JP2003522719A - Luteinizing hormone (LH) antagonists useful as estrogen deficiency treatment or contraceptives - Google Patents

Abstract

  (57) [Summary] Pharmaceutical compositions comprising an LH antagonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are useful for delaying the onset of menopause.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions, the use of LH antagonists for the preparation of a medicament for the treatment of hot flashes (ie vasomotor neuropathy during menopause), estrogen deficiency Use of an LH antagonist for the preparation of a medicament for treatment, to delay the onset of menopause and subsequent symptoms associated with estrogen deficiency by reducing follicular loss during and before menopause. To the use of LH antagonists for the preparation of a medicament. The invention further relates to the use of LH antagonists for the preparation of contraceptives. BACKGROUND OF THE INVENTION Mammalian females are naturally equipped with meiotically arrested oocytes in the ovaries that are fixed in number and then decline in number. Oocytes covered with a monolayer of squamous cells form primordial follicles and constitute a pool of fixed resting cells. The oocytes are collected from within the ovaries during the reproductive period. An unknown signal initiates a group of primordial follicles to differentiate into primary, secondary, and eventual Graaf follicles.

There are about one million primitive follicles in the ovaries of human neonates. The functional activity of the human ovary depends on the amount of follicle accumulation. It has been speculated that there are about 1000 to 2000 oocyte thresholds involved in arrest of menopause or cyclic activity in the ovary (Gosden, 1986, Serno Symposium, Leeds). Although primordial follicles do not retain follicle-stimulating hormone (FSH) or LH receptors, once follicles grow to a certain size, gonadotropins (gonadotropins) play a major role in regulating growth and ovulation. Make up. At the beginning of reproductive life,
Primitive follicles disappear from the ovaries at a relatively constant rate. Around 35 to 40 years old, this disappearing speed seems to accelerate. The reason for this dramatic disappearance is unknown.

Bone deficiency associated with menopause continues to represent a major public health problem. While remaining indeterminate, cumulative bone loss potentially compromises the structural integrity of the bone, resulting in fractures due to pain and weakness in the wrist, spine, and femur. Efforts to reduce the risk and incidence of fractures have focused on the development of treatments that maintain bone mass by inhibiting bone resorption. Among various treatment modalities, estrogens continue to be the preferred means of preventing postmenopausal osteoporosis (Lindsey R, Hart DM
, MacClean A 1978, "The role of estrogen / progestogen in the management o
f the menopause ", Cooke ID, ed, Proceedings of University of Sheffield s
ymposium on the role of estrogen and progestogen in the management of th
e menopause, Lancaster, UK: MTP Press Ltd. pp. 9-25; Marshall DH, Horsma
nn A, Nordin BEC 1977, "The prevention and management of post-menopausal
osteoporosis. ", Acta Obstet Gynecol Scand (Suppl) 65: 49-56; Recker RR
, Saville PD, Heaney RP 1977, "Effect of estrogen and calcium carbonate
on bone loss in post-menopausal women ", Ann Intern Med. 87: 649-655; Na
chtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM 1979, "Estrogen re
placement therapy ", Obstet Gynecol. 53: 277-281), and now it is accepted that estrogen significantly reduces the incidence and risk of fractures (Kr.
ieger N, Kelsey JL, Holford TR, O'Connor T 1982, "An epidemiological stu
dy of hip fracture in postmenopausal women ", Am J Epidemiol. 116: 141-1
48; Hutchinson TA, Polansky SM, Feinstein AR 1979, "Postmenopausal estro
gens protect against fractures of hip and distal radius: A case-control
study ", Lancet 2: 705-709; Paginini-Hill A, Ross RK, Gerkins VR, Hende
rson BE, Arthur M, Mack TM 1981, "Menopausal oestrogen therapy and hip f
ractures ", Ann Intern Med. 95: 28-31; Weiss NS, Ure CL, Ballard JH, Wil
liams AR, Daling JR 1980, "Decreased risk of fractures on the hip and lo
wer forearm with post-menopausal use of estrogen ", N Eng J Med. 303: 11
95-1198).

