WO2022186649A1 - Anticancer drug use of phthalazinone derivative as cancer treatment agent for patients with resistance to parp inhibitor - Google Patents
Anticancer drug use of phthalazinone derivative as cancer treatment agent for patients with resistance to parp inhibitor Download PDFInfo
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- WO2022186649A1 WO2022186649A1 PCT/KR2022/003073 KR2022003073W WO2022186649A1 WO 2022186649 A1 WO2022186649 A1 WO 2022186649A1 KR 2022003073 W KR2022003073 W KR 2022003073W WO 2022186649 A1 WO2022186649 A1 WO 2022186649A1
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- WIPO (PCT)
- Prior art keywords
- cancer
- compound
- acid
- parp inhibitor
- olaparib
- Prior art date
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Images
Classifications
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the term “pharmaceutically acceptable salt” refers to the free base form of the compound of Formula 1 can be prepared by any suitable method in the art.
- the free base can be combined with an inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), an organic acid (eg acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid).
- an inorganic acid eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.
- an organic acid eg acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition containing a phthalazinone derivative as an active ingredient for treating PARP inhibitor-resistant cancer. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating PARP inhibitor-resistant cancer, the composition containing a phthalazinone derivative of chemical formula 1 as an active ingredient. The pharmaceutical composition containing the phthalazinone derivative according to the present invention exhibits an effective antiapoptotic effect on PARP inhibitor-resistant cancer cells.
Description
본 발명은 인간 폴리(ADP 리보스) 폴리머라제 억제제(PARP 억제제) 내성 암 치료를 위한 유효성분으로 프탈라지논 유도체를 함유하는 약학 조성물에 관한 것이다. 보다 구체적으로, 본 발명은 하기 화학식 1의 화합물 4-[3-(3-[(사이클로프로필아미노)메틸]아제티딘-1-카르보닐)-4-플루오로벤질]프탈라진-1(2H)-온 또는 이의 제약상 허용되는 염을 유효성분으로 함유하는, PARP 억제제 내성 암의 예방 또는 치료용 약학 조성물에 관한 것이며, 상기 조성물을 이용하여 PARP 억제제 내성 암을 예방 또는 치료하는 방법에 관한 것이다. The present invention relates to a pharmaceutical composition containing a phthalazinone derivative as an active ingredient for the treatment of human poly(ADP ribose) polymerase inhibitor (PARP inhibitor)-resistant cancer. More specifically, the present invention relates to a compound of Formula 1 below 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H )-On or a pharmaceutically acceptable salt thereof, as an active ingredient, relates to a pharmaceutical composition for preventing or treating PARP inhibitor-resistant cancer, and to a method for preventing or treating PARP inhibitor-resistant cancer using the composition .
방사선 요법 및/또는 화학 요법 및 표적 요법과 같은 기존 요법에 대해 일부 암환자는 완전 반응(완전 관해)를 달성하나, 대다수의 암환자는 중간 및 비반응을 나타내며; 대부분의 암환자에서 질병이 진행한다. 또한, 질병의 진행은 이러한 치료를 받은 특정 수의 암환자에게도 발생한다. 이러한 기존 요법으로 치료하거나 유지 요법으로 일부 진행성 암 환자를 치료하려는 시도는 제한적이다.Some cancer patients achieve a complete response (complete remission) to conventional therapies such as radiation therapy and/or chemotherapy and targeted therapy, but the majority of cancer patients are moderate and non-response; The disease progresses in most cancer patients. Progression of the disease also occurs in a certain number of cancer patients who have received such treatment. Attempts to treat some advanced cancer patients with these conventional therapies or with maintenance therapy are limited.
암 치료제에 대한 상대적으로 빠른 내성 획득은 성공적인 암 치료의 주요 장애물로 남아 있다. 일부 특정 내성을 부여하는 돌연변이가 실제로 많은 암환자에서 획득된 약물 내성을 나타내는 것으로 확인되었으나, 돌연변이 및 비-돌연변이 기전이 약물 내성에 미치는 상대적 기여도와 종양 세포 하위 집단의 역할은 다소 불분명하다. The relatively rapid acquisition of resistance to cancer therapeutics remains a major obstacle to successful cancer treatment. Although mutations conferring some specific resistance have indeed been shown to represent acquired drug resistance in many cancer patients, the relative contribution of mutations and non-mutant mechanisms to drug resistance and the role of tumor cell subpopulations are somewhat unclear.
암세포 집단 내 이질성과 치료에 내성이 있는 암세포의 출현을 성공적으로 해결하려면 새로운 치료 방법이 필요하다.New therapeutic approaches are needed to successfully address heterogeneity within cancer cell populations and the emergence of treatment-resistant cancer cells.
올라파립은 인간 폴리(ADP 리보스) 폴리머라제[Poly(ADP Ribose) Polymerase; PARP-1, PARP-2 및 PARP-3; 이하, 통틀어 'PARP'라 한다)]의 강한 억제제이며, 단독 요법 또는 확립된 항암화학요법과의 병용 요법으로 in vitro에서 특정 종양 세포주의 증식 그리고, in vivo에서 종양 증식을 억제한다.Olaparib is human poly (ADP ribose) polymerase [Poly (ADP Ribose) Polymerase; PARP-1, PARP-2 and PARP-3; Hereinafter, collectively referred to as 'PARP')], it inhibits the proliferation of specific tumor cell lines in vitro and tumor growth in vivo as a monotherapy or combination therapy with established chemotherapy.
PARP는 DNA 수선에 수반된 효소의 패밀리로, 18개의 구성요소로 이루어져 있다. 이들 효소들은 세포핵에 위치하고 DNA 손상의 회복에 관여한다. DNA 단일 가닥 절단(SSBs: single-strand breaks)을 받는 BRCA1/2-결실 세포(defective cell)를 표적(target)하기 위해 PARP 억제제가 사용되어 왔다.PARP is a family of enzymes involved in DNA repair and consists of 18 components. These enzymes are located in the cell nucleus and are involved in the repair of DNA damage. PARP inhibitors have been used to target BRCA1/2-defective cells that undergo DNA single-strand breaks (SSBs).
BRCA1 또는 BRCA2 유전자는 손상된 이중 가닥 DNA의 상동 재조합-매개 회복(homologous-mediated repair)의 원인이 된다. 그러나 BRCA1/2 유전자가 결실된 세포에 PARP를 사용하면 PARP 억제제의 존재 하에서 이들 DNA 단일 가닥 절단(SSBs)이 증가하고, 이러한 단일 가닥 절단(SSBs)은 복제 동안 회복할 수 없는 독성 이중 가닥 절단(DSBs: double-strand breaks)으로 전환되어 결국에는 손상된 상동-매개 회복계(impaired homologous-mediated repair system)에 의한 게놈 불안정성으로 인해 세포사를 유발한다.The BRCA1 or BRCA2 gene is responsible for homologous-mediated repair of damaged double-stranded DNA. However, the use of PARP in cells in which the BRCA1/2 gene is deleted increases these DNA single-strand breaks (SSBs) in the presence of a PARP inhibitor, and these single-strand breaks (SSBs) cause irreversible toxic double-strand breaks during replication ( DSBs: double-strand breaks, eventually leading to cell death due to genomic instability caused by an impaired homologous-mediated repair system.
