KR20230083904A - Composition for preventing or treating hearing loss or tinnitus - Google Patents
Composition for preventing or treating hearing loss or tinnitus Download PDFInfo
- Publication number
- KR20230083904A KR20230083904A KR1020210172347A KR20210172347A KR20230083904A KR 20230083904 A KR20230083904 A KR 20230083904A KR 1020210172347 A KR1020210172347 A KR 1020210172347A KR 20210172347 A KR20210172347 A KR 20210172347A KR 20230083904 A KR20230083904 A KR 20230083904A
- Authority
- KR
- South Korea
- Prior art keywords
- hearing loss
- tinnitus
- oxobutyl
- fluorophenyl
- piperidin
- Prior art date
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Abstract
본 발명은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 치료용 약학 조성물에 관한 것이다.3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, a pharmaceutically acceptable salt thereof , It relates to a pharmaceutical composition for preventing or treating hearing loss or tinnitus containing a solvate, tautomer or hydrate.
Description
본 발명은 난청 또는 이명의 예방 또는 치료용 조성물에 관한 것으로, 보다 바람직하게는 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 난청 또는 이명의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating hearing loss or tinnitus, more preferably 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H - It relates to a composition for preventing or treating hearing loss or tinnitus containing benzimidazol-2-one.
현대 사회에서는 소음 노출의 증가 및 인구의 고령화 등으로 인하여 염증 기반의 귀 관련 질환 보다는 세포나 신경 손상에 의한 난청 그리고 이명과 관련된 문제가 더 크게 대두되고 있다. In modern society, due to the increase in noise exposure and the aging of the population, problems related to hearing loss and tinnitus caused by cell or nerve damage are emerging more than inflammation-based ear-related diseases.
일반인들도 대부분 세균성 외이염, 악성 이염, 균성 외이염, 이진균증, 중이염, 또는 내이염 등의 염증이 원인이 되는 귀 관련 질환과 난청 및 이명의 질환 차이를 구별할 수 있을 정도로, 난청과 이명은 현대 사회에 발병률이 높고 널리 알려진 질환 중 하나이다. Hearing loss and tinnitus are so common that most people can distinguish the difference between ear-related diseases caused by inflammation, such as bacterial otitis externa, malignant otitis media, fungal otitis externa, otomycosis, otitis media, or otitis media, and hearing loss and tinnitus. It is one of the most common and widely known diseases.
난청의 치료를 위해서 다수의 전문의 및 의약 업계 관련 종사자들은 여전히 기존의 항생제 또는 항염증제에 기반을 둔 치료제로써 위 질환의 치료를 목적하고 있으나, 이는 난청과 관련하여 적합한 치료제로 이용될 수 없다. 위와 같은 기존 치료제의 이용은 첫 번째로 난청과 관련된 치료제가 알려진 것이 없기 때문이며 두 번째로 난청에 대한 치료법에 대해 다수의 전문의 및 의약 업계 관련 종사자들이 명확히 인지하지 못하기 때문이다. 이러한 문제점에 의해 난청의 치료를 적절히 수행하지 못하는 문제점이 지속적으로 발생하고 있다. For the treatment of hearing loss, many specialists and medical practitioners still aim to treat the above diseases with conventional antibiotics or anti-inflammatory drugs based treatments, but these cannot be used as suitable treatments for hearing loss. The use of existing treatments as described above is, firstly, because there is no known treatment for hearing loss, and secondly, because many specialists and people in the pharmaceutical industry are not clearly aware of a treatment for hearing loss. Due to these problems, the problem of not properly performing the treatment of hearing loss continues to occur.
특히, 항생제의 사용은 이독성을 가져 큰 문제점을 나타낸다. 예컨대, 아미노글리코사이드 항생제는 내이에서 청력과 평형 기능장애를 유발하는 이독성과 신장독성의 부작용을 가지고 있는데, 이는 과다복용뿐만 아니라 치료 용량으로 장기간 복용시 발생할 수 있으며 일부에서는 단기간 적정용량에도 이독성이 발생하는 경우도 있다. 아미노글리코사이드 항생제 이독성은 사용자의 약 15%에서 전정기능 장애, 10-30%에서 청력감소를 보이며 주로 4000Hz 이상의 고주파수에서 급격한 고도 난청의 형태로 양측 귀 모두에 발생한다.In particular, the use of antibiotics presents a major problem due to ototoxicity. For example, aminoglycoside antibiotics have side effects of ototoxicity and renal toxicity that cause hearing and equilibrium dysfunction in the inner ear, which can occur not only with overdose but also with long-term use in therapeutic doses. Sometimes this happens. Ototoxicity of aminoglycoside antibiotics causes vestibular dysfunction in about 15% of users, hearing loss in 10-30%, and occurs in both ears in the form of sudden severe hearing loss, mainly at high frequencies of 4000 Hz or higher.
또한, 이명은 흔히 귀울림(음향 신호의 외부 공급원의 부재하에 소리의 지각)이라고 한다. 이명증(耳鳴症), 이명, 또는 귀울림은 상응하는 외부의 소리가 없는데 사람의 귀에서 소리를 인식하는 것이다. 쉽게 말하자면, 외부에서 발생하지 않은 소리가 내부에서 들리는 것이다. 통계상, 성인의 약 15 내지 20%가 다양한 이명을 경험하며, 그 중 4%가 심각한 이명 경험이 있다. 또한 난청인의 경우 70-80%가 이명을 경험한다고 한다. Tinnitus is also commonly referred to as tinnitus (the perception of sound in the absence of an external source of acoustic signals). Tinnitus, tinnitus, or tinnitus is the perception of sound in the human ear when there is no corresponding external sound. To put it simply, sounds that do not originate from the outside are heard from the inside. Statistically, about 15 to 20% of adults experience tinnitus of various kinds, of which 4% experience severe tinnitus. In addition, it is said that 70-80% of people with hearing loss experience tinnitus.
이명의 치료와 관련하여서는 대부분의 치료가 재활을 통한 이명 완화에 초점이 맞춰져 있다. 예를 들면 보청기처럼 생긴 기구를 통해 환자의 이명과 유사한 소리를 외부에서 이명보다 더 큰 음량으로 들려주어서 이명이 들리지 않게 하는 이명 차폐법(masking method), 넓은 주파수에 걸쳐 실제 이명보다 작은 소리를 지속적으로 들려주어 난청을 동반하지 않으면서 이명을 치료하는 이명 재훈련치료(retraining therapy) 등이 있다. 현재까지 미 식약성(FDA)에서 승인된 이명 치료제는 없다. Regarding the treatment of tinnitus, most treatments are focused on relieving tinnitus through rehabilitation. For example, a tinnitus masking method in which a sound similar to the patient's tinnitus is heard at a louder volume than the tinnitus from the outside through a device resembling a hearing aid, and a tinnitus masking method that makes the tinnitus inaudible, and a sound that is smaller than the actual tinnitus continuously over a wide frequency range There is a tinnitus retraining therapy that treats tinnitus without accompanying hearing loss by listening to it. To date, there is no treatment for tinnitus approved by the US Food and Drug Administration (FDA).
