KR100890633B1 - Compounds having serotonin receptor affinity - Google Patents

Abstract

The present invention relates to a compound having an affinity for serotonin receptors, more particularly serotonin 5-HT _2A Central nervous system diseases such as anxiety, depression, seizures, compulsive neuroses, psychosis, schizophrenia, suicidal tendency, Alzheimer's dementia, Parkinson's disease, Huntington chorea (Huntington's chorea), sleep disorders, appetite disorders, withdrawal symptoms due to substance abuse, and migraine headaches, and the like.

Serotonin (5-HT), 5-HT2A Receptor, Depression, Schizophrenia

Description

Compounds having affinity for serotonin receptors

The present invention relates to a compound having an affinity for serotonin receptors, and more particularly, because it has excellent antagonistic activity against serotonin 5-HT _2a receptors, such as central nervous system diseases such as anxiety, depression, seizures, obsessive-nose drugs, Psychosis, schizophrenia, suicidal tendency, Alzheimer's dementia, Parkinson's disease, Huntington's chorea, sleep disorders, appetite disorders, withdrawal symptoms due to drug abuse, And compounds useful as therapeutic and prophylactic agents in migraine headaches and the like.

Serotonin is a mental disorder (e.g., depression, aggressiveness, seizures, compulsive neurosis, psychosis, schizophrenia, suicidal tendency), degenerative neuropathy (e.g. Alzheimer's dementia, Parkinson's). It is known to play an important role in various types of pathological conditions, such as disease, Huntington's chorea, anorexia, bulimia, alcoholism-related disorders, cerebral vascular accidents and migraine headaches [Meltzer, Neuropsychopharmacology , 21: 106 S-115S (1999); Barnes & Sharp, Neuropharmacology , 38: 1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev. , 14:35 (1990). Serotonin (5-hydroxytryptamine, 5-HT) receptors are distributed throughout the body of humans and animals and play an important role in physiological and behavioral functions. There are currently about 15 clones with genetically different 5-HT receptor subtypes, each representing a unique distribution and varying preferences and correlations for ligands. Recently, the 5-HT ₂ receptor subtype has been described as hypertension, thrombosis, migraine, vaspaspasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders ( has been linked to the pathogenesis of medical conditions such as appetite disorders. In addition, compounds useful as antagonists for the serotonin 5-HT _2A receptor and effective as therapeutic agents for central nervous system diseases are described in International Patents WO 95/21844, WO 01/068585 and WO 03/057220; Med. Chem ., 2002, 45 , 54-71, Eur, J. Pharm ., 2000, 406 , 163-169; Bioorg. Med. Chem. Lett ., 2005, 15 , 4989-4993.

Although the cause of depression and the mechanism of action of antidepressants are not fully understood, the lack of a monoamine neurotransmitter, serotonin (5-HT) in the central nervous system, is most commonly the cause of depression. It is a strong hypothesis. The mechanism of action of all antidepressants is to increase the amount of serotonin present on the synapse. Representative antidepressants are known as imipramine and iproniazid. These drugs have been shown to activate the monoamine nervous system, particularly serotonin, in the brain and to express the effects [Coppen A., Br. . J. Psychiat ., 1967, 113 , pp. 1237-1264; Lapin IP & Oxenkrug GF, Lancet 1969, 1 , pp. 132-136]. Paxil and Prozac, which are currently the most popular antidepressants, are also representative drugs that act as Selective Serotonin Reuptake Inhibitors (SSRIs).

The development of selective treatment for depression by the selective serotonin reuptake inhibitors (SSRI) has greatly improved the field of antidepressant development, especially, these drugs are excellent in the treatment of depression, while the side effects are significantly less than the existing drugs are highlighted. However, these drugs are only effective in about 60% of patients, and the antidepressant effect has a disadvantage that appears slowly only 2 to 4 weeks after drug administration. Recently, adolescents with antidepressants who are taking these antidepressants have reported that side effects causing suicidal thoughts should be restricted.

