TW201729808A - Pharmaceutical combination of NK3 receptor antagonist and biguanides - Google Patents

Abstract

The present invention describes a synergistic composition comprising of NK3 receptor antagonist or a pharmaceutically effective salts thereof and biguanides or a pharmaceutically effective salts thereof for the treatment of PCOS and related diseases. The present invention is directed to a synergistic combination comprising combinations of a NK3 receptor antagonist or pharmaceutically effective salts thereof and biguanides or pharmaceutically effective salts thereof in a single unit pharmaceutical composition. The invention is further related to methods of preparing such pharmaceutical composition in separate in either a kit form containing both the active agents and methods of treating a subject with the same.

Description

NK3 receptor antagonist and biguanide pharmaceutical composition

The present invention describes a synergistic composition comprising an NK3 receptor antagonist or a pharmaceutically effective salt thereof and a biguanide or a pharmaceutically effective salt thereof for use in the treatment of PCOS (polycystic ovarian syndrome) and related diseases. The present invention is a synergistic composition comprising a combination of a NK3 receptor antagonist or a pharmaceutically effective salt thereof and a biguanide or a pharmaceutically effective salt thereof in a single unit pharmaceutical composition. The present invention is also directed to methods of separately preparing such pharmaceutical compositions, each of which is in the form of a kit comprising two active agents, and a method of treating a subject with the composition.

Disturbance in the synthesis of ovarian steroids Polycystic ovary syndrome (PCOS) is a disease that occurs in women and is characterized by excessive androgen. PCOS represents a class of phenotypes associated with follicular growth arrest, chronic anovulation, minimal granulosa cell proliferation, hyperproliferation of cells, hyperandrogenemia, central obesity, and insulin resistance. Among PCOS, cytoplasmic luteinizing hormone (LH) is high and FSH is low, increasing the LH/FSH ratio, typically due to increased LH or GnRH (gonadotropin-releasing hormone) pulses (Semin Reprod Med. 2002 Nov; 20 (4): 317-26). In PCOS, perturbation occurs in the synthesis of ovarian steroids, one of the conditions that increases androgen production and stimulates LH and increases LH/GnRH secretion. The neuroendocrine defect of GnRH secretion leads to sustained high secretion of LH in non-obese PCOS patients (Endocrinol Metab Clin) North Am. 1999 Jun; 28(2): 295-324.). Many women with PCOS suffer from abnormal menstrual cycles, hirsutism and infertility (Hum Reprod Update. 2015 Sep; 21(5): 575-92).

There is no successful approved treatment for PCOS (Syst Rev. 2015 Sep 23; 4(1): 125). The best first-line PCOS treatment for puberty remains controversial. Changes in lifestyle (modification of diet and exercise) followed by oral contraceptive pill (OCP) to control the symptoms of androgen excess are often recommended, with a clinical success rate of no more than 50%. However, there is significant variability in clinical practice, depending on whether the primary treatment goal of the doctor and the patient is to treat symptoms of excessive androgen or metabolic syndrome. In addition, anti-androgen drugs such as spironolactone, flutamide or pioglitazone are used as additional therapies for PCOS in clinical practice when oral contraceptive pills (OCP) or Metformin does not produce clinically desirable results. However, its use in adolescent population has not been recommended. The anti-male analog is a spirone ketone which is the second choice because of its risk of electrolyte imbalance. GnRH analogs are the next line of treatment to reduce androgen, which lacks potency and requires additional hormonal therapies to counteract the chemical menopause it induces. Metformin can be administered to reduce androgen concentrations, improve regularity and fertility of the menstrual cycle, and insulin resistance. Clomiphene has or does not add Metformin to improve the rate of conception and has an increased risk of ovarian hyperstimulation and multiple pregnancies (J Clin Endocrinol Metab. 2013 Dec; 98(12): 4565-92).

Because the current treatment strategy for PCOS is limited and there is no consistent guidance for its use, we need to be able to treat the underlying pathophysiology, modified LH pulse and treatment associated with the hypothalamic-genus-gonadal (HPG) axis. Treatment options with metabolic disorders without significant side effects.

