JP6952320B2 - New NK3 receptor agonist - Google Patents

Description

The present invention relates to a peptide having a neurokinin 3 receptor (NK3 receptor) agonistic action and its use. More specifically, the present invention relates to a peptide having a selective and strong binding affinity to the NK3 receptor and an agonistic action, and capable of sustainably acting in vivo, and its use.

The anterior hypothalamic kisspeptin neuron population is the ovulation center that controls the surge-like secretion of gonadotropin-releasing hormone (GnRH) by the positive feedback action of estrogen, and kisspeptins are expected as new drugs that regulate ovulation induction. Has been done.
On the other hand, in recent years, various reports have been made on the pulsed secretion of GnRH, which is thought to be involved in follicle development, and kisspeptin neurons in the arcuate nucleus of the hypothalamus simultaneously express neurokinin B (NKB) and dynorphin ( It has been reported that it plays a role as a center for promoting pulsed secretion of GnRH (Non-Patent Document 1) (Non-Patent Document 2). We also succeeded in recording the firing activity in this neuron as a transient increase in multineuron firing activity (MUA) (MUA volley), which is completely synchronized with the luteinizing hormone (LH) pulse. It has been reported that this is the case (Non-Patent Documents 3 and 4).
Against this background, the present inventors have assumed that the NK3 receptor ligand (agonist) known as a receptor for NKB can be a drug that regulates GnRH pulse and LH pulse and controls follicle development. We have begun to create a new NK3 receptor ligand.
Previously reported NK3 receptor-selective agonists include [MePhe ⁷ ] -NKB and senktide (Non-Patent Documents 5 and 6). These peptides, which are already commercially available as research reagents, are used in various basic studies related to tachykinins and neurokinin receptors. The present inventors have ^{developed a structure-activity relationship study for the purpose of obtaining knowledge on the activity of [MePhe 7} ] -NKB and the structural requirement characteristics of receptor selectivity, and in this process, they are highly active against the NK3 receptor. Moreover, a novel NKB derivative that acts with high selectivity has been found (Patent Documents 1 and 2 and Non-Patent Documents 7 to 9).
Although the peptides found so far are excellent NK3 receptor-selective ligands, repeated administration was required to maintain their effects. When considering clinical applications that require control of reproductive physiology such as livestock, the provision of sustained effects after drug administration is an important issue. In addition, it is expected to use continuous administration of the drug or a long-acting preparation encapsulated in an appropriate base in anticipation of a long-lasting effect, but in the case of a drug with fast clearance, a considerable amount of drug substance is required. Therefore, it was necessary to develop a drug with slow clearance while maintaining the same activity.

International Publication 2014/061772 International Publication 2015/083816

Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ. Endocrinology, 148, 5752-5760 (2007) Maeda K, Ohkura S, Uenoyama Y, Wakabayashi Y, Oka Y, Tsukamura H, Okamura H. Brain Res. 1364, 103-115 (2010) Ohkura S, Takase K, Matsuyama S, Mogi K, Ichimaru T, Wakabayashi Y, Uenoyama Y, Mori Y, Steiner RA, Tsukamura H, Maeda KI, Okamura H. J. Neuroendocrinol. 21, 813-821 (2009) Wakabayashi Y, Nakada T, Murata K, Ohkura S, Mogi K, Navarro VM, Clifton DK, Mori Y, Tsukamura H, Maeda KI, Steiner RA, Okamura H. J. Neurosci. 30, 3124-3132 (2010) Drapeau G, D'Orleans-Juste P, Dion S, Rhaleb NE, Rouissi NE, Regoli D. Neuropeptides. 10 (1) 43-54 (1987) Laufer R, Gilon C, Chorev M, Selinger Z. J Biol Chem. 261: 10257-10263 (1986) Misu R, Noguchi T, Ohno H, Oishi S, Fujii N. Bioorg. Med. Chem. 21 (8) 2413-2417 (2013) Misu R, Oishi S, Yamada A, Yamamura T, Matsuda F, Yamamoto K, Noguchi T, Ohno H, Okamura H, Ohkura S, Fujii N. J Med Chem. 57 (20) 8646-8651 (2014) Misu R, Yamamoto K, Yamada A, Noguchi T, Ohno H, Yamamura T, Okamura H, Matsuda F, Ohkura S, Oishi S, Fujii N. MedChemComm, 6 (3) 469-476 (2015)

An object of the present invention is to provide a novel NK3 receptor-selective ligand that is expected to act continuously in vivo with high activity and high selectivity.

So far, senktide has been reported as one of the NK3 receptor-selective agonists. Based on the structure-activity relationship information of tachykinins reported so far, the present inventors have found ^{that a derivative in which aspartic acid (Asp 1} ) of senktide is replaced with glutamic acid (Glu) is a strong and highly selective NK3 receptor. It has been found to exhibit body agonist activity. Therefore, using such a peptide as a lead compound, we attempted to develop a derivative that can act more sustainably in vivo.
First, the present inventors prepared a derivative in which polyethylene glycol (PEG) chains having various chain lengths were covalently bonded to the Glu side chain via an ester bond as a senktide derivative that can be cleaved by esterase in blood. Unexpectedly, these peptides were not degraded in plasma and did not regenerate senktide derivatives. However, it was found that these peptides maintain the NK3 receptor agonist activity even in the structure in which the PEG chain remains covalently bound to the peptide sequence.
Based on such findings, the present inventors prepared various PEG-modified senkitide derivatives, evaluated the NK3 receptor agonist activity, and performed in vivo evaluation. As a result, the present invention has been completed by finding a novel derivative in which in vivo activity is maintained for a long period of time while maintaining the same biological activity as senktide.
That is, the present invention is as follows.
[1] Equation (I)

[In the formula, X1 represents an R1-A1 or dicarboxylic acid residue modified directly or via a linker with polyethylene glycol (PEG) having a molecular weight of 1 or 2 or a derivative thereof;
R1 is a hydrogen atom, an acetyl group, an oxalyl group, a succinyl group, an aminocarbonyl group, a hydroxyaminocarbonyl group, a hydradinocarbonyl group, a methoxydicarbonyl group, an aminodicarbonyl group, an aminosulfonyl group, N, N-dicarboxymethyl. Represents an aspartic acid residue or an N-carboxymethyl aspartic acid residue;
A1 represents L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, L-glutamine, D-glutamine, or L-α-aminoadipate residue;
A2 represents L-phenylalanine, L-tyrosine, L-aspartic acid, D-aspartic acid, L-glutamic acid, or D-glutamic acid residue;
A3 represents the residue of L-N-methylphenylalanine, L-N-methylvaline, L-N-methylisoleucine, L-N-methyltyrosine, or L-N-methyltryptophan;
X4-X5 represents Gly-Leu or its dipeptide equivalent;
Gly represents a glycine residue;
Leu represents a leucine residue;
Met-NH ₂ represents a methionine amide] or a physiologically acceptable salt thereof.
[2] The compound according to the above [1] or a physiologically acceptable salt thereof, wherein the modification with PEG or a derivative thereof is due to an ester bond or an amide bond.
[3] The compound according to claim 1 or 2, or a physiologically acceptable salt thereof, wherein the linker is a group represented by the following formula.

[In the formula, m is 1 or 2;
* A indicates the binding site with X1;
* B indicates a binding site with PEG or a derivative thereof.
[4] R1 is a succinyl group, A1 is an L-glutamine or L-glutamine residue, A2 is an L-phenylalanine residue, A3 is an L-N-methylphenylalanine residue, and X4-X5 is Gly-Leu. The compound according to [1] to [3] or a physiologically acceptable salt thereof.
[5] The compound according to the above [1] to [4] or a physiologically acceptable salt thereof, wherein the molecular weight of PEG or a derivative thereof is 750 to 2,000.
[6] Any of the above [1] to [5], wherein PEG or a derivative thereof is selected from polyethylene glycol, polyethylene glycol monomethyl ether, polyethylene glycol monoethyl ether, polyethylene glycol monopropyl ether, and methoxypolyethylene glycol amine. The compound according to the above or a physiologically acceptable salt thereof.
[7] A drug containing the compound according to the above [1] to [6] or a physiologically acceptable salt thereof.
[8] The medicament according to the above [7], which is a neurokinin receptor agonist.
[9] The medicament according to the above [8], wherein the neurokinin receptor is the NK3 receptor.
[10] The medicament according to the above [7], which is a reproductive center control agent.
[11] The medicament according to the above [7], which is for promoting and / or improving follicle growth.
[12] The medicament according to the above [7], wherein tachykinins and / or neurokinin receptors are therapeutic agents for diseases involved in the onset and progression thereof.
[13] The medicament according to the above [12], wherein the disease is sexual dysfunction associated with pain or excess / deficiency of sex hormone secretion.
[14] A reagent containing the compound according to the above [1] or a physiologically acceptable salt thereof.
[15] A compound represented by the following formula or a physiologically acceptable salt thereof.

