KR102026337B1 - Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same - Google Patents
Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same Download PDFInfo
- Publication number
- KR102026337B1 KR102026337B1 KR1020170086719A KR20170086719A KR102026337B1 KR 102026337 B1 KR102026337 B1 KR 102026337B1 KR 1020170086719 A KR1020170086719 A KR 1020170086719A KR 20170086719 A KR20170086719 A KR 20170086719A KR 102026337 B1 KR102026337 B1 KR 102026337B1
- Authority
- KR
- South Korea
- Prior art keywords
- phenyl
- dimethylphenylsulfanyl
- piperazine
- formate
- nicotinate
- Prior art date
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
본 발명은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 및 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염, 이들의 제조방법 및 상기 염을 포함하는 약학적 조성물을 제공한다. 본 발명의 새로운 염들은 안정성, 흡습성, 용해도가 모두 우수하여 안정적으로 제형화가 가능하며, 장기 보관이 가능한 장점이 있어, 이를 포함하는 약학적 조성물은 우울증 또는 불안증 예방 또는 치료에 유용하다.The present invention relates to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate and 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate, their preparation It provides a method and a pharmaceutical composition comprising the salt. The new salts of the present invention are all stable, hygroscopic, solubility, so that they can be formulated stably and have long-term storage, and thus pharmaceutical compositions containing the same are useful for preventing or treating depression or anxiety.
Description
본 발명은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 새로운 염, 특히 니코틴산염(Nicotinate), 포름산염(Formate), 이의 제조 방법 및 상기 염을 포함하는 약학적 조성물에 관한 것이다.The present invention relates to novel salts of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, in particular nicotinate, formate, methods for their preparation and pharmaceuticals comprising such salts. To a composition.
1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 화합물은 하기 화학식 3의 구조를 갖는다.The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine compound has the structure of formula (3) below.
[화학식 3][Formula 3]
1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 또는 이의 약제학적으로 허용 가능한 염은 세로토닌 재흡수 억제제로서 우울증 및 불안증 치료에 사용되며, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 원 개발사인 룬드백 제약 회사에서 이의 브롬화수소산염을 유효성분으로 하는 브린텔릭스(Brintellix®)라는 상품으로 시판 중이다.1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine or a pharmaceutically acceptable salt thereof is a serotonin reuptake inhibitor used in the treatment of depression and anxiety, 1- [2- (2,4 Lundbeck Pharmaceuticals, the original developer of -dimethylphenylsulfanyl) phenyl] piperazine, is commercially available as Brintellix®, a product of its hydrobromide.
1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 또는 이의 약제학적으로 허용 가능한 염은 대한민국 등록특허 제10-0770194호에 기재되어 있고, 상기 특허문헌에는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 브롬화수소산염이 기재되어 있다.1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine or a pharmaceutically acceptable salt thereof is described in Korean Patent No. 10-0770194, which discloses 1- [2- Hydrobromide salts of (2,4-dimethylphenylsulfanyl) phenyl] piperazine are described.
또한 대한민국 등록특허 제10-1445514호, 등록특허 제10-1627901호, 등록특허 제10-1459168호, 국제공개특허공보 WO 제2015-166379호, WO 제2015-114395호 및 WO 제2016-079751호 등에는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 다양한 염들이 보고된 바 있다.In addition, the Republic of Korea Patent No. 10-1445514, Patent No. 10-1627901, Patent No. 10-1459168, WO 2015-166379, WO 2015-114395 and WO 2016-079751 Et al. Have reported various salts of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine.
한편, 일반적으로 의약품은 항상성을 유지하기 위해서는 제품의 제조 단계에서부터 보관 기간 중 유효성분의 함량 저하를 억제해야 하며, 불순물 또는 유연물질의 증가를 최소한으로 유지하여 하여야 한다.On the other hand, in order to maintain homeostasis, generally, pharmaceuticals should suppress the decrease of the content of the active ingredient during the storage period from the manufacturing stage of the product, and should keep the increase of impurities or soft substances to a minimum.
이에, 본 발명자들은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 항상성 개선을 위하여 예의 연구한 결과, 예기치 않게 기존의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염과 동등 이상의 물리화학적 안정성, 비흡습성, 용해도가 우수한 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 신규염을 개발하게 되어 본 발명을 완성하였다. Accordingly, the present inventors earnestly studied for improving the homeostasis of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, and as a result, unexpectedly 1- [2- (2,4-dimethylphenyl Development of a novel salt of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine excellent in physicochemical stability, non-hygroscopicity and solubility equivalent to or higher than that of sulfanyl) phenyl] piperazine hydrobromide Was completed.
따라서, 본 발명의 목적은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 허용 가능한 염들 중 물리화학적 안정성, 비흡습성 및 용해도가 우수한 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 신규 염 및 이의 제조방법을 제공하는데 있다.Accordingly, an object of the present invention is 1- [2- (2,4, which is excellent in physicochemical stability, non-hygroscopicity and solubility among acceptable salts of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine -Dimethylphenylsulfanyl) phenyl] piperazine novel salt and method for preparing the same.
본 발명의 또 다른 목적은 상기 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 신규 염을 포함하는 약학적 조성물을 제공하는 것이다. Still another object of the present invention is to provide a pharmaceutical composition comprising the novel salt of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine.
상기 과제를 해결하기 위하여, 본 발명은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 신규 염, 이의 제조 방법 및 상기 염을 포함하는 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a novel salt of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, a preparation method thereof, and a pharmaceutical composition comprising the salt.
이하에서는, 본 발명에 관하여 보다 상세히 설명한다. Hereinafter, the present invention will be described in more detail.