NK3 receptor antagonists have been disclosed in WO 95/32948, WO 97/19927, WO 97/19928, WO 97/19926, WO 97/21680, WO2000031037, WO2006137789, WO2009019163, WO2010086259, WO2010094667, WO0031037, WO0238548, WO 006137789 .

WO 95/32948 discloses compounds of the formula:

Talnetant (SB 223412) is an NK3 receptor antagonist, 3-hydroxy-2-phenyl-N-(1-phenylpropyl)quinolin-4-carboxamide of formula (I) and It is disclosed in WO 95/32948, the disclosure of which is incorporated herein in its entirety.

Biguanide refers to a group of oral type 2 diabetes drugs whose role is to increase the body's sensitivity to insulin and reduce the amount of sugar absorbed by the small intestine by preventing glucose production in the liver.

The major biguanides, Metformin and Phenformin, were retrospectively back to the 1950s as a glucose-lowering agent for the treatment of non-insulin-dependent diabetes. Currently, the only available bismuth drug is Metformin, which is often used as a first-line treatment for type 2 diabetes (ie, type 2 diabetes that cannot control its blood sugar by meals and exercise alone). The first choice). Metformin has traditionally been used as an oral medication to help control diabetes.

Despite recent advances, we continue to need new and improved methods to treat and prevent PCOS and related conditions. Because it is currently known that the effects of therapies are limited, there is also a need for a PCOS therapeutic combination with enhanced effects and less undesirable side effects such as infertility, electrolyte imbalance, early onset menstruation, ovarian hyperstimulation, multiple pregnancy and metabolic disorders. The present invention provides a combination comprising an NK3 receptor antagonist or a pharmaceutically effective salt thereof and a biguanide or a pharmaceutically acceptable salt thereof In response to this problem, the composition is useful in the treatment and prevention of PCOS and related disorders.

At present, we have found that a combination of an NK3 receptor antagonist or a pharmaceutically effective salt thereof and a biguanide or a pharmaceutically acceptable salt thereof is useful for the treatment and prevention of PCOS and related disorders. In particular, it has been surprisingly found that a combination of an NK3 receptor antagonist or a pharmaceutically effective salt thereof and a biguanide or a pharmaceutically acceptable salt thereof exhibits unanticipated advantageous results. It has surprisingly been found that the compositions of the present invention are advantageous, and surprisingly the synergistic result in the treatment of PCOS outweighs the use of an NK3 receptor antagonist or a biguanide alone.

Specific examples of the invention

In a first aspect, the invention relates to a pharmaceutical composition comprising an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof and a biguanide or a pharmaceutically effective carrier, if desired, a pharmaceutically acceptable carrier, and a combination comprising the same Appropriate pharmaceutical composition. The invention also contemplates combining the pharmaceutical compositions of the two separate drugs in a kit format.

In a second aspect, the present invention provides a synergistic composition for the treatment of PCOS and related diseases comprising a low dose of a compound which is an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof and a biguanide or a medicament thereof Acceptable salts.

In a third aspect, the present invention provides a synergistic composition for human therapy comprising a low dose of a compound which is an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof and a bismuth or a pharmaceutically acceptable compound thereof Salt. In a specific example, the NK3 receptor antagonist can be selected from the group consisting of Talnetant (SB223412), AZD-4901, AZD-2624 and the biguanide is Metformin.

In another embodiment, a pharmaceutical composition comprising an effective amount of a synergistic composition suitable for the treatment of PCOS and related diseases as disclosed in the present specification is provided.

In yet another specific embodiment, an NK3 receptor antagonist or a pharmaceutically acceptable amount thereof is provided A method of preparing a pharmaceutical composition of a salt and a biguanide or a pharmaceutically acceptable salt thereof.

Detailed description of the invention

In a first aspect, the invention relates to a pharmaceutical composition comprising an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof and a biguanide or a pharmaceutically effective salt thereof, optionally having a pharmaceutically acceptable carrier, and comprising the same A suitable pharmaceutical composition combined.

The NK3 receptor antagonist of the present invention may be selected from the group consisting of Talnetant (SB223412), AZD-4901, AZD-2624 and the biguanide is Metformin.

