WO2014114183A1

WO2014114183A1 - Platinum (ii) compound for treating tumor cell proliferative disease

Info

Publication number: WO2014114183A1
Application number: PCT/CN2014/000061
Authority: WO
Inventors: 陈小平; 高泽军; 孟小平; 温守明; 闫亚矢; 赵锋
Original assignee: 北京市丰硕维康技术开发有限责任公司
Priority date: 2013-01-23
Filing date: 2014-01-17
Publication date: 2014-07-31
Also published as: CN104995201B; CN104995201A

Abstract

Disclosed are a platinum compound with the leaving group malonic derivative "2" position substituent containing a primary amino, a secondary amino, a tertiary amino, and a quaternary amino, as well as pharmaceutically acceptable salt, preparation method thereof, and pharmaceutical composition containing the compound. Also disclosed are uses of the compound for treating cell proliferative diseases, particularly cancers. The platinum compound of the present invention has the high water solubility and the low toxicity.

Description

Platinum (Π) compound for treating tumor cell proliferative diseases

The present invention relates to a platinum compound against cell proliferative diseases, in particular to a type of leaving group malonate derivative

A platinum compound having a "2" substituent containing a primary amino group, a secondary amino group, a tertiary amino group, a quaternary amino group of a malonic acid derivative, a preparation method, and an application thereof.

Background technique

Cancer (malignant tumor) is one of the most important diseases that currently threaten human life. In recent years, the incidence and mortality of tumors have risen sharply. The trend of tumor development disclosed by the World Health Organization shows that since 1996, the number of newly diagnosed tumor patients worldwide has exceeded 10 million. By the end of 1999, the total number of cancer patients worldwide has exceeded 4,000. 10,000 people, about 7 million people die of various tumors every year in the world. In 2001, the world cancer morbidity and mortality rate increased by 22% compared with 1990, which is the second leading cause of death after cardiovascular and cerebrovascular diseases. The cancers are lung cancer, breast cancer, colorectal cancer, stomach cancer, liver cancer, cervical cancer, esophageal cancer and bladder cancer. According to the authoritative survey data of the 10th National Conference on Clinical Oncology in 2006, there were about 2.12 million new cancer patients each year. Among malignant tumor mortality, lung cancer ranks first in malignant tumors. Experts predict that by 2020, the annual death toll will exceed 4 million; by 2025, cancer will be the number one cause of death worldwide.

Clinically, there are three main ways of treating tumors: surgery, radiotherapy and drug chemotherapy. Anti-tumor drugs are the most common treatment method. In 2008, global anti-cancer drug market sales were US$48 billion. At present, clinical anti-tumor drugs are mainly divided into sputum agents, antimetabolites, metal platinum, plant alkaloids and other natural drugs, cytotoxic antibiotics and other major categories. Platinum antineoplastic agents are one of the most important antitumor drugs, and were the first anticancer drugs developed in the 1960s. An important difference from traditional cytotoxic anti-tumor drugs is that they have a unique mechanism of action and good anti-tumor selectivity. Its main target is DNA, which is interlinked between DNA strands and chains, forms platinum complexes ~ DNA complexes, interferes with DNA replication, or binds to nuclear proteins and cytoplasmic proteins. It is a cyclic non-specific drug. Has successfully developed cis-dichlorodiamine platinum, cisplatin

(Cisplatin), cis-1, 1-cyclobutanecarboxylic acid diammine platinum, carboplatin, cis-glycolic acid-diammine platinum, nedaplatin, oxalic acid - (trans - L_l, 2-cyclohexanediamine) Platinum or oxaliplatin

(Oxal iplatin), cis-[(4R, 5R) _4, 5_bis(aminomethyl)-2-ylisopropyl 1,3 -dioxan] (double-tooth) Platinum is sulphate (Sunpla) and 1, 2 diaminomethyl-cyclobutyl hydrazine-lactate platinum, such as Lobaplatin, etc., platinum anti-tumor drugs have anti-tumor spectrum, strong effect, and platinum anti-tumor drugs and other anti-tumor The drug has a good synergistic effect, which not only improves the inhibition rate of existing tumors, but also expands the anti-tumor spectrum, thereby consolidating the status of platinum anti-tumor drugs in clinical treatment. In 1995, WHO ranked hundreds of anti-tumor drugs, cisplatin in terms of efficacy and market. The comprehensive evaluation is in the second place. Statistics show that 70% to 80% of all chemotherapy regimens in China are platinum-based or platinum-based drugs.

However, platinum antitumor drugs are currently more toxic, such as myelosuppression, renal toxicity, nerve damage, etc., poor solubility, relatively narrow anticancer spectrum, and drug resistance. Therefore, the design and synthesis of novel platinum antitumor drugs is still one of the main directions of anticancer drug research (MA Jakuper, M. Galanski, BK Keppler. Tumour-inhibit ing platinum complexes-state of art and future perspect ives, Rev. Physiol Biochem Pharmacol, 2003, 146, 1-53).

In the past two years, a large number of studies have been conducted to reduce the side effects of platinum-based chemotherapy drugs, improve the efficacy, reduce tumor recurrence and avoid drug resistance, and increase the water solubility of platinum compounds. For example, the solubility of oxaplatin is 2.65 mg/ml, the solubility of later oxaliplatin is 7.9 mg/ml, the solubility of nedaplatin is 8 mg/ml, and the solubility of carboplatin is 17.8 mg/ml. The solubility is 27 mg/ml, and the toxic side effects of oxaliplatin and carboplatin are lower than that of cisplatin. The solubility of the above-mentioned so-called water-soluble platinum compound is still slightly soluble or slightly soluble, and The antitumor activity is much lower than that of cisplatin. Murray A. Plan et al. prepared a sodium alkoxide of a platinum compound to effectively increase the solubility in vitro (US4322362A), but the compound must be dissolved above pHIO, and the toxicity problem has not been effectively solved. A series of platinum compounds have also been prepared by Giul ia C et al. However, the solubility of these compounds has not been significantly improved (Chem Med Chera, 2009, 4 (10), 1677-1685). W02006091790A1 also discloses a series of platinum compounds having a specific structure, but the same is not successfully solved for solubility problems and toxicity problems. Summary of the invention

The present invention provides a class of platinum compounds for treating proliferative diseases, in particular, a leaving group containing a primary amino group, a secondary amino group, a tertiary amino group, a quaternary amino group, a malonate derivative, which is pharmaceutically acceptable. Compared with the anti-tumor platinum of the prior art, the salt, the solvate, the stereoisomer or the prodrug thereof have strong anti-tumor effect in vivo and in vitro, and the solubility is greatly improved, and the toxic and side-effect is significantly reduced. Unexpected technical effects. The structure of this class of compounds is shown in formula A:

Wherein: R includes, but is not limited to, hydrogen, fluorenyl, cyclodecyl, decyloxyalkyl, alkylaminoindolyl, heterocyclic, alkenyl, alkynyl, above alkyl, cyclodecyl, alkenyl, The alkynyl, alkoxyfluorenyl, anthranylamino and heterocyclic rings may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, decyl, alkoxyalkyl, Substituted by cycloalkyl, nonylamino, amino, heterocyclic.