While the beneficial effects of estrogens on bone are clearly significant, there is also considerable evidence of the positive effects of estrogens on the cardiovascular system. In previous studies, these effects were attributed to the effects of estrogens on serum lipids, but recent data show that, in addition to their effects on lipid profiles, estrogens also have a direct effect on vascular wall elasticity. Have been shown to be able to reduce peripheral resistance and prevent atherosclerosis (Lobo RA 1990, "Cardi
ovascular implication of estrogen replacement therapy ", Obstetrics and G
ynaecology, 75: 18S-24S; Mendelson ME, Karas RH 1994, "Estrogen and the
blood vessel wall ", Current Opinion in Cardiology, 1994 (9): 619-626).
Based on available epidemiological data, the overall impact of the physiological and pharmacological effects of these estrogens is an age-independent reduction in cardiovascular mortality and morbidity in women (Kannel WH, Hjortland M, McNamara PM 1976 "Menopause
and risk of cardiovascular disease: The Framingham Study ", Ann Int Med,
85: 447-552). In addition, recent further analysis concludes that postmenopausal estrogen therapy reduces the risk of cardiovascular disease by about 50% (Stampfer MJ,
Colditz GA 1991, "Estrogen replacement therapy and coronary heart disea
se: a quantitative assessment of the epidemiological evidence ", Prevent
ive Medicine, 20: 47-63.).

In addition to the positive effects of estrogen on the bone and cardiovascular system, recent data indicate that the central nervous system can also benefit from estrogen. Short-term studies in humans have shown that elevated estrogen levels are associated with increased memory in postmenopausal women (Kampen DL, Sherw
in BB 1994, "Estrogen use and verbal memory in healthy postmenopausal w
Omen ", Obstetrics and Gynecology, 83 (6): 979-983). Furthermore, surgical administration of exogenous estrogen to post-menopausal women obviously improves short-term memory. The effects on force appear not to be limited to short-term effects, such as the epidemiological finding that estrogen therapy significantly reduces the risk of Alzheimer-type senile dementia in women (Paganini -Hil
l A, Henderson VW, 1994, "Estrogen deficiency and risk of Alzheimer's di
sease in women ", Am J Epidemiol, 140: 256-261; Ohkura T, Isse K, Akazaw
a K, Hamamoto M, Yoshimasa Y, Hagino N, 1995, "Long-term estrogen replac
ement therapy in female patients with dementia of the Alzheimer Type: 7
case reports ", Dementia, 6: 99-107). Although the mechanism by which estrogen enhances cognitive function is not known, cerebral blood flow (Goldman H, Skelley Eb, Sandman CA, Kas
tin AJ, Murphy S, 1976, "Hormones and regional brain blood flow", Pharma
col Biochem Rev. 5 (suppl 1): 165-169; Ohkura T, Teshima Y, Isse K, Mat
suda H, Inoue T, Sakai Y, Iwasaki N, Yaoi Y, 1995, "Estrogen increases c
erebral and cerebellar blood flows in postmenopausal women ", Menopause:
J North Am Menopause Soc. 2 (1): 13-18) and neuronal activity, (Singh M, M
eyer EM, Simpkins JW, 1995, "The effect of ovariectomy and estradiol rep
lacement on brain-derived neurotrophic factor messenger ribonucleic acid
expression in cortical and hippocampal brain regions of female Sprague-
Dawley rats ", Endocrinology, 136: 2320-2324; McMillan PJ, Singer CA, Do
rsa DM, 1996, "The effects of ovariectomy and estrogen replacement on tr
kA and choline acetyltransferase mRNA expression in the basal forebrain
of the adult female Sprague-Dawley rat ", J Neurosci., 16 (5): 1860-1865
It is possible to speculate that the direct effect of estrogen on) is a potential effector of these beneficial effects.