1-[2-(2,4-1- [2- (2,4- 디메틸페닐설파닐Dimethylphenylsulfanyl )페닐]피페라진 ) Phenyl] piperazine 니코틴산염Nicotinate 및 이의 제조방법 And preparation method thereof
하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염에 관한 것이다. As an aspect, the present invention relates to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate represented by the following general formula (1).
[화학식 1][Formula 1]
본 발명에 있어서, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염은 결정형인 것이 바람직하다.In the present invention, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate is preferably in crystalline form.
또한, 바람직한 양태에서, 본 발명은 X선 분말 회절 패턴 분석(X-ray powder diffraction pattern)에서 2θ 회절각이 바람직하게는 8.5°±0.2°, 13.7°±0.2°, 16.5°±0.2°및 19.9°±0.2°의 회절 패턴을 가지며, 더욱 바람직하게는 8.5°±0.2°, 11.6°±0.2°, 13.4°±0.2°, 13.7°±0.2°, 14.4°±0.2°, 16.5°±0.2°, 17.0°±0.2°, 18.0°±0.2°, 18.6°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 20.5°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.0°±0.2°, 24.0°±0.2°, 25.3°±0.2°, 26.2°±0.2°, 27.7°±0.2°및 29.0°±0.2°의 회절 패턴을 가지는 것을 특징으로 한다.Further, in a preferred embodiment, the present invention preferably has a 2θ diffraction angle in the X-ray powder diffraction pattern, preferably 8.5 ° ± 0.2 °, 13.7 ° ± 0.2 °, 16.5 ° ± 0.2 ° and 19.9. Has a diffraction pattern of ° ± 0.2 °, more preferably 8.5 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.4 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.4 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.0 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.6 ° ± 0.2 °, 19.6 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.1 ° ± 0.2 °, 22.6 ° And diffraction patterns of ± 0.2 °, 23.0 ° ± 0.2 °, 24.0 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.7 ° ± 0.2 ° and 29.0 ° ± 0.2 °.
또한, 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 순도가 약 99.90% 이상 이고, 시차주사 열량(DSC) 분석에서 승온 속도가 5℃/min 일 때, 133.3℃의 개시온도(oneset) 및 134.0±1.5℃의 흡열 피크가 나타나며, 칼-피셔(Karl-Fisher) 수분측정법을 통해 포함된 물분자수를 확인해본 결과, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염은 수분함량이 0.06%로 무수물임이 확인되었다. In addition, the purity of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention is about 99.90% or more, and the temperature increase rate is 5 ° C / min in differential scanning calorimetry (DSC) analysis. When the start temperature (oneset) of 133.3 ℃ and the endothermic peak of 134.0 ± 1.5 ℃ appears, the number of water molecules contained through Karl-Fisher moisture measurement method, 1- [2- (2, It was confirmed that 4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate was anhydrous with a water content of 0.06%.
본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염은 물리화학적 안정성, 비흡습성, 용해도가 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 공지된 염인 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염 보다 동등 이상으로 우수하며, 특히 용해도의 경우 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염보다 현저히 우수함이 확인 되었다. 따라서, 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염은 우울증 또는 불안증 치료제의 유효성분으로 유용하게 사용할 수 있다.1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention has physicochemical stability, non-hygroscopicity, and solubility of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Better than or equal to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide, a known salt of piperazine, especially 1- [2- (2,4- for solubility Dimethylphenylsulfanyl) phenyl] piperazine hydrobromide was found to be significantly superior. Therefore, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention can be usefully used as an active ingredient for treatment of depression or anxiety.
또 다른 하나의 양태로서, 본 발명은 반응용매 중에서 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진과 니코틴산을 반응시켜 결정화하는 것을 포함하는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형의 제조방법을 제공한다. In another embodiment, the present invention relates to crystallization of 1- [2- (2,2) comprising reacting 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with nicotinic acid in a reaction solvent. Provided is a method for preparing the crystalline form of 4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate.
본 발명의 제조방법에서, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진은 시중에서 판매되는 것을 사용하거나 공지된 방법(대한민국 등록특허 제10-1627901호)으로 제조하여 사용할 수 있으며, 니코틴산 역시 시중에서 판매되는 것을 사용할 수 있다. In the production method of the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is commercially available or prepared by a known method (Korean Patent No. 10-1627901). Nicotinic acid may also be used commercially.
본 발명의 제조방법에서, 니코틴산의 양은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 1 당량에 대해 0.8 내지 2.0 당량, 바람직하게는 0.9 내지 1.1 당량을 사용한다. 만일 니코틴산의 양이 0.8 당량 미만이면 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 수율이 감소하며, 2.0 당량 이상이면 과량의 니코틴산의 사용으로 인한 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 함량의 감소와 비용 증가를 초래할 수 있다. In the preparation method of the present invention, the amount of nicotinic acid is used in the amount of 0.8 to 2.0 equivalents, preferably 0.9 to 1.1 equivalents to 1 equivalent of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. If the amount of nicotinic acid is less than 0.8 equivalent, the yield of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate is reduced, and if it is more than 2.0 equivalent, 1- [2 due to the use of excess nicotinic acid -(2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate content can lead to a decrease in cost and an increase in cost.