이러한 배경하에서, 난청 및/또는 이명의 예방 및 치료에 효과적인 물질을 찾기 위한 연구로서 다양한 약물들에 대한 전임상 연구가 보고되고 있으나, 임상실험으로 진행하기에는 한계가 있음이 확인되었다. 또한, 현재까지 난청 및/또는 이명의 예방 및 치료와 관련하여 승인된 약물은 없다. 더욱이, 인체에 독성 또는 위험성 없이 사용할 수 있는 난청 및/또는 이명 치료제에 대해서는 개발된 약물을 거의 찾아볼 수 없다. 즉, 염증에 의해 유발되는 귀 관련 질환과 달리 난청 및/또는 이명에 대해 적합한 치료제가 전혀 개발되지 않은 실정이다. Under this background, preclinical studies on various drugs have been reported as studies to find substances effective for the prevention and treatment of hearing loss and/or tinnitus, but it has been confirmed that there are limitations to proceeding with clinical trials. In addition, there are currently no drugs approved for the prevention and treatment of hearing loss and/or tinnitus. Moreover, there are few drugs developed for the treatment of hearing loss and/or tinnitus that can be used without toxicity or risk to the human body. That is, unlike ear-related diseases caused by inflammation, a suitable treatment for hearing loss and/or tinnitus has not been developed at all.
본 발명의 목적은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 치료용 약학 조성물을 제공하는 것이다.An object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, which is pharmaceutically acceptable. It is to provide a pharmaceutical composition for preventing or treating hearing loss or tinnitus, including possible salts, solvates, tautomers or hydrates.
본 발명의 다른 하나의 목적은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 이를 필요로 하는 개체에게 투여하는 단계를 난청 또는 이명의 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, its pharmaceutical To provide a method for preventing or treating hearing loss or tinnitus, wherein the step of administering a generally acceptable salt, solvate, tautomer or hydrate to a subject in need thereof.
본 발명의 다른 하나의 목적은 난청 또는 이명의 예방 또는 치료를 위한 의약을 제조하기 위한 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물의 용도를 제공하는 것이다.Another object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] for preparing a medicament for the prevention or treatment of hearing loss or tinnitus. -1H-benzimidazol-2-one, a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof is provided.
본 발명의 다른 하나의 목적은 난청 또는 이명의 예방 또는 치료에 사용하기 위한 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 조성물을 제공하는 것이다.Another object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H- for use in the prevention or treatment of hearing loss or tinnitus. It is to provide a composition comprising benzimidazol-2-one, a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof.
본 발명의 다른 하나의 목적은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 식품학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, its food To provide a food composition for preventing or improving hearing loss or tinnitus containing a chemically acceptable salt, solvate, tautomer or hydrate.
본 발명의 다른 하나의 목적은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 식품학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Another object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, its food To provide a health functional food for preventing or improving hearing loss or tinnitus containing a chemically acceptable salt, solvate, tautomer or hydrate.
본 발명의 다른 또 하나의 목적은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 식품학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 개선용 사료 조성물을 제공하는 것이다.Another object of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, It is to provide a feed composition for preventing or improving hearing loss or tinnitus containing a food-acceptable salt, solvate, tautomer or hydrate.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 출원에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 출원에서 개시된 다양한 요소들의 모든 조합이 본 출원의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 출원의 범주가 제한된다고 볼 수 없다.A detailed description of this is as follows. Meanwhile, each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of various elements disclosed in this application fall within the scope of this application. In addition, the scope of the present application is not to be construed as being limited by the specific descriptions described below.
3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 난청 또는 이명의 예방 또는 치료용 약학 조성물Pharmaceuticals for preventing or treating hearing loss or tinnitus, including 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one composition
상기한 과제를 해결하기 위하여, 본 발명의 하나의 양태는 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 치료용 약학 조성물을 제공한다.In order to solve the above problems, one aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazole -2-one, a pharmaceutical composition for preventing or treating hearing loss or tinnitus containing a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof is provided.
본 발명에서, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온은 하기 화학식 1로 표시되는 화합물일 수 있다.In the present invention, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one is represented by the following formula (1) can be a compound.
[화학식 1][Formula 1]
상기 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온은 벤페리돌(Benperidol)이라 칭하기도 한다.The 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one is also referred to as Benperidol. do.
본 발명자들은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 약학 조성물이 난청으로 인한 청력 역치의 상승과 유모세포 손상을 효과적으로 억제시킴으로써 난청에 우수한 치료 효과를 가지는 것을 확인하였다.The present inventors have found that a pharmaceutical composition containing 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one is effective for hearing loss. It was confirmed that it has an excellent therapeutic effect on hearing loss by effectively suppressing the increase in hearing threshold and hair cell damage due to
본 발명에서 "난청(hearing loss)"이란 청각이 저하 또는 상실된 모든 상태를 의미한다. 난청은 전음성 난청(conductive hearing loss) 및 감각신경성 난청(sensorineural hearing loss)을 포함할 수 있으나, 이에 제한되지 않는다.In the present invention, "hearing loss" means any condition in which hearing is reduced or lost. Hearing loss may include, but is not limited to, conductive hearing loss and sensorineural hearing loss.
상기 전음성 난청은 귀 질환에 의한 난청으로, 소리를 전달하는 기관인 고막과 이소골 등의 기관에 문제가 생겨 발생하는 난청이다. 상기 난청은 여러 원인, 예컨대 감염, 손상, 염증, 종양 및 약물이나 기타 화학제에 대한 좋지 않은 반응에 의한 것일 수 있다.The conductive hearing loss is hearing loss caused by an ear disease, and is a hearing loss caused by problems in organs such as the eardrum and ossicles, which are organs that transmit sound. The hearing loss may be due to several causes, such as infections, injuries, inflammation, tumors, and adverse reactions to drugs or other chemicals.
상기 감각신경성 난청은 소리를 감지하는 기관인 달팽이관과 전기적 에너지로 소리를 전달하는 청신경, 그리고 소리의 변별, 이해 등 종합적인 역할을 하는 청각을 담당하는 뇌에 문제가 생겨 발생하는 난청이다. 감각신경성 난청의 원인은 소음, 약물, 노화, 외상 등에 의해 발생하는 난청일 수 있고, 예컨대 이독성 난청일 수 있다. 상기 이독성 난청은 이독성 약물인 젠타마이신(gentamicin), 스트렙토마이신(streptomycin), 가나마이신(kanamycin), 네오마이신(neomycin), 아미카신(amikacin), 토브라마이신(tobramycin), 네틸마이신(netilmicin), 디베카신(dibekacin), 시소마이신(sisomycin), 리보도마이신(livodomycin), 시스플라틴(cisplatin), 카르보플라틴(carboplatin) 및 옥살리플라틴(oxaliplatin)으로 구성된 군으로부터 선택된 어느 하나 이상의 약물의 투여로 인한 난청일 수 있다.The sensorineural hearing loss is a hearing loss caused by problems in the cochlea, which is an organ that detects sound, the auditory nerve, which transmits sound with electrical energy, and the brain responsible for hearing, which plays a comprehensive role in discriminating and understanding sound. The cause of sensorineural hearing loss may be hearing loss caused by noise, drugs, aging, trauma, or the like, and may be, for example, ototoxic hearing loss. The ototoxic hearing loss is caused by ototoxic drugs such as gentamicin, streptomycin, kanamycin, neomycin, amikacin, tobramycin, netylmycin ( Administration of one or more drugs selected from the group consisting of netilmicin), dibekacin, sisomycin, ribodomycin, cisplatin, carboplatin, and oxaliplatin It may be due to hearing loss.
또한, 상기 난청은 소음성 난청, 노인성 난청, 돌발성 난청, 당뇨병으로 인한 청신경병증, 이독성 난청, 외상성 난청, 바이러스성 난청 등을 포함할 수 있다.In addition, the hearing loss may include noise-induced hearing loss, presbyopia, sudden hearing loss, acoustic neuropathy due to diabetes, ototoxic hearing loss, traumatic hearing loss, viral hearing loss, and the like.
