JP2013503888A - Compounds and compositions for treating cancer - Google Patents

Abstract

The present invention relates to compounds and compositions for the treatment and prevention of cancer. The present invention is also directed to all diseases that can be treated by selectively adjusting the concentration of reactive oxygen species between diseased cells and normal cells. Also disclosed are methods of preparing and administering the above compositions.

Description

[Cross-reference of related applications]
This application claims priority to US Provisional Patent Application No. 61 / 275,754 entitled “COMPOUNDS AND COMPOSITIONS FOR TREATING CANCER” filed on September 2, 2009. The patent application is incorporated herein by reference in its entirety.

The present invention relates to compounds and compositions for the treatment and prevention of cancer. The present invention also covers all diseases that can be treated by selectively adjusting the concentration of reactive oxygen species between abnormal cells and normal cells. Also disclosed are methods of preparing and administering the above compositions.

The present invention relates to compounds and compositions for the treatment and prevention of cancer or for reducing the intensity or shortening the duration of cancer. The present invention also covers all diseases that can be treated by selectively adjusting the concentration of reactive oxygen species between abnormal cells and normal cells.

All aerobic cells are usually exposed to some reactive oxygen species (ROS), but as ROS levels increase, oxidative stress (OS) occurs, oxygen and oxygen-derived oxidants are generated, and the rate of cytotoxicity is increased. To rise. Cells are exposed to both endogenous and exogenous ROS sources. High concentrations of ROS can cause physiological dysfunction through DNA, proteins, lipids, and other macromolecules, which can cause certain conditions in humans such as cancer, neurodegenerative diseases, cardiovascular diseases, and aging. is there. Furthermore, ROS is also important in mediating apoptosis.

Increasing the ROS concentration selectively only in cancer cells but not normal cells may be a safe and effective method for cancer treatment.

Treatment of neurodegenerative diseases and inflammation by lowering ROS concentration, and neurodegenerative diseases, chronic inflammatory diseases, inflammatory bowel diseases, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxic shock, osteoporosis, Alzheimer's disease A wide range of diseases can be treated, including congestive heart failure and skin diseases.

There remains a need for compositions that can increase the ROS concentration in cancer cells and decrease or maintain the ROS concentration in normal cells.

環Aは次から成る群から選択される。一以上の単環式アリール、一以上のヘテロアリール、3〜7員の飽和または部分的に不飽和の環状炭素、8〜10員の二環式の飽和、部分的に不飽和またはアリール環、窒素、酸素またはイオウから独立して選択される1〜4個のヘテロ原子を含む5〜6員の単環式ヘテロアリール、窒素、酸素またはイオウから独立して選択される1〜3個のヘテロ原子を含む4〜7員の飽和または部分的に不飽和の複素環、窒素、酸素またはイオウから独立して選択される1〜5個のヘテロ原子を含む7〜10員の二環式の飽和または部分的に不飽和の複素環、または窒素、酸素またはイオウから独立して選択される1〜5個のヘテロ原子を含む8〜10員の二環式ヘテロアリール環。

各R¹、R²、およびR³は次から成る群から独立して選択される。水素、ハロゲン、重水素、CF₃、CN、 OR、SR、NRR、NRCOR、NRCONRR、NRCO₂R、COR、CO₂R、NOR、NO_2、CONRR、OC(O)NRR、SO₂R、SO₂NRR、NRSO₂R、NRSO₂NRR、C(O)C(O)R、またはC(O)CH₂C(O)R、アルキル、アリール、ヘテロアリールおよびモルホリノ。
ここで、R¹とR²またはR²とR³のいずれかを随意に選び、それらを合わせ、窒素、酸素、イオウから独立して選択される0〜3個のヘテロ原子を含む4〜8員の飽和、部分的に不飽和、または完全に不飽和の環を形成する。
および、zは0、1または2である。

各Rは水素または随意に置換されたC₁からC₄の脂肪族鎖である。ここで、
またはその代わりに、同じ窒素原子に結合した2個のR鎖を窒素原子と共に随意に選び、窒素、酸素または硫黄から独立して選択される1〜2個の追加のヘテロ原子を含む3〜7員の飽和、部分的に不飽和、または完全に不飽和の環を形成する。
Bは以下から選択される：

ここで
R⁴、R⁵、R⁶およびR⁷は、置換もしくは非置換のC₁からC₁₂のアルキル、置換もしくは非置換のC₁からC₁₂のアルケニル、または置換もしくは非置換のC₁からC₁₂のアルキニルから独立して選択される。
XはO、Sであり、および
CはN、OまたはSから独立して選択される一以上のヘテロ原子を含む飽和もしくは不飽和のヘテロアリールまたは飽和 もしくは不飽和のC1からC7の複素環である。
またはCは縮合環である。および
ここで、任意の一以上のHが、随意に重水素で置換される。
本発明の化合物は出発物質としてピペルロングミンを使い生成してもよく、しかもピペルロングミンと比較して多数の優位性を提供する。実験的研究を実施中に、ピペルロングミンリン酸緩衝生理食塩水または水で1:10に希釈したところ、DMSO中で0.25 mg/mlを超える量のピペルロングミンが沈殿することが判明した。また、ピペルロングミンは0.1 mg/mLで水に対する可溶性を示した。本発明の化合物は、25mg/mL以上の濃度で水に対して高度の可溶性を示し、薬学上の調製および投薬を容易にする。多くの化学療法剤が、癌細胞と正常細胞の両方で一時的にROS濃度を上昇させる。対照的に、本発明の化合物は、治療濃度域が広く、正常細胞でROSを上昇させず、DNA損傷を引き起こさない。エトポシド、5-フルオロウラシル、シスプラチンおよびタキソールなどの現在の標準化学療法剤と比較し、対照に対するパーセント値で表す癌細胞（黒色腫、卵巣癌、腎癌、神経膠芽腫、薬剤耐性非小細胞肺癌の株化細胞）の正味の増殖に対する有効性において、本薬は同等である。 Compounds and compositions useful for the treatment and prevention of cancer are provided. The present invention is a composition of the following formula IA or a salt, derivative or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutically acceptable derivative thereof. here,

Ring A is selected from the group consisting of: One or more monocyclic aryls, one or more heteroaryls, 3-7 membered saturated or partially unsaturated cyclic carbons, 8-10 membered bicyclic saturated, partially unsaturated or aryl rings, 1 to 3 heteroaryls independently selected from 5 to 6-membered monocyclic heteroaryl, 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, nitrogen, oxygen or sulfur 7-10 membered bicyclic saturation containing 1-5 heteroatoms independently selected from 4-7 membered saturated or partially unsaturated heterocycles containing atoms, nitrogen, oxygen or sulfur Or a partially unsaturated heterocycle, or an 8-10 membered bicyclic heteroaryl ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Each R ¹ , R ² , and R ³ is independently selected from the group consisting of: Hydrogen, halogen, deuterium, CF ₃ , CN, OR, SR, NRR, NRCOR, NRCONRR, NRCO ₂ R, COR, CO ₂ R, NOR, NO _2, CONRR, OC (O) NRR, SO ₂ R, SO ₂ NRR, NRSO ₂ R, NRSO ₂ NRR, C (O) C (O) R, or C (O) CH ₂ C (O) R, alkyl, aryl, heteroaryl and morpholino.
Here, any one of R ¹ and R ² or R ² and R ³ is optionally selected and combined to contain 4 to 8 containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Forms a member saturated, partially unsaturated or fully unsaturated ring.
And z is 0, 1 or 2.