Ro may or may not exist, as R. When present, the compounds of the invention are quaternary ammonium salts and must have corresponding negative ions present simultaneously. When R. When present, the compound of the invention is a tertiary amine, a secondary amine or a primary amine compound; when R. When present, R. It may be, but not limited to, an anthracenyl group, a cycloalkyl group, an alkoxyalkyl group, an alkylaminoalkyl group, a heterocyclic ring, an alkenyl group, an alkynyl group, a above fluorenyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, The decyloxy group, the alkylaminoalkyl group and the heterocyclic ring may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, alkyl, alkoxyalkyl, cyclodecyl, a hydrazine amino group, an amino group, a heterocyclic ring;

! And R ₂ may be the same or different and include, but are not limited to, hydrogen, alkyl, cycloalkyl, decyloxy, fluorenylamino, heterocyclic, alkenyl, alkynyl, fluorenyl, fluorenyl The base, alkenyl group, chain block group, alkoxyfluorenyl group, nonylamino group and heterocyclic ring may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, fluorenyl, Alkoxycarbonyl, cyclodecyl, alkylamino, amino, heterocyclic substituted under the condition of R. Or if it contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;

! And R ₂ and the nitrogen atom to which they are attached may also form a closed saturated or unsaturated heterocyclic ring, for example, may be a ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered ring, and the above ring may also be It is optionally fused to other rings and may be optionally substituted by halogen, hydroxy, alkoxy, decyl, decyloxy, cyclodecyl, heterocyclic, aryl, provided that! If ^ or ^ contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;

It may be, but is not limited to, an anthracenyl group, a cyclodecyl group, -R ₃₁ -0-R ₃₂ -, R ₃ , and _{2 are} independently selected from a bond or a hydrocarbon group, and R ₃₁ is bonded to a nitrogen atom in the formula, provided that If R ₃₁ contains an unsaturated bond, the atom of the unsaturated bond cannot be directly bonded to the nitrogen atom; the above alkyl or cycloalkyl group may be unsubstituted or optionally substituted, preferably by halogen or hydroxy group. Substituted with methoxy, decyl, alkoxyalkyl, cycloalkyl, alkylamino, amino, heterocyclic, etc.;

! ^ with R, R. , R, R ₂ and the atoms to which they are attached may also form a closed saturated or unsaturated ring, for example, may be a ternary, quaternary, five-membered, six-membered, seven- or eight-membered ring, the above ring It may also optionally be fused to other rings, and may be optionally substituted by halogen, hydroxy, decyloxy, decyl, decyloxy, cycloalkyl, heterocyclic, aryl; for example, ! ^And! ^ and their commonly associated atoms together can also form a closed saturated or unsaturated ternary, quaternary, five-membered, six-membered, seven- or eight-membered ring; it can also be connected to its common The atoms together form a closed saturated or unsaturated ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered ring; or an atom connected to 1^ and its co-phase to form a closed saturated or unsaturated three Yuan, quaternary, five-yuan, six-member, seven- or eight-membered ring; or ^ and R, and The atoms connected together form a closed saturated or unsaturated ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered ring; and R ₅ may be the same or different and may be, but not limited to: hydrogen, hydroxyl , fluorenyl, cyclodecyl, decyloxy, decyloxy, heterocyclic, alkenyl, alkynyl, above alkyl, alkenyl, alkynyl, cycloalkyl, decyl fluorenyl The mercaptoamino group and the heterocyclic ring may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, linear or branched fluorenyl, fluorenyl fluorenyl, cyclodecyl, Alkyne, amino, heterocyclic;

! And R ₅ and the atoms to which they are attached may also form a closed ring, such as a five-, six-, seven-, or eight-membered ring, which may optionally be fused to other rings, and may Optionally replaced.

Preferably, R is selected from the group consisting of hydrogen, alkyl, cycloalkyl; R. And and are selected from the group consisting of hydrogen, C, _-8 alkyl, cyclodecyl, alkoxy fluorenyl, amino, hydrazinoalkyl, heterocyclic; R ₃ may be, but not limited to: C, _{s s} decyl, hydrazine R; and R _{5 are} selected from the group consisting of hydrogen, hydroxy, C, -s decyl, cyclodecyl, alkoxy, decyloxy, heterocyclic.

When R is selected from substituted or unsubstituted indenyl, cycloalkyl, nonyloxyindenyl, alkylaminoindenyl, heterocyclic, alkenyl, alkynyl, R. R, R ₂ , R ₃ , and R _{5 are} as described above.

When R is H, it is preferred! ^ and the nitrogen atom to which they are attached together form a closed saturated or unsaturated heterocyclic ring, such as a ternary, quaternary, quaternary, hexavalent, seven- or eight-membered ring, optionally further Ring is fused, and may be optionally substituted by halogen, hydroxy, decyloxy, alkyl, decyloxy, cyclodecyl, heterocyclic, aryl, but excluding compound B, and B ₂ , Preferred! ^ Together with the atoms they are connected to form a closed saturated or unsaturated ternary, quaternary, five-, six-, seven- or eight-membered ring, or! ^And! ^ The atoms they are connected together form a closed saturated or unsaturated ternary, quaternary, five-, six-, seven- or eight-membered ring; or! ^ Together with R, , ^ and their associated atoms form a closed saturated or unsaturated ternary, quaternary, quaternary, hexavalent, seven- or eight-membered ring.

( B2 )

Further, based on the above structural compound, the present invention also provides a compound of the formula C and a pharmaceutically acceptable salt thereof, that is, a compound obtained when R ₄ and R ₅ and the atom to which they are bonded form a closed ring, as follows:

Among them, R, R. , R, R ₂ . R _{3 is} selected from the group as described above

H ₂ N,,

w is preferred but not limited to:

And the above structure may also be optionally linked by various suitable substituents.

The platinum compound of the formula (C), Re may be, but not limited to, (C3⁄4), wherein n = 1 - 6, preferably 3-5, most preferably 4, some of which - CH ₂ - may be -0- Substituting one or more hydrogens of ((3⁄4) „ may be substituted by halogen, thiol, hydroxy or decyloxy, etc. Preferred compounds are (s) trans 1,2-hexyl, pentane, butyl and propyl Amine platinum (ruthenium).

R ₇ may be, but is not limited to, (CH ₂ ), wherein n = 0 - 3, preferably n = 0 - 2, some of which -CH ₂ - may be substituted by -◦-, one or more of (CH ₂ ) The hydrogen may be substituted by halogen, thiol, hydroxy, hydroxydecyl or alkoxy.

And may be, but are not limited to, hydrogen, halogen, hydroxy, hydroxydecyl, anthracenyl, decyloxy, heterocyclic, etc., and 13⁄4 The same or different, a hydroxymethyl group (F) is preferred.

. And Rn may be, but not limited to, hydrogen, halogen, hydroxyalkyl, alkane, alkoxy, heterocyclic, etc., R,. And ^ may be the same or different, and a hydroxymethyl group is preferred.

R ₁₂ may be, but is not limited to, (CH ₂ ) „, wherein n=2- 4, some of which -C3⁄4- may be substituted by -0-, one or more hydrogens of (CH ₂ ) may be halogen, fluorenyl Substituted by a hydroxyl group or an alkoxy group.

R ₁₃ may be -CH ₂ - or -0-, preferably -CH ₂ -.

^ may be hydrogen, halogen, fluorenyl, decyloxy, hydroxydecyl or hydroxy, and R ₁₄ is preferably hydrogen.

^ may be, but is not limited to, (CH ₂ ) „, wherein one or more hydrogens of n=l-3, -C-0- or -0_, (CH ₂ ) may be sulfhydryl, decyloxy, hydroxy, Instead of hydroxyindenyl or the like, -CH ₂ - 0-CH ₂ - is preferred. Preferred compounds have the following structure:

(F) T/CN2014/000061

(G)

(J) Listed below are definitions of various terms used to describe the present invention. Unless otherwise defined in the particular case, the following terms apply to the entire specification and claims (either alone or as part of a large group).