본 발명의 제조방법에서, 반응용매는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 형성 반응에 관여하지 않는 용매라면 대부분 사용 가능하며, 예를 들어, 유기용매로서 에테르류(메틸에테르, t-부틸메틸에테르 등), 니트릴류(아세토니트릴, 프로피오니트릴 등) 등이 있다. 바람직하게는 t-부틸메틸에테르 및 아세토니트릴로 이루어진 군으로부터 선택되는 하나 이상의 용매를 사용하는 것이다. 본 발명에 사용된 용매는 단독으로 사용되는 것이 바람직하나 임의의 용매를 2종류 이상 사용하는 것도 가능하다. 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 생성반응에 사용되는 용매의 사용량은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 1 중량에 대하여 1 내지 30배 부피비이며, 바람직하게는 5 내지 20배 부피비이다. In the production method of the present invention, the reaction solvent can be used as long as it is a solvent that does not participate in the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate formation reaction, for example, an organic solvent Examples thereof include ethers (methyl ether, t-butyl methyl ether and the like), nitriles (acetonitrile, propionitrile and the like). Preferably at least one solvent selected from the group consisting of t-butylmethylether and acetonitrile is used. The solvent used in the present invention is preferably used alone, but it is also possible to use two or more kinds of arbitrary solvents. The amount of the solvent used for 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate production reaction is 1- [2- (2,4-dimethylphenylsulfanyl) phenyl]
본 발명의 제조방법에서, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 생성반응의 온도는 0 내지 70℃이며, 바람직하게는 10 내지 45℃이다. In the production method of the present invention, the temperature of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate production reaction is 0 to 70 ° C, preferably 10 to 45 ° C.
구체적인 일 실시양태에서, 본 발명에 따른 제조방법에서 상기 반응용매에서 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진을 반응용매에 용해시킨 후, 이에 염의 생성을 위해 상기 온도 범위로 유지하면서 니코틴산을 첨가할 수 있다. 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진에 니코틴산을 첨가하는 방법은 특별히 제한은 없으나, 용매에 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진을 넣고 교반하여 용해한 후 니코틴산을 일시에 투입하거나, 고체를 분할 투입 할 수 있다.In one specific embodiment, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine in the reaction solvent in the production method according to the present invention, and then dissolved in the reaction solvent, so as to produce the salt Nicotinic acid can be added while maintaining the temperature range. The method of adding nicotinic acid to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is not particularly limited, but 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] is added to the solvent. After adding piperazine and stirring to dissolve, nicotinic acid may be added at a time or the solid may be added in portions.
1-[2-(2,4-1- [2- (2,4- 디메틸페닐설파닐Dimethylphenylsulfanyl )페닐]피페라진 ) Phenyl] piperazine 포름산염Formate 및 이의 제조방법 And preparation method thereof
또 하나의 양태로서, 본 발명은 하기 화학식 2로 표시되는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염에 관한 것이다.As another aspect, the present invention relates to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate represented by the following formula (2).
[화학식 2][Formula 2]
본 발명에 있어서, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염은 결정형인 것이 바람직하다.In the present invention, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is preferably in crystalline form.
또한, 바람직한 양태에서, 본 발명은 X선 분말 회절 패턴 분석(X-ray powder diffraction pattern)에서 2θ 회절각이 9.8°±0.2°, 12.7°±0.2°, 16.4°±0.2°, 19.7°±0.2°및 22.7°±0.2°의 패턴을 가지며, 더욱 바람직하게는 9.8°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 16.4°±0.2°, 18.5°±0.2°, 19.7°±0.2°, 21.9°±0.2°, 22.7°±0.2°, 23.5°±0.2°, 24.5°±0.2°및 28.7°±0.2°의 회절 패턴을 가지는 것을 특징으로 한다.Further, in a preferred embodiment, the present invention provides a 2θ diffraction angle of 9.8 ° ± 0.2 °, 12.7 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.7 ° ± 0.2 in X-ray powder diffraction pattern. ° and 22.7 ° ± 0.2 °, more preferably 9.8 ° ± 0.2 °, 12.7 ° ± 0.2 °, 14.8 ° ± 0.2 °, 16.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.7 ° ± 0.2 And a diffraction pattern of 21.9 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° and 28.7 ° ± 0.2 °.
또한, 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 순도가 약 99.80% 이상 이고, 시차주사 열량(DSC) 분석에서 승온 속도가 5℃/min 일 때, 144.3℃의 개시온도(oneset) 및 144.9±1.5℃, 147.7±1.5℃의 흡열 피크가 나타나며, 칼-피셔(Karl-Fisher) 수분측정법을 통해 포함된 물분자수를 확인해본 결과, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염은 수분함량이 0.10%로 무수물임이 확인되었다. In addition, the purity of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate of the present invention is about 99.80% or more, and the temperature increase rate is 5 ° C / min in differential scanning calorimetry (DSC) analysis. When the initial temperature (oneset) of 144.3 ℃, and the endothermic peak of 144.9 ± 1.5 ℃, 147.7 ± 1.5 ℃ appears, the number of water molecules included through Karl-Fisher moisture measurement method, 1- [ It was confirmed that 2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate was anhydrous with a water content of 0.10%.
본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염 역시 물리화학적 안정성, 비흡습성, 용해도가 공지의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진염인 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염 보다 동등 이상으로 우수함이 확인 되었다. 따라서, 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염은 우울증 및 불안증 치료제의 유효성분으로 유용하게 사용할 수 있다. 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate of the present invention is also known as physicochemical stability, non-hygroscopicity, solubility of 1- [2- (2,4-dimethylphenylsulfanyl It was confirmed that it is equal to or better than 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide which is) phenyl] piperazine salt. Therefore, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate of the present invention can be usefully used as an active ingredient for treating depression and anxiety.
본 발명은 반응용매 중에서 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진과 포름산을 반응시켜 결정화하는 것을 포함하는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형의 제조방법을 제공한다.The present invention relates to 1- [2- (2,4-dimethylphenylsulfanyl) comprising crystallization by reacting 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with formic acid in a reaction solvent. Provided is a method for preparing a crystalline form of phenyl] piperazine formate.