Each R is hydrogen or an optionally substituted C ₁ to C ₄ aliphatic chain. here,
Or alternatively, two R chains bonded to the same nitrogen atom are optionally chosen together with the nitrogen atom, and contain 3 to 7 additional heteroatoms independently selected from nitrogen, oxygen or sulfur Forms a member saturated, partially unsaturated or fully unsaturated ring.
B is selected from:

here
R ⁴ , R ⁵ , R ⁶ and R ⁷ are substituted or unsubstituted C ₁ to C ₁₂ alkyl, substituted or unsubstituted C ₁ to C ₁₂ alkenyl, or substituted or unsubstituted C ₁ to C ₁₂ Independently selected from alkynyl.
X is O, S, and
C is a saturated or unsaturated heteroaryl containing one or more heteroatoms independently selected from N, O or S, or a saturated or unsaturated C1 to C7 heterocycle.
Or C is a condensed ring. And where any one or more of H is optionally replaced with deuterium.
The compounds of the present invention may be made using piperlongamine as a starting material and provide a number of advantages over piperlongmin. During the experimental study, dilution of 1:10 with piperlongamine phosphate buffered saline or water was found to precipitate more than 0.25 mg / ml piperlongmin in DMSO. Piperlongmine was soluble in water at 0.1 mg / mL. The compounds of the present invention are highly soluble in water at concentrations of 25 mg / mL and above, facilitating pharmaceutical preparation and dosing. Many chemotherapeutic agents temporarily increase ROS levels in both cancer cells and normal cells. In contrast, the compounds of the present invention have a wide therapeutic window, do not increase ROS in normal cells, and do not cause DNA damage. Cancer cells (melanoma, ovarian cancer, renal cancer, glioblastoma, drug-resistant non-small cell lung cancer) expressed as a percentage of controls compared to current standard chemotherapeutic agents such as etoposide, 5-fluorouracil, cisplatin and taxol In terms of efficacy against net growth of

FIG. 1 shows the effectiveness of the compound on pancreatic cells. FIG. 2 shows the survival rate of normal breast epithelium in the presence of the compounds of the present invention. FIG. 3 shows the effectiveness of the compounds against EJ bladder cancer cells. FIG. 4 shows the effectiveness of the compounds against pancreatic cancer. FIG. 5 shows the efficacy of SP2007 and SP83 on mice with bladder tumor xenografts. FIG. 6 shows cancer therapies that target various salient features of cancer.

Definition
The term “about” or “approximately” means within an acceptable error range for a particular value determined by those skilled in the art, and that range is partly limited to the measurement or determination method of the value, ie the limit of the measurement method. Depends on. For example, “about” may mean within one or more standard deviations, in accordance with practice among those skilled in the art. Alternatively, “about” for a formulation may indicate a range of up to 10%, preferably up to 5%.

“Alkyl”, “alkenyl”, “alkoxy”, “alkylene”, “alkenylene”, “alkenyl”, “alkyl (arylene)”, “alkynyl” and “aryl (alkylene)” are linear and branched, respectively. Including, but not limited to, alkyl, alkenyl, alkoxy, alkylene, alkenylene, alkyl (arylene) and aryl (alkylene) groups.

The phrase “pharmaceutically acceptable” typically refers to allergic or similar adverse reactions, such as stomach upset, dizziness, and similar symptoms when administered to a mammal. Means a compound or composition not shown.

An “effective amount of a compound” is an amount of a compound or one or more thereof sufficient to enhance the therapeutic or prophylactic effect when administered to a mammal to treat or prevent a disease state, disorder or disease. Means a salt, including solvates, active metabolites, prodrugs, or racemates or enantiomers thereof (assuming the salt has a chiral center). An “effective amount” will vary depending on the active ingredient, the condition, disorder or disease to be treated and its severity, and the age, weight, health status, and responsiveness of the mammal to be treated. According to one embodiment of the invention, the therapeutically effective amount of the compound is an amount effective to treat any of the aforementioned disorders. The compound or one or more salts thereof may be augmented with a second drug, such as a chemotherapeutic or adjuvant chemotherapeutic agent for treating any of the aforementioned disorders such as malignancy.

An “effective amount of a pharmaceutical formulation” is an amount of a pharmaceutical agent that is described as being effective for treating or preventing a disease in a patient receiving medication over a period of time, eg, exhibiting a therapeutic effect during a desired dosing interval. It is a formulation. In general, an effective amount of a pharmaceutical formulation comprises an amount of a compound or one or more salts thereof for treating or preventing a desired disease for a desired period of time.

As used herein, the term “treating” includes one or more of the following.
(a) To suppress a disorder, delay its onset (ie, the period prior to clinical manifestation of the disease), and / or reduce the risk of its progression or worsening.
(b) To reduce or alleviate one or more symptoms of a disorder including, for example, cancer in a mammal. Or
(c) reduce the intensity and / or duration of manifestation of a disorder experienced by a mammal, including but not limited to those responding to any stimulus (eg pressure, tissue injury or low temperature); Or relax.

The term “treat” refers to the prophylactic prevention, treatment, cure, alleviation, alleviation, modification of a disease (eg, illness), disease symptoms, or predisposition to a disease. , Improve, ameliorate, improve, or affect.

As used herein, the term “sustained release” refers to the release of an active ingredient over an extended period of time, resulting in a lower peak plasma concentration and an extended T _max compared to a “fast acting” formulation of the same active ingredient. Means that

The term “bioavailability” means the rate and extent to which an active ingredient (compound or one or more salts thereof) or active chain is absorbed from a formulation and becomes available systemically.

The term “polymorph” means different crystallographic forms of a substance.

The term “hydrate” as used herein includes, but is not limited to: (i) a substance comprising water bound in molecular form, and (ii) a crystalline substance comprising one or more crystal waters or a crystalline substance comprising free water.

The term “solvate” as used herein includes, but is not limited to, a molecular or ionic complex of a molecule or ion of a solvent and a molecule or ion of a compound or one or more salts thereof.

The term “adjuvant chemotherapeutic agent” includes agents that treat, alleviate, reduce or ameliorate the side effects of chemotherapeutic agents. Such agents include those that alter the growth and maturation of blood cells. Examples of adjuvant chemotherapeutic agents include, but are not limited to, filgrastim and erythropoietin.

The term “salt” includes complex salts, complexes, and active metabolites, and prodrugs, racemates, enantiomers, and hydrates thereof.