The term "mercapto" refers to a straight or branched saturated monovalent hydrocarbon group. Specifically, the fluorenyl group has 1-20 (C _1-2 ), 1-15 (d- ₁₅ ), 1-10 (C, - ₁₀ ) , a linear saturated monovalent hydrocarbon group of 7 (Cw) or Η (CH) carbon atoms, or 3 - 20 (C ₃ - ₂₀ ), Branched saturated monovalent hydrocarbon groups of 3- 15 (C ₃ - ₁₅ ) , 3- 10 (C ₃ - , .), 3-7 (C ₃ - ₇ ) or 3- 4 (C ₃ - ₄ ) carbon atoms . Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomeric forms), hexyl (including all isomeric forms), heptyl (including all isomeric forms), octyl (including all isomeric forms), thiol (including all isomeric forms), thiol (including all isomers) Form), undecyl (including all isomeric forms), dodecyl (including all isomeric forms), tridecyl (including all isomeric forms), tetradecyl (including all isoforms) In the form of a structure, fifteen fluorenyl (including all isomeric forms), hexadecyl (including all isomeric forms), heptadecyl (including all isomeric forms), octadecyl (including All isomeric forms), nonadecyl (including all isomeric forms) and decyl (including all isomeric forms). For example, C _W thiol refers to a linear saturated monovalent hydrocarbon radical of 1 to 7 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 7 carbon atoms.

"Mercapto" may be optionally substituted by one, two, three or four of the following substituents: halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cyclodecyloxy, heteroepoxy Base, oxo, chain decanoyl, aryloxy, decanoyloxy, amino, alkylamino, arylamino, arylmethylamino, cyclodecylamino, heterocyclic amino, substituted tertiary ammonia (of which 2 nitrogen The substituent is selected from decyl, aryl or aryl fluorenyl, alkanoylamino, aroylamino, aryl decanoylamino, substituted alkanoylamino, substituted arylamino, substituted aryl decanoyl, thiol, hydrazine Thiothio, arylthio, aralkylthio, cycloalkylthio, heterocyclicthio, alkylthiocarbonyl, arylthiocarbonyl, arylsulfonylthio, decylsulfonyl, aryl Sulfonyl, arylsulfonylsulfonyl, sulfinylamino (eg S0 ₂ NH ₂ ), substituted sulfonamido, nitro, cyano, carboxy, carbamoyl (eg C0NH ₂ ), substituted carbamoyl (eg C0NH fluorenyl, C0NH aryl, C0NH aryl fluorenyl or two substituents on the nitrogen) In the case of an alkyl group, an aryl group or an aryl group, an alkoxycarbonyl group, an aryl group, a substituted aryl group, a fluorenyl group and a heterocyclic group (for example, an anthracenyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group) , pyrrolidinyl, pyridyl, pyrimidinyl, etc.). The above substituent may be further substituted with a halogen, a mercapto group, an alkoxy group, an aryl group or an aryl group.

The term "alkoxy" refers to a straight one having 1 ^OO^ 1-15 (CBu ₁₅ ), 1-10 ((:, —, .), l_7 (Cw) or 1- 4 (C^) carbon atoms. or a saturated monovalent hydrocarbon chain of _{3-20 (C 3 2.),} 3- 15 (- 3-10 (C: MO), 3-7 (C 3 - 7) or 3- 4 (C _M) carbon atoms a branched group of a saturated monovalent hydrocarbon group bonded to an oxygen atom. Examples of the decyloxy group include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, and an isobutyl group. Oxyl, sec-butoxy, tert-butoxy, pentyloxy (including all isomeric forms), hexyloxy (including all isomeric forms), heptyloxy (including all isomeric forms), octyl Oxyl (including all isomeric forms), decyloxy (including all isomeric forms), decyloxy (including all isomeric forms), undecyloxy (including all isomeric forms), ten Dialaloxy (including all isomeric forms), tridecyloxy (including all isomeric forms), tetradecyloxy (including all isomeric forms), fifteen decyloxy (including all isomeric) Constructive form), hexadecyloxy (including In the form of isomers), heptadecyloxy (including all isomeric forms), octadecyloxy (including all isomeric forms), nineteen decyloxy (including all isomeric forms) and Decaconoxy (including all isomeric forms).

The term "alkylamino" means that 1 or 2 of H of - ₂ are each having 1 - 10 θ _ιη ), 1-6 or 1-4 (C, - ₄ ) a linear sulfhydryl group of a carbon atom or a branched group substituted with 3-10 (C _:M .), 3- 6 (C) or 3-4 (C) carbon atoms; when the above two H are simultaneously When substituted, the substituents may be the same or different. Examples of alkylamino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, n-butylamino, isobutylamino, t-butylamino, Di-n-butylamino, diisobutylamino, di-tert-butylamino, pentylamino, dipentylamino, hexylamino, dihexylamino, heptylamino, diheptylamino, octylamino, dioctylamino, decylamino, dinonylamino, Amidino, di-amino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-isopropylamino, N-methyl-N-butyl Amino, N-methyl-N-isobutylamino, N-methyl-N-tert-butylamino, N-methyl-N-pentylamino, N-methyl-N-hexylamino, N-A -N-heptylamino, N-methyl-N-octylamino, N-methyl-N-decylamino, N-methyl-N-decylamino, N-ethylpropylamino, N -ethyl-N-isopropylamino, N-ethyl-N-butylamino, N-ethyl-N-isobutylamino, N-ethyl-N-tert-butylamino, N-ethyl -N-pentylamino, N-ethyl-N-hexylamino, N-ethyl-N-heptylamino, N- Ethyl-N-octylamino, N-ethyl-N-decylamino, N-ethyl-N-decylamino, N-propyl-N-isopropylamino, N-propyl-N- Butylamino, N-propyl-N-isobutylamino, N-propyl-N-tert-butylamino, N-propyl-N-pentylamino, N-propyl-N-hexylamino, N -propyl-N-heptylamino, N-propyl-N-octylamino, N-propyl-N-decylamino, N-propyl-N-decylamino, N-isopropyl-N -butylamino, N-isopropyl-N-isobutylamino, N-isopropyl-N-tert-butylamino, N-isopropyl-N-pentylamino, N-isopropyl-N -hexylamino, N-isopropyl-N-heptylamino, N-isopropyl-N-octylamino, N-isopropyl-N-decylamino, N-isopropyl-N-fluorenyl Amino, N-butyl-N-isobutylamino, N-butyl-N-tert-butylamino, N-butyl-N-pentylamino, N-butyl-N-hexylamino, N-butyl -N-heptylamino, N-butyl-N-octylamino, N-butyl-N-decylamino, N-butyl-N-decylamino, N-isobutyl-N-tert Butylamino, N-isobutyl-N-pentylamino, N-isobutyl-N-hexylamino, N-isobutyl-N-heptylamino, N-isobutyl -N-octylamino, N-isobutyl-N-decylamino, N-isobutyl-N-decylamino, N-tert-butyl-N-pentylamino, N-tert-butyl-N -hexylamino, N-tert-butyl-N-heptylamino, N-tert-butyl-N-octylamino, N-tert-butyl-N-decylamino, N-tert-butyl-N-fluorenyl Amino, N-pentyl-N-hexylamino, N-pentyl-N-heptylamino, N-pentyl-N-octylamino, N-pentyl-N-decylamino, N-pentyl- N-decylamino, N-hexyl-N-heptylamino, N-hexyl-N-octylamino, N-hexyl-N-decylamino, N-hexyl-N-decylamino, N-heptyl -N - octylamino, N-heptyl-N-decylamino, N-heptyl-N-decylamino, N-octyl-N-decylamino, N-octyl-N-decylamino , N-fluorenyl-N-decylamino, and all isomeric forms of the above amino groups, and the like.

The term "halogen" or "halo" refers to fluoro, chloro, bromo and iodo.