PARP-1 및 PARP-2 모두의 DNA-결합 도메인은 DNA 손상 부위에의 회복 효소의 이동을 촉진하는 두 개의 징크 핑커 모티프(zinc finger motif)를 함유한다. PARP-1 및 PARP-2는 니코틴아미드 아데닌 디뉴클레오티드(NAD+)로부터 핵수용체 단백질로의 ADP-리보스 단위체들의 이동에 촉매로 작용하여 ADP-리보스 중합체의 형성을 유발한다. 이는 염기 절제 회복(BER: base-excision repair)-매개 단일 가닥 절단 회복을 통해 DNA-손상 화학요법제 및 방사선에 의한 DNA 손상을 회복하는 핵심과정이다. 따라서 PARP 저해는 DNA 손상 수선 기전에 결함이 있는 암세포의 사멸을 야기한다.The DNA-binding domains of both PARP-1 and PARP-2 contain two zinc finger motifs that promote migration of repair enzymes to the site of DNA damage. PARP-1 and PARP-2 catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear receptor proteins, resulting in the formation of ADP-ribose polymers. This is a key process for repairing DNA damage caused by DNA-damaging chemotherapeutic agents and radiation through base-excision repair (BER)-mediated single-strand break repair. Therefore, PARP inhibition causes the death of cancer cells with defective DNA damage repair mechanisms.
PARP 억제제의 예로서, 올라파립(Olaparib, AZD-2281), 루카파립(Rucaparib, AG-014699), 니라파립(Niraparib, MK-4827), 탈라조파립(Talazoparib, BMN-673), 벨리파립(Veliparib, ATB-888), 플루조파립(Fluzoparib, SHR-3162), 파미파립(Pamiparib, BGN-290), 세나파립(Senaparib, IMP-4297), 스테노파립(Stenoparib, 2X-121), AZD-5305 등을 들 수 있다.As an example of a PARP inhibitor, olaparib (Olaparib, AZD-2281), rucaparib (Rucaparib, AG-014699), niraparib (Niraparib, MK-4827), talazoparib (Talazoparib, BMN-673), veliparib ( Veliparib, ATB-888), Fluzoparib (SHR-3162), Pamiparib (BGN-290), Senaparib (Senaparib, IMP-4297), Stenoparib (Stenoparib, 2X-121), AZD -5305 etc. are mentioned.
한편 미국 등록특허 9,682,973에는 PARP 억제제로서 항암 활성이 있는 하기 화학식 1의 화합물 4-[3-(3-[(사이클로프로필아미노)메틸]아제티딘-1-카르보닐)-4-플루오로벤질]프탈라진-1(2H)-온 또는 이의 제약상 허용되는 염이 개시되어 있다. 특히 화학식 1의 화합물의 염산염은 항암제로서 유망한 치료 약물 후보군 중 하나이다.On the other hand, US Patent No. 9,682,973 discloses that the compound of Formula 1 below has anticancer activity as a PARP inhibitor 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]p Thalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof, is disclosed. In particular, the hydrochloride salt of the compound of Formula 1 is one of the promising therapeutic drug candidates as anticancer agents.
이러한 종래 효과적인 항암제로서 공지된 PARP 억제제 또한, 암 치료에 대한 내성을 유발하여 성공적인 암 치료에 장애가 되는 것으로 알려져 있다. 이러한 PARP 억제제 유도 내성은 다양한 기전에 의해 발생되는 것으로 알려져 있다(Cancers 2020, 12, 1607; doi:10.3390/cancers12061607). 이러한 다양한 내성 발생 기전 중, BRCA2 유전자의 복귀 돌연변이(reversion mutation)가 PARP 억제제 내성의 주된 원인인 것으로 알려져 있다(Pettitt et al. CANCER DISCOVERY, October, 2020; DOI: 10.1158/2159-8290.CD-19-1485). 또한, 이러한 BRCA와 같은 유전자에서의 복귀 돌연변이는 여러 임상적으로 시험된 PARP 억제제, 예를 들어 올라파립, 탈라조파립, 및 루카파립에 대해 관찰된 획득 내성 기전임을 개시하고 있다(Lin et al. Cancer Discov, February, 2019; DOI: 10.1158/2159-8290.CD-18-071) .PARP inhibitors known as such conventional effective anticancer agents are also known to cause resistance to cancer treatment, thereby becoming an obstacle to successful cancer treatment. It is known that such PARP inhibitor-induced resistance is caused by various mechanisms (Cancers 2020, 12, 1607; doi:10.3390/cancers12061607). Among these various resistance development mechanisms, a reversion mutation of the BRCA2 gene is known to be the main cause of PARP inhibitor resistance (Pettitt et al. CANCER DISCOVERY , October, 2020; DOI: 10.1158/2159-8290.CD-19). -1485 ). It is also disclosed that backmutations in these genes, such as BRCA, are the mechanism of acquired resistance observed against several clinically tested PARP inhibitors, such as olaparib, thalazoparib, and rucaparib (Lin et al. Cancer Discov , February , 2019; DOI: 10.1158/2159-8290.CD-18-071 ).
[선행기술문헌][Prior art literature]
[특허문헌][Patent Literature]
미국 등록특허 9,682,973US Patent 9,682,973
[비특허문헌][Non-patent literature]
Cancers 2020, 12, 334; doi: 10.3390/cancers12020334Cancers 2020, 12, 334; doi: 10.3390/cancers12020334
Cancers 2020, 12, 1607; doi:10.3390/cancers12061607Cancers 2020, 12, 1607; doi:10.3390/cancers12061607
Pettitt et al. CANCER DISCOVERY, October, 2020; DOI: 10.1158/2159-8290.CD-19-1485
Petittt et al. CANCER DISCOVERY , October, 2020; DOI: 10.1158/2159-8290.CD-19-1485
Lin et al. Cancer Discov, February, 2019; DOI: 10.1158/2159-8290.CD-18-071
Lin et al. Cancer Discov, February, 2019; DOI: 10.1158/2159-8290.CD-18-071
본 발명의 발명자들은 화학식 1의 화합물 4-[3-(3-[(사이클로프로필아미노)메틸]아제티딘-1-카르보닐)-4-플루오로벤질]프탈라진-1(2H)-온 또는 이의 제약상 허용되는 염이 각종 암 뿐만 아니라 올라파립을 비롯한 PARP 억제제에 내성을 지닌 암 치료에도 유용하게 사용될 수 있음을 확인함으로써 본 발명을 완성하였다.The present inventors have identified the compound of formula 1 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one Or, the present invention was completed by confirming that a pharmaceutically acceptable salt thereof can be usefully used not only for various cancers but also for the treatment of cancers resistant to PARP inhibitors, including olaparib.