The pharmaceutically acceptable carrier can be selected from the group consisting of sugars such as: lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethylcellulose, B Cellulose and methylcellulose; calcium phosphate such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearate such as hard Magnesium citrate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cotton oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymer; - cyclodextrin; fatty alcohol; and hydrolyzed cereal solids, as well as other non-toxic compatible fillings, binders, disintegrants, buffers, preservatives, antioxidants, tableting lubricants, flavoring agents, and Similar to the agents commonly used in drug formulation.

The invention also relates to combining separate pharmaceutical compositions in a kit format. That is, a kit that combines two separate units: an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof and a biguanide or a pharmaceutically effective salt thereof. This kit format is particularly advantageous when the separate ingredients must be applied in different dosage forms or at different application intervals.

These pharmaceutical preparations are intended for enteral administration, such as oral administration, as well as rectal or parenteral, to administer a compound having pharmacological activity, either alone or in combination with a conventional pharmaceutical auxiliary substance, to a warm-blooded animal. For example, the pharmaceutical preparation will comprise from about 0.1% to about 90%, preferably from about 1% to about 80%, of the active compound.

Enteric or parenterally administered pharmaceutical preparations are administered, for example, in the form of unit dosages, such as coated lozenges, tablets, capsules or sachets, and ampoules.

The pharmaceutical compositions are prepared in a manner previously known, for example, using conventional mixing, granulating and coating outer coatings, by dissolution or freeze drying. Thus, a pharmaceutical preparation for oral use can be obtained by combining the active compound with a solid excipient, if necessary, granulating the obtained mixture, and if necessary or necessary, adding the appropriate auxiliary substance The mixture is processed or agglomerated into a lozenge or coated lozenge core.

The dosage of the active compound can be a variety of factors, such as the mode of administration, the type of thermostat, age, and/or individual conditions.

Preferred dosages of the active ingredients of the pharmaceutical compositions according to the invention are medically effective doses, especially those which are commercially available.

In one aspect, the invention provides a synergistic composition comprising Talnetant and Metformin in a dosage range from 1 mg to 1000 mg per dose. In a preferred embodiment, the invention provides such a pharmacological combination comprising Talnetant ranging from 1 mg to 50 mg and Metformin ranging from 10 mg to 500 mg.

Generally, in the case of oral administration, it is estimated that, for example, a daily dose of a combination agent for a patient weighing about 75 kg is about 1 mg to about 360 mg.

In a third aspect, the present invention provides a synergistic composition comprising a low dose NK3 receptor antagonist or a pharmaceutically effective salt thereof and a biguanide or a pharmaceutically effective salt thereof for the treatment of PCOS and related diseases.

Many PCOS symptoms are not only related to increased LH pulse, but also due to insulin resistance and hyperinsulinemia. The synergistic effect of insulin and LH promotes the production of follicular sheath cells in PCOS, leading to excessive proliferation of cells to form follicular cysts. Insulin also inhibits sex hormone binding globulin (SHBG) in the liver of women with PCOS, increasing the rate of bioavailable androgens and thereby causing excessive androgen. Insulin also enhances the potential of ACTH-regulated adrenal androgen production Potential. There is sufficient evidence for a functional link between insulin and hypothalamic ovarian (HPO) axis activity (Am. J. Transl. Res., 5(1): 15-20 (2013). Symptoms like menstruation Unregulated, low menstruation and cessation of ovulation can be caused by these HPG axis disturbances and hyperinsulinemia. Thus, the NK3 antagonist SB223412 (Talnetant) or its acceptable salts and Metformin or its acceptable Salt compositions are used to treat irregular menstruation, low menstruation, and cessation of ovulation.

In one embodiment, the use of the compositions of the invention is to modify PCOS by modulating the hypothalamic-genus-gonadal (HPG) axis and modulating the amount of LH or GnRH pulses.

The use of a compound of the invention in another embodiment is directed to the treatment of infertility and the formation of polyvesicles. The advantages of the compositions of the present invention outweigh the combination of Clomiphene and Metformin, which improves the conception rate but has the risk of ovarian hyperstimulation and multiple pregnancy. In another embodiment, the compounds of the invention are used to reduce the concentration of testosterone in puberty and adult women suffering from PCOS.