The beneficial effect of prolonging the naturally-occurring period of estrogen as a result of delaying menopause is not limited to chronic conditions such as those mentioned above. In fact, the more classical applications of estrogen therapy also include: : Reduction of menopausal symptoms (ie flushing and genitourinary regression); oral contraception; prevention of imminent or habitual abortion; reduction of dysmenorrhea; reduction of uterine bleeding dysfunction; promotion of ovarian development; treatment of acne Reduction of excessive hair growth (hirsutism) in women; treatment of prostate cancer; and suppression of postpartum lactation [Goodman and Gilman, The Pharmacological Basis of The
rapentics (Seventh Edition) Macmillar Publishing Company, 1985, pages 14
21-1423].

“Transient sensation” is a sudden, temporary sensation that ranges from warmth to intense heat and provides flushing and sweating. This is the classic signal of menopause and is the predominant complaint of menopausal women. Epidemiological studies report that many menopausal women experience hot flashes, but the frequency and extent vary greatly (Trea.
tment of the Postmenopansal Women, Basic and Clinical Aspects, Raven Pre
ss 1994, ed. RA Lobo).

While it appears that maintenance of endogenous estrogen secretion has beneficial effects on a wide variety of organs and tissues, the concentration and duration of estrogen exposure depend on the risk of endometriosis and cancer. It is related to the increase of. The combination with cyclic progestins considerably reduces the risk of endometrial disease, but is achieved at the expense of normal physiological circulation or maintenance, which is an unfavorable result for many patients. In addition to the effects of estrogen on the endometrium, debate remains on reports of long-term estrogen exposure and association with breast cancer (Be.
rgkvist L, Adami HO, Persson I, Hoover R, Schairer C, 1989, "The risk of
breast cancer after estrogen and estrogen-progestin replacement ", N Eng
J Med, 321: 293-297; Colditz GA, Hankinson SE, Hunter DJ, Willett WC,
Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE, 1995, "The us
e of estrogens and progestins and the risk of breast cancer in postmenop
ausal women ", N Eng J Med, 332 (24): 1589-1593).

Oocytes are formed early in life as the oocytes begin meiosis in the female ovary. At the beginning of the first prophase, the oocyte arrests in the arrest phase and remains arrested until the final stage of oocyte maturation. The final stage begins and progresses with resumption of meiosis during adolescence. During this process of follicle development, the oocyte undergoes a dramatic anagen period during which it acquires the ability to complete the meiotic process. When LH occurs in the plasma, the oocytes in the Graafian follicles before ovulation resume mitosis and, after ovulation, experience the ultimate maturation that is essential for subsequent fertilization.

[0010] Essentially, much is not known about the mechanism by which the primordial follicles assemble. SUMMARY OF THE INVENTION The present invention provides a method of protecting the brain and ovarian LH receptors, especially against gonadotropin increased LH levels, thereby preventing hot flushes and ovary. It slows the rate of follicle loss from the body and delays the symptoms of menopause and subsequent estrogen deficiency.

The present invention further provides a method of contraception by preventing the action of LH on follicles and thereby inhibiting oocyte maturation and subsequent fertilization. The use of LH receptor antagonists does not alter the release of FSH and LH from the pituitary, thereby affecting the important FSH / estrogen / GNRH (gonadotropin releasing hormone) feedback. The use of potent / complete LH receptor antagonists may be associated with altered ovulation mechanisms or consequent inhibition of ovulation and follicular luteinization, resulting in reduced plasma progesterone levels. If desired, the present invention can be used in combination with auxiliary progesterone.

The object of the present invention is to provide a pharmaceutical composition for delaying menopause. Another object of the invention is to provide a pharmaceutical composition for the treatment of hot flashes. A further object of the invention is to provide a pharmaceutical composition for the treatment of estrogen deficiency in perimenopausal women.

Further objects will be clarified by the following description. DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention provides an LH antagonist or a pharmaceutically acceptable salt thereof,
And a pharmaceutically acceptable excipient, carrier or diluent. LH antagonists reduce or block some or all of the biological effects of endogenous secreted LH. Preferred LH antagonists reduce the biological effects of endogenous secreted LH, thereby avoiding adjunctive treatment with progesterone. Preferred LH antagonists are defective antagonists, eg competitive or non-competitive antagonists.