The term "hydrocarbyl" refers to a functional group containing only two atoms of carbon and hydrogen.

The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenylyl and diphenyl, each of which may be substituted.

"Aryl" may be optionally substituted by the following substituents: for example, fluorenyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, decyloxy, cycloalkoxy, heterocyclooxy, alkanoyl , chain decanoyloxy, amino, alkylamino, aralkylamine Base, cyclodecylamino, heterocyclic amino, dinonylamino, decanoylamino, thiol, decylthio, cyclodecylthio, heterocyclic thio, ureido, nitro, cyano, carboxy And a carboxy fluorenyl group, a carbamoyl group, a decyloxycarbonyl group, a fluorenylthiocarbonyl group, an arylthiocarbonyl group, a decylsulfonyl group, a sulfinylamino group, an aryloxy group or the like. The substituent may be further substituted with a halogen, a hydroxyl group, a decyl group, a decyloxy group or an aryl group.

The term "aryl" refers to an aryl group bonded directly through a thiol group, such as benzyl, phenethyl, phenylpropyl.

The term "alkenyl" refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, most preferably from 2 to 6 carbon atoms, having from one to four double bonds, and also includes Groups having "cis" and "trans" configurations, or "E" and "Z" configurations, will be understood by those skilled in the art.

"Alkenyl" may be optionally substituted by, for example, halogen, hydroxy, alkoxy, alkanoyl. Alkanoyloxy, amino, mercaptoamino, dinonylamino, alkanoylamino, thiol, alkylthio, decylthiocarbonyl, alkylsulfonyl, sulfinamide, nitro, a cyano group, a carboxyl group, a carbamoyl group, a substituted carbamoyl group, a fluorenyl group, and a heterocyclic group, such as a fluorenyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group, etc. .

The term "alkynyl" or "alkynyl" refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, and most preferably from 2 to 6 carbon atoms, having from one to four triple bonds. The groups also include groups having the "cis" and "trans" configurations, or the "E" and "Z" configurations, as will be understood by those skilled in the art.

"Alkynyl" may be optionally substituted by the following substituents: halogen, hydroxy, alkoxy, alkanoyl, decanoyloxy, amino, decylamino, dimethylamino, decanoylamino, sulphur Hydroxy, alkylthio, decylthiol, alkylsulfonyl, sulfinamido, nitro, cyano, carboxy, carbamoyl, substituted carbamoyl, fluorenyl and heterocyclic, eg imidazole A group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group or the like.

The term "cycloalkyl" refers to an optionally substituted, saturated ring containing preferably from 1 to 3 rings and each ring (which may be further fused to an unsaturated C ₃ -C ₇ carbocycle) containing from 3 to 7 carbons. Cyclic hydrocarbon ring system. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododedecyl and adamantyl. Exemplary substituents include one or more sulfhydryl groups as described above, or one or more thiol substituents as described above.

The terms "heterocyclic", "heterocyclic" and "heterocyclyl" refer to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic ring group, for example, the ring is a 4-7 membered monocyclic ring, A 7- to 11-membered bicyclic or 10-15 membered tricyclic system containing at least one heteroatom on a ring containing at least one carbon atom. The hetero atom-containing heterocyclic group may have 1, 2, 3 or 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom on each ring, wherein the nitrogen and sulfur hetero atoms may also optionally be The oxidized and nitrogen heteroatoms can also optionally be quaternized. The heterocyclic group can be attached to any hetero atom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indenyl, pyrazolyl, oxabutyryl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolyl, oxazolyl, Oxazolidine, isoxazolinyl, isoxazolyl, thiazolyl, thiadipine Azyl, thiazolyl, isothiazolyl, isothiazolyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperrazinyl, 2-oxo Piperidinyl, 2-oxopyrrolenyl, 2-oxoazepine, azetyl, 4-piperidinone, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl , pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, tetrahydrothiopyranyl sulfone, thiamorpholinyl sulfone, 1, 3-dioxolanyl and tetrahydro-1,1-dioxothiophenyl, dioxolane, isothiazolidinyl, thiabutanyl, thiirane, triazinyl and Triazolyl and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, iso Quinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromenyl, coumarinyl, 1,2-naphthyridinyl, quinoxalinyl, anthracene Azyl, pyrrolopyridyl, furopyridinyl (eg, furo[2,3-c]pyridyl, furo[3,1-b]pyridyl or furo[2,3-b]pyridinyl) , dihydroisoindolyl, dihydroquinazolinyl (eg 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazepine Azinyl, benzofuranyl, benzothiopyranyl, benzotriazolyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzothiopyranyl, dihydrogen Benzothiopyranyl sulfone, dihydrobenzopyranyl, indanyl, isochroman, isoindoline, 1,5-naphthyridinyl, 2, 3 - diaza naphthyl, 3, 4-methylenedioxybenzyl Purine-yl, pyridyl and pyridyl, quinazolinyl, tetrahydroquinolinyl, thienyl and furyl, thienyl and pyridyl, thienyl and thienyl group.

Smaller heterocycles such as epoxides and aziridines are also included.

The term "heteroatom" includes oxygen, sulfur and nitrogen.

The term "pharmaceutically acceptable salt" includes salts of the active compounds which are prepared according to the particular substituents present on the compounds described herein using relatively non-toxic acids or bases. When a compound of the invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either alone or in a suitable inert solvent. Examples of the salt derived from a pharmaceutically acceptable inorganic base include aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamino, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine , theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound of the invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either alone or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as nitrates, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, sulfates, Hydrogen sulphate, phosphite, hydrochloride, hydrobromide, hydroiodide, etc.; from relatively non-toxic organic acids a derivative salt, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluene Sulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid or galactonic acid. Preferred are nitrates, carbonates, hydrogencarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, sulfates, hydrogen sulfates, phosphites, acetates, propionates, isobutyrates, propylene Acid salt, benzoate, succinate, suberate, fumarate, mandelate, phthalate, besylate, p-toluenesulfonate, citrate, tartrate, Methanesulfonate, arginine salt, glucuronate or galactate.

In some embodiments provided herein, the leaving group of the compound of the present invention contains a basic group which can be salted with an acid, and a salt of the platinum (I I) compound can be prepared by a method well known to those skilled in the art. Corresponding salts can also be formed with inorganic acids such as nitric acid, carbonic acid, sulfuric acid or phosphoric acid. The acids which can be used include organic acids, inorganic acids and the like. For example, a lower sulfonic acid such as methanesulfonic acid or trifluoromethanesulfonic acid can form a methanesulfonate or a triflate; and an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid. Forming p-toluenesulfonate, besylate, camphorsulfonate; with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, lactic acid or citric acid Forming the corresponding salt; forming an glutamate or aspartate with an amino acid such as glutamic acid or aspartic acid.

The form of the compound of the present invention and its salt can be converted into each other by a conventional method in the art, for example, by contacting the salt with a base or an acid and then separating the compound in a free form in a conventional manner, or by adding the compound to an acid or a base. The salt form is isolated by conventional methods. Certain physical properties of the free form of the compound, e.g., solubility in polar solvents, differ from the various salt forms, but for the purposes of the present invention, the salt has the same antitumor effect as the parent form of the compound.

In addition to the salt form, the invention provides a compound in the form of a prodrug ester. "Prodrugs" of the compounds described herein are those compounds which readily undergo chemical changes under physiological conditions to give the compounds of the invention. Alternatively, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the invention when placed in a transdermal patch reservoir containing a suitable enzyme or chemical reagent. Prodrugs are often pharmacologically inert compounds prior to conversion to the active drug, but this is not required. The "precursor moiety" of the active drug can be obtained by masking a functional group of the drug that may be required for the active moiety with a "precursor group" (defined below) to form a functional group that can be converted (eg, cleaved under specific conditions of use) to release the functional group. ", get a prodrug. The precursor moiety can be catalyzed or induced, for example, by a hydrolysis reaction, or by another substrate (such as an enzyme, light, acid or base) or physical or environmental parameter changes (such as temperature changes) or exposure to physical or environmental parameters. , for spontaneous lysis. The agent may be endogenous to the environment of use, such as an enzyme present in the cells to which the prodrug is administered or an acidic environment of the stomach, or may be provided by an exogenous source.