The compound of the present invention is observed to maintain in vivo activity for a long period of time while maintaining biological activity equal to or higher than that of senktide. Therefore, the highly active and highly selective NK3 receptor agonist obtained by the present invention is a therapeutic agent for diseases associated with excessive or deficient secretion of takinins, such as pain and sexual function associated with excessive or deficient secretion of sex hormones. It is useful as a drug for improving disorders, a reagent for basic scientific experiments for the development of therapeutic drugs for these diseases, and the like.

The figure which shows the result of having investigated the influence of the senktide (control peptide) and the peptide of this invention (peptide 9; Example 2) on the MUA volley which reflects the neural activity of the arcuate nucleus kisspeptin neuron which secretes GnRH in a pulse shape. Is. The vertical axis shows the number of spikes per 20 seconds, and the horizontal axis shows the elapsed time (seconds). The test compound was administered at the time indicated by the arrow. The R value indicates the duration of action, and the V value indicates the number of MUA volleys. It is a figure which shows the result of having investigated the influence of the peptide (peptide 12; Example 5) of this invention on the blood luteinizing hormone (LH) concentration of a goat in a follicular phase. The vertical axis shows the LH concentration in blood (ng / ml), and the horizontal axis shows the elapsed time (time). The test compound was administered at the time indicated by the arrow. It is a figure which shows the result of having investigated the influence of the peptide (peptide 12; Example 5) of this invention on the blood luteinizing hormone (LH) concentration of a goat in the luteal phase. The vertical axis shows the LH concentration in blood (ng / ml), and the horizontal axis shows the elapsed time (time). The test compound was administered at the time indicated by the arrow.

In this specification, when amino acids and the like are indicated by abbreviations, they are based on the abbreviations according to the IUPAC-IUB Commission on Biochemical Nomenclature or the conventional abbreviations in the art, and examples thereof are described below. When there may be optical isomers of amino acids, "L-" indicates L-form (for example, "L-Ala" is L-form Ala), and "D-" indicates D-form. It indicates the body (for example, "D-Ala" is D-form Ala), and when it is indicated as "DL-", it indicates the D-form and L-form racemic (for example, "DL-Ala" is D). Racemic mixture of body Ala and L body Ala). In the present invention, the amino acid residue may be D-form or L-form, but is preferably L-form.
Gly or G: Glycine Ala or A: Alanin Val or V: Valine Leu or L: Leucine Ile or I: Isoleucine Ser or S: Serine Thr or T: Threonine Cys or C: Cysteine Met or M: Methionine Glu or E: Glutamine Asp or D: aspartate Lys or K: lysine Arg or R: arginine His or H: histidine Ph or F: phenylalanine Tyr or Y: tyrosine Trp or W: tryptophan Pro or P: proline Asn or N: asparagine Gln or Q Glutamine pGlu: Pyroglutamic acid MePhe: N-methylphenylalanine MeVal: N-methylvaline MeIle: N-methylisoleucine MeTyr: N-methyltyrosine MeTrp: N-methyltryptophan MeLeu: N-methylleucine Meleu: N-methylleucine Me -Aminoadipic acid

Furthermore, the abbreviations used in this specification mean those shown below unless otherwise specified.
Me: Methyl group (-CH ₃ )
Succinyl: -CO-CH ₂ CH ₂ -COOH
Oxalyl: -CO-COOH
Ac: Acetyl group (-COCH ₃ )
Ph: Phenyl group (-C ₆ H ₅ )

The present invention provides a compound having an agonistic action specific for a neurokinin receptor, specifically, an NK3 receptor. Specifically, the formula (I)

[In the formula, X1 represents an R1-A1 or dicarboxylic acid residue modified with 1 or 2 polyethylene glycol (PEG) having a molecular weight of 500 to 5,000 or a derivative thereof, either directly or via a linker; preferably. ,
R1 is a hydrogen atom, an acetyl group, an oxalyl group, a succinyl group, an aminocarbonyl group, a hydroxyaminocarbonyl group, a hydradinocarbonyl group, a methoxydicarbonyl group, an aminodicarbonyl group, an aminosulfonyl group, N, N-dicarboxymethyl. Represents an aspartic acid residue or an N-carboxymethyl aspartic acid residue;
A1 represents L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, L-glutamine, D-glutamine, or L-α-aminoadipate residue;
A2 represents L-phenylalanine, L-tyrosine, L-aspartic acid, D-aspartic acid, L-glutamic acid, or D-glutamic acid residue;
A3 represents the residue of L-N-methylphenylalanine, L-N-methylvaline, L-N-methylisoleucine, L-N-methyltyrosine, or L-N-methyltryptophan;
X4-X5 represents Gly-Leu or its dipeptide equivalent;
Gly represents a glycine residue;
Leu represents a leucine residue;
Met-NH ₂ represents a methionine amide] (also referred to herein as compound (I)) or a physiologically acceptable salt thereof.

In formula (I), X1 represents an R1-A1 or dicarboxylic acid residue modified with 1 or 2 polyethylene glycol (PEG) having a molecular weight of 500 to 5,000 or a derivative thereof, either directly or via a linker. .. Here, R1 can be any group, but preferably R1 is a hydrogen atom, an acetyl group, an oxalyl group, a succinyl group, an aminocarbonyl group, a hydroxyaminocarbonyl group, a hydrazinocarbonyl group, a methoxydicarbonyl group, It represents an aminodicarbonyl group, an aminosulfonyl group, an N, N-dicarboxymethyl aspartic acid residue, or an N-carboxymethyl aspartic acid residue, and A1 is L-aspartic acid, D-aspartic acid, L-glutamic acid. , D-Glutamic acid, L-Glutamine, D-Glutamine, or L-α-aminoadipate residue. The dicarboxylic acid residue as X1 is not particularly limited as long as it has a structure having two carboxyl groups or a modifying group corresponding thereto. Preferably, R1 is a succinyl group and A1 is an L-glutamic acid or L-glutamine residue.

In the present invention, in formula (I), X1 is a polyethylene glycol (PEG) or a derivative thereof having a molecular weight of 1 or 2 of 500 to 5,000, preferably 750 to 5,000, and more preferably 750 to 2,000. It is characterized by being modified (hereinafter, also referred to as PEG modification or PEGylation). The PEG modification in X1 is performed at any modifiable position, preferably for R1 or A1, and more preferably for A1. Modification with PEG is performed directly on X1, i.e. R1 or A1 (preferably A1) or via a linker. Here, the linker is not particularly limited as long as it has a site capable of binding to 1 or 2 PEG and a site capable of binding to R1 or A1 (preferably A1), but is specifically represented by the following formula. The group to be used is mentioned.

[In the formula, m is 1 or 2;
* A indicates the binding site with X1;
* B indicates a binding site with PEG or a derivative thereof.
For example, amino acid residues, preferably aspartic acid residues and glutamic acid residues, more preferably aspartic acid residues can be mentioned. If the molecular weight of PEG is too small / too large, it is difficult to obtain a continuous enhancing effect of neural activity in the reproductive center.

Here, PEG or a derivative thereof is usually represented by the following formula. A hydroxyl group (-OH) or an amino group (-NH ₂ ) is used for binding to the peptide chain (or linker).

In the formula, R represents a hydrogen atom and an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl).
In addition to the above, examples of PEG derivatives include compounds having PEG as a basic skeleton and having functional groups such as a thiol group, a maleimide group, and a succinimidyl ester group at both ends thereof.
Generally, commercially available PEG is a mixture obtained by polymerizing a monomer such as ethylene oxide and separated by a rough molecular weight. The high molecular weight PEG has a molecular weight distribution and has a molecular weight of about ± 10 to 30%. There is variation. It is generally expressed using the average molecular weight. For example, PEG1000 means that the average molecular weight is 1,000, and PEG2k means that the average molecular weight is 2,000.
The molecular weight of one unit (-CH ₂ CH ₂ O-) structure of PEG (hereinafter, also referred to as PEG unit structure) is 44, and therefore, for example, in the case of PEG500, the number (n) of PEG unit structures is 500/44 ≈ 11.4. Experimentally, the value of n on the normal distribution, which peaks at n = 11 and n = 12, is observed. Similarly, in the case of PEG5000, the number of unit structures of PEG is 5000/44≈113.6, and the value of n on the normal distribution vertices of n = 113 and n = 114 is observed.

