Non-peptide GnRH agents capable of inhibiting the effect of gonadotropin-releasing hormone are of the following general formula, where X.sub.1, X.sub.2, Y, and are defined variables: ##STR1## 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.

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 relates
 to non-peptide GnRH antagonists or agonists and to their preparation.
 These non-peptide GnRH agents have advantageous physical, chemical and
 biological properties, and are useful medicaments for diseases or
 conditions mediated by modulation of the pituitary-gonadal axis. The
 compounds of the invention avoid the degradation and biodistribution
 problems of peptide agents.
 BACKGROUND OF THE INVENTION
 The release of a hormone (a biochemical substance that is produced by a
 specific cell or tissue and causes a change or an activity in a cell or
 tissue located elsewhere in the organism) by the anterior lobe of the
 pituitary gland (which is located at the base of the brain and secretes
 hormones related to growth and sexual development) usually requires the
 prior release of another class of hormones produced by the hypothalamus (a
 structure in the lower part of the brain that is connected to and controls
 the pituitary gland). One of the hypothalamic hormones acts as a factor
 that triggers the release of the gonadotropic hormones, particularly LH
 (luteinizing hormone, which is the pituitary hormone that causes the
 testicles in men and ovaries in women to manufacture sex hormones) and FSH
 (follicle-stimulating hormone, which is the pituitary hormone that
 stimulates follicle growth in women and sperm formation in men). This
 hormone is referred to herein as "GnRH" (gonadotropin-releasing hormone)
 and/or "LH-RH" (luteinizing hormone-releasing hormone). GnRH is a
 decapeptide hormone produced by the arcuate nuclei of the hypothalamus (an
 arcuate nucleus is any of the cellular masses in the thalamus,
 hypothalamus, or medulla oblongata) that controls the pituitary gland's
 production and release of gonadotropins (hormones including FSH and LH
 that are produced by the pituitary gland that control reproductive
 function). GnRH (LH-RH) may be represented by the sequence
 pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2 or, in the
 single-letter code designation, pyro-EHWSYGLRPG-NH.sub.2. GnRH acts on
 high-affinity pituitary receptors to stimulate LH and FSH production and
 release.
 The pituitary response to GnRH varies greatly throughout life. GnRH and the
 gonadotropins first appear in the fetus at about ten weeks of gestation.
 The sensitivity to GnRH declines, after a brief rise during the first
 three months after birth, until the onset of puberty. Before puberty, the
 FSH response to GnRH is greater than that of LH. Once puberty begins,
 sensitivity to GnRH increases, and pulsatile LH secretion ensues. Later in
 puberty and throughout the reproductive years, pulsations occur throughout
 the day, with LH responsiveness being greater than that of FSH. After
 menopause, FSH and LH concentrations rise, and postmenopausal FSH levels
 are higher than those of LH.
 Pulsatile GnRH release results in pulsatile LH and FSH release. However,
 sustained infusion of GnRH and its analogs results in inhibition of LH and
 FSH release. This phenomenon has been utilized in the successful treatment
 of gonadotropin-mediated precocious puberty by the sustained
 administration of LH-RH or its analogs. Conversely, in people with GnRH
 deficiency, the pulsatile administration of LH-RH can restore a normal
 menstrual cycle or normal sperm and testosterone production.
 GnRH agonists, which are compounds that stimulate the pituitary gland to
 release or modulate FSH and LH, have been the mode of choice for treating
 sex-steroid-dependent pathophysiologies, owing to the limited number of
 suitable antagonists available for clinical evaluation. GnRH antagonists,
 which are compounds that suppress the pituitary gland from releasing FSH
 and LH, however, are now being considered.
 GnRH antagonists may be useful for suppressing gonadotropin secretions and
 preventing ovulation in female mammals. GnRH antagonists have been
 investigated for contraception and for regulating conception periods, as
 well as for treating infertility, for controlling induction of ovulation
 in women with chronic anovulation, and for in vitro fertilization. GnRH
 antagonists may also be useful for the treatment of precocious puberty,
 endometriosis (including endometriosis with pain), acne, amenorrhea (e.g.,
 secondary amenorrhea), uterine myoma, ovarian and mammary cystic diseases
 (including polycystic ovarian disease), and breast and gynecological
 cancers. GnRH antagonists may also be useful in the symptomatic relief of
 premenstrual syndrome (PMS). They may also be used to treat ovarian
 hyperandrogenism and hirsutism. Antagonists have also been found useful to
 regulate the secretion of gonadotropins in male mammals and may be
 employed to arrest spennatogenesis, e.g., as male contraceptives for
 treatment of male sex offenders, and for treatment of prostatic
 hypertrophy. More specifically, GnRH antagonists may be used to treat
 steroid-dependent tumors, such as prostatic and mammary tumors, and for
 the control of the timing of ovulation for in vitro fertilization. GnRH
 antagonists may also be used to treat patients having illnesses, such as
 AIDS, wherein stimulation of the thymus to produce T-cells would be
 beneficial. All such uses relate to the ability of the GnRH antagonist to
 block the activity of GnRH.