Various studies have been conducted worldwide to develop antidepressants with a novel mechanism of action that overcomes the disadvantages of serotonin reuptake inhibitors, the most active of which is the direct blocking of serotonin receptors, especially serotonin 5-HT _2A receptors. Development of drugs. The 5-HT _2A receptor is one of the serotonin receptor subtypes, expressed in the human brain, including the cerebral cortex, limbic system and whole brain region, and is involved in the regulation of advanced cognitive and emotional functions. In particular, the number of 5-HT _2A receptors in the brain of patients who committed suicide due to severe depression increased [Mann JJ, Nat. Med ., 1998, 4 , 25-30], suicidal impulses are also known to be closely associated with 5-HT _2A receptor gene polymorphism [Du L. et al, Am. J. Med. Genetics 2000, 96 , 56-60]. In addition, long-term administration of antidepressants has been shown to reduce the ability and function of 5-HT _2A receptors in tissues [Peroutka SJ & Snyder SH, Science 1980, 210 , 88-90], and studies using animal models in 5-HT _2A The relevance of receptors for mental illness (depression, anxiety, schizophrenia, etc.) has been widely demonstrated [Skrebuhhova T. et al., Med. Sci. Res . 1999, 27 , 277-280; Weisstaub NV et al, Science 2006, 313 , 536-40; de Angelis L., Curr Opin Investig Drugs 2002, 3, 106-12.

As mentioned earlier, Fluoxetin (Prozac ™), a typical serotonine reuptake inhibitor (SSRIs), takes two to four weeks to take effect, and it is also effective in all patients with depression. Staying at 60-70%. In recent years, overdose has also raised the issue of suicidal thoughts in adolescents. Therefore, in order to reduce these side effects and shorten the action time, attempts to combine serotonin receptor direct blockers with existing SSRIs drugs are gradually increasing.

Accordingly, the present inventors have newly introduced serotonin 5- to 12 known compounds such as methyl naphthalene-2-sulfonic acid- (1-methyl-piperidin-4-yl) -amide through high efficiency drug search (HTS). We have identified the activity as an HT _2A receptor antagonist, and based on this, we developed a novel therapeutic agent for central nervous system disease using a unique derivative with 5-HT _2A receptor antagonism alone or in combination with an existing serotonin reuptake inhibitor. The invention was completed.

The present invention provides a medical use using 12 known compounds such as methyl naphthalene-2-sulfonic acid methyl- (1-methyl-piperidin-4-yl) -amide as a serotonin 5-HT _2A receptor antagonist. have.

In addition, the present invention relates to the central nervous system associated with serotonin 5-HT _2A receptor comprising 12 known compounds such as methyl naphthalene-2-sulfonic acid methyl- (1-methyl-piperidin-4-yl) -amide as an active substance. It is an object to provide a pharmaceutical composition for the treatment and prevention of diseases.

The present invention is characterized by a pharmaceutical composition for the treatment and prophylaxis of central nervous system diseases associated with serotonin 5-HT _2A receptors comprising a compound selected below or a pharmaceutically acceptable salt thereof.

Naphthalene-2-sulfonic acid methyl- (1-methyl-piperidin-4-yl) -amide (compound 1),

1- (5-Bromo-2-methoxy-benzenesulfonyl) -4- (2-thiophen-2-yl-ethyl) -piperazine (Compound 2),

1- (1-benzyl-piperidin-4-yl) -3- (4-trifluoromethylsulfanyl-phenyl) -urea (compound 3),

8- [4- (3-phenyl-aryl) -piperazine-1-sulfonyl] -quinoline (Compound 4),

1- (1-benzyl-pyrrolidin-3-yl) -3- (4-trifluoromethylsulfanyl-phenyl) -urea (compound 5),

1- (4-butoxy-benzenesulfonyl) -4-methyl- [1,4] diazepane (compound 6),

1- [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] -3-phenoxy-propan-2-one (compound 7),

Biphenyl-4-sulfonic acid [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -amide (compound 8),

1- (2,5-dichloro-benzenesulfonyl) -4-phenethyl-piperazine (Compound 9),

1-phenethyl-4- (toluene-4-sulfonyl) -piperazine (Compound 10),

1- (2-fluoro-5-methyl-benzenesulfonyl) -4-phenethyl-piperazine (Compound 11),

1- (4-Bromo-benzenesulfonyl) -4-phenethyl-piperazine (Compound 12).