In another aspect, the present invention provides LH for the preparation of a medicament for the treatment of hot flashes.
It relates to the use of antagonists or pharmaceutically acceptable salts thereof. Many menopausal women experience hot flushes, and treatment with LH antagonists during menopause will reduce or inhibit hot flushes. As a further aspect, the present invention relates to the use of an antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of estrogen deficiency near or after menopause, preferably around menopause. Such estrogen deficiency is associated with bone loss such as osteoporosis, cardiovascular disease, cognitive impairment, senile dementia of the Alzheimer's type, menopausal symptoms of flushing, genitourinary regression, depression, mania and schizophrenia. Disease, incontinence, obesity, control of glucose metabolism, dysmenorrhea, imminent abortion, habitual abortion,
Uterine bleeding dysfunction, acne, hirsutism, prostate cancer, estrogen-dependent cancers such as breast cancer, and postpartum milk juice. Each of these estrogen deficiencies represents an aspect of the invention;

And in a still further aspect, the present invention relates to the use of an LH antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for delaying the onset of menopause.
By delaying the onset of menopause, estrogen deficiency is also delayed. In a further aspect, the invention relates to the use of LH antagonists or pharmaceutically acceptable salts thereof for the preparation of contraceptives.

In a still further aspect, the present invention comprises administering an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof to a subject in need thereof, eg a woman. A method for treating a hot sensation. In a further aspect, the present invention provides a method for treating estrogen deficiency in the vicinity of menopause, which comprises administering an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a woman. Regarding treatment methods.

In a still further aspect, the invention provides a menopausal onset comprising administering to a subject in need thereof, eg, a woman, an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof. Regarding the method for delaying. In a further aspect, the present invention relates to a method of contraception comprising administering an effective amount of an LH antagonist or pharmaceutically acceptable salt thereof to a subject in need thereof, eg a woman.

As a further aspect, the present invention relates to a method for detecting an LH antagonist, which method comprises a) in vitro binding assay [substantially Acta Endocrinol. Vol. 121, 1 pp. 46-54, (1989)] and b) in vitro assay for determining the function of LH receptor interaction [substantially Tertin-Clary et
al. (1980) FEBS LETTERS, Vol. 118, 1 pp. 77-80]]. The term "substantially" means that minor modifications known to those skilled in the art would have been introduced using standard principles known in the art.

Whether a molecule possesses both LH receptor binding affinity and functional LH receptor interactions is determined using standard principles known in the art. In one aspect, the LH antagonists or pharmaceutically acceptable salts thereof can be used to treat hot flashes. In another aspect, the LH antagonists or pharmaceutically acceptable salts thereof can be used for the treatment of estrogen deficiency near the perimenopause.

In a further aspect, the LH antagonists or pharmaceutically acceptable salts thereof can be used to delay menopause in women. In an even further aspect, the LH antagonist or pharmaceutically acceptable salts thereof can be used as a contraceptive. In a further aspect, the LH antagonist or pharmaceutically acceptable salt thereof is administered to a subject in need thereof in a range of about 0.01 mg to about 100 g per subject per day, preferably per day, About 1 to about 1000 mg per patient
Is administered in an effective amount within the range.

In yet a further aspect, the LH antagonist or pharmaceutically acceptable salt thereof is combined with the adjunct administration of progesterone. The progesterone can be administered in the range of about 0.01 mg to about 100 g per subject per day. In a further embodiment, the LH antagonist has the formula (1):

[0022]

[Equation 1]

[Wherein X is bonded to a carbon atom and represents O, S, or NH; and ring A contains a carbon atom bonded to X in its structure, and is saturated, unsaturated, or An aromatic system, wherein the system is a 5 to 6 sided monocyclic system containing 1 to 6 carbon atoms and optionally 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen; or 4 to 10 9 to 10 sided mixed systems containing 4 carbon atoms and optionally 1 to 6 heteroatoms selected from nitrogen, sulfur and oxygen; or optionally from 7 to 14 carbon atoms and nitrogen, sulfur and oxygen Fused systems of 13 to 14 sides containing 1 to 7 heteroatoms selected; these are optionally one or more C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. Or t-butyl; cyano,
It may be substituted with halogen, for example chlorine, bromine, iodine or fluorine; or aryl such as phenyl. And X is 0 in a preferred embodiment of the compound having a molecular weight of 1500 daltons or less. In another preferred embodiment, the compound comprises in its structure one or more, preferably one or two rings selected independently of formula (1).