본 발명의 목적은 화학식 1의 화합물 4-[3-(3-[(사이클로프로필아미노)메틸]아제티딘-1-카르보닐)-4-플루오로벤질]프탈라진-1(2H)-온 또는 이의 제약상 허용되는 염을 유효성분으로 함유하는, PARP 억제제에 내성을 가진 암의 예방 또는 치료용 약학 조성물을 제공하기 위한 것이다.An object of the present invention is the compound of formula 1 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one Or to provide a pharmaceutical composition for preventing or treating cancer with resistance to a PARP inhibitor, containing a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 목적은 상기 조성물을 개체에 투여하는 것을 포함하는, PARP 억제제에 내성을 가진 암의 예방 또는 치료 방법을 제공하기 위한 것이다.Another object of the present invention is to provide a method for preventing or treating cancer having resistance to a PARP inhibitor, comprising administering the composition to a subject.
상기와 같은 목적을 달성하기 위한 하나의 양태로서, 본 발명은 화학식 1의 화합물 4-[3-(3-[(사이클로프로필아미노)메틸]아제티딘-1-카르보닐)-4-플루오로벤질]프탈라진-1(2H)-온을 유효성분으로 함유하는, PARP 억제제 내성 암의 예방 또는 치료용 약학 조성물을 제공한다.In one aspect for achieving the above object, the present invention provides a compound of Formula 1 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl ]Provides a pharmaceutical composition for preventing or treating PARP inhibitor-resistant cancer, containing phthalazin-1(2H)-one as an active ingredient.
또한 화학식 1 화합물(화합물 1)의 염 형태도 본 발명의 범주에 포함될 수 있다. 예를 들어 무기산(염산, 히드로브롬산, 인산, 질산, 황산 등), 유기 카르복실산(아세트산, 트리플루오로아세트산과 같은 할로 아세트산, 프로피온산, 말레산, 숙신산, 말산, 시트르산, 타르타르산, 살리실산 등), 및 산성 당(글루쿠론산, 갈락투론산, 글루콘산, 아스코르브산 등), 산성 폴리사카리드(히알우론산, 콘드로이틴술페이트, 아르기닌산 등), 또는 콘드로이틴 술페이트와 같은 술폰산, 당 에스테르를 포함하는 유기 술폰산(메탄술폰산, p-톨루엔 술폰산 등) 등이 포함될 수 있다.Also, a salt form of the compound of Formula 1 (Compound 1) may be included in the scope of the present invention. For example, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, etc.), organic carboxylic acids (acetic acid, haloacetic acid such as trifluoroacetic acid, propionic acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, salicylic acid, etc.) ), and acidic sugars (glucuronic acid, galacturonic acid, gluconic acid, ascorbic acid, etc.), acidic polysaccharides (hyaluronic acid, chondroitin sulfate, arginic acid, etc.), or sulfonic acids, such as chondroitin sulfate, sugar esters organic sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid, etc.) may be included.
본 발명에서 용어 "고형암(solid cancer)"은 혈액암과는 구별되는 특징을 지니고, 방광, 유방, 장, 신장, 폐, 간, 뇌, 식도, 쓸개, 난소, 췌장, 위, 자궁경부, 갑상선, 전립선 및 피부 등의 여러 고형 장기(solid organ)에 비정상적으로 세포가 성장하여 발생한 덩어리로 이루어진 암으로, 본 발명의 조성물은 이에 한정되지는 않으나 PARP 억제제 내성 고형암 치료시에 유용하게 사용될 수 있다.In the present invention, the term "solid cancer" has characteristics distinguishing it from blood cancer, and includes bladder, breast, intestine, kidney, lung, liver, brain, esophagus, gallbladder, ovary, pancreas, stomach, cervix, and thyroid gland. It is a cancer consisting of a mass caused by abnormal cell growth in various solid organs such as , prostate and skin.
본 발명에서 용어 "PARP 억제제 내성 암"은 난소암, 유방암 등의 고형암 및 혈액암 등 암치료에 주로 사용되어 오고 있는 항암제인 PARP 억제제를 반복적으로 장기간 사용함에 따라 내성이 유발되는 암이다. 암세포의 세포 분열을 억제하여 처음에는 뚜렷한 치료효과를 보이는 PARP 억제제를 암환자에게 장기간 지속적으로 투여하게 되면, 그 치료효과가 감소하게 되는데, 이는 생체 내에서 PARP 억제제에 대하여 내성을 획득한 암세포가 출현하기 때문이다. 본 발명에서 PARP 억제제에 대한 내성을 지닌 암에는, 이에 제한되지는 않으나, 유방암, 난소암, 췌장암, 전립선암, 위암, 혈액암 등이 포함될 수 있다. In the present invention, the term "PARP inhibitor-resistant cancer" refers to a cancer in which resistance is induced by repeated and long-term use of a PARP inhibitor, an anticancer agent that has been mainly used for cancer treatment such as solid cancers such as ovarian cancer and breast cancer, and blood cancer. When a PARP inhibitor, which initially exhibits a clear therapeutic effect by inhibiting cell division of cancer cells, is continuously administered to cancer patients for a long period of time, the therapeutic effect decreases. because it does Cancers resistant to PARP inhibitors in the present invention include, but are not limited to, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, blood cancer, and the like.
본 발명에서 용어 "PARP 억제제"는 인간 폴리(ADP 리보스) 폴리머라제 억제제의 약어로서, 당해 기술분야에 공지된 PARP 억제제 및 추후 개발될 PARP 억제제를 포함한다. PARP 억제제에는 올라파립(Olaparib, AZD-2281), 루카파립(Rucaparib, AG-014699), 니라파립(Niraparib, MK-4827), 탈라조파립(Talazoparib, BMN-673), 벨리파립(Veliparib, ATB-888), 플루조파립(Fluzoparib, SHR-3162), 파미파립(Pamiparib, BGN-290), 세나파립(Senaparib, IMP-4297), 스테노파립(Stenoparib, 2X-121), AZD-5305 등이 있으나, 이에 한정되는 것은 아니다.In the present invention, the term “PARP inhibitor” is an abbreviation for human poly(ADP ribose) polymerase inhibitor, and includes PARP inhibitors known in the art and PARP inhibitors to be developed later. PARP inhibitors include Olaparib (AZD-2281), Rucaparib (AG-014699), Niraparib (MK-4827), Talazoparib (BMN-673), Veliparib (Veliparib, ATB) -888), fluzoparib (SHR-3162), pamiparib (Pamiparib, BGN-290), senaparib (Senaparib, IMP-4297), stenoparib (Stenoparib, 2X-121), AZD-5305, etc. However, it is not limited thereto.