In another embodiment, a compound of the invention is used to treat precocious puberty, endometriosis, hypertransoremia, uterine fibroids, pregnancy toxemia, male acne, benign prostate hypertrophy, and/or association with PCOS Androgen-type alopecia.

The amount of NK3 receptor antagonist or its acceptable salt administered to the patient to be treated will vary and vary from about 0.1 mg to 1000 mg per day. The amount of Metformin or its acceptable salt varies from about 100 mg to 1000 mg per day, depending on the patient's profile.

The NK3 antagonist or an acceptable salt thereof and Metformin or an acceptable salt thereof can be administered to a patient in combination with continuous and individual therapeutic ingredients.

Compounds of formula (I) can be prepared by the general methods and examples disclosed in WO 9532948. Metformin for use in the present invention is commercially available or can be conveniently prepared by prior art methods.

Figure 1A: Effect of in vivo NK3 antagonist Talnetant on the feeding and body weight changes of overnight fasted mice at doses of 5, 10 and 20 mg/kg.

Figure IB: Effect of in vivo Metformin on feeding and body weight changes in overnight fasted mice at doses of 50, 100 and 300 mg/kg.

Figure 2: Effect of in vivo NK3 antagonists Talnetant and Metformin on glucose tolerance response in mice overnight fasted.

Figure 3: Effect of feeding responses of C57 mice vaccinated overnight by the in vivo NK3 antagonists Talnetant, Metformin and their compositions.

Figure 4: Effect of the in vivo NK3 antagonists Talnetant, Metformin and their compositions on the glucose tolerance response of overnight fasted C57 mice.

Figure 5A: Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on body weight in DHT-induced PCOS experimental rats.

Figure 5B: Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on insulin resistance test in experimental rats fasted for six hours.

Figure 5C: Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on the glucose tolerance response of experimental rats fasted overnight.

Figure-5D: Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on the ovarian weight of experimental rats.

Experiment-1 Effect of in vivo NK3 antagonists Talnetant and Metformin on the feeding response of overnight fasting C57 mice

Animals fasted for 20 hours were orally administered with Talnetant (5, 10 and 20 mg/kg) and Metformin (50, 100 and 300 mg/kg) or vehicle. Food intake was measured for four hours and body weight was recorded at 0 and 4 hours. 5, 10 and 20 mg/kg, respectively. (Talnetant) reduced food intake by 1.9, 8.6, and 9.5%, and decreased body weight by 8.5, 16.0, and 20.8%, as shown in Figure-1A. At 50, 100, and 300 mg/kg, respectively, Metformin reduced food intake by 11.0, 16.4, and 18.7%, and decreased weight gain by 17, 37, and 41%. Metformin 50 and 100 mg/kg showed significant reductions in food intake and weight gain, respectively, when compared to the vehicle control group. Data represent means ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test (n = 6).

Experiment-2-In vivo effects of NK3 antagonists Talnetant and Metformin on glucose tolerance in mice overnight fasting

Animals fasted for 20 hours were orally administered with Talnetant (5, 10 and 20 mg/kg) and Metformin (50, 100 and 300 mg/kg) or vehicle. Glucose load (5 g/kg) was administered 15 minutes after oral treatment. Glucose was measured by a one touch ultra blood glucose meter at -15, 0, 15, 30, 60 and 120 minutes after the glucose load was applied. The results indicate that in Figure 2, Talnetant showed a decrease in AUC glucose of 1.4, 3.3, and 10.8% at 5, 10, and 15 mg/kg, respectively, as shown in Figure 2. Metformin reduced AUC glucose (120 min*mg/dL) by 4.7, 15.2 and 32.1% at 50, 100 and 300 mg/kg, respectively. Only Metformin 100 and 300 mg/kg significantly reduced AUC glucose by 120 min*mg/dL when compared to the vehicle group. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Experiment - Effect of feeding reaction of C57 mice with overnight NK3 antagonist Talnetant, Metformin and their compositions

Animals fasted for 20 hours were orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), a composition or a transport agent. Food intake was measured for four hours and body weight was recorded at 0 and 4 hours. The results indicated that Talnetant reduced food intake by 1.9% and weight gain by 12.6% when compared to vehicle; Metformin significantly reduced food intake by 19.3% and body weight when compared to vehicle. The change was 43.2%; and the composition of the composition significantly reduced food intake by 24% and body weight change by 37.9% when compared to the vehicle. Treatment of the composition showed synergistic effects on reducing food intake. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Experiment 4 Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on glucose tolerance response in overnight fasting C57 mice