In a further embodiment, the 5- to 6-sided monocyclic ring system is 0, 1, or 2 selected from nitrogen.
Includes 4 heteroatoms. In another embodiment, the fused system of sides 9 to 10 contains 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen. As a further aspect,
Fused systems on the 13th to 14th side have 1 heteroatom independently selected from nitrogen and oxygen.
, 2 or 3 included. In a still further aspect, the LH antagonist has a molecular weight of 200 to 1000 Daltons, such as 200 to 800 Daltons, and has within its structure the formula (1
) Is a compound containing one ring.

[0025]   Preferred rings of formula (1) are selected from:

[0026]

[Chemical 3]

Is selected from In a further aspect, LH antagonists include NG-LH, milrinone, silostamide,
Amrinone, enoximone, CI-930, anagrelide, pimobendan, sigazodan (SKF-94836), lixazinone (RS-82856), imazodan (CI-914), indoridan (LY195115), quazinone, SK.
F 94120, Org 30029, Ajibendan (BM 14,478),
APP 201-533, carbazelan, cilostazol, E-1020, IP
S-1251, Nanterinone (UK-61260), Perrinone, RMI 82
249, UD-CG 212, Vemarinone (ORF-16,600) CK-21
30, motapizone, OPC-3911, Ro 13-6438, salmazole,
Vesnarinone (OPC-8212), buquinane, DPN 205-734,
ICI-170777, isomazole (LY175326), MCI-154,
MS-857, OPC-8490, Pyroximon (MLD 19205), RS
-1893, saterinone, ZSY-39, ICI 118233, and the following compounds:

[0028]

[Chemical 4]

[0029]

[Chemical 5]

Or a pharmaceutically acceptable salt thereof. Each of the above compounds,
1 illustrates an aspect of the present invention. An effective, eg, therapeutically effective amount of an LH antagonist depends on the mode of administration, the desired therapy, the mode of administration, the subject being treated and the weight of the subject being treated,
And depending on the preferences or experience of the attending physician or veterinarian.

As used herein, the term “patient” or “subject” benefits from treatment with an LH antagonist, such as humans, particularly pre-menopausal, near-menopausal, or post-menopausal women. Comprised of mammals capable of However, "patient" or "subject" is not limited to women. The term “treatment” as used herein is intended to also include prophylactic treatment.

The term “LH antagonist” or “LH receptor antagonist” as used herein refers to a partial, complete, competitive and / or non-mammalian, preferably human, LH receptor. Attenuating any or all of the biological effects of any compound exhibiting a competitive antagonizing effect, such as an antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably small molecule or peptide, and endogenous secreted LH. Alternatively, it is meant to include an LH receptor that interferes, preferably reduces.

As an example of an LH antagonist, nitroguanidyl-lutropine (NG-LH) is FE
BS LETTERS, Vol. 118, no. 1, p. 77-80, August 1980. There is no mention of a medicinal effect. Examples of other suitable LH antagonists include milrinone, silostamide, amrinone, enoximone, CI-930, anagrelide, pimobendan, sigazodan (SKF-94836), lixazinone (RS-828).
56), Imazodan (CI-914), Indoridan (LY195115), Quazinone, SKF 94120, Org 30029, Ajibendan (BM 1).
4, 478), APP 201-533, carbazelan, cilostazol, E-
1020, IPS-1251, Nanterinone (UK-61260), Perrinone, RMI 82249, UD-CG 212, Vemarinone (ORF-16, 60).
0) CK-2130, motapizone, OPC-3911, Ro 13-6438,
Salmazole, vesnarinone (OPC-8212), buquinane, DPN2
05-734, ICI-170777, isomazole (LY175326), M
CI-154, MS-857, OPC-8490, Pyroximon (MLD 19
205), RS-1893, saterinone, ZSY-39, ICI 118233.
And the following compounds