청각이 저하 또는 상실된 상태에 해당한다면 본 발명의 상기 난청의 범주에 제한되지 않고 질환 범위로 포함될 수 있다.If hearing is reduced or lost, it is not limited to the scope of the hearing loss of the present invention and may be included in the range of diseases.
또한, 본 발명자들은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 약학 조성물이 이명으로 인한 이상 행동의 감소와 청력 진폭을 정상으로 되돌리는 효과를 가짐으로써 이명에 우수한 치료 효과를 가지는 것을 확인하였다.In addition, the present inventors found that a pharmaceutical composition comprising 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one It was confirmed that it has an excellent treatment effect on tinnitus by reducing abnormal behavior caused by tinnitus and returning the hearing amplitude to normal.
본 발명에서 "이명(Tinnitus)"이란 음향 신호의 외부 공급원의 부재하에 소리의 지각이 나타나는 것으로, 타각적 이명, 자각적 이명, 말초적 이명 및 중추적 이명을 포함하는 것일 수 있으나, 이에 제한되지 않는다. 구체적으로는, 소음, 약물, 노화, 외상, 바이러스 등의 다양한 원인에 의해 발생하는 자각적 이명을 포함할 수 있으나, 이에 제한되지 않는다.In the present invention, “tinnitus” refers to the perception of sound in the absence of an external source of sound signals, and may include objective tinnitus, subjective tinnitus, peripheral tinnitus, and central tinnitus, but is not limited thereto. Specifically, it may include subjective tinnitus caused by various causes such as noise, drugs, aging, trauma, and viruses, but is not limited thereto.
상기 타각적 이명(또는 객관적 이명)은 외부에서도 들리는 이명이고, 상기 자각적 이명(또는 주관적 이명)은 이명 환자 본인만 들리고 외부에서 들리지 않는 이명을 의미한다. 또한, 이명은 병에 걸린 개인에 의해 지각되는 방법의 차이를 기초로 하여 말초성 이명 및 중추성 이명으로 분류될 수 있다. 말초적(또는 와우성) 이명은 말초 신경계 및 와우로부터 유래하는 것으로 추정되고, 중추적 이명은 청각 피질로부터 유래하는 것으로 추정된다.The objective tinnitus (or objective tinnitus) is tinnitus that can be heard from the outside, and the subjective tinnitus (or subjective tinnitus) means tinnitus that is heard only by the tinnitus patient and cannot be heard from the outside. Tinnitus can also be classified into peripheral tinnitus and central tinnitus based on differences in how it is perceived by affected individuals. Peripheral (or cochlear) tinnitus is presumed to originate from the peripheral nervous system and cochlea, and central tinnitus is presumed to originate from the auditory cortex.
그러나, 이명에 해당한다면 본 발명의 상기 이명의 범주에 제한되지 않고 질환 범위로 포함될 수 있다.However, if it corresponds to tinnitus, it is not limited to the scope of the tinnitus of the present invention and may be included in the range of diseases.
본 발명에 있어서, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산에 의해 형성된 산 부가염이 유용하다. 본 명세서에 사용된 바와 같이 "약학적으로 허용 가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 이로운 효능을 저하시키지 않는 임의의 모든 유기 또는 무기 부가염을 의미한다.In the present invention, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one is pharmaceutically acceptable. It may exist in the form of a salt. As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, "pharmaceutically acceptable salt" is a concentration that has an effective effect that is relatively non-toxic and harmless to patients, and the side effects caused by this salt are 3-[1-[4-(4-fluorophenyl )-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one means any and all organic or inorganic addition salts which do not diminish the beneficial effects of the
이때, 부가염으로서 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고, 유기산으로는 메탄설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산, 석신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산 등을 사용할 수 있으며, 이들에 제한되지 않는다.At this time, as an addition salt, inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used, and organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, Benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid etc. can be used, but is not limited thereto.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 칼슘, 마그네슘염 또는 이들의 혼합 염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable for preparing sodium, potassium, calcium, magnesium salts or mixed salts thereof, but is not limited thereto.
본 발명에 있어서, 용어 "용매화물(solvate)"은 달리 나타내지 않는 한, 본원에서 제공된 화합물에 하나 또는 그 이상의 용매분자가 연합으로부터의 형성된 용매화물을 의미한다. 용어 "용매화물"은 수화물(예를 들어, 일수화물, 이수화물, 삼수화물, 사수화물 등)을 포함한다.As used herein, the term "solvate", unless otherwise indicated, refers to a solvate formed from association of one or more solvent molecules in a compound provided herein. The term "solvate" includes hydrates (eg, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).
용어 “호변체”는 동일한 화학식 또는 분자식을 가지지만 구성원자들의 연결방식이 다른 구조이성질체의 한 종류로서, 예를 들어, 케토-에놀(keto-eno) 구조처럼 계속 양쪽 이성질체 사이를 왕복하며 그 구조가 변화는 것을 의미한다. 또한, 아마이드기(CONH) 관련 이미드산(imidic acid)에서 아미드(amide)로 호변체화(tautomerization)이 일어날 수 있다.The term “tautomer” is a type of structural isomer that has the same chemical or molecular formula but differs in the way the members are connected, such as the keto-eno structure, which continuously shuttles between both isomers. means change. In addition, tautomerization may occur from imidic acid related to the amide group (CONH) to amide.
용어 “수화물(hydrate)”은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다.The term “hydrate” refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.
본 발명의 약학 조성물은 약학적으로 허용가능한 담체를 포함할 수 있으며, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화될 수 있다.The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, and may be prepared according to conventional methods, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, external preparations, suppositories, and the like. It can be formulated in the form of a sterile injectable solution.
상기 약제학적으로 허용가능한 담체는 당업계에서 통상적으로 사용되는 것들, 예컨대 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 포함하나 이에 국한되지 않는다. 또한, 본 발명의 약학 조성물은 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제, 기타 약제학적으로 허용가능한 첨가제를 포함할 수 있으나, 이에 국한되지 않는다.The pharmaceutically acceptable carrier includes those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition, the pharmaceutical composition of the present invention may include diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives, but is not limited thereto.
본 발명의 약학 조성물이 경구용 고형 제제로 제제화된 경우 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토즈, 젤라틴 등을 포함할 수 있으며, 마그네슘 스테아레이트, 탈크 같은 윤활제 등을 포함하나 이에 국한되지 않는다. When the pharmaceutical composition of the present invention is formulated into oral solid preparations, it includes tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient such as starch, calcium carbonate, It may include sucrose or lactose, gelatin, and the like, and include, but are not limited to, lubricants such as magnesium stearate and talc.
본 발명의 약학 조성물이 경구용 액상 제제화된 경우 현탁제, 내용액제, 유제, 시럽제 등을 포함하며, 물, 리퀴드 파라핀 등의 희석제, 습윤제, 감미제, 방향제, 보존제 등을 포함하나 이에 국한되지 않는다. When the pharmaceutical composition of the present invention is formulated in liquid form for oral use, it includes suspensions, internal solutions, emulsions, syrups, etc., and diluents such as water and liquid paraffin, wetting agents, sweeteners, aromatics, preservatives, etc., but are not limited thereto.