본 발명의 제조방법에서, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진은 시중에서 판매되는 것을 사용하거나 공지된 방법(대한민국 특허 제10-1627901호)으로 제조하여 사용할 수 있으며, 포름산 역시 시중에서 판매되는 것을 사용할 수 있다. In the production method of the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is commercially available or prepared by a known method (Korean Patent No. 10-1627901). Formic acid can also be used on the market.
본 발명의 제조방법에서, 포름산의 양은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 1 당량에 대해 0.9 내지 3.0 당량, 바람직하게는 1.0 내지 2.0 당량을 사용한다. 만일 포름산의 양이 0.9 당량 미만이면 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 수율이 감소하며, 3.0 당량 이상이면 과량의 포름산의 사용으로 인한 함량의 감소와 비용 증가를 초래할 수 있다.In the preparation method of the present invention, the amount of formic acid is used in the amount of 0.9 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to 1 equivalent of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. If the amount of formic acid is less than 0.9 equivalent, the yield of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is reduced, and if it is more than 3.0 equivalent, the amount of formic acid decreases due to the use of excess formic acid. This can lead to an increase in cost.
본 발명의 제조방법에서, 반응용매는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염 형성 반응에 관여하지 않는 용매라면 대부분 사용 가능하며, 예를 들어, 유기용매로서 에테르류(메틸에테르, t-부틸메틸에테르 등), 니트릴류(아세토니트릴, 프로피오니트릴 등) 등이 있다. 바람직하게는 t-부틸메틸에테르, 아세토니트릴을 사용하는 것이다. 본 발명에 사용된 용매는 단독으로 사용되는 것이 바람직하나 임의의 용매를 2종류 이상 사용하는 것도 가능하다. 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염 생성반응에 사용되는 용매의 사용량은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 1 중량에 대하여 1 내지 30배 부피비이며, 바람직하게는 5 내지 20배 부피비이다. In the production method of the present invention, the reaction solvent can be used as long as it is a solvent that does not participate in the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate formation reaction, for example, an organic solvent Examples thereof include ethers (methyl ether, t-butyl methyl ether and the like), nitriles (acetonitrile, propionitrile and the like). Preferably, t-butyl methyl ether and acetonitrile are used. The solvent used in the present invention is preferably used alone, but it is also possible to use two or more kinds of arbitrary solvents. The amount of the solvent used for 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate production reaction is 1- [2- (2,4-dimethylphenylsulfanyl) phenyl]
본 발명의 제조방법에서, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염 생성반응의 온도는 0 내지 70℃이며, 바람직하게는 10 내지 45℃이다. In the production method of the present invention, the temperature of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate production reaction is 0 to 70 ° C, preferably 10 to 45 ° C.
구체적인 일 실시양태에서, 본 발명에 따른 제조방법에서 상기 반응용매에서 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진을 반응용매에 용해시킨 후, 이에 염의 생성을 위해 상기 온도 범위로 유지하면서 포름산을 첨가할 수 있다. 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진에 포름산을 첨가하는 방법은 특별히 제한은 없으나, 용매에 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진을 넣고 교반하여 용해한 후 포름산을 일시에 투입하거나, 액체를 분할 투입 할 수 있다.In one specific embodiment, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine in the reaction solvent in the production method according to the present invention, and then dissolved in the reaction solvent, so as to produce the salt Formic acid can be added while maintaining the temperature range. The method of adding formic acid to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is not particularly limited, but 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] is added to the solvent. After adding piperazine and stirring to dissolve, formic acid may be added at a time or the liquid may be added in portions.
1-[2-(2,4-1- [2- (2,4- 디메틸페닐설파닐Dimethylphenylsulfanyl )페닐]피페라진 ) Phenyl] piperazine 니코틴산염Nicotinate 및/또는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 And / or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine 포름산염을Formate 포함하는 약학적 조성물 Pharmaceutical composition comprising
또 다른 하나의 양태로서, 본 발명은 상기 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 및/또는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염을 포함하는 약학적 조성물에 관한 것이다. 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진은 이미 세로토닌 재흡수 억제제로서 우울증 또는 불안증 치료에 사용됨이 알려져 있는바, 이의 약학적으로 허용가능한 신규염인 본 발명에 따른 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 또는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염을 포함하는 약학적 조성물은 우울증 또는 불안증의 예방 또는 치료용일 수 있다. 바람직하게, 본 발명에 따른 약학적 조성물에는 상기 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 또는 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염과 함께 약학적으로 허용가능한 담체, 부형제 및/또는 첨가제를 더 포함할 수 있고, 이들은 공지의 방법에 따라 다양한 경구 또는 비경구 제제로 제형화될 수 있다. In another embodiment, the present invention provides the above-mentioned 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate and / or 1- [2- (2,4-dimethylphenylsulfanyl) It relates to a pharmaceutical composition comprising phenyl] piperazine formate. 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is already known to be used in the treatment of depression or anxiety as an inhibitor of serotonin reuptake, according to the invention a pharmaceutically acceptable novel salt thereof. Pharmaceutical compositions comprising 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate It may be for the prevention or treatment of depression or anxiety. Preferably, the pharmaceutical composition according to the present invention comprises 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Piperazin formate may further comprise pharmaceutically acceptable carriers, excipients and / or additives, which may be formulated into a variety of oral or parenteral preparations according to known methods.
본 발명에 따르면, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 및 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염은 우수한 물리화학적 안정성, 흡습성, 용해도를 나타낸다. According to the invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate and 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate are excellent Physical and chemical stability, hygroscopicity, and solubility are shown.
도 1은 실시예 1에 따라 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형태의 XRD 패턴을 나타낸다.
도 2는 실시예 1에 따라 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형태의 시차주사 열량(DSC) 분석도를 나타낸다.
도 3은 실시예 1에 따라 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형태의 수소 핵자기공명 스펙트럼(NMR) 분석도를 나타낸다.