본 발명에서 용어 "예방"이란 본 발명에 따른 약학 조성물의 투여에 의해 암의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미하고, "치료"란 상기 약학 조성물의 투여에 의해 암의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention, and "treatment" refers to any activity that causes suspicion of cancer by administration of the pharmaceutical composition. And it means any action that improves or beneficially changes the symptoms of the affected individual.
본 발명의 조성물에 의해 예방 또는 치료될 수 있는 암은 유방암, 난소암, 췌장암, 전립선암, 위암, 혈액암 등으로, 바람직하게는 올라파립 내성 암일 수 있으나, 이에 제한되지 않는다.Cancers that can be prevented or treated by the composition of the present invention include breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, blood cancer, and the like, preferably olaparib-resistant cancer, but is not limited thereto.
본 발명의 구체적인 실시예에 따르면, 상기 본 발명의 조성물, 예컨대 화학식 1 화합물의 염산염이 올라파립에 내성을 나타내는 암 세포주(SNU 601/Olaparib-resistant cells, SNU-638/Olaparib-resistant cells, SNU-668/Olaparib-resistant cells, MCF7/Olaparib-resistant cells, MDA-MD-468/Olaparib-resistant cells, SNU-5126)에 대해서는 농도 의존적으로 항증식효과(antiproliferative effect)를 나타내는 것을 확인하였다(도 3). 또한, 화학식 1 화합물의 염산염이 종래 BRCA2 복귀 돌연변이를 가지며, PARP 억제제에 내성을 갖는 것으로 공지된 입수된 암 세포주(HCC1428)에 대해서도 농도 의존적으로 항증식효과(antiproliferative effect)를 나타내는 것을 확인하였다(도 2 및 표 5). 종래 BRCA2 복귀 돌연변이가 PARP 억제제에 대한 암세포의 내성이 유도되는 주된 기전임이 공지되어 있음을 고려하면, 화학식 1 화합물의 염산염은 올라파립 내성 암뿐만 아니라, PARP 억제제 내성 암에 광범위하게 적용될 수 있을 것으로 기대된다.According to a specific embodiment of the present invention, the composition of the present invention, for example, the hydrochloride of the compound of Formula 1 shows resistance to olaparib cancer cell lines (SNU 601/Olaparib-resistant cells, SNU-638/Olaparib-resistant cells, SNU- 668/Olaparib-resistant cells, MCF7/Olaparib-resistant cells, MDA-MD-468/Olaparib-resistant cells, SNU-5126) were confirmed to exhibit a concentration-dependent antiproliferative effect (FIG. 3) . In addition, it was confirmed that the hydrochloride of the compound of Formula 1 exhibits an antiproliferative effect in a concentration-dependent manner against the obtained cancer cell line (HCC1428), which has a conventional BRCA2 back mutation and is known to have resistance to a PARP inhibitor (Fig. 2 and Table 5). Considering that the conventional BRCA2 reversion mutation is known to be the main mechanism for inducing resistance of cancer cells to PARP inhibitors, the hydrochloride salt of the compound of Formula 1 can be widely applied not only to olaparib-resistant cancers, but also to PARP inhibitor-resistant cancers. It is expected.
상기 본 발명의 약학 조성물은 약학적으로 허용가능한 담체를 추가로 포함할 수 있다. 본 발명의 용어 "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제, 기제, 부형제, 윤활제 등 당업계에 공지된 것이라면 제한없이 사용할 수 있다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable” means exhibiting non-toxic properties to cells or humans exposed to the composition. The carrier may be used without limitation as long as it is known in the art, such as buffers, preservatives, softening agents, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants, and the like.
또한 본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 나아가, 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤 형태의 피부 외용제의 형태로 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.In addition, the pharmaceutical composition of the present invention can be used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. have. Furthermore, it may be used in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel, or gel-form external preparation for skin. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화학식 1의 프탈라지논 유도체에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 61(tween 61), 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, for example, starch, calcium carbonate (calcium) in the phthalazinone derivative of Formula 1 above. carbonate), sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, etc. may be used.
한편, 본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 암의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.On the other hand, the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, Cancer type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로, 본 발명의 조성물에 함유된 화학식 1의 프탈라지논 유도체 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 본 발명의 화학식 1의 화합물(화합물 1)은 고형분을 기준으로 1일 0.1 내지 1000 mg, 바람직하게는 1 내지 500 mg, 보다 바람직하게는 1 내지 300 mg을 매일 또는 격일, 간헐적으로 투여하거나 1일 1회 내지 3회로 나누어 투여할 수 있다. 그러나, 투여량은 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the phthalazinone derivative compound of Formula 1 contained in the composition of the present invention may vary depending on the age, sex, and weight of the patient. In general, the compound of Formula 1 (Compound 1) of the present invention contains a solid content 0.1 to 1000 mg per day, preferably 1 to 500 mg, more preferably 1 to 300 mg daily or every other day, intermittently, or divided into 1 to 3 times a day may be administered. However, the dosage may be increased or decreased depending on the route of administration, disease severity, sex, weight, age, etc., so the dosage does not limit the scope of the present invention in any way.
다른 하나의 양태로서, 본 발명은 화학식 1의 화합물 또는 이의 제약상 허용되는 염을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, PARP 억제제 내성 암을 예방 또는 치료하는 방법을 제공한다.In another aspect, the present invention provides a method for preventing or treating PARP inhibitor-resistant cancer, comprising administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.
본 발명의 용어 "개체"란, 상기 암이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학 조성물을 개체에게 투여함으로써 상기 암을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학 조성물은 기존의 치료제와 병행하여 투여될 수 있다.As used herein, the term "individual" refers to monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, including humans, who have or can develop the cancer. It means all animals, including, and can effectively prevent or treat the cancer by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention may be administered in parallel with a conventional therapeutic agent.
본 발명의 용어 "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 본 발명의 약학 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, may be administered intrarectally, but is not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell. Preferred administration modes and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like. For injection, aqueous solvents such as physiological saline and Ringer's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) Stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, to inhibit microbial growth Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
본 발명의 약학 조성물은 유효성분으로서 화학식 1의 화합물 또는 이의 제약상 허용되는 염 이외에 공지된 항암제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선치료, 호르몬 치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include a known anticancer agent in addition to the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapies, immunotherapy, and the like.
