WO2010139090A1

WO2010139090A1 - N-phenyl dichloroacetamide and their derivatives, preparation methods and uses theirof

Info

Publication number: WO2010139090A1
Application number: PCT/CN2009/000616
Authority: WO
Inventors: 成昌梅; 杨永冲; 常智杰; 陈哲生; 张峰; 王冬春; 陆爱军
Original assignee: 清华大学
Priority date: 2009-06-02
Filing date: 2009-06-02
Publication date: 2010-12-09

Abstract

N-Phenyl dichloroacetamide and their derivatives which belong to pharmaceutical chemistry and organic synthesis fields are provided. These compounds have the structures of general formula I, in which N-{3-chloro-4-[(trifluoromethyl)sulfonyl]phenyl}dichloroacetamide is preferred. The preparation methods of these compounds are also provided, which are easy to conduct. There is no need to use any catalyst in these methods. Additionally, the uses of these compounds in the preparation of anticancer drugs which have high-effective and low toxic anticancer activities are provided.

Description

N-phenyldichloroacetamide and derivatives thereof and preparation method and application thereof TECHNICAL FIELD The present invention belongs to the fields of medicinal chemistry and organic synthesis. Specifically, it relates to N-phenyldichloroacetamide and derivatives thereof, a process for their preparation, and their use in the preparation of antitumor drugs. Background technique

Cancer is the number one killer of human life. Although scientists have developed a variety of weapons to fight cancer, cancer still devours human life. In China, the number of people dying from cancer is 1.4 million to 1.5 million a year, and this number is on the rise. Humanity has not yet achieved a decisive victory in the protracted war of cancer. Therefore, trying new methods and developing new drugs is a significant and urgent issue. Inducing the apoptosis of cancer cells by regulating the metabolic pathway of mitochondria is a promising new research direction for anticancer drugs.

In cell energy metabolism, glucose metabolism is the most important metabolism, which includes two pathways of glycolysis and oxidative phosphorylation. Glucose is hydrolyzed to produce pyruvate, which is irreversibly oxidatively decarboxylated by pyruvate dehydrogenase (PDH) to form acetyl-CoA, which then enters the Krebs cycle, thereby initiating the metabolic pathway of mitochondrial oxidative phosphorylation. In this process, the activity of pyruvate dehydrogenase is regulated by reversible phosphorylation of PDK (pyruvate dehydrogenase kinase), that is, PDK is acidified to inhibit PDH. In cancer cells or hypoxic cells, the metabolic pathway relies on inefficient glycolysis, that is, pyruvate is reversibly converted to lactic acid by lactate dehydrogenase to obtain energy.

An important feature of cancer cells different from normal cells is that they have different energy metabolism pathways. The energy metabolism pathway of normal cells is aerobic oxidation; while cancer cells are hypoxic, so it relies on glycolysis to obtain energy (Gatenby RA, And Gillies RJ, Nat. Rev. Cancer, 2004, 4, 891-899). That is, cancer cells rely on glycolysis to gain energy, even in the presence of aerobic conditions. This is the famous Warburg effect (Warburg 0, 1930, London: Constable:). Moreover, he believes that this is the result of mitochondrial dysfunction (glycolysis), rather than what is often said, cell cancer leading to mitochondrial dysfunction.

Studies have shown that mitochondria are also important organelles for performing apoptosis, which is closely related to apoptosis. There are many substances related to apoptosis in mitochondria, such as reactive oxygen species, cytochrome c (CytC), apoptosis-inducing factor. (AIF), restriction endonuclease G CEndoG), etc. Mitochondria increase mitochondrial membrane permeability, decrease membrane potential, and release apoptotic factors such as CytC, AIF, EndoG from mitochondria to cytoplasm after receiving apoptosis signals. Mitochondria release into the cytoplasm and form Apoptotic Complex with Apaf-1, Caspase-9 zymogen, and activate Caspase-9, then activate downstream The Caspase cascade, which ultimately produces activated Caspase-3, leads to apoptosis; AIF and EndoG are released from the mitochondria and enter the nucleus via the cytoplasm, cleavage of the DNA, leading to apoptosis.

The above information shows that pyruvate dehydrogenase plays a very important role in energy metabolism and the Krebs cycle, while pyruvate dehydrogenase is indirectly related to apoptosis. Inhibition of PDK activation of PDH not only converts metabolic pathways that rely on glycolytic energy to oxidative phosphorylation, but also activates mitochondrial apoptotic pathways.

In cancer cells, mitochondria have serious defects and cannot work normally. Therefore, they can only rely on the pathway of glycolysis to obtain energy. In addition, the permeability of mitochondrial membrane in cancer cells is not high, and the high membrane potential causes the withering in the membrane gap. Apoptotic factors such as death-inducing factor (AIF) and cytochrome C cannot be released normally. Therefore, the endogenous apoptotic pathway is that the apoptosis of the mitochondrial pathway is blocked, which increases the apoptosis resistance of cancer cells, that is, the cancer cells are "Not dead" state. Therefore, inhibition of PDK, activation of PDH, initiation of the tricarboxylic acid cycle, restart of mitochondria work, reduction of membrane potential, increase of mitochondrial membrane permeability, enabling release of apoptosis-inducing factor (AIF), cytochrome C and other apoptotic factors, Activate the apoptotic program of the mitochondrial pathway. Therefore, activation of PDH by inhibition of PDK, increase of oxidative decarboxylation of pyruvate to produce acetyl-CoA, reactivation of mitochondria, and initiation of the mitochondrial pathway of apoptosis have become hot topics. In this process, inhibition of PDK activates PDH, which converts the metabolic pathway of cancer cells from glycolysis to oxidative phosphorylation. This initiates the metabolic pathway of mitochondria. When the mitochondria are activated, the normal apoptosis process of the cells is initiated, the apoptosis resistance of the cancer cells is greatly reduced, and the cancer cells "not dead" will cease to exist.

Sodium dichloroacetate (DCA) is a classic PDK inhibitor (Masato Kato, Jun Li, Structure, 2007, 15, 992-1004), commonly used to treat mitochondrial diseases such as lactic acidosis. Recently, the University of Alberta, Canada reported that DCA can induce cancer cell apoptosis without significant side effects (Bonnet et al, Cancer Cell, 2007, 11, 37-51). The main mechanism is that DCA inhibits PDK, activates PDH, increases the amount of pyruvic acid entering the mitochondria, and generates a large amount of acetyl-CoA (the substrate of the tricarboxylic acid cycle) to initiate the tricarboxylic acid cycle. A large amount of electrons are released on the electron transport chain (ETC), and the combination of electrons and oxygen produces reactive oxygen species (ROS) and a decrease in the mitochondrial membrane potential. Mitochondrial function begins to normalize, Kv ion channel expression increases, voltage and redox-sensitive mitochondrial transition pores (ΜΤΡ) open, and some pro-apoptotic mediators such as cytochrome C, apoptosis-inducing factor AIF are released In the cytoplasm, cancer cell apoptosis is irreversible.

However, DCA also has obvious problems: The anticancer activity is not high enough (IC ₅ o is on the order of lmmol/L), and the dosage is very large (25-100 mg/kg) (PW Stacpoole, GW Moore and DM Kornhauser, Negl. J. Med. , 1978, 298, 526-530; G W. Moore, LI Swift, D. Rabinowitz, OB CrofFord, J. A Oates and PW Stacpoole, Arherosclerosis, 1979, 33, 285-293; PW Stacpoole, GW Barnes, MD Hurbanis , SL Cannon and DS Kerr, a review, Arch. Dis. Child), In addition, DCA cannot be used for a long time because of its toxicity. The organs of DCA toxicity are mainly (PW Stacpoole et al, Drug metabolism reviews, 1998, 30(3), 499-539): liver, Kidney, nervous system, testicles, eyes.

Summary of the invention

A first object of the present invention is to overcome the disadvantages of the prior art and to provide N-phenyldichloroacetamide and derivatives which enhance anticancer activity. '

A second object of the present invention is to provide a process for producing the above N-phenyldichloroacetamide and derivatives.

A third object of the present invention is to provide the use of the above N-phenyldichloroacetamide and derivatives and pharmaceutically acceptable salts thereof for the preparation of an antitumor medicament.

N-phenyldichloroacetamide and derivatives having the structure of formula I:

HCI

Formula I

Wherein the groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ have the following meanings:

R ¹ is -H, -OH, -SH, -F, -CI, -Br, -I, -CN, -CHO, -COOH, -OCHO, -N0 ₂ , -NO, -N ₃ , -NH ₂ , -NH-NH ₂ , -S0 ₃ H, -SOCH3, -SOCF3, -S0 ₂ CH ₃ , -S0 ₂ CF _3> -CF ₃ , S0 ₃ F _; decyl, alkenyl, alkynyl group of dC ₆ ; 3⁄4 ₈ fluorenyl, cycloalkenyl, cycloalkynyl; ^-^ alkyl, haloalkenyl, haloalkynyl; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl One of the groups;

Or R ¹ is -OR, wherein R is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; a hydroxy-substituted C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, Cycloalkynyl; hydroxy-substituted C ₃ -C ₈ _3⁄4 cycloalkyl, cycloalkenyl, ring block;

Or R ¹ is -NR'R", wherein R', R" are the same or different and are one of the following groups, alkyl, alkenyl, alkynyl of C _r C ₆ ; amino substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; amino-substituted C ₃ -C ₈ halo ring, cycloalkenyl, cycloalkynyl;

Or R ¹ is -SR ', wherein, R' is one of the following radicals, C _r C alkyl with ₆ alkenyl group, alkynyl group; a mercapto group substituted by a C ₃ -C ₈ cycloalkyl group embankment, cycloolefin Base, cycloalkynyl; fluorenyl substituted C ₃ -C ₈ -free cycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the groups described below, a methylthio-substituted indenyl, alkenyl, alkynyl group; a methylthio-substituted 3⁄4-3⁄4 cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; Thio-substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the groups described below, a CN substituted dC ₆ fluorenyl, alkenyl, alkynyl group; a cyano substituted C ₃ -C ₈ cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group; Cyano substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is -ArR, wherein R is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; aryl ring-substituted c ₃ -c ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl; or R ¹ is -COOR', wherein R' is one of the following groups, -C ₆ alkyl, alkenyl, alkynyl; -COOH substituted 3⁄4-3⁄4 cyclodecyl, cycloalkenyl, cycloalkynyl; -COOH substituted C ₃ -C ₈ ^-cycloalkyl, cycloalkenyl, cycloalkynyl; or R ¹ is -COR', wherein R' is one of the following groups, a decyl, alkenyl, alkynyl group of dC ₆ -OCOH substituted 3⁄4 ₈ cyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, 0 = substituted fluorenyl, alkenyl, alkynyl group of QC ₆ ; 0 = substituted -3⁄4 cycloalkyl, cycloalkenyl, cycloalkynyl; 0 = substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, S = substituted -C ₆ . fluorenyl, alkenyl, alkynyl; S = substituted C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkyne S = substituted C ₃ -C ₈ -cyclocyclic fluorenyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -N _{2 2} substituted -C ₆ alkyl, alkenyl, alkynyl; -N _{2 2} substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, ring Alkynyl; -N0 ₂ substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -NO substituted dC ₆ fluorenyl, fluorenyl, alkynyl; -NO substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; -NO substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -N ₃ substituted C _r C ₆ fluorenyl, alkenyl, alkynyl; -N ₃ substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, Cycloalkynyl; -N ₃ substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -S0 ₃ H substituted dC ₆ alkyl, alkenyl, alkynyl; -S0 ₃ H substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, Cycloalkynyl; -S0 ₃ H substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -S0 ₃ F substituted C _r C ₆ fluorenyl, alkenyl, alkynyl; -S0 ₃ F substituted C ₃ -C ₈ cyclodecyl, cycloalkenene a cycloalkynyl group; -S0 ₃ F substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is -NH-NHR', wherein R' is one of the following groups, -alkyl, alkenyl, alkynyl; cyclodecyl, cycloalkenyl, cycloalkynyl; halo ring Mercapto, cycloalkenyl, cycloalkynyl

Or R ¹ is ^one of the following groups, alkyl, alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkynyl; C ₃ -C ₈ halo -S-, -SS-, -0-, -NH -, -NH-NH-, -N=N-, -CH= are inserted between any CC bond in a cycloalkenyl group, a cycloalkenyl group. N-, -PH-, - (C = 0) -, - (S = 0) -, - S0 2 -, - (PH = 0) -, - (C = 0) NH-, -S-NH- , -N = CH-NH-, -N = CH-0-, -N = CH-S-, -NH (C = 0) -, -S0 2 NH -, -NHS0 2 -, - (PH = 0 ) NH-, -NH (PH = 0 ) -, - (C = 0) NHNH-, -NHNH (C = 0) -, -S0 2 NHNH-, -NHNHS0 2 -, - (PH = 0) NHNH- , -NHNH (PH=0)-, -(C=0)0-, -0(C=0)-, -0(C=0)0-, -S0 ₂ -0-, -0-S0 ₂ -, -(S=0)-0-, -0( S=0)-, -(PH=0)-0-, -0-(PH=0)-,-0-(PH=0)0 - the group;

Or R ¹ is

among them,

X is one of the following groups, -S -, -SS-, -0-, -NH-, -NH-NH-, -N=N-, -CH=N -, -PH-, - _{CO-, -SO-, -S0 2 -,} -PH (= 0) -, - (C = 0) NH-, -NH (C = 0) -, -S0 2 NH -, -NHS0 2 -, - S0NH-, -NHS0-, -(PH=0)NH -, -NH(PH=0)-, -(C=0)NHNH-, -NHNH (C=0)-, -S0 ₂ NHNH-, - NHNHS0 ₂ -, -S0NHNH-, -NHNHS0-, -(PH=0)NHNH -, -NHNH(PH=0)-, -(C=0)0-, -0(C=0)-, -0 (C=0)0-, -S0 ₂ -0-, - 0-S0 ₂ -, -(S=0)-0-, -0(S=0)-, -(PH=0)-0- , -0-(PH=0)-, -0-(PH=0)0-, -S-NH-, -N=CH-NH -, -N=CH-0-, -N=CH-S -, Ct- fluorenyl, alkenyl, alkynyl; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; -C6 haloalkyl, haloalkenyl, haloalkynyl; C _3- C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl; hydroxy, amino, fluorenyl, cyano, aryl-substituted alkyl, alkenyl, alkynyl; hydroxy, amino, decyl, cyano, Aromatic ring-substituted C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkynyl; hydroxy, amino, fluorenyl substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

R ⁶ is one of the following groups, - anthracenyl, alkenyl, alkynyl; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; -C6 halogenated fluorenyl, halogenated Alkenyl, haloalkynyl;

Or R ⁶ is one of the following groups, an alkyl group at -C ₆ , an alkenyl group, an alkynyl group; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; -S-, - SS-, -0-, -NH-, -NH-NH-, -Ν=Ν-, -CH=N between any CC bond in a haloalkenyl group or a haloalkynyl group -, -PH -, -(C=0)-, - (S=0) -, -S0 ₂ -, -(PH=0)-, -(C=0)NH-, -S-NH-, -N = CH-NH-, -N = CH-0-, -N = CH-S -, -NH (C = 0) -, -S0 2 NH -, -NHS0 2 -, - (PH = 0) NH- , -NH(PH=0)-, -(C=0)NHNH -, -NHNH (C=0)-, -S0 ₂ NHNH -, -NHNHS0 ₂ -, -(PH=0)NHNH -, -NHNH (PH=0)-, -(C=0)0-, -0(C=0)-, -0(C=0)0-, -S0 ₂ -0-, - 0-S0 ₂ - , -(S=0)-0-, - 0( S=0)-, -(PH=0)-0-, -0-(PH=0)-,-0-(PH=0)0- Group

Or R ⁶ is one of the following groups, -H, -OH, -SH, -F, -CI, -Br, -1, -CN, -CHO, -COOH, -OCHO, -N0 ₂ , -NO, -N ₃ , -NH ₂ , -NH-NH ₂ , -S0 ₃ H, -SOCH ₃ , -SOCF ₃ , -S0 ₂ CH ₃ , -S0 ₂ CF ₃ , -CF ₃ , S0 ₃ F, -S-NH-, -N=CH-NH -, -N=CH-0-, -N=CH-S- _;

Or R ⁶ is OR', wherein R' is one of the following groups, - anthracenyl, alkenyl, block; hydroxy-substituted C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkyne a hydroxy-substituted C ₃ -C ₈ halocycloalkyl group, a cycloalkenyl group, a cycloalkynyl group;

Or R ⁶ is NR'R", wherein R' and R" are the same or different and are one of the following groups, a sulfhydryl group, Alkenyl, alkynyl; amino-substituted-3⁄4 cycloalkyl, cycloalkenyl, cycloalkynyl; amino-substituted c ₃ -c ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ⁶ is SR, wherein R is one of the following groups, an alkyl group, an alkenyl group, an alkynyl group of dC ₆ ; ₃ -cyclodecyl, cycloalkenyl, cycloalkynyl; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or is COOR ,, wherein R ^6, R 'is one of the following radicals, C _r C alkyl group, alkenyl group, alkynyl group of _6; C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkynyl group; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ⁶ is COR, wherein R is one of the following groups, an alkyl group, an alkenyl group, an alkynyl group of QC ₆ ; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ⁶ is -NH-NHR', wherein R' is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a ring Alkynyl; C ₃ -C ₈ -alkylcycloalkyl, cycloalkenyl, cycloalkynyl;

R ⁷ , R ⁸ , R ⁹ , and R ^{1Q are the} same or different, and are each one selected from the group defined by R ⁶ ;

Or R ¹ is a Y- ^R ",

Wherein Y is one of the following groups, -S -, -SS-, -0-, -NH-, -NH-NH-, -N=N-, -CH=N -, -PH - _{, -CO-, -SO-, -S0 2 -} , -PH (= 0) -, - (C = 0) NH-, -NH (C = 0) -, -S0 2 NH-, -NHS0 2 - , - (PH = 0) NH- , -NH (PH = 0) -, - (C = 0) NHNH-, -NHNH (C = 0) -, -S0 2 NHNH-, -NHNHS0 2 -, - ( ΡΗ=0)ΝΗΝΗ-, -NHNH (PH=0)-, -(C=0)0-, -0(C=0)-, -0(C=0)0-, -S0 ₂ -0- , -0-S0 ₂ -, -(S=0)-0-, - 0( S=0)-, -(PH=0)-0-, -0-(PH=0)-, -0- (PH=0)0-, -S-NH-, -N=CH-NH-, -N=CH-0-, -N=CH-S- _;

R ¹¹ is one of the following radicals, C _r C ₆ alkyl with, alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl group Huan, cycloalkenyl, cycloalkynyl; dC halogenated alkyl with ₆ , haloalkenyl, haloalkynyl; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹¹ is one of the following groups in ^ 'alkyl group, alkenyl group, alkynyl group of _6; C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkynyl; halogenated alkyl with C , halo-drying group, haloalkynyl group; C ₃ -C ₈ halocycloalkyl group, cycloalkenyl group, cyclo-alkynyl group inserted between any CC bond -S-, -SS-, -0-, -NH -, -NH-NH-, -N=N -, -CH=N-, -PH -, -(C=0)-, -

(S=0) -, -S0 ₂ -, -(PH=0)-, -(C=0)NH -, -S-NH-, -N=CH-NH -, -N=CH-0- , -N=CH-S -, -NH(C=0)-, -SO2NH-, -NHSO2-, -(PH=0)NH -, -NH(PH=0)-, -(C=0) NHNH -, -NHNH (CO) - , -S0 2 NHNH-, -NHNHS0 2 -, - (PH = 0) NHNH-, -NHNH (PH = 0) -, - (C = 0) 0-, -0 (C=0)-, -0(C=0)0-, -SO2-O-, -O-SO2-, -(S=0)-0-, - 0(S=0)', -( PH=0)-0-, -0-(PH=0)-, -0-(PII=0)0- group;

The ^{^{^{R 2, R 3, R 4}}} , R 5 are the same or different from R ^1, R ¹ is optionally from one of the groups defined.

The compounds preferably R ¹ or R ⁵ is -H, -F, -CI, -Br, -I, -CN, -NH 2, -N0 2, dC alkyl with ₆ One of an alkenyl group; an alkynyl group;

R ² or R ⁴ is -H, -F, -Cl, -Br, -I , -N0 ₂ , - CN, -CF ₃ , -CF ₂ CF ₃ , -SCF ₃ , -SCF ₂ CF ₃ , - S0 ₂ F, -S0 ₂ CF ₃ , -S0 ₂ CF ₂ CF ₃ , -OCF3 , -OCF ₂ CF ₃ , an alkyl group, an alkenyl group, an alkynyl group;

R ³ is -H, -F, -CI, -Br, -I , -N0 ₂ , -CN, -CF ₃ , -CF ₂ CF ₃ , -SCF ₃ , -SCF ₂ CF ₃ , - S0 ₂ F, _{_{_{-S0 2 CF 3, -S0 2 CF}}} 2 CF 3, -0CF 3, -OCF 2 CF 3, -C ₆ alkyl group, alkenyl group, alkynyl group of one;

Or R ³ is ^{^{-S- R 12, -S0- R 12,}} -S0 2 - R 12, -0-R 12, -0 (C = 0) -R 12, - (C = 0) 0- R 12 One of them. The R ¹² is _{_{_{CF 3, CF 2 CF 3,}}} C r C ₆ alkyl with, alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl group embankment, cycloalkenyl, cycloalkynyl; dC halogenated embankment ₆ of a one of a C ₃ -C ₈ halocyclodecyl group, a cycloalkenyl group, a cycloalkynyl group.

The fluorenyl, alkenyl, alkynyl group of C _r C ₆ may be a straight or a branched chain.

The compound is further preferably N-(4-methyl-phenyl)dichloroacetamide, N-(3-methyl-phenyl)dichloroacetamide, N-(4-chloro-phenyl)dichloro Acetamide, N-(3-chloro-phenyl)dichloroacetamide, N-(3-chloro-4-fluoro-phenyl)dichloroacetamide, N-(3,5-dichloro-phenyl) Dichloroacetamide, N-(2,5-dichloro-phenyl)dichloroacetamide, N-(2,3-dichloro-phenyl)dichloroacetamide, N-(2-methyl-5 -Chloro-phenyl) Dichloroacetamide, N-(3-chloro-4-methyl-phenyl)dichloroacetamide, N-(2,4,5-trichloro-phenyl)dichloroacetamide , N-(3,4-dichloro-phenyl)dichloroacetamide, N-(2-fluoro-5-chloro-phenyl)dichloroacetamide, N-(4-bromo-phenyl)dichloride Acetamide, N-(4-iodo-phenyl) dichloroacetamide, N-

(4-methoxy-phenyl) dichloroacetamide, N-(3-chloro-4-bromo-phenyl)dichloroacetamide, N-(3-chloro-4-ethoxycarbonyl-phenyl) Dichloroacetamide, N-(3-chloro-4-iodo-phenyl)dichloroacetamide, N-(3-bromo-phenyl)dichloroacetamide, N-(3-iodo-phenyl) Chloroacetamide, N-(3-ethynyl-phenyl)dichloroacetamide, N-(3-cyano-phenyl)dichloroacetamide, N-(3-methoxy-phenyl) dichloride Acetamide, N-(2-methyl-4-fluoro-5-bromo-phenyl)dichloroacetamide, N-(3-trifluoromethyl-phenyl)dichloroacetamide, N- (3- Trifluoromethylthio-phenyl) Dichloroacetamide, N-(4-trifluoromethylthio-phenyl)dichloroacetamide, N-(3-trifluoromethyl-4-nitro-phenyl Dichloroacetamide, N-(3-trifluoromethoxy-phenyl)dichloroacetamide, N-(3-chloro-4-trifluoromethylthio-phenyl)dichloroacetamide, N- (2-bromo-4-trifluoromethylthio-phenyl)dichloroacetamide, N-(2,6-dibromo-4-trifluoromethylthio-phenyl)dichloroacetamide, N- ( 2-iodo-4-trifluoromethylthio-phenyl)dichloroacetamide, N-(2,6-diiodo-4-trifluoromethylthio-phenyl) Dichloroacetamide, N-(3-chloro-4-nitro-phenyl)dichloroacetamide, N-

(3-chloro-4-trifluoromethanesulfonyl-phenyl) dichloroacetamide, N-(4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(3-trifluoromethanesulfonyl -phenyl)dichloroacetamide, N-(2-bromo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(2,6-dibromo-4-trifluoromethanesulfonyl- Phenyl) dichloroacetamide, N-(2-iodo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(3-chloro-5-indolyl-phenyl)dichloroacetamide, N-(3-chloro-5-iodo-phenyl)dichloroacetamide, N-(3,5-dibromo-phenyl)dichloroacetamide, N-(3-bromo-5-iodo-phenyl Dichloroacetamide or N-(3,5-diiodo-phenyl)dichloroacetamide.

Most preferably, the compound is N-(3-chloro-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide. The preparation method of N-phenyldichloroacetamide and derivatives is as follows:

Dissolving aniline or its derivative and dichloroacetyl chloride in a toluene solution, wherein the molar ratio of aniline or its derivative to dichloroacetyl chloride is 1: 1-2.6, at room temperature, dichloroacetyl chloride solution After adding to the aniline or its derivative solution, the temperature is raised to reflux, wherein the reaction temperature is 90-120 ° C for 1-5 hours, and then the solvent toluene, unreacted dichloroacetyl chloride and hydrochloric acid are removed by rotary distillation under reduced pressure. The gas gives the target compound.

After the above-mentioned decompression steaming, the following steps are further included: adding to the compound to dissolve the solution, adding an equal amount of saturated brine, extracting, removing the water layer, and sequentially washing with a saturated sodium hydrogen carbonate solution; -3 times, washed with saturated brine for 2-5 times, and finally dried over anhydrous sodium sulfate overnight, filtered and evaporated to give the title compound.

For the preparation of a compound in which R ¹ , R ² , R ³ , R ⁴ or R ⁵ is -S0 ₂ CF ₃ or -S0 ₂ CF ₂ CF ₃ , the corresponding compound synthesized by the above method, that is, R ¹ , R ² , R ³ , R ⁴ or R ⁵ is SCF ₃ or -SCF ₂ CF ₃ . As a raw material, it is synthesized by oxidation of hydrogen peroxide.

The preparation of a compound in which R ¹ , ² , R ³ , R ⁴ or R ⁵ is -N0 ₂ can be synthesized by a nitration reaction.

The pharmaceutically acceptable salt of the N-phenyldichloroacetamide and the derivative means a pharmaceutically acceptable salt, for example, a salt formed with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, or with citric acid or succinic acid. a salt formed from an organic acid such as tartaric acid or methanesulfonic acid.

The use of the N-phenyldichloroacetamide and derivatives thereof and pharmaceutically acceptable salts thereof for the preparation of anticancer drugs.

Advantageous Effects of Invention The N-phenyldichloroacetamide compound has high-efficiency and low-toxic anticancer activity, and the synthesis process is simple, and it is not necessary to add any catalyst.

detailed description

Examples 1-23 The preparation of the compounds of the invention.

Example 1 Synthesis of N-phenyldichloroacetamide

Into a 50 ml two-neck round bottom flask was placed 20 ml of dry toluene, 0.487 g (5.2 mmol) of aniline. 5 ml of dry toluene and 0.992 g (6.8 mmol, 1.3 eqv) of dichloroacetyl chloride were added to a constant pressure dropping funnel, and the two round bottom flasks were slowly dropped at room temperature, and the temperature was raised to reflux, and the reaction temperature was 110-115 O. hour. The reaction was completely detected by TLC, and solvent toluene, hydrogen chloride and unreacted dichloroacetyl chloride were evaporated under reduced pressure to give a white powder of 1.062 g. The yield was 99%.

Table 1 provides a part of the compound synthesized by the method of Example 1 and its raw materials, and the yields were all above 96%.

Table 1 Some compounds synthesized by the method of Example 1

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9T9000/600ZN3/X3d 0606 bacteria 0Ζ OAV 40 N- (3, 3,5-two 0.079 110-115 1 'HNMRpOOMHz'CDC ) 5-dibromo-bromo-benzene 88.11 (s, lH), 7.72 (s, 2H), 7.5 phenyl) amine 0 ( s, lH), 6.03 (s, lH).

Dichloroethane

0.064

Amide ~ - 3⁄4 B

Acyl chloride

0.049

41 N-( 3-NHCOCHCI ₂ 3-Mo-5- 0.075 110-115 1 'HNMRpOOMHz'CDC ) Bromo-5-iodoiodo-benzene δ 8.03 (s, 1H), 7.87 (t, J = -phenyl) Amine 0.05 1.7, lH), 7.79 (t, J = 1.7, lH), 7

~ -Wind B Dichloroethane .69 ( =1.7,lH), 6.02 (s,lH) Amide Acyl Chloride

0.033

42 N- (3, NHCOCHCI ₂ 3,5- 2 0.050 110-115 1 'HNMRiSOOMHz.CDCb) 5-diiodo-indole iodine-benzene 57.99 (s, lH), 7.92 (d^l.4, phenyl) Amine 2H), 7.89 (d^l.4, lH), 6.01

~ - Qi B 0.038 (s, lH).

Amide

Acyl chloride

0.022

Starting materials of the compound 38-42 of the present invention 3-chloro-5-bromo-aniline, 3-chloro-5-iodo-aniline, 3,5-dibromo-aniline, 3-bromo-5-iodo-aniline and 3,5 -Diiodo-aniline reference synthesis (Stephanie H. Chanteau and James M. Tour., J. Org. Chem., 2003, 68 (23): 8750-8766; Gerd-Jan ten Brink. et al. Tetrahedron, 2002 , 58: 3977-3983 ).

Example 2 Synthesis of N-(2-chloro-4-ethoxycarbonyl-phenyl)dichloroacetamide (Compound 43)

The synthetic reaction formula is as follows:

' Compound 43

The steps are as follows:

Add 9 ml of dry ethanol to a 25 mL round bottom flask, cool to -10 ° C in an ice salt bath, slowly add 2.4 ml of SOCl ₂ , control the temperature below zero during the addition, and then add 0.516 g of 3-chloro-4-amino-benzene. Formic acid (3 mmol), after half an hour, the ice salt bath was removed. After the temperature was raised to room temperature, the mixture was heated to 50 ° C, and reacted for 20 hours. Ethanol and hydrogen chloride gas were evaporated under reduced pressure to give 2-chloro-4-ethoxycarbonyl-aniline salt. The acid salt was 0.675 g, and the yield was 95%.

Using the 2-chloro-4-ethoxycarbonyl-aniline hydrochloride obtained by the above method, the target product compound 43, 2-chloro-4-ethoxycarbonyl-aniline salt of the present example was synthesized by the synthesis method of Example 1. The amount of acid salt and dichloroacetyl chloride added are 0.144 g, 0.117 g, reaction temperature 110-120'C, reaction time 2 h, product 0.186 g, yield 98%.

NMR NMR (300 MHz, DMSO-D ₆ ) δ 10.43 (s, 1 Η), 8.02 (s, 1H), 7.95 (s, 2H), 6.89 (s, 1H), 4.32 (q, J = 7.1, 2H) , 1.32 (t, J= 7.1, 3H).

Example 3 Synthesis of N-(2-chloro-4-isopropyloxycarbonyl-phenyl)dichloroacetamide (Compound 44)

Compound 44

60 ml of dry isopropanol was added to a 100 ml round bottom flask, cooled to -10 ° C in an ice salt bath, and 12 ml of SOCl ₂ was slowly added dropwise. The temperature was controlled below zero during the dropwise addition, and then 5.16 g of 3-chloro-4-amino group was added. Benzoic acid (30mm _O l), remove the ice salt bath after half an hour, after the temperature is raised to room temperature, heat to 82 ° C reflux, the reaction is 36 hours, distill off the isopropanol and hydrogen chloride gas to obtain 2-chloro-4- Isopropoxycarbonyl-aniline hydrochloride 7.20 g, yield 96%.

Using the 2-chloro-4-isopropoxycarbonyl-aniline hydrochloride obtained by the above method, the target compound 44, 2-chloro-4-isopropoxycarbonyl- of the present example was synthesized by the synthesis method of Example 1. The addition amounts of aniline hydrochloride and dichloroacetyl chloride were 0.531 g and 0.407 g, respectively, and the reaction temperature was 110-120 ° C, and the reaction time was 2 h to obtain 0.678 g of a product, and the yield was 98%.

NMR NMR (300 MHz, DMSO-D ₆ ) δ 10.44 (s, 1H), 8.01 (s, 1H), 7.94 (s, 2H), 6.89 (s, 1H), 5.14 (dt, J = 12.5, 6.2, 1H), 1.32 (d, J= 6.2, 6H).

Example 4 Synthesis of N-(3-chloro-4-ethoxycarbonyl-phenyl)dichloroacetamide (Compound 45)

Compound 45

The preparation method of N-(3-chloro-4-ethoxycarbonyl-phenyl)dichloroacetamide is the same as that of the second embodiment. The starting material for synthesizing the compound is 3-chloro-4carboxy-aniline, which is obtained by ethylation. The product 3-chloro-4-ethoxycarbonyl-aniline hydrochloride is then reacted with dichloroacetyl chloride to give the final product N-(3-chloro-4-ethoxycarbonyl-phenyl)dichloroacetamide. 3-chloro-4-ethoxycarbonyl-aniline hydrochloride, dichloroacetyl chloride, the amount of addition was 0.322g, 0.261g, reaction temperature 110-120 ° C, reaction time 2h, the product was obtained 0.412 g, yield 97 %.

1H NMR (300 MHz, DMSO-D ₆ ) δ 11.08 (s, 1H), 7.89 (s, 1H), 7.88 (d, J = 8.6, 1H), 7.62 (dd, J = 8.6, 1.9, 1H), 6.61 (s, 1H), 4.30 (q, J= 7.1, 2H), 1.31 (t, J= 7.1, 3H). Example 5 Synthesis of N-(3-Trifluoromethyl-phenyl)dichloroacetamide (Compound 46)

CI

Compound 46

In a 50 ml two-neck round bottom flask, 20 ml of dry toluene, 0.984 g (6.1 mmol) of 3-CF ₃ -aniline were added, and 5 ml of dry toluene and 1.158 g (7.9 mmol, 1.3 eq.) of dichloroacetyl chloride were added to a constant pressure dropping funnel. The two round bottom flasks were slowly dropped at room temperature, and the temperature was raised to reflux, and the reaction temperature was 110-120 ° C for two hours. The reaction was completely detected by TLC, and solvent toluene and unreacted dichloroacetyl chloride were removed by rotary distillation under reduced pressure. The mixture was dissolved in 25 ml of dichloromethane, and 25 ml of water was added thereto, and the aqueous layer was removed, and then washed successively with a saturated sodium hydrogencarbonate solution and twice with saturated brine. Then, the residue was dried over anhydrous sodium sulfate and filtered, and then evaporated. The yield was 93%.

1H NMR (300 MHz, CDCL ₃ ) δ 8.31 (s, 1H), 7.85 (s, 1H), 7.77 (d, J = 7.6, 1H), 7.52 (d, J = 7.9, 1H) 7.47 (dd, J = 7.6, 7.9, 1H), 6.07 (s, 1H). ESI-MS: 271.3 (MH) - EXAMPLE 6 Synthesis of N-( 3-trifluoromethylthio-phenyl)dichloroacetamide (Compound 47)

I

Compound 47

The preparation method is the same as that in Example 5. The raw material for synthesizing the compound is 3-trifluoromethylthioaniline and dichloroacetyl chloride, and the addition amount is 0.340 g, 0.334 g, the reaction temperature is 110-120 ° C, and the reaction time is 2 h. The product was 0.494 g, and the yield was 92%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.19 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 7.7, 1H), 7.50 (d, J = 7.9, 1H), 7.46 (dd, J= 7.9, 7.7, 1H), 6.06 (s, 1H).

Example 7 Synthesis of N-(4-Trifluoromethylthio-phenyl)dichloroacetamide (Compound 48)

CHCI

Compound 48

The preparation method is the same as that in Example 5. The starting material for synthesizing the compound is 4-trifluoromethylthioaniline and dichloroacetyl chloride, and the addition amount is 0.470 g, 0.462 g, the reaction temperature is 110-120 ° C, and the reaction time is 2 h. The product was 0.688 g, and the yield was 93%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.21 (s, 1H), 7.66 (s, 4H), 6.07 (s, 1H)

Example 8 Synthesis of N-(3-Trifluoromethyl-4-nitro-phenyl)dichloroacetamide (Compound 49) CI.

Compound 49

The preparation method is the same as that in Example 5. The starting material for synthesizing the compound is 3-trifluoromethyl-4-nitro-aniline and dichloroacetyl chloride, and the addition amount is 0.192 g and 0.176 g, respectively, and the reaction temperature is 110-120 ° C. The reaction time was 2 h, and the product was obtained in 0.283 g, yield 96%.

_{1H NMR (300 MHz, CDC1 3} ) δ 8.46 (s, 1H), 8.04 (s, 3H), 6.09 (s, 1H) ESI-MS:. 339.1 (M + Na) + Example 9 N- (3- three Synthesis of fluoromethoxy-phenyl) dichloroacetamide (Compound 50)

Compound 50

The preparation method is the same as that in the same example 5. The raw materials for synthesizing the compound are 3-trifluoromethoxy-aniline and dichloroacetyl chloride, and the addition amounts are 0.797 g and 0.853 g, respectively, the reaction temperature is 110-120 ° C, and the reaction time is 2 h. The product was obtained in 1.220 g with a yield of 94%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.24 (s, 1H), 7.56 (s, 1H), 7.41 (t, J = 7.91, 2H), 7.37 (d, J = 7.91, 1H ), 7.09 (d, J = 7.57,1H), 6.06 (s, 1H).

Example 10 Synthesis of N-(3-chloro-4-trifluoromethylthio-phenyl)dichloroacetamide (Compound 51)

Compound 51

The preparation method is the same as that in Example 5. The starting material for synthesizing the compound is 3-chloro-4-trifluoromethylthio-aniline and dichloroacetyl chloride, and the addition amounts are 5.242 g, 4.073 g, respectively, and the reaction temperature is 110-120 ° C. The reaction time was 5 h, and the product was obtained 7.262 g, yield 93%.

1H NMR (300 MHz, DMSO-D ₆ ) δ 11.17 (s, 1H), 8.04 (d, J = 2.2, 1H), 7.87 (d, J = 8.6, 1H), 7.67 (dd, J = 8.6, 2.2 , 1H), 6.64 (s, 1H).

ESI-MS: 337.4 (M-H) - Example 11 Synthesis of N-(2-bromo-4-trifluoromethylthio-phenyl)dichloroacetamide (Compound 52)

Compound 52

1) Preparation of 2-bromo-4-trifluoromethylthio-aniline

1.74 g (9 mmol) 4-trifluoromethylthioaniline was added to a 50 ml round bottom flask, and further dissolved in 20 ml of glacial acetic acid, and 1.467 g (9.18 mmol, 1.02 equivalent) of liquid bromine diluted with 10 ml of glacial acetic acid was added dropwise for 20 minutes. The addition is complete. The reaction was poured into 100 ml of water for 2 h, and unreacted bromine was removed by adding 2 g of Na ₂ S ₂ 0 ₃ and filtered. Ethyl acetate: petroleum ether = 1: 8 Column chromatography separation gave 2-bromo-4-trifluoromethylthioaniline 0.490 g yield 20% and 2,6-dibromo-4-trifluoromethylthioaniline 1.74 g yield 55%.

2) Preparation of compound 52

The preparation method is the same as that in Example 5. The starting material for synthesizing the compound is 2-bromo-4-trifluoromethylthio-aniline obtained in the first step, the amount of addition is 0.243 g, and the amount of dichloroacetyl chloride added is 0.149 g, the reaction temperature. 110-120 ° C, reaction time 2 h, the product was obtained 0.230 g, yield 67%.

1H NM (300 MHz, CDC1 ₃ ) 5 8.94 (s, 1H), 8.43 (d, J = 8.7, 1H), 7.90 (s, 1H), 7.66 (d, J = 8.6: 1H), 6.06 (d, J = 11.9, 1H). ESI-MS: 413.7 (MH

Example 12 Synthesis of N-(2,6-dibromo-4-trifluoromethylthio-phenyl)dichloroacetamide (Compound 53)

HCI

Compound 53

Using the 2,6-dibromo-4-trifluoromethylthio-aniline obtained in the first step of Example 11, the compound 53 was synthesized by the preparation method of Example 5, wherein 2,6-dibromo-4-trifluoro Methylthio-aniline and dichloroacetyl chloride were added in an amount of 0.200 g, 0.107 g, a reaction temperature of 110-120 ° C, and a reaction time of 2 h to obtain a product of 0.205 g, a yield of 78%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.08 (s, 1H), 7.90 (s, 2H), 6.10 (s, 1H). ESI-MS: 493.3 (M+Cl) - Example 13 N- (2-Iodo Synthesis of -4-trifluoromethylthio-phenyl)dichloroacetamide (Compound 54)

1.51 g of 4-trifluoromethylthioaniline was placed in a 100 ml round bottom flask, and further dissolved in 50 ml of glacial acetic acid, and a solution of 1.904 g (1.5 equivalents) of iodine chloride diluted with 10 ml of glacial acetic acid was added dropwise, and the addition was completed for 20 minutes. The temperature was raised to 50 to 70 ° C, and the reaction was poured into 100 ml of water for 24 hours, and unreacted iodine chloride was removed by adding 2 g of Na ₂ S ₂ 0 ₃ and filtered. Ethyl acetate: petroleum ether = 1: 15 column chromatography separation to give 2-iodo-4-trifluoromethylthioaniline 0.750 g yield 30% and 2,6-diiodo-4-trifluoromethylthioaniline 1.290 g yield 37%.

2) Preparation of compound 54

The preparation method is the same as that in Example 5. The raw material for synthesizing the compound is the amount of 2-iodo-4-trifluoromethylthio-aniline obtained in the step 1 and the amount of the dichloroacetyl chloride added is 0'.149 g. The temperature was 110-120 ° C, and the reaction time was 2 h to obtain 0.230 g of a product, yield 67%.

¹ H NMR (300 MHz, CDC1 ₃ ) δ 8.78 (s, 1H), 8.33 (d, J = 8.5, 1H), 8.12 (s, 1H), 7.69 (d, J = 8.5, 1H), 6.07 (s , 1H).

Example 14 Synthesis of N-(2,6-diiodo-4-trifluoromethylthio-phenyl)dichloroacetamide (Compound 55)

Compound 55

Using the 2,6-diiodo-4-trifluoromethylthio-aniline obtained in the first step of Example 13, the compound 55 was synthesized by the preparation method of Example 5, wherein 2,6-diiodo-4-trifluoro Methylthio-aniline and dichloroacetyl chloride were added in an amount of 0.200 g, 0.107 g, a reaction temperature of 110-120 ° C, and a reaction time of 2 h to obtain a product of 0.205 g, a yield of 78%.

NMR NMR (300 MHz, CDCI3) δ 8.27 - 8.12 (m, 2H), 8.02 (s, 1H), 6.09 (s, 1H).

Example 15 Synthesis of N-(3-chloro-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide (Compound 56)

Compound 56

Synthetic reaction formula:

HCI

Take compound 51 N-(3-chloro-4-trifluoromethylthio-phenyl)dichloroacetamide 0.6g synthesized in Example 10, add 40 ml of glacial acetic acid, 20 ml of 27% 3⁄40 _{2 in a} 100 ml round bottom flask, and heat up to 35Ό, reaction for 48h. TLC (ethyl acetate: petroleum ether = 1 : 4) was observed and the reaction was completed, and the solvent acetic acid, H ₂ 0 ₂ and 3⁄40 were removed by evaporation under reduced pressure. After adding 30 ml of dichloromethane, the solution was washed once with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic phase was washed once again with 20 ml of brine. It was then dried over anhydrous sodium sulfate overnight, filtered, and then evaporated.

NMR NMR (300 MHz, CDCI3) δ = 8.32 (s, 1H), 8.02 (d, J=8.7, 1H), 8.01 (d, J 2.1, 1H), 7.66 (dd, J=8.7, 2.1, 1H) , 6.06 (s, 1H).

Example 16 Synthesis of N-(4-trifluoromethanesulfonyl-phenyl)dichloroacetamide (Compound 57)

Compound 57

The preparation method was the same as that in Example 15. The starting material for synthesizing the compound was the compound 48 N - (4-trifluoromethylthio-phenyl)dichloroacetamide synthesized in Example 7, and the amount of the compound was 0.100 g, the ratio of glacial acetic acid to hydrogen peroxide. The reaction temperature was 35-40 ° C and the reaction time was 48 h. The product was obtained as 0.101 g, and the yield was 91%.

1H NMR (300 MHz, CDCI3) δ 8.48 (s, 1H), 8.05 (d, J = 8.9, 2H), 7.92 (d, J = 8.9, 2H), 6.08 (s, 1H). ESI-MS: 335.4 (MH)-Example 17 Synthesis of N-(3-trifluoromethanesulfonyl-phenyl)dichloroacetamide (Compound 58)

Compound 58 The preparation method was the same as that in Example 15. The starting material for synthesizing the compound was the compound 47 N - (3-trifluoromethylthio-phenyl)dichloroacetamide synthesized in Example 6, and the amount of the compound was 0.100 g, and the ratio of glacial acetic acid to hydrogen peroxide was used. The reaction temperature was 35-4 CTC and the reaction time was 48 h to obtain a product of 0.096 g, yield 87%.

¹ H NMR (300 MHz, CDC1 ₃ ) δ 8.80 (s, 1H), 8.22 (s, 2H) „ 7.85 (d, J = 7.5, 1H), 7.69 (t, J = 7.9, 1H), 6.10 (s , 1H).

Example 18 Synthesis of N-(2-bromo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide (Compound 59)

HCI

Compound 59

The preparation method was the same as that in Example 15. The starting material for synthesizing the compound was the compound 52 N-(2-bromo-4-trifluoromethylsulfanyl-phenyl)dichloroacetamide synthesized in Example 11, and the amount was 0.135 g, glacial acetic acid. The ratio with hydrogen peroxide is 2:1, the reaction temperature is 35~40 °C, the reaction time is 48h, and the product is 0.114 g, and the yield is 77%.

NMR NMR (300 MHz, CDCI3) δ 9.16 (s, 1H), 8.72 (d, J = 8.7, 1H), 8.26 (s, 1H), 8.04 (d, J = 8.7: 1H), 6.10 (s, 1H) ).

ESI-MS: 413.8 (M-H) - Example 19 Synthesis of N-(2,6-dibromo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide (Compound 60)

Compound 60

The preparation method was the same as that in Example 15. The starting material for synthesizing the compound was the compound 5.3 synthesized in Example 12, the amount of which was 0.120 g, the ratio of glacial acetic acid to hydrogen peroxide was 2:1, the reaction temperature was 35-40 ° C, and the reaction time was 48 h. Product 0.096 g, yield 75%

¹ H NMR (300 MHz, CDCI3 ) δ 8.25 (s, 2H), 8.19 (s, 1H), 6.11 (s, 1H).

Example 20 Synthesis of N-(2-iodo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide (Compound 61)

Compound 61

The preparation method was the same as that in Example 15. The starting material for synthesizing the compound was the compound 54 synthesized in Example 13, and the amount of the compound was 0.019 g, the ratio of glacial acetic acid to hydrogen peroxide was ·2 _: 1, the reaction temperature was 35-40 ° C, and the reaction time was 48 h. The product was obtained in 0.015 g, and the yield was 75%.

NMR NMR (300 MHz, CDC1 ₃ ) δ 9.01 (s, 1H), 8.62 (d, J = 8.8, 1H), 8.45 (d, J = 2.0, 1H), 8.05 (dd, J = 8.8, 2.0, 1H ), 6.10 (s, 1H).

Example 21 Synthesis of N-(3-chloro-4-nitro-phenyl)dichloroacetamide (Compound 62)

HCI

Compound 62

Synthetic reaction formula:

8.82g of compound 7 synthesized compound N-phenyldichloroacetamide, 10 ml of glacial acetic acid was added to a 100 ml round bottom flask and stirred well. 15 ml of concentrated sulfuric acid was slowly added in a water bath, and then the configured HN0 ₃ (3.5) Ml) /H ₂ S0 ₄ (5 ml) The mixed acid was slowly added dropwise to a round bottom flask. The control temperature should not exceed 20 ° C. After the completion of the dropwise addition, the reaction was continued at room temperature for 30 min. The reaction was completed by TLC and the reaction was stopped. It was poured into a beaker containing 50 ml of ice-water mixture, and extracted with 50 ml of ethyl acetate. The organic phase was combined and dried over anhydrous magnesium sulfate Ethyl acetate: petroleum ether (1: 40) mobile phase column separation, the first component is N-(3-chloro-6-nitro-phenyl)dichloroacetamide 3.160g, the second component N- ( 2.51 g of 3-chloro-4,6-dinitro-phenyl)dichloroacetamide, the third component was 0.928 g of N-(3-chloro-4-nitro-phenyl)dichloroacetamide.

1H NMR (300 MHz, DMSO-D ₆ ) δ 11.30 (s, 1H), 8.16 (d, J = 9.0, 1H), 8.01 (d, J = 2.2, 1H), 7.73 (dd, J = 9.0, 2.2 , 1H), 6.64 (s, 1H).

Example 22 Synthesis of N-(3-chloro-4,6-dinitro-phenyl)dichloroacetamide (Compound 6)

The preparation method was the same as in Example 21.

HCI

Compound 63 NMR NMR (300 MHz, DMSO-D ₆ ) δ 11.39 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 6.89 (s, 1H). ESI-MS: 326 (MH) - Example Synthesis of 23 N-(3-chloro-4-bromo-phenyl)dichloroacetamide (Compound 64)

HCI

Compound 64

Synthetic reaction formula:

2.549g (10. 9mmol) of compound 7 N-(3-chloro-phenyl)dichloroacetamide, 15 ml of glacial acetic acid was added to a 50 ml round bottom flask, cooled to 15 ° C, and 5 ml of diluted 1.67 ml of liquid bromine was slowly added dropwise ( 32.7 mmol), stirred for 2 h, poured into 100 ml of ice water, filtered and dried to give N-(3-chloro-4-bromo-phenyl)dichloroacetamide 3.320, yield 96%.

Ή, R (300 MHz, DMSO-D ₆ ) δ 10.94 (s, 1H), 7.95 (d, J = 2.4, 1H), 7.76 (d, J = 8.8, 1H), 7.47 (dd, J = 8.8, 2.4, 1H), 6.60 (s, 1H).

ESI-MS: 318.3 (M-H) - Example 24-25 Anticancer activity and toxicity test of the compound of the present invention

Example 24 Inhibitory activity of N-phenyldichloroacetamide and derivatives against four cancer cells

This example measures the antitumor activity of 66 kinds of N-phenyldichloroacetamide compounds of the present invention. Topotecan and DCA (purchased from Alfa Aesar) were used as positive control drugs, and the cell strains used were: human non-small cell lung cancer cell line (A549), human oral epithelial cell line (KB), human hepatoma cell line (BEL- 7402), human gastric cancer cell line (BGC-823), all of which were purchased from ATCC. The measurement was carried out by using the tetrazolium bromide blue (MTT) method. The succinate dehydrogenase in the mitochondria of living cells reduces the exogenous tetrazolium bromide to a poorly soluble blue-violet crystal (Formazan) and deposits in the cells, whereas dead cells do not. Dimethyl sulfoxide (DMSO) is capable of lysing purple crystals in cells, and its light absorption value is measured by an enzyme-linked immunosorbent assay, which indirectly reflects the number of viable cells.

1) Reagents used in the experiment:

HyQR modified RPMI 1640 medium, purchased from HyClone;

F-12Kaighn, S medium, purchased from GIBCO;

MTT and trypsin, purchased from Promega; CCK-8, purchased from Dojindo; The triple reagent was prepared by dissolving in 20% SDS, 10% isobutanol, 0.024 mol/L HCl, and distilled water.

2) Experimental method

Cell culture: human liver cancer cell line (BEL-7402), human gastric cancer cell line (BGC-823), human oral epithelial cell line (KB): using RPMI 1640 medium containing 10% fetal bovine serum at 37 ° C, Culture in a 5% CO ₂ incubator; human non-small cell lung cancer cell line (A549): cultured in F-12Kaighn, S medium with 10% fetal bovine serum at 37 ° C, 5% CO ₂ incubator .

Cell treatment: Take the above cells in the exponential growth phase and in good condition, add appropriate amount of trypsin to digest the cells, collect the cells for centrifugation, and discard the supernatant. The cells were resuspended with the corresponding culture medium containing the above serum, then counted, and the cell density was diluted to a density of 1.67×10 ⁴ /ml. Cell seeding: The cell suspension was inoculated into a 96-well plate at 180 ul/well (containing 3000 cells/well of tumor cells). The plate was transferred to a constant temperature CO ₂ incubator, and cultured at 37 ° C, 5% CO ₂ and saturated humidity for 24 hours. Preparation of Test Compound: The 66 compounds of the present invention and the positive control drug Topotecan were first prepared into a 0.1 M stock solution using DMS0, and then 10 dilutions were obtained, and the concentrations were ΑΧΙθΛ 1Χ10"\4Χ10' ⁵ , 2Χ10· ^{^{5, 1Χ1 (Τ 5, 4Χ1}} (Τ 6, 2X10 "6, 1X10" 6, 4Χ10 "\ 1Χ10 '7 Μ, control drug test concentrations of DCA concentration above expanded tenfold compared sequentially.

The test compound was added: 20 ul/well, cultured for 72 hours, 3 parallel wells per group, and the experiment was repeated three times. RESULTS: After 72 hours of compound action, 5 mg/ml of MTT was added to a 96-well plate at 20 ul/well, placed in an incubator for 4 hours, then triple reagent, 50 uL/well, and overnight at 570 nm. Absorbance value.

Calculation of cell inhibition rate:

Average negative 0D value of the control group - average 0D value of the administration group

Inhibition rate = X100%

Negative control group average 0D value '

Calculation of IC ₅ o: For compounds with inhibition rates above 50%, IC ₅ o values were calculated using SPSS software.

The results are shown in Table 2. It can be seen from Table 2 that the compound IC ₅ o of the present invention is significantly lower than DCA, and the IC _{50 of} some compounds is close to that of topotecan. In comparison, most of the compounds we synthesized were much more active than DCA, especially N-(3-chloro-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide (compound 56), IC ₅ . Increased by 1600 times.

Table 2 Inhibitory activity of the N-phenylacetamide-containing compound of the present invention on four kinds of cancer cells

9T9000/600ZN3/X3d 0606 bacteria OAV 46 142.54 8.86±1.28 12.18±10·25 5.97±1.77

47 122.88 4.84±1.85 14.07±4.67 6.54±3.44

48 203.35±164.98 2.08±1.12 10.56±9.73 3.61±3.72

49 172.66 17.34±10.70 10.03±3.86 10.10±0.34

50 142.14 7.41±2.17 15.05±5.38 10.28±4.44

51 15.13±4.37 1.39±0.36 3.46±1.14 4.26±4.65

52 164.73 45.44±10.42 38.04±11.69 30.66±20.45

53 ― 34.55±17.99 ― 114.17±77.94

54 123.42 27.42±23.91 42.25±20.86 44.95±24.78

55 89. 7 366.70±19.69 ― 106.66±96.97

56 1 1.54±1.72 0.60±4.77 3.05±0.70

57 146.50 9.71±3·36 8.50±4.51 72.82 士 3.20

58 63.98士13.39 20.55±18.95 6.53±1.52 9.01±2.57

59 273.21 92.78 115.57±12.62 141.61±139.75

60 152.69±58.49 18.08 ± 6.02 67.18±23.34 19.87±3.12

61 ― 143.38±97.12 197.47 218.72

62 41.64±21.04 36.13±16.34 28.35±22.34 22.39±12.58

63 50.67±17.52 36.20±12.87 39.39±14.17 35.54±18.54

64 / 8.56 ± 5.74 3.96 ± 66.18 8.45 ± 9.76

65 / 78.0H42.08 41.74±44.73 81.61i51.04

66 238.06±28.60 72.96士 18.48 36.20±19.60 39.12±34.46

Wherein, the chemical name of the compound 65 is N-(2-chloro-4-methoxycarbonyl-phenyl)dichloroacetamide;

Compound 66

The structural formula is N-(3-chloro-4-methoxycarbonyl-phenyl)dichloroacetamide. Example 25 Acute Toxicity Test of N-Phenyldichloroacetamide and Derivatives of the Invention

This example exemplifies the toxicity measurement results of the nine compounds in the present invention.

Experimental methods: The test compounds were prepared by using 0.5% sodium carboxymethylcellulose solution as a suspension. The concentration of lOmg/mL Kunming healthy mice, weighing 18-20g, both male and female, were randomly divided into 5 dose groups. The amount is shown in Table 3. Each group of 10 small mice was administered by fasting gavage with a dose of 0.4 ml/10 g. Kaerber's method to calculate the median lethal dose (LD ₅ o) and 95% Confidence interval.

As can be seen from Table 3, the test compounds were all moderate to low toxicity, wherein LD _{5 () of the} test compound 56 was 676 nig/kg, which was in moderately toxic water, and the results are shown in Table 3.

Table 3 Results of acute toxicity test of N-phenyldichloroacetamide compounds of the present invention

Note: The numbers of the compounds in Tables 2 and 3 are consistent with the numbers of the compounds in the preparation examples.

references

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4 Bonnet et al. A Mitochondria-K ⁺ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth, Cancer Cell, 2007, 11, 37-51

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6 G W. Moore, L. I. Swift, D. Rabinowitz, O. B. Crofford, J. A Oates and P. W. Stacpoole, Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dicholroacetate, Arherosclerosis, 1979, 33, 285-293

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Claims

Claim

1. N-phenyldichloroacetamide and a derivative thereof, wherein the compound has the formula:

Formula I

R ¹ is -H, -OH, -SH, -F, -CI, -Br, -I, -CN, -CHO, -COOH, -OCHO, -N0 ₂ , -NO, -N ₃ , -NH ₂ , -NH-NH ₂ , -S0 ₃ H, -SOCH3, -SOCF3, -S0 ₂ CH ₃ , -S0 ₂ CF ₃₎ -CF ₃ , S0 ₃ F; decyl, alkenyl, alkynyl group of dC ₆ ; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; C _r C ₆ haloalkyl, haloalkenyl, haloalkynyl; C ₃ -C ₈ halocyclodecyl, cycloalkenyl One of a cycloalkynyl group;

Or R ¹ is -OR', wherein R' is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; a hydroxy-substituted C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, Cycloalkynyl; hydroxy-substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is -NR'R", wherein R', R" are the same or different and are one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; an amino-substituted C ₃ -C _8- cyclodecyl, cycloalkenyl, cycloalkynyl; amino-substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is -SR', wherein R' is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; a mercapto-substituted C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, Cycloalkynyl; fluorenyl substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is one of the following the groups, the methylthio-substituted alkyl with ₆ -C, alkenyl group, alkynyl group; a methylthio group substituted by C ₃ -C ₈ cycloalkyl, cycloalkenyl, a cycloalkynyl group; a methylthio-substituted C ₃ -C ₈ halocycloalkyl group, a cycloalkenyl group, a cycloalkynyl group; or R ¹ is ^one of the groups described below, a CN-substituted dC ₆ fluorenyl group , alkenyl, alkynyl; cyano substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; cyano substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl ;

Or R ¹ is -ArR', wherein R' is one of the following groups, -C _{6 is} an alkyl group, an alkenyl group, an alkynyl group; an aromatic ring-substituted C ₃ -C ₈ cyclodecyl group, a cycloolefin a cycloalkynyl group; an aromatic ring-substituted C ₃ -C ₈ halocycloalkyl group, a cycloalkenyl group, a cycloalkynyl group;

Or R ¹ is -COOR', wherein R' is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; - a COOH -substituted C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group , cycloalkynyl; -C00H substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl; or R ¹ is -COR', wherein R' is one of the following groups, Alkyl, alkenyl, alkynyl group of dC ₆ ; -OCOH substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, 0 = substituted -C ₆ alkyl, alkenyl, alkynyl; 0 = substituted. 3 ₈ ring Indenyl, cycloalkenyl, cycloalkynyl; 0 = substituted c ₃ -c ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, S = substituted decyl, alkenyl, alkynyl group of dC ₆ ; S = substituted CC ₈ i3⁄4^ group, cycloalkenyl group, cycloalkynyl group; s=substituted C ₃ -c ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -N _{2 2} substituted dC ₆ fluorenyl, alkenyl, alkynyl; -N02 substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl -N0 ₂ substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -NO substituted dC ₆ fluorenyl, alkenyl, alkynyl; -NO substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; -NO substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -N ₃ substituted dC ₆ fluorenyl, alkenyl, alkynyl; -N ₃ substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkyne -N ₃ substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -S0 ₃ H substituted dC ₆ fluorenyl, alkenyl, alkynyl; -S0 ₃ H substituted C ₃ -C ₈ cyclodecyl, cycloalkenyl, Cycloalkynyl; -S0 ₃ H substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, -S0 ₃ F substituted dC ₆ alkyl, alkenyl, alkynyl; -S0 ₃ F substituted C ₃ -C ₈ cycloalkyl, cycloalkenyl, Cycloalkynyl; -S0 ₃ F substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is -NH-NHR', wherein R' is one of the following groups, -C ₆ alkyl, alkenyl, alkynyl; cyclodecyl, cycloalkenyl, cycloalkynyl; Substituted fluorenyl, cycloalkenyl, cycloalkynyl;

Or R ¹ is ^one of the following groups, an alkyl group at C _r C ₆ , an alkenyl group, an alkynyl group; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; C ₃ -C ₈ -S -, -SS-, -0-, -NH-, -NH-NH-, -N=N-, -CH are inserted between any CC bond in a halogenated cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group. =N -, -PH -, -(C=0)-, - (S=0) -, - S0 ₂ -, -(PH=0)-, -(C=0)NH-, -S-NH -, -N = CH-NH-, -N = CH-0-, -N = CH-S -, -NH (C = 0) -, -S0 2 NH -, -NHS0 2 -, - (PH = 0) NH -, -NH(PH=0)-, -(C=0)NHNH-, -NHNH(C=0)-, -S0 ₂ NHNH -, -NHNHS0 ₂ -, -(PH=0)NHNH -, -NHNH (PH=0)-, -(C=0)0-, -0(C=0)-, -0(C=0)0-, -S0 ₂ -0-, -0-S0 ₂ -, -(S=0)-0-, -0( S=0)-,

a group of -(PH=0)-0-, -o-(ra=o)-, -o-(PH=o)o-;

Or R ¹ is

among them,

X is one of the following groups, -S -, -SS -, -0-, -NH-, -NH-NH -, -N=N -, -CH=N -, -PH-, - _{CO-, -SO-, -S0 2 -,} -PH (-O) -, - (C = 0) NH-, -NH (C = 0) -, -S0 2 NH-, -NHS0 2 -, - SONH-, -NHSO-, -(ΡΗ=0)ΝΗ-, -NH(PH=0)-, -(C=0)NHNH-, -NHNH (C=0)-, -S0 ₂ NHNH -, -NHNHS0 ₂ -, -SONHNH- , -NHNHSO-, -(PH=0)NHNH- -NHNH(PH=0)- , -(C=0)0-, -0(C=0)-, -0(C=0)0-, -S0 ₂ -0-, - 0-S0 ₂ -, -(S=0)-0-, -0(S=0)-, -(PH=0)-0-, -O-(PH-O ), -0-(PH=0)0-, -S-NH-, -N=CH-NH -, -N=CH-0-, -N=CH-S-, the sulfhydryl group of dC ₆ , Alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkynyl; -C ₆ haloalkyl, haloalkenyl, haloalkynyl; C ₃ -C ₈ halocyclodecyl , cycloalkenyl, cycloalkynyl; hydroxy, amino, decyl, cyano, aryl ring substituted alkyl, alkenyl, alkynyl; hydroxy, amino, fluorenyl, cyano, aromatic ring substituted C ₃ -C ₈ Cyclodecyl, cycloalkenyl, cycloalkynyl; hydroxy, amino, fluorenyl substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

R ⁶ is one of the following groups, -C ₆ fluorenyl, alkenyl, alkynyl; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; dC ₆ halogenated fluorenyl, Haloalkenyl, haloalkynyl;

Or R ⁶ is one of the following groups, an alkyl group at ₆ , an alkenyl group, an alkynyl group; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; a halogenated fluorenyl group of -C6; In the haloalkenyl group, any CC bond in the haloalkynyl group is inserted -S-, -SS-, -0-, -NH-, -NH-NH -, -N=N-, -CH=N -, -PH-, -(C=0)-, - (S=0) -, -S0 ₂ -, -(PH=0)-, -(C=0)NH-, -S-NH-, -N = CH-NH -, -N = CH-0-, -N = CH-S-, -NH (C = 0) -, -S0 2 NH -, -NHS0 2 -, - (PH = 0) NH- , -NH(PH=0)-, -(C=0)NHNH-, -NHNH (C=0)-, -S0 ₂ NHNH -, -NHNHS0 ₂ -, -(PH=0)NHNH -, -NHNH (PH=0)-, -(C=0)0-, -0(0=0)-, -0(C=0)0-, -S0 ₂ -0-, - 0-S0 ₂ -, - (S=0)-0-, - 0(S=0)-, -(PH=0)-0-, -0-(PH=0)-, -0-(PH=0)0-based group;

Or R ⁶ is one of the following groups, -H, -OH, -SH, -F, -Cl, -Br, -1, -CN, -CHO, -C00H, -0CH0, -N0 ₂ , -NO, -N ₃ , -NH ₂ , -NH-NH ₂ , -S0 ₃ H, -S0CH ₃ , -S0CF ₃ , -S0 ₂ CH ₃ , -S0 ₂ CF ₃ , -CF ₃ , S0 ₃ F, -S-NH-, -N=CH-NH -, -N=CH-0-, -N=CH-S-;

Or R ⁶ is 0R', wherein R' is one of the following groups, -C _{6 is} an alkyl group, an alkenyl group, an alkynyl group; a hydroxy-substituted C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, Cycloalkynyl; hydroxy-substituted C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl;

Or NR'R", wherein R' and R" are the same or different and are one of the following groups, an alkyl group of an alkyl group, an alkenyl group, an alkynyl group; an amino-substituted C ₃ -C ₈ naphthenic group Alkyl, cycloalkenyl, cycloalkynyl; amino-substituted C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ⁶ is SR', wherein R' is one of the following groups, an alkyl group of dC ₆ , an alkenyl group, an alkynyl group; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ⁶ is C00R′, wherein R′ is one of the following groups, an indenyl group, an alkenyl group, an alkynyl group of CrC ₆ ; a C ₃ -C ₈ cyclodecyl group, a cycloalkenyl group, a cycloalkynyl group; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ⁶ is COR, wherein R is one of the following groups, -C ₆ alkyl, alkenyl, alkynyl; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cycloalkynyl; Or R ⁶ is -NH-NHR ', wherein, R' is one of the following radicals, C _r C ₆ alkyl with, alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl group embankment, cycloalkenyl , cycloalkynyl; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

R ⁷ , R ⁸ , R ⁹ , and R ^{1Q are the} same or different and are each selected from the group defined by R ⁶ ; or R ¹ is —Y— ^R ",

Wherein Y is one of the following groups, -S -, -SS-, -0-, -NH-, -NH-NH -, -N=N -, -CH-N-, -PH- _{, -CO-, -SO-, -S0 2 -} , -PH (= 0) -, - (C = 0) NH-, -NH (C = 0) -, -S0 2 NH-, -NHS0 2 - , -(PH=0)NH -, -NH(PH=0)-, -(C=0)NHNH-, -NHNH (C=0)-, -S0 ₂ NHNH -, -NHNHS0 ₂ -, -( PH=0)NHNH-, -NHNH (PH=0)-, -(C=0)0-, -0(C=0)-, -0(C=0)0-, -S0 ₂ -0- , -0-S0 ₂ -, -(S=0)-0-, - 0( S=0)-, -(PH=0)-0-, -0-(PH=0)-, -0- (PH=0)0-, -S-NH-, -N=CH-NH-, -N=CH-0-, -N=CH-S- _;

R ¹¹ is one of the following radicals, C _r C ₆ alkyl with, alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl, cycloalkenyl, cycloalkynyl; - alkyl with halo, Haloalkenyl, halo block; C ₃ -C ₈ halocycloalkyl, cycloalkenyl, cycloalkynyl;

Or R ¹¹ is one of the following radicals, the alkyl with ₆ CC, alkenyl, alkynyl; C ₃ -C ₈ cycloalkyl group embankment, cycloalkenyl, cycloalkynyl; - alkyl with halo, Haloalkenyl, haloalkynyl; C ₃ -C ₈ halocyclodecyl, cycloalkenyl, cyclo-alkynyl----, -SS-, -0-, -NH - , -NH-NH-, -N=N -, -CH=N -, -PH -, -(C=0)-, -

(S=0) -, -S0 ₂ -, -(PH=0)-, -(C=0)NH-, -S-NH-, -N=CH-NH -, -N=CH-0- , -N=CH-S-, -NH(C=0)-, -S0 ₂ NH-, -NHS0 ₂ -, -(ΡΗ=0)ΝΗ-, -NH(PH=0)-, -(C =0) NHNH -, -NHNH (C=0)-, -SO2NHNH-, -NHNHSO2-, -(PH=0)NHNH-, -NHNH (PH=0)-, -(C=0)0-, -0(C=0)- , -0(C=0)0-, -S0 ₂ -0-, -0-S0 ₂ -, -(S=0)-0-, - 0( S=0) -, -(PH=0)-0-, -0-(PH=0)-, -0-(PH=0)0- group;

The N-phenyldichloroacetamide and derivative according to claim 1, wherein the compound is in the formula I,

R ¹ or R ⁵ is one of -H, -F, -CI, -Br, -I, -CN, -NH ₂ , -N0 ₂ , -C ₆ thiol, alkenyl, alkynyl group ;

R ² or R ⁴ is -H, -F, -CI, -Br, -I , -N0 ₂ , -CN, -CF ₃ , -CF ₂ CF ₃ , -SCF ₃ , -SCF ₂ CF ₃ , - S0 ₂ F, -S0 ₂ CF ₃ , -S0 ₂ CF ₂ CF ₃ , -OCF ₃ , -OCF ₂ CF ₃ , one of the sulfhydryl, alkenyl, alkynyl groups of C _r C ₆ ;

R ³ is -H, -F, -CI, -Br, -I , -N0 ₂ , -CN, -CF ₃ , -CF ₂ CF ₃ , -SCF ₃ , -SCF ₂ CF ₃ , - S0 ₂ F, -S0 ₂ CF ₃ , -S0 ₂ CF ₂ CF ₃ , -OCF ₃ , -OCF ₂ CF ₃ , one of -C ₆ alkyl, alkenyl, alkynyl groups;

Or R ³ is -S- R ¹² , -SO- R ¹² , -S0 ₂ - R ¹² , -OR ¹² , -0(C=0)-R ¹² , -(C=0)0- R ¹² One.

The N-phenyldichloroacetamide and derivative according to claim 2, wherein R ¹² is a fluorenyl group, an alkenyl group or an alkynyl group of CF ₃ , CF ₂ CF ₃ , CC ₆ ; C ₃ -C ₈ cyclodecyl, cycloalkenyl, cycloalkynyl; -C ₆ haloalkyl, haloalkenyl, a haloalkynyl group; one of a C ₃ -C ₈ halocyclodecyl group, a cycloalkenyl group, a cycloalkynyl group.

The N-phenyldichloroacetamide and derivative according to claim 2, wherein the compound is N-(4-methyl-phenyl)dichloroacetamide, N-(3- Methyl-phenyl) dichloroacetamide, N-(4-chloro-phenyl)dichloroacetamide, N-

(3-chloro-phenyl) dichloroacetamide, N-(3-chloro-4-fluoro-phenyl)dichloroacetamide, N-(3,5-dichloro-phenyl)dichloroacetamide, N-(2,5-Dichloro-phenyl)dichloroacetamide, N-(2,3-dichloro-phenyl)dichloroacetamide, N-(2-methyl-5-chloro-phenyl Dichloroacetamide, N-(3-chloro-4-methyl-phenyl)dichloroacetamide, N-(2,4,5-trichloro-phenyl)dichloroacetamide, N- ( 3 , 4-dichloro-phenyl) dichloroacetamide, N-(2-fluoro-5-chloro-phenyl)dichloroacetamide, N-(4-bromo-phenyl)dichloroacetamide, N- (4-iodo-phenyl) dichloroacetamide, N-(4-methoxy-phenyl)dichloroacetamide, N-(3-chloro-4-bromo-phenyl)dichloroacetamide, N - (3-Chloro-4-ethoxycarbonyl-phenyl) Dichloroacetamide, N-(3-chloro-4-iodo-phenyl)dichloroacetamide, N-(3-bromo-phenyl) Chloroacetamide, N-(3-iodo-phenyl)dichloroacetamide, N-(3-ethynyl-phenyl)dichloroacetamide, N-(3-cyano-phenyl)dichloroacetamide , N-(3-methoxy-phenyl)dichloroacetamide, N-(2-methyl-4-fluoro-5-bromo-phenyl)dichloroacetyl , N-(3-trifluoromethyl-phenyl)dichloroacetamide, N-(3-trifluoromethylthio-phenyl)dichloroacetamide, N-(4-trifluoromethylthio-benzene Dichloroacetamide, N-(3-trifluoromethyl-4-nitro-phenyl)dichloroacetamide, N-(3-trifluoromethoxy-phenyl)dichloroacetamide, N - (3-Chloro-4-trifluoromethylthio-phenyl) Dichloroacetamide, N-(2-bromo-4-trifluoromethylthio-phenyl)dichloroacetamide, N- (2, 6-Dibromo-4-trifluoromethylthio-phenyl) Dichloroacetamide, N-(2-iodo-4-trifluoromethylthio-phenyl) Dichloroacetamide, N- (2, 6 -diiodo-4-trifluoromethylthio-phenyl) dichloroacetamide, N-(3-chloro-4-nitro-phenyl)dichloroacetamide, N-(3-chloro-4-III Fluoromethylsulfonyl-phenyl)dichloroacetamide, N-(4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(3-trifluoromethanesulfonyl-phenyl)dichloroacetamide , N-(2-bromo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(2,6-dibromo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(2-Iodo-4-trifluoromethanesulfonyl-phenyl)dichloroacetamide, N-(3-chloro-5-bromo-phenyl)dichloroethane Amide, N-(3-chloro-5-iodo-phenyl)dichloroacetamide, N-(3,5-dibromo-phenyl)dichloroacetamide, N-(3-bromo-5-iodine- Phenyl) Dichloroacetamide or N-(3,5-diiodo-phenyl)dichloroacetamide.

The method for preparing N-phenyldichloroacetamide and a derivative according to claim 1, characterized in that aniline or a derivative thereof and dichloroacetyl chloride are respectively dissolved in a toluene solution, wherein aniline or its derivative The molar ratio of the product to the dichloroacetyl chloride is 1 _: 1-2.6. After adding the dichloroacetyl chloride solution to the aniline or its derivative solution at room temperature, the temperature is raised to reflux, wherein the reaction temperature is 90-120 ° C. The time was 1-5 hours, and then the solvent toluene, the unreacted dichloroacetyl chloride and the hydrochloric acid gas were removed by distillation under reduced pressure to give the title compound.

The method for producing N-phenyldichloroacetamide and a derivative according to claim 5, which further comprises the following steps after the steam distillation under reduced pressure: adding methylene chloride to the compound Dissolve, add an equal amount of saturated brine, extract, remove the water layer, wash 1-3 times with saturated sodium bicarbonate solution, wash 2 to 5 times with saturated brine, and finally dry overnight with anhydrous sodium sulfate, filter The target compound is obtained after decompression. A pharmaceutically acceptable salt of N-phenyldichloroacetamide and a derivative according to claim 1.

The use of the N-phenyldichloroacetamide and the derivative of claim 1 and a pharmaceutically acceptable salt thereof for the preparation of an anticancer drug.