Pharmaceutically acceptable salts in the present invention may be prepared by conventional methods in the art, and include, for example, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid, or Salts with organic acids such as acetylsalicylic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methane Salts with sulfonic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like, metal salts by reaction with alkali metals such as sodium and potassium, or ammonium Salts with ions;

In addition, the pharmaceutical composition of the present invention may contain, as an active substance, a conventional drug known as a serotonin antagonist together with the above-mentioned compound.

In addition, the pharmaceutical composition of the present invention contains a compound selected from the above 12 species or an existing serotonin antagonist as the active substance, and in addition to the conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, etc. Formulations conventional in the art can be formulated into oral or parenteral formulations such as tablets, capsules, powders, troches, solutions, suspensions and the like. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

The present invention also encompasses a method for treating or preventing central nervous system diseases consisting of administering the above 12 compounds to a patient therapeutically at a dose that may exhibit affinity for the serotonin 5-HT _2A receptor.

Patients to which the pharmaceutical composition of the present invention is applied include anxiety, depression, seizures, compulsive neuroses, psychosis, schizophrenia, suicidal tendency, Alzheimer's dementia, Parkinson's disease, Huntington's chorea ), Warm-blooded animals or mammals, including those with central nervous system diseases such as sleep disorders, appetite disorders, withdrawal symptoms from drug abuse, and migraine headaches. Diagnosis of patients with central nervous system disease is within the capabilities and knowledge of those skilled in the art. Skilled clinicians skilled in the art can readily determine this using clinical trials, physical examinations, medical examination / family history.

Effective dosages of the 12 compounds described above can be readily determined using conventional techniques and by observing results obtained under similar circumstances. In determining the effective dosage, the size, age, and general health of the patient, the severity or severity of the disease, the response of each patient, the specific compound administered, the dosage form, the bioavailability of the administered agent, the selected dosage form, and whether the medication is public Many factors can be considered, including. Based on an adult patient having a weight of 70 kg is generally 0.01 to 1000 mg / day, and may be divided or administered once a day to several times at regular intervals according to the judgment of the doctor or pharmacist. When treating a patient, the active compound can be administered in any form or method, including oral and parenteral, to have bioavailability within an effective amount range. The compound can be administered, for example, orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like, in particular oral administration is preferred. One skilled in the art of formulation formulation can readily select the appropriate formulation and mode of administration depending on the severity of the disease and other relevant circumstances.

The compounds of the present invention may be administered in the form of a pharmaceutical composition or medicament prepared in combination with a pharmaceutically acceptable carrier or excipient and the proportions and types of the carrier or excipient are determined in accordance with the route of administration chosen and general pharmaceutical standard guidelines. . Pharmaceutical compositions or medicaments are prepared by methods known in the pharmaceutical art.

Formulation method and serotonin antagonistic activity of the pharmaceutical composition of the present invention as described above will be described in detail by the following formulation examples and experimental examples. However, 12 kinds of compounds which are used as active substances in the preparation of the pharmaceutical composition of the present invention are known compounds and can be easily obtained by general methods in the art.

Preparation Example Formulation Method of Pharmaceutical Composition

The pharmaceutical composition according to the present invention can be formulated in various forms according to the purpose, and the following will illustrate some formulation methods, but the present invention is not limited thereto.

1. Preparation of Tablets

A tablet was prepared by mixing the serotonin antagonist compound or its pharmaceutically acceptable salt 100 mg, corn starch 100 mg, lactose 100 mg, magnesium stearate 2 mg, and then tableting according to the conventional manufacturing method.

2. Preparation of Capsule

Serotonin antagonist compounds or pharmaceutically acceptable salts thereof 100 mg, corn starch 100 mg, lactose 100 mg, and magnesium stearate 2 mg are mixed, and then filled into gelatin capsules according to the conventional method for preparing capsules Was prepared.