본 발명의 약학 조성물에 포함될 수 있는 항암제의 예시에는 DNA 알킬화제(DNA alkylating agents)로 메클로 에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부술판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 옥살리플라틴(oxaliplatin), 플루오로우라실(5-Fluorouracil, 5-FU), 젬시타빈(gemcitabine), 항암 항생제(anti-cancer antibiotics)로 닥티노마이신(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), liposomal doxorubicin, 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신 C(mitomycin C) 및 블레오마이신(bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 비노렐빈(vinorelbine), 에리불린(eribulin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 납-파클리탁셀(nab-paclitaxel), 에토포시드(etoposide), 테니포시드(teniposide), 토포테칸(topotecan) 및 이리노테칸(irinotecan) 등이 포함되지만, 이에 한정되는 것은 아니다.Examples of anticancer agents that may be included in the pharmaceutical composition of the present invention include mechloethamine, chlorambucil, phenylalanine, mustard, cyclophospha as DNA alkylating agents. Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin ( cisplatin) and carboplatin; oxaliplatin, fluorouracil (5-Fluorouracil, 5-FU), gemcitabine, dactinomycin (actinomycin D) as anti-cancer antibiotics, doxorubicin (adriamycin), liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin C and bleomycin; And as plant alkaloids vincristine, vinblastine, vinorelbine, eribulin, paclitaxel, docetaxel, lead-paclitaxel (nab-paclitaxel) ), etoposide, teniposide, topotecan and irinotecan, and the like, but are not limited thereto.
또 다른 하나의 양태로서, 본 발명은 PARP 억제제 내성 암의 예방 또는 치료에 사용하기 위한 화학식 1의 화합물 4-[3-(3-[(사이클로프로필아미노)메틸]아제티딘-1-카르보닐)-4-플루오로벤질]프탈라진-1(2H)-온, 또는 그의 의약 용도를 제공한다.In another embodiment, the present invention provides compound 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl) of Formula 1 for use in the prevention or treatment of PARP inhibitor-resistant cancer -4-fluorobenzyl]phthalazin-1(2H)-one, or a pharmaceutical use thereof.
본 양태의 상세는, 상기 일 양태에 따른 약학 조성물에 대한 상기 설명 및 다른 양태에 따른 PARP 억제제 내성 암을 예방 또는 치료하는 방법에 대한 상기 설명이 그대로 적용될 수 있다.In the details of this aspect, the above description of the pharmaceutical composition according to the one aspect and the above description of the method for preventing or treating PARP inhibitor-resistant cancer according to another aspect may be applied as it is.
본 발명에 따르면 화학식 1의 프탈라지논 유도체를 유효성분으로 함유하는 조성물은 PARP 억제제 내성 암세포의 효과적인 사멸효과를 나타낸다. 그러므로 본 발명의 화학식 1의 화합물(화합물 1) 또는 이의 제약상 허용되는 염을 유효성분으로 함유하는 조성물은 PARP 억제제 내성 암의 예방 또는 치료를 위한 약학 조성물로 유용하게 이용될 수 있다. According to the present invention, the composition containing the phthalazinone derivative of Formula 1 as an active ingredient exhibits an effective killing effect of PARP inhibitor-resistant cancer cells. Therefore, the composition containing the compound of Formula 1 (Compound 1) or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient can be usefully used as a pharmaceutical composition for the prevention or treatment of PARP inhibitor-resistant cancer.
도 1은 유방암세포주와 위암세포주에서 화합물 1의 염산염의 농도에 따른 세포생존율(%)과 항증식효과를 나타낸 그래프이다.1 is a graph showing the cell viability (%) and antiproliferative effect according to the concentration of the hydrochloride of Compound 1 in breast cancer cell lines and gastric cancer cell lines.
도 1a는 유방암세포주와 위암세포주에서 화합물 1의 염산염의 농도에 따른 세포생존율(%) 결과를 나타낸 그래프이다.1a is a graph showing the cell viability (%) results according to the concentration of the hydrochloride of Compound 1 in breast cancer cell lines and gastric cancer cell lines.
도 1b는 유방암세포주와 위암세포주에서 화합물 1의 염산염의 농도에 따른 항증식효과를 나타낸 도이다.Figure 1b is a diagram showing the anti-proliferative effect according to the concentration of the hydrochloride of Compound 1 in breast cancer cell lines and gastric cancer cell lines.
도 2a는 올라파립 내성 세포주에서 화합물 1의 염산염의 농도에 따른 세포생존율(%) 결과를 나타낸 그래프이다.Figure 2a is a graph showing the cell viability (%) results according to the concentration of the hydrochloride of Compound 1 in olaparib-resistant cell lines.
도 2b는 BRCA2 복귀 돌연변이를 갖는 유방암 세포주에서 화합물 1의 염산염의 농도에 따른 세포생존율(%) 결과를 나타낸 그래프이다.Figure 2b is a graph showing the cell viability (%) results according to the concentration of the hydrochloride of Compound 1 in a breast cancer cell line having a BRCA2 back mutation.
도 3a는 올라파립 내성 세포주에서 화합물 1의 염산염의 농도에 따른 항증식효과를 나타낸 도이다.Figure 3a is a diagram showing the anti-proliferative effect according to the concentration of the hydrochloride of Compound 1 in olaparib-resistant cell lines.
도 3b는 화합물 1의 염산염 농도에 따른 올라파립 내성 환자의 PDX 모델에서 유래한 세포주에서 항증식효과를 나타낸 도이다.Figure 3b is a diagram showing the anti-proliferative effect in the cell line derived from the PDX model of olaparib-resistant patients according to the hydrochloride concentration of Compound 1.
도 3c는 BRCA2 복귀 돌연변이를 갖는 유방암 세포주에서 화합물 1의 염산염의 농도에 따른 항증식효과를 나타낸 도이다.Figure 3c is a diagram showing the antiproliferative effect according to the concentration of the hydrochloride of Compound 1 in a breast cancer cell line having a BRCA2 back mutation.
본 발명에서 용어 "화학식 1의 화합물"은 간단히 "화학식 1 화합물", "화합물 1" 또는 "본 발명의 화합물"로도 지칭된다. 유사하게, "화학식 1의 화합물의 염"은, "화학식 1 화합물의 염", "화합물 1의 염" 또는 "본 발명의 염 화합물"로도 지칭된다. 예를 들어, 화학식 1의 화합물이 염산염 형태로 존재하는 경우, "화학식 1 화합물의 염산염", "화합물 1의 염산염" 또는 "본 발명의 염산염 화합물"로 지칭될 수 있다.In the present invention, the term "compound of formula 1" is also simply referred to as "compound of formula 1", "compound 1" or "compound of the present invention". Similarly, “salt of compound of formula 1” is also referred to as “salt of compound of formula 1”, “salt of compound 1” or “salt compound of the present invention”. For example, when the compound of Formula 1 exists in the form of a hydrochloride salt, it may be referred to as "hydrochloride salt of the compound of formula 1", "hydrochloride salt of compound 1", or "hydrochloride compound of the present invention".