[0034]

[Chemical 6]

[0035]

[Chemical 7]

Is selected from the group consisting of: The present invention is not limited to the above compounds, which are for illustrative purposes only. The LH antagonists according to the invention may be prepared in the form of pharmaceutically acceptable salts, especially acid addition salts, including salts of organic and mineral acids. Examples of such salts are formic acid,
Fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid,
It includes salts of organic acids such as succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and the like salts thereof. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts can be found in the Journal of Pharmacentical Science, 66, known to those skilled in the art.
2 (1977), including pharmaceutically acceptable salts.

Hydrates that the present LH antagonists are able to form are also meant as pharmaceutically acceptable acid addition salts. Acid addition salts can be obtained as a direct product of compound synthesis. Alternatively, the salt is isolated by dissolving the free base in a suitable solvent containing a suitable acid and evaporating the solution or otherwise separating the salt and solvent.

LH antagonists may form solvates with standard low molecular weight solvents using methods known in the art. The LH antagonist may be administered in the form of a pharmaceutically acceptable acid addition salt, or in the form of a suitable alkali metal or alkaline earth metal salt or lower alkylammonium salt. It is considered that such a salt form shows almost the same activity value as the free base form. Pharmaceutical Composition A pharmaceutical composition intended for use in accordance with the invention comprises an LH antagonist, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier. The composition may comprise one or more LH antagonists as active ingredients, and one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions containing LH antagonists may be prepared by conventional techniques, eg Remington: The Scienc
^{e and Practise of Pharmacy, 19 th} Ed., 1995. The compositions may appear
in conventional forms, for example capsules, tablets, aerosols, solution
s, suspensions or topical applications. The dosage of the LH antagonist required to block LH action on the follicle or to reduce follicular loss during and near premenopause may depend on the particular compound and route of administration, as described below. Ah Generally, an effective amount to reduce follicular loss is an amount of about 0.0001 to about 10 mg / kg once or twice daily. Further guidance on effective amounts of the particular compounds described herein may be obtained from the recommended dosages for the product.

The dosage will be determined based in part on the pharmacokinetics of the LH antagonist used, using standard pharmacokinetic principles known in the art. A typical composition comprises an LH antagonist or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutically acceptable excipient which is a carrier or diluent or an excipient diluted with a carrier, Alternatively, it may be contained in a carrier that may take the form of a capsule, satchet, paper or other container.

In preparing the compositions, conventional techniques for the preparation of pharmaceutical compositions can be used.
For example, the active compound is usually mixed with the carrier, diluted with the carrier, or encapsulated in the carrier in the form of ampoules, capsules, sachets, paper, or another container. When the carrier serves as a diluent, it is a vehicle for the active compound,
A solid, semi-solid, or liquid substance that functions as an excipient or medium. The active compound may be adsorbed on a granular solid carrier, for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba,
Sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, low alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid Esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.

Similarly, the carrier or diluent may include any sustained release agent known in the art, such as glyceryl monostearic acid or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, prophylactic agents, sweetening agents or flavoring agents. The formulations of the present invention may be prepared such that the active ingredient is rapidly delivered, maintained, or its release is extended after administration to a patient using techniques known in the art. As used herein, "carrier" is understood to include all of the above possibilities, such as diluents, carriers, fillers, excipients and the like.

The pharmaceutical compositions should be sterile and, if desired, adjuvants, emulsifiers, salts which influence the osmolarity, buffers and / or coloring agents and the like, which do not have a harmful effect on the active compounds. Can be mixed. The route of administration may be any route that effectively delivers the active LH antagonist to a suitable or desired site, such as oral, nasal, pulmonary, transdermal, passive or iontophoretic administration, or non-administration. The oral route is, for example, rectal, depot, subcutaneous, intravenous, intrauterine, intramuscular, intranasal, ophthalmic solution or ointment route.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is used, the preparation may also be in the form of a sterile injectable liquid such as a syrup, emulsion, soft gelatin capsule or aqueous or non-aqueous liquid suspension or solution.