본 발명의 약학 조성물이 비경구용 제제화된 경우 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제를 포함하며, 비수성 용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르류 등을 포함하나 이에 국한되지 않는다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있으나 이에 국한되지 않는다.When the pharmaceutical composition of the present invention is formulated for parenteral use, it includes a sterilized aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository, and the non-aqueous solvent and suspension include propylene glycol, polyethylene glycol, and olive vegetable oils such as oils, injectable esters such as ethyl oleate, and the like, but are not limited thereto. As a base material for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin paper, glycerogelatin, etc. may be used, but are not limited thereto.
상기 조성물은 약학적으로 유효한 양으로 단일 또는 다중 투여될 수 있다. 본 발명의 용어 "약학적으로 유효한 양"이란 의학적 예방 또는 치료에 적용가능한 합리적인 수혜/위험 비율로 질환을 예방 또는 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율, 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 예를 들면, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온은 1일 0.0001 내지 100 mg/kg으로, 바람직하게는 0.01 내지 50 mg/kg의 용량으로 투여할 수 있으며, 상기 투여는 하루에 한 번 또는 수회 나누어 투여할 수도 있다.The composition may be administered singly or in multiple doses in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to prevent or treat a disease with a reasonable benefit / risk ratio applicable to medical prevention or treatment, and the effective dose level is the severity of the disease, the activity of the drug, Age, weight, health, sex of the patient, sensitivity to the drug of the patient, administration time of the composition of the present invention used, route of administration and excretion rate, treatment period, including drugs used in combination or simultaneous use with the composition of the present invention used factors and other factors well known in the medical field. For example, 0.0001 to 100 mg of 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one per day. /kg, preferably at a dose of 0.01 to 50 mg/kg, and the administration may be administered once a day or divided into several times.
본 발명의 약학 조성물은 랫트, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로, 예를 들면, 경구 투여, 내이, 복강 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans by various routes, for example, oral administration, inner ear, abdominal cavity or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection. It can be.
본 발명의 약학 조성물은 조성물 총 중량에 대하여 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 0.01 내지 95 중량%, 바람직하게는 1 내지 80 중량%로 포함할 수 있다. The pharmaceutical composition of the present invention contains 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one based on the total weight of the composition. 0.01 to 95% by weight, preferably 1 to 80% by weight.
본 발명의 난청 또는 이명의 예방 또는 치료용 약학 조성물은 난청 또는 이명으로 인한 이상 행동의 감소시킴으로써 난청 또는 이명에 우수한 치료 효과를 가진다.The pharmaceutical composition for preventing or treating hearing loss or tinnitus of the present invention has an excellent therapeutic effect on hearing loss or tinnitus by reducing abnormal behavior caused by hearing loss or tinnitus.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학 조성물의 투여에 의해 난청 또는 이명을 억제시키거나 난청의 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that suppresses hearing loss or tinnitus or delays the onset of hearing loss by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학 조성물의 투여에 의해 난청 또는 이명의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" refers to all activities that improve or beneficially change symptoms of hearing loss or tinnitus by administration of the pharmaceutical composition according to the present invention.
3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 이를 필요로하는 개체에 투여하는 단계를 포함하는 난청 또는 이명의 예방 또는 치료 방법, 및 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 용도administering 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one to a subject in need thereof A method for preventing or treating hearing loss or tinnitus comprising, and 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one use of
본 발명의 다른 하나의 양태는 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는 난청 또는 이명의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, its pharmaceutical Provided is a method for preventing or treating hearing loss or tinnitus comprising administering an acceptable salt, solvate, tautomer or hydrate to a subject in need thereof.
본 발명에서 용어 "3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온", "난청" 또는 “이명”은 전술한 바와 같다.In the present invention, the term "3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one", "hearing loss" or “Tinnitus” is as described above.
본 발명의 용어 "개체"란 난청 또는 이명이 발병하였거나 발병할 수 있는 모든 동물을 의미하며, 전형적으로 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 이용한 치료로 유익한 효과를 나타낼 수 있는 동물일 수 있으나, 난청 또는 이명의 증상을 갖거나 이러한 증상을 가질 가능성이 있는 개체이면 제한없이 포함한다. 전술한 바와 같이, 본 발명의 약학 조성물을 개체에게 투여함으로써 상기 난청 또는 이명을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학 조성물은 개별 치료제로 투여하거나, 기존의 난청 또는 이명 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다.As used herein, the term "individual" means any animal that has or may develop hearing loss or tinnitus, and is typically 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidine -4-yl] -1H-benzimidazol-2-one, a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof may be an animal that can exhibit a beneficial effect, but is deaf. Alternatively, any subject having symptoms of tinnitus or possibly having such symptoms is included without limitation. As described above, the hearing loss or tinnitus can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent, or in combination with an existing therapeutic agent for hearing loss or tinnitus, and may be administered sequentially or simultaneously with conventional therapeutic agents.
본 발명의 용어 "투여"란 적절한 방법으로 환자에게 소정의 물질을 도입하는 것을 의미하며 상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 또한, 본 발명의 약학 조성물은 활성 물질이 목적 조직으로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 예를 들면, 경구 투여, 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여, 내이 투여될 수 있으나, 이에 제한되지는 않는다. 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다.The term "administration" of the present invention means introducing a predetermined substance into a patient by an appropriate method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target tissue. For example, oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, inner ear administration may be used, but is not limited thereto. does not Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
본 발명의 약학적 조성물의 투여는 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양으로 투여할 수 있으며, 이는 당업자에 의해 용이하게 결정될 수 있다.Administration of the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Considering all of the above factors, it can be administered in an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 다른 하나의 양태는 난청 또는 이명의 예방 또는 치료를 위한 의약을 제조하기 위한 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물의 용도를 제공한다.Another aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] for preparing a medicament for the prevention or treatment of hearing loss or tinnitus. -1H-benzimidazol-2-one, a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof.
본 발명의 다른 또 하나의 양태는 난청 또는 이명의 예방 또는 치료에 사용하기 위한 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 조성물을 제공한다.Another aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H for use in the prevention or treatment of hearing loss or tinnitus - A composition containing benzimidazol-2-one, a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof is provided.
3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 식품 조성물, 건강기능식품 및 사료 조성물Food composition, health functional food and feed containing 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one composition
본 발명의 다른 하나의 양태는 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 식품학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 개선용 식품 조성물을 제공한다.Another aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, food thereof Provided is a food composition for preventing or improving hearing loss or tinnitus containing a chemically acceptable salt, solvate, tautomer or hydrate.
본 발명의 다른 하나의 양태는 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 식품학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 개선용 건강기능식품을 제공한다.Another aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, food thereof Provided is a health functional food for preventing or improving hearing loss or tinnitus containing a chemically acceptable salt, solvate, tautomer or hydrate.
본 발명에서 용어 "3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온", “용매화물”, “호변체”, “수화물”, "난청" 또는 “이명”은 전술한 바와 같다.In the present invention, the term "3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one", "solvate" , “tautomer”, “hydrate”, “hearing loss” or “tinnitus” are as described above.
본 발명에 있어서, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온은 식품학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 식품학적으로 허용가능한 유리산에 의해 형성된 산 부가염이 유용하다. 본 명세서에 사용된 바와 같이 "식품학적으로 허용 가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 이로운 효능을 저하시키지 않는 임의의 모든 유기 또는 무기 부가염을 의미한다. 여기서 상기 염은 앞서 약학 조성물에서 살핀 바와 같다. In the present invention, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one is food-acceptable It may exist in the form of a salt. As the salt, an acid addition salt formed by a free acid that is acceptable in food science is useful. As used herein, "food acceptable salt" is a concentration that has an effective effect that is relatively non-toxic and harmless to patients, and the side effects caused by this salt are 3-[1-[4-(4-fluorophenyl )-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one means any and all organic or inorganic addition salts which do not diminish the beneficial effects of the Here, the salt is as described above in the pharmaceutical composition.
본 발명의 용어, “개선”이란, 본 발명의 조성물의 투여로 난청 또는 이명이 호전 또는 이롭게 변경되는 모든 행위를 의미한다.The term of the present invention, "improvement" refers to all activities in which hearing loss or tinnitus is improved or advantageously changed by administration of the composition of the present invention.
본 발명의 식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The food composition of the present invention may include conventional food additives, and the suitability as the "food additive" is determined according to the general rules of the food additive code approved by the Ministry of Food and Drug Safety and general test methods, etc., unless otherwise specified. It is judged according to the specifications and standards for the item.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류들을 들 수 있다.Items listed in the "Food Additive Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, goyang pigment, guar gum, and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.
또한, 본 발명의 식품 조성물은 난청 또는 이명의 예방 및/또는 개선을 목적으로, 정제, 캡슐, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.In addition, the food composition of the present invention can be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing and/or improving hearing loss or tinnitus.
본 발명의 식품 조성물은 건강기능식품으로서 사용될 수 있다. 상기 "건강기능식품"이라 함은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The food composition of the present invention can be used as a health functional food. The term “health functional food” refers to food manufactured and processed using raw materials or ingredients having useful functionalities for the human body in accordance with the Health Functional Food Act, and “functional” refers to food that is not related to the structure and function of the human body. It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological functions.
본 발명의 다른 또 하나의 양태는 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 식품학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 난청 또는 이명의 예방 또는 개선용 사료 조성물을 제공한다.Another aspect of the present invention is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, Provided is a feed composition for preventing or improving hearing loss or tinnitus containing a food grade acceptable salt, solvate, tautomer or hydrate.
본 발명에서 용어 "3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온", “용매화물”, “호변체”, “수화물”, "난청" 또는 “이명”은 전술한 바와 같다.In the present invention, the term "3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one", "solvate" , “tautomer”, “hydrate”, “hearing loss” or “tinnitus” are as described above.
본 발명에 있어서 상기 사료는 어류, 조류 또는 포유류의 사료일 수 있으며, 바람직하게, 축산법 제2조 제1호 및 동법 시행규칙 제2조 각호에서 정의하고 있는, 야생습성이 순화되어 사육하기에 적합하며 농가의 소득증대에 기여할수 있는 가축 또는 수산생물의 사료일 수 있다. 상기 가축에는 소, 말, 노새, 당나귀, 염소, 산양, 면양, 사슴, 돼지, 토끼, 가금류 등일 수 있으며, 가금류에는 닭, 칠면조, 오리, 타조, 거위, 메추리 등, 바람직하게는 닭일 수 있으나, 사육하여 축산물을 얻기에 적합한 것이라면 이에 제한되는 것은 아니다. 상기 "축산물"은 축산법 제2조 3호의 정의인, 가축에서 생산된 고기, 젖, 알, 꿀과 이들의 가공품, 원피(원모피를 포함한다), 원모, 기타 가축의 생산물로서 농림부령이 정하는 것을 의미한다. 또한 반려동물을 포함하여 개, 고양이 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the feed may be fish, bird, or mammal feed, and preferably, the wild habits defined in Article 2, Subparagraph 1 of the Livestock Act and each subparagraph of the Enforcement Rule of the same Act are purified and suitable for breeding. It can be feed for livestock or aquatic organisms that can contribute to farm household income increase. The livestock may be cattle, horses, mules, donkeys, goats, goats, sheep, deer, pigs, rabbits, poultry, etc., and poultry may be chickens, turkeys, ducks, ostriches, geese, quails, etc., preferably chickens, It is not limited thereto as long as it is suitable for breeding and obtaining livestock products. The above "livestock products" are meat, milk, eggs, honey and their processed products, hides (including raw fur), raw wool, and other livestock products produced from livestock, which are defined in Article 2, Subparagraph 3 of the Livestock Act, as determined by the Ordinance of the Ministry of Agriculture and Forestry. means that In addition, it may be a dog, cat, etc., including companion animals, but is not limited thereto.
발명의 용어 "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미한다. 일 양태로, 본 발명의 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 함유하는 사료용 조성물에는 농후사료, 조사료 및/또는 특수사료가 포함될 수 있다.The term "feed" in the present invention means any natural or artificial diet, meal, etc. or component of said meal, intended for or suitable for eating, ingestion and digestion by an animal. In one aspect, for feed containing 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one of the present invention The composition may include concentrates, roughage and/or special diets.
농후사료에는 밀, 귀리, 옥수수 등의 곡류를 포함하는 종자열매류, 곡물을 정제하고 얻는 부산물로서 쌀겨, 밀기울, 보릿겨 등을 포함하는 겨류, 콩, 유체, 깨, 아마인, 코코야자 등을 채유하고 얻는 부산물인 깻묵류와 고구마, 감자 등에서 녹말을 뺀 나머지인 녹말찌꺼기의 주성분인 잔존녹말질류 등의 찌꺼기류, 어분, 물고기찌꺼기, 어류에서 얻은 신선한 액상물을 농축시킨 것인 피시솔루블, 육분, 혈분, 우모분, 탈지분유, 우유에서 치즈, 탈지유에서 카제인을 제조할 때의 잔액인 훼이(whey)를 건조한 건조훼이 등의 동물질사료, 효모, 클로렐라, 해조류 등이 있다.Concentrated feed includes seed fruits including grains such as wheat, oats, and corn, bran including rice bran, wheat bran, and barley bran as by-products obtained after refining grains, soybeans, fluids, sesame seeds, linseed, and coco palm oil. Fish meal, which is a by-product obtained by extracting starch from sweet potatoes and potatoes, and residual starch, which is the main component of starch residues, fish meal, fish residue, and fish soluble, meat meal, which are concentrated fresh liquids obtained from fish. , animal feed such as blood meal, feather meal, skim milk powder, dried whey obtained by drying whey, which is the balance when cheese is produced from milk and casein is produced from skim milk, yeast, chlorella, and seaweed.
조사료에는 야초, 목초, 풋베기 등의 생초(生草)사료, 사료용 순무, 사료용 비트, 순무의 일종인 루터베어거 등의 뿌리채소류, 생초, 풋베기작물, 곡실(穀實)등을 사일로에 채워 놓고 젖산발효시킨 저장사료인 사일리지(silage), 야초, 목초를 베어 건조시킨 건초, 종축용(種畜用) 작물의 짚, 콩과 식물의 나뭇잎 등이 있다. 특수 사료에는 굴껍떼기, 암염 등의 미네랄 사료, 요소나 그 유도체인 디우레이드이소부탄 등의 요소사료, 천연사료 원료만을 배합했을 때 부족하기 쉬운 성분을 보충하거나, 사료의 저장성을 높이기 위해서 배합사료에 미량으로 첨가하는 물질인 사료첨가물 등이 있다.Forage, raw grass feed such as wild grass, grass, and green cutting, turnip for feed, beet for feed, root vegetables such as Lutherbearer, a type of turnip, raw grass, green cut crops, grain, etc. are put into silos. There are silage (silage), which is a stored feed filled and fermented with lactic acid, grass, hay cut and dried, straw from breeding crops, and leaves of leguminous plants. Special feeds include mineral feeds such as oyster shells and rock salt, urea feeds such as urea or its derivative, diureide isobutane, and supplements for ingredients that tend to be insufficient when only natural feed ingredients are mixed, or formulated feeds to improve the storage life of feeds. There are feed additives, which are substances added in small amounts.