 Heretofore, available GnRH antagonists have primarily been peptide analogs
 of GnRH. See, e.g., International Publication No. WO 93/03058. Peptide
 antagonists of peptide hormones are often quite potent; however, the use
 of peptide antagonists is typically associated with problems because
 peptides are degraded by physiological enzymes and often poorly
 distributed within the organism being treated. Thus, they have limited
 effectiveness as drugs. Consequently, there presently exists a need for
 non-peptide antagonists of the peptide hormone GnRH.
 SUMMARY OF THE INVENTION
 An object of the invention is therefore to provide non-peptide compounds
 that are GnRH agents (agonists or antagonists) that bind to GnRH receptors
 and thus modulate activity, especially those that are potent GnRH
 antagonists. Another object of the invention is to provide effective
 therapies for individuals needing therapeutic regulation of GnRH and to
 provide methods for treating diseases and conditions mediated by GnRH
 regulation.
 Such objects have been achieved by the non-peptide GnRH compounds of the
 invention, which are useful as pharmaceuticals for indications mediated by
 GnRH regulation. The inventive compounds are pharmaceutically advantageous
 over peptide compounds since they provide better biodistribution and
 tolerance to degradation by physiological enzymes. The invention further
 provides methods of synthesizing the compounds as well as intermediate
 compounds useful for making the compounds. GnRH agents of the invention
 are of the general Formula I:
 ##STR2##
 wherein:
 Z is a group selected from substituted and unsubstituted alkyl, alkenyl,
 alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH.sub.2 OR, and
 C(O)OR, where R is substituted or unsubstituted alkyl, alkenyl, alkynyl,
 cycloalkyl, aryl, or heteroaryl, and where the total number of carbon
 atoms present in Z, not including optional substituents, ranges from 1 to
 12;
 Y is a lipophilic group selected from substituted and unsubstituted alkyl,
 alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, where the total number
 of carbon atoms present in Y, not including optional substituents, ranges
 from 6 to 20;
 X.sub.1 is a structural unit, or spacer, used to connect the CH.sub.2
 NC(O), X.sub.2, Y, and Z functional units in 3-dimensional space, that is
 selected from substituted and unsubstituted alkyl, alkenyl, alkynyl,
 cycloalkyl, aryl, and heteroaryl such that the atom count in the chain
 portion of the unit linking the central nitrogen (the N atom in Formula I
 is referred to as the "central nitrogen" to avoid confusion with any other
 nitrogen-bearing substituents) to X.sub.2 ranges from 3 to 8, preferably
 from 4 to 6; and
 X.sub.2 is a basic group having a pK.sub.a greater than about 8 that is
 preferably selected from substituted and unsubstituted guanidinyl,
 amidinyl, acylamidinyl, azetidinyl, and amino.
 In addition to compounds of the Formula I, GnRH agents of the invention
 include pharmaceutically acceptable salts, multimeric forms, prodrugs, and
 active metabolites of compounds of the Formula I. Such non-peptide 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.
 Moreover, the invention relates to methods for regulating the secretion of
 gonadotropins in mammals, comprising administering therapeutically
 effective amounts of GnRH agents of the invention.
 The invention further relates to processes for synthesizing the compounds
 as well as to intermediate compounds useful for making the compounds.
 Intermediate compounds useful for making compounds of the Formula I are
 those encompassed by the following Formulae II, III, and IV:
 ##STR3##
 wherein:
 j is 1 or 2;
 k is 1, 2, 3, 4 or 5;
 R.sup.8 is H or substituted or unsubstituted lower alkyl;
 R.sup.9 is H or substituted or unsubstituted lower alkyl, CN, NO.sub.2 or
 CO.sub.2 R.sup.1 ;
 R.sup.10 is H or substituted or unsubstituted lower alkyl, CH.sub.2
 OR.sup.1, (CH.sub.2).sub.p OR.sup.1, CO.sub.2 R.sup.1, or (CH.sub.2).sub.p
 C(O)R.sup.2, where p is an integer from 1 to 6, and R.sup.2 is H,
 OR.sup.1, SR.sup.1, N(R.sup.1).sub.2, or C(R.sup.1).sub.3 ;
 R.sup.11 is H or substituted or unsubstituted lower alkyl, CH.sub.2
 O-phenyl, CH.sub.2 O-benzyl, phenyl, or benzyl;
 or any two of R.sup.8, R.sup.9, R.sup.10, and R.sup.11 (R.sup.8 and
 R.sup.9, or R.sup.8 and R.sup.11, or R.sup.8 and R.sup.10, or R.sup.9 and
 R.sup.10, or R.sup.9 and R.sup.11, or R.sup.10 and R.sup.11) taken
 together form a 5- or 6-membered heterocycle;
 and where each R.sup.1 is independently selected from H and substituted or
 unsubstituted lower alkyl, O-lower alkyl, and S-lower alkyl.
 Other features, objects, and advantages of the invention will become
 apparent from the following detailed description of the invention and its
 preferred embodiments.