the GnRH antagonist would be expected to reduce the elevation mediated by GnRH of LH levels. Antide, a peptide antagonist of GnRH, reduces LH in the castrated rat model (figure 4). Compound 11, a small molecule GnRH antagonist, also suppresses LH in the castrated rat model (Figure 4).

PHARMACOKINETIC STUDIES Experimental protocol: Rats are prepared with intravenous catheters inserted into the superior vena cava through the incision in the right external jugular vein and allowed to recover. The drugs are dissolved in a mixture of 10% DMSO, 10% cremaphor and 80% saline, and i.v. at a dose of 10 mg / kg. The blood samples are taken at the indicated times and the compounds are extracted from 0.2 ml of plaema with butyl chloride containing an internal standard. The units are analyzed by CLAR in a Beta-Baeic device with a C18 4x50 mm column using a 40-80% acetonitrile gradient in 10 mM ammonium phosphate buffer, at a flow rate of 1 ml / min. The detection of the sample is carried out by UV absorbance at 260 nm. Results and discussion: Compound 11, which has excellent affinity in the rat GnRH receptor, has a half-life in rat plasma of about 3 hours and has a plasma concentration of 100-200 nM four hours after the i.v injection. (figure 5). The binding of the reference peptides to the rat, mouse, bovine and human GnRH receptors agrees well with those reported in the literature. The non-peptidic compounds of the invention exhibit marked differences between species in their binding profile. Several of these compounds have high affinity (<100 nM) in the human GnRH receptor. Functionally, all of these non-peptidic compounds tested for activity in an inositol phosphate assay act as antagonists of the accumulation of total inositol phosphate stimulated by GnRH in cells containing recombinant human GnRH receptors. Intravenous administration of compound 11 reduces plasma concentrations of LH in castrated male genus rats, a model for chronically increasing plasma LH concentrations. This component has a half-life of tree horae and the plaematic concentration correlates with efficacy. Taken together, this data suggest that non-peptidic compounds may have utility as a GnRH receptor antagonist. Agonist and peptide antagonists used as reference compounds: Antide Leuprolide Human GnRH GnRH-A [D-ALA6, DES-GLY10] -LH-RH ETHYLAMIDE The data in the following compounds are obtained as follows: Cell culture Lae GH3 cells stably tranefected with the rat GnRH receptor (GGH3) are provided by Dr. William Chin (Harvard Medical School, Boston, MA). These cells have been extensively characterized in advance (Kaiser et al., 1997). These cells grow in Dulbecco's low-glucoe-modified Eagle's medium (DMEM) containing: lOOU / ml of penicillin / eetreptomycin 0.6 g / l of G418 and heat inactivated fetal bovine serum 10% (FBS). The cDNA for the human GnRH receptor is cloned into the plasmid expression vector, pcDNA 3 (In Vitrogen) and stably transfected in HEK 293 cells (hGnRH-R / 293). This cell line is provided by Dr. Stuart Sealfon, Mount Sinai Medical School, New York, NY. These cells are grown in DMEM supplemented with 0.2 g / 1 of G418, 100 U / ml of penicillin / streptomycin and 10% FBS. The cells both GGH3 and hGnRH-R / 293 are used both for the measurement of inositol phosphate and for microphysiometry determinations of the efficacy of the compound.

Preparation of radioligand Radioligand is used as an iodinated radio-agonist analog of GnRH, [des-Gly10, D-Ala6] GnRH ethylamide (125I-GnRH-A). Dilute 1 μg of GnRH-A in 0.1M acetic acid and add it to a borosilicate glass tube coated with Iodogen ™ (Pierce) containing 35 μl of 0.05 M phosphate buffer (pH 7.4-7.6) and 1 mCi of Na [125I]. The reaction mixture is vortexed and incubated for 1 minute at room temperature. After 1 minute, the mixture is vortexed and allowed to incubate for an additional 1 minute. 2 ml of 0.5 M acetic acid / 1% BSA are added to the reaction tube and the mixture is added to a C18 Sep-Pak cartridge. The cartridge is washed with subsequent washes of 5 ml of H20 and 5 ml of 0.5M acetic acid and then eluted with 5 x 1 ml of 60% CH3CN / 40% 0.5M acetic acid. The eluate is diluted with 3x buffer volumes for HPLC A (0.1% TFA in H, 0) and loaded onto a C18 column. The iodinated product is eluted for 20-25 min with a 25-100% CH3CN gradient containing 0.1% TFA. The radioactive fractions (750 μl / fraction). They are collected in clean polypropylene tubes containing 100 μl of 10% BSA. The fractions are determined to determine the biological activity by radioligand binding. The specific activity of the radioligand is approximately 2200 Ci / mmol.

Microfiometry The Cytoeensor ™ microphysiometer (Molecular Devices, Sunnyvale, CA) is a non-reactive, real-time non-invasive semiconductor based system for monitoring cellular responses to various stimuli. It is based on a silicon detector senesible at pH, the light-addressable potentiometric detector which is part of a microvolume flow chamber in which cultured cells are immobilized (Pitchford et al., 1995; Parce et al., 1989; Owicki, et al., 1994).

Reference additional: Owicki, J.C., L.J. Boueee, D.G. Hafeman, G.L. Kirk, J.D. Oleon, H.G. Wada and J.W. Parce. The light-addreeeable potentiometric sensor: principies and biological applications. Ann. Rev. Biophys. Bio ol. Struc. 23: 87-113, 1994. Parce, J.W., J.C. Owicki, K. M. Kerceo, G.B. Sigal, H.G. Wada, V.C. Muir, L.J. Boueee, K.L. Ross, B.I. Sikic, H.M. McConnell. Detection of cell-affecting agents with a silicon bioseneor. Science 246: 243-247, 1989. Pitchford, S., K. DeMoor, and B.S. Glaeser Nerve growth factor stimulates rapid metabolic responses in PC12 cells. Am. J. Physiol. 268 (Cell Physiol. 37): C936-C943, 1995.

GGH3 cells are seeded in low minimum essential medium in buffer (MEM, Sigma) containing 25 mM NaCl and 0.1% BSA at a density of 500,000 cells / capsule on the polycarbonate membrane (poroeity 3 μm) of the cell capsule cups (Molecular Devices, Sunnyvale, CA). The capsule cups are transferred to detector chambers where cells are kept in close proximity to a silicon detector inside the detector chamber, which measures small changes in the pH in the microvolume in the detector chamber. The poorly buffered medium is continuously pumped through the cells at a rate of about 100 μl / min from one of the fluid reservoirs. A selection valve determines which built-up reservoir is perfused over the cells. The Cytosensor microphiometer "R generates a voltage signal, which is a linear pH function, every second." In order to measure the acidification rates, the flow of the detector chamber containing the cells interrupts periodically, allowing The excreted acid metabolites accumulate in the extracellular fluid of the cells.In these experiments the cells are maintained at 37 ° C over a two-minute flow cycle and with cells irrigated with medium for 80 seconds followed by 40 seconds in which stops the flow of medium, during this interval of 40 seconds, the acidification rates are measured during an interval of 30 seconds. In this way, ee calculates every two minutes a unique acidification rate. The CytosensorMR microphysiometer device contains eight detector units that allow eight simultaneous experiments to be performed. Each unit is programmed individually using a computer linked to the system. The GGH3 cells are initially equilibrated with low MEM medium in buffer for a period of 30-60 minutes in which baeal acidification rates are measured (measured as μV / sec) in the absence of any stimulus. When the rate of basal acidification changes by less than 10% during a period of twenty minutes, the experiments are initiated. The experiments in curet over time are performed to determine the optimum time for exposure of agonieta antee of the measurement of acidification rate and the duration of exposure necessary to obtain the maximum acidification responses to various agonistae. From these time course experiments, it is determined that the cells must be exposed to GnRH peptide agonites at least one minute prior to their collection of acidification rate data. The maximum acidification rates usually occur in the first exposure cycle of two minutes. In order to retain the peak response to GnRH, the cells are exposed to the agonist for a total of four minutes. The cells are exposed to Compounds for 20-60 minutes before a four minute stimulation with GnRH (1.0 nM - 10 μM) alone or in combination with diverse test concentrations of each compound. All compounds are tested in a final concentration of 1% DMSO in low MEM medium in buffer described above.

Selectivity profile In order to determine the binding specificity of the compounds to GnRH receptors, the compounds are tested in various binding and functional assays to determine their activity. Table 2 below shows the activity of compound 20 in another eneayoe.

Table 2. Binding affinity or functional determination of compound 20 in various tests 50 for testing the basal stam e e Figure 6 shows the effect of compound 136 on the increment of GnRH in the rate of extracellular acidification in cells with GGH3. GnRH produces a dose-dependent increase in the speed of Intercellular acidification of GGH3 cells. Compound 136 causes a direct shift in the dose-response curves to GnRH without decreasing the maximum response to GnRH. This suggests that this compound is a competitive receptor antagonist of GnRH in this receptor. The values shown are from an experiment. An example of the preparation methods for the compounds according to the invention is as follows: A1C1, Nitromethane 2) SOC1, DIPEA 4- (3-methylphenoxy) -2-butanone: To m-cresol (4.0 g, 37 mmol), methyl vinyl ketone (3.2 ml, 37 mmol) in 25 ml of chloroform, and diieopropylethylamine was added. The mixture is refluxed for 16 h, allowed to cool to room temperature and evaporated. The waste has 50% product and 50% initial material. The starting material is separated as t-butyldimethylsilylether. The product is isolated through plug filtration. Yield 4.5 g (68%). 2-methyl-4 (3-methylphenoxy) -2-butanol To a solution of methylmagnesium bromide in 50 ml of ether, prepared from Mg (572 mg, 23.56 mmol) and Mel (3.34 g, 23.56 mmol) is added 4- (3-methylphenoxy) -2-butanone (2.1 g, 11.78 mmol) in 10 ml of ether. The solution is stirred at room temperature for 30 minutes, after which it is suspended with water and dilute hydrochloric acid. The organic layer is separated, dried over sodium sulfate, filtered through a plug of silica. Colorless syrup 1.91 g (83%). 4,4, 7-trimethylchroman: A aluminum (1.3 g, 9.79 mmol) in 40 ml of carbon disulfide chloride, 2-methyl-4 (3-methylphenoxy) -2-butanol (1.9 g, 9.79 mmol) was added in 10 ml of carbon disulfide. The mixture is refluxed for 2 h. The solvent is evaporated, the residue is diluted with 50 ml of ethyl acetate and 10 ml of water. The organic layer is separated, dried over sodium sulfate and purified through a rapid column. Syrup light yellow 1.5 g (87%). Ethyl -5- [(4,4, 7-trimethyl-3, 4-dihydro-2H-chromen-6-di methyl] -2-furoate and ethyl-5- [(4,4,7-trimethyl-3, 4 -dihydro-2H-chromen-8-yl) methyl] -2-furoate: furoate (656 mg, 3.48 - A zinc (950 mg, 6.97 mmol) in 20 ml of nitromethane a mixture of 4, 4, 7- trimethylchroman (1.23 g, 6.97 mmol) and 5-chloromethyl -2 added mmoles) in 15 ml of nitromethane. The mixture Stir at room temperature for 16 h. It is evaporated to dryness and triturated with ethyl acetate-water (1: 1, 100 ml). The organic layer under usual treatment and filtration of the plug using hexane: ethyl acetate (9: 1) provides a mixture of these two compounds. 1.34 g (46%, based on chroman). N- (2, 4,6-trimethoxyphenyl) -5- [(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl) met il] -2-furamide and N- (2 , 4,6-trimethoxyphenyl) -5 - [(4,4, 7-trimethyl-3,4-dihydro-2H-chromen-8-yl) methyl] -2-furamide: To a mixture of ethyl-5- [(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl) methyl] -2-furoate yetil-5 - [(4,4,7- trimethyl -3,4-dihydro-2H-chromen-8-yl) methyl] -2-furoate (1.34 g, 3.74 mmol) in THF-MeOH-H, 0 (7: 5: 5, 20 mL) is added monohydride of lithium hydroxide (784 mg, 18.7 mmol). The mixture is stirred at 4 h at room temperature. The mixture is evaporated to dryness, diluted with 30 ml of ethyl acetate and 50 ml of water. mixture of corresponding acids, 1.03 g (quantitative). The acids can not be separated using column chromatography or crystallization. To the mixture of acids (200 mg, 0.66 mmol) in 30 ml of dichloromethane is added thionyl chloride (392 mg, 3.3 mmol). The mixture is refluxed for 1 h and evaporated. The residue is dissolved in hexane-ethyl acetate (9: 1, 20 ml) and filtered through a plug of silica gel (0.5 cm X 1.0 cm). To the residue in 10 ml of ethyl acetate is added 2,4,6-trimethoxyphenylamine hydrochloride (145 mg, 0.66 mmol) followed by diisopropylethylamine (256 mg, 1.98 mmol). The mixture is stirred at room temperature for 16 h. The reaction is suspended with 10 ml of water, and the ethyl acetate layer is separated. The combination and purification in column and by CLAR provides 15 mg and 21 mg of two components (12%). The bioavailability of the compuets of the invention is shown in the following table. The in vivo pharmacology of some of the compounds of the invention is tested as follows: In vivo experiments: general aspects.