When PEGylation is performed on R1, the following structure can be mentioned as an example of X1 (when R is a methyl group, R1 is an oxalyl group, and A1 is a glutamic acid or glutamine residue).

In the formula, n indicates the unit structure of PEG, is an arbitrary integer set to have a molecular weight of 500 to 5,000, and is usually 11 to 113. It is preferably an arbitrary integer set to have a molecular weight of 750 to 5,000, usually 17 to 113. More preferably, it is an arbitrary integer set to have a molecular weight of 750 to 2,000, and is usually 17 to 46. X is -O- or -NH-.

When PEGylation is performed on A1, the following structure can be mentioned as an example of X1 (when R is a methyl group, R1 is a succinyl group, and A1 is a glutamic acid or glutamine residue).

In the formula, n indicates the unit structure of PEG, is an arbitrary integer set to have a molecular weight of 500 to 5,000, and is usually 11 to 113. It is preferably an arbitrary integer set to have a molecular weight of 750 to 5,000, usually 17 to 113. More preferably, it is an arbitrary integer set to have a molecular weight of 750 to 2,000, and is usually 17 to 46. X is -O- or -NH-.

When PEGylation is performed on A1 via a linker, examples of X1 include the following structures (R is a methyl group, R1 is a succinyl group, A1 is a glutamic acid or glutamine residue, and the linker is aspartic acid. For residues).

In the formula, n represents the unit structure of PEG. The n PEGs may be the same or different, but are preferably the same and are convenient. n is an arbitrary integer set so that the PEG1 molecule has a molecular weight of 500 to 5,000, and is usually 11 to 113. It is preferably an arbitrary integer set to have a molecular weight of 750 to 5,000, usually 17 to 113. More preferably, it is an arbitrary integer set to have a molecular weight of 750 to 2,000, and is usually 17 to 46. The two Xs are the same and are -O- or -NH-.

In the above formula (I), A2 represents L-phenylalanine, L-tyrosine, L-aspartic acid, D-aspartic acid, L-glutamic acid, or D-glutamic acid residue. It is preferably an L-phenylalanine residue.

In the above formula (I), A3 represents an L-N-methylphenylalanine, an L-N-methylvaline, an L-N-methylisoleucine, an L-N-methyltyrosine, or an L-N-methyltryptophan residue. It is preferably an L-N-methylphenylalanine residue.

In the above formula (I), X4-X5 represents Gly-Leu or a dipeptide equivalent thereof. Gly-Leu represents a residue of a dipeptide in which glycine and leucine are bound by a peptide bond, and is shown by the following structure.

A dipeptide equivalent of Gly-Leu is one in which the peptide bond (-CONH-) of Gly-Leu is replaced with another bond, and the other bond is -CH = CH-, -CH _2- CH _2- , -CH ₂ -CH =, -C (= N-OH) -NH-, -C (= NH) -NH-, etc. can be mentioned. Such a dipeptide equivalent may be referred to herein as GlyψLeu.
As X4-X5, it is preferably Gly-Leu.

As compound (I), in R1-A1 which is preferably X1, R1 is a succinyl group, A1 is a glutamine acid or glutamine residue, A2 is an L-phenylalanine residue, A3 is an N-methylphenylalanine residue, and X4-X5. Is Gly-Leu, a compound in which A1 is PEG-modified, and more preferably a compound represented by the formula (II) shown in the following table (hereinafter, also referred to as compound (II)).

MPEG500, MPEG750, MPEG1k, MPEG2k, and MPEG5k mean residues derived from polyethylene glycol monomethyl ethers having average molecular weights of 500, 750, 1,000, 2,000, and 5,000, respectively. (AA) means the type of amino acid corresponding to A1 in the formula (I), and the amino acid is PEG-modified either directly or via a linker such as an amino acid.
Including compound (I) and compound (II), hereinafter, also referred to as the compound of the present invention or the peptide of the present invention.

The compound of the present invention may be in the form of a salt. Examples of such a salt include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine. And so on. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid. Examples thereof include salts with acids, p-toluene sulfonic acids and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Be done.
Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.), When the ammonium salt or the like also has a basic functional group in the compound, for example, a salt with an inorganic acid accompanied by hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid. , Succinic acid, tartrate acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and other organic acids are preferred.

The compound of the present invention is a peptide and can be produced according to a method for synthesizing a peptide known per se. PEGylation may be carried out on an amino acid raw material or a peptide after synthesis, but it is preferably carried out on an amino acid raw material. PEGylation can be carried out using methods commonly practiced in the art, specifically by a condensation reaction. The following reactions are exemplified, but the reagents can be appropriately changed according to the desired peptide or the raw material to be used, and the reaction conditions such as volume, reaction temperature, and reaction time can be appropriately set.

When R1 is PEGylated, for example, when R1 is an oxalyl group, PEG or a derivative thereof and oxalyl chloride are reacted in an organic solvent (eg, dry diethyl ether or the like).
When A1 is PEGylated, for example, when A1 is a glutamate residue, glutamate having both ends protected with protecting groups (eg, Fmoc and Bn) and PEG or a derivative thereof are placed in an organic solvent (eg, dichloromethane, etc.). , Bases (eg, 4-dimethylaminopyridine (DMAP), diisopropylethylamine (DIPEA), etc.) and condensing agents (eg, HATU, DCC, EDCl · HCl / HOBt), followed by optionally Deprotection by hydrogenation with a catalyst.
More specifically, it can be carried out by the method described in Examples and a method similar thereto.

As the peptide synthesis method, for example, either a solid phase synthesis method or a liquid phase synthesis method may be used. That is, the desired peptide can be produced by repeating the condensation of the partial peptide or amino acid that can constitute the compound of the present invention and the residual portion according to a desired sequence. When the product having the desired sequence has a protecting group, the desired peptide can be produced by removing the protecting group. Examples of known condensation methods and protective group elimination methods include the methods described in (1) to (5) below.
(1) M. Bodanszky and MA Ondetti, Peptide Synthesis, Interscience Publishers, New York (1966)
(2) Schroeder and Luebke, The Peptide, Academic Press, New York (1965)
(3) Nobuo Izumiya et al., Basics and Experiments of Peptide Synthesis, Maruzen Co., Ltd. (1975)
(4) Haruaki Yajima and Shunpei Sakakibara, Biochemistry Experiment Course 1, Protein Chemistry IV, 205, (1977)
(5) Supervised by Haruaki Yajima, Development of continued pharmaceuticals Vol. 14 Peptide synthesis Hirokawa Shoten After the reaction, a combination of conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc. The peptide of the present invention can be purified and isolated. When the peptide obtained by the above method is a free form, it can be converted into an appropriate salt by a known method, and conversely, when it is obtained by a salt, it can be converted into a free form by a known method. ..
The raw material compound may be a salt, and examples of such a salt include the same salts as those described above as the salts of the peptides of the present invention.