도 4는 실시예 2에 따라 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형태의 XRD 패턴을 나타낸다.
도 5는 실시예 2에 따라 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형태의 시차주사 열량(DSC) 분석도를 나타낸다.
도 6은 실시예 2에 따라 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형태의 수소 핵자기공명(NMR) 스펙트럼 분석도를 나타낸다.1 shows an XRD pattern of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate prepared according to Example 1. FIG.
FIG. 2 shows a differential scanning calorimetry (DSC) analysis of the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate prepared according to Example 1. FIG.
FIG. 3 shows a hydrogen nuclear magnetic resonance spectrum (NMR) analysis of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate prepared according to Example 1. FIG.
4 shows the XRD pattern of the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate prepared according to Example 2. FIG.
FIG. 5 shows a differential scanning calorimetry (DSC) analysis of the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate prepared according to Example 2. FIG.
6 shows a hydrogen nuclear magnetic resonance (NMR) spectrum analysis of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate prepared according to Example 2. FIG.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, preferred examples are provided to help understanding of the present invention, but the following examples are merely to illustrate the present invention, and the scope of the present invention is not limited to the following examples.
이하, 실시예에서 사용한 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진의 제조사는 Shandong Kangmeile Pharmaceutical Technology Co.,Ltd.사의 제품이며, 특별히 제조사의 언급이 없는 시약 및 용매는 Sigma, Aldrich로부터 구입한 것을 사용하였다.Hereinafter, the manufacturer of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine used in Examples is a product of Shandong Kangmeile Pharmaceutical Technology Co., Ltd., and reagents and solvents are not specifically mentioned by the manufacturer. Was used from Sigma, Aldrich.
실시예Example 1: 11: 1 -[2-(2,4--[2- (2,4- 디메틸페닐설파닐Dimethylphenylsulfanyl )페닐]피페라진 ) Phenyl] piperazine 니코틴산염Nicotinate 결정형의 제조 Preparation of Crystal Form
1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 20g을 t-부틸메틸에테르 400mL에 용해시킨 후 40℃ ~ 45℃까지 승온하였다. 여기에 니코틴산 7.4g을 투입하였다. 40℃ ~ 45℃ 유지하면서 2 ~ 3 시간 교반하면서 결정화하였다. 혼합액의 온도를 20℃ ~ 25℃로 냉각하고 1시간 동안 교반하여 결정을 숙성시킨 후 고체를 여과하고, t-부틸메틸에테르 100ml로 세척하였다. 30℃에서 진공 건조하여 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염 결정형을 수득하였다(23.9g, 84.7%).After dissolving 20 g of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine in 400 mL of t-butyl methyl ether, the temperature was raised to 40 ° C to 45 ° C. 7.4 g of nicotinic acid was added thereto. Crystallization was carried out for 2 to 3 hours while maintaining at 40 ° C to 45 ° C. The temperature of the mixed solution was cooled to 20 ° C. to 25 ° C. and stirred for 1 hour to ripen the crystals, and then the solid was filtered and washed with 100 ml of t-butyl methyl ether. Vacuum drying at 30 ° C. afforded 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate crystalline form (23.9 g, 84.7%).
1H NMR (400MHz , CD3OD) : 9.07 (dd, 1H) ; 8.55(dd, 1H) ; 8.33(dt, 1H) ; 7.44(ddd, 1H) ; 7.30(d, 1H) ; 7.20(bs, 1H) ; 7.16-7.10(m, 2H) ; 7.06(ddd, 1H) ; 6.93(ddd, 1H) ; 6.53(dd, 1H) ; 3.38-3.35(m, 4H) ; 3.27(dd, 4H) ; 2.35(s, 3H) ; 2.27(s, 3H) 1 H NMR (400MHz, CD 3 OD): 9.07 (dd, 1H); 8.55 (dd, 1 H); 8.33 (dt, 1 H); 7.44 (ddd, 1 H); 7.30 (d, 1 H); 7.20 (bs, 1 H); 7.16-7.10 (m, 2H); 7.06 (ddd, 1 H); 6.93 (ddd, 1 H); 6.53 (dd, 1 H); 3.38-3. 35 (m, 4H); 3.27 (dd, 4H); 2.35 (s, 3 H); 2.27 (s, 3H)
실시예Example 2: 12: 1 -[2-(2,4--[2- (2,4- 디메틸페닐설파닐Dimethylphenylsulfanyl )페닐]피페라진 ) Phenyl] piperazine 포름산염Formate 결정형의 제조 Preparation of Crystal Form
1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 20g을 t-부틸메틸에테르 400mL에 용해시킨 후 40℃ ~ 45℃까지 승온하였다. 여기에 포름산 3.39g을 5분동안 투입하였다. 40℃ ~ 45℃ 유지하면서 1 ~ 2 시간 교반하면서 결정화하였다. 혼합액의 온도를 25℃ ~ 30℃로 냉각하고 1시간 동안 교반하여 결정을 숙성시킨 후 고체를 여과하고, t-부틸메틸에테르 100ml로 세척하였다. 30℃에서 진공 건조하여 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염 결정형을 수득하였다 (22.4g, 97.0%).After dissolving 20 g of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine in 400 mL of t-butyl methyl ether, the temperature was raised to 40 ° C to 45 ° C. 3.39 g of formic acid was added thereto for 5 minutes. Crystallization was carried out for 1 to 2 hours while maintaining at 40 ° C to 45 ° C. The temperature of the mixed solution was cooled to 25 ° C. to 30 ° C. and stirred for 1 hour to ripen the crystals, and then the solid was filtered and washed with 100 ml of t-butyl methyl ether. Drying in vacuo at 30 ° C. gave 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate crystalline form (22.4 g, 97.0%).