3. Manufacture of powder

A powder was prepared by mixing 2 g of a serotonin antagonist compound or a pharmaceutically acceptable salt thereof with 1 g of lactose and filling it in an airtight bag.

Experimental Example Affinity Test for Serotonin 5-HT _2A Receptor

In this Experimental Example, to test the serotonin 5-HT _2A receptor affinity for the 12 compounds described above was tested by the following method.

Human recombinant 5-HT _2A receptor expressed on CHO-K1 cells was purchased from Euroscreen (Euroscreen, Belgium) and used as a radioisotope [ ³ H] Ketanserin (PerkinElmer Life and Analytical Sciences, USA). Was used.

Serotonin 5-HT _2A receptor binding tests were performed using [ ³ H] Ketanserin 1 nM, 5-HT _2A receptor membrane (15 μg / well), various concentrations of test drug, 5 mM CaCl ₂ , 0.1% ascorbic acid and 10 μg / 50 mM Tris-HCl buffer (pH 7.4) and the like containing mL saponin were added to make a reaction volume with a final volume of 0.25 mL and incubated at 25 ° C. for 60 minutes. After incubation, the reaction was terminated by filtration through a Whatman GF / C glass fiber filter pre-soaked with 0.05% Brij using an Inotech harvester (Inotech) and washed with cold 50 mM Tris-HCl buffer. The filter was covered with MeltiLex, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac). Nonspecific binding was measured in the presence of 0.5 μM Mianserin. The IC ₅₀ value of the test drug was obtained by calculating the isotherm obtained by repeated experiments of two to eight levels of the drug three times in two test tubes by nonlinear regression analysis (GraphPad Prism Program, San Diego, USA). The results are shown in Table 1 below.

As shown in Table 1, the 12 compounds of the present invention exhibited relatively good serotonin 5-HT _2A receptor affinity (IC ₅₀ : <50 nM), in particular compounds 1 and 2 were very good at less than 10 nM. HT _2A receptor affinity was shown.

As described above, since the 12 compounds of the present invention have an excellent binding affinity for serotonin 5-HT _2A receptors, human anxiety, depression, seizures, obsessive compulsive neurosis, psychosis, schizophrenia and suicide Suicidal tendency, Alzheimer's dementia, Parkinson's disease, Huntington's chorea, sleep disorders, appetite disorders, cocaine, ethanol, nicotine, and It can be usefully used as a prophylactic or therapeutic agent for withdrawal symptoms due to drug abuse such as benzodiazepines and the central nervous system diseases such as migraine.

Claims (7)

delete delete delete Naphthalene-2-sulfonic acid methyl- (1-methyl-piperidin-4-yl) -amide (compound 1), 1- (5-Bromo-2-methoxy-benzenesulfonyl) -4- (2-thiophen-2-yl-ethyl) -piperazine (Compound 2), 8- [4- (3-phenyl-aryl) -piperazine-1-sulfonyl] -quinoline (Compound 4), 1- (4-butoxy-benzenesulfonyl) -4-methyl- [1,4] diazepane (compound 6), Biphenyl-4-sulfonic acid [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -amide (compound 8), 1- (2,5-dichloro-benzenesulfonyl) -4-phenethyl-piperazine (Compound 9), 1-phenethyl-4- (toluene-4-sulfonyl) -piperazine (Compound 10), 1- (2-fluoro-5-methyl-benzenesulfonyl) -4-phenethyl-piperazine (Compound 11), 1- (4-bromo-benzenesulfonyl) -4-phenethyl-piperazine (Compound 12), or a pharmaceutically acceptable salt thereof, characterized in that Anxiety, depression, seizures, compulsive neuroses, psychosis, schizophrenia, suicidal tendency, Alzheimer's dementia, Parkinson's disease, Huntington's chorea, sleep disorders, appetite disorders (appetite disorders), withdrawal symptoms due to drug abuse, and a pharmaceutical composition for the treatment and prevention of central nervous system diseases selected from migraine headaches. delete delete The method of claim 4, wherein A pharmaceutical composition, characterized in that it is formulated in a dosage form selected from the group consisting of tablets, capsules, solutions, syrups, suspensions and injections.