Adult male Sprague-Dawley rats are purchased from Harán Sprague Dawley (San Diego). The animals are housed two per cage and are kept in a room with controlled temperature (22 ± 2 ° C) with a photoperiod of 12 h of light / 12 h of darkness (lae lucee ee turn on lae 0600 h). Food is provided for ratae (diet for Teklad rats) and running water ad Ubi tum.

Animal models to access activity of GnRH antagonists; Castrated male rat model Reasoning: Surgical excision of the gonads removes circulating teetoeterone and eliminates the negative feedback of teetoeterone in the hypothalamus. As a result, GnRH is increased and consequently LH rises (Figure # 1). A GnRH antagonist can be expected to reduce GnRH-mediated elevations of LH levels. Antide, a GnRH peptide antagonist reduces LH levels in decayed rats (Figure # 8). This model seems to be suitable for evaluating small molecule GnRH antagonists. Protocol: Male Sprague-Dawley rats (200-225 g) are castrated by approximation by the low alneenenee anesthetic. The animals are allowed to stand 14 days after the operation before the study. Thirteen days after castration the animals were anesthetized with alotano and subjected to instrumentation with a cannula inserted into the jugular vein. The details of the cannulation procedure have been previously described. { Harms and Ojeda, 1974.}. . On the day of the study, the animals are allowed to acclimate to the procedure room while they are in their original cage. They extract samples of baeal blood from all animals. Immediately after basal sampling, test vehicle compounds are administered by various routes. The administration routes used are intravenous (iv), intramuscular (im), intraperitoneal (ip), subcutaneous (se) and oral (po). Blood samples are delivered in tubes containing heparin at multiple time points and after treatment. The blood is centrifuged immediately, the plaema is collected and stored in a freezer at -20 ° until the tests are performed. The plasma samples are analyzed using a DSL-4600 ACTIVE LH coated immunoradiometric test kit from Diagnoetic Syetems Laboratories, Inc.

Formulations of the compounds: Formulation # 1 (indicated with sub-1): DMSO 10%, Cremophor EL 10% and physiological saline 80%. Formulation # 2 (indicated with index 2): Cremophor EL 10% and physiological saline 90%.

Results See Figures 9 to 11 and Table.

Male rats intact Reasoning: Testosterone is a hormone regulated by the hypothalamic-pituitary-gonadal axis. GnRH is secreted in pulse from the hypothalamus and stimulates the anterior pituitary gland to release gonadotropic hormones LH and FSH. Testoeterone occurs when the testes are stimulated by LH. The amount of secreted testosterone increases approximately in direct proportion to the amount of LH dieponible (Guyton, 1986). GnRH antagonists are expected to reduce the level of testosterone by inhibiting LH.

Protocol 1: Eolae ratae male Sprague-Dawley (250-275 g) are housed and allowed to acclimate for 1 week before the study. On the day of the study the animals are dosed with vehicle or with test compound by various routes of administration that include ip, se, or po. Blood samples are obtained by cardiac puncture under halothane anesthesia of individual animals at predetermined time points after treatment. Blood samples are drawn in tubes containing heparin. The blood is centrifuged immediately, the plasma is collected and stored in a -20 ° freezer until tests are performed. Plasma samples are analyzed using DSL-4000 ACTIVE Testoeterone coated tube radioimmunoassay equipment from Diagnostic Systems Laboratories, Inc.

Protocol 2: Machae Sprague-Dawley rats (250-275 g) are housed and allowed to acclimate for 1 week after the study. We developed a technique to allow repeated sampling from the jugular vein using microrenathane catheters (MRE) implanted 7 days before the study. The details of the surgical procedure have been previously described. { Harms and Ojeda, 1974.}. . On the day of the study, you are allowed to be encouraged to acclimate to the procedure room while in their own cages. Samples of basal blood are extracted from all animals. Immediately after basal grinding, they are administered by divereae via the vehicle or test cartridges. Lae administration routes used were intravenous (iv), intramuscular (im) and oral (po). Blood samples are drawn into tubes containing heparin at multiple time points after treatment. The blood is centrifuged immediately, plasma is collected and stored in a freezer at -20 ° until the tests are performed. Plasma samples are analyzed using DSL-4000 ACTIVE Testosterone coated radioimmunoassay equipment from Diagnostic Systeme Laboratories, Inc.

Protocol 3: Compound No. 134 of a repeated dosing study Male Sprague-Dawley rats (250-275 g) are housed in pairs and allowed to acclimate for one week before the study. The daily vehicle treatments are administered either im, se or po between 8:00 and 9:00 am during this day. On day 8, between 8:00 and 9:00 a.m., blood samples are taken by cardiac puncture under halothane anesthesia. The procedure is completed in 45-60 seconds. During the following 7 days a group of animals continues to receive treatments with vehicles while another group of animals does not receive treatment. The samples are collected as described in the previous paragraph after the seventh day of this treatment regimen. Testosterone levels are not different between vehicle treated animals and untreated animals. The daily dosage im of compound 134 (100 mg / kg) or vehicle is carried out between 8:00 and 9:00 a.m. during seven days. The samples are collected as described above after the seventh day of treatment. All blood samples are collected in tubes containing heparins. The sample is immediately centrifuged, the plasma is collected and stored in a -20 ° freezer until the next day. The plastic sphygmomanome anal y z an ut i l i z oro coated tube radioimmunoassay equipment DSL-4000 ACTIVE Testosterone from Diagnostic Syetems Laboratories, Inc.

Results See Table 2 and figures 12-14.

Legends of the figures Figure 7: Bar graph showing the basal levels of LH and testoeterone in castrated (X) and intact ratae. LH rises in CX rats. Testoeterone is present in ratae CX. Figure 8.- Line graph that shows the level of LH expressed as a percentage of basal LH in animals treated with vehicle and with Antide. Antide (2.0 and 20 μg, -sc) euprime LH in CX rats. Figure 9: Graph of lines showing the LH levels expressed as a percentage of basal LH in animals treated with vehicles with compound. Compound 134 (1.0, 5.0, and 10 mg / kg, - iv) produces an LH-dependent supreion of the dosie in rat CX. Figure 10: Graph of lines showing the levels of LH expressed as a percentage of LH baeal in vehicle and animals treated with compounds. Compound 134 (20 or 100 mg / kg ip) suppresses LH in CX rats. Figure 11: Line plot showing the levels of LH expressed as a percentage of basal LH in animals treated with vehicles with compound. Compound 134 (20 mg / kg; im) suppresses LH in CX rats.

Table 1 GnRH compounds in the castrated rat model NS = No expression ND = Not determined Legends of the figure Representation of protocol 1: Figure 12: Bar graph showing testosterone levels in animals treated with vehicle and with compound 6 hours after ip injection. Compound 136 suppresses testosterone levels compared to heavy animals with vehicle * = p < 0.05, test t.

Representative of protocol 2: Figure 13: Line chart showing testosterone levels over a 12-hour time course and a 24-hour time point in rats treated with vehicle and with compoteto 134. The vehicle and compound 134 are supplied by tube feeding . The highest dose of compound 134 suppresses testosterone throughout the course of the study.

Representative of protocol 3: Figure 14: Bar graph showing levels of testoeterone for animalee treated with vehicle, with compoteto 134 and with control. White lae barrae represent levels of pretreatment teetosterone and solid bars represent testoeterone levels after 7 days of repeated treatment. Compound 134 significantly suppresses the level of testosterone compared to pretreatment or vehicle treated and control animals. * = p0.05, test t.

Table 2 GnRH Compounds in intact male rat NS = No expression ND = Not determined Procedural notes It has been documented that some of the procedures commonly expressed in endocrine studies and in animals such as anesthesia, fasting, surgery can affect the levels of hormone being studied (B.E. Howland, et al., Experentia, 1974). Luteinizing hormone and testosterone are sensitive to stressors. Numerous reports are inconclusive regarding the effects of stressors in the HPG when the same species and estreeantee are used. For example, male rats that are restricted or immobilized have been reported to have low LH concentrations (Kruhlich et al., 1974; DuRuisseau et al., 1978), normal (Tache et al., 1980; Charpenet et al. ., 1982; Collu et al., 1984), or elevated (Briski et al, 1984). Similarly, it has been reported that plasma levels of testosterone change after exposure to stress situations, but again the data appear contradictory and therefore difficult to interpret. For example, during intense physical exercise, it has been reported that plasma testosterone levels increase (Deseypris et al., 1976), decrease (Sutton et al., 1973) or remain unchanged (Lamb, 1975). The effects of immobilization on testoeterone concentrations have been more consistent with most of the research that reports a decline in circulating values (Tache) et al., 1980; Charpenet et al., 1982; Collu et al., 1984). However, it has been found that stressors induce changes in circulating testosterone and the type of stress used. Duration and severity cause different stress-induced changes in testoeterone concentrations. By -sensing the susceptibility of LH and testoeterone to the eetrée, heme optimized protocol to evaluate LH and testosterone under conditions which minimize stress. The compounds according to the invention that have been prepared are shown in the attached tables. The compueetos can be prepared with the general experimental part that is provided before. The specific examples are provided in the following.

Compounds containing pyrimidine Preparation of 2-chloro-N- [(2R) -tetrahydro-2-furanmethyl] -4-pyrimidinamine 1 and 4-chloro-N- [(2R) -tetrahydro-2-furanmethyl] -2-pyridinamine 2: To a 250 ml round bottom flask was placed 2,4-dichloropyrimidine (5.0 g, 33.56 mmole) and 200 ml of THF. To this solution is added triethylamine (14.0 ml, 100.68 mmol) and [R] -tetrahydrofurfurylamine. The solution is stirred overnight. The reaction mixture is poured into water and extracted with methylene chloride. The separated organic layer is washed with brine, dried over magnesium sulfate and concentrated on a rotary evaporator. The crude compound is purified by chromatography on silica gel with hexane / ethyl acetate (4: 1 v / v to 1: 1 v / v) to give 2 (1.3 g) and 1 (3.98 g).

Preparation of N - [3 - (aminome t i 1) ene i 1] - 2, 2, 2 -trifluoroacetamide 3.

To a solution of m-xylene diamine (28.76 g, 211.15 mmol) in THF (300 mL, .7 M) is added dropwise a solution of ethyl trifluoroacetate (10 g, 70.38 mmol) in THF (50 mL, 1.4M). The solution is stirred at room temperature overnight. The reaction is monitored by CCD. The solvent is concentrated and the residue acidified to pH 2 with 4N HCl and dissolved in water and washed with ethyl acetate. The separated aqueous layer is made basic to pH 11 using NH40H and the compound is extracted with dichloromethane. The separated organic layer is washed with water / brine, dried over magnesium sulfate and concentrated to give 3. (8.71 g, 53% yield).

Synthesis of 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthaleniDmethyl] -N- (3- { [(2- { [( 2R) -tetrahydro-2-furanylmethyl] amino.} -4-pyrimidinyl) amino] methyl.} Benzyl) -2 -furamide 9.

K2C? 3 Preparation of ethyl 3- (aminomethyl) benzylcarbamate 5.

To a solution of N- [3- (aminomethyl) benzyl] -2,2,2-trifluoroacetamide 3 (10.6 g, 43.1 mmol) is added 1 eq of ethyl chloroformate followed by triethylamine. The reaction is stirred at room temperature for 30 min. The crude product is extracted with methylene chloride and concentrated to provide 3-. { [(trifluoroacetyl) amino] methyl} ethyl benzyl carbamate 4. This crude product is dissolved in 100 ml of methanol and 100 ml of 2N K2C03, and stirred overnight. The reaction mixture is made basic to pH 14 with 20% NaOH, extracted with methylene chloride, washed with brine and dried over magnesium sulfate to give 5 (5.2 g).

Preparation of 3-. { [(2- {[[2R] -tetrahydro-2-furanylmethyl] amino] -4-pyrimidinyl) amino] methyl} benzylcarbamate 6 To a solution of ethyl 3- (aminomethyl) benzylcarbamate 5 gives 4-chloro-N- [(2R) -tetrahydro-2-furanmethyl] -2-pyridinamine 2 in chlorobenzene, triethylamine is added. The reaction mixture is refluxed overnight. The solution is cooled to room temperature and loaded onto a column of silica gel and eluted with hexane / ethyl acetate (1: 1 v / v) to provide 3 -. { [(2 - { [(2R) - tetrahydro- 2 - furanylmethyl] amino} -4-pyrimidinyl) amino] methyl} Benzylcarbamate 6 (73% yield). Dissolves 3 -. { [(2 - { [(2 R) - t e t r a h i d r o-2-furanylmethyl] amino] -4-pyrimidanyl) amino] methyl} benzyl carbamate 6 in ethylene glycol and potassium hydroxide (1: 1 v / v). The solution is heated at 100 ° C overnight. The mixture is cooled to room temperature and extracted with chloroform, washed with brine and dried over magnesium sulfate to give N4- [3- (aminomethyl-benzyl] -N2- [(2R) -tetrahydro-2-furanylmethyl] -2, 4-pyrimidindiamine 7 (82% yield).

Preparation of 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthaleniD ethyl] -N- (3- { [(2- { [ (2R) -tetrahydro-2-furanylmethyl] amino.} - 4-pyrimidinyl) amino] methyl.} Benzyl) -2 -furamide 9.

Dissolve 3 { [(2- {[[2R] -tetrahydro-2-furanylmethyl] amino} -4-pyrimidinyl) amino] methyl} benzyl carbamate of 6 in ethylene glycol and potassium hydroxide (1: 1 v / v). The solution is heated at 100 ° C overnight. The mixture is cooled to room temperature and extracted with chloroform, washed with brine and dried over magnesium sulfate to give N4- [3- (aminomethyl-benzyl] -N2- [(2R) -tetrahydro-2-furanylmethyl] -2, 4-pyrimidinediamine 7 (82% yield) This product, 7 (182 mg, 0.580 mmol) and the chloride reagent 2-furoyl 8 is dissolved in dichloromethane followed by triethylamine. The reaction is stirred at room temperature overnight. The crude compound is purified on a column of silica gel and eluted with ethyl acetate / hexane (4: 1 v / v) to provide 5 - [(3,5,5,8,8-pentamethyl-5,6 , 7,8-tetrahydro-2-naphthalenyl) methyl] -N- (3- {[[(2- {[[(2R) -tetrahydro-2-furanylmethyl] amino} -4-pyrimidinyl) amino] methyl.} benzyl) -2-furamide 9 (159.1 mg). LH NMR (CDC13): d 1.19 (s, 6H), 1.26 (s, 6H), 1.65 (m, 5H), 1.92 (m, 3H), 2.23 (e, 3H), 3.45 (m, ÍH), 3.5 (m, HH), 3.7 (m, HH), 3.9 (m, 3H), 4.05 (m, HH), 4.50 (d, 2H), 4.58 (d, 2H), 5.01 (broad d, HH), 5.30 (d broad, ÍH), 5.71 (d, lh), 6.03 (d, ÍH), 6.61 (t, ÍH), 6.99 (s, ÍH), 7.06 (?, ÍH), 7.07 (s, ÍH), 7.28 (m, 4H), 7.80 (d, ÍH). MS: 622.4 (M + 1).

Synthesis of 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6, 1, 8-tetrahydro-2-naphthalencylmethyl] -N- (3- [[(4- { [(2S)] -tetrahydro-2-furanylmethyl] amino.} -2-pyrimidinyl) amino] methyl.} benz i 1) -2-f uramide 12. fifteen 12 Preparation of N- [3 - (aminomethyl) benzyl] -5- [(3, 5, 5, 8, 8-pentamethyl-5, 6,7, 8-tetrahydro-2-naph taleniDmethyl] -2-furamide 11.

To a solution of N- [3- (aminomethyl) benzyl] -2,2-trifluoroacetamide 3. and 2-furoyl chloride reagent 8. triethylamine is added. The reaction mixture is stirred at room temperature for 1 hour. The crude mixture is purified by chromatography on silica gel eluting with hexane / ethyl acetate (4: 1 v / v) to provide 5- [(3,5,5,8,8-pentamethyl-5,6,7, 8- tetrahydro-2-naph taleniDmethyl] -N- (3-. {[[(Trifluoroacetyl) amino] methyl} benzyl) -2-furamide 10. The purified compound is dissolved in 100 ml of methanol and sodium carbonate. potassium in water (2M, 100 ml) The reaction is heated at 70 ° C overnight The solution is cooled to room temperature, made basic with 20% NaOH to pH 14, extracted with methylene chloride, washed brine and dried over magnesium sulfate to provide N- [3- (2-aminomethyl) benzyl] -5- [(3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro- 2 -naf talenyl) met il] -2- uramide 11 (4.97 g, 85.1% yield).

Preparation of 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6,7, 8-tetrahydro-2-naphthalenyl) methyl] -N- (3- [[(4- { [( 2S) -tetrahydro-2-furanylmethyl] amino.} -2-pyrimidinyl) amino] methyl.} Benzyl) -2-uramide 12.

To a solution of N- [3 - (aminomethyl) benzyl] -5 - [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naph taleniDmethyl] -2-furamide In chlorobenzene, 2-chloro-N- [(2S) -tetrahydro-2-furane] -4-pyrimidinamine and triethylamine are added.The reaction mixture is refluxed overnight.The cooled mixture is then purified by chromatography on silica gel followed by HPLC to provide 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)) methyl] -N- (3 - [[(4-. {[[(2S) - tetrahydro-2-f urani-lmet-il-amino]} - 2-pyrimidinyl) amino] methyl} benzyl) -2-furamide 12. XH NMR ( CDC13): d 1.01 (S, 6H), 1.25 (s, 6H), 1.43 (m, ÍH), 1.56 (s, 4H), 1.70-1.98 (m, 3H), 2.13 (s, 3H), 3.24 ( m, ÍH), 3.61 (m, ÍH), 3.63-3.80 (m, 2H), 3.82 (s, 2H), 3.87-4.06 (m, ÍH), 4.37-4.60 4.37 (d, 2H), 4.60 (d , 2H), 5.73 (d, ÍH), 5.92 (d, ÍH), 6.3 (broad d, ÍH), 6.75 (broad d, ÍH), 6.92 (s, ÍH), 6.98 (d, ÍH), 7.0 ( s, ÍH), 7.09-7 .26 (m, 4H), 7.4 (s, ÍH), 9.5 (broad d, ÍH). MS (APCI): 622.3 (M + 1).

Examples of compounds containing heterocyclic A1C1, Nitromethane 2) SOCL DIPEA 4- (3-methylphenoxy) -2-butanone: To m-cresol (4.0 g, 37 mmol), methyl vinyl ketone (3.2 ml, 37 mmol) in 25 ml of chloroform and diisopropylethylamine is added. The mixture is refluxed for 16 h, allowed to cool to room temperature and evaporated. The waste has 50% product and 50% initial material. The starting material is separated as t-butyldimethylsilylether. The product is isolated by plug filtration using silica gel, 50% hexane / ethyl acetate. Yield 4.5 g (68%). As an alternative procedure of purification, the crude reaction mixture is evaporated, dissolved in 0.2M DMF and 0.5 equivalents of imidazole and 0.5 equivalents of tBDMSCl are added. The reaction is stirred for 3 h at room temperature and then the solvents are removed in vacuo. To the residue is added 75 ml of ethyl acetate and 75 ml of water (1/1 ratio). The ethyl acetate layer is separated and dried over Na2SO4. The solvents are removed in vacuo. The crude material is placed on a pad of silica gel and the eilated m-cresol is removed with hexanes. The product is obtained by eluting with 5-10% ethyl acetate in hexanes. The solvents are removed in vacuo to provide the desired product. XE (CDC13): 7.15 (t, ÍH), 6.65-6.80 (m, 2H), 4.25 (t, 2H), 2.75 (t, 2H), 2.25 and 2.35 (2s, every 3H). 2 - . 2-methyl-4 (3-methylphenoxy) -2-butanol: To a solution of methylmagnesium bromide in 50 ml of ether, prepared from Mg (572 mg, 23.56 mmolee) and Mel (3.34 g, 23.56 mmole), add 4- (3-methylphenoxy) -2-butanone (2.1 g, 11.78 mmol) in 10 ml of ether. The solution is stirred at room temperature for 30 minutes, after which it is suspended with water and dilute hydrochloric acid. The organic layer is separated, dried over sodium sulfate, filtered through a plug of silica to provide a colorless syrup, 1.91 g (83%) mass spectral analysis using APCI + ve 177 (M + -OH). 4,4, 7-trimethylchroman: A aluminum (1.3 g, 9.79 mmol) in 40 ml of carbon disulfide chloride, 2-methyl-4 (3-methylphenoxy) -2-butanol (1.9 g, 9.79 mmol) was added in 10 ml of carbon disulfide. The mixture is refluxed for 2 h. The solvent is evaporated, the residue is diluted with 50 ml of ethyl acetate and 10 ml of water. The organic layer is separated, dried over sodium sulfate and purified by column chromatography to give a light yellow syrup, 1.5 g (87%). E (CDC13): d 7.05 (broad d, ÍH), 6.87 (dd, ÍH), 6.69 (d, ÍH), 4.20 (t, 2H), 2.35 (s, 3H), 1.80 (t, 2H), 1.40 (s, 6H).

Ethyl-5- [(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl) methyl] -2-furoate and ethyl-5- [(4,4,7-trimethyl-3) , 4-dihydro-2H-chromen-8-iDmethyl] -2-furoate: To zinc chloride (950 mg, 6.97 mmol) in 20 ml of nitromethane is added a mixture of 4, 4, 7-trimethylchroman (1.23 g, 6.97 mmol) and ethyl-5-chloromethyl-2-furoate (656 mg, 3.48 g). mmoles) in 15 ml of nitromethane. The mixture is stirred at room temperature for 16 h. The reaction is evaporated to dryness and triturated with ethyl acetate-water (1: 1, 100 ml). The organic layer under usual treatment and plug filtration using hexanes in ethyl acetate (9: 1) provides a mixture of these two compounds. 1.34 g (46% based on chroman).

N- (2,4,6-trimethoxyphenyl) -5 - [(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl) methyl] -2-furamide and N- (2, 4,6-trimethoxyphenyl) -5 - [(4,4,7-trimethyl-3,4-dihydro-2H-chromen-8-yl) methyl] -2-furamide: To a mixture of ethyl 5- [(4, 4, 4-trimethyl-3, 4-dihydro-2H-chromen-6-yl) methyl] -2-furoate and et-5 - [(4, 4, Ethyl 7-trimethyl-3, 4-dihydro-2H-chromen-8-yl) methyl] -2-furoate (1.34 g, 3.74 mmol) in THF-MeOH-H20 (7: 5: 5, 20 mL) ee add lithium hydroxide monohydrate (784 mg, 18.7 mmolee). The mixture is stirred for 4 h at room temperature. The mixture is evaporated to dryness, diluted with 30 ml of ethyl acetate and 50 ml of water. After acidification with dilute HCl, a layer of ethyl acetate, dry ee, is separated and evaporated in vacuo to give a mixture of the corresponding acids, 1.03 g, (quantitative). These acids are not separable using column chromatography or typical crietalization. To the mixture of the acid (200 mg, 0.66 mmol) in 30 ml of dichloromethane was added thionyl chloride (392 mg, 3.3 mmol). The mixture is refluxed for 1 h and Dissolve in hexane-ethyl acetate (9: 1, 20 ml) and filter through a plug of silica gel (0.5 cm X 1.0 cm). To the residue in 10 ml of ethyl acetate is added hydrochloride 2, 4,6-trimethoxyphenylamine (145 mg, 0.66 mmol) followed by diisopropylethylamine (256 mg, 1.98 mmol). The mixture is stirred at room temperature for 16 h. The reaction is quenched with 10 ml of water, and the ethyl acetate layer is separated. The combination of column purification and CLAR provides 15 mg and 21 mg of the two components (12%). The isomers are separated using reverse phase HPLC chromatography. Linear isomer: ÍH (CDC13): 7.46 (s broad, ÍH), 7.23 (s broad, ÍH), 7.14 (s, broad, ÍH), 7.02 (s, 2H), 6.63 (e, ÍH), 6.15 (e, 2H), 6.0 (d, ÍH), 4.17 (t, 2H), 3.93 (e, 3H), 3.81 (3.80 (2e, each 3H), 2.21 (e, 3H), 1.81 (t, 2H), 1.29 (e, 6H) M + a 466.2.Anomer angular: AXC07302: 7.25 (s broad, ÍH), 6.91 (d, ÍH), 6.88 (d, hidden, ÍH), 6.53 (d, ÍH), 5.95 (s, 2H), 5.72 (d, ÍH), 3.96 (t, 2H), 3.8 (s, 3H), 3.6 (s, 6H), 2.07 (s, 3H), 1.59 (t, 2H), 1.11 (s, 6H) M + a 466.1.

Examples of aromatic compounds Compound A to. Ethyl acetate, triethylamine, overnight Compound B to. HATU, diisopropylethylamine, DMF, 24 hours b. potassium t-butoxide in 20% MeOH / DMF, 30 min, c. Bromide reagent, 20% MeOH / DMF, 48 hours Compound 183 1.0 mol equivalents, 33.3 mmol and methyl 5- (chloromethyl) -2 -furoate (1.0 equivalent, 33.3 mmol in nitromethane (120 ml, 0.2M) are dissolved. Aluminum trichloride (1.0 equivalent, 33.3 mmol) is dissolved in 25 ml. ml of nitromethane are added to the above solution under nitrogen and heated to gentle reflux for 10 min.The heat is quenched and left under nitrogen overnight.The reaction is suspended in 100 ml of water and extracted with chloromethane. The crude mixture is evaporated to dryness and loaded onto a plug chromatography column (ratio of crude 1 g / 100 g of silica gel.) The column is eluted with 7 and 11% ethyl acetate / hexanes to provide the desired product (2.9 g, 30%) The ester is hydrolyzed to acid by lithium hydroxide in THF / MeOH / H20 (35/25/25).

To a solution containing 5- (4-hydroxy-5-iopropyl-2-methylbenzyl) -2-furoic acid (1.0 equivalent, 3. 6 mmoles, 0.5M) and 2,6-dimethoxyaniline (1.0 equivalent, 3. 6 mmol) is dissolved in DMF. To this mixture is added HATU (1.0 equivalent, 3.6 mmol) and diisopropylethylamine (1.0 equivalent, 3.6 mmol), and stirred overnight. The mixture is heated for 10 min and at 45 ° C. The solution is placed in ethyl acetate (3x volumes) and washed with water.

The organic layer is evaporated to a syrup and eluted in plug column chromatography (1: 100 g crude / g silica gel) in 30 and 50% ethyl acetate / hexane to provide: N- (2.6 -dimethoxyphenyl) -5- (4-hydroxy-5-iopropyl-2-methylbenzyl) -2-furamide (820 mg, 55% yield). *? NMR (CDC13) 7.22 ppm (ΔI, t, J = 8.68 Hz), 7.08 ppm, (ΔI, d, J = 3.40 Hz), 6.99 ppm (ΔI, s), 6.64 ppm (2H, d, J = 8.68 Hz) ), 6.61 ppm (HH, s), 5.97 ppm, (HH, d, J = 3.40 Hz), 3.95 ppm, 2H, e), 3.85 ppm, (6H, s), 3.17 ppm, (HH, penteth, J = 6.8 Hz) 2.23 ppm, (3H, s), 1.25 ppm (3H, s), and 1.23 ppm (3H, s). Potassium t-butoxide (1.05 equivalent, 0.128 mmolee) is dissolved in 24 μl of MeOH. To the previous solution, furamide (1.0 equivalent, 0.122 mmol, 1M) in DMF, t-butoxide selection was added and stirred for 30 minutes. The 2-bromoethyl methyl ether (1.0 equivalent, 0.122 mmol) is added (20% MeOH / DMF, 1M) and stirred at room temperature for 48 hours and purified by HPLC in reverse phase (method 35- 75%, 90 min in acetonitrile in 0.1% aqueous TFA) to provide (8.5 mg, 15% yield). * H NMR (CDC13): 7.04 ppm (H, J = 8.31 Hz, t), 6.85 ppm (H, J = 3.40, d), 6.80 ppm (H, e), 6.53 ppm (H, s), 6.48 ( 2H, J = 8.31 Hz, d), 5.76 (HI, J = 3.40 Hz, d), 3.88 (2H, J = 3.40 / 4.53 Hz, dd), 3.78 (2H, s), 3.58 (6H, s), 3.54 (2H, J = 3.40 / 4.54 Hz, dd), 3.20 (3H, s), 3.07 (ÍH, J = 7.2 Hz, penteto), 2.04 (3H, e), 0.97 (3H, s), 0.95 (3H , s).

Compound A 1, 1, 6-Trimethyl-1,2,3,4-tetrahydronaphthalene is suspended from the reference: John J. Parlow Tetrahedron Vol. 49 (13) 2577. It is then connected with 5- (chloromethyl) -2- Methyl furoate by Friedles-Crafte reaction as previously established to provide two major regioisomers. The desired isomer is eeparated by hydrolysis using three to five successive recrystallizations from a 10% acetone / heptane (1 g / 10 ml). The acid is then converted to acid chloride with thionyl chloride, as previously stated. To a solution of 5- [(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl) methyl] -2-furoyl chloride (1.0 equivalent, 0.32 mmol, 0.2 M) in 2 ml of ethyl acetate, the hydrochloride salt of 2, 4, 6 is added trimethoxymonoaniline (1.0 equivalent, 0.32 mmol). To this mixture triethylamine (excess) is added and this mixture is stirred overnight. The crude product is dried under vacuum and purified by plug column chromatography (ratio of crude mass / silica gel 1: 100) by eluting with a solution of 20 and 30 percent ethyl acetate / hexane. In some cases, the shallow regioi are separated by recrystallization from 25 percent ethyl acetate / hexane (1 g / 75 ml of compound / volume) to give N- (2,4,6-trimethoxy-1-phenyl) -5- [(3, 8, 8 -trimethyl -5,6,7,8-tetrahydro-2-naphthaleniDmethyl] -2-furamide (120 mg, 82% yield) XH NMR (CDC13): 7.28 ppm (1H, broad), 7.12 ( ÍH, s), 7.08 (HH, J = 3.40 Hz, d), 6.89 (HH, s), 6.19 (2H, s), 6.00 (HH, J = 3.40 Hz, d), 3.97 (2H, s), 3.83 (3H, s), 3.82 (6H, s) 2.73 (2H, J = 6.05 Hz, t), 2.25 (3H, s), 1.84-1.76 (2H, multiplet), 1.69-1.63 (2H, multiplet), 1.59 (3H, s), 1.26 (6H, s) elemental analysis: expected C (72.55), H (7.18), N (3.02); real C (72.67), H (7.22), N (2.98).

Compound 228 emp. nte II III IV Compoteto II. To a solution of 3,5-dimethoxyaniline (compound I, 1.53 g, 10 mmol) in 20 ml of DCM is added methanesulfonyl chloride (0.88 ml, 10 mmol). TEA (1.40 ml, 10 mmol) is added dropwise. The reaction mixture is stirred at room temperature for 15 h. The crude product is taken up in vacuo and purified by inantaentaneous chromatography (30% ethyl acetate / hexanes, which gives compound II (2.10 g, 91%) as a white solid XH NMR d (300 Hz, CDC13): 2.96 (s, 3H), 3.71 (e, 6H), 6.20 (d, ÍH, J = 3Hz), 6.34 (d, 2H, J = 3Hz), 6.76 (s, ÍH), APCI-MS m / z 232 (M + H) + .Compound III.To a solution of (CH3) 4NN03 (1.12 g, 7.89 mmolee) in 10 ml of DCM, triflic anhydride is added dropwise The reaction mixture is stirred at 0 ° C for 1.5 h Into a dropping funnel, compound II (1.75 g, 7.51 mmol) is placed in 10 ml of DCM and the solution is added to a nitronium triflate reaction mixture at -78 [deg.] C. The reaction mixture is kept in a -78 ° C for 30 min and gradually warmed to room temperature, stirring for 15 h The reaction is suspended with 50 ml of 5% NaHCO 3, the mixture is stirred for 30 min The aqueous layer is extracted with DCM (3X20 ml). The combined DCM layer is dried over Na, S04. The crude product is purified by HPLC, which provides compound III (250 mg, 11%) as a white solid. lE NMR d (300 Hz, CDC13) 3.03 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 6.32 (d, ÍH, J = 3Hz), 6.88 (d, ÍH, J = 3Hz), 8.31 (s, ÍH). APCI-MS m / z 275 (M-H) -. Compound IV. To a solution of compound III (106 mg, 0.38 mmol) in 2 ml of EtOH are added 20 mg of Pd / C and 1 ml of NH2NH2. The reaction mixture is refluxed for 9 h. The reaction mixture is passed through a pad of Celite. The solution is taken to dryness to provide compound IV as a brown solid (90 mg, 95%). This compound is used directly in the next stage.

Compound 228 To a solution of compound IV (39 mg, 0.16 mmol), 5 - [(3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl] -2-furoyl chloride (60 mg, 0.174 mmol) in 1 ml of DCM is added TEA (44 μl, 0.31 mmol) .The reaction mixture is stirred at room temperature overnight.Short chromatography (30% ethyl acetate / hexanes) provides the Compound 228 (65 mg, 74%) as a white solid H-NMR d (300 Hz, CDC13): 1.04 (m, 12H), 1.45 (m, 4H), 2.09 (s, 3H), 2.71 (s, 3H) ), 3.60 (s, 3H), 3.63 (s, 3H), 3.78 (s, 2H), 5.89 (d, ÍH, J = 3Hz), 6.17 (d, ÍH, J = 3Hz), 6.58 (d, ÍH) , J = 3Hz), 6.85 (s, ÍH), 6.90 (e, ÍH), 6.96 (d, ÍH, J = 3Hz), 7.90 (e, ÍH), 8.24 (s, ÍH). APCI-MS m / z 556 (M + H) +.

Additional examples (NMR) of some compounds are shown below Compound 20 t NMR d (300 Hz, CDC13): 1.26 (m, 12H), 1.66 (m, 4H), 2.28 (s, 3H), 3.82 (s, 6H), 3.96 (s, 2H), 6.04 (d, HI) , J = 6Hz), 6.60 (s, ÍH), 6.62 (s, ÍH), 7.05 (m, 3H), 7.23 (t, ÍH, J = 6Hz), 7.44 (s, ÍH). APCI-MS m / z 462 (M + H) +.

Compound 126 ? E NMR d (300 Hz, DMSO) 2.20 (e, 3H), 2.27 (e, 6H), 3. 71 (s, 6H), 3.98 (s, 2H), 5.93 (d, ÍH, J = 3H), 6.68 (s, ÍH), 6.69 (e, ÍH), 6.86 (d, 2H, J = 3Hz), 7.10 (d, ÍH, J = 3Hz), 7. 23 (t, ÍH, J = 7Hz), 9.04 (e, ÍH). APCI-MS m / z 379 (M + H) +.

Compound 140 'E NMR d (300 Hz, DMSO) 2.28 (s, 3H), 2.32 (e, 3H), 2. 42 (s, 3H), 3.72 (s, 6H), 4.10 (s, 2H), 6.00 (d, ÍH, J = 3Hz), 6.60 (s, ÍH), 6.68 (s, ÍH), 6.71 (s, ÍH), 7.10 (m, 2H), 7. 24 (t, ÍH, J = 6Hz), 9.04 (e, ÍH). APCI-MS m / z 458 (M + H) +.

Compoteto 211 XE NMR d (300 Hz, CDC13): 3.76-3.83 (m, 15H), 4.07 (s, 2H), 5.95 (d, ÍH, J = 3Hz), 6.60 (s, ÍH), 6.57-6.62 (m, 3H), 6.78 (d, ÍH, J = 9Hz), 7.03 (d, ÍH, J = 3Hz), 7.19 (t, ÍH, J = 6Hz), 7.46 (e, ÍH). APCI-MS m / z 428 (M + H) +.

Compoteto 220 * H NMR d (300 Hz, CDC13): 3.72-3.77 (m, 15H), 3.90 (e, 2H), 5.78 (d, ÍH, J = 3Hz), 6.08 (e, 2H), 6.52-6.55 (m, 2H), 6.94 (d, ÍH, J = 9Hz), 7.12 (t, ÍH, J = 9Hz ), 7.39 (e, ÍH). APCI-MS m / z 428 (M + H) +.

Compoteto 226 ? NMR d (300 Hz, CD30D): 2.33-2.48 (m, 12H), 3.84 (e, 6H), 4.19 (s, 2H), 5.81 (d, ÍH, J = 3Hz), 6.73 (d, 2H, J = 9Hz), 7.06 (d, ÍH, J = 3Hz), 7.29 (t, ÍH, J = 9Hz). APCI-MS / z 472 (M + H) +.

Compoteto 231 E NMR 6 (300 Hz, CDC13): 0.67 (t, 3H, J = 6Hz), 1.27 (m, 6H), 1.70 (m, 2H), 3.62 (e, 3H), 3.80-3.83 (m, 6H), 4.02 (s, 2H), 6.02 (d, ÍH, J = 3Hz), 6.60 (d , 2H, J = 9Hz), 6.83 (d, ÍH, J = 3Hz), 7.07-7.19 (m, 4H), 7.43 (s, ÍH). APCI-EM m / z 438 (M + H) +.

Compoteto 232"? NMR d (300 Hz, CDC13): 0.66 (t, 3H, J = 6Hz), 1.23 (m, 6H), 1.54-1.62 (m, 2H), 3.80-3.81 (m, 12H), 4.01 (s) , 2H), 6.00 (d, ÍH, J = 3Hz), 6.81 (d, 2H, J = 9Hz), 6.82 (d, ÍH, J = 3Hz), 7.06-7.28 (m, 4H), APCI-EM / z 468 (M + H) +.

Examples of other compounds containing aromatic portions Synthesis of 5 - (5-cyclohexy 1 - 2 -me t i lbenci 1) -N- (2, 4, 6 trimethoxy-enyl) -2-furamide To a mixture of compounds 1 (5.0 g, 20.3 mmol) and methyl furoate (3.5 g, 20.3 mmol) in 100 ml of nitromethane is added a solution of A1C13 (5.4 g, 40.6 mmolee) in 50 ml of CH3NO, a room temperature. The solution is heated to 70-75 ° C overnight. The dark brown mixture is cooled to room temperature and poured slowly into 300 ml of ice water. The mixture extract with ethyl acetate. The concentrated organic layer is purified by chromatography on silica gel and eluted with hexane / ethyl acetate (15: 1 to 9: 1, v / v) to provide 920 mg of compound 2, which after hydrolysis and coupling with trimethoxyaniline according to the general procedure to provide the compound in good yield. lH NMR (CDC13): s 1.23-1.48 (m, 5H), 1.73-1.86 (m, 5H), 2.31 (s, 3H), 2.51 (m, ÍH), 3.83 (s, ÍH), 4.02 (s, 2H), 6.03 (s, ÍH), 7.44 (s, ÍH), MS (APCI): 464.2 (M + l).

AICI3 CH3N02 or II or OH I Synthesis of 5- (5-acetyl-2-4,4-dimethylbenzyl) -N- (2,4,6-trimethoxyphenyl) -2-furamide A mixture of compound 3 (14 g, 94.4 mmole), methyl furoate (16.4 g, 94.4 mmole) and A1C13 (25 g, 189 mmoles) in 200 ml of nitromethane is stirred and heated at 80 ° C overnight. The mixture is worked and purified by column of silica gel, eluted with hexane / ethyl acetate (9: 1 v / v) to give a mixture of 4 and 5 (3: 1, 16.2 g total). The mixture of 4 and 5 (2.0 g) is hydrolyzed in 2N NaOH / MeOH (1: 1 v / v) at room temperature to give a mixture of 6. and 7, which is recrystallized from acetone and heptane to provide 460 mg Of 6 . Compound 6. (150 mg, 0.55 mmol) is treated with thionyl chloride and coupled with trimethoxyaniline to provide 124 mg of AXC07485. * H NMR (CDC13: s 2.31 (e, 3H), 2.50 (s, 3H), 2.54 (s, 3H), 3.80 (e, 9H), 4.02 (s, 2H), 6.00 (d, lh), 6.16 (s, 2H), 7.08 (s, ÍH), 7.35 (s, ÍH), 7.52 (e, ÍH), EM (APCI): 438.7 (M + l) Synthesis of 5- (5-isopropenyl) -2,4-dimethylbenzyl) -N- (2, 4,6-trimethoxyphenyl) -2-furamide A solution of compound 6. (250 mg, 0.92 mmol) in 5 ml of dry THF at 0 ° C under N2 is added methyl lithium (1.4M in hexanes, 3 equivalents). The solution is stirred at 0 ° C for 3 hours, suspended with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The crude compound is treated with S0C12 and coupled with trimethoxyaniline to provide 36 mg of AXC 07499. * H NMR (CDC13) s 1.80 (s, 3H), 2.06 (s, 3h), 2.11 (s, 3h0, 3.59 (s) , 9H), 3.75 (e, 2H), 4.60 (d, ÍH), 4.95 (d, ÍH), 5.81 (d, ÍH), 5.95 (e, 2H), 6.71 (e, ÍH), 6.79 (s, ÍH), 6.89 (d, ÍH), 7.18 (s, 1H), MS (APCI): 436.2 (M + l).

Synthesis of 5- [(4,6-dimethylthi, 1'-biphenyl] -3-yl) methyl] -N- (2,4,6-trimethoxyphenyl) -2-furamide 12 The Friedal-Crafte reaction of compoteto 9 (10 g, 57. 3 mmole), methyl furoate (12.7 g, 68.7 mmolee) and A1C13 (9.1 g, 68.7 mmole) is carried out in nitromethane at 80 ° C for 2 hours. The solution was poured into 200 ml of ice water and extracted with ethyl acetate. The organic layer is concentrated and purified by column of silica gel eluting with hexane / ethyl acetate (9: 1 v / v) to give a mixture of regioisomers of 10 and 11 (15.5 g) with a ratio of 2: 1. The mixture is hydrolyzed in 2N NaOH / MeOH (1: 1 v / v) to provide a mixture of acid analogues.

The mixture of acid (2.3 g, 7.4 mmol), benzeneboronic acid (1.1 g, 8.9 mmol), [P (Ph) 3] 4Pd, and potassium carbonate (2N, 11 mL) in 20 mL of DMF is heated to 80 ° C during the night. After the aqueous treatment, the residue is passed through a column of silica gel and eluted with a solvent mixture of hexane / ethyl acetate / acetic acid. (7: 3: 1 v / v / v) to provide a mixture of 2 regioisomers which recrystallize from hexane and ethyl acetate to provide 610 mg of 12. Compound 12 is coupled with trimethoxyaniline through a standard or conventional method to provide AXC07468 with good performance.

'H NMR (CDC13): s 2.24 (d, 3H), 2.33 (d, 3H), 3.82 (s, 6H), 3.84 (e, 3H), 4.02 (s, 2H), 6.03 (d, ÍH), 6.18 (s, 2H), 7.06 (s, 2H), 7.12 (S, ÍH), 7.29-7.40 (m, 5H). MS (APCI): 472.1 (M + 1).

Synthesis of 5- [5- (2,2-dimethylpropanoyl) -2,4-dimethoxybenzyl] -N- (2,4,6-trimethoxyphenyl) -2-furamide temp. environment 14 Compound 15. is prepared in two stages in a Friedal Crafte reaction (see general procedure) from step 13. with moderate performance and good regioselectivity. Comet 15 is hydrolyzed and coupled with trimethoxyaniline to provide the compound. E NMR (CDC13): O 1.18 (s, 9H), 3.79 (s, 3H), 3.81 (s, 6H), 3.85 (s, 6H), 3.93 (e, 2H), 6.03 (d, ÍH), 6.15 (e, 2H), 6.45 (e, ÍH), 6.86 (e, ÍH), 7.11 (e, ÍH), 7.40 (S, ÍH). MS (APCI) 512.1 (M + 1).

Synthesis of 5- [(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthalenyl) carbonyl] -N- (2, 4, 6-trimethylphenyl) -2 -furamide and 5- [hydroxy (3, 5, 5, 8, 8-pen tame ti 1-5, 6,7, 8-tetrahydro-2-naph taleniDmethyl] -N- (2,4, 6-trimethoxy-enyl) -2-furamide 19 20 A mixture of compound 19 (9.0 g, 27.5 mmol) and Mn04 (8.2 g, 82.7 mmol) in a mixture of chloroform and dichloroethane is heated at 70 ° C overnight. After aqueous treatment, compound 2.0 per column on silica gel and eluting with hexane / ethyl acetate / acetic acid (90: 10: 1 v / v / v). AXC07042 is obtained by the general procedure of amide bond formation. 1 H NMR (CDC13): s 1.26-1.31 (2s, 12H), 1.70 (e, 4H), 3.81 (e, 6H), 3.83 (e, 3H), 6.18 (s, 2H), 7.05 (d, ÍH) , 7.22 (s, ÍH), 7.29 (d, ÍH), 7.52 (s, ÍH), 7.68 (e, ÍH). MS (APCI): 506.2 (M + 1). 50 mg of compound are treated with 1.5 equivalent of NaBH 4 in 2 ml of ethanol and 0.5 ml of diethyl ether. The solution is stirred at room temperature for 1.5 hours, quenched with water and extracted with ethyl acetate. The organic layer is concentrated to provide the compound as a white solid. 'E NMR (CDC13): s 1.24, 1.28, 1.29 (3s, 12H), 1.66, 1.67 (2e, 4H), 2.29 (e, 3H), 2.55 (d, ÍH), 3.80 (s, 6H), 3.82 (s, 3H), . 98 (d, ÍH), 6.17 (s, 2H), 7.08, 7.10 (2s, 2H), 7.38 (s, ÍH), 7.41 (S, ÍH). MS (APCI): 508.2 (M + 1).

Synthesis of 5- (5- { L- [(ethylamino) carbonyl] cyclopropyl.} -2-methylbenzyl) -N- (2,4,6-trimethoxyphenyl) -2-furamide A1C13, CH3N02 22 23 A solution of 22 (2.0 g, 11.3 mmol) in 8 ml of thionyl chloride is heated at reflux for 3 minutes. Unreacted thionyl chloride is removed by rotary evaporator. The concentrated residue is dissolved in CH2C12. To this solution is added excess ethylamine to provide 1.3 g of compound 23 .. The compound is converted to AXC07555 by 3 steps (Friedal Crafts reaction, hydrolysis and amide bond formation) as prescribed in the general procedures. tE NMR (CDC13): s 0.94-1.02 (m, 5H), 1.59 (m, 2H), 2.34 (s, 3H), 3.17 (c, 2h), 3.80, 3.81 (2s, 9H), 4.01 (s, 2H), 5.39 (d broad, ÍH), 6.01 (d, ÍH), 6.17 (9s, 2H), 7.11 (d, ÍH), 7.21 (m, 2H), 7.31 9s, ÍH). MS (APCI): 493.2 (M + 1).

Additional examples twenty A useful intermediary can be prepared as follows: Preparation of methyl-5- (chloromethyl) -2-furoate H20 > 99% Necessary materials Detailed procedure for a scale batch of 2.88 moles of methyl 5- (chloromethyl) -2-furoate (2) A 3-neck round bottom flask of 12 1 (r.b.) is equipped with an addition funnel, - an euperior electric heater; a thermocouple; and an ice bath (a nitrogen atmosphere is recommended, although it is not necessary in a necessary way) - 2.2 1 of DCM are charged to r.b. followed by 2.2 1 of concentrated HCl (no significant exothermic reaction observed, doe layers are formed) Agitation is started (proper mixing of both phases is ensured) - 1.1 1 of H2SO4 is charged to the addition funnel as space allows . The reactor is cooled to 0-10 ° C. The addition of sulfuric acid to droplets is initially started until an exothermic reaction occurs (approximately 1/2 addition) and then the rate of addition to a light vapor is increased (keeping the temperature below 20 ° C for safety purposes). ). The cooling bath is changed to a water bath at room temperature (this will act as a re-coating for the subsequent addition without significantly decreasing the reaction rates) 0.371 kg of methyl 2-furoate are charged at r.b. in a portion (no exothermic reaction, green / coffee solution). 0.520 kg in ZnCl2 are loaded in many portions 5 (some bubbling is carried out by HCl gas, the exothermic reaction is controlled by the water bath). 0.731 1 of formaldehyde is charged to rinse the addition funnel. They are added to the reactor for 2.5-3.5 hours (room temperature is maintained by a water bath, slow addition results in few polymerization reactions between "free" formaldehyde). It is stirred overnight at temperature atmosphere. When the reaction is completed by CCD (see below) by dripping the aqueous layer. The organic layer is filtered through a 0.550 kg silica plug (dry packed, approximately 10 cm thick). It is eluted with approximately 4 1 of DCM until no additional product is separated as indicated by CCD (the assurance of this stage is carried out with proper ventilation, since they will still be present some acid vapors, even in the filtrate). It is concentrated to give an oil that varies in color from yellow to brown (approximately 0.5 1). An equal amount of DCM is charged, approximately 0.5 1. It is washed with 2 x 0.2 1 of distilled water. The organic layer is then washed with 0.05 1 of saturated NaHCO 3 in 0.15 1 of distilled water (a pH of 7-10 is assured, there is no significant loss of product in the aqueous layer). The aqueous layer and the dried organic material are dripped with Na 2 SO 4. It is filtered through 0.05 kg of silica (approximately 5 cm of thickness). It is eluted with DCM haeta that no additional product is separated. It is concentrated by rotary evaporation using home vacuum. Oil is then placed in the high vacuum pump overnight (yellow to light brown oil) Performance range: 95-100% Purity range: 95-98% (HPLC A%) Additional comments Visual: The reaction is monitored by CCD (254 nm) using EtoAc 30% / hexanes (r.f. initial material - 0.52, r.f. product - 0.40). CLAR: TFA method (method and annexed spectrum). Initial material retention time = 12.67 min, product retention time = 17.37 min. NMR:? E (CDC13) (attached spectra) 3.93 (s, 3H), 4.63 (s, 2H), 6.52 (d, ÍH), 7.18 (d, ÍH). If the reaction has not been completed, you can add every 4 hours and 10% of the original volume of formaldehyde. The effects of temperature have not yet been studied extensively, but it has been convenient to maintain container temperatures at the intervals specified for each stage. The vapors of acid present in the organic layer and even after filtration make handling outside the smoke hood problematic, so caution should be exercised when transferring material outside the hood, until the pH is neutralized. If the rate of formaldehyde addition is increased, the formation of polymers will prevent the reaction from being terminated due to formaldehyde consumption. The arrangements with the safety department must be made before the beginning of this process so that arrangements are made to accommodate the large volumes of acid that are discarded in the aqueous layer that may be produced. The Neutralization of the aqueous acid layer requires large volumes of base, produces a considerable exotherm and requires a prolonged addition period, and is therefore not recommended. The final product must be kept cold, so there is no stability data of this product available. Keeping the product in a Nalgene container at -20 ° C causes the product to crystallize, slightly darkening the material, but seems to have no effect on subsequent reactions using this material. The compounds of the present invention may be useful for treating: 1. cancers / hormone-dependent tumors 2. hormone-independent cancers / tumors by direct interactions 3. use in other mechanisms of action It is considered that the invention of the applicants includes many other modalities which are not specifically described in the foregoing, as a consequence, this description should not be read as limited by the foregoing examples of the preferred embodiments. The following compounds have been developed as discussed in the above. Some properties of some of the compounds have been measured using techniques discussed above. S% R is the remaining substrate. The closer it is to zero, Z% R, the closer it is to 100% inhibition. t L? or o (1 t to H L? or L? or L? t H H L? or L? OR t to Lp or L? or L? to M L? o o t to H L? or L? to to L? or L? to t L? or o (l t to L? or t to L? or o L? to to L? or O L? Or O L? t t L? or L? L? o o Lp or L? or L? L? oo t to L? or o L? t \ J o l-1 L? Or L? O p 00 to t L? or L? to H H L? Or Ui or L? t t L? or o L? to H ui or Ul L? to to Lp or L? or L? t to H H L? or ui O to H L? or ui ui to t H ui or ui o l to H H L? or L? or to to H ui o? i ui to H L? o o to to H u? or o L? to to L? or o L? to Ul or L? to H H u? or L? or Lp to H L? O ui O to H H u? or Ul O L? to? o L? or L? L? to H L? o o to H H Lp O Ul O Ul to t H ui or Ul o ui NJ to L? o o ui to H L? Or L? Ul to t H ui o L? or L? t to L? O l to to L? o o i to t Ul or L? or L? NJ tO H Ul O L? L? t to Ul o o t L? or o L? NJ NJ H L? or L? L? NJ NJ Ul O O Lp NJ NJ Ul O O L? NJ NJ H Ul O Ul NJ NJ H Ul O L? L? NJ NJ Ui or NJ NJ H Lp or Ul u? NJ NJ H M Ul O Ul O to NJ l-1 Ul O Ul O NJ NJ H L? or Ul L? NJ NJ H H u u? or Ul Oui to NJ L? O Lp NJ NJ H Ul O Ul Ul NJ NJ H -1 Ul O Ul or L? t NJ ui O Ul O NJ oo NJ NJ H L? o O ui NJ NJ H L? or Ul O L? NJ NJ Ul O O Ul to NJ L? or Ul Ul NJ NJ L? or L? or NJ NJ H Ul O Ul O to NJ Ul O O L? NJ NJ L? or L? NJ NJ Ul O O NJ NJ u? O O NJ NJ H L? o Lp Ul NJ NJ Ul O L? NJ tp NJ NJ Ul O L? L? Compound No. bGnRH IC50 (nM) IrGnRH IC50 (nM) ImGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 11 320 50 Antagonist 22 NJ L? NJ 17101 310 1100 23 28301 730 2100 Antagonist NJ to L? O ui or ui Compound No. IbGnRH IC50 (nM) rGnRH IC50 (nM) JmGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 27 28 NJ L? OJ Compound No. bGnRH IC50 (nM) jrGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 24 I; 7601 1 501 560 25 NJ L? 940 260 950 26 to NJ L? o o Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) ImGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 29 NJ L? L? . 5 NJ NJ H Ul O Ul Ul NJ L? NJ NJ L? o o NJ L? NJ NJ H Lp or Ul O Ul Compound No.! bGnRH IC50 (nM). rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 37 37. 5 NJ? oo 38 NJ NJ H L? L? or L? to NJ H ui O L? L? NJ NJ H Ul O L? NJ NJ NJ NJ H L? o Ul O NJ NJ H Ul O L? ui NJ NJ H Ul O L? Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 58 59 NJ L? 60 17 670 30 80 NJ NJ H H Ul O Ul O Ul Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 18 * " 460 40 115 19 605 60 160 NJ- 61 NJ NJ Ul O Lp o Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 62 twenty DO NOT 130, 20 Antagon? Sta (rat) 9 (rat) 63 to NJ Lp O to NJ L? or? or ui bGnRH IC50 (nM) TrGnRH IC50 (nM) ImGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 1 160 N (Ti VO 890 1010 NJ NJ L? or L? or Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 70 43 Antagonist (rat) 8 (rat) 71 NJ O 72 1440, 84 85 NJ NJ H Ul O Ul Oui Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 77 8450 78 1 300 79 NJ NJ 370 80 5610 to NJ H L? or u? to NJ H H L? or L? or Compound No. bGnRH IC50 (nM) | rGnRH ICdOTnM) f mGnRH IC50 (nM) Functional JGnRH GnRH Kb (nM) 85 > 10000 86 NJ 510 NJ NJ L? or Compound No bGnRH IC50 (nM) rGnRH 1C50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 86 5 2050 NJ 87 IU 2340 ' NJ to L? or Lp NJ NJ L? o o Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 92 27 42 93 NJ - ^ 1 5470 NJ NJ I-1 Ul O or Ul NJ NJ H H Ul O Ul O Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 95 60 21 96 NJ 90! 1 30 VO 97 1690 NJ NJ Ul O L? UI NJ NJ H Ul L? NJ NJ H Lp O u? OR Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 104 1 260 105 NJ 00 N) 250. 200 106 510 t NJ L? OR NJ NJ H L? or L? UI NJ NJ H L? or L? or L? Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 113 300 114 NJ 00 7000 L? 115 5130 NJ NJ H Lp or Ul o Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 118 430 119 NJ 00 1300! to NJ Ul O Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 120 > 10000 1 21 NJ 00 00 122 1 260 NJ NJ H Ul O Lp O L? Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 123 124 NJ 00 VD 750 125 560 1050 NJ NJ H ui O L? or L? to NJ L? O ui Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 129 1 390 130 590 131 NJ vo 1 32 NJ NJ H L? or L? or L? oQ ost No ^ bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 133 134 NJ Antagonist 13 (rpH) 13 (hPI) VO NJ 135 to NJ Ul O Ul O L? Compound No. bGnRH IC50 (nM) IrGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 136 4. 7 8.6 Antagonist 6.3 &8rataPl, pH 137 NJ VO oo 4001 360 138 1630 1570 139 113 150 Compound No IbGnRH IC50 (nM rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 142 l 143 NJ vo L? 144 NJ NJ H ui O L? OR Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 145 146 NJ VO < 7? 147 NJ to Ul or L? or ui NJ NJ L? o o NJ NJ H Ul O Ul O Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 155" 156 NJ 270 400 vo VO 157 NJ NJ H L? or Ul ui Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 158" 159 oo o o 16 160 NJ NJ H Ui or O Ul NJ NJ Ul O Ul Ul 00 or NJ NJ NJ L? or L? Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 167 168 00 or oo 130 130 169 Antagonist 117 (rat) NJ NJ H H L? o Ul O NJ NJ H L? or L? NJ NJ H L? O Ul Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 175 176 00 o 177 . 7 7.3 Antagonist! 9 (rat) NJ NJ H L? o Ul O NJ NJ H Ul O Ul O Ul Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 182 183 27 Antagonist 11 0 (rat) 00 or 184 oo 185 250 270 NJ NJ Ul O O L? t NJ Ul O Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 1 89 190 i oo I-1 or 190 5 I NJ NJ Lp O L? or NJ NJ H L? or L? or u? Compound No. IbGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 197 i 198 i oo r- > 00 I 199 96l 15! NJ NJ H Ul O L? Or L? Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 200 2 8 13 Antagonist 0.9 nM (rat) 200.5 i oo 4-. I 201 NJ NJ H Ul O Ul O Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 202 203 i oo L? I 58 62 204 NJ NJ Ul O O Ul NJ NJ L? or Ul or ui Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 208" 209 i 00 I-1 -J I 210 NJ NJ L? or ui o Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 212 i oo 00 I 12! 62 NJ NJ H L? o o Lp Compound No bGnRH IC50 (nM) | rGnRH IC50 (nM) | mGnRH IC50 (nM) | Functional GnRH GnRH Kb (nM) 21 3 i LO VO I 214 NJ NJ Ul O Lp or u? Compound No. bGnRH IC50 (nM) IrGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 21 5 ~ 216 oo N) O 217 21 1 1 NJ J H H L? or L? or Lp Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) ImGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 218 219 oo NJ 220 NJ NJ L? or ui ui to NJ H ui O O Compound No. bGnR rC50 (nM) | rGnRH IC50 (nM) jmGnRH IC50 (nM) | Functional GnRH GnRH Kb (nM) 223 224 00 NJ 00 NJ NJ H L? or Lp ui NJ NJ Lp or Ui O ui Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 228 57 14 229 oo NJ L? 230 NJ NJ H1 Ul O L? OR Compound No. bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 231 51 24 232 oo NJ (Ti 7 233 51 68 NJ NJ H L? or L? L? Compound No bGnRH IC50 (nM) rGnRH IC50 (nM) | mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 234 235 oo NJ | 236 NJ NJ L? Or O L? 00 NJ 00 NJ NJ L? o Ul o CojTfuestc ^ Nc bGnRH IC50 (nM) rGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 3. 1 301 00 NJ 381 vo 302 220 1 19 Compound No. bGnRH IC50 (nM) IrGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) 303" 304 oo 00 o AXC07047 NJ NJ I-1 Ul O L? or Compound G bGnRH IC50 (nM) IrGnRH IC50 (nM) mGnRH IC50 (nM) Functional GnRH GnRH Kb (nM) AXC06675 2800 AXC07450 oo oo AXC07350 NJ NJ Ul O Ul O L? C mpuest ^ No. 5-HT7 Ki (nM) [5-HT2a Ki nM) | D2 DA Ki JnM) ^ | lL8 IC50 (nM] NPY Y1 IC50 (nM) 9 ^ oo LO NJ! 12701 12001 550 6400¡ 97001 21 NJ NJ L? or NJ NJ H L? or L? O ui NJ NJ H H Ul O Ul O l Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 27 28 oo 00 op NJ NJ H Lp or Ul O Compound No. 5-HT7 Ki (nM) | d-HT2a Ki (nM) | D2 DA Ki (nM) | IL8 IC50 (nM) NPY Y1 IC50 (nM) 29 00 oo (Ti . 5 t to H L? or ui or ui NJ NJ H L? O Ul O Compound No 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 1 3 > 4400 > 3200 > 10000 > 10000 34 oo oo 00 36 NJ NJ u? or o L? Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) D2 DA Ki (nM) l lL8 IC50 (nM) NPY Y1 IC50 (nM) 38.5 39 LO * - O 40 NJ NJ Ul O Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) | D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 41 42 oo 4-. 43 44 NJ to L? or o L? Na compound 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 45 46 47 00 ¿> NJ 48 > 4400 > 3200 > 10000 > 10000 Compound No. 5-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 ICdO (nM) 14 49 00 50 oo 51 NJ NJ H Ul O Ul O Compound No 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 52 53 00 64 1 6 NJ NJ H I-1 L? or Ul O L? NJ NJ L? or Lp Ui NJ NJ H L? or Ul ui Compound No. d-HT7 Ki (nM) | d-HT2a Ki (nM) I D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 ICdO (nM) 18" 19 oo 4 61 NJ NJ Ul O L? L? Compound No. 5-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 62 twenty oo oo > 4400 > 3200 > 10000 > 10000 63 NJ NJ H H L? o Ul O NJ NJ H L? or ui O L? Compound No. 5-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 ICdO (nM) 67 68 oo op O 69 NJ NJ H Lp O L? L? Compound No; d-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 70 71 Lp 72 to NJ M ui or Ui O L? Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 73 73 oo Lp NJ 75 76 NJ NJ Lp or Ul Ripposed No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 77 78 00 VJ1 00.

NJ NJ H Ul O Ul Compound No. 6-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 81 82 oo L? NJ NJ H u? O Ul Ul oo op L? NJ NJ H L? o o Compound No. 6-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 86. d 00 op 87 (Ti 88 NJ NJ Ul O L? NJ NJ Ul O Ul L? NJ NJ H Ul O L? NJ NJ L? or ui Compound No. 5-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 95 96 oo (Ti O 97 to NJ u? or L? L? NJ NJ H L? o Ul o 00 (Ti NJ oo (Ti 00 106 NJ to H Ul or L? L? NJ NJ H L? or L? ui NJ NJ H L? or L? Ui Compound No. 5-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 IC50 (nM) 113 114 oo (Ti 115 NJ NJ Lp or O Ul oo n NJ NJ L? o o oo < n oo NJ NJ H L? or Ul O L? Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 120 121 OJ (Ti VO 122 NJ NJ H H1 u? or L? O Lp Compound No. 5-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC60 (nM) NPY Y1 IC50 (nM) 123 1 24 00 or 125 NJ NJ L? o Ul O Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) | D2 DA Ki (nM) IL8 ICdO nM) NPY Y1 IC50 (nM) 126 127 oo 128 NJ NJ u? Or L? or L? 00 NJ NJ NJ H L? or o L? Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 133 134 oo > 4400 3720 2400 00 135 NJ NJ Ul O Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) [D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 136 2400 160 137 LO 4 ^ 138 139 NJ NJ H L? or L? UI 00 L? NJ NJ H L? or L? or Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 142 143 OJ (Ti 144 f NJ NJ H L? or L? Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 145 146 oo 147 NJ NJ Ul O L? or NJ to H H Ul or Ul O L? 00 vo NJ NJ L? or L? OO 00 o NJ NJ H L? or L? or L? Compound No. 6-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 1 58 1 59 oo 00 160 NJ NJ Lp or Lp L? 00 00 NJ NJ NJ H Ul O Ul O Ul oo oo Oo NJ NJ Ul O L? NJ NJ H H Ul O Ul O Ul (Compound No 5-HT7 Ki (nM) | 5-HT2a Ki (nM) | D2 DA Ki (nM) | lL8 IC50 (nM) NPY Y1 IC50 (nM) 170 171 oo oo L? 172 NJ NJ H Ul O L? ui 00 00 < t > NJ to H Lp or Ul or L? NJ NJ Lp O Compound No. 5-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 178 179 oo oo oo 180 181 NJ NJ H Ul O Ul O Compound No ld HT7 K? (nM) | d HT2a Ki (nM) I D2 DA Ki (nM) | lL8 IC50 (nM) NPY Y1 IC50 (nM) 182 183 00 00 vo 184 185 NJ NJ L? or L? or Compound No. 5-HT7 Ki (nM) d-HT2a Ki (nM) I D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 186 187 oo vo o 188 NJ to l- > L? or ui or ui (Compound No ld-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 189 190 oo vo 190. 5 NJ NJ Lp or u? or ui Compound No. d-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 191 1 92 oo vo NJ 193 to NJ ui O? i or L? Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 1 94 1 95 - oo J oo ag NJ NJ Lp or Lp 00 vo NJ NJ H Ul O L? O ui Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) | D2 DA Ki (nM) | lL8 IC50 (nM) NPY Y1 IC50 (nM) 200 200. 5 oo vo op 201 Compound No. 6-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC60 (nM) NPY Y1 IC50 (nM) 202 203 oo vo si 204 NJ NJ Lp or ui Compound No. 5-HT7 Ki (nM) | 5-HT2a Ki (nM) D2 DA Ki (nM) | IL8 IC50 (nM) NPY Y1 IC50 (nM) 205 206 oo vo ^ j 207 NJ NJ L? or Ul Compound No 5-HT7 Ki (nM) d-HT2a K? (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 208 209 OJ VD 00 210 NJ NJ Ul O O Ul Compound No 6-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 ICdO (nM) 211 212 oo LO THE NJ NJ L? or ui O Ul Compound No d ~ HT7 Ki (nM) | d-HT2a ~? 7 (nM) D2 DA Ki (nM) 111_8 ICdJj nM) NPY Y1 IC50 (nM) 213 4-. O O 1214 NJ NJ L? or Ul Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 215 216 s 217 NJ J H L? or o L? Compound No 6-HT7 Ki (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 21 8 219 O NJ 220 o LO to NJ H u? O Ul Oui NJ NJ Ul O Ul Ul Compound No. _ J 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 IC50 (nM) 225 226 O Ln 227 NJ NJ Ul Ou? or L? Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 228 229 s? 230 NJ NJ H Lp or Lp or Ui NJ NJ H H ui O Lp O Ul Compound No. 5-HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 ICdO (nM) 234 235 4 »O 00 236 NJ NJ L? or ui or L? Compound No d HT7 Ki (nM) 5-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 IC50 (nM) 237 238 or 299 vo to NJ H H ui O u? O Ul Compound No d-HT7 Ki (nM) | d-HT2a Ki (nM) D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 300" 301 i * l-1 O I 302 to NJ h-1 Lp O Ul O L? Compound No. d-HT7 Ki (nM) Td-HT2a Ki (nM) I D2 DA Ki (nM) IL8 ICdO (nM) NPY Y1 ICdO (nM) 303 304 i 4 * AXC07047 NJ NJ H Ul O L? or Compound No! D-HT7 K? (nM) d-HT2a Ki (nM) D2 DA Ki (nM) IL8 IC50 (nM) NPY Y1 ICdO (nM) AXC0667d ~ AXC07460 i * h-1 NJ AXC07350 I NJ NJ H H ui O L? OR Compound No. Glucagon IC50 (nM) GLP-1 IC50 (nM) 11 3200 '> 10000 i 22 I 2. 3 NJ NJ Ul O Lp ui Compound No. i Glucagon IC50 (nM) [GLP-1 IC50 (nM) 24 i 4 = > (- • L? I 26 NJ NJ L? or Ul ui Compound Not ÍGlucagon ICdO (nM) 'GLP-1 IC50 (nM) 27 28 i 4 ^. I-1 in i L? or Ul O L? Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 29 i 4-. t-1 I . 6 NJ NJ H L? or Ul NJ NJ Ul O Ul O Ul I VO I Compound No. Glucagon ICdO (nM) GLP-1 IC50 (nM) 37 37.5 NJ O 38 NJ NJ L? or Ul L? Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 38. d 39 40 NJ NJ H L? or L? or L? Compound No. Glucagon IC50 (nM) lGLP-1 IC50 (nM) 41 42 43 4-. NJ NJ 44 NJ NJ H ui O Ul O ui Compound No. Glucagon IC50 (nM) GLP-1 IC50 (nM) 45 46 4 NJ 47 OJ 48 6300 | > 10000 NJ NJ H Lp or Ul NJ 4-.

NJ NJ Ul O O Lp Compound No. Glucagon IC50 (nM) GLP-1 ICdOjnM) 52 d3 54 NJ L? fifteen NJ NJ H L? or ui O L? NJ NJ H Ul O Ul Ul Compound No. Glucagon IC50 (nM) lGLP-1 IC50 (nM) 58 59 NJ 60 17 to NJ H L? or L? Compound No. Glucagon ICdO (nM) lGLP-1 IC50 (n ~ M) 18 19 NJ 00 61 NJ NJ H Ul O Ul O L? 4-. NJ VO NJ NJ H Ul O Lp or L? NJ NJ H Ul O Ul L? Compound No. Glucagon ICdO (nM) [GLP-1 ICdO (nM) 67 68 ^ OO 69 NJ NJ L? or L? L? NJ NJ H Ul O Ul ui NJ NJ Lp O NJ NJ H H Ul O Lp O L? Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 81 82 ^ OJ 83 L? 84 NJ NJ H -1 L? or L? O Lp Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 86 86 4- > LO in to NJ H -1 ui Ul O Ul (Compound No. Glucagon ICdO (nM) lGLP-1 ICdOJnM) 86. d " 4-. LO ^ 1 87 88 NJ NJ Lp O H Ul H O ui Oo 00 NJ NJ H H Lp O Ul O Ul 4 ^ 00 LO NJ NJ ui O O ui Compound No. Glucagon ICdO (nM) [GLP-1 ICdO (nM) 94 94. 2 O 94. d NJ NJ H L? or? or ui NJ NJ H L? or L? or L? Compound No. Glucagon ICdO (nM) JGLP-1 ICdO nM) 101 102 00 103 NJ NJ H Ul O L? or L? Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 104 106 * 4-. 4-. 106 NJ NJ Ul O H L? O ui 4-- L? NJ NJ H Ul O L? O ui Compound No. Glucagon ICdO (nM) μ3LP-1 Cd0 (nM) 110 111 in 112 NJ NJ Ul O Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 113 114 4-. 115 NJ NJ H Ul O Ul O Ul NJ NJ L? or L? Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 118 119 4-. VO NJ NJ Ul O Ul Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 120 121 ^? OR 122 NJ NJ H H L? or ui O L? Non-Glucagon Compound IC50 (nM) [GLP-1 ICdO (nM | 123 124 IU 1125 NJ NJ Ul O L? or NJ NJ L? O Ul ui NJ NJ H Ul O L? or L? Compound No. Glucagon IC50 (nM) lGLP-1 IC50 (nM) 133 134 L? 4-. 13d to NJ L? or Non-Glucagon Compound ICdO (nM) GLP-1 ICdO (nM) 136 137 4 L? L? 138 139 NJ NJ H L? O ui L? Compound No. Glucagon IC50 (nM) GLP-1 IC50 (nM) 140 141 4- »L? (YOU NJ NJ Ul - 'O L? or Lp Non-Glucagon Compound IC50 (nM) GLP-1 IC50 (nM) 142 143 L? 144 NJ NJ Ul O L? or L? NJ NJ H Lp O L? Or L? vo 151 NJ NJ Lp O Ul ui Compound No. Glucagon ICdO (nM) GLP-1 IC50 (nM) I52 ^ 153 *. < do not 154 NJ J L? or Ul u? Non-Glucagon Compound IC50 (nM) (GLP-1 IC50 (nM) 155 156 4-. in 157 Compound No. Glucagon IC50 (nM) GLP-1 IC50 (nM) 1d8 169 (Ti NJ 160 NJ NJ H H ui O Ul O L? NJ NJ Ul O Ul O NJ NJ Ul O L? Compound No. Glucagon ICdOJnM) GLP-1 ICdO (nM) 167 168 4-- 169 NJ NJ Ul O L? Compound No. Glucagon ICdO (? "MT ~ [GLP-1 ICdO (nM) 170 171 . s-? in 172 NJ NJ L? or L? O Ul Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 173 l 174 I I | 4 »C7 I NJ NJ H L? or Ul Ul Compound Non-Glucagon ICdO (nM) GLP-1 ICdO (nM) 17d i. 176 in oo 177 NJ NJ L? or Compound Non-Glucagon IC50 (nM) GLP-1 IC50 (nM) 182 183 OR 184 185 NJ to L? or Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 186 187 4-. 188 NJ J H L? or ui L? NJ NJ NJ Ul O Ui L? 00 NJ NJ Ul H O O L? NJ NJ Ul O L? 4-. L? NJ NJ Ul O L? L? Compound No. Glucagon IC50 (nM) | GLP-1 IC50 (nM) 200 200. 5 - > 201 NJ NJ H Ul O Ul Non-Glucagon Compound ICdO (nM) GLP-1 IC60 (nM) 202 203 Four . 204 NJ to H H L? or L? or ui Compound No. Glucagon ICdO (nM) | GLP-1? _] C50JnM) 20d 206 4 -J 00 207 NJ NJ H Ul O L? or Compound No. Glucagon IC60 (nM) l GLP-1 IC60 (nM) 208 209 4 ^ ^ J VO 210 NJ NJ L? or L? L? to to L? o o ui Compound No ^ Glucagon ICdO (nM) IGGL-1 ICdO (nM] 213 4". oo 1214 NJ NJ H L? or Ul ui Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 21 d 216 4- > 00 NJ 217 NJ NJ H H Ul O L? Or L? Compound No. Glucagon ICdO (nM) JGLP-1 ICdO (nM) 218 219 4-. oo LO 220 NJ to H L? or L? or NJ NJ Ul O O Ul Compound No. Glucagon ICdO (nM) [GLP-1 ICdO (nM) 22d 226 oo in 227 NJ to Lp O Ui Ul Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 228 229 4 ^ 00 230 to NJ H L? or L? Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 231 232 00 oo 233 Compound No. iGlucagon ICdO (nM) GLP-1 ICdO (pM) 234 23d 4-. 00 VO 236 NJ NJ H L? or L? UI NJ NJ Ul O Ul Compound No. Glucagon ICdO (nM) GLP-1 ICdO (nM) 300 301 4-. VO 302 Compound No. Glucagon ICdO (nM) GL.P-1 ICdO (nM) 303 304 VO NJ AXC07047 This table shows the bioavailability of the compoteto according to the invention. The properties were determined using the method previously described. The table is in two parts.

NJ NJ H L? o Lp O 4- > VO 4 NJ NJ H H L? or L? or ui NJ NJ L? or L? NJ NJ H H Ul O ui O ui NJ NJ H L? or O Ul NJ NJ H H Lp or Ul O Ul fsi r-l oo i vnl NJ NJ H Ul O Ul Lp O vo NJ NJ H H L? or L? Or L? No. Female rat Dog Mono pmol min mg 1/2 p.o. pmol 'tilin mg p ol min mg 1 μM μM 1 μM 1 μM eleven i Ul 23 O I 12 13 38 1.9 h NJ NJ H Lp O Ul Oui 109 126 19h 002 30 min '2% (10 mg / kg) 1 i Ul L? I 134 94 17h 231 24% (20 mg / kg) 1 2159 9277 136 271 32h 024 25h 8% (20 mg / kg) 1 3071 5959 137 182 79h 023 1 li 1% (10 mg / kg) ' NJ NJ H Ul O O Ul I L? < t > I fifteen twenty NJ NJ H L? or ui 170 176 i L? oo I 177 2456 3120 181 139 1.9 h 3.64 4 h 59% (20 mg / kg) ' NJ NJ H Ul O Ul Ul 182 3.2 h 1 1 1.5 h 33% (10 mg / kg) 183 64 3.6 h 0.51 I h 37% (10 mg / kg) i L? I-1 vo I 188 185 224 NJ NJ H Ul O ui O 190. 5 194 205 L? NJ or 199 181 1.5 h 0.08 4h I0% (10mgkg) ' 200 86 2.0 h 0.96 1.5 h 3% (10 mg / kg) ' NJ NJ H L? or O Ul 201 2.5 h 1.9 30 min 21% (10 mg / kg) 206 730 L? NJ 207 159 1.6 h 2.81 1 h 41% (10 mg / kg) '212 430 1.6 h 0.05 lh!% (! () Mg / kg)' NJ NJ H L? or L? ? L? NJ NJ NJ NJ Ul O Ul 226 173 4.6 h 0.42 1 -5 34% (10mg / kg) ' 228 227 2.4 h 0.07 0.5 h 2% (l () mgkg) L? NJ THE 233 338 1.4 h 0.34 1 h 34% (10 mg / kg) '299 2.4 h 1.74 1 l? 72% (10mg / kg) ' NJ NJ H Ul O L? ui 300 21 h 036 1 h 10% (10 mg / kg) 'No. L? NJ 134 Fpo f? E0%) The following compounds have been developed and tested using the procedures discussed previously. The data are in two parts and show the binding of a compound to a receptor. • - twenty - - • - • - - - - - - - - - • - - - - - - - - - - - - - - - - - - - • - • - - - - - • - • - - • - - - - - - - • - • - - - - - - - • - - - - - - - - - - - - - • - - - - - - - - - - - - Molecular Structure% Inhib @ luM hGnRH Repetitions @ 1uM hGnRH 40 49 57 58 86 93 - - 26 26 20 24 15 - - 27 31 62 67 50 62 - - 38 41 86 90 52 54 75 92 47 52 49 50 - - - - 57 64 18 -21 -23 33 89 - - -12 -9 83 86 63 64 66 76 83 84 24 35 -22 -25 -34 -38 -4 55 60 22 28 80 90 • - 25 -17 -31 -11 -8 32 44 - - 42 -3 32 36 71 76 100 101 -16 -2 - - 79 91 -12 14 12 59 60 70 72 17 26 26 - - 89 92 82 85 41 -10 -12 31 42 72 72 51 54 36 - - 61 71 -18 -25 -4 - - - - 52 52 68 71 19 29 53 64 21 69 71 78 84 17 20 53 58 -4 -14 -24 -18 24 26 34 -40 17 -6 16 -15 -20 62 -10 -9 11 16 • - 93 95 10 11 15 • - - - - - Molecular Structure% Inhib. @ 10uM mGnRH 82 103 1 01 71 104 65 94 99 Chiral 89 102 86 82 73 96 66 58 34 43 74 91 66 100 97 49 44 51 103 75 98 61 102 17 96 31 98 63 twenty 96 31 33 79 88 53 72 84 56 72 81 73 28 58 91 76 80 74 30 87 2014 27 42 93 102 57 65 83 94 91 91 98 57 48 47 39 93 79 44 65 77 52 96 92 15 20 25 Molecular structure I-06- - - - - - fi - 20 25 Molecular structure fivfiH.

- - CH, - - - - - - - - - - - - - - - • - - - - • - • ooet- S -frozt- - - - H.H -esst- Molecular Structure% of Inhib. @ 10uM hGnRH repetitions @ 10uM hGnRH 89 94 38 32 1 7 18 12 -13 11 23 39 51 41 14 18 99 95 102 96 101 95 38 43 110 91 20 71 63 12 10 13 22 22 12 13 13 14 15 17 28 18 26 18 50 54 13 14 17 fifteen 72 68 17 12 23 39 49 -8 18 14 21 18 90 92 29 42 24 16 42 46 21 22 91 77 36 23 29 43 54 52 108 102 103 102 99 95 25 33 18 52 55 24 22 12 19 34 100 92 101 86 22 30 62 79 48 57 18 23 22 24 25 12 24 21 103 96 19 23 27 20 80 90 30 32 67 67 14 17 22 24 44 47 36 38 -52 -56 17 23 59 60 45 52 19 42 46 56 59 57 61 31 33 34 38 20 24 97 98 87 89 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

1. Having described the invention as above, the content of the following claims is claimed as property: 1. A compound having a formula that is selected from the group consisting of: or a pharmaceutically acceptable salt, multimer, precursor or active metabolite thereof.
2. 2. A compound having a formula characterized in that it is selected from the group consisting of: or a pharmaceutically acceptable salt, multimer, precursor or active metabolite thereof.
3. A compound characterized in that it has the formula: or a pharmaceutically acceptable salt, multimer, precursor or active metabolite thereof.
4. 4. A compound characterized in that it has a formula that is selected from the group consisting of: or a pharmaceutically acceptable salt, multimer, precursor or active metabolite thereof.
5. 5. A compound characterized in that it has the formula: or a pharmaceutically acceptable salt, multimer, precursor or active metabolite thereof.
6. 6. A compound characterized in that it has a formula that is selected from the group consisting of: or a pharmaceutically acceptable salt, multimer, precursor or active metabolite thereof.
7. 7. A pharmaceutical composition, characterized in that it coses: an effective amount of a compound, a salt, multimer, precursor or pharmaceutically acceptable active metabolite, according to any of claims 1 to 6, and a pharmaceutically acceptable carrier or diluent.
8. 8. Use of a compound, a salt, multimer, precursor or active metabolite, for the manufacture of a medicine to regulate the secretion of gonadotropins.
9. A compound of formula I, characterized in that: X is selected from C = 0, C = S, S = 0, and S (0) 2; is a 5-membered heterocyclic ring that contains 1 to 4, preferably 2 or 3 heteroatoms which are selected from N, 0 and S, wherein the ring may be saturated, partially unsaturated or completely unsaturated and can be aromatic; R1 and R2 are independently selected from H and lower alkyl; R3 is selected from H, halogen and from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, OR and C (0) 0R, wherein R is selected from the substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the total number of carbon atoms present without including any optional substituent ranges from 1 to 12, - R4 and Rs are independently selected from H, halogen and the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, OR and C (0) OR, wherein R is as defined above, - and wherein the total number of atoms present carbon do not include any optional substituent ranges from 1 to 12; R6 and R7 are independently selected from H, halogen and the substituted and unsubstituted form of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH-OR, OR and C (0) 0R; wherein R is as defined in the foregoing, and wherein the total number of carbon atoms present, not including any optional substituents, ranges from 1 to 12, - or R6 and R7 taken together with the atoms to which they are attached united form an optionally substituted 5 or 6 membered ring having up to 4 heteroatoms selected from 0, N and S; R8 is a lipophilic moiety that is selected from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH20R, OR and C (0) 0R, wherein R is as defined above, and wherein the total number of carbon atoms present, not including any optional substituent, ranges from 6 to 20; and R9 is selected from H and substituted and unsubstituted alkyl, preferably lower alkyl.
10. 10. A compound of formula I: characterized in that: X is selected from C = 0, C = S, S = 0, and S (0) 2; you? is a 5-membered heterocyclic ring containing 1 to 4, preferably 2 or 3 heteroatoms which are selected from N, 0 and S, wherein the ring may be saturated, partially unsaturated or completely unsaturated and can be aromatic, - R1 and R2 are independently selected from H and lower alkyl; R3 is selected from H, halogen and from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, OR and C (0) OR, wherein R is selected from the substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, and wherein the total number of carbon atoms present without including any optional substituents ranges from 1 to 12, - R4 and Rs are independently selected from H, halogen and the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH2OR, OR and C (0) OR, wherein R is as defined above, - and wherein the total number of atoms present carbon do not include any optional substituent ranges from 1 to 12; R6 and R7 are independently selected from H, halogen and the substituted and unsubstituted form of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH20R, OR and C (0) OR; wherein R is as defined in the above, and wherein the total number of carbon atoms present, not including any optional substituent, varies from 1 to 12; or R6 and R7 taken together with the atoms to which they are attached form an optionally substituted 5 or 6 membered ring having up to 4 heteroatoms which are selected from O, N and S; R8 is a lipophilic moiety that is selected from the substituted and unsubstituted forms of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH20R, OR and C (0) OR, wherein R is as defined above, and wherein the total number of carbon atoms present, not including any optional substituent, ranges from 6 to 20; and R9 is selected from H and substituted and unsubstituted alkyl; or R1 or R2 can be -OH or = 0; or Rβ can also be hydrogen; or R can be COR or hydrogen, - or R8 can have any desired number of carbon atoms, - or R8 and R9 can also form a ring; or any adjacent R group, such as R5 and R6 or R3 and R4 can form a ring, such as those described for R6 and R7; or R6 can be COR; or the group (het) may be substituted or unsubstituted, or R8 or R9, or both, may be selected from heterocyclic groups or from any compound that forms an amide bond with the nitrogen of the formula.