1H NMR (400MHz , CD3OD) : 8.54 (s, 1H) ; 7.30(d, 1H) ; 7.20(bs, 1H) ; 7.17-7.11(m, 2H) ; 7.07(d, 1H) ; 6.94(ddd, 1H) ; 6.53(dd, 1H) ; 3.36-3.33(m, 4H) ; 3.27(dd, 4H) ; 2.34(s, 3H) ; 2.28(s, 3H) 1 H NMR (400 MHz, CD 3 OD): 8.54 (s, 1 H); 7.30 (d, 1 H); 7.20 (bs, 1 H); 7.17-7. 11 (m, 2 H); 7.07 (d, 1 H); 6.94 (ddd, 1 H); 6.53 (dd, 1 H); 3.36-3. 33 (m, 4H); 3.27 (dd, 4H); 2.34 (s, 3 H); 2.28 (s, 3 H)
비교예Comparative example : 1-[2-(2,4-: 1- [2- (2,4- 디메틸페닐설파닐Dimethylphenylsulfanyl )페닐]피페라진 ) Phenyl] piperazine 브롬화수소산염의Hydrobromide 제조 Produce
대한민국 등록특허 제10-1627901호의 개시된 방법에 따라 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염을 제조하였다. 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide was prepared according to the method disclosed in Korean Patent No. 10-1627901.
시험예Test Example 1: 안정성 시험(가속) 1: Stability Test (Acceleration)
의약품의 안정성 시험은 의약품의 저장방법 및 사용기간 등을 설정하기 위하여 일정한 조건에서 안정성을 확인한다.The stability test checks the stability under certain conditions in order to establish the storage method and duration of use.
실시예 1 내지 2에서 제조된 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형을 비교예에서 제조한 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염과 안정성을 비교하였다. 구체적으로 ICH 가이드라인에 따라 가속 조건에서의 안정성 시험을 하고, 고속액체크로마토그래피(HPLC) 분석법을 이용하여 분석 하였다. 그 결과를 하기 표 1에 나타내었다.Crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] The crystal form of piperazine formate was compared with 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide prepared in Comparative Example. Specifically, the stability test under the accelerated conditions in accordance with the ICH guidelines, and analyzed using high-performance liquid chromatography (HPLC) method. The results are shown in Table 1 below.
브롬화수소산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide
니코틴산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate
포름산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate
상기 표 1를 참고하면, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형 모두 상기 가속 조건에서 34일 동안의 가속 안정성 시험 결과 0.01% 이하의 순도의 변화를 보였으며, 따라서 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형은 가속 조건에서 큰 순도 변화를 보이지 않아 매우 안정한 것으로 확인되었으며, 유연물질 증가와 연관된 보관 조건을 용이하게 할 수 있고, 장기간 보관할 수 있는 약물임을 알 수 있었다.Referring to Table 1 above, the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formic acid All of the crystalline forms of the salt showed a change in purity of 0.01% or less as a result of 34 days of accelerated stability test under the accelerated conditions, and thus the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid The crystalline form of the salt, crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate, was found to be very stable due to no significant change in purity under accelerated conditions and facilitated storage conditions associated with an increase in lead. It can be seen that the drug can be stored for a long time.
시험예Test Example 2: 흡습성 시험 2: hygroscopic test
비흡습성은 의약품의 가공 및 보관을 위한 매우 중요한 요소 중 하나로 화합물이 의약품 원료로 사용될 수 있는지 여부를 확인하기 위하여 실시예 1 내지 2에서 제조된 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형에 대한 흡습성 시험을 실시하였다. 그 결과를 하기 표 2에 나타내었다.Non-hygroscopicity is one of the most important factors for the processing and storage of pharmaceutical products. The 1- [2- (2,4-dimethyl of the present invention prepared in Examples 1 to 2 to confirm whether the compound can be used as a pharmaceutical raw material. Hygroscopicity test was carried out for the crystalline form of phenylsulfanyl) phenyl] piperazine nicotinate and the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate. The results are shown in Table 2 below.
브롬화수소산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide
니코틴산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate
포름산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate
제제학적 관점에서 보면 약물이 높은 수분의 환경에서도 흡습하지 않고 초기의 수분과 형태를 유지하는 것이 바람직하다.From a pharmaceutical standpoint, it is desirable for the drug to maintain its initial moisture and form without being hygroscopic even in a high moisture environment.
상기 표 2를 참고하면, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형 모두 온도 25℃ ±2℃, 상대습도 80% ±5%, 24시간 동안의 함수량(K.F. 수분 %)을 측정한 결과, 비흡습성을 보여 주었다.Referring to Table 2, the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formic acid The crystalline forms of the salts showed non-hygroscopicity as a result of measuring the temperature of 25 ° C. ± 2 ° C., the relative humidity of 80% ± 5%, and the water content (KF moisture%) for 24 hours.
시험예Test Example 3: 용해도 평가 3: solubility evaluation
용해도는 약품의 제품화에 있어 중요한 요인이다. 약효가 우수하더라도 낮은 용해도로 인해 제품 개발이 어려울 수 있다. 용해도가 낮으면, 석출되어 침전상태로 존재하고 이는 경구 흡수를 감소시키는 큰 요인이 된다. 실시예 1 내지 2에서 제조된 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형에 대하여 pH에 따른 용해도 평가를 실시하였다. 대조군으로는 비교예에서 제조된 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염을 사용하였다. 그 결과를 하기 표 3에 나타내었다.Solubility is an important factor in the commercialization of drugs. Even with good efficacy, low solubility can make product development difficult. If the solubility is low, it precipitates out and is present in a precipitated state, which is a major factor in reducing oral absorption. Crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Solubility evaluation with pH was performed about the crystal form of piperazine formate. As a control, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide prepared in Comparative Example was used. The results are shown in Table 3 below.