본 발명에 따른 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온, 이의 약학적으로 허용 가능한 염, 용매화물, 호변체(tautomer) 또는 수화물을 포함하는 조성물은 난청으로 인한 청력상승은 물론 항생제 사용에 의해 유발되는 유모세포의 손상을 효과적으로 억제할 수 있고, 이명으로 인해 유발되는 행동 등을 억제하여 난청 또는 이명의 예방, 치료 또는 개선에 유용하므로 약학 조성물 또는 건강기능식품으로 유용하게 사용될 수 있다.3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one according to the present invention, its pharmaceutically acceptable Compositions containing salts, solvates, tautomers, or hydrates can effectively inhibit hair cell damage caused by antibiotic use as well as increase hearing due to hearing loss, and inhibit behaviors caused by tinnitus. It is useful for preventing, treating or improving hearing loss or tinnitus, so it can be usefully used as a pharmaceutical composition or health functional food.
도 1은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 네오마이신 처리에 의한 유모세포 손상에 대한 억제 효과를 나타낸 도이다. NOR은 네오마이신 미처리 정상 대조군을, NM은 네오마이신만을 처리한 비교군을, Benperidol은 0.1 μM 농도로 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 처리한 실험군을 나타낸다.Figure 1 shows hair cells by neomycin treatment with 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one. It is a diagram showing the inhibitory effect on damage. NOR is the normal control group without neomycin treatment, NM is the control group treated only with neomycin, and Benperidol is 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidine at a concentration of 0.1 μM. The experimental group treated with -4-yl] -1H-benzimidazol-2-one is shown.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.
<실시예><Example>
실시예 1. 이독성 난청 제브라피시 모델에 대한 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 효과Example 1. 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazole-2- on ototoxic hearing loss zebrafish model on's effect
수정 6일 후의 제브라피시 치어(larvae)를 24웰에 위치시킨 후 네오마이신을 2 μM 농도로 처리하여 1시간 동안 노출시켜 이독성 난청 모델을 제조하였다. 이와 함께 네오마이신을 처리하지 않은 미처리 정상 대조군을 준비하였다.Zebrafish fry (larvae) 6 days after fertilization were placed in 24 wells, treated with neomycin at a concentration of 2 μM, and exposed for 1 hour to prepare an ototoxic hearing loss model. In addition, an untreated normal control group that was not treated with neomycin was prepared.
상기 준비한 이독성 난청 제브라피시 모델에 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 0.1 μM 농도로 처리하여 6시간 동안 노출시켰다. 비교군으로는 0.03% 해수염용액(sea salt solution)을 사용하였다. 정상 대조군 및 이독성 난청 모델에 각각 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온 및 해수염용액을 처리한 실험군과 비교군의 제브라피시 치어를 0.02% 트리카인으로 마취시키고, 유모세포를 0.1% YO-PRO로 30분 동안 염색하여, 형광현미경(Olympus 1×70, Olympus, Japan)을 사용하여 육안으로 직접 관찰하였다. 구체적으로, 육안으로 관찰되는 유모세포의 갯수를 세어 그래프로 작성하고, 형광 이미지를 사진으로 찍어 도 1에 나타내었다.3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one was added to the ototoxic deafness zebrafish model prepared above. It was treated with a concentration of μM and exposed for 6 hours. As a comparison group, 0.03% sea salt solution was used. 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one and seawater were administered to normal controls and ototoxic hearing loss models, respectively. The zebrafish fry of the experimental group and the control group treated with salt solution were anesthetized with 0.02% tricaine, and the hair cells were stained with 0.1% YO-PRO for 30 minutes and examined under a fluorescence microscope (Olympus 1 × 70, Olympus, Japan). was observed directly with the naked eye. Specifically, the number of hair cells observed with the naked eye was counted and graphed, and a fluorescence image was taken and shown in FIG. 1 .
도 1에 나타난 바와 같이, 정상 대조군에 비해 이독성 난청 유도 제브라피시 모델에 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 처리하지 않은 비교군에서는 유모세포의 갯수가 현저하게 감소한 반면, 상기 이독성 난청 유도 제프라피시에 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 처리한 실험군에서는 유모세포의 갯수가 유의적으로 증가하였다. 이를 통해 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 처리가 이독성 난청에 의한 유모세포 손상을 감소시켜 난청의 예방 및 치료에 효과가 있음을 확인하였다.As shown in Figure 1, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H in the ototoxic hearing loss induced zebrafish model compared to the normal control group. -While the number of hair cells was significantly reduced in the control group not treated with benzimidazol-2-one, 3-[1-[4-(4-fluorophenyl)- In the experimental group treated with 4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, the number of hair cells was significantly increased. Through this, the treatment of 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one is effective for ototoxic deafness. It was confirmed that it is effective in preventing and treating hearing loss by reducing cell damage.
실시예 2. 소음 노출 후 난청의 개선 효과 확인Example 2. Confirmation of improvement effect of hearing loss after exposure to noise
실시예 2-1. 광대역 자극음인 클릭(click)음을 이용한 청력역치 확인Example 2-1. Confirmation of hearing threshold using click sound, which is a broadband stimulus sound
3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온가 소음 노출 후 청력역치에 미치는 영향을 확인하기 위해 청성유발전위를 이용한 청력역치 측정 실험을 수행하였다. 청성유발전위(auditory brainstem response, ABR) 측정법은 소리자극이 청신경에서 전기적인 신호로 전달될 때, 상기 전기적인 에너지를 측정하여 소리에 대한 반응을 평가하는 방법이다. 소리가 외이와 중이 그리고 달팽이관을 거쳐 청신경에 도달했을 때의 반응은 외이, 중이, 달팽이관의 상태를 모두 반영하는 것으로 이는 뇌까지 소리 에너지가 도달하는 실제적인 소리 에너지를 반영하는 것이다. 청력역치라 함은 겨우 들을 수 있는 소리의 최소 감각지점을 말하는 것으로 정상 마우스의 경우 평균적으로 20 dB의 작은 소리에서도 반응이 관찰된다.To determine the effect of 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one on hearing threshold after exposure to noise To this end, a hearing threshold measurement experiment using the auditory evoked potential was performed. An auditory brainstem response (ABR) measurement method is a method of evaluating a response to sound by measuring the electrical energy when a sound stimulus is transmitted as an electrical signal from the auditory nerve. When sound reaches the auditory nerve via the outer ear, middle ear, and cochlea, the response reflects the condition of the outer ear, middle ear, and cochlea, which reflects the actual sound energy reaching the brain. Hearing threshold refers to the minimum sensory point of barely audible sound, and in the case of a normal mouse, a response is observed even to a small sound of 20 dB on average.
구체적으로, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 투여할 마우스와 미처리 대조군 마우스를 나누어 평가하였다. Specifically, mice to which 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one was administered and untreated control mice was evaluated separately.
소음은 115 dB 복합음으로 90분 동안 노출시켰으며, 소음 노출 24시간 후에 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 매일 같은 시간에 경구투여하였다. Noise was exposed to 115 dB complex sounds for 90 minutes, and after 24 hours of noise exposure, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H- Benzimidazol-2-one was orally administered at the same time every day.