The term “chemotherapeutic agent” refers to an agent that treats, prevents, cures, cures, alleviates, reduces, modifies, ameliorates, ameliorates, improves, or affects a malignant tumor and its metastases. Including. Examples of such agents (also called “anticancer agents”) include prednisone, fluorouracil (eg, 5-fluorouracil (5-FU)), anastrozole, bicalutamide, carboplatin, cisplatin, chlorambucil, docetaxel, doxorubicin, flutamide, interferon wherein the alpha, letrozole, leuprolide, megestrol, mitomycin, paclitaxel, plicamycin (Mitorashin ^TM), tamoxifen, thiotepa, topotecan, valrubicin, vinblastine, vincristine, and that any combination of any of the drugs, they It is not limited to.

The term “hydrogen” or “H” includes any form of hydrogen, including deuterium.

または、その薬学的に許容される塩または薬学的に許容される誘導体を含む。ここで：
環Aは一以上の単環式アリール、一以上のヘテロアリール、3〜7員の飽和または部分的に不飽和の環状炭素、8〜10員の二環式の飽和、部分的に不飽和またはアリール環、窒素、酸素またはイオウから独立して選択される1〜4個のヘテロ原子を含む5〜6員の単環式ヘテロアリール、窒素、酸素またはイオウから独立して選択される1〜3個のヘテロ原子を含む4〜7員の飽和または部分的に不飽和の複素環、窒素、酸素またはイオウから独立して選択される1〜5個のヘテロ原子を含む7〜10員の二環式の飽和または部分的に不飽和の複素環、または窒素、酸素またはイオウから独立して選択される1〜5個のヘテロ原子を含む8〜10員の二環式ヘテロアリール環である。 Compound
The present invention provides compounds and compositions for treating and preventing cancer. The compounds of the present invention include compounds having the following formula:
I:

Or a pharmaceutically acceptable salt or pharmaceutically acceptable derivative thereof. here:
Ring A is one or more monocyclic aryl, one or more heteroaryl, 3-7 membered saturated or partially unsaturated cyclic carbon, 8-10 membered bicyclic saturated, partially unsaturated or 1-3 independently selected from 5-6 membered monocyclic heteroaryl, containing 1-4 heteroatoms independently selected from aryl rings, nitrogen, oxygen or sulfur, nitrogen, oxygen or sulfur 4- to 7-membered saturated or partially unsaturated heterocycles containing 1 to 5 heteroatoms, 7 to 10-membered bicycles containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur A saturated or partially unsaturated heterocycle of the formula or an 8 to 10 membered bicyclic heteroaryl ring containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Each R ¹ , R ² , and R ³ is hydrogen, halogen, deuterium, CF ₃ , CN, OR, SR, NRR, NRCOR, NRCONRR, NRCO ₂ R, COR, CO ₂ R, NOR, NO _2, CONRR, A group composed of OC (O) NRR, SO ₂ R, SO ₂ NRR, NRSO ₂ R, NRSO ₂ NRR, C (O) C (O) R or C (O) CH ₂ C (O) R, alkyl Independently selected from aryl, heteroaryl and morpholino.

Here, any one of R ¹ and R ² or R ² and R ³ is optionally selected and combined to contain 4 to 8 containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Forms a member saturated, partially unsaturated or fully unsaturated ring.

And z is 0, 1 or 2.

ここで
R⁴、R⁵、R⁶およびR⁷は、置換もしくは非置換のC₁からC₁₂のアルキル、置換もしくは非置換のC₁からC₁₂のアルケニル、または置換もしくは非置換のC₁からC₁₂のアルキニルから独立して選択される。 Each R is hydrogen or an optionally substituted C ₁ to C ₄ aliphatic chain (ie alkyl, alkenyl or alkynyl). here:
Or alternatively, two R chains bonded to the same nitrogen atom are optionally chosen together with the nitrogen atom, and contain 3 to 7 additional heteroatoms independently selected from nitrogen, oxygen or sulfur Forms a member saturated, partially unsaturated or fully unsaturated ring.
B is selected from:

here
R ⁴ , R ⁵ , R ⁶ and R ⁷ are substituted or unsubstituted C ₁ to C ₁₂ alkyl, substituted or unsubstituted C ₁ to C ₁₂ alkenyl, or substituted or unsubstituted C ₁ to C ₁₂ Independently selected from alkynyl.

X is O, S, and

C is a saturated or unsaturated heteroaryl containing one or more heteroatoms independently selected from N, O or S, or a saturated or unsaturated C1 to C7 heterocycle.
Or C is a condensed ring. And where any one or more of H is optionally replaced with deuterium.

ここで、この環は前述のように定義されたR1、R2およびR3を含む。
ここでYはN、OまたはSである。および
Cは以下から選択される。

ここで環は随意に一以上のR¹⁰およびR¹¹（R¹⁰およびR¹¹は置換もしくは非置換のC₁からC₁₂のアルキル、置換もしくは非置換のC₁からC₁₂のアルケニル、または置換もしくは非置換のC₁からC₁₂のアルキニルから独立して選択される）、エーテル、チオエーテル、アリールで置換される。

nは1、2または3である。
X₁はOまたはSである。 In another embodiment, a compound of the invention is a compound of formula I above, wherein ring A is selected from:

Here, this ring comprises R1, R2 and R3 as defined above.
Here, Y is N, O or S. and
C is selected from the following.

Wherein the ring is optionally one or more of R ¹⁰ and R ¹¹ (where R ¹⁰ and R ¹¹ are substituted or unsubstituted C ₁ to C ₁₂ alkyl, substituted or unsubstituted C ₁ to C ₁₂ alkenyl, or substituted or Independently selected from unsubstituted C ₁ to C ₁₂ alkynyl), substituted with ether, thioether, aryl.

n is 1, 2 or 3.
X ₁ is O or S.

In a preferred embodiment, compounds of formula I are represented by the following compounds:

In one embodiment, a compound of the invention reacts with a protein and increases ROS in cancer cells and not in normal cells. In one embodiment, the compounds of the invention increase phosphor-JNK concentrations. In one embodiment, the compounds of the invention increase p53 activity. In one embodiment, the compounds of the invention increase p21 activity. In one embodiment, the compounds of the invention reduce pro-survival gene activity. In one embodiment, the compounds of the invention induce apoptosis in cancer cell lines.

In another embodiment, one or more compounds of the present invention are used to treat cancer. Another embodiment includes a method of increasing apoptosis by administering a compound of the invention. Another embodiment includes a method of increasing the activity of p53 by administering one or more compounds of the invention. Another embodiment includes a method of increasing the activity of p21 by administering one or more compounds of the invention. Another embodiment includes a method of preferentially inducing DNA damage in cancer cells by administering one or more compounds of the invention. Another embodiment is a method of inhibiting DNA damage in normal cells by administering one or more compounds of the invention.

In another embodiment, the present invention provides a method of improving the expression of a protein associated with normal cell survival. In another embodiment, the present invention provides a method of killing cancer cells while saving normal cells.