For nasal administration, the formulation may include a LH antagonist dissolved or suspended in a liquid carrier for spraying, especially an aqueous carrier. The carrier may include additives such as solubilizers such as propylene glycol, surfactants, absorption enhancers such as preservatives such as lecithin (phosphatidylcholine) or cyclodextrins or parabens. For parenteral administration, injectable solutions or suspensions, preferably aqueous solutions containing the active compound dissolved in preferably polyhydroxyethoxylated castor oil, are suitable. Tablets, dragees or capsules with talc and / or a carbohydrate carrier or binder or the like, are particularly suitable for oral administration. Tablets, dragees,
Alternatively, preferred carriers for capsules include lactose, corn starch and / or potato starch. A syrup or elixir can be used when a sweetener can be used.

A typical tablet, which may be prepared by conventional tabletting techniques, may include: : Core: Active LH antagonist (excluding compounds or salts thereof) 10 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcrystalline (Avicel) 70 mg Improved cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Add salt Coating: HPMC about 9 mg ^* Mywacett 9-40T about 0.9 mg * Use acylated monoglyceride as a plasticizer for film coating.

Any novel feature or combination of features described herein is considered necessary for the present invention. Example 1) Human Luteinizing Hormone (hLH) hLH is a glycoprotein hormone synthesized and secreted in the anterior pituitary gland. L
H is a dimer consisting of two protein chains (α chain and β chain) held together by a non-covalent bond and an ionic bond. The α-chain in LH is identical to that of two other pituitary dimer glycoprotein hormones, FSH and thyroid stimulating hormone (FSH), so the β-chain is a hormone-specific action of these hormones. Is the cause.

The LH hormone is secreted into the circulating blood and reaches this target cell, which expresses the membrane-bound LH receptor, by this pathway. The biological half-life of LH in plasma is very short (min). (Reference: The Physiology of Reproducti
on. Eds. Knobil, E. & Neill, JD pp. 487-540, Raven Press, New York, 19
94). 2) Screening Assay The human LH receptor has already been identified, sequenced and cloned. This receptor is expressed in differently transformed cell lines that have been integrated into a reporter system (Gi-protein signaling system). This is done by screening compounds that assay for receptor binding and functional activity. Compounds that bind to the receptor but have no effect are tested ex-vivo and in vivo for their ability to counteract LH action.

The ex vivo system consists of isolated cultured mouse follicles, which respond to increased LH by the introduction of oocyte maturation. A screening tree comprising some or all of the following assay groups is used to assay compound libraries and newly synthesized compounds due to the properties of LH antagonists. A) In vitro assays are used to determine functional LH receptor interactions. (As an example, Tertrin-Clary et al. (1980) FEBS LETTERS, Vol. 118, 1 pp.
77-80, cAMP assay using rat ovarian homogenate). LH is cA
Compounds that act as positive controls to elevate MP levels above baseline and also show antagonistic effects, reduce cAMP accumulation from baseline. B) In vitro binding assay using displacement / interaction of compounds that bind to mouse ovarian homogenate together with [125I] -hCG (Ding and Huhtaniemi (1989) A
Cta Endocrinol. Vol. 121, 1 pp. 46-54) is used to screen LH receptor affinity. The compound showing an affinity for the LH receptor is [12
5I] significantly replaces labeled hCG. C) A commercially available cell line expressing the cloned human LH receptor using the cAMP reporter gene (Christinmaitre & Bouchard (1996) Molecular
and Cellular Endocrinology Vol. 125, 1-2 pp. 151-159) are used to test the antagonistic effect of compounds on added LH. D) Ex vivo culture system of rodent follicles (Lindner et al. (1974) Res. Prog. H
Orm. Res. Vol. 30, pp. 79-138) is used to assess the ability of compounds to counteract LH's action on steroid biosynthesis and oocyte maturation. Compounds that inhibit oocyte maturation are candidates for contraceptives. E) An in vivo transient hot sensation model is used to test compounds that have a direct effect on skin temperature in response to naloxone in morphine-dependent rats (Katovich &O'Meara (1987). Can. J. Physiol. Pharmacol. Vol. 65 pp
.563-567). Compounds that have an indirect effect on hot flashes due to delayed onset of menopause cannot be tested in this particular assay. F) transgenic mice overexpressing the β subunit of LH
Used to test compounds that have the effect of protecting the ovary from rapid follicular loss in vivo. Compounds that reverse the phenotype of LH β-subunit transgenic mice, that is, those that reverse the accelerated loss of follicles, cause the onset of female menopause, which reverses the accelerated loss of follicles experienced before menopause. It is a candidate for a delayed drug.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/5025 A61K 31/5025 31/519 31/519 A61P 5/30 A61P 5/30 15/00 15 / 00 15/12 15/12 15/18 15/18 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, C , CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW F term (reference) 4C084 AA17 NA14 ZA052 ZA122 ZA152 ZA162 ZA182 ZA702 ZA812 ZA862 ZA972 ZB212 ZB262 ZC032 ZC352 4C086 BC41BC17BC1717 GA07 GA08 MA01 MA04 NA14 ZA05 ZA12 ZA15 ZA16 ZA18 ZA70 ZA81 ZA86 ZA97 ZB26 ZC03 ZC35

Claims (20)

[Claims] 1. A pharmaceutical composition comprising an LH antagonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 2. A composition according to claim 1 for the treatment of hot flashes. 3. A composition according to claim 1 for the treatment of estrogen deficiency. 4. A composition according to claim 1 for delaying the onset of menopause. 5. A composition according to claim 1 for use as a contraceptive. 6. An LH antagonist is administered to a subject in need thereof at about 0.
6. The composition of any one of claims 1-5, which is administered as an effective amount within the range of 01 mg to about 100 g. 7. The composition according to claim 1, wherein the subject is a woman. 8. The LH antagonist is nitroguanidyl-LH (NG-LH) milrinone, silostamide, amrinone, enoximone, CI-930, anagrelide, pimobendan, sigazodan (SKF-94836), lixazinone (RS).
-82856), Imazodan (CI-914), Indoridan (LY19511).
5), quazinone, SKF 94120, Org 30029, adibendan (
BM 14,478), APP 201-533, carbazelan, cilostazol, E-1020, IPS-1251, nanterinone (UK-61260), perlinone, RMI 82249, UD-CG 212, bemarinone (ORF-1).
6,600) CK-2130, motapizone, OPC-3911, Ro 13-6
438, salmazole, vesnarinone (OPC-8212), buquinane, D
PN 205-734, ICI-170777, isomazole (LY17532
6), MCI-154, MS-857, OPC-8490, Pyroximon (ML
D 19205), RS-1893, saterinone, ZSY-39, ICI 11
8233, [Chemical 2] Or a pharmaceutically acceptable salt thereof, the composition according to any one of claims 1 to 7. 9. Use of an LH antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hot flashes. 10. L for the preparation of a medicament for the treatment of estrogen deficiency
Use of an H antagonist or a pharmaceutically acceptable salt thereof. 11. Use of an LH antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for delaying the onset of menopause. 12. Use of an LH antagonist or a pharmaceutically acceptable salt thereof for the preparation of a contraceptive. 13. The LH antagonist is administered to a subject in need thereof in an effective amount within the range of about 0.01 mg to about 100 g per day.
The use according to any one of 1. 14. The use according to any one of claims 9 to 13, wherein the subject is a woman. 15. A method for treating transient heat sensation, which comprises administering an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. 16. A method for treating estrogen deficiency, which comprises administering an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. 17. A method of delaying the onset of menopause, which comprises administering an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. 18. A method for preventing pregnancy, which comprises administering an effective amount of an LH antagonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. 19. The LH antagonist or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an effective amount within the range of about 0.01 mg to about 100 g per day. The method according to any one of items. 20. The method of any one of claims 15-19, wherein the subject is a woman.