본 발명에서 용어 "제약상 허용되는 염"은, 유리 염기 형태의 화학식 1의 화합물을 당해 기술분야에서 임의의 적합한 방법을 통해 제조될 수 있다. 예를 들어, 상기 유리 염기를 무기산(예: 염산, 브롬산, 황산, 질산, 메탄설폰산, 인산 등), 유기산(예: 아세트산, 트리플루오로아세트산, 말레산, 석신산, 만델산, 푸마르산, 말론산, 피루브산, 옥살산, 글리콜산, 살리실산, 피라노시딜산(예: 글루쿠론산 또는 갈락투론산), 알파 하이드록실산(예: 구연산 또는 주석산), 아미노산(예: 아스파르트산 또는 글루탐산), 방향족 산(예: 벤조산 또는 신남산), 설폰산(예: p-톨루엔설폰산 또는 에탄설폰산) 등으로 처리함으로써 제조될 수 있다. 화학식 1의 화합물의 염산염이 가장 바람직하다.As used herein, the term “pharmaceutically acceptable salt” refers to the free base form of the compound of Formula 1 can be prepared by any suitable method in the art. For example, the free base can be combined with an inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), an organic acid (eg acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid). , malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (such as glucuronic or galacturonic acid), alpha hydroxyl acid (such as citric or tartaric acid), amino acids (such as aspartic or glutamic acid), It can be prepared by treatment with an aromatic acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. The hydrochloride salt of the compound of formula (1) is most preferred.
본 발명의 화학식 1 화합물 또는 그의 제약상 허용되는 염은, 예를 들어, 미국 등록특허 9,682,973에 기재된 방법에 의해, 또는 그것에 준하여 제조함으로써 용이하게 입수 가능하다.The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be easily obtained by, for example, the method described in US Patent No. 9,682,973, or by preparation according thereto.
화학식 1 화합물 또는 그의 제약상 허용되는 염은, PARP 저해 활성을 나타내어 암 치료용으로 유용하게 사용될 수 있다. The compound of Formula 1 or a pharmaceutically acceptable salt thereof exhibits PARP inhibitory activity and can be usefully used for cancer treatment.
본 발명의 약학 조성물에는, 본 발명의 효과를 달성할 수 있는 범위에서, 1종 이상의 제약상 허용되는 부형제를 적절히 포함한다. In the pharmaceutical composition of the present invention, one or more pharmaceutically acceptable excipients are suitably included in the range capable of achieving the effects of the present invention.
본 발명에서 용어 "부형제"는 제약 제제의 제조에서 사용되는 제약상 허용되는 불활성 성분을 나타낸다. 부형제로서는, 예를 들어, 희석제, 결합제, 붕해제, 초강력 붕해제, 활택제, pH 조절제, 윤활제, 충전제, 안정화제, 항산화제, 필름 코팅제를 포함하나, 이로 제한되는 것은 아니다. 본 발명에 사용되는 부형제는 당업계에 알려진 문헌, 예를 들어, 본원에 참고문헌으로 인용되는 문헌[Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press]을 참고하여 적절히 선택될 수 있다. As used herein, the term "excipient" refers to a pharmaceutically acceptable inert ingredient used in the manufacture of pharmaceutical formulations. Excipients include, but are not limited to, for example, diluents, binders, disintegrants, super-strong disintegrants, glidants, pH adjusters, lubricants, fillers, stabilizers, antioxidants, film coatings. The excipient used in the present invention may be appropriately selected by referring to literature known in the art, for example, Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, which is incorporated herein by reference.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예는 본 발명을 예시하기 위한 것이며, 본 발명이 하기 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, the following examples are for illustrating the present invention, and the present invention is not limited by the following examples.
재료 및 방법Materials and Methods
[세포배양][Cell Culture]
TNBC 유방암 세포주인 MDA-MB-468은 ATCC에서 구입하여 공급업체의 지침에 따라 배양하였다. MCF-7 및 HCC1428은 luminal 유방암 세포주이고, SNU-601, SNU-638, 및 SNU-668은 위암 세포주로서, KCLB에서 구입하여 공급업체의 지침에 따라 배양하였다. SNU-5126 세포는 BRCA2 580del4 변이 및 HR-positive, HER2-negative IDC 유방암 환자이며 올라파립에 대하여 내성을 가진 환자로부터 획득하였다(기탁번호: KCLRF-BP-00510). 간략하게, 각 세포들은 10% 소 태아 혈청(FBS), 10μg/ml gentamicin이 보충된 RPMI1640 배지에서 배양온도 37℃ 및 5% CO2 조건 하에서 배양하였다. 실시예에 사용된 세포주의 정보를 표 1에 나타내었다.The TNBC breast cancer cell line, MDA-MB-468, was purchased from ATCC and cultured according to the supplier's instructions. MCF-7 and HCC1428 were luminal breast cancer cell lines, and SNU-601, SNU-638, and SNU-668 were gastric cancer cell lines, purchased from KCLB and cultured according to the supplier's instructions. SNU-5126 cells were obtained from a patient with BRCA2 580del4 mutation and HR-positive, HER2-negative IDC breast cancer and resistant to olaparib (Accession No.: KCLRF-BP-00510). Briefly, each cell was cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 10 μg/ml gentamicin at 37° C. and 5% CO 2 conditions. Information on the cell lines used in Examples is shown in Table 1.
실시예 1 : 화합물 1의 염산염의 항암 효과 평가Example 1: Evaluation of the anticancer effect of the hydrochloride of Compound 1
실시예 1-1 : 세포주의 배가시간 확인Example 1-1: Confirmation of doubling time of cell lines
세포주를 6웰 플레이트에 1 x 105의 세포수로 분주한 후, 배양 온도 37℃ 및 CO2 5% 조건하에서 하룻밤동안 배양하였다. 세포주를 매 24시간 또는 48시간 마다 측정하였다. 매일의 성장률을 첫날의 값으로 정규화(normalized)하였다. 세포주의 배가시간을 표 2에 나타내었다.The cell line was aliquoted in a 6-well plate with a cell number of 1 x 10 5 and then cultured overnight at 37° C. and 5% CO 2 conditions. Cell lines were measured every 24 or 48 hours. The daily growth rate was normalized to the value of the first day. The doubling times of the cell lines are shown in Table 2.
세포배양은 11일 동안 진행되었고(세포분열 5회 이상의 시간에 해당된다), 세포의 평균 배가시간(doubling time)은 47시간이었으며 세포주는 11일 간 실험에 적합한 상태임을 확인하였다.Cell culture was carried out for 11 days (corresponding to 5 or more cell divisions), the average doubling time of cells was 47 hours, and it was confirmed that the cell line was in a state suitable for the experiment for 11 days.