브롬화수소산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide
니코틴산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate
포름산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate
상기 표 3을 참고하면, pH 1.2, pH 4.0, pH 5.2, pH 6.8, 정제수에서 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염보다 1337배 내지 3990배의 높은 용해도를 가지며, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 브롬화수소산염보다 605배 내지 2220배의 높은 용해도를 가짐을 확인하였다. 따라서, 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형은 약물의 물리화학적 성질을 크게 개선시킴으로서 약물의 흡수 및 용출에 매우 유리하게 작용하여 제품화에 유리하다.Referring to Table 3 above, the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate in pH 1.2, pH 4.0, pH 5.2, pH 6.8, and purified water is 1- [2- ( 2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrochloride 1337 to 3990 times higher solubility, crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate It was confirmed that silver has a solubility of 605 to 2220 times higher than 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide. Thus, the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention, the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate Is very beneficial to the absorption and elution of the drug by greatly improving the physicochemical properties of the drug is advantageous to commercialization.
시험예Test Example 4: X선 4: X-ray 회절분광도Diffraction 분석 analysis
실시예 1 내지 2에서 제조된 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형을 X선 회절 분석기를 사용하여 분석 하였다. 상기 X선 회절 분석기(XRD) 측정조건은 다음과 같으며, 이 결과를 각각 도 1(1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염) 및 도 4(1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염)에 나타내었다. Crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] The crystalline form of piperazine formate was analyzed using an X-ray diffractometer. The X-ray diffraction analyzer (XRD) measurement conditions are as follows, and the results are shown in FIG. 1 (1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate) and FIG. -[2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate).
1) 장치: D8 Advance(Bruker)1) Device: D8 Advance (Bruker)
2) Detector: Lynxeye2) Detector: Lynxeye
3) X선 광원의 파장: 1.5405ÅA3) Wavelength of X-ray light source: 1.5405ÅA
시험예Test Example 5: 시차주사 열량( 5: differential scanning calories ( DSCDSC ) 분석) analysis
실시예 1 내지 2에서 제조된 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형의 물리적 특성을 확인하였다. 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염을 질소하에서 DSC 분석을 실시하였다. 그 결과를 하기 표 4, 도 2(1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염) 및 도 5(1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염)에 나타내었다. 상기 시차주사 열량계 측정조건은 다음과 같다.Crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] The physical properties of the crystalline form of piperazine formate were confirmed. Crystalline Form of 1- [2- (2,4-Dimethylphenylsulfanyl) phenyl] piperazine Nicotinate, DSC Analysis of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine Formate Under Nitrogen Was carried out. The results are shown in Table 4, FIG. 2 (1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate) and FIG. 5 (1- [2- (2,4-dimethylphenylsulfanyl). ) Phenyl] piperazine formate). The differential scanning calorimeter measurement conditions are as follows.
1) 장치: DSC 823e(Mettler Toledo)1) Device: DSC 823e (Mettler Toledo)
2) 측정범위: 25 내지 350℃2) Measuring range: 25 to 350 ℃
3) 승온간격: 5℃/min3) Temperature interval: 5 ℃ / min
브롬화수소산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide
니코틴산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate
포름산염1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate
시험예Test Example 6: 수소 핵자기공명 스펙트럼(NMR) 분석 6: Hydrogen Nuclear Magnetic Resonance Spectrum (NMR) Analysis
실시예 1 내지 2에서 제조된 본 발명의 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염의 결정형, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염의 결정형에 대하여 수소 핵자기공명 스펙트럼(NMR) 분석을 실시 하였다. 상기 수소 핵자기공명 스페트럼(NMR) 측정조건은 다음과 같고, 그 결과를 도 3(1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 니코틴산염) 및 도 6(1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염)에 나타내었다. Crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Hydrogen magnetic resonance spectroscopy (NMR) was performed on the crystal form of piperazine formate. The hydrogen nuclear magnetic resonance spectrum (NMR) measurement conditions are as follows, and the results are shown in FIG. 3 (1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate) and FIG. 6 (1). -[2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate).
1) 장치: Bruker Model AVANCE II 4001) Device: Bruker Model AVANCE II 400
2) 측정범위: -0.5 ~ 10ppm2) Measuring range: -0.5 ~ 10ppm
3) 스캔 횟수: 163) Scan count: 16
Claims (21)
[화학식 1]
이때, 상기 니코틴산염은 결정형이며, 8.5°±0.2°, 13.7°±0.2°, 16.5°±0.2°및 19.9°±0.2°의 2θ에서 피크를 갖는 XRD 패턴을 나타낸다.1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate represented by the following formula (1):
[Formula 1]
At this time, the nicotinate is crystalline and exhibits an XRD pattern having peaks at 2θ of 8.5 ° ± 0.2 °, 13.7 ° ± 0.2 °, 16.5 ° ± 0.2 °, and 19.9 ° ± 0.2 °.
[화학식 1]
이때, 상기 결정형은 8.5°±0.2°, 13.7°±0.2°, 16.5°±0.2°및 19.9°±0.2°의 2θ에서 피크를 갖는 XRD 패턴을 나타낸다.Reaction of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with nicotinic acid in at least one organic solvent selected from the group consisting of t-butyl methyl ether and acetonitrile, Method for preparing 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate crystalline form represented by Formula 1:
[Formula 1]
In this case, the crystalline form exhibits an XRD pattern having peaks at 2θ of 8.5 ° ± 0.2 °, 13.7 ° ± 0.2 °, 16.5 ° ± 0.2 ° and 19.9 ° ± 0.2 °.