In another embodiment, the present invention provides a method of administering a compound of the present invention at a dose of about 100 mg / kg to about 3000 mg / kg. In another embodiment, the present invention provides a method of administering a compound of the present invention at a dose of about 2.5 mg / kg to about 10 mg / kg. In some embodiments, the therapeutically effective amount is less than 50 mg / kg, such as less than 45 mg / kg, less than 40 mg / kg, less than 35 mg / kg, less than 30 mg / kg, 25 mg / kg. Less than, less than 20 mg / kg, or less than 15 mg / kg. In some embodiments, the therapeutically effective amount is less than 10 mg / kg, such as less than 9 mg / kg, less than 8 mg / kg, less than 7 mg / kg, less than 6 mg / kg, 5 mg / kg. Less than, less than 4 mg / kg, less than 3 mg / kg, or less than 2 mg / kg. In some embodiments, the therapeutically effective amount is less than 1.5 mg / kg, such as less than 1.4 mg / kg, less than 1.3 mg / kg, less than 1.2 mg / kg, less than 1.1 mg / kg, 1 mg / kg. Less than 0.9 mg / kg, less than 0.8 mg / kg, less than 0.7 mg / kg, less than 0.6 mg / kg, less than 0.5 mg / kg, less than 0.4 mg / kg, less than 0.3 mg / kg, less than 0.2 mg / kg, Or less than 0.1 mg / kg.

In another embodiment, the present invention provides a method of inhibiting cell proliferation. In some embodiments, a method of inhibiting cell growth comprises contacting the cell with an effective amount of a composition comprising a compound of the present invention to inhibit the growth of the cell. In some embodiments, the method further comprises contacting the cell with a compound of the present invention and a chemotherapeutic agent. In another aspect, the present invention provides a method for increasing apoptosis in a single cell or group of cells. In some embodiments, a method of increasing apoptosis in a cell or group of cells comprises an effective amount of a composition comprising a compound of the invention and the cell or cell to increase apoptosis in that cell or group of cells. Contacting the cell population. In some embodiments, the number of apoptotic cells in the cell population is increased by a factor of 2 or more. In some embodiments, the number of apoptotic cells in the cell population is increased by a factor of 5 or more. In some embodiments, the number of apoptotic cells in the cell population is increased by a factor of 10 or more. In some embodiments, the method further comprises contacting the cell with a compound of the present invention and a chemotherapeutic agent.

In another embodiment, one or more compounds of the invention are administered with one or more chemotherapeutic agents. In another embodiment, one or more compounds of the invention are administered prior to one or more chemotherapeutic agents. In another embodiment, one or more compounds of the invention are administered after one or more chemotherapeutic agents.

Chemotherapeutic agents include, but are not limited to, drugs administered to patients for the purpose of treating cancer. Chemotherapeutic agents include, but are not limited to, anti-proliferative compounds, anti-neoplastic compounds, anti-cancer effect enhancing agents and radiochemotherapy agents. Those skilled in the art are familiar with various chemotherapeutic agents or can find drugs well known among those skilled in the medical arts to treat cancer.