Animals fasted for 20 hours were orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), a composition or a transport agent. Glucose load (5 g/kg) was administered 15 minutes after oral administration. Glucose was measured by a one touch ultra blood glucose meter at -15, 0, 15, 30, 60 and 120 minutes after the glucose load was applied. The results showed that the use of Talnetant, Metformin and their compositions reduced AUC glucose (120 min*mg/dL) by 3.1%, 20.5% and 31.4%, respectively, when compared to the vehicle control group. Treatment of the composition showed a synergistic effect on the reduction of AUC glucose (120 min*mg/dL) compared to treatment with Talnetant and Metformin alone. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Table 4: Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on glucose tolerance response in overnight fasted C57 mice

Experiment-5A-In vivo NK3 antagonists Talnetant, Metformin and their compositions in DHT-induced PCOS experimental rats on body weight

Animals were treated intraperitoneally (IP) with 20 mg/kg DHT (dihydrotinosterone) for eight weeks and a normal control group without DHT treatment was set up. All DHT-treated animals were grouped according to their body weight and orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), composition or vehicle for 30 days. Body weight was recorded every other day throughout the study period. The results in Figure-5A show the weights of Talnetant (10 mg/kg), Metformin (100 mg/kg), the composition and the normal control group, respectively, compared to the vehicle group. Reduced by 3.3, 2.1, 9.9 and 19.7%. Composition treatment showed a synergistic effect on weight loss. The body weight in the normal control group was significantly lower than that in the DHT control group. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Experiment-5B - Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on insulin resistance test in rats subjected to fasting for six hours

Eight weeks after treatment with 20 mg/kg DHT (dihydrocretinone), animals were grouped according to body weight and orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), composition Or transport agent for 30 days. After 30 days of DHT treatment, all fasted six hour animals were given Talnetant (10 mg/kg), Metformin (100 mg/kg), composition or vehicle. After the drug treatment, insulin (0.5 IU/kg) was administered intraperitoneally for 15 minutes. Glucose was measured by a one touch ultra blood glucose meter at -15, 0, 15, 30, 60 and 120 minutes after insulin treatment. The results are shown in Figure-5B, treated with Talnetant, Metformin, composition and normal control, AUC glucose decreased by 15.6%, 20.6%, 23.6% and 29.1%, respectively. The group of compositions significantly normalizes insulin sensitivity when compared to a group of carriers, and is preferably used alone than Talnetant and Metformin. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Experiment - 5C - Effect of in vivo NK3 antagonists Talnetant, Metformin and their compositions on the glucose tolerance response of rats in overnight fasting experiments.

Eight weeks after treatment with 20 mg/kg DHT (dihydrocretinone), animals were grouped according to body weight and orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), composition Or transport agent for 30 days. Over 30 days later, rats that were fasted overnight were given Talnetant (10 mg/kg), Metformin (100 mg/kg), a composition or a transport agent. A glucose load of 5 g/kg was administered 15 minutes after drug treatment. Glucose was measured by a one touch ultra blood glucose meter at -15, 0, 15, 30, 60 and 120 minutes after the glucose load was applied. The results are shown in Figure-5C, when compared to the vehicle control group, Talnetant, Metformin, the composition, and the normal control group reduced AUC glucose by 1.1%, 12.7%, 19.9%, and 20.8%. Composition treatment showed synergistically improved glucose tolerance. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Experiment - 5D - Effect of the in vivo NK3 antagonists Talnetant, Metformin and their compositions on the ovarian weight of experimental rats.

After eight weeks of treatment with 20 mg/kg DHT (dihydroxosterone), animals were grouped according to body weight and orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), combination Or transport agent for 30 days. At the end of the study, all animals were sacrificed by posterior cervical dislocation and both ovaries were collected and weighed and stored in 10% formalin for histopathological studies. The results are shown in Figure-5D, when compared to the vehicle-delivered group, Talnetant, Metformin, composition treatment, and normal control group reduced ovarian weight by 15.7%, 28.3%, respectively. 40.2% and 33.2%. The composition is treated synergistically to normalize ovarian weight. Data represent mean ± SEM, n = 6 per group, analyzed by one-way ANOVA followed by Dunnett-t test.