청력역치는 소음 노출 전, 노출 후 1일째, 10일째, 및 20일째에 평가하였다.Hearing threshold was evaluated before noise exposure and on day 1, day 10, and
청성유발전위 검사를 위하여 케타민(4.57 mg/kg)과 실라진(0.43 mg/kg)을 마우스에게 근육 주사하여 마취시킨 뒤 체온 37±0.5℃를 유지시키면서 평가하였다. 청성유발전위 검사시 자극음은 광대역 자극음인 클릭(click)음으로 80 dB부터 점차적으로 5 dB씩 소리를 낮춰가며 평가했으며 반응이 나오는 가장 작은 소리를 역치로 하였다.For the auditory evoked potential test, mice were anesthetized by intramuscular injection of ketamine (4.57 mg/kg) and xylazine (0.43 mg/kg), and then evaluated while maintaining body temperature at 37±0.5°C. In the auditory evoked potential test, the stimulus was evaluated by gradually lowering the sound by 5 dB from 80 dB with a click sound, which is a broadband stimulus sound, and the lowest sound that responded was set as the threshold.
실시예 2-2. 16 kHz TB 자극음을 이용한 청력역치 확인Example 2-2. Hearing Threshold Verification Using 16 kHz TB Stimulus
청성유발전위 검사시 자극음을 16 kHz pure tone로 하여 80 dB 부터 점차적으로 5 dB씩 소리를 낮춰가며 평가하였다.In the auditory evoked potential test, the stimulus sound was evaluated as a 16 kHz pure tone, gradually lowering the sound by 5 dB from 80 dB.
실시예 3. 달팽이관 유모세포의 보호 효과 평가Example 3. Evaluation of the protective effect of cochlear hair cells
실시예 2-1과 같은 방법으로 진행하였으며, 유모세포가 손상되지 않은 정상군, 소음에 노출되어 유모세포가 손상된 군(NIHL, Noise-induced hearing loss) 및 소음 노출 후 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 처리한 군(NIHL + Benperidol)을 평가하였다.It was performed in the same manner as in Example 2-1, a normal group with intact hair cells, a group with damaged hair cells due to exposure to noise (NIHL, Noise-induced hearing loss), and a group after noise exposure 3-[1-[4 The group treated with -(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one (NIHL + Benperidol) was evaluated.
20일째 역치 평가 실험 종료 후 마우스 달팽이관을 분리하였다. 분리한 달팽이관은 4℃에서 12시간 동안 4% 파라포름알데히드에 보관하고, 그 뒤 0.1 M EDTA를 5일 동안 처리한 후, Corti의 기관을 현미경으로 미세 해부하였다. 유모세포 확인을 위하여 5 U/mL 로다민팔로이딘으로 염색하여 현미경으로 확인하였다. After the end of the threshold evaluation experiment on
실시예 4. 살리실산으로 유발된 이명 제브라피시 모델에서 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 이명 억제 평가Example 4. 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazole-2 in salicylic acid induced tinnitus zebrafish model -On's assessment of tinnitus suppression
물리적 스트레스 없이 제브라피쉬에 이명을 유발하여 평가할 수 있는 행동 반응 시험법을 이용하여 이명에 대한 치료 효과를 확인하였다. The treatment effect on tinnitus was confirmed using a behavioral response test method that can evaluate tinnitus by inducing tinnitus in zebrafish without physical stress.
구체적으로, 제브라피쉬 성어를 이명을 유발시키지 않은 대조군 (NOR), 살리실산 3 mM 에 5시간 노출시켜 이명이 유발된 실험군 (SS), 살리실산 3 mM에 5시간 노출된 직후 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 17시간 노출시킨 실험군 (Benperidol)으로 나누었다. 이 때, Benperidol 실험군은 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 조성물 10 ug/ml, 100 ug/ml, 200 ug/ml 농도에 제브라피쉬 성어를 노출시켜 실험을 진행하였다. 모든 실험은 0.03% 해수염 용액(sea salt solution)을 기본으로 용액으로 사용하며, 측정 직전 모든 실험군은 0.03% 해수염 용액에 1시간 동안 적응시켰다.Specifically, the control group (NOR) in which adult zebrafish did not induce tinnitus, the experimental group (SS) in which tinnitus was induced by exposure to 3 mM salicylic acid for 5 hours, and the 3-[1-[4] immediately after exposure to 3 mM salicylic acid for 5 hours -(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one was divided into an experimental group (Benperidol) exposed for 17 hours. At this time, the Benperidol experimental group was composition 10 containing 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one Experiments were conducted by exposing adult zebrafish to concentrations of ug/ml, 100 ug/ml, and 200 ug/ml. All experiments use 0.03% sea salt solution as a basic solution, and all experimental groups were adapted to 0.03% sea salt solution for 1 hour immediately before measurement.
3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 효과 확인을 위해, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 포함하는 조성물에 노출된 제브라피시를 수조 (75(W) x 45(D) x 45(H) cm)에 위치한 투명관 (외경 25 mm, 내경 21 mm, 총 길이 60 cm)에 통과시켜, 통과한 시간 및 투명관 내에서의 회전 횟수를 분석하였다. 수온은 수조 내 수중히터기를 설치하여 수온은 28℃로 유지하였다. To confirm the effect of 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one, 3-[1- Zebrafish exposed to a composition containing [4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one in a water tank (75(W) x 45 (D) x 45 (H) cm) located in the transparent tube (outer diameter 25 mm, inner diameter 21 mm, total length 60 cm), the passing time and the number of rotations in the transparent tube were analyzed. The water temperature was maintained at 28 ℃ by installing an underwater heater in the water tank.
실시예 5. 살리실산으로 유발된 이명 랫트 모델에서 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 스키너 행동반응 평가Example 5. 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazole-2- in a rat model of tinnitus induced by salicylic acid Evaluation of On's Skinner Behavioral Response
훈련이 된 랫트로 스키너 행동반응 평가 시, 이명이 유발된 동물의 경우 cue tone이 없을 때 trigger를 누르는 반응이 증가하는 경향을 보인다. 이때 동물은 이명소리를 cue tone으로 오인하여 trigger를 누르는 행동을 보이는 것으로 이명유발을 확인할 수 있다. 이때 정반응 (true positive)은 cue tone을 제공하였을 때 먹이를 습득하기 위해 trigger를 누르는 횟수를 말하며, 오반응 (false positive) 은 cue tone이 없을 때에 trigger를 누르는 횟수를 말한다. When evaluating Skinner's behavioral response in trained rats, in the case of tinnitus-induced animals, the response to pressing the trigger when there is no cue tone tends to increase. At this time, the induction of tinnitus can be confirmed by the animal mistaking the tinnitus sound as a cue tone and showing the action of pressing the trigger. At this time, a true positive refers to the number of times the trigger is pressed to acquire food when a cue tone is provided, and a false positive refers to the number of times the trigger is pressed when there is no cue tone.
3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 이용하여 이명이 유발되지 않은 대조군 (NOR), 이명이 유발된 실험군 (SS), 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온 투여 실험군 (SS+Benperidol) 를 각 3마리씩 세 그룹으로 나누어 평가하였다. A non-tinnitus-inducing control (NOR ), tinnitus-induced experimental group (SS), 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one The administration experimental group (SS+Benperidol) was evaluated by dividing into three groups of three animals each.
실험에서 SS 그룹과 Benperidol 그룹은 이명을 유발하기 위해 일반적으로 이명 유발 동물모델에 사용하는 살리실산을 이용하였고, 350 mg/kg를 검사 3시간 전에 경구 투약하였다. SS 그룹은 살리실산만 경구 투약하여 검사를 진행하였고, SS+Benperidol 그룹은 이명 유발 후 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온을 검사하기 1시간 30분 전에 경구 투약하였다.In the experiment, the SS group and the Benperidol group used salicylic acid, which is generally used in tinnitus-induced animal models, to induce tinnitus, and 350 mg/kg was orally administered 3 hours before the test. In the SS group, only salicylic acid was administered orally, and in the SS+Benperidol group, after inducing tinnitus, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] -1H-benzimidazol-2-one was administered orally 1 hour and 30 minutes before the examination.
실험 일정은 투약 전 검사 1일 (Base), 살리실산과 동시 투약 후 검사 3일 (1 ~ 3 Day), 이명 회복 기간 중 검사 3일 (4 ~ 6 Day)로 진행하였다. SS 그룹의 경우 1 ~ 3일차 시 검사 3시간 전 살리실산 투약 후 검사 1시간 30분 전 물을 투약하였고, 4 ~ 6일차 시 검사 1시간 30분 전 물만 경구 투약하였다. SS+Benperidol 그룹의 경우 1 ~ 3일차 시 검사 3시간 전 살리실산 투약 후 검사 1시간 30분 전 Benperidol을 투약하였고, 4 ~ 6일차 시 검사 1시간 30분 전 Benperidol만 경구 투약하였다.The experiment schedule consisted of 1 day of examination before administration (Base), 3 days of examination after concurrent administration with salicylic acid (1 to 3 Days), and 3 days of examination during the tinnitus recovery period (4 to 6 Days). In the case of the SS group, water was administered 1 hour and 30 minutes before the test after salicylic acid was administered 3 hours before the test on the 1st to 3rd days, and only water was administered orally 1 hour 30 minutes before the test on the 4th to 6th day. In the SS+Benperidol group, on days 1 to 3, salicylic acid was administered 3 hours before the test, then Benperidol was administered 1 hour and 30 minutes before the test, and on days 4 to 6, only Benperidol was administered orally 1 hour and 30 minutes before the test.
행동반응 분석을 위해서 정반응률 (Silence activity ratio, SA ratio) 및 오반응률 (False positive ratio, FP ratio) 수치를 사용하였다. SA ratio 은 cue tone이 없을 때 반응한 횟수에서 cue tone을 제공한 시간 중 반응한 횟수를 나누어 계산한 것이며, FP ratio는 전체 반응한 횟수에서 cue tone이 없을 때 반응한 횟수를 비율로 계산한 것이다.For behavioral response analysis, Silence activity ratio (SA ratio) and False positive ratio (FP ratio) were used. The SA ratio is calculated by dividing the number of responses when there is no cue tone by the number of responses during the time when the cue tone is provided, and the FP ratio is calculated as a ratio of the number of responses when there is no cue tone to the total number of responses .
실시예 6. 이명 랫트 모델에서 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 청력 진폭 확인Example 6. Hearing Amplitude of 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one in a tinnitus rat model. check
이명 유발 후 청력 진폭을 측정하여 소리의 유무에 대한 감각에 있어서 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온의 효과를 확인하기 위해 청성유발전위를 이용한 청력 진폭 측정 실험을 수행하였다.3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimid in the sense of the presence or absence of sound by measuring hearing amplitude after tinnitus induction In order to confirm the effect of dazol-2-one, a hearing amplitude measurement experiment using auditory evoked potential was performed.
청성유발전위(auditory brainstem response, ABR) 측정법은 소리자극이 청신경에서 전기적인 신호로 전달될 때, 상기 전기적인 에너지를 측정하여 소리에 대한 반응을 평가하는 방법이다. 소리가 외이와 중이 그리고 달팽이관을 거쳐 청신경에 도달했을 때의 반응은 외이, 중이, 달팽이관의 상태를 모두 반영하는 것으로 이는 뇌까지 소리 에너지가 도달하는 실제적인 소리 에너지를 반영하는 것이다. 청력역치라 함은 겨우 들을 수 있는 소리의 최소 감각지점을 말하는 것으로 정상 마우스의 경우 평균적으로 20 dB의 작은 소리에서도 반응이 관찰된다.An auditory brainstem response (ABR) measurement method is a method of evaluating a response to sound by measuring the electrical energy when a sound stimulus is transmitted as an electrical signal from the auditory nerve. When sound reaches the auditory nerve via the outer ear, middle ear, and cochlea, the response reflects the condition of the outer ear, middle ear, and cochlea, which reflects the actual sound energy reaching the brain. Hearing threshold refers to the minimum sensory point of barely audible sound, and in the case of a normal mouse, a response is observed even to a small sound of 20 dB on average.
청력 진폭 측정 시, 통상 5개의 진폭이 관찰된다 (단위: μV, Wave Ⅰ ~ Wave Ⅴ). 1번 진폭에서 3번 진폭 (Wave Ⅰ ~ Ⅲ) 은 8번째 뇌신경 및 그 이하 신경으로부터 뻗어나온 청각 가지로 인해 형성된다. 여기서 1번 진폭은 청각 신경 섬유의 수상돌기로부터, 2번 진폭은 와우핵으로부터 생성되며, 3번 진폭은 와우핵으로부터 청각 정보를 받아들이는 상올리브 복합체 (superior olivary complex) 의 활성정도를 나타낸다. 또한 4번 진폭과 5번 진폭 (Wave Ⅳ ~ Ⅴ) 은 상뇌간 (upper brainstem) 으로부터 형성되며 외측섬유대 (lateral lemniscus)와 관련이 있다.When measuring hearing amplitude, five amplitudes are usually observed (unit: μV, Wave Ⅰ ~ Wave Ⅴ). Amplitudes 1 to 3 (Wave I to III) are formed by auditory branches extending from the 8th cranial nerve and lower nerves. Here, amplitude 1 is generated from the dendrite of the auditory nerve fiber, amplitude 2 is generated from the cochlear nucleus, and amplitude 3 represents the activity level of the superior olivary complex that receives auditory information from the cochlear nucleus. Also, amplitudes 4 and 5 (Wave IV ~ V) are formed from the upper brainstem and are related to the lateral lemniscus.
클릭 자극 검사 전의 일정 및 실험군 그룹은 실시예 5의 일정과 동일하며, 3-[1-[4-(4-플루오로페닐)-4-옥소부틸]피페리딘-4-일]-1H-벤즈이미다졸-2-온 경구 투여 5일째에 클릭 자극 검사를 시행 및 평가하였다. The schedule before the click stimulation test and the experimental groups are the same as those of Example 5, and 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H- A click stimulation test was performed and evaluated on the 5th day after oral administration of benzimidazol-2-one.
청성유발전위 검사를 위하여 케타민(11.43 mg/kg)과 실라진(1.08 mg/kg)을 랫드에게 근육 주사하여 마취시킨 뒤 체온 37±0.5℃를 유지시키면서 평가하였다. 청성유발전위 검사시 자극음은 광대역 자극음인 클릭(click)음으로 90 dB부터 점차적으로 5 dB씩 소리를 낮춰가며 평가했으며 반응이 나오는 가장 작은 소리를 역치로 하였다.For the auditory evoked potential test, ketamine (11.43 mg/kg) and xylazine (1.08 mg/kg) were injected intramuscularly to anesthetize rats, and then the body temperature was maintained at 37±0.5°C. In the auditory evoked potential test, the stimulus was evaluated by gradually lowering the sound by 5 dB from 90 dB with a click sound, which is a broadband stimulus sound, and the lowest sound that responded was set as the threshold.
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