실시예 1-2 : 화합물 1의 염산염의 항 증식 효과 평가 : CFA 분석Example 1-2: Evaluation of the anti-proliferative effect of the hydrochloride salt of Compound 1: CFA analysis
지정된 수의 세포를 6 웰 플레이트에 분주하고 5 % CO2에서 37℃에서 36 시간 배양했다. 배양 후, 세포를 다양한 농도의 화학식 1 화합물의 염산염(화합물 1의 염산염)으로 11 일 동안 처리하였다(세포분열 5회 이상의 시간임). 배양액을 제거한 후 세포를 인산 완충 식염수 (PBS)로 세척하고 0.1 % 쿠마시 블루 용액(Sigma Aldrich)으로 1 시간 동안 실온에서 염색하였다. 다음 단계에서 과잉 염색 용액을 제거하고 플레이트를 PBS로 세척하고 공기 건조하였다. 세포 콜로니는 콜로니 카운터(Bid-Rad, California, USA); 화합물 1의 염산염의 세포 생존율 및 IC50은 SigmaPlot 소프트웨어 버전 10.0 (SPSS)을 사용하여 측정하였다. 각 실험은 3회 반복실험을 하였다.A designated number of cells was aliquoted into a 6-well plate and incubated at 37° C. in 5% CO 2 for 36 hours. After incubation, the cells were treated with various concentrations of the hydrochloride salt of the compound of formula 1 (the hydrochloride of compound 1) for 11 days (a time period of 5 or more cell divisions). After removing the culture medium, the cells were washed with phosphate buffered saline (PBS) and stained with 0.1% Coomassie blue solution (Sigma Aldrich) for 1 hour at room temperature. In the next step, excess staining solution was removed and the plates were washed with PBS and air dried. Cell colonies were colony counter (Bid-Rad, California, USA); Cell viability and IC 50 of hydrochloride of compound 1 were determined using SigmaPlot software version 10.0 (SPSS). Each experiment was repeated three times.
유방암세포주와 위암세포주에서 화합물 1의 염산염의 농도에 따른 세포생존율(%) 결과는 표 3 및 도 1에 나타내었다.The cell viability (%) results according to the concentration of the hydrochloride of Compound 1 in breast cancer cell lines and gastric cancer cell lines are shown in Table 3 and FIG. 1 .
실시예 2 : 올라파립 내성 유방암 및 위암, 및 BRCA2 복귀 돌연변이를 갖는 유방암에서의 화합물 1의 염산염의 항암 효과 평가Example 2: Evaluation of the anticancer effect of compound 1 hydrochloride in olaparib-resistant breast cancer and gastric cancer, and breast cancer with BRCA2 back mutation
PARP 억제제인 올라파립은 난소암, 유방암 등의 치료에 사용되는 약물이다. 하지만 올라파립과 같은 PARP 억제제를 장기투여할 경우 PARP 억제제에 대해 암세포가 반응하지 않는 내성을 유발시킨다.Olaparib, a PARP inhibitor, is a drug used for the treatment of ovarian cancer and breast cancer. However, long-term administration of PARP inhibitors such as olaparib induces resistance in cancer cells that do not respond to PARP inhibitors.
실시예 2-1 : 올라파립 내성 유방암 및 위암 세포주의 확립Example 2-1: Establishment of olaparib-resistant breast cancer and gastric cancer cell lines
유방암 및 위암 세포주를 7개월 동안 올라파립 농도를 0.1 μM부터 10 μM까지 점진적으로 농도를 증가시키면서 노출시켜 올라파립 내성 세포주를 확립하였다. 올라파립 내성 세포주는 RPMI1640 배지에 10% 우태아 혈청(Fetal bovine serum), 10ug/mL gentamicin을 첨가하여 37℃, 5% 이산화탄소 농도의 배양기에서 배양할 때, 10 μM의 올라파립이 CFA(colony forming assay) 방법에 의해 14 일 동안 세포 생존율을 20% 미만으로 감소시켰을 때로 정의되며, DNA 지문 분석(DNA fingerprinting analysis)을 통해 내성 세포주의 확립을 검증하였다.Breast cancer and gastric cancer cell lines were exposed to olaparib concentrations from 0.1 μM to 10 μM for 7 months while gradually increasing concentrations to establish olaparib-resistant cell lines. When the olaparib-resistant cell line is cultured in an incubator at 37°C and 5% carbon dioxide concentration by adding 10% fetal bovine serum and 10ug/mL gentamicin to RPMI1640 medium, 10 μM olaparib is produced by colony forming (CFA). assay) was defined as when the cell viability was reduced to less than 20% for 14 days by the method, and the establishment of a resistant cell line was verified through DNA fingerprinting analysis.
실시예 2-2 : 올라파립 내성 유방암 및 위암, 및 BRCA2 복귀 돌연변이를 갖는 유방암의 항 증식 효과 확인Example 2-2: Confirmation of anti-proliferative effect of olaparib-resistant breast cancer and gastric cancer, and breast cancer with BRCA2 reversion mutation
[규칙 제91조에 의한 정정 20.04.2022]
실시예 2-1의 방법으로 올라파립으로 전 처리한 올라파립 내성 유방암과 위암 세포주 각각에 화학식 1 화합물의 염산염 0, 0.001, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, 10 μM의 농도로 처리한 후, 11일 째 되는 날에 0.1% DMSO만 처리한 대조군의 colony 갯수와 비교하였을 때 형성된 colony 개수를 %로 계산하였을 때, 올라파립 내성 유방암 및 위암 세포주에서 화합물 1의 염산염이 우수한 항 증식 효과를 나타내는 것을 CFA 수행 결과를 통해 확인하였다(도 3). 올라파립 내성 세포주에 대한 화학식 1 화합물의 염산염의 IC50를 하기 표 5 및 도 2a에 나타내었다. 또한, 종래 BRCA2 복귀 돌연변이 및 PARP 억제제 내성을 갖는 것으로 공지된 암 세포주 HCC1428 (출처: 한국세포주연구재단 KCLB)에 대해서도 실시예 1-2에서와 동일한 실험을 수행하여 그 결과를 하기 표 5 및 도 2b, 3c에 함께 나타내었다.[Correction by Rule 91 20.04.2022]
0, 0.001, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, 10 μM of the hydrochloride salt of the compound ofFormula 1 in each of the olaparib-resistant breast cancer and gastric cancer cell lines pretreated with olaparib in the method of Example 2-1 After treatment with a concentration of It was confirmed through the CFA performance result that it exhibits an excellent anti-proliferative effect (FIG. 3). The IC 50 of the hydrochloride salt of the compound of Formula 1 against olaparib-resistant cell lines is shown in Table 5 and FIG. 2a below. In addition, the same experiment as in Example 1-2 was also performed on the cancer cell line HCC1428 (source: Korea Cell Line Research Foundation KCLB) known to have conventional BRCA2 reversion mutation and PARP inhibitor resistance, and the results are shown in Table 5 and FIG. 2b below. , are shown together in 3c.