Insulin resistance and compensatory hyperinsulinemia are type 2 diabetes, dyslipidemia, hypertension, and arteriosclerosis, a risk factor known as the discovery group for metabolic syndrome (J Am Sci 2013;9(12):54-62 ). Insulin resistance and compensatory hyperinsulinemia are also polycystic ovarian disease An important feature of PCOS, a condition characterized by chronic anovulation and excessive androgen, affecting women of reproductive age. In women affected by PCOS, hyperinsulinemia may lead to the onset of polycystic ovarian syndrome by promoting abnormal and normal androgen secretion and blocking follicular production and menstrual cycle (Azziz, 2003 and Feng et Al., 2013). In PCOS, the LH concentration increases and the FSH concentration decreases resulting in an elevated LH/FSH ratio (Semin Reprod Med. 2002 Nov; 20(4): 317-26). The characteristics of the experimental model of DHT-induced PCOS are closely related to the pathophysiological results of PCOS in patients, including: follicular growth pause, chronic anovulation, minimal ovarian granulosa cell proliferation, hyperproliferation of cells, hyperandrogenemia Central obesity, glucose intolerance, and insulin resistance (J Am Sci 2013; 9(12): 54-62, Endocrine Reviews, October 2015, 36(5): 487-525). Our data demonstrate that after acute treatment, the combination of Talnetant and Metformin synergistically reduces body weight and food intake, while composition is observed for weight and ovarian weight after chronic treatment. Synergistic effects with glucose tolerance and additive effects on insulin sensitivity. The findings in these studies support the combination of Metformin and NK3 antagonists as an effective method to restore PCOS and associated abnormal conditions.

Claims (13)

A synergistic composition comprising (i) an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof, (ii) biguanide or a pharmaceutically effective salt thereof. A synergistic composition according to claim 1, wherein the NK3 receptor antagonist is selected from the group consisting of Talnetant (SB223412), AZD-4901 and AZD-2624. A synergistic composition according to claim 1, wherein the biguanide is Metformin. A synergistic composition according to claim 1 for use in the treatment of PCOS and its selected from the hypothalamic-cerebral sinus-gonadal (HPG) axis, modified LH pulse and therapeutic premature aging, endometriosis, hypermenstrual hyperemia Symptoms, uterine fibroids, pregnancy toxemia, male acne, benign prostate hypertrophy, and/or androgen-type alopecia. A pharmaceutical composition comprising (i) an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof, (ii) biguanide or a pharmaceutically effective salt thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a suitable binder, extender, lubricant, eliminator, disintegrant, and humectant. The pharmaceutical composition according to claim 5, which may be in the form of a troche, a capsule, a powder, a granule, a lozenge, a suppository, a reconstitutable powder, or a liquid preparation. The pharmaceutical composition according to any one of claims 5 to 7, which comprises (i) an NK3 receptor antagonist or a pharmaceutically acceptable salt thereof, (ii) biguanide or a pharmaceutically effective salt thereof for use in therapy PCOS3 and its selection from the hypothalamus-cerebral gland-gonadal (HPG) axis, modified LH pulse and therapeutic precocious puberty, endometriosis, hypermenstrual hyperemia, uterine fibroids, pregnancy toxemia, male acne, A condition associated with benign prostate hypertrophy and/or androgenetic alopecia. The pharmaceutical composition according to any one of claims 5 to 8, wherein the composition is in a unit dosage form. According to the pharmaceutical composition of claim 5, the NK3 receptor system is selected from the group consisting of rituxan and the bismuth is selected from the group consisting of memantine. The pharmaceutical composition according to claim 5, wherein the doses of talnetan and memantine range from 1 mg to 1000 mg. The pharmaceutical composition according to claim 3, wherein the range of the statin is from 1 mg to 50 mg, and the range of melamine is from 10 mg to 500 mg. A kit comprising, in a single package, a medicinal composition in a separate container, comprising a pharmaceutical composition comprising thatanant in a container thereof, and a pharmaceutical composition comprising melamine in the second container Things.