[화학식 2]
이때, 상기 포름산염은 결정형이며, 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염은 9.8°±0.2°, 12.7°±0.2°, 16.4°±0.2°, 19.7°±0.2°및 22.7°±0.2°의 2θ에서 피크를 갖는 XRD 패턴을 나타낸다.1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate represented by the following formula (2):
[Formula 2]
In this case, the formate is crystalline form, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is 9.8 ° ± 0.2 °, 12.7 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.7 XRD patterns with peaks at 2θ of ° ± 0.2 ° and 22.7 ° ± 0.2 °.
[화학식 2]
이때, 상기 결정형은 1-[2-(2,4-디메틸페닐설파닐)페닐]피페라진 포름산염은 9.8°±0.2°, 12.7°±0.2°, 16.4°±0.2°, 19.7°±0.2°및 22.7°±0.2°의 2θ에서 피크를 갖는 XRD 패턴을 나타낸다.Reaction of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with formic acid in one or more organic solvents selected from the group consisting of t-butyl methyl ether and acetonitrile, followed by crystallization Process for preparing 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate crystalline form represented by Formula 2:
[Formula 2]
At this time, the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is 9.8 ° ± 0.2 °, 12.7 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.7 ° ± 0.2 ° And an XRD pattern with peaks at 2θ of 22.7 ° ± 0.2 °.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170086719A KR102026337B1 (en) | 2017-07-07 | 2017-07-07 | Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170086719A KR102026337B1 (en) | 2017-07-07 | 2017-07-07 | Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20190005679A KR20190005679A (en) | 2019-01-16 |
| KR102026337B1 true KR102026337B1 (en) | 2019-09-27 |
Family
ID=65280896
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170086719A KR102026337B1 (en) | 2017-07-07 | 2017-07-07 | Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR102026337B1 (en) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA81749C2 (en) | 2001-10-04 | 2008-02-11 | Х. Луннбек А/С | Derivated of phenylpiperazine as serotonin reuptake inhibitorS |
| SI2044043T2 (en) | 2006-06-16 | 2021-04-30 | H. Lundbeck A/S | 1- yš- (2, 4-dimethylphenylsulfanyl) -phenylćpiperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment |
| TW200848411A (en) | 2007-03-20 | 2008-12-16 | Lundbeck & Co As H | Novel therapeutic uses of 1-[2-(2, 4-dimethylphenylsulfanyl)phenyl]-piperazine |
| JP5787882B2 (en) * | 2010-04-30 | 2015-09-30 | 武田薬品工業株式会社 | Enteric tablets |
| US9822086B2 (en) | 2014-01-31 | 2017-11-21 | Egis Gyogyszergyar Zrt. | Process for the preparation of vortioxetine salts |
| CA2940097A1 (en) | 2014-04-28 | 2015-11-05 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
| WO2016079751A2 (en) | 2014-11-17 | 2016-05-26 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
-
2017
- 2017-07-07 KR KR1020170086719A patent/KR102026337B1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| KR20190005679A (en) | 2019-01-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2749579C (en) | 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester-methanesulphonate and use thereof as a medicament | |
| EP2791141B1 (en) | Tofacitinib mono-tartrate salt | |
| JP2008509953A (en) | 4-[[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl] amino] -3-methoxy-N- ( 1-methyl-4-piperidinyl) benzamide hydrates and polymorphs, processes for their preparation and their use as drugs | |
| EP0579681B1 (en) | Crystalline tiagabine hydrochloride monohydrate, its preparation and use | |
| CN111995582B (en) | Eutectic of olaparib and urea and preparation method thereof | |
| CN111689905B (en) | Eutectic of olaparib and maleic acid and preparation method thereof | |
| KR101319516B1 (en) | Purine derivatives | |
| CA3117559C (en) | Hydrogen sulfate salt of a bcl-2 inhibitor, related crystalline form,method for preparing the same and pharmaceutical compositions containing the same | |
| CN111825621A (en) | Eutectic of olaparib and malonic acid and preparation method thereof | |
| CA3108007C (en) | Highly stable crystalline eltrombopag monoethanolamine salt form d1 | |
| KR102026337B1 (en) | Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same | |
| EP3702350A1 (en) | Crystalline form of alkynyl pyridine prolyl hydroxylase inhibitor and method for preparing same | |
| US4297357A (en) | N-Phenethylacetamide compounds and process for preparation thereof | |
| CA3087474A1 (en) | Crystalline forms of acalabrutinib, processes for preparation and use thereof | |
| KR102514961B1 (en) | Crystal of Edoxaban benzenesulfonate monohydrate and its preparing method | |
| US10717729B2 (en) | Thiamine-organic acid salt | |
| EP3604284B1 (en) | Crystalline eltrombopag monoethanolamine salt form d | |
| KR20170060035A (en) | L-proline compound of sodium-glucose cotransporter 2 inhibitor, and monohydrate and crystal of l-proline compound | |
| EP3812384B1 (en) | Maleate of benzothiophene compound, crystalline form thereof and use thereof | |
| KR102544543B1 (en) | Individual co-crystal of l, d-erdosteine | |
| CN109384739B (en) | New crystal form of cocoa betahistine and preparation method thereof | |
| CN109796400B (en) | Sorafenib tosylate crystal form and preparation method thereof | |
| KR101653816B1 (en) | Crystalline Form of Sarpogrelate Oxalate Monohydrate or Sarpogrelate Oxalate Anhydride | |
| KR20230092805A (en) | Novel acid addition salt and crystalline form of (2R, 3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol | |
| KR100857342B1 (en) | A novel sibutramine organic acid salt and manufacturing process thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |