WO2013064029A1

WO2013064029A1 - Benzoylurea derivative with anticancer activity and preparation method and use thereof

Info

Publication number: WO2013064029A1
Application number: PCT/CN2012/083431
Authority: WO
Inventors: 白骅; 赵旭阳; 龚永祥; 钟金清; 朱齐凤; 刘晓宇; 刘礼飞; 林海鸣
Original assignee: 浙江海正药业股份有限公司
Priority date: 2011-11-04
Filing date: 2012-10-24
Publication date: 2013-05-10
Also published as: CN103086925A; CN103086925B

Abstract

Provided in the present invention are a benzoylurea derivative of formula (I) with anticancer activity or the pharmaceutically acceptable salt or prodrug thereof, and the preparation of such a derivative and the use thereof in preparing a drug for treating diseases relating to a poly(ADP-ribose)polymerase(PARP) inhibitor, such as a drug for treating a cancer.

Description

Benzoyl urea derivative having anticancer activity, preparation method and use thereof

The present invention relates to a benzoylurea derivative having an anticancer activity and a metabolite thereof. The invention also relates to the synthesis of such anticancer drugs and methods of using such compounds to treat cancer. Background technique

Poly(ADP-ribose) polymerase (PARP) inhibitors are a new class of anticancer drugs. Currently, most anticancer drugs kill cancer cells by damaging the DNA in cancer cells, but cancer cells can be regenerated by repairing damaged DNA strands by poly(ADP-ribose) polymerase. Therefore, inhibition of poly(ADP-ribose) polymerase can inhibit the repair of damaged DNA strands in cancer cells, thereby helping standard cancer (chemotherapy or radiotherapy) to kill cancer cells (Ossovskaya et al. US 20090149397; Sherman et al. US 20090131529 and 20090123419 ).

Interestingly, halogenated nitro and nitroso estrogen compounds can be used to treat cancer, especially breast cancer; more interestingly, simple aromatic halonitro and nitroso compounds have also been found to be highly Antitumor activity, especially for breast cancer, has been shown to be a poly(ADP-ribose) polymerase (PARP) inhibitor (Kun et al. US 5464871). In fact, the aromatic nitro compound is first converted into an aromatic nitroso compound in the body, and the latter is an active compound that inhibits tumor growth. Since aromatic nitroso compounds are relatively poor in water solubility at physiological pH and have limited stability, it is difficult to predict whether these compounds can reach cancer cells, and aromatic nitro compounds do not have these problems, so they are aromatic nitroso An ideal prodrug for a compound. The most advanced drug in poly(ADP-ribose) polymerase inhibitors is Sanofi-Aventis' Iniparib (BSI-201), an aromatic nitro compound that is a promising anticancer drug.

Iniparib has shown a good therapeutic effect in the second-stage clinically spread, triple-negative breast cancer (mTNBC) (O'Shaughnessy et al. NEJM, 2011, 364 (3), 205); Sanofi-Aventis A brief three-phase clinical trial of the drug for mTNBC has also been reported - if cancer patients have not previously used other anticancer drugs, Iniparib cannot prolong the lives of these patients or slow the progression of cancer, but if cancer patients have previously used Pass one or two For cancer drugs, the efficacy of Iniparib is consistent with the phase II clinical results. Currently, clinical trials of Iniparib for the treatment of breast, lung and other cancers continue.

The chemical structure of Iniparib is 4-iodo-3-nitrobenzamide, a new class of benzamide derivatives have been found to have stronger anticancer activity compared to the anticancer activity of Iniparib (WO2012058866) _o this The invention provides a new class of benzoylurea derivatives, which are also more potent anticancer drugs than Iniparib. Summary of the invention

One of the objects of the present invention is to disclose a new class of anticancer drugs, benzoylurea derivatives or pharmaceutically acceptable salts thereof.

The compounds of the invention may be represented by formula (I):

among them

R ¹ , R ² and R ^{3 are} independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _r C ₅ )alkyl, substituted or unsubstituted (c ₃ -c ₅ )alkenyl, substituted or unsubstituted Substituted (c ₃ -c ₅ )alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ¹ and R ² may also be cyclized to form a substituted or unsubstituted five, six or seven member Rings; R ² and R ³ may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring; wherein the above substituted or unsubstituted (C ₃ -C ₅ )alkenyl group, substituted or unsubstituted Preferably, the (C ₃ -C ₅ ) alkynyl group is a double bond of an alkenyl group and a triple bond of an alkynyl group is not directly bonded to the N atom of the urea;

R ⁴ is a nitro group or a nitroso group;

R ⁵ is iodine or ethynyl;

Or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The term "substituted" as used above means a group which may be selected from the group consisting of a hydroxyl group, a (dC ₅ ) alkyl group, (C ₂ -C ₅ )alkenyl, (C ₂ -C ₅ ) alkynyl, (C ₃ -C ₅ )cycloalkyl, (dC ₅ )alkoxy, amino, (d-C ₅ )alkylamino a substituent of a di(d-C ₅ )alkylamino group, a (dC ₅ )alkylthio group, a halogen, preferably a hydroxy group, a methoxy group, an amino group, a methylamino group, a dimethylamino group, a methylthio group, and a halogen. .

Wherein said RR ² and R ^{3 are} preferably selected from hydrogen, substituted or unsubstituted (dC ₅ )alkyl; R ¹ and R ² are taken together to form a substituted or unsubstituted five, six or seven membered ring; R ² and R ^{The 3} rings are combined to form a substituted or unsubstituted four, five, six or seven membered ring.

More preferably, RR ² and R ^{3 are} independently selected from hydrogen, substituted or unsubstituted (dC ₅ )alkyl.

Most preferably, RR ² and R ^{3 are} independently selected from hydrogen, methyl, ethyl, propyl or n-butyl. Wherein R ⁴ is preferably a nitro group; and R ⁵ is preferably iodine.

More specifically, wherein the compound of formula (I) is selected from:

1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (1-1);

1-(4-iodo-3-nitrobenzoyl)urea (1-2);

1-(4-indol-3-octylbenzoyl)-3-methylurea (1-3);

1-(4-iodo-3-nitrobenzoyl)-3-ethylurea (1-4);

1-(4-iodo-3-nitrobenzoyl)-3-propylurea (1-5);

1-(4-iodo-3-nitrobenzoyl)-3-butylurea (1-6);

1-(4-iodo 3-nitrobenzoyl)-3-pentylurea (1-7);

1-(4-iodo-3-nitrobenzoyl)-3-isopropylurea (1-8);

1-(4-iodo-3-nitrobenzoyl)-3-isobutylurea (1-9);

1-(4-iodo-3-nitrobenzoyl)-3-methyl-3-ethylurea (1-10);

1-(4-iodo-3-nitrobenzoyl)-1,3-dimethylurea (1-11);

1-(4-iodo-3-nitrobenzoyl)-3,3-diethylurea (1-12);

1-(4-iodo-3-nitrobenzoyl)-3,3-dipropylurea (1-13);

1-(4-iodo-3-nitrobenzoyl)-2-imidazolidinone (1-14);

1-(4-iodo-3-nitrobenzoyl)-3-methyl-2-imidazolidinone (1-15);

N-(4-iodo-3-nitrobenzoyl)pyrrolidine-1-ylformamide (1-16);

N-(4-iodo-3-nitrobenzoyl)-1-azide-1-carboxamide (1-17); 1-(4-iodo-3-nitrobenzoyl)-1,3,3-trimethylurea (1-18);

1-(4-iodo-3-nitrobenzoyl)-1-ethyl-3,3-dimethylurea (1-19);

1-(4-iodo-3-nitrobenzoyl)-1-propyl-3,3-dimethylurea (1-20);

1-(4-iodo-3-nitrobenzoyl)-1-butyl-3,3-dimethylurea (1-21);

1-(4-iodo-3-nitrobenzoyl)-1-methyl-3,3-diethylurea (1-22);

1-(4-iodo-3-nitrobenzoyl)-1-methyl-3,3-dipropylurea (1-23);

1-(4-iodo-3-nitrobenzoyl)-1-ethyl-3,3-dipropylurea (1-24);

1-(4-iodo-3-nitrobenzoyl)-1,3,3-tripropylurea (1-25);

1-(4-iodo-3-nitrobenzoyl)-1-butyl-3,3-dipropylurea (1-26);

1-(4-ethynyl-3-nitrobenzoyl)-3,3-diethylurea (1-27);

1-(4-ethynyl-3-nitrobenzoyl)-3-pentylurea (1-28);

1-(4-ethynyl-3-nitrobenzoyl)-3-methyl-3-ethylurea (1-29);

1-(4-ethynyl-3-nitrobenzoyl)-3,3-dipropylurea (1-30);

1-(4-ethynyl-3-nitrobenzoyl)-3,3-dibutylurea (1-31);

N-(4-ethynyl-3-nitrobenzoyl)pyrrolidin-1-ylformamide (1-32);

N-(4-ethynyl-3-nitrobenzoyl)-1-azide-1-enecarboxamide (1-33);

1-(4-ethynyl-3-nitrobenzoyl)-3,3-dimethylurea (1-34);

1-(4-ethynyl-3-nitrobenzoyl)urea (1-35);

1-(4-ethynyl-3-nitrobenzoyl)-3-methylurea (1-36);

1-(4-ethynyl-3-nitrobenzoyl)-3-ethylurea (1-37);

1-(4-ethynyl-3-nitrobenzoyl)-3-propylurea (1-38);

1-(4-ethynyl-3-nitrobenzoyl)-3-butylurea (1-39);

1-(4-ethynyl-3-nitrobenzoyl)-3-isopropylurea (1-40);

1-(4-ethynyl-3-nitrobenzoyl)-3-isobutylurea (1-41);

1-(4-ethynyl-3-nitrobenzoyl)-1,3-dimethylurea (1-42);

1-(4-ethynyl-3-nitrobenzoyl)-1,3,3-trimethylurea (1-43);

1-(4-ethynyl-3-nitrobenzoyl)-1-ethyl-3,3-dimethylurea (1-44);

1-(4-ethynyl-3-nitrobenzoyl)-1-propyl-3,3-dimethylurea (1-45);

1-(4-ethynyl-3-nitrobenzoyl)-1-butyl-3,3-dimethylurea (1-46); 1-(4-ethynyl-3-nitrobenzoyl)-1-methyl-3,3-diethylurea (1-47); 1-(4-ethynyl-3-nitrobenzene Acyl)-1-methyl-3,3-dipropylurea (1-48); 1-(4-ethynyl-3-nitrobenzoyl)-1-ethyl-3, 3-dipropane Base urea (1-49); 1-(4-ethynyl-3-nitrobenzoyl)-1,3,3-tripropylurea (1-50);

1-(4-ethynyl-3-nitrobenzoyl)-1-butyl-3,3-dipropylurea (1-51); 1-(4-ethynyl-3-nitrobenzoic acid Acyl)-2-imidazolidinone (1-52);

1-(4-ethynyl-3-nitrobenzoyl)-3-methyl-2-imidazolidinone (1-53).

The second aspect of the invention also discloses the use of a compound of the formula (I) and a pharmaceutical composition thereof for the preparation of a medicament for the treatment of cancer. The cancer includes colon cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, acute leukemia, chronic leukemia, prostate cancer, human uterine cancer, pancreatic cancer, liver cancer, brain cancer, CNS tumor, bladder cancer, kidney cancer, skin cancer, Cervical cancer, muscle tumors, lymphoma, bone cancer, and other types of cancer. Also disclosed is the use of the compound represented by the general formula (I) and a pharmaceutical composition for the preparation of a medicament for treating a disorder, associated or concomitant disorder caused by cell proliferation and/or angiogenesis.

A further aspect of the invention resides in the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease associated with a poly(ADP-ribose) polymerase (PARP) inhibitor. Diseases associated with poly(ADP-ribose) polymerase (PARP) inhibitors include cancer, Stroke, Myocardial infarction, and Neuodegenerative diseases.

A further aspect of the present invention provides the use of an effective amount of the compound represented by the formula (I) or a pharmaceutical composition comprising the compound represented by the formula (I), alone or in combination with other drugs, for treatment by cell proliferation and/or A method of causing, associated or concomitant disorders of angiogenesis.

Pharmaceutically acceptable carriers compatible with the compounds of formula (I) may also be included in the pharmaceutical compositions of the invention. The compound of the formula (I) can be administered in a usual dosage form, such as an injection form and an oral form, including a capsule, a tablet, a powder, a sputum, a suspension or a solution, preferably administered by injection. The dosage form and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives, as well as conventional techniques. The pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, moisturizers A slipper, a flavoring agent, a thickener, a colorant, an emulsifier, and the like.

Another aspect of the present invention is to disclose a process for producing the benzoylurea derivative.

Accordingly, it is still another object of the present invention to provide a process for the preparation of a compound of formula (I) (shown below in Scheme 1). This method is applicable to the compound of formula (I) wherein RR ² , R ³ is hydrogen, substituted or unsubstituted (C _r C ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or not Substituted (C ₃ -C ₅ ) alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ¹ and R ² may also be cyclized to form a substituted or unsubstituted five, six or seven member Ring; R ² and R ³ may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring, R ⁴ is a nitro group, and when R ⁵ is iodine, as used in the preparation of compound 1-1 , Compound 1-2, Compound 1-3, Compound 1-4, Compound 1-5, Compound 1-6, Compound 1-7, Compound 1-8, Compound 1-9, Compound 1-10, Compound 1-11 , Compound 1-12, Compound 1-13, Compound 1-14, Compound 1-15, Compound 1-16, Compound 1-17.

Further, another object of the present invention is to provide a process for producing a compound of the formula (I) using the compound III as a raw material (shown as the following Reaction Scheme 2). This method is applicable to the compound of formula (I) wherein R ² , R ³ are hydrogen, substituted or unsubstituted (dC ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or unsubstituted (C ₃ -C ₅ ) alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ² and R ³ may also be cyclized to form a substituted or unsubstituted four, five, six or seven member Ring, R ¹ is a substituted or unsubstituted (C _r C ₅ ) alkyl group, a substituted or unsubstituted (C ₃ -C ₅ ) alkenyl group, a substituted or unsubstituted (C ₃ -C ₅ ) alkynyl group, a substitution Or unsubstituted (C ₃ -C ₅ )cycloalkyl, R ⁴ is a nitro group, and R ⁵ is iodine, as used in the preparation of compound 1-18, compound 1-19, compound 1-20, compound 1- 21, Compound 1-22, Compound 1-23, Compound 1-24, Compound 1-25, Compound 1-26. Wherein X is a halogen.

A further object of the present invention is to provide a process for preparing a compound of the formula (I) (shown as the following Reaction Scheme 3). This method is applicable to the compound of formula (I) wherein R ² , R ³ are hydrogen, substituted or unsubstituted (C _r C ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or not Substituted (C ₃ -C ₅ ) alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ² and R ³ may also be cyclized to form a substituted or unsubstituted four, five, six or a seven-membered ring, wherein R ¹ is hydrogen, R ⁴ is a nitro group, and R ⁵ is an ethynyl group, as used in the preparation of compound 1-27, compound 1-28, compound 1-29, compound 1-30, compound 1 -31, Compound 1-32, Compound 1-33.

Reaction formula 3

A further object of the present invention is to provide a process for the preparation of a compound of formula (I) (shown below in Scheme 4). This method is applicable to the compound of formula (I) wherein RR ² , R ³ is hydrogen, substituted or unsubstituted (C _r C ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or not Substituted (C ₃ -C ₅ )alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ¹ and R ² may also be cyclized to form a substituted or unsubstituted five, six or seven member Rings; R ² and R ³ may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring, R ⁴ is a nitro group, and R ⁵ is an ethynyl group, as used in the preparation of compound 1- 34, Compound 1-35, Compound 1-36, Compound 1-37, Compound 1-38, Compound 1-39, Compound 1-40, Compound 1-41, Compound 1-42, Compound 1-43, Compound 1- 44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, Compound 1-49, Compound 1-50, Compound 1-51, Compound 1-52, Compound 1-53<

VI V

The four terms used in the present invention are defined as follows:

"Halogen" means fluorine, chlorine, bromine and iodine.

"Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group. The alkyl group of CC _{5 is} preferred. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like.

"Alkenyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight-chain or branched. Preferred is an alkenyl group of c ₃ -c ₅ . Examples of alkenyl groups include, but are not limited to, allyl, 2-butenyl and the like.

"Alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight-chain or branched. Preference is given to C ₃ -C ₅ alkynyl groups. Examples of alkynyl groups include, but are not limited to, propargyl, 2-butynyl, and the like.

Further, the term "pharmaceutically acceptable salt" refers to certain salts of the above compounds which retain their original biological activity and are suitable for medical use. The pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt, an amine salt formed with a suitable acid; the metal salt is preferably an alkali metal or an alkaline earth metal salt, and suitable acids include inorganic acids and organic acids, for example Acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, mala Acid, mandelic acid, methanesulfonic acid, nitric acid, brick acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like, particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is a hydrochloride.

"Cycloalkyl" means a saturated or partially saturated carbocyclic ring. A ring composed of 3-5 carbon atoms is preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like. "Alkoxy" means a group of (alkyl-0-). Among them, the alkyl group is defined in the relevant definition herein. The alkoxy group of dC ₅ is preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

We have found that the compounds of the invention are highly active tumor growth inhibitors.

The invention is further illustrated by the following examples. The examples show the preparation of representative compounds represented by formula (I) and related structural identification data. It is to be understood that the following examples are intended to illustrate the invention and not to limit the invention.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, various starting materials and reagents are commercially available. Commercially available starting materials and reagents are used without further purification unless otherwise indicated.

The glassware i is dried in an oven and/or dried by heating. The reaction was followed by glass silica gel - 60 F254 plate (0.25 mm) (TLC). Analytical thin layer chromatography was carried out and developed in a suitable solvent ratio (v/v). The end point of the reaction was taken as the starting material was depleted on the TLC.

^The H NMR image was measured using a Bruker instrument (400 MHz) and the chemical shift was expressed in ppm. The internal standard of tetramethylsilane (O.OOppm) was used. ^ NMR representation: s = singlet, d = doublet, 1 = triplet, 111 = multiplet, ^ = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, its unit is Hz.

The succinct is measured by LC/MS, and the ionization method can be ESI or APCI.

All melting points have not been corrected.

However, there are no restrictions on the synthesis method. The compounds which are not listed below can also be prepared by the same synthetic route and synthesis method as below, by selecting appropriate starting materials, and adjusting the reaction conditions with appropriate appropriate common-sense conditions as necessary. Specific implementation

Example 1: Preparation of 1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (Compound 1-1):

II-l Add 70 g (0.239 mol) of 4-iodo-3-nitrobenzoic acid (Compound II-1) and 350 ml of N, N-dimethylformamide (DMF) to the reaction flask, and dissolve and dissolve. The mixture water bath was cooled to 0~10 ° C, and 61 liters (0.84 moles) of thionyl chloride was added dropwise. After the dropwise addition, the solution was taken to a water bath, and reacted at room temperature for 1 hour, and then cooled to 0 to 10 ° C. Add 490 liters (6.1 moles) of pyridine, 105 grams (1.19 moles) of 1,1-dimethylurea, and react for 1 hour. Pour the reaction solution into 4 liters of 1% dilute hydrochloric acid, stir, precipitate a solid, filter, water Wash to neutral. Then add 2 liters of ethyl acetate to the filter cake, heat to 75 ° C until it is completely dissolved, add 200 grams of anhydrous sodium gram, decolorize 20 grams of activated carbon, filter, concentrate the filtrate, gradually precipitate solids, filter, dry Ip_(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (Compound 1-1) 36.4 g, yield 42%. iHNMRWOOMHz, DMSO- ₆ ): δ 2.94 (s, 6H), 7.83 (d, 1 H, /= 8.1 Hz), 8.25 (d, 1 H, J=8.2 Hz), 8.35 (s, 1 H), 10.45 (s, 1 H); MS (m/z): 364 [M+H] „

The following compounds were prepared according to the procedure of Example 1 using 4-iodo-3-nitrobenzoic acid (Compound II-l) as the starting material: Example product name structure 1H NMR (400 MHz) and MS (m/z )

⁰丫丫^NH 2

1H NMR (DMSO-J ₆ ): 57.53 (s, 1 H),

1-(4-iodo-3-nitro 7.91 (m, 2H), 8.25 (d, 1 H, J = 8.2

2

Benzoyl)urea Hz), 8.46 (d, 1 H, J = 2.0 Hz), 10.85

(s, 1 H); MS (m/z): 334 [M-H]

1

1-2

Example 18: Preparation of 1-(4-iodo-3-nitrobenzoyl)-1,3,3-trimethylurea (Compound 1-18):

Il 1-18 Add 10 g (0.0275 mol) of 1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (compound 1-1) and 100 to a 250-liter single-mouth bottle. Soaring N, N-dimethylformamide, stirring and stirring, then adding 12.7 g (0.092 mol) of anhydrous carbonic acid clock and 16.7 liters (0.268 mol) of methyl iodide, reacting at room temperature for 1 hour, TLC detection reaction is completed, add 100 Soaring water, Ethyl acetate (200 liters x 3) was extracted, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / n-hexane as eluent). -3-Nitrobenzoyl)-1,3,3-trimethylurea (Compound 1-18) 5.5 g, yield 53%. ^NMR (400MHz, DMSO- ₆ ): δ 2.86 (brs, 6Η), 3.10 (s, 3 Η), 7.45 (dd, 1 Η, /=8.1, 1.4 Hz), 8.01 (d, 1 H, /= 1.4 Hz), 8.18 (d, 1 H, J=8.1 Hz); MS (m/z): 378 [M+H] „

The following compounds were prepared as in Example 18 using the appropriate starting materials (Compound 1-1, Compound 1-12, Compound 1-13) and the appropriate reagents:

Example 27: Preparation of 1-(4-ethynyl-3-nitrobenzoyl)-3,3-diethylurea (Compound-27):

IV 1-27 Add 10 g (52.6 亳mol) of 4-ethynyl-3-nitrobenzamide (Compound IV) to the reaction flask (the preparation of this compound refers to the patent WO2012058866) and 300 liters 1,2-two Ethyl chloride, water salt bath was cooled to -6 ° C, 3.3 liters (37 亳 mole) of oxalyl chloride was added, reacted at room temperature for 4 hours, then heated to 60 ° C for 0.5 hour, the reaction was completed, and the solvent was evaporated under reduced pressure. Add 75 liters of tetrahydrofuran, cool in a water bath, add 5.2 liters (51 Torr) of diethylamine, react to precipitate a solid, filter, and wash the filter cake with ethyl acetate / n-hexane (1:1). Crystallization gave 1-(4-ethynyl-3-nitrobenzoyl)-3,3-diethylurea (Compound 1-27) 3 g, yield 19.7%. iHNMR OOMHz, DMSO- ₆ ): δ 1.12 (t, 6H, J = 7.0 Hz), 3.34 (q, 4H, /= 7.0Hz), 4.97 (s, 1 H), 7.93 (d, 1 H, J= 8.0 Hz), 8.14 (dd, 1 H, /=8.1, 1.5 Hz), 8.50 (d, 1 H, /= 1.4 Hz), 10.48 (s, 1 H); MS (m/z): 288 [MH ]„

The following compounds were prepared according to the method of Example 27 using 4 - ethynyl-3- 3 - nitrobenzamide (Compound IV ) as the starting material, using the appropriate reagents:

(d,

Example 34: Preparation of 1-(4-ethynyl-3-nitrobenzoyl)-3,3-dimethylurea (1-34):

Step 1: Add 5 g (13.77 mmol) of 1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (compound 1-1) to a single-mouth vial, 4.3 liters of three Ethylamine and 75 liters of tetrahydrofuran, nitrogen protection, magnetic stirring, then add 0.5 g (0.712 亳mol) of bis(triphenyl brick) palladium dichloride, 0.3 g (1.57 mol) of cuprous iodide, 7.4 liters (52 亳mol) trimethylsilylacetylene, reacted at room temperature for 15 minutes, the reaction was completed by TLC, the solvent was evaporated under reduced pressure, and extracted with 100 liters of ethyl acetate. The organic phase was combined and washed with 50 liters of aqueous ammonium chloride solution three times. Drying with anhydrous sodium sulfate, decolorizing activated carbon, filtering, concentrating the filtrate to dryness, separation by column chromatography

(ethyl acetate/n-hexane as eluent), crystallized to give 1-[4-(2-trimethylsilyl)ethynyl-3-nitrobenzoyl]-3,3-dimethylurea ( Compound V-1) 2.5 g, yield 54.5%. ^{_{! HNMR (400MHz, DMSO- 6)}} : δ 0.27 (s, 9Η), 2.94 (s, 6Η), 7.86 (d, 1 Η, J = 1.1 Hz), 8.13 (d, 1 H, J = 7.6 Hz) , 8.50 (s, 1 H), 10.39 (s, 1 H); MS (m/z): 334 [M+H] „

Step 2: Add 2.5 g (7.5 mmol) of 1-[4-(2-trimethylsilyl)ethynyl-3-nitrobenzoyl]-3,3-dimethylurea to the reaction flask. Compound V-1) and 25 liters of tetrahydrofuran, magnetically stirred, liquid nitrogen was cooled to below -35 ° C, and 20 liters of a solution of 2 g (6.34 亳mol) of tetrabutylammonium fluoride in tetrahydrofuran was added, after 3 minutes. After the reaction is completed, the reaction solution is poured into a 1N aqueous hydrochloric acid solution to precipitate a solid, which is filtered, washed with water to neutrality, dried, decolorized by activated carbon, and recrystallized from ethyl acetate to give 1-(4-ethynyl-3-nitrate Benzoyl)-3,3-dimethylurea

(Compound 1-34) 1.2 g, yield 61.2%. iHNMR OOMHz, DMSO- ₆ ): δ 2.96 (s, 6H), 4.96 (s, 1 H), 7.93 (d, 1 H, J = 8.1 Hz), 8.17 (dd, 1 H, /=8.1, 1.8 Hz), 8.54 (d, 1 H, /= 1.7 Hz), 10.52 (s, 1 H); MS (m/z): 260 [MH] „ The appropriate starting materials are selected (Compound 1-2, Compound 1-3, Compound 1-4, Compound 1-5, Compound 1-6, Compound 1-8, Compound 1-9, Compound 1-11, Compound 1-18, Compound 1-19, Compound 1-20, Compound 1-21, Compound 1-22, Compound 1-23, Compound 1-24, Compound 1-25, Compound 1-26, Compound 1-14, Compound 1-15) With the appropriate reagents, the following compounds were prepared as in Example 34:

(dd,

The pharmacodynamic screening of the compounds of the invention is carried out as follows: Cell culture Human colon cancer cell lines (COLO205 and HCT-116), human breast cancer cell lines (MCF-7 and MDA-MB435), human lung cancer cell lines (A549 and NCI460), human leukemia (HL-60), human prostate cancer ( BXPC-3) and human uterine cancer (HELA) were obtained from ATCC. COLO205, HL-60 cells were cultured in RPMI 1640 containing 2 mM/L-glutamine, 10% FBS, 1.0 mM sodium pyruvate. HCT-116, MCF-7, A549, NCI460, BXPC-3, HELA cells were cultured in DMEM containing 2 mM/L-glutamine and 10% FBS. MDA-MB435 cells were cultured in L-15 containing 2 mM/L-glutamine, 10% FBS. COLO205 and HL-60 cells were seeded in 96-well plates, 150 μ! 7 wells, 8000 cells per well, and 96-well plates were pre-incubated for 24 hours at 37 ° C, 5% C0 ₂ , 100% relative humidity incubator. HCT-116, MCF-7 > NCI460, HELA and MDA-MB435 cells were seeded in 96-well plates at 5000 cells per well; A549 and BXPC-3 cells were seeded in 96-well plates at 10,000 cells per well. The 96-well plates were pre-incubated for 24 hours at 37 ° C, 5% C0 ₂ , 100% relative humidity incubator to allow the cells to adhere.

2. Screening compounds

50 μM of pre-cooled 50% (mass/volume) TCA-fixed cells were added to the time zero control well of each cell line. Add 50 μΙ^ of different concentrations of compound to other wells for 48 h, set 3 replicate wells for each drug concentration, and set blank control (cell culture medium, no cells), no drug control well (no drug, plus, etc.) The complete medium was tested, and the positive drug control BSI-201 was placed in a 5% C0 ₂ incubator at 37 ° C for 48 h under total humidity (100% relative humidity).

3. Cell detection

50 pre-cooled 50% (mass/volume) TCA fixed cells were added to the culture fluid level. Then, it was allowed to stand at 4 ° C for 1 h, the supernatant was discarded, and each well was washed 5 times with deionized water to remove TCA and serum proteins. After drying in air, add a sufficient amount of 0.4% SRB (prepared with 1% acetic acid) to each well for about 100 L, and leave it at room temperature for 20-30 min. The liquid in each well was discarded and quickly washed 5 times with 1% acetic acid to remove unbound dye until the unbound dye was rinsed clean. Allow to dry in air until moisture is not visible, dissolve in 200 L Tris base, shake on a plate shaker for 5 min or beat up and down with a Tip head and mix on the multifunction meter (M5 detection system, MD Group Ltd. The 690 nm blank was zeroed and the detection wavelength was 515 nm.

Dose response curves were plotted using XL-fit to determine their GI ₅ o values. 4. Screening results

By in vitro pharmacodynamic screening experiments, BSI-201 (Iniparib) was used as a positive drug, and the results showed that compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-8, 1 -9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21 , 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1 -34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46 , 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53 inhibit tumor cell proliferation; Compound 1-7 also has certain tumor suppressor activity, but its GI ₅ . Values were not measured under the test conditions used. Among them, compound 1-27 was more than 20 times more potent than the positive drug BSI-201 on the 9 tumor cell lines tested; 1-32, 1-36, 1-44, 1-45 and 1-27 Close; 1-29, 1-42, 1-48 efficacy slightly worse than 1-27. The screening results are shown in Table 1:

Table 1 Compound (I) inhibitory activity against tumor cells Partial data Cell line/GI ₅₀ (uM) MDA-MB435 NCI460 HCT116 HL60 COLO205 A549 BXPC3 HELA MCF-7

BSI-201 67.949 90.034 98.595 39.180 131.86 104.500 81.172 51.265 60.355

1-1 39.930 - 84.733 15.294 58.838 - - 100.264 79.824

1-2 32.485 17.497 85.022 7.826 28.884 8.137 55.287 18.995 52.365

1-3 ND - - - - - 140.980 - -

1-4 46.743 - - - - - ND - -

1-5 - - 203.852 171.046 - - - - -

1-6 - - 218.589 ND - - - - -

1-7 - - - ND - - - - -

1-8 - - ND 201.853 - - - - -

1-9 - - - 227.28 - - - - -

1-10 37.452 75.107 50.084 21.700 61.129 81.570 52.042 43.136 51.833

1-11 54.129 21.065 55.245 26.698 86.138 6.910 77.244 36.785 81.999

1-12 - - 177.565 96.700 - - - - -

1-13 50.568 - - - - - - 70.758 123.168

1-14 103.691 - - - - - - 113.879 166.451

1-15 - 86.584 - 63.067 - - - - 92.866

1-16 57.431 - - - - - 59.544 103.581

1-17 - 208.4 - 206.787 - - - - 153.200

1-18 64.659 151.178 76.779 12.335 33.634 72.782 47.390 32.629 13.308

1-19 23.201 46.169 52.207 - - - - 21.146 127.273

1-20 14.224 44.390 54.504 10.835 58.751 45.461 61.310 31.398 46.903

1-21 83.087 70.664 97.126 25.538 113.133 20.296 72.843 65.266 56.031

1-22 100.950 - - - - - - 104.527 158.651

1-23 24.483 81.382 - 36.794 - 82.404 - - 54.740 Cell line/GI ₅₀ (uM) MDA-MB435 NCI460 HCT116 HL60 COLO205 Α549 BXPC3 HELA MCF-7

1-24 - 99.951 - 32.300 - - - - 57.730

1-25 - 51.311 - - - - - - 94.433

1-26 - 189.06 - - - - - - 156.952

1-27 3.719 13.232 5.135 1.346 3.132 3.916 1.656 11.947 8.954

1-28 - - - 7.983 93.975 - - - -

1-29 8.490 22.747 13.335 2.676 9.580 25.385 4.169 8.215 8.560

1-30 14.518 10.953 10.325 3.764 1.240 2.294 12.002 4.993 22.000

1-31 2.137 ND - 8.397 - - ND - 32.234

1-32 2.565 11.167 10.430 5.379 2.559 3.512 3.080 5.329 6.619

1-33 3.539 27.187 11.654 12.458 2.089 2.764 3.305 6.219 6.637

1-34 7.352 20.103 4.665 7.446 8.238 4.112 7.808 18.040 7.952

1-35 - - 36.324 - - - - - -

1-36 4.023 10.208 2.670 4.840 4.801 5.511 4.876 19.690 6.222

1-37 23.906 43.577 26.353 47.027 33.071 46.235 42.161 129.851 35.165

1-38 - - - 34.087 ND - - - -

1-39 - - - 21.768 42.122 - - - -

1-40 21.528 55.342 25.245 39.015 24.693 ND 103.154 ND 60.780

1-41 - - - 9.583 32.002 - - - -

1-42 6.237 20.111 21.331 2.943 8.638 15.218 8.678 26.981 10.52

1-43 8.564 25.003 3.158 2.130 6.845 6.376 9.330 14.431 3.169

1-44 16.092 12.821 4.775 4.607 11.200 9.579 19.057 9.951 6.657

1-45 3.698 20.741 8.640 3.194 7.937 19.31 9.327 19.298 8.398

1-46 6.989 3.977 4.349 5.839 5.520 9.858 7.109 8.091 10.049

1-47 11.663 13.876 4.711 2.563 8.613 7.128 8.650 7.509 4.184

1-48 3.145 25.043 14.838 2.885 4.570 5.660 7.571 7.730 5.437

1-49 - - - - - - - 12.681 11.581

1-50 - - - - - - - 38.753 23.172

1-51 - - - - - - - 38.079 39.904

1-52 - 38.993 - - - - - 36.074 -

1-53 5.913 28.100 27.063 7.660 6.328 4.587 11.469 6.493

Explanation: (-) in Table 1 indicates that the activity was not tested; (ND) indicates that the compound was active, but the GI ₅ o value was not measured under the conditions of the test used.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that the above-described equivalents of the present invention are also intended to be within the scope of the appended claims.

Claims

Claim

A compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

(I) where

R ¹ , R ² and R ^{3 are} independently selected from the group consisting of hydrogen, substituted or unsubstituted (C _r C ₅ )alkyl, substituted or unsubstituted (c ₃ -c ₅ )alkenyl, substituted or unsubstituted Substituted (c ₃ -c ₅ )alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ¹ and R ² may also be cyclized to form a substituted or unsubstituted five, six or seven member Ring; R ² and R ³ may also be cyclized to form a substituted or unsubstituted tetra, five or seven-membered ring ^

R ⁴ is a nitro group or a nitroso group;

R ⁵ is iodine or ethynyl.

2. The compound according to claim 1, wherein RR ² and R ^{3 are} independently selected from hydrogen, substituted or unsubstituted (CH^)alkyl; and R ¹ and R ² may also be cyclized to form a substitution or not. a substituted five, six or seven membered ring; R ² and R ³ may also be cyclized to form a substituted or unsubstituted four, five, six or seven membered ring

3. The compound according to claim 2, wherein RR ² and R ^{3 are} independently selected from hydrogen, substituted or unsubstituted (dC ₅ )alkyl.

4. The compound of claim 3, wherein RR ² and R ^{3 are} independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or pentyl, preferably hydrogen, Methyl, ethyl, propyl or n-butyl.

The compound according to any one of claims 1 to 4, wherein R ⁴ is a nitro group.

The compound according to any one of claims 1 to 5, wherein R ⁵ is iodine.

The compound according to any one of claims 1 to 5, wherein R ⁵ is an ethynyl group.

Double bond (C ₃ -C ₅₎ alkenyl group women 8. The compound according to claim 1, wherein said substituted or unsubstituted, and a substituted or unsubstituted (C ₃ -C ₅₎ alkynyl The triple bond of the alkynyl group is not directly bonded to the N atom of the urea.

The compound according to claim 1, wherein the compound of the formula (I) is selected from the group consisting of: 1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea;

1-(4-iodo-3-nitrobenzoyl)urea;

1-(4-iodo-3-nitrobenzoyl)-3-mercaptourea;

1-(4-iodo-3-nitrobenzoyl)-3-ethylurea;

1-(4-iodo-3-nitrobenzoyl)-3-propylurea;

1-(4-iodo-3-nitrobenzoyl)-3-butylurea;

1-(4-iodo 3-nitrobenzoyl)-3-pentylurea;

1-(4-iodo-3-nitrobenzoyl)-3-isopropylurea;

1-(4-iodo-3-nitrobenzoyl)-3-isobutylurea;

1-(4-iodo-3-nitrobenzoyl)-3-methyl-3-ethylurea; 1-(4-indole-3-nitrobenzoyl)-1,3-dimethyl Urea

1-(4-indol-3-nitrobenzoyl)-3,3-diethylurea;

1-(4-iodo-3-nitrobenzoyl)-3,3-dipropylurea;

1-(4-iodo-3-nitrobenzoyl)-2-imidazolidinone;

1-(4-iodo-3-nitrobenzoyl)-3-methyl-2-imidazolidinone;

N-(4-iodo-3-nitrobenzoyl)pyrrolidine small formamide;

N-(4-iodo-3-nitrobenzoyl) small azacyclohexane-1-carboxamide;

1-(4-iodo-3-nitrobenzoyl)-1,3,3-trimethylurea;

1-(4-iodo-3-nitrobenzoyl)-1-ethyl-3,3-dimethylurea;

1-(4-iodo-3-nitrobenzoyl)-1-propyl-3,3-dimethylurea;

1-(4-iodo-3-nitrobenzoyl)-1-butyl-3,3-dimethylurea;

1-(4-iodo-3-nitrobenzoyl)-1-methyl-3,3-diethylurea;

1-(4-iodo-3-nitrobenzoyl)-1-methyl-3,3-dipropylurea; 1-(4-iodo-3-nitrobenzoyl)-1-ethyl-3,3-dipropylurea;

1-(4-iodo-3-nitrobenzoyl)-1,3,3-tripropylurea;

1-(4-iodo-3-nitrobenzoyl)-1-butyl-3,3-dipropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3,3-diethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3-pentylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3-methyl-3-ethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3,3-dipropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3,3-dibutylurea;

N-(4-ethynyl-3-nitrobenzoyl)pyrrolidine-1-ylcarboxamide;

N-(4-ethynyl-3-nitrobenzoyl) small azacyclohexane-1-carboxamide;

1-(4-ethynyl-3-nitrobenzoyl)-3,3-dimethylurea;

1-(4-ethynyl-3-nitrobenzoyl)urea;

1-(4-ethynyl-3-nitrobenzoyl)-3-mercaptourea;

1-(4-ethynyl-3-nitrobenzoyl)-3-ethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3-propylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3-butylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3-isopropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-3-isobutylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1,3-dimethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1,3,3-trimethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1-ethyl-3,3-dimethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1-propyl-3,3-dimercaptourea;

1-(4-ethynyl-3-nitrobenzoyl)-1-butyl-3,3-dimethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1-methyl-3,3-diethylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1-methyl-3,3-dipropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1-ethyl-3,3-dipropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1,3,3-tripropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-1-butyl-3,3-dipropylurea;

1-(4-ethynyl-3-nitrobenzoyl)-2-imidazolidinone; 1-(4-ethynyl-3-nitrobenzoyl)-3-methyl-2-imidazolidinone.

10. A process for the preparation of a compound of formula (I) according to claim 1, which comprises: reacting a compound of formula II with urea of formula VII to give:

Wherein RR ² , R ³ are hydrogen, substituted or unsubstituted (C _r C ₅ ) alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or unsubstituted (C ₃ -C ₅ Alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ¹ and R ² may also be cyclized to form a substituted or unsubstituted five, six or seven membered ring; R ² and R ³ are also It may be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring, R ⁴ is a nitro group, and R ⁵ is iodine.

11. A process for the preparation of a compound of formula (I) according to claim 1, which comprises: reacting a compound of formula III with:

Ffl wherein, R ² , R ³ are hydrogen, substituted or unsubstituted (CC ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or unsubstituted (C ₃ -C ₅ ) Alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ² and R ³ may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring, and R ¹ is substituted or Unsubstituted (dC ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or unsubstituted (C ₃ -C ₅ ) alkynyl, substituted or unsubstituted (C ₃ -C ₅ ) cycloalkyl, R ⁴ Is a nitro group, R ⁵ is iodine, and X is a halogen.

12. A process for the preparation of a compound of formula (I) according to claim 1, which comprises: reacting a compound of formula IV with an amine of formula VIII to give:

Wherein R ² , R ³ are hydrogen, substituted or unsubstituted (CC ₅ ) alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or unsubstituted (C ₃ -C ₅ ) alkyne a substituted, unsubstituted or unsubstituted (C ₃ -C ₅ ) cycloalkyl group; R ² and R ³ may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring, R ¹ being hydrogen, R ⁴ is a nitro group and R ⁵ is an ethynyl group.

13. A process for the preparation of a compound of formula (I) according to claim 1, the process comprising: desiliconizing a compound of formula V to give:

Wherein RR ² , R ³ are hydrogen, substituted or unsubstituted (dC ₅ )alkyl, substituted or unsubstituted (C ₃ -C ₅ )alkenyl, substituted or unsubstituted (C ₃ -C ₅ ) Alkynyl, substituted or unsubstituted (C ₃ -C ₅ )cycloalkyl; R ¹ and R ² may also be cyclized to form a substituted or unsubstituted five, six or seven membered ring; R ² and R ³ may also be The cyclization forms a substituted or unsubstituted tetra, five, six or seven membered ring, R ⁴ is a fluorenyl group, and R ⁵ is an ethynyl group.

14. A pharmaceutical composition comprising an effective amount of any one of claims 1-9 A compound of formula (I) or a pharmaceutically acceptable salt thereof or a prodrug thereof.

15. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a disease associated with a poly(ADP-ribose) polymerase (PARP) inhibitor.

16. The use according to claim 15, wherein the disease associated with a poly(ADP-ribose) polymerase (PARP) inhibitor is selected from the group consisting of cancer, stroke, myocardial infarction, neurodegenerative disease.

17. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of cancer.

18. The use according to claim 17, wherein the cancer comprises colon cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, acute leukemia, chronic leukemia, prostate cancer, human uterine cancer, pancreatic cancer, liver cancer, brain cancer, CNS tumors, bladder cancer, kidney cancer, skin cancer, cervical cancer, muscle tumors, lymphoma, bone cancer, and other types of cancer.