For the condensation of protected amino acids or peptides, various activation reagents that can be used for peptide synthesis can be used, and in particular, trisphosphonium salts, tetramethyluronium salts, carbodiimides and the like are preferable. Trisphosphonium salts include benzotriazole-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphosphate (PyBOP), bromotris (pyrrolidino) phosphonium hexafluorophosphosphate (PyBroP), 7-azabenzotriazole- 1-Iloxytris (pyrrolidino) phosphonium hexafluorophosphosphate (PyAOP), 2- (1H-benzotriazol-1-yl) -1,1,3,3-hexafluoro as tetramethyluronium salts Phosphate (HBTU), 2- (7-azabenzotriazol-1-yl) -1,1,3,3-hexafluorophosphofate (HATU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (5-norbornene-2,3-dicarboxyimide) -1,1,3,3-tetramethyluronium tetra Fluorobolate (TNTU), O- (N-succimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), DCC as carbodiimides, N, N'-diisopropylcarbodiimide (DIPCDI) ), N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI · HCl) and the like. Racemization inhibitors (eg, N-hydroxy-5-norbornene-2,3-dicarboxyimide (HONB), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (eg, N-hydroxy-5-norbornene-2,3-dicarboxyimide (HONB)), 1-hydroxy-7-azabenzotriazole (eg HOAt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), etc.) is preferably added. As the solvent used for the condensation, a solvent known to be usable for the peptide condensation reaction can be appropriately selected. For example, anhydrous or hydrous N, N-dimethylformamide, N, N-dimethylacetamide, acid amides such as N-methylpyrrolidone, halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as trifluoroethanol and phenol. , Sulfoxides such as dimethylsulfoxide, tertiary amines such as pyridine, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate and ethyl acetate, or appropriate mixtures thereof, etc. Is used. The reaction temperature is appropriately selected from the range known to be usable for the peptide bond forming reaction, and is usually appropriately selected from the range of about −20 ° C. to 50 ° C. Activated amino acid derivatives are usually used in 1.5 to 6 fold excesses. In the case of solid-phase synthesis, as a result of a test using a ninhydrin reaction, if the condensation is insufficient, sufficient condensation can be performed by repeating the condensation reaction without removing the protecting group. When sufficient condensation cannot be obtained even after repeating the reaction, the unreacted amino acid can be acylated with acetic anhydride, acetylimidazole, or the like so as not to affect the subsequent reaction.

Examples of the protecting group for the amino group of the raw material amino acid include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl and Cl-Z. , Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulphenyl, diphenylphosphinochi oil, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl (Trt) and the like. ..
The protecting group of the carboxyl groups in the starting amino acids, for example, tert- butyl (Bu ^t) group, benzyl (Bzl) _{group, C 1-6 alkyl, C 3-10} cycloalkyl _group, the _{C 7-14} aralkyl group Other examples include allyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl and benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and the like.
The hydroxyl groups of serine and threonine can be protected, for example, by esterification or etherification. Examples of the group suitable for this esterification include a lower (C _2-4 ) alkanoyl group such as an acetyl group, an aroyl group such as a benzoyl group, and a group derived from an organic acid. Examples of a group appropriately used for the etherification include benzyl, tetrahydropyranyl, Bu ^t, a Trt like.
Examples of groups for protecting the phenolic hydroxyl group of tyrosine include Bzl, 2,6-di-chlorobenzyl, 2-nitrobenzyl, Br-Z, Bu ^t, and the like.
Examples of the protecting group for imidazole of histidine include p-toluenesulfonyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), 2,4-dinitrophenyl (DNP), and benzyloxymethyl (Bom). ), tert-butoxymethyl (Bum), Boc, Trt, Fmoc and the like.
Protecting groups for the guanidino group of arginine include, for example, Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8. -Pentamethylchroman-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO _2, etc. Can be mentioned.
Protecting groups for the side chain amino groups of lysine include, for example, Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde). ) Etc. can be mentioned.
Examples of tryptophan indrill protecting groups include formyl (For), Z, Boc, Mts, Mtr and the like.
Examples of the protecting group for asparagine and glutamine include Trt, xanthyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob) and the like.
Activated carboxyl groups of the raw material include, for example, the corresponding acid anhydrides, azides, active esters [alcohols (eg, pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyano). Methyl alcohol, paranitrophenol, HONB, N-hydroxysuccimid, HOBt, ester with HOAt) and the like. Activated amino groups of the raw material include, for example, the corresponding phosphite amides.

Protecting group removal (desorption) methods include catalytic reduction in a hydrogen stream in the presence of a catalyst such as Pd black or Pd carbon, and anhydrous hydrogen fluoride, methanesulfonic acid, and trifluoromethanesulfonic acid. , Trifluoroacetic acid, trimesylsilane bromide (TMSBr), trimethylsilyltrifluoromethanesulfonate, tetrafluoroborate, tris (trifluoro) boron, boron tribromide or acid treatment with a mixture thereof, diisopropylethylamine, triethylamine , Basic treatment with piperidine, piperazine, etc., reduction with sodium in liquid ammonia, and the like. The desorption reaction by the above acid treatment is generally carried out at a temperature of -20 ° C to 40 ° C, but in the acid treatment, cation scavengers such as anisole, phenol, thioanisole, metacresol and paracresol, dimethylsulfide, 1 , 4-Butandithiol, 1,2-ethanedithiol and the like are effective. The 2,4-dinitrophenyl group used as the imidazole protecting group of histidine is removed by thiophenol treatment, and the formyl group used as the indol protecting group of tryptophan is the above 1,2-ethanedithiol and 1,4-butane. In addition to deprotection by acid treatment in the presence of dithiol or the like, it is also removed by alkali treatment with dilute sodium hydroxide, dilute ammonia or the like.
The protection and protecting groups of functional groups that should not be involved in the reaction of the raw materials, the elimination of the protecting groups, the activation of the functional groups involved in the reaction, and the like can be appropriately selected from known protecting groups or known means.

The compound of the present invention has a methionine amide at the C-terminal. As a method for obtaining an amide compound of a peptide, solid-phase synthesis is performed using a resin for amide compound synthesis, or the α-carboxyl group of a carboxyl-terminal amino acid is amidated, and then a peptide chain is provided on the amino group side to a desired chain length. After extension, a peptide in which only the N-terminal α-amino group protective group of the peptide chain was removed and a peptide (or amino acid) in which only the C-terminal carboxyl group protective group was removed were produced, and both peptides were prepared. Condensate in a mixed solvent as described above. The details of the condensation reaction are the same as above. After purifying the protected peptide obtained by condensation, all protecting groups can be removed by the above method to obtain a desired crude polypeptide. This crude peptide can be purified by making full use of various known purification means, and the main fraction can be freeze-dried to obtain an amide compound of the desired peptide.

When the compound of the present invention exists as a configuration isomer (conformer isomer) such as an enantiomer, a diastereomer, etc., a conformer (conformer isomer), etc., these are also contained as the compound of the present invention, and if desired. , Each of which can be isolated by means known per se, the above-mentioned separation and purification means. When the compound of the present invention is a racemate, it can be separated into an S-form and an R-form by ordinary optical resolution means. When a steric isomer is present in the compound of the present invention, the compound of the present invention includes the case where the isomer is alone or a mixture thereof.
Further, the compound of the present invention may be a solvate (eg, hydrate) or a non-solvate (eg, non-hydrate).
The compounds of the present invention ^{may be labeled with isotopes (eg, 3} H, ¹⁴ C, ³⁵ S, ¹²⁵ I) and the like.
Further, the compound of the present invention may be a deuterium converter obtained by converting ¹ H to ^{2 H (D).}

Peptides in the present specification are N-terminal (amino-terminal) at the left end and C-terminal (carboxyl-terminal) at the right end according to the convention of peptide notation. When the N-terminal amino acid of the peptide is labeled as "H-", it indicates that the terminal amino group is not derivatized. When the C-terminal amino acid of the peptide is labeled as "-NH ₂ ", it indicates that the terminal carboxyl group is amidated.

The compound of the present invention may be a crystal, and the crystal form of the crystal may be single or plural. The crystal can be produced by using a crystallization method known per se.
The compound of the present invention may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
The crystals of the compounds of the present invention have excellent physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), medicinal effects), and are suitable as pharmaceuticals. Extremely useful.

The compound of the present invention has an NK3 receptor agonistic action. From this effect, the compounds of the present invention accept tachykinins and / or neurokinins in mammals (eg, humans, monkeys, cats, pigs, horses, cows, goats, mice, rats, guinea pigs, dogs, rabbits, etc.). It is useful as a prophylactic or therapeutic agent for diseases and pathological conditions in which the body is involved in its onset and progression. Therefore, the present invention presents an effective amount of the compound of the present invention to a subject requiring it (eg, human, monkey, cat, pig, horse, cow, goat, mouse, rat, guinea pig, dog, rabbit, etc .; especially human. ) Provided a method for treating a disease in which tachykinins and / or neurokinin receptors are involved in the onset and progression thereof, including administration to.
Examples of such diseases and pathological conditions include excessive / deficient sex hormone secretion, sexual dysfunction / stunted growth due to insufficient secretion, benign tumors, malignant tumors, metabolic disorders, and the like.
Furthermore, the compound of the present invention has a stimulating effect on the reproductive center that controls follicle development, and acts centrally to continuously enhance the neural activity of the kisspeptin / neurokinin nerve. From this action, the compounds of the present invention are used for promoting and / or improving follicle growth in mammals (eg, humans, monkeys, cats, pigs, horses, cows, goats, mice, rats, guinea pigs, dogs, rabbits, etc.). It is useful as a medicine for dogs. In addition, compound (I) is useful as a reproductive center control agent that acts on the reproductive center. Therefore, the present invention states that an effective amount of the compound of the present invention is administered to livestock (eg, cattle, goats, sheep, etc.). Provided are methods of controlling the breeding of the livestock, including. According to the present invention, the frequency of LH pulses involved in follicle development can be increased, and the production cycle of livestock (eg, cattle, goats, sheep, etc.) can be shortened.

The compound of the present invention is used as a medicine as it is or by formulating it with a pharmacologically acceptable carrier according to a means known per se, for example, the method described in the Japanese Pharmacopoeia.

A drug containing the compound of the present invention has low toxicity, and the compound of the present invention is mixed as it is or with a pharmacologically acceptable carrier according to a self-known means generally used in a method for producing a pharmaceutical preparation. Then, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), powders, granules, capsules (including soft capsules and microcapsules), liquids, troches, syrups, emulsions. , Suspensions, injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments), suppositories Oral or parenteral (eg, topical, rectal, intravenous administration) as pharmaceutical preparations such as agents (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, transpulmonary agents (inhalants), drip agents, etc. Etc.) can be safely administered.
In addition, these preparations may be release control preparations (eg, sustained release microcapsules) such as immediate release preparations or sustained release preparations.
The content of the compound of the present invention in the pharmaceutical preparation is about 0.01 to about 100% by weight of the entire preparation.
The dose of the compound of the present invention is appropriately selected depending on the administration subject, symptom, administration method and the like. For example, when the compound of the present invention is orally administered, the dose to a human (assuming a body weight of 60 kg) is about 0.1 to 100 mg, preferably about 1.0 to 50 mg, and more preferably about 1.0 to 20 mg per day. Is. When the compound of the present invention is administered parenterally, the dose to a human (assuming a body weight of 60 kg) is about 0.01 to 30 mg, preferably about 0.1 to 20 mg, more preferably about 0.5 to a day. It is 10 mg. This amount can be administered in 1 to several divided doses a day.

Pharmacologically acceptable carriers that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, for example, excipients, lubricants, etc. in solid preparations. Examples thereof include binders and disintegrants, or solvents, solubilizers, suspending agents, tonicity agents, buffering agents and soothing agents in liquid formulations. Further, if necessary, an appropriate amount of additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, and wetting agents can be used.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic acid anhydride and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, and carboxy. Examples thereof include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates.
Examples of the soothing agent include benzyl alcohol and the like.
Examples of preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.
Examples of the colorant include water-soluble edible tar pigments (eg, edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2 and the like), and water-insoluble rake dyes (eg, edible rake dyes). Examples include the aluminum salt of the water-soluble food coloring (aluminum salt), natural pigments (eg, β-carotene, chlorophyll, red iron oxide) and the like.
Examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.
Examples of the adsorbent include perforated starch, calcium silicate (trade name: Fluorite RE), magnesium aluminometasilicate (trade name: Neucillin), and light anhydrous silicic acid (trade name: Syricia).
Examples of the wetting agent include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

When producing the oral preparation, if necessary, coating may be applied for the purpose of masking the taste, enteric properties or persistence.

Examples of the coating base used for coating include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base.

As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

Examples of the water-soluble film coating base include cellulosic polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)). ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as purulan.

Examples of the enteric film coating base include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; metaacrylic acid copolymer L [Eudragit L (trade name)). ], Acrylic acid-based polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as cellac.

Examples of the sustained-release film coating base include cellulose-based polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], and ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit]. NE (trade name)] and other acrylic acid-based polymers can be mentioned.

The above-mentioned coating base may be used by mixing two or more of them in an appropriate ratio. Further, at the time of coating, for example, a light-shielding agent such as titanium oxide or iron sesquioxide may be used.

The NK3 receptor is known to be involved in various in vivo phenomena. Therefore, compound (I) having an NK3 receptor agonistic action can be a useful tool for elucidating various in vivo phenomena in which the NK3 receptor is involved. Therefore, the compound of the present invention is also useful as a research reagent.

The present invention will be further described in detail by the following Examples and Test Examples, but these examples are merely embodiments, do not limit the present invention, and are changed without departing from the scope of the present invention. You may.

Production Example 1 Construction of Protective Peptide Resin
_{Fmoc-protected amino acid (0.30 mmol) or Fmoc-protected dipeptide equivalent, HOBt · H 2} O (46.0 mg, 46.0 mg,) on NovaSyn® TGR resin (384.6 mg, 0.10 mmol) or Rink Amide resin (166.6 mg, 0.10 mmol) A protected peptide resin was constructed by the Fmoc solid-phase synthesis method using 0.30 mmol) and DIC (46.4 μL, 0.30 mmol). Fmoc-protected amino acids (0.30 mmol) and HATU (114.0 mg, 0.30 mmol) / (i-Pr) ₂ NEt (52.2 μL, 0.30 mmol) were used for acylation to N-methyl amino acids.

Production Example 2 Succinylization of the N-terminal of the peptide chain After constructing a protected peptide resin (0.10 mmol) according to the procedure of Production Example 1, the Fmoc group was removed with 20% piperidine / DMF, and succinic anhydride (50.0 mg, 0.50) was added to the DMF. The desired modified protected peptide chain was obtained by adding (mmol) and (i-Pr) ₂ NEt (87.2 μL, 0.50 mmol) and reacting at room temperature for 1.5 hours.

Production Example 3 Deprotection and Purification of Protecting Peptide Resin The obtained resin is _{treated in a reaction solution of TFA / m-cresol / thioanisole / EDT / H 2} O (80: 5: 5: 5: 5) for 2 hours. Cutting from the resin was performed with the removal of the side chain protecting group. The resin was removed by filtration, TFA in the filtrate was azeotropically distilled with toluene, and then cold diethyl ether was added to precipitate the peptide. The obtained crude peptide was washed three times and then purified by HPLC to obtain the desired peptide.

Production Example 4 Acetylation of N-terminal peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, acetic anhydride and pyridine are added to DMF and reacted at room temperature to obtain the desired modified protected peptide chain. ..

Production Example 5 Oxalylation of N-terminal peptide chain After constructing a protective peptide resin according to the procedure of Production Example 1, tert-butyl chloro (oxo) acetate and (i-Pr) ₂ NEt are added in dichloromethane and reacted at room temperature. To obtain the desired modified protective peptide chain.

Production Example 6 Carbamoylation of the N-terminal of the peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, chlorosulfonyl isocyanate and pyridine are added in dichloromethane and reacted at room temperature. Then, H ₂ O is added and reacted to obtain the desired modified protective peptide chain.

Production Example 7 Hydroxycarbamoylation of the N-terminal of the peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, p-nitrophenyl chloroformate and (i-Pr) ₂ NEt were added in THF / dichloromethane (1: 1), and the mixture was added. The reaction was carried out at room temperature. Then, in a DMF solvent, hydroxylamine hydrochloride and (i-Pr) ₂ NEt are added and reacted to obtain the desired modified protected peptide chain.

Production Example 8 Hydrazinecarbonylation of N-terminal peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, a solution of p-nitrophenyl chloroformate, tert-butyl carbazate and N-methylmorpholine mixed in THF and triethylamine were added. By reacting at room temperature, the desired modified protected peptide chain (Boc protectant) is obtained.

Production Example 9 Methyl oxalylation of N-terminal peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, methyl oxalyl chloride and pyridine are added to dichloromethane and reacted at room temperature to obtain the desired modified protected peptide chain. To get.

Production Example 10 Oxamide formation of the N-terminal of the peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, oxamic acid, DIC and HOBt · H ₂ O are added in dichloromethane and reacted at room temperature to obtain the desired substance. Obtain a modified protective peptide chain.

Production Example 11 Sulfonamide of the N-terminal of the peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, a solution of chlorosulfonyl isocyanate and tert-butanol and triethylamine are added in dichloromethane and reacted at room temperature. , Obtain the desired modified protected peptide chain (Boc protector).

Production Example 12 Carboxymethylation of the N-terminal of the peptide chain After constructing a protected peptide resin according to the procedure of Production Example 1, tert-butyl bromoacetate and (i-Pr) ₂ NEt are added to DMF and reacted at room temperature. , Obtain the desired modified protected peptide chain (tert-Bu protectant).

Production Example 13 Bis (carboxymethylation) at the N-terminal of the peptide chain
N-Fmoc-L-Asp (O-tBu) -OH, triethylamine and benzyl bromide are mixed in a DMF solvent and reacted at room temperature to cause N-Fmoc-L-Asp (O-tBu) -OBn. To get. HL-Asp (O-tBu) -OBn is obtained by adding diethylamine in DMF and reacting the product at room temperature. Then, N, N-bis (tert-butyloxycarbonylmethyl) -L-aspartic acid was added to the product in an anhydrous DMF solvent by adding tert-butyl bromoacetate and potassium carbonate and reacting at room temperature. Obtain 4-tert-butyl 1-benzyl. N, N-bis (tert-butyloxycarbonylmethyl) -L-aspartate 4-tert- was added to the product in an EtOH solvent and reacted at room temperature in a hydrogen atmosphere. Obtain butyl. This is applied to the Fmoc solid-phase synthesis method of Production Example 1 and introduced into a protected peptide resin to construct a desired modified protected peptide resin (tert-Bu protectant).

In the formula (I), the compound in which A1 in X1 is PEG-modified (bonded to the peptide chain via -O-) (in the formula (II), X is -O-; Examples 1 to 3) is represented by the following scheme. Synthesized according to 1.
[Scheme 1]

Example 1 MPEG750 modification via an ester bond of the N-terminal glutamic acid side chain of the peptide chain

Reaction of Fmoc-Glu-OBn (2.0 g, 4.36 mmol), polyethylene glycol monomethyl ether 750 (3.59 g, 4.79 mmol), DCC (1.12 g, 5.45 mmol) and DMAP (53.3 mg, 0.436 mmol) in dichloromethane. Then, 4.17 g of the target Fmoc-Glu (O-MPEG750) -OBn was obtained.
Next, the desired Fmoc was reacted with 10% Pd / C (350 mg, 0.33 mmol) in a dehydrated ethanol (29.2 mL) solvent with respect to the obtained product (2.0 g, 1.68 mmol) under a hydrogen atmosphere. -Glu (O-MPEG750) -OH was obtained in 955 mg. Subsequently, using the above amino acids, the target peptide 8 was obtained by the procedures of Production Example 1, Production Example 2, and Production Example 3.

Example 2 MPEG2k modification via an ester bond of the N-terminal glutamic acid side chain of the peptide chain

Reaction of Fmoc-Glu-OBn (1.0 g, 2.17 mmol), polyethylene glycol monomethyl ether 2 k (4.79 g, 2.39 mmol), DCC (560 mg, 2.72 mmol) and DMAP (26.6 mg, 0.217 mmol) in dichloromethane. Then, 5.10 g of the target Fmoc-Glu (O-MPEG2k) -OBn was obtained. The resulting product (5.10 g, 2.09 mmol) is reacted with 10% Pd / C (222 mg, 0.209 mmol) in a mixed solvent of ethanol (30 mL) -chloroform (5.0 mL) under a hydrogen atmosphere. The target Fmoc-Glu (O-MPEG2k) -OH was obtained in 3.89 g. Subsequently, the amino acids (3.53 g, 1.5 mmol), HATU (570 mg, 1.5 mmol) and (i-Pr) ₂ NEt (i-Pr) 2 NEt (i-Pr) were added to the protected peptide resin A (0.5 mmol) obtained by the procedure of Production Example 1. The target peptide 9 (PEG2k ester) was obtained by condensation using 261 μL, 1.5 mmol) and the procedures of Production Example 2 and Production Example 3.

Example 3 MPEG5k modification via an ester bond of the N-terminal glutamic acid side chain of the peptide chain

Reaction of Fmoc-Glu-OtBu (531 mg, 1.25 mmol), polyethylene glycol monomethyl ether 5 k (6.87 g, 1.37 mmol), DCC (322 mg, 1.56 mmol) and DMAP (15.3 mg, 0.125 mmol) in dichloromethane. Then, 6.21 g of the target Fmoc-Glu (O-MPEG5k) -OBn was obtained. Next, 1.92 g of the desired Fmoc-Glu (O-MPEG5 k) -OH was obtained by reacting the obtained product (2.0 g, 0.37 mmol) in a TFA (20 mL) solvent. _{Subsequently, the above amino acids (1.05 g, 0.20 mmol), HOBt · H 2} O (459 mg, 3.0 mmol) and DIC (464 μL) were added to the protected peptide resin A (0.05 mmol) obtained by the procedure of Production Example 1. , 3.0 mmol) was used to condense twice at 60 ° C. Further, the N-terminal succinylization was performed twice in the procedure of Production Example 2, and the target peptide 10 was obtained by cutting out from the resin in the procedure of Production Example 3.

In formula (I), a compound in which A1 in X1 is PEG-modified (bonded to a peptide chain via -NH-) (in formula (II), X is -NH-; Examples 4 to 8) is represented by the following scheme. Synthesized according to 2.
[Scheme 2]

Example 4 MPEG500 modification via the amide bond of the N-terminal glutamic acid side chain of the peptide chain

Peptide (iv) (150 mg, 0.153 mmol) obtained in the procedures of Production Example 1 and Production Example 3 with respect to methoxypolyethylene glycolamine 500 (69 mg, 0.138 mmol) and WSC · HCl (44.1 mg, 0.230 mmol). , HOBt · H ₂ O (35.2 mg, 0.230 mmol) and (i-Pr) ₂ NEt (40.1 μL, 0.230 mmol) were reacted in dichloromethane, and the desired product was obtained by HPLC purification. Fmoc groups were deprotected by adding 50% diethylamine / dichloromethane to the obtained product and reacting for 1 hour. Then, the target peptide 11 was obtained by succinylizing the N-terminal of the peptide in the procedure of Production Example 2.

Example 5 MPEG750 modification via the amide bond of the N-terminal glutamic acid side chain of the peptide chain

The target peptide 12 was obtained in the same manner as in Example 4 except that methoxypolyethylene glycolamine 750 was used instead of methoxypolyethylene glycolamine 500.

Example 6 MPEG1k modification via the amide bond of the N-terminal glutamic acid side chain of the peptide chain

The target peptide 13 was obtained in the same manner as in Example 4 except that methoxypolyethylene glycolamine 1k was used instead of methoxypolyethylene glycolamine 500.

Example 7 MPEG2k modification via amide bond at N-terminal peptide chain

The target peptide 14 was obtained in the same manner as in Example 4 except that methoxypolyethylene glycolamine 2k was used instead of methoxypolyethylene glycolamine 500.

Example 8 MPEG5k modification via amide bond at N-terminal peptide chain

The target peptide 15 was obtained in the same manner as in Example 4 except that methoxypolyethylene glycolamine 5k was used instead of methoxypolyethylene glycolamine 500.

Example 9 MPEG750 modification at the N-terminus of the peptide chain via an oxalyl group

In formula (I), a compound in which R1 in X1 was PEG-modified (bonded to a peptide chain via −O—) was synthesized according to the following scheme 3.
[Scheme 3]

After dissolving oxalyl chloride (0.65 ml, 7.6 mmol) in diethyl ether, polyethylene glycol monomethyl ether 750 (2.85 g, 3.8 mmol) was slowly added dropwise under an argon atmosphere, and the mixture was stirred at room temperature for 3 hours. _{The obtained oxalylated MPEG750 (858 mg, 1.0 mmol) and (i-Pr) 2} NEt (176 μL, 1.0 mmol) were added to the protected peptide resin B (0.10 mmol) constructed according to the procedure of Production Example 1. The reaction was carried out at room temperature for 2 hours. Subsequently, the target peptide 6 was obtained by cutting out from the resin in the procedure of Production Example 3.

In formula (I), a compound (Examples 10 to 13) in which A1 in X1 is PEG-modified (bonded to the linker via -NH-) on its side chain functional group via a linker is subjected to the following scheme 4. Synthesized.
[Scheme 4]

Example 10 Two molecules of MPEG500 modification via aspartic acid on the N-terminal glutamic acid side chain of the peptide chain

Fmoc-Asp-OH (35.5 mg, 0.10 mmol), methoxypolyethylene glycolamine 500 (110 mg, 0.22 mmol), WSC · HCl (96 mg, 0.50 mmol), HOBt · H ₂ O (76.5 mg, 0.50 mmol) and (i-Pr) ₂ NEt (87 μl, 0.50 mmol) was reacted in dichloromethane and purified by silica gel chromatography to obtain Fmoc-Asp (NH-MPEG500) -NH-MPEG500. Next, a 50% diethylamine / dichloromethane solution was added to Fmoc-Asp (NH-MPEG500) -NH-MPEG500, and the mixture was reacted for 1 hour to deprotect the Fmoc group. Reversed phase chromatography purification gave H-Asp (NH-MPEG500) -NH-MPEG500 (v, 90.5 mg). H-Asp (NH-MPEG500) -NH-MPEG500 (90.5 mg, 0.082 mmol), WSC / HCl, with respect to the peptide (iv) (88.9 mg, 0.091 mmol) obtained in the procedures of Production Example 1 and Production Example 3. (23.9 mg, 0.124 mmol), HOBt · H ₂ O (19.0 mg, 0.124 mmol) and (i-Pr) ₂ NEt (21.6 μL, 0.124 mmol) were reacted in dichloromethane and the desired product was purified by reverse phase chromatography. Got A 50% diethylamine / dichloromethane solution was added to the obtained product, and the mixture was reacted for 1 hour to deprotect the Fmoc group. Subsequently, the target peptide 18 was obtained by succinylizing the N-terminal of the peptide in the procedure of Production Example 2.

Example 11 Two molecules of MPEG750 modification via aspartic acid on the N-terminal glutamic acid side chain of the peptide chain

The target peptide 19 was obtained in the same manner as in Example 10 except that methoxypolyethylene glycolamine 750 was used instead of methoxypolyethylene glycolamine 500.

Example 12 MPEG1k modification of two molecules of peptide chain N-terminal glutamic acid side chain via aspartic acid

The target peptide 20 was obtained in the same manner as in Example 10 except that methoxypolyethylene glycolamine 1k was used instead of methoxypolyethylene glycolamine 500.

Example 13 MPEG2k modification of two molecules of peptide chain N-terminal glutamic acid side chain via aspartic acid

H-Asp (OtBu) -OtBu · HCl (31.0 mg, 0.11 mmol), WSC · HCl (29.0 mg, 0.15 mmol), HOBt · H ₂ O (23.0 mmol) vs. peptide (iv) (97.7 mg, 0.10 mmol) The reaction of mg, 0.15 mmol) and (i-Pr) ₂ NEt (26.1 μL, 0.15 mmol) was carried out in dichloromethane, and the desired product (122.6 mg) was obtained by HPLC purification. The obtained product was reacted in TFA for 1 hour to deprotect the tBu group. For the obtained peptide (43.7 mg, 0.04 mmol), methoxypolyethylene glycolamine 2k (160.0 mg, 0.08 mmol), WSC · HCl (23.2 mg, 0.12 mmol), HOBt · H ₂ O (18.4 mg, 0.12 mmol) And (i-Pr) ₂ NEt (20.8 μl, 0.12 mmol) were reacted in dichloromethane. After distilling off the solvent, the desired product (98.7 mg) was obtained by HPLC purification. A 50% diethylamine / dichloromethane solution was added thereto, and the mixture was reacted for 1 hour to deprotect the Fmoc group. Subsequently, the target peptide 21 was obtained by succinylizing the N-terminal of the peptide in the procedure of Production Example 2.

Comparative Example 1 MPEG (molecular weight less than 500) modification at the N-terminal of the peptide chain

A PEG-modified peptide using Methyl-PEG _12- NHS (NHS: N-hydroxysuccinimide active ester) was synthesized according to Scheme 5 below.
[Scheme 5]

After constructing the protective peptide resin B (0.05 mmol) according to the procedure of Production Example 1, methyl-PEG _12- NHS (50.3 mg, 0.075 mmol) and (i-Pr) ₂ NEt (26.2 μL, 0.15 mmol) in DMF solvent. Was added and reacted at room temperature for 1.5 hours. Subsequently, the target peptide 4 was obtained by cutting out from the resin in the procedure of Production Example 3.

Comparative Example 2
The target peptide 1 was synthesized in the same manner as in Production Examples 1 to 3.

Peptides subjected to chemical modifications other than PEG modification (Comparative Examples 3 to 8) were synthesized according to Schemes 6 and 7 below.
[Scheme 6]

Comparative Example 3 Sugar chain modification to the N-terminal amino acid of the peptide chain

After constructing the protective peptide resin A (0.025 mmol) according to the procedure of Production Example 1, Fmoc-Asn (Ac ₃ AcNH-β-Glc) -OH (17.1 mg, 0.025 mmol), HOBt · H ₂ O ( 5.75 mg, 0.038 mmol) and DIC (5.76 μL, 0.038 mmol) were added and reacted at room temperature for 1.5 hours. Next, acetic anhydride (11.8 μL, 0.125 mmol) and pyridine (20.1 μL, 0.25 mmol) were added to the DMF solvent and subjected to a reaction for 10 minutes. Protected with. Subsequently, after succinylation was carried out according to the procedure of Example 2, deacetylation was carried out with sodium methoxide (20.25 mg, 0.375 mmol) in a mixed solvent of DMF-methanol. Finally, the target peptide 2 was obtained by cutting out from the resin in the procedure of Production Example 3.

Comparative Example 4 Fatty acid modification at the N-terminal of the peptide chain

After constructing the protective peptide resin B (0.10 mmol) according to the procedure of Production Example 1, palmitic acid (76.5 mg, 0.30 mmol), HOBt · H ₂ O (46.0 mg, 0.30 mmol) and DIC (46.4 μL,) in a DMF solvent. 0.30 mmol) was added, and the mixture was reacted at room temperature for 1.5 hours. Subsequently, the target peptide 3 was obtained by cutting out from the resin in the procedure of Production Example 3.

Comparative Example 5 Long-chain alkyl modification at the N-terminal of the peptide chain via an oxalyl group

After dissolving oxalyl chloride (2.6 ml, 29.2 mmol) in diethyl ether, hexadecanol (3.6 g, 14.6 mmol) was slowly added dropwise under an argon atmosphere, and the mixture was stirred at room temperature for 4 hours. Next, after constructing the protected peptide resin B (0.05 mmol) according to the procedure of Production Example 1, the obtained oxalylated hexadecanol (83.5 mg, 0.25 mmol) and (i-Pr) ₂ NEt (88 μL) were obtained in a dichloromethane solvent. , 0.5 mmol) was added and reacted at room temperature for 2 hours. Subsequently, the target peptide 5 was obtained by cutting out from the resin in the procedure of Production Example 3.

Comparative Example 6 Long-chain alkyl modification via an ester bond of the N-terminal glutamic acid side chain of the peptide chain

Fmoc-Glu-OBn (459.5 mg, 1.0 mmol), hexadecanol (291 mg, 1.2 mmol), EDCI HCl (230.0 mg, 1.2 mmol) and DMAP (12.2 mg, 0.1 mmol) in dichloromethane at room temperature 2.5 Fmoc-Glu (OC ₁₆ H ₃₃ ) -OBn was obtained by stirring for hours. Reaction of the obtained product (210 mg, 0.30 mmol) in a mixed solvent of ethanol (6.0 mL) -ethyl acetate (3.0 mL) in the presence of 10% Pd / C (16 mg, 0.015 mmol) in a hydrogen atmosphere. Fmoc-Glu (OC ₁₆ H ₃₃ ) -OH was obtained in an amount of 233 mg. Subsequently, using the above amino acids, peptide 7 was obtained by the procedures of Production Example 1, Production Example 2, and Production Example 3.
[Scheme 6]

Comparative Example 7 Modification of aspartic acid to the N-terminal glutamic acid side chain of the peptide chain

H-Asp (OtBu) -OtBu · HCl (31.0 mg, 0.11 mmol), WSC · HCl (29.0 mg, 0.15 mmol), HOBt · H ₂ O (23.0 mmol) vs. peptide (iv) (97.7 mg, 0.10 mmol) The reaction of mg, 0.15 mmol) and (i-Pr) ₂ NEt (26.1 μL, 0.15 mmol) was carried out in dichloromethane, the solvent was distilled off, and the desired product (61.2 mg) was obtained by silica gel chromatography. TFA was added to the obtained product and reacted for 1 hour to deprotect the tBu group. This peptide (33.2 mg, 0.028 mmol) was reacted with 50% diethylamine / dichloromethane for 1 hour to deprotect the Fmoc group. The target peptide 16 was obtained by succinylizing the N-terminal of the peptide in the procedure of Production Example 2 and then reacting in TFA for 1 hour.

Comparative Example 8 Modification of N, N'-dimethylasparagine to the N-terminal glutamic acid side chain of the peptide chain

Fmoc-Asp-OH (86.8 mg, 0.245 mmol), aqueous methylamine solution (63.5 μL, 0.735 mmol), WSC · HCl (141 mg, 0.735 mmol), HOBt · H ₂ O (112 mg, 0.735 mmol) and (i -Pr) ₂ NEt (127 μl, 0.735 mmol) was reacted in dichloromethane, the solvent was distilled off, and the mixture was purified by silica gel chromatography. The Fmoc group was then deprotected by adding a 50% diethylamine / DMF solution to the resulting product and reacting for 1 hour. For peptide (iv) (239 mg, 0.245 mmol), the above amino acids, WSC · HCl (56.7 mg, 0.294 mmol), HOBt · H ₂ O (45.0 mg, 0.294 mmol) and (i-Pr) ₂ NEt (51.2) μL, 0.294 mmol) was reacted in DMF to obtain the desired peptide. The Fmoc group was deprotected by adding 50% diethylamine / dichloromethane to the obtained product and reacting for 1 hour. The target peptide 17 was obtained by succinylizing the N-terminal of the peptide in the procedure of Production Example 2.

Tables 2-1 and 2-below show the peptides of Examples 1 to 9 and Comparative Examples 1 to 6, and Examples 10 to 13 and Comparative Examples 7 to 8 together with their mass spectrometric values (analysis by MALDI-TOF MS). It is summarized in 2 and Table 3. senktide is a known NK3 receptor agonist.

Test Example 1 Evaluation of NK3 receptor agonist activity by the compound of the present invention The change in intracellular calcium concentration when the Flp-In CHO cells forcibly expressing the NK3 receptor were stimulated with various peptides was quantified.
First, NK3 receptor-expressing CHO cells were collected using trypsin and seeded on a 96-well plate at ^{4 × 10 4 cells / well.} After culturing at 37 ° C. overnight, 100 μL of calcium indicator was added, and the cells were further cultured for 1 hour. Subsequently, 25 μL of the peptide solution prepared by 5-fold concentration was added dropwise, and the change over time in the intracellular calcium concentration was observed with FlexStation for 60 seconds.

Test Example 2 Evaluation of stability of the compound of the present invention in goat serum Under ice-cooling, 1 μL of a peptide solution was added to 49 μL of each animal tissue fluid, mixed, and incubated at 37 ° C. Next, during the incubation, 20 μL of the evaluation solution was collected every response time. To the collected evaluation solution, 60 μL of acetonitrile was added under ice-cooling to precipitate the tissue protein. After shaking, the mixture was centrifuged (4 ° C., 13000 g, 10 min), and the obtained supernatant was analyzed by HPLC. Both showed excellent stability.

Test Example 3 Evaluation of the activity of the compound of the present invention on the neural activity of the reproductive center of goats Four ovariectomized goats were tested, and recording electrodes were surgically placed near the kisspeptin neurons of the arcuate nucleus of the hypothalamus. After a recovery period of about 1 month, neural activity was measured in real time as MUA in awakened goats, and it was confirmed that a transient increase in neural activity (MUA volley) lasting about 2 minutes occurred in a regular cycle. bottom. The MUA volley reflects the neural activity of kisspeptin neurons that pulse GnRH. In ovariectomized goats, the length of the endogenous MUA volley cycle is about 25 minutes (about ± 5 minutes), which varies slightly from individual to individual, but within the same individual the cycle length is almost constant.
On the day of the test, the MUA measuring device was set and MUA was continuously recorded throughout the day. In addition, a jugular vein catheter for sample administration was placed. First, several endogenous MUA volleys that occurred during the control time of about 2 hours were confirmed in each individual, and the average value (T) of the volley intervals (minutes) was calculated. Next, after the expression of any MUA volley, the test sample solution was administered into the jugular vein at a timing of 1 / 2T. When MUA volley develops within 4 minutes after drug administration, NK3 receptor agonist activity is positive, and the time from the time of drug administration until the volley interval recovers to 80% of T is the duration of the effect of the drug (R). And said. In addition, the number of volleys (V) observed during this duration R was counted.
The test sample solution was prepared as follows. On the day of the test, 50 μL of the test sample adjusted to a concentration of 10 mM in DMSO was dissolved in 4.45 mL of sterile distilled water. After confirming that the solution was completely dissolved without precipitation, 0.5 mL of sterilized 9% NaCl was added, and the final concentration of the solution was adjusted to the test sample: 500 nmol / 5 mL, NaCl: 0.9%, DMSO: 1%. bottom. From here, 2 mL (200 nmol) was taken in a syringe and used for activity evaluation. In addition, as a general rule, the activity was evaluated using 2 to 3 animals for one test sample.
As an example, FIG. 1 shows a chart comparing the peptide of the present invention (peptide 9; Example 2) with Senktide as a control peptide. Furthermore, Table 4 shows the results of comparing the biological activities of Senktide and the compound of the present invention based on Test Examples 1 and 3.

Persistent central nervous system activity upon peripheral administration to goats in PEG-modified peptides, especially peptides with PEG chains having a molecular weight of more than 500, preferably a chain length greater than 750, more preferably a molecular weight of 750-2,000. Activation was observed.

Test Example 4 Evaluation of the effect of administration of the compound of the present invention on blood luteinizing hormone concentration to goats Peptide 12 (200 nmol) was administered once into follicular and luteal phase venous blood of Shibayagi. Blood was collected at 10-minute intervals from 2 hours before administration to 6 hours after administration for several hours after administration, and the blood luteinizing hormone (LH) concentration was quantified. Based on Test Example 4, the results of administration of peptide 12 to the follicular phase and luteal phase Shibayagi are shown in FIGS. 2 and 3, respectively.

Immediately after the administration of peptide 12, an increase in LH concentration was observed, and this effect was not observed when the same amount of existing agonist was administered. Therefore, peptide 12 was compared with the existing agonist. It was considered to have excellent in vivo stability and promoted the secretion of gonadotropin for a long period of time.

[Sequence list free text]
SEQ ID NO: 1; Peptide 1
SEQ ID NO: 2; Peptide 2
SEQ ID NO: 3; Peptide 3
SEQ ID NO: 4; Peptide 4
SEQ ID NO: 5; Peptide 5
SEQ ID NO: 6; Peptide 6
SEQ ID NO: 7; Peptide 7
SEQ ID NO: 8; Peptide 8
SEQ ID NO: 9; Peptide 9
SEQ ID NO: 10; Peptide 10
SEQ ID NO: 11; Peptide 11
SEQ ID NO: 12; Peptide 12
SEQ ID NO: 13; Peptide 13
SEQ ID NO: 14; Peptide 14
SEQ ID NO: 15; Peptide 15
SEQ ID NO: 16; Peptide 16
SEQ ID NO: 17; Peptide 17
SEQ ID NO: 18; Peptide 18
SEQ ID NO: 19; Peptide 19
SEQ ID NO: 20; Peptide 20
SEQ ID NO: 21; Peptide 21

The highly active and highly selective NK3 receptor agonist obtained by the present invention is a therapeutic agent for diseases associated with excessive or deficient secretion of takinins, for example, pain, sexual dysfunction associated with excessive or deficient secretion of sex hormones. It is useful as a drug for improvement, a reagent for basic scientific experiments for the development of therapeutic drugs for these diseases, and the like.

Claims (10)

Or

The compound represented by or a physiologically acceptable salt thereof. A medicament containing the compound according to claim 1 or a physiologically acceptable salt thereof. The medicament according to claim 2 , which is a neurokinin receptor agonist. The medicament according to claim 3 , wherein the neurokinin receptor is an NK3 receptor. The medicament according to claim 2 , which is a reproductive center control agent. The medicament according to claim 2 , which is for promoting and / or improving follicle growth. The medicament according to claim 2 , wherein the tachykinins and / or neurokinin receptors are therapeutic agents for diseases involved in the onset and progression thereof. The medicament according to claim 7 , wherein the disease is sexual dysfunction associated with pain or excess / deficiency of sex hormone secretion. A reagent containing the compound according to claim 1 or a physiologically acceptable salt thereof. The medicament according to claim 2, which is characterized by acting centrally.

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