실시예 2-1의 방법으로 올라파립으로 전 처리한 올라파립 내성 유방암과 위암 세포주 각각에 화학식 1 화합물의 염산염 0, 0.001, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, 10 μM의 농도로 처리한 후, 11일 째 되는 날에 0.1% DMSO만 처리한 대조군의 colony 갯수와 비교하였을 때 형성된 colony 개수를 %로 계산하였을 때, 올라파립 내성 유방암 및 위암 세포주에서 화합물 1의 염산염이 우수한 항 증식 효과를 나타내는 것을 CFA 수행 결과를 통해 확인하였다(도 3). 올라파립 내성 세포주에 대한 화학식 1 화합물의 염산염의 IC50를 하기 표 5 및 도 2a에 나타내었다. 또한, 종래 BRCA2 복귀 돌연변이 및 PARP 억제제 내성을 갖는 것으로 공지된 암 세포주 HCC1428 (출처: 한국세포주연구재단 KCLB)에 대해서도 실시예 1-2에서와 동일한 실험을 수행하여 그 결과를 하기 표 5 및 도 2b, 3c에 함께 나타내었다.[Correction by Rule 91 20.04.2022]
0, 0.001, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, 10 μM of the hydrochloride salt of the compound of
화합물 1의 염산염은 올라파립 내성을 획득한 세포주에서 허용 가능한 농도(화합물 1의 염산염의 임상시험에서 확인된 항정상태의 평균 혈중 농도 : 1.4~5.6 μM)에서 세포 증식 활성을 효과적으로 억제했다. 항정상태는 약물의 투여량과 제거량이 동일하여 혈장농도가 일정한 값으로 유지되는 상태를 의미한다.Hydrochloride of Compound 1 effectively inhibited cell proliferation activity at an acceptable concentration (average steady-state blood concentration confirmed in clinical trials of hydrochloride of Compound 1: 1.4 to 5.6 μM) in cell lines that acquired resistance to olaparib. Steady state refers to a state in which the plasma concentration is maintained at a constant value because the dose and removal amount of the drug are the same.
그 결과, 내성이 생기지 않은 유방암(MCF7/parental cells, MDA-MB-468/parental cells) 및 위암(SNU-601/parental cells, SNU-638/parental cells, SNU-668/ parental cells)과 비교하여, 올라파립 내성 유방암 세포주(MCF7/Olaparib-resistant cells, MDA-MB-468/Olaparib-resistant cells, SNU-5126)와 올라파립 내성 위암 세포주(SNU-601/Olaparib-resistant cells, SNU-638/Olaparib-resistant cells, SNU-668/Olaparib-resistant cells)에서도 화합물 1의 염산염이 여전히 항암 효능을 보였음을 확인할 수 있었다. 또한, 종래 BRCA2 복귀 돌연변이 및 PARP 저해제에 내성을 갖는 것으로 공지된 암 세포주 HCC1428에 대해서도 화합물 1의 염산염이 항암 효능을 보였음을 확인할 수 있었다.As a result, compared with non-resistant breast cancer (MCF7/parental cells, MDA-MB-468/parental cells) and gastric cancer (SNU-601/parental cells, SNU-638/parental cells, SNU-668/parental cells), , Olaparib-resistant breast cancer cell line (MCF7/Olaparib-resistant cells, MDA-MB-468/Olaparib-resistant cells, SNU-5126) and olaparib-resistant gastric cancer cell line (SNU-601/Olaparib-resistant cells, SNU-638/Olaparib) -resistant cells, SNU-668/Olaparib-resistant cells), it was confirmed that the hydrochloride of compound 1 still showed anticancer efficacy. In addition, it was confirmed that the hydrochloride of Compound 1 showed anticancer efficacy against HCC1428, a cancer cell line known to have resistance to conventional BRCA2 reversion mutations and PARP inhibitors.
Claims (5)
- 활성 성분으로서 하기 화학식 1의 화합물 또는 그의 제약상 허용되는 염, 및 1 종 이상의 제약상 허용되는 부형제를 포함하는, 인간 폴리(ADP 리보스) 폴리머라제 억제제(PARP 억제제) 내성 암의 예방 또는 치료용 약학 조성물:A pharmaceutical for the prophylaxis or treatment of human poly(ADP ribose) polymerase inhibitor (PARP inhibitor)-resistant cancer, comprising as an active ingredient a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients Composition:
- 제1항에 있어서, 상기 PARP 억제제는 올라파립(Olaparib, AZD-2281), 루카파립(Rucaparib, AG-014699), 니라파립(Niraparib, MK-4827), 탈라조파립(Talazoparib, BMN-673), 벨리파립(Veliparib, ATB-888), 플루조파립(Fluzoparib, SHR-3162), 파미파립(Pamiparib, BGN-290), 세나파립(Senaparib, IMP-4297), 스테노파립(Stenoparib, 2X-121), 및 이들의 임의의 조합으로 구성된 그룹에서 선택되는 것인, 약학 조성물.According to claim 1, wherein the PARP inhibitor is olaparib (Olaparib, AZD-2281), rucaparib (Rucaparib, AG-014699), niraparib (Niraparib, MK-4827), talazoparib (Talazoparib, BMN-673) , Veliparib (ATB-888), Fluzoparib (Fluzoparib, SHR-3162), Pamiparib (BGN-290), Senaparib (Senaparib, IMP-4297), Stenoparib (Stenoparib, 2X- 121), and any combination thereof.
- 제1항에 있어서, 상기 PARP 억제제는 올라파립인 것인, 약학 조성물.The pharmaceutical composition of claim 1, wherein the PARP inhibitor is olaparib.
- 제1항에 있어서, 상기 활성 성분이 화학식 1의 화합물의 염산염인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 1, wherein the active ingredient is the hydrochloride salt of the compound of formula (1).
- 제1항 내지 제4항 중 어느 하나의 항의 약학 조성물을 인간을 제외한 개체에 투여하는 것을 포함하는 PARP 억제제 내성 암의 예방 또는 치료 방법. A method for preventing or treating PARP inhibitor-resistant cancer, comprising administering the pharmaceutical composition of any one of claims 1 to 4 to a subject other than a human.
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KR20170037116A (en) * | 2015-09-25 | 2017-04-04 | 일동제약(주) | A novel fluoro substituted phthalazinone derivatives and manufacturing process thereof |
WO2019195443A1 (en) * | 2018-04-04 | 2019-10-10 | The Wistar Institute Of Anatomy And Biology | Methods of treating cancers overexpressing carm1 with ezh2 inhibitors and a parp inhibitor |
CN111671902A (en) * | 2020-03-19 | 2020-09-18 | 中山大学孙逸仙纪念医院 | Sensitizer drug, drug composition and application |
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KR20150031196A (en) * | 2013-09-13 | 2015-03-23 | 일동제약주식회사 | A novel phtalazinone derivatives and manufacturing process thereof |
KR20170037116A (en) * | 2015-09-25 | 2017-04-04 | 일동제약(주) | A novel fluoro substituted phthalazinone derivatives and manufacturing process thereof |
WO2019195443A1 (en) * | 2018-04-04 | 2019-10-10 | The Wistar Institute Of Anatomy And Biology | Methods of treating cancers overexpressing carm1 with ezh2 inhibitors and a parp inhibitor |
US20200392153A1 (en) * | 2019-05-23 | 2020-12-17 | Gilead Sciences, Inc. | Substituted eneoxindoles and uses thereof |
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