Chemotherapeutic agents include, but are not limited to, the following compound subclasses: Anti-neoplastic agents such as: acivicin, aclarubicin, acodazole hydrochloride, acronin, adzelesin, adriamycin, aldesleukin, altretamine, ambomycin, amethanetron acetate , Aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene, bisnafide dimesylate, biselecin, bleomycin sulfate, brequinar sodium, bropyrimine , Busulfan, kactinomycin, carsterone, camptothecin, caracemide, carbetimer, carboplatin, carmus , Carbisine hydrochloride, calzeresin, cedefhingol, chlorambucil, cilolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, DACA (N- [2- (dimethyl-amino) ethyl] acridine-4-carboxamide ), Dactinomycin, daunorubicin hydrochloride, daunomycin, decitabine, dexolmaplatin, dezaguanine, dezaguanine mesylate, diazicon, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone citrate propionate, duazomycin , Edatrexate, eflornithine hydrochloride, ellipticine, elsamitrucin, enroplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozo , Esorubicin hydrochloride, Estramustine, Estramustine sodium phosphate, Etanidazole, Ethiodido oil I 131, Etoposide, Etoposide phosphate, Etoprine, Fadrozol hydrochloride, Fazarabine, Fenretinide, Floxyuridine, Fludarabine phosphate, Fluorouracil, 5-FdUMP, Flurocitabine , Hosquidone, Phosphotriesin sodium, Gemcitabine, Gemcitabine hydrochloride, Gold Au 198, Hydroxyurea, Idarubicin hydrochloride, Ifosfamide, Ilmofosin, Interferon alfa-2a, Interferon alfa-2b, Interferon alfa-nl, Interferon alfa-n3, Interferon beta- Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leup acetate Ido, riarosol hydrochloride, lometrexol sodium, lomustine, rosoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogalyl, mercaptopurine, methotrexate, methotrexate sodium, methoprine, metredepa, mitidomid, Mitocalcin, mitochromin, mitodiline, mitomarcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogaramycin, ormaplatin, oxythran, paclitaxel, pegaspargase, periomycin, pentamuthine, pepromycin, porphanfamide , Pyroxanthrone hydrochloride, Prica Mycin, promestan, porfimer sodium, porphyromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ribopurine, logretimide, saphingol, saphingol hydrochloride, semustine, simtrazene, spulfosate sodium, spursomycin, Spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, strontium chloride Sr 89, throfenur, thalisomycin, taxane, taxoid, tecogalane sodium, tegafur, teloxantrone hydrochloride, temoporfin hydrochloride, teniposide, teroxylone, test lactone, Thiamipurine, thioguanine, thiotepa, timitac, thiazofurin, tirapazamine, tomdec , TOP53, topotecan hydrochloride, tremifen citrate, trestron acetate acetate, triciribine phosphate, trimethrexate, trimethrexate glucuronate, triptorelin, tubulosol hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vinblastine sulfate, vincristine, Vincristine sulfate, vindesine, vindesine sulfate, vindespine sulfate, vinlicine sulfate, vinlicurine sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, borozol, zeniplatin, dinostatin, zorubicin hydrochloride, 2-chlorodeoxyadenosine, 2'deoxyformycin, 9 -Aminocamptothecin, raltitrexed, N-propargyl-5,8-dideazafolate, 2-chloro-2'-arabino-fluoro-2'-deoxya Noshin, 2-chloro-2'-deoxyadenosine, anisomycin, trichostatin A, hPRL-G129R, CEP-751, Linomide, piritrexim isethionate, Shitogurushido, tamsulosin hydrochloride, Pentomon. Anti-proliferative compounds include, but are not limited to: 20-pi-1,25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambmustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide , Anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, anti-dorsalization morphogenic protein-1, anti-androgen, prostate cancer, anti-estrogen, anti-neoplaston, antisense oligonucleotide , Aphidicolin glycinate, apoptosis gene regulator, apoptosis regulator, aprinic acid, ara-CDP-DL-PTBA, arginine deaminase, aslacrin, atamesta , Aristostine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, valanol, batimastat, BCR / ABL antagonist, benzochlorin, benzoylstaurosporine, beta-lactam derivative, Beta-alletin, betaclamicin B, betulinic acid, bFGF inhibitor, bicalutamide, bisantren, bisaziridinylspermine, bisnafide, bistratene A, biselecin, breflate, bropirimine, bud titanium, butionine sulfoximine, calcipotriol, Calfostin C, camptothecin derivatives (e.g. 10-hydroxy-camptothecin), canarypox IL-2, capecitabine, carboxamide-amino-triazole, carboxamidotriazole, CaRest M 3, CARN 700, cartilage-derived inhibitor, calzeresin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, chlorin, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analog, clotrimer Zole, Chorismycin A, Chorismycin B, Combretastatin A4, Combretastatin analog, Conagenin, clambecidin 816, Crisnatol, Cryptophycin 8, Cryptophycin A derivative, Curacain A, Cyclopentanetraquinone, Cycloplatam, Cipemycin, Cytarabine okphosphatate, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin, dexifphosphamide, dexrazoxane, dexverapamil , Diadiquan, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, dihydrotaxol, dioxamycin, diphenylspiromustine, discodermolide, docosanol, dolasetron, doxyfluridine, droloxifene, dronabinol, duocarmycin SA, Ebselen, ecomustine, edelfosin, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epothilone, episilon, epristeride, estramustine analog, estrogen agonist, estrogen antagonist, etanidazole, etoposide, etoposide 4'-metophosphonate (eposide) Fadrozole, Fazarabine, Fenretinide, Filgrastim, Finasteride, Flavopi Dole, Frezerastin, Fluasterone, Fludarabine, Fluorodaunorubicin hydrochloride, Forfenimex, Formestane, Hostriecin, Fotemustine, Gadolinium texaphyrin, Gallium nitrate, Galocitabine, Ganirelix, Gelatinase inhibitor, Gemcitabine, Glutathione inhibitor, Hepsulfam, Helegrin hexamethylene Cetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramanton, ilmofosin, ilomasterat, imidazoacridone, imiquimod, immunostimulatory peptide, insulin-like growth factor-1 receptor inhibitor, interferon agonist, interferon, interleukin, iovenguan , Iododoxorubicin, ipomeanol, irinotecan, iropract, Sogradine, isobengazole, isohomochalchondrin B, itasetron, jaspraquinolide, kahalalide F, lamellarin-N triacetate, lanreotide, reinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + Estrogen + progesterone, leuprorelin, levamisole, riarosol, linear polyamine analogues, fat-soluble disaccharide peptides, fat-soluble platinum compounds, risocrine amide 7, lovacplatin, lombricin, lometrexol, lonidamine, rosoxanthrone, lovastatin, loxoribine, lututocan , Lutetium texaphyrin, lysophylline, dissolved peptide, maytansine, mannostatin A, marimastat, masopro Cole, Maspin, Matrilysin inhibitor, Matrix metalloproteinase inhibitor, Menogalyl, Melvalon, Meterelin, Methioninase, Metoclopramide, MIF inhibitor, Ifepristone, Miltefosin, Milimostim, Mismatched double-stranded RNA, Mitrosine, Mitguazone, Mitractol, Mitomycin analog , Mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofarotene, morglamostim, monoclonal antibody, human chorionic gonadotropin, monophosphoryl lipid A + myobacterium cell wall sk, mopidamol, multidrug resistance gene inhibitor, multiple tumor Suppressor 1-based therapeutics, mustard anticancer agent, mica peroxide B, mycobacterial cell wall extract, myriapolone, N-acetyldinarine, N-substituted vector Zamide, nafarelin, nagres chip, naloxone + pentazocine, napabin, naphtherpine, nartograstim, nedaplatin, nemorubicin, neridronate, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulator, nitroxide antioxidant, nitrulline, 06-benzyl Guanine, octreotide, oxenone, oligonucleotide, onapristone, ondansetron, olacin, oral cytokine inducer, olmaplatin, osaterone, oxaliplatin, oxaunomycin, paclitaxel analog, paclitaxel derivative, parauamine, palmitoyl lysoxin, pamidronic acid , Panaxitriol, panomiphene, parabactin, parsliptin, pegase pargase, perdesin, pentosan polysulfate Sodium salt, pentostatin, pentrozole, perflubrone, perphosphamide, perillyl alcohol, phenazinomycin, phenylacetic acid, phosphatase inhibitor, picibanil, pilocarpine hydrochloride, pirarubicin, pyritrexim, pracetin A, prasetin B, plasminogen activator inhibitor, platinum Complexes, platinum compounds, platinum-triamine complexes, podophyllotoxin, porfimer sodium, porphyromycin, propylbis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors , Protein kinase C inhibitor (microalgae), protein tyrosine phosphatase inhibitor, purine nucleoside phosphorylase inhibitor, purpurin, pyrazoloacridine, Pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonist, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitor, ras inhibitor, ras-GAP inhibitor, demethylated retelliptin, etidronate rhenium Re 186, lysoxin, ribozyme, RII retinamide , Logretimide, Rohitkin, Romultide, Rokinimex, Rubigimone B1, Ruboxil, Safingaol, Sintopin, SarCNU, Sarcophytol A, Sargramostim, Sdi 1 mimetic, Semustine, Aging-derived inhibitor 1, Sense oligonucleotide, Signaling inhibitor, Signal Transcriptional regulator, single chain antigen binding protein, schizophyllan, sobuzoxane, borocaptato sodium, sodium phenylacetate, sorberol, somatomedin binding Protein, Sonermin, Sparfos acid, Spicamycin D, Spiromycin, Splenopentine, Spongostatin 1, Squalamine, Stem cell inhibitor, Stem cell division inhibitor, Stipamide, Stromelysin inhibitor, Sulfinosin, Superactive vasoactive intestinal peptide antagonist , Sladista, suramin, swainsonine, synthetic glycosaminoglycan, talimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalane sodium, tegafur, tellurapyrylium, telomerase inhibitor, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, Tetrazomine, salivlastine, thalidomide, thiocoraline, thrombopoietin, thrombopoietin mimetic, simulfacin, thymopoietin receptor Nist, thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topotecan, topcentin, toremifene, totipotent stem cell factor, translation inhibitor, tretinoin, triacetyluridine, triciribine, trimethrexate, triptorelin, tropisetron , Turosteride, tyrosine kinase inhibitor, tyrphostin, UBC inhibitor, ubenimex, urogenital sinus growth inhibitor, urokinase receptor antagonist, bapreotide, variolin B, vector system, erythrocyte gene therapy drug, veraresol, veramine, verdins, verteporfin , Vinorelbine, vinxartine, vitaxin, borozole, zanoterone, xeniplatin, dilascorb, dinostatin styramar. Anti-cancer effect enhancers include, but are not limited to: Tricyclic antidepressants (eg imipramine, desipramine, amitriptyline, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine, maprotiline), non-tricyclic antidepressants (eg sertraline, trazodone, citalopram), Ca2 + antagonist ( Eg verapamil, nifedipine, nitrendipine, caroverine), calmodulin inhibitors (eg prenylamine, trifluoroperazine, clomipramine), amphotericin B, triparanol analogues (eg tamoxifen), antiarrhythmic drugs (eg quinidine), antihypertensive drugs (eg reserpine) , Thiol depleting drugs (eg, buthionine and sulfoximine), and multidrug resistance reducing agents such as Cremafor E. The compounds of the present invention can also be administered with cytokines such as granulocyte colony stimulating factor.

Radiochemotherapeutic agents include, but are not limited to: Fibrinogen I 125, fludeoxyglucose F 18, fluorodopa F 18, insulin I 125, insulin I 131, iobenguan I 123, iodipamamide sodium I 131, iodoantipyrine I 131, iodocholesterol I 131, iodohiplate sodium I 123 , Iodohippurate sodium I 125, iodohiplate sodium I 131, iodopyrracet I 125, iodopyrase I 131, iophetamine hydrochloride I 123, iometin I 125, iometin I 131, sodium iotalamate I 125, sodium iotaramate I 131, iotyrosine I 131, liothyronine I 125, liothyronine I 131, merisoprol acetate Hg 197, merisoprol acetate Hg 203, merisoprol HG 197, selenomethionine Se 75, technetium Tc 99m antimony trisulfide colloid, technetium Tc 99m bisissite, technetium Tc 99m di Phenine, Technetium Tc 99m etidronate, Technetium Tc 99m Exametadim, Technetium Tc 99m Friphosmin, Technetium Tc 99m Glucceptate, Technetium Tc 99m Lidophenine, Technetium Tc 99m Mebrofenine, Technetium Tc 99m Medronate, Technetium T Technetium Tc 99m oxidronate, technetium Tc 99m pentetate, technetium Tc 99m pentetate calcium 3 sodium, technetium Tc 99m sestamibi, technetium Tc 99m siboxime, technetium Tc 99m saccimer, technetium Tc 99m sulfur colloid, technetium 99m Tetrofosmin, technetium Tc 99m thiatide, thyroxine I 125, thyroxine I 131, torpovidone I 131 Triolein I 125, triolein I 131.

The compounds of the present invention are effective in the treatment and / or prevention of a wide range of cancers. Such cancers include but are not limited to lung cancer, bladder cancer, melanoma, bladder carcinoma, pancreatic cancer, breast cancer.

In one aspect, the present invention provides a method for the treatment of cancer. As used herein, the term “cancer” refers to uncontrolled cell growth that interferes with the normal functioning of the body's organs and organ systems. Cancer that migrates from the initial location and origin, vital organs, ultimately causes death of the patient through a decline in the function of the affected organs. Carcinomas are malignant tumors arising from epithelial cells, including adenocarcinoma and squamous cell carcinoma. Sarcomas are connective and supportive tissue cancers, including osteosarcoma, chondrosarcoma, and gastrointestinal stromal tumors. Hematopoietic cancers, such as leukemia, can win the competition with the patient's normal hematopoietic compartment, resulting in the patient developing hematopoietic failure (anemia, thrombocytopenia and neutropenia) and eventually Die. Those skilled in the art can classify cancers as sarcomas, adenomas or hematopoietic cancers. The cancers used herein include the following types of cancer. Breast cancer, cholangiocarcinoma, bladder cancer, brain tumors including glioblastoma and medulloblastoma, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, acute lymphoid and myeloid leukemia Hematological neoplasms including, T-cell acute lymphoblastic leukemia / lymphoma, hairy cell leukemia, chronic myelogenous leukemia, multiple myeloma, AIDS-related leukemia and adult T-cell leukemia / lymphoma, Bowen's disease and Paget's disease Intraepithelial neoplasia, liver cancer, lung cancer, lymphoma including Hodgkin's disease and lymphocytic lymphoma, neuroblastoma, oral cancer including squamous cell carcinoma, epithelial cells, stromal cells, germ cells and mesenchyme Ovarian cancer, including pancreatic cancer, pancreatic cancer, prostate cancer, rectal cancer, leiomyosarcoma, rhabdomyosarcoma, sarcoma including liposarcoma, fibrosarcoma and osteosarcoma, melanoma, Kaposi sarcoma, basal cell carcinoma And flat Skin cancer, including cutaneous cell cancer, seminoma, non-seminoma (teratoma, choriocarcinoma), testicular cancer, including embryonic tumors such as stromal tumors and germ cell tumors, thyroid cancers, including thyroid and medullary cancers, adenocarcinomas, and Kidney cancer, including Wilms tumor. Other cancers are known to those skilled in the art.

The present compounds may take the form of carboxylic acids and / or their salts. Said salts include organic and inorganic salts, but are not limited thereto, for example, alkali metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as magnesium, calcium or barium, basic amino acids such as lysine or arginine And organic amines such as dimethylamine or pyridine. Preferably, the salt is tartaric acid and becomes the hydrochloride salt. The salt may be a monovalent or polyvalent salt, such as the monosodium salt and the disodium salt. The salt may be a solvate, such as an ethanol solvate.

The compounds described herein can be readily prepared synthetically by the methods described herein. For example, the compound may be prepared by the method of Example 1. Other adjustment methods are known to those skilled in the art and can be found, for example, in the following literature. Synthesis of diverse analogues of Oenostacin and their antibacterial activities (Vandana, Bioorganic & Medicinal Chemistry 15 (2007) 518-525), A Simple Regioselective Demethylation of p-Aryl Methyl Ethers Using Aluminum Chloride-Dichloromethane System (Negi, Synthetic Communications, 35: 15-21, 2005), Antiplatelet Activities of Newly Synthesized Derivatives of Piperlongumine (Park, Phytother. Res. 22, 1195-1199 (2008)), On the structure of Pipertine and a synthesis of dihydropiplartine (Joshi, Tetrahedron Letters No. 20 , pp. 2395-2420, 1968), Synthesis and Molecular Structure of Piplartine (Boll, Tetrahedron Letters No. 40, pp. 171-175, 1984), Isolation, Synthesis and Evolutionary Ecology of Piper Amides: June 2004 (Dyer), Inter- and Intraspecific Compararisons of Antiherbivore Defenses in Three Species of Rainforest Understory Shrubs (Fincher, J Chem Ecol (2008) 34: 558-557). The contents of these references and these methods are incorporated herein by reference in their entirety.

Salts of this compound may be prepared by methods known to those skilled in the art. For example, the sodium salt may be prepared by dissolving the compound in ethanol and adding an aqueous sodium hydroxide solution. The hydrochloride and tartrate salts are prepared as described in Examples 1 and 2.

Figure I shows a method for preparing the compound and its tartrate salt.

Another embodiment is a method for preparing a compound of the invention. In yet another embodiment, the preparation of a representative compound of the invention is illustrated by Figure II.

Without being bound by any particular theory of mechanism of action, the compounds of the present invention reduce oxidative stress and thereby increase ROS levels in cancer cells while reducing damage to DNA in normal cells, Increase the therapeutic effect. The effect that appears as a result of exposure to reactive oxygen species (ROS) is often a change in cell differentiation, and apoptosis that eventually occurs after a long period of time. In the absence of stress, GSTP1 inhibits JNK phosphorylation by sequestering the JNK-c-JUN complex. Stress factors cause GSTP1 oligomerization, resulting in dissociation of the JNK-c-JUN complex. Subsequently, phosphorylation of JNK becomes possible, and downstream kinases and transcription factors are activated.

Reactive oxygen molecular species (ROS) have been shown to increase, for example, in EJ bladder cancer cells and breast cancer cells, and removal of GSTJI has been shown to block the increase in ROS. SP2007 has been shown to increase ROS and cause apoptosis in cancer cells. Other compounds of the invention have been shown to be effective against pancreatic cancer cells, breast epithelial cells and EJ bladder cancer cells in vivo.

Furthermore, the compound of the present invention is superior to the conventional parent molecule derived from Piper longum in that it is highly soluble. For example, the amount dissolved in water is 0.1 mg / mL for the parent molecule derived from Piper longum, while it is much higher for the compounds of the present invention. For example, the tartrate salt of Compound 1 of the present invention is dissolved in water at 100 mg / mL.

Dosage forms Dosage compositions may take the form of solids such as tablets or capsules or granulars such as powders or sachets. A solid dosage form may be prepared by mixing a solid form of the compound with a solid form of the active agent. Alternatively, solids may be obtained from a solution of the compound and active agent by methods known to those skilled in the art such as lyophilization, crystallization and solid dispersion.

The amount of compound used in the dosage composition of the invention is that amount effective to achieve the purpose of the particular compound. Provided, however, that when the composition is used in dosage unit form, the dosage unit form comprises a plurality of compound compositions, or comprises a divided pharmaceutically, biologically, therapeutically or chemically effective amount The amount can be less than that amount. Thus, an effective total amount can be dispensed in the form of a cumulative unit containing a total effective amount of active agent.

The total amount of compounds used can be determined by methods known to those skilled in the art.

The compounds disclosed herein are particularly oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, enteral, rectal, vaginal, transmucosal, transpulmonary, transdermal, intradermal, parenteral, Any dosage form known to those skilled in the art may be taken that is particularly suitable for intravenous, intrathecal, intramuscular, intraocular administration, and administration across the blood brain barrier. The compounds may be prepared for injection and are administered by infusion into a vein or artery or direct injection into the peritoneum, bladder, or tumor. The preparation of external preparations such as creams, ointments, jellies, lotions or transdermal patches is also conceivable as dosage forms.

The dosage unit form is an excipient, diluent, disintegrant, lubricant, plasticizer, colorant, flavoring agent, flavoring agent, sugar, sweetener, salt, or combinations thereof, and water, 1, Administration media may include, but are not limited to, 2-propanediol, ethanol, olive oil, or any combination thereof.

The compounds and compositions of the present invention provide biologically or chemically active agents for birds such as chickens, rodents, cows, pigs, dogs, cats, primates, and mammals such as especially humans, and Useful for administration to any animal, including but not limited to insects.

The compounds of the present invention can be administered to animals and humans directly or with commonly used vehicles. The dosage form is not particularly limited, and is appropriately selected as necessary at the time of use, including oral drugs such as tablets, capsules, granules, granules and powders, or parenteral drugs such as injections and suppositories.

Oral medications are prepared in conventional ways using starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, or inorganic salts.

In this type of agent, in addition to the media described above, binders, disintegrants, surfactants, lubricants, flow promoters, flavors, colorants, flavors and the like can be used. Examples of these substances are listed below, but are not limited thereto.
Binders: starch, dextrin, acacia powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.
Disintegrants: starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low substituted hydroxypropylcellulose.
Surfactants: sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, and polysorbate 80.
Lubricants: talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.
Fluidity promoters: light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.

The compounds of the present invention can also be administered in the form of suspensions, emulsions, syrups or elixirs. These drug forms may contain flavors, fragrances and colorants.

Parenteral drugs can be prepared in the usual manner, using diluents such as distilled water for injection, saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, or polyethylene glycol May be. If necessary, bactericides, preservatives, and stabilizers may be added. The parenteral drug can be filled into a vial or similar container, frozen, and the water removed by conventional lyophilization techniques. Solutions can be reconstituted from lyophilized drugs immediately prior to administration. In addition, isotonic solutions, stabilizers, preservatives, preservatives, sedatives and the like may be added.

Compositions comprising the compounds are useful in the treatment of cancer.

DESCRIPTION OF PREFERRED EMBODIMENTS The following examples are illustrative of the present invention and are not intended to be limiting. Unless otherwise specified, all parts are expressed by weight.

Example 1
Compound preparation
1a. Process for preparing compound 1 and its tartrate salt Figure I shows the process for preparing compound 1 and its tartrate salt.

Preparation of BPS-02083-01 To piperlongine (5.60 g, 17.6 mmol) dissolved in anhydrous DCM and stirred, AlCl ₃ (23.3 g, 174 mmol) was added at 28 ^° C. AlCl ₃ could not be completely dissolved in the solution, and the red suspension became a yellow suspension while stirring at 28 ^° C. for 15 minutes. Saturated NaHCO ₃ was added and the mixture was extracted with dichloromethane (150 mL * 2). The organic layers were combined, washed with brine (50 mL * 3), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, washed with dichloromethane / petroleum ether (v / v = 2: 3), yellow BPS-02083-01 (3.5 g, 11.6 mmol, 66%) was obtained as a solid. MS (ESI / FT-MS): 304 [M + H] ⁺ , predicted value 304.

Compound I preparation
Intermediate BPS-02083-01 (1.94 g, 6.4 mmol), 2-morpholinoethanol (1.0 g, 7.7 mmol) and PPh3 (2.52 g, 9.6 mmol) were dissolved in anhydrous dichloromethane (80 mL) and stirred, A solution of DEAD (1.67 g, 9.6 mmol) in dichloromethane (20 mL) was added slowly at 0 ^° C. in N ₂ atmosphere. The mixture was slowly warmed to room temperature and stirred overnight. Remove the solvent under reduced pressure and purify by chromatography on silica gel (petroleum ether ethyl acetate = 1: 1 to 2: 1) as a pale yellow oil BPS-02083-00 (1.4 g, 3.37 mmol, 53% ) MS (ESI / FT-MS): 417 [M + H] ⁺ , predicted value 417.

Compound 1 L-tartrate
To a solution of BPS-02083-00 [Compound 1] (4.16 g, 10.0 mmol) in dichloromethane (25 mL) was added L-tartaric acid (1.50 g, 10.0 mmol) in dichloromethane methanol (10 mL). The solvent was removed under reduced pressure to give BPS-02083-00 L-tartrate (5.66 g, 10.0 mmol, 100%) as a colorless solid. MS (ESI / FT-MS): 417 [M + H] ⁺ , predicted value 417 same as free base.

Example 2
5 grams of free base of Compound I (concentrated oil) (approximately 97% by HPLC) attempted to obtain hydrochloride salt of Compound I. BPS-02083-00 (100 mg) was dissolved in ether (2.0 mL) and cooled to −10 ^° C. HCl (saturated) dissolved in ether was added and stirred for 10 minutes. The solvent was removed (<25 ^° C.) to give a colorless solid (BPS-02083-00-HCl). The spectrum indicated that this was not the hydrochloride salt of BPS-02083-00. Its structure is B (HCl added to the double bond).

Example 3
Process intermediates for representative compounds of the invention were prepared according to Example I. The procedure for cleaving the Boc group to form a byproduct is as follows. HCl (g) was added to a solution of BPS-02085 (about 35 mg) in methanol (5.0 mL) and allowed to react at room temperature (20 ^° C.) for 15 minutes. The solvent was removed under reduced pressure and the residue was purified by TLC (DCM: MA: NH3H2O = 70: 4: 1) to give a by-product (confirmed by 1 NMR and LCMS). Examples of compounds that may be prepared by cleavage of the Boc group described in Example 3 are shown below, but are not limited thereto.

Example 4
Report of representative compounds

Example 5
Effectiveness of compounds on pro-survival gene expression suppression Additional studies have shown that the compounds of the present invention do not affect normal cells such as fibroblasts and keratocytes, and tumors such as EJ and HCT116 cells Killing the cells will demonstrate a large therapeutic range. Studies will also demonstrate that DNA in normal cells is not affected by the compounds of the present invention and ROS in normal cells is not increased.

Figure 1-4 shows the in vivo efficacy of this compound against pancreatic cancer cells, breast epithelial cancer cells, and EJ bladder cancer cells.

Example 6

Anti-tumor effect of SP2007 and SP83 on bladder tumor xenograft mice A study was conducted on the anti-tumor effect of SP2007 and SP83 in bladder tumor xenograft mice

About 0.02 Kg nude / nude mice were fasted overnight and anesthetized by intraperitoneal injection of 250 mg / kg body weight of avertin (2,2,2-tribromoethanol). A total of 2 × 10 ⁶ EJ cells (obtained from a cell bank in Japan) were subcutaneously implanted into the bilateral abdomen of each of 4 nude / nude mice in each administration group. From time to time, mice were fed food and water. When the tumor volume increased to about 2-5 mm in diameter, the control vehicle, SP2007 or SP83 (total 2 mg / kg) was administered intraperitoneally every 24 hours for 25 days. Anti-tumor effects were observed in tumor mice administered SP2007 and SP83 compared to control tumor mice administered DMSO. The results are shown in FIG.

Although the present invention has been described with examples having some degree of speciality, it should be understood that the disclosed contents are merely examples, and the configuration and arrangement of the parts are not deviated from the spirit and scope of the present invention. Many changes may be made in detail. Those skilled in the art will envision many variations of the present invention in light of the above detailed description. All such obvious variations are within the full intended scope of the appended claims.

US Patent Publication No. US2008 / 0227829

Claims (15)

Compounds of formula I:

Or a pharmaceutically acceptable salt or pharmaceutically acceptable derivative thereof. here,

Ring A is selected from the group consisting of: One or more monocyclic aryls, one or more heteroaryls, 3-7 membered saturated or partially unsaturated cyclic carbons, 8-10 membered bicyclic saturated, partially unsaturated or aryl rings, 1 to 3 heteroaryls independently selected from 5 to 6-membered monocyclic heteroaryl, 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, nitrogen, oxygen or sulfur 7-10 membered bicyclic saturation containing 1-5 heteroatoms independently selected from 4-7 membered saturated or partially unsaturated heterocycles containing atoms, nitrogen, oxygen or sulfur Or a partially unsaturated heterocycle, or an 8-10 membered bicyclic heteroaryl ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Each R ¹ , R ² , and R ³ is independently selected from the group consisting of: Hydrogen, halogen, deuterium, CF ₃ , CN, OR, SR, NRR, NRCOR, NRCONRR, NRCO ₂ R, COR, CO ₂ R, NOR, NO _2, CONRR, OC (O) NRR, SO ₂ R, SO ₂ NRR, NRSO ₂ R, NRSO ₂ NRR, C (O) C (O) R, or C (O) CH ₂ C (O) R, alkyl, aryl, heteroaryl and morpholino.
Here, any one of R ¹ and R ² or R ² and R ³ is optionally selected and combined to contain 4 to 8 containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Forms a member saturated, partially unsaturated or fully unsaturated ring.


Each R is hydrogen or an optionally substituted C ₁ to C ₄ aliphatic chain (ie, alkyl, alkenyl, or alkynyl). here:
Or alternatively, two R chains bonded to the same nitrogen atom are optionally chosen together with the nitrogen atom, and contain 3 to 7 additional heteroatoms independently selected from nitrogen, oxygen or sulfur Forms a member saturated, partially unsaturated or fully unsaturated ring.
B is selected from:

here
R ⁴ , R ⁵ , R ⁶ and R ⁷ are substituted or unsubstituted C ₁ to C ₁₂ alkyl, substituted or unsubstituted C ₁ to C ₁₂ alkenyl, or substituted or unsubstituted C ₁ to C ₁₂ Independently selected from alkynyl.

X is O, S, and

C is a saturated or unsaturated heteroaryl containing one or more heteroatoms independently selected from N, O or S, or a saturated or unsaturated C1 to C7 heterocycle.
Or C is a condensed ring. And where any one or more of H is optionally replaced with deuterium. 2. The compound of claim 1. here,
Ring A is selected from:

Y is N, O or S. and

C is selected from the following.

Wherein the ring of C is optionally one or more of R ¹⁰ and R ¹¹ (where R ¹⁰ and R ¹¹ are substituted or unsubstituted C ₁ to C ₁₂ alkyl, substituted or unsubstituted C ₁ to C ₁₂ alkenyl, or Substituted or unsubstituted C ₁ to C ₁₂ alkynyl independently selected), ether, thioether, aryl.

n is 1, 2 or 3.
X ₁ is O or S. A compound or a pharmaceutically acceptable salt or pharmaceutically acceptable derivative thereof, wherein the compound is selected from:

A pharmaceutical composition comprising one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 5. The pharmaceutical composition of claim 4, further comprising one or more chemotherapeutic agents. 9. A kit comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a salt or analog thereof, and instructions for the preparation and / or administration of the pharmaceutical composition. 7. The kit of claim 6, further comprising one or more chemotherapeutic agents. A method for treating cancer in a patient, the method comprising: Administering a therapeutically effective amount of the compound of claim 1 to a patient in need of said treatment, or administering a salt or analog thereof to an individual in need thereof. 9. The method of claim 8, wherein the treatment inhibits further growth of the cancer. 11. The method according to any one of claims 8 to 10, wherein the cancer is a cell tumor, sarcoma, melanoma, pancreatic cancer, breast cancer or bladder cancer. 11. The method of any of claims 8 to 10, wherein the effective amount is from about 2.5 mg / kg to about 100 mg / kg of the compound of formula I. A method for inhibiting cell proliferation, the method comprising: In order to inhibit cell growth, the cell is contacted with an effective amount of a composition comprising a compound of claim 1. A method of increasing apoptosis of a cell or group of cells, the method comprising: In order to increase apoptosis in the cell or group of cells, the cell or group of cells is contacted with an effective amount of a composition comprising the compound of claim 1. A method for increasing the activity of p53 in a cell or group of cells, the method comprising: In order to increase the activity of p53 in the cell or group of cells, the cell or group of cells is contacted with an effective amount of a composition comprising a compound of claim 1. 2. The compound of claim 1, wherein the salt is selected from tartrate or hydrochloride.

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