"Precursor group" refers to a class of protecting groups that are capable of converting a drug into a prodrug when used to mask a functional group in the active drug to form a "precursor moiety." The precursor group is typically linked to the functional group of the drug by a bond which is cleavable under the particular conditions of use. Thus, the precursor group is part of a precursor moiety that is cleaved under specific conditions of use and released Functional group. As a specific example, the formula -NH-C (0) CH ₃ amide promoiety comprising a precursor group - C (0) CH _3.

A wide variety of precursor groups suitable for masking functional groups in the active compound to give prodrugs and the resulting precursor moieties are well known in the art. For example, the hydroxy functionality can be masked to a sulfonate, ester (e.g., acetate or maleate) or carbonate precursor moiety which can be hydrolyzed in vivo to provide a hydroxyl group. The amino functional group can be masked to an amide, carbamate, imine, urea, phenylphosphino, pity acyl or oxythio precursor moiety which can be hydrolyzed in vivo to give an amino group. The carboxyl group can be masked as an ester (including methyl, ethyl, pivaloyloxymethyl, silicylide, and thioester), an amide or a hydrazide precursor which can be hydrolyzed in vivo to give a carboxyl group. The present invention includes those esters and acyl groups known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. Specific examples of suitable precursor groups and their corresponding precursor moieties will be apparent to those skilled in the art.

Certain compounds of the invention may exist in unsolvated as well as solvated forms including hydrated forms. "Solvate" means a complex formed by the combination of a solvent molecule and a molecule or ion of a solute. The solvent may be an organic compound, an inorganic compound or a mixture of the two. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in a polymorphic or amorphous form. In general, all physical forms are the same and are within the scope of the invention for the purposes contemplated by the present invention.

Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (eg, isolated enantiomers) All are included in the scope of the invention. These isomers may be resolved or asymmetrically synthesized by conventional methods to render the isomer "optically pure", i.e., substantially free of other isomers thereof. For example, if a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved. The pure desired enantiomer is obtained. Alternatively, when the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, an asymmetrically active salt is formed with a suitable optically active acid or base, and then the resulting non-form is formed by fractional crystallization or chromatographic methods well known in the art. The enantiomers are resolved and the pure enantiomers are recovered.

The compounds of the invention may also contain an unusual proportion of atomic isotopes in one or more of the atoms that make up the compound. For example, the compound can be labeled with a radioactive isotope such as hydrazine (3⁄4), iodine-125 ( ^'25 1) or carbon-14 ( ¹⁴ C). All isotopic forms of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention.

Another object of the present invention is to provide a process for the preparation of the aforementioned compounds.

1. The preparation method of the formula (A) comprises the following steps:

(1): Take potassium chloroplatinate and add water, stir and dissolve at room temperature, take potassium iodide and dissolve in water, put it into the above potassium chloroplatinate solution, and react under nitrogen and water bath conditions;

(2): Take 1? ₄ ^1 ₂ dissolved in water, and then added dropwise to the reaction solution of (1), and the reaction is carried out under water bath conditions; (3): The reaction solution is cooled to room temperature or lower, dissolved in 1 ^ water, added dropwise to the reaction solution of (2), and reacted in a water bath to form a large amount of yellow precipitate. The temperature in the reaction solution is cooled to room temperature and filtered. After washing, diiododiamine platinum (11) is obtained.

(4): Ag ₂ S0Jm is stirred in water, and the above diiododiamine platinum (II) is added to the reaction solution, water is added, and the reaction is carried out under nitrogen-protected water bath, and filtered to obtain dihydrated diamine. Platinum (II) · Sulfate.

(5): Take diethyl malonate, and Br-R ₃ -Br in a flask, add K ₂ C (3⁄4, tetrabutylammonium bromide, stir, heat, filter, remove solids and wash, The filtrate was combined, the organic layer was washed, dried, and the solvent was evaporated under reduced pressure, and the distillate was collected.

(6): Diethyl 2-Br-R ₃ -malonate was placed in a flask, and anhydrous 1 ( ₂ (0 _{3 )} , and acetonitrile was added and stirred.

The reaction mixture is added to the reaction mixture, the reaction is heated, and the insoluble material is filtered off. The filtrate is dried, dissolved in an organic solvent, washed with an aqueous solution, and dried over organic solvent.

(7): The product of (6) was placed in a flask, and a NaOH solution was added thereto, followed by stirring at room temperature.

(8): Take (7) the product, adjust the pH with an acid solution, add the product of (4) above, and heat the reaction.

The preferred preparation method is as follows:

(1): Take potassium chloroplatinate and add water, stir and dissolve at room temperature, take potassium iodide and dissolve in water, put it into the above potassium chloroplatinate solution, protect with N ₂ , take care to avoid light, and react in water bath at 40~60 °C. ~60min;

(2): taking R ₄ NH ₂ dissolved in water, adding dropwise to the reaction solution of (1), and reacting in a water bath at 40-60 ° C for 30-60 min;

(3): The reaction solution is cooled to below 20 ° C, dissolved in R ₅ NH ₂ with water, added dropwise to the reaction solution of (2), and reacted in a water bath at 40-60 ° C for 30-60 min, and a large amount of yellow precipitate is formed. The temperature in the reaction liquid was cooled to 20 ° C or less and filtered under suction, and washed with water, anhydrous ethanol and diethyl ether to obtain diiododiamine platinum (11).

(4): Ag ₂ S0 _{4 is} added to the water and stirred. The above diiododiamine platinum (II) is added to the reaction solution, water is added, protected, and reacted at 40 to 60 ° C for 4 to 8 hours in the dark. The dihydrate diamine platinum (II) sulfate was filtered.

(5): Take diethyl malonate, and Br-R ₃ -Br in a flask, add K ₂ C, stir the tetrabutyl bromide, heat the reaction in an oil bath, filter by suction, remove the solid and wash with ether. The filtrate was combined, the organic layer was washed with water, dried, and the solvent was evaporated under reduced pressure to collect a distillate of a vacuum.

(6): 2-Br-R ₃ -malonic acid diethyl ester was placed in a three-necked flask, and anhydrous 1 ( ₂ (:0 ₃ ) was added and stirred with acetonitrile.

Also take _B ^R '>. The reaction mixture was added to the reaction mixture, and the reaction was heated in an oil bath. The insoluble material was filtered off. The filtrate was evaporated, and then ethyl acetate was dissolved. The mixture was washed with a saturated aqueous solution of NaCI, and the organic layer was dried.

(7): The product of (6) was placed in a flask, and the above NaOH solution was added thereto, followed by stirring at room temperature. (8): Take (7) the product, adjust with an acid solution, then add the product of (4) above, heat the reaction -

1

^Cl/ "'.

H ₂

2. The preparation method of formula (c) is as follows:

(1): Take potassium chloroplatinate and add water, stir and dissolve at room temperature, take potassium iodide and dissolve in water, put it into the above potassium chloroplatinate solution, and react under nitrogen-protected water bath conditions;

(2): The bidentate ammonia NH ₂ -X-NH ₂ is dissolved in water and added dropwise to the reaction solution of (1). The reaction is carried out in a water bath, and a large amount of yellow precipitate is formed. The temperature in the reaction liquid is cooled to room temperature and filtered. After washing, bidentate diiododiamine platinum (11) is obtained.

(3): Ag ₂ S0 _{4 is} added to water and stirred, and the above diiododiamine platinum (ruthenium) is added to the reaction liquid, water is added, and the reaction is carried out under nitrogen-protected conditions under a nitrogen bath, and filtered to obtain dihydrated diamine. Platinum (II) · Sulfate.

(4): Take ethyl malonate, and Br-R ₃ -Br in a flask, add 1 UX) ₃ , stir the tetrabutylammonium bromide, heat the reaction, suction filtration, remove the solid and wash, and combine the filtrate. The organic layer was washed, dried, and the solvent was evaporated under reduced pressure to distill.

(5): 2-Br-R ₃ -malonic acid ethyl ester was placed in a flask, anhydrous K ₂ CO _{3 3 was added} , and acetonitrile was stirred.

Also take, . After the reaction mixture was added, the reaction mixture was heated, and the insoluble material was filtered. The filtrate was evaporated, and then ethyl acetate was dissolved, washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried.

(6): The product of (5) was placed in a flask, and a NaOH solution was added thereto, followed by stirring at room temperature.

(7): Take (6) the product, adjust with an acid solution, then add the product of the above (3), and heat the reaction. Preferred

(2): Take the bidentate ammonia NH ₂ -X-NH ₂ dissolved in water and then add dropwise to the reaction solution of (1). The reaction is carried out in a water bath at 40-60 ° C for 30-60 min. A large amount of yellow precipitate is formed, and the reaction solution is formed. The internal temperature was cooled to below 20 ° C and filtered under suction, followed by washing with water, absolute ethanol and diethyl ether to obtain a bidentate diiododiamine platinum (11).

(3): Take Ag ₂ S0 „ add water to stir, take the above diiododiamine platinum (II) into the reaction solution, add water, protect with N ₂ and react at 40~60′C for 4~8h in the dark. , suction filtration to obtain dihydrate diamine platinum (Π) · sulfate.

(4): Take ethyl malonate, and Br-R ₃ -Br in a flask, add K ₂ C0 ₃ , stir the tetrabutylammonium bromide, heat the reaction in an oil bath, filter by suction, remove the solid and wash with ether. The filtrate was combined, and the organic layer was washed with water, dried, and the solvent was evaporated under reduced pressure to collect a distill.

(5): Ethyl 2-Br-R ₃ -malonate was placed in a three-necked flask, anhydrous K ₂ C0 _{3 was added} , and acetonitrile was stirred. Further, R, _NH-R _{2 is} added to the reaction solution, and the reaction is heated in an oil bath. The insoluble matter is filtered off, the filtrate is drained, dissolved in ethyl acetate, washed with a saturated aqueous solution of NaCl, and the organic layer is dried. , purified.

(6): The product of (5) was placed in a flask, and the above NaOH solution was added thereto, followed by stirring at room temperature.

(7): Take (6) the product, adjust the pH with an acid solution, add the product of (3), and heat the reaction.

" ^CI// ', 丄, ",,, ci 4KI X

1〃"',,一,,,,,\|

'Pt" NH.

CI

The product obtained above can also be further prepared as a chiral compound and other pharmaceutically acceptable salts by conventional methods in the art. For example, the obtained product is made into a free base at a pH of 9-11, dissolved in an organic solvent such as methanol or ethanol, and reacted with a different acid to form a corresponding salt; or The obtained compound is dissolved by adding water, cooled, and then filled with an anion exchange resin (0H type) column to be converted into a quaternary ammonium hydroxide obtained by replacing the other anion radicals with a hydroxyl group, and the corresponding salt is obtained by adding an acid; In the chiral center, the obtained compound can also be made into a free base under the condition of pH 9-11, dissolved in a small molecule alcohol such as methanol, ethanol and the like, and an appropriate amount of chiral mandelic acid solution is obtained. The chiral mandelic acid salt crystallizes and can be obtained by repeated operations to obtain a pure chiral product. The present invention also provides a pharmaceutical composition comprising the above compound, a pharmaceutically acceptable salt, a stereoisomer, a prodrug or a solvate thereof, and a pharmaceutically acceptable carrier and/or excipient. The composition contains from 0.01% to 100%, preferably from 0.1% to 100%, more preferably from 1% to 100%, still more preferably from 20% to 100% by weight, of one or more compounds of the invention, the remainder Part of it consists of a suitable pharmaceutical carrier and/or excipient. Compositions of the compounds of the invention may be combined with the routes of administration by methods well known in the art using suitable carriers and/or excipients.

The amount of active compound in a unit dosage formulation may vary from 0.001 mg to 1000 mg, preferably from 0.1 mg to 500 tng, more preferably from 1 mg to 100 mg, most preferably from 10 mg to 50 mg.

Administration can be, for example, oral, topical, intravenous, subcutaneous, transdermal, transdermal, intramuscular, intra-articular, parenteral, intra-arterial, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, intranasal , rectal, vaginal, inhaled or through an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered intravenously. The formulations of the invention may be designed to be fast acting, immediate release or long lasting. Still further, the compound can be administered by topical rather than systemic means, e.g., administration (e.g., injection) of a sustained release formulation. According to a representative embodiment, the compositions of the invention may be formulated as a medicament for administration to a mammal, preferably a human.

The composition comprising one or more of the invention may be administered repeatedly, for example at least 2, 3, 4, 5, 6, 7, 8 or more times, or the composition may be administered by continuous infusion. Suitable sites for administration include, but are not limited to, blood vessels, muscles, skin, bronchi, gastrointestinal, anus, vagina, eyes and ears. The preparation may be in the form of a liquid dosage form, a lyophilized powder form, a solid or a semi-solid, such as a solution, a suspension, an emulsion, a tablet, a pill, a capsule, a powder, a suppository, a retention enema, a cream, an ointment, a lotion A gelling agent, an aerosol, or the like is preferably suitable for simply administering an accurate dosage unit dosage form.

For parenteral administration, the compositions may be in the form of a sterile injectable solution and a sterile packaged powder. Preferably, the injection is prepared in 114. 5-7.

The compositions of the invention in sterile injectable form are aqueous or oily suspensions. These suspensions may be formulated with suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension or dispersion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are often used as solvents. Or suspending the matrix. For this purpose, any brand of non-volatile oil including synthetic mono- or diglycerides can be used. In the same manner as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated form, fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable preparations. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersions typically used in formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Agent. Other commonly used surfactants such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms are also useful for formulation purposes. Compounds for parenteral administration by injection, for example, bolus injection or continuous infusion, can be formulated. Unit dosage forms for injection can be in ampoules or in multi-dose containers.

Compositions of the invention may also be provided in lyophilized form. Such compositions may comprise a buffer such as a hydrogencarbonate for reconstitution prior to administration, or a buffer may be included in the lyophilized composition for, for example, water reconstitution. The lyophilized composition may also contain a suitable vasoconstrictor, such as epinephrine. The lyophilized composition can be provided by syringe, optionally packaged with a buffer for reconstitution, so that the reconstituted composition can be administered to the patient immediately.

The pharmaceutical composition of the present invention may also be in any orally acceptable dosage form, including tablets, capsules, cachets, emulsions, suspensions, solutions, syrups, elixirs, sprays, pills, troches, powders. , granules and sustained release preparations. Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. A lubricant such as magnesium stearate is usually also added. For capsules, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is mixed with emulsifying and suspending agents. Some sweeteners, flavoring agents or coloring agents may also be added as appropriate.

It may be formed, for example, for oral administration by dissolving or dispersing one or more compounds of the invention and optionally one or more pharmaceutically acceptable excipients in a carrier such as a saline solution, aqueous dextrose, glycerol, ethanol or the like. A liquid or composition is prepared by topical or intravenous administration of a solution or suspension. Pharmaceutical preparations in the form of liquid suspensions or solutions may be prepared using sterile liquids such as oil, water, ethanol, and combinations thereof. For oral or parenteral administration, a suitable surfactant, suspending agent or emulsifier may be added to the agent. The suspension may contain oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. The suspension formulation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate; fatty acid glycerides and acetyl fatty acid glycerides. The suspension formulation may contain an alcohol such as ethanol, isopropanol, cetyl alcohol, glycerol and propylene glycol. Ethers such as poly(ethylene glycol); petroleum hydrocarbons such as mineral oil and petrolatum, water can also be used in suspension formulations.

The composition may be in the form of a pill, a tablet or a capsule, and thus, the composition may contain one or more diluents such as lactose, sucrose, dicalcium phosphate, etc.; a disintegrating agent such as starch or a derivative thereof; Lubricants, such as magnesium stearate, and the like; and/or binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, and derivatives thereof. Tablets can be prepared by any compression or molding process known to those skilled in the art. Can be optionally and assisted by pressing in a suitable machine A compressed tablet of the present invention in a free-flowing form (e.g., powder or granule) in admixture (e.g., a binder, a lubricant, a diluent, a disintegrant, or a dispersing agent) is prepared. Molded tablets may be made by molding in a suitable machine a powder mixture of the compound of the invention and any suitable carrier.

Alternatively, the pharmaceutical compositions of the invention may be in the form of a suppository for rectal administration. These suppositories can be prepared by admixing the drug with suitable suitable non-irritating excipients which are solid at room temperature but liquid at the rectal temperature and thereby release the drug in the rectum. Such materials include cocoa butter, beeswax, polyethylene glycol, hard fat and/or hydrogenated cocoglyceride. Compositions suitable for rectal administration may also contain rectal enema units containing one or more compounds of the invention and a pharmaceutically acceptable vehicle (for example, a 50% aqueous solution of ethanol or saline), such vehicles and rectal and / or the colon is physiologically compatible. The rectal enema unit contains an applicator tip protected by an inert lid which preferably consists of polyethylene, lubricated with a lubricant such as white petrolatum, preferably protected by a one-way valve to prevent backflow of the ejected drug. The rectal enema unit is also of sufficient length, preferably 2 inches, to be inserted through the anus into the colon.

The pharmaceutical compositions of the present invention may also be in the form of topical administration, especially when the therapeutic target includes areas or organs which are easily accessible by topical application, and diseases of these organs include diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations for use in these areas or organs or organs in these organs are readily prepared. For topical administration, compositions containing one or more compounds of the invention may be in the form of emulsions, lotions, gels, foams, creams, jellies, solutions, suspensions, ointments and transdermal patches. .

Topical administration in the lower intestinal tract can be achieved by a rectal suppository formulation or a suitable enema formulation. Topical transdermal patches can also be used. For topical administration, a pharmaceutical composition in the form of a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers may be formulated. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, a pharmaceutical composition in the form of a suitable lotion or cream may be formulated containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, Span-60, Tween-60, cetyl ester, wax, cetyl alcohol, 2-octyl decadiol, benzyl alcohol and water.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. For delivery by inhalation, a dry powder or liquid form of the composition can be delivered by a nebulizer. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation, and may be employed in saline, with benzyl alcohol or other suitable preservatives, bioavailability absorption enhancers, fluorocarbons and/or other conventional solubilizing agents or A dispersant prepares a composition in the form of a solution.

Pharmaceutically acceptable carriers which can be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate; glycine, sorbic acid, potassium sorbate a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. Examples of suitable excipients include, but are not limited to, water, saline, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acid, such as carbopol. The compositions may also contain lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers; suspending agents; preservatives such as methyl-, ethyl- and propyl-hydroxy-benzoates; Regulators such as inorganic and organic acids and bases; sweeteners; and flavoring agents.

In addition to those representative dosage forms described above, other pharmaceutically acceptable excipients and carriers and dosage forms are generally known to those skilled in the art and are included in the present invention. It will be understood that the particular dosage and treatment regimen of any particular patient will depend on a variety of factors, including the activity of the particular compound employed, the age, weight, general health, sex, condition, time of administration, rate of excretion, The combination of the drug, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of active ingredient will also depend on the particular compound and, if present, other therapeutic agents in the composition.

The above pharmaceutical compositions may further comprise other active ingredients for the treatment or adjuvant treatment of proliferative diseases, or in combination with other drugs for the treatment or adjuvant treatment of proliferative diseases. For example, an anti-proliferative agent, an immunomodulator, an anticancer drug, a cytotoxic agent, and an antitumor auxiliary drug other than the present invention are used in combination.

Examples of other such therapeutic agents include: anti-proliferative agents such as methotrexate, FK506 ( _Futomycin , Pro _gra f), mycophenolic mofetil; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-α inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptors, such as etanercept (Enbrel); rapamycin, Ieflunimide, and cyclooxygenase-2 (C0X-2) inhibitors, such as Celecoxib and rofecoxib, or derivatives thereof; and PTK inhibitors disclosed in the prior art.

Typical types of anticancer and cytotoxic agents include, but are not limited to, alkylating agents such as nitrogen mustard, alkyl sulfonates, nitroureas, aziridines and triazene; antimetabolites such as folic acid Salt antagonists, purine analogs and pyrimidine analogs; antibiotics such as anthracycline, bleomycin, mitomycin, dactinomycin and plenummycin, enzymes such as L-asparaginase; Nylon protein transferase inhibitors; hormone agents, for example, glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progesterone, luteinizing hormone releasing hormone antagonists, acetic acid, and microtubule destruction Agents such as echinosin or analogues and derivatives thereof; microtubule stabilizers, such as paclitaxel, docetaxel, and othi lone or analogs or derivatives thereof; plant-derived products, such as vinca alkaloids, table ghosts Scorpion toxin, taxane; topoisomerase inhibitor; isoprenyl protein transferase inhibitor; heterogeneous reagent, for example, hydroxyurea, procarbazine, chlorobenzoic acid, hexamethylene Amine, Platinum coordination complexes such as cisplatin and carboplatin; and other agents and cytotoxic agents for anticancer, such as biological response modifiers, growth factors; immunomodulators and monoclonal antibodies. The compounds of the invention may also be used in combination with radiation therapy.

Examples of these classes of anticancer and cytotoxic agents include, but are not limited to, nitrogen mustard, cyclophosphamide, chlorambucil, anti-tumorine, ifosfamide, busulfan, carmustine, ring Nitrosourea, nitrosourea, streptozotocin, thiotepa, dacarbazine, methotrexate, thiopterin, guanidinium, fludarabine, pentastat in, claripine, a Sugar Cytidine, fluorouracil, doxorubicin hydrochloride, daunorubicin, demethoxydaunorubicin, bleomycin sulfate, mitomycin (:, actinomycin D, safracins, small nomiline, quinocarcins , discodermol ides, vincristine, vinblastine, vinorelbine tartrate, etoposide, podophyllotoxin, paclitaxel, tamoxifen, estramustine, estradiol sodium salt, fluridine, fluritan Relin, Lipian, pteridine, diacetylene, levamisole, aflacoru interferon, interleukin, aldileukin, philsidine, bone marrow growth factor, rituximab, BCG, retinoic acid, irinotecan Hydrochloride, betamethasone, gemcitabine hydrochloride, hexamethyleneamine and topotecan, and any analogs or derivatives thereof.

Preferred members of these categories include, but are not limited to: paclitaxel, cisplatin, carboplatin, doxorubicin, noredamycin, daunorubicin, aminoguanidine, methotrexate, methylhydrazine, silk Mycomycin (:, ecteinascidin, buffomycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytarabine, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or ghost Lethiophene glycosides, anti-tyrosine, vinblastine, vincristine, isovinblastine, vindesine, and vinorelbine.

Examples of antineoplastic agents and other cytotoxic agents include: US6262094, DE4138042, W097/19086, W098/2246K W098/25929, W098/38192, W099/01124, W099/02224 W099/02514, W099/03848, W099/07692, W099/27890, W099/28324> W099/43653, W099/54330 W099/54318, W099/54319, W099/65913, W099/67252, W099/67253, and epothi lone derivatives in WOOO/00485; W099/24416 Cyclin dependent kinase inhibitors; and isoprenyl protein transferase inhibitors such as W097/30992 and W098/54966.

The above other therapeutic agents, when used together with the compounds of the present invention, can be used, for example, in the dosages indicated in the clinical manual, or in dosages determined by those of ordinary skill in the art.

Finally, the invention also provides a method of treating a cell proliferative disorder comprising administering to a patient in need thereof an effective amount of a compound of formula A.

"Cell proliferative disorder" refers to a disorder characterized by abnormal proliferation of cells. Proliferative disease does not imply any limitation on the rate of cell growth, but merely indicates loss of normal control of growth and cell division. Thus, cells of proliferative disease can have the same rate of cell division as normal cells, but do not respond to signals that limit this growth. "Cell proliferative disease" is in the range of neoplasms or tumors, and neoplasms or tumors are abnormal growth of tissues. "Cancer" refers to any of a variety of malignant tumors characterized by cell proliferation that have the ability to invade surrounding tissues and/or metastasize to new colonization sites.

In general, cell proliferative disorders that can be treated with the compounds disclosed herein involve any disorder characterized by abnormal cell proliferation. These include a variety of benign or malignant, metastatic or non-metastatic tumors and cancers. The specific properties of cancer, such as tissue invasiveness or metastasis, can be combated by the methods described herein. Cell proliferative diseases include a variety of cancers, including but not limited to: cancer: including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, Gastric cancer, gallbladder cancer, cervical cancer, thyroid cancer, skin cancer, and squamous cell carcinoma; Hematopoietic tumors of the lymphatic system: including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, beta-cell lymphoma, T-cell lymphoma, Hodgkins' lymphoma, non-Hodgkins' lymphoma, villous cell lymphoma and Burketts'lymphoma;

Hematopoietic tumors of the myeloid system: including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;

Tumors of the central and peripheral nervous system: including astrocytoma, neuroblastoma, glioma, and schwannomas; interstitial-derived tumors: including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma;

Other tumors include melanoma, xenoderma pigmentos aminated acanthoma, seminoma, thyroid follicular carcinoma and teratocarcinoma.

A cell proliferative disorder that can be treated with the compound is a blood tumor that is a cell malformation of the hematopoietic system. Hematological tumors include lymphomas in which abnormal cells are derived from lymphoid cell lineage cells and/or exhibit a characteristic phenotype of lymphoid cell lineage cells. Lymphoid cell tumors can be subdivided into B cell tumors, T and NK cell tumors, and Hodgkin's lymphoma. B cell tumors can be subdivided into primordial B cell tumors and mature/peripheral B cell tumors. An example of B-cell tumor is precursor B lymphocytic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia), mature/peripheral B-cell tumor is B-cell chronic lymphocytic leukemia/small lymphoma, B-cell Lymphocytic leukemia, lymphoplasmic lymphoma, spleen border B-cell lymphoma, hairy cell leukemia, plasma cell myeloma/plasma tumor, MALT-type pan-domain B-cell lymphoma, marginal zone B-cell lymphoma , Follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, primary osmotic lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. T cells and Nk cell tumors are subdivided into precursor T cell carcinoma and mature (peripheral) T cell tumors. Precursor T-cell tumor is precursor T-lymphocytic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia), mature (peripheral) T-cell tumor is T-cell lymphocytic leukemia, T-cell granulosa leukemia, aggressive NK cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1), extranodal nasal type NK/T-cell lymphoma; nasal type, pathogenic T-cell lymphoma, hepatosplenic sputum - δ sputum cell lymphoma, subcutaneous Panniculitis-like sputum cell lymphoma, early granuloma/Sessley syndrome, degenerative large cell lymphoma; sputum/ineffective cells, primary cutaneous peripheral sputum cell lymphoma, vascular immunoblasts not otherwise characterized Sputum cell lymphoma, degenerative large cell lymphoma, sputum/ineffective cells, primary systemic type. The third of lymphoid cell tumors is Hodgkin's lymphoma, also known as Hodgkin's disease. The diagnosis of such diseases that can be treated with the compounds includes, but is not limited to, nodular lymphocyte super-dominant Hodgkin's lymphoma and various classical forms of Hodgkin's disease, wherein the sclerosing hardening Hodgkin's lymphoma (Grade 1 and Grade 2), classical Hodgkin's lymphoma enriched in lymphocytes, mixed cells constitute Hodgkin's lymphoma and lymphocytes deplete Hodgkin's lymphoma.

Hematological tumors also include myeloma. Such tumors include a large class of cell proliferative disorders that are involved in or display characteristic phenotypes of myeloid lineage cells. Myeloid cells can be subdivided into myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, and acute myeloid leukemia. Myeloproliferative diseases are chronic myelogenous leukemia, chronic neutrophil white blood Disease, chronic eosinophilic leukemia/eosinophilic syndrome, chronic spontaneous myelofibrosis, erythrocytosis, and essential thrombocytosis. Myelodysplastic/myeloproliferative disorders are chronic mononuclear myeloid leukemia, atypical chronic myelogenous leukemia and adolescent mononuclear myeloid leukemia. Myelodysplastic syndrome is a refractory anemia with ring-like high-iron red blood cells and non-circular high-iron red blood cells, refractory cytopenia with multiple dysplasia (myelodysplastic syndrome), and stubbornness with excessive blasts Anemia (myelodysplastic syndrome), 5ci-syndrome and myelodysplastic syndrome. Any myeloma can be treated and treated with the compounds of the invention.

The compounds can be used to treat acute myeloid leukemia (AML), which represents a large class of myeloid tumors with re-segmentable conditions. These branches include, but are not limited to, AM with polymorphic dysplasia with recurrent cytogenetic translocation and other unclassified AML. AML with recurrent cellular genetic translocations includes, but is not limited to, AML with t (8; 21 ) (q22 ; q22), AML1 (CBF-a) / ET0, acute promyelocytic leukemia (with t (15; 17) (q22 _; ql l- 12) AML and variants, PML/RAR-a), with abnormal bone marrow eosinophils (inv (16) (pl 3q22) or t (16; 16) (pl 3 ; qll ) CBFb /MLHl lX) AML and AML with ll q23 (MLL) exception. AML with multiple dysplasia is those associated with or not associated with premyelodysplastic syndrome. Other acute myeloid leukemias not classified in any definable class include minimally differentiated AML, immature AML, mature AML, acute mononuclear myeloid leukemia, acute mononuclear leukemia, acute erythroid leukemia, acute megakaryocyte type Leukemia, acute basophilic leukemia, and acute whole myeloid leukemia with myelofibrosis.

Preferred tumors to be treated are breast cancer, lung cancer, colon cancer, gastric cancer, esophageal cancer, ovarian cancer, osteosarcoma, cervical cancer, liver cancer, brain tumor, prostate cancer, melanoma.

"Treatment" in the context of the present invention means alleviating the symptoms associated with the condition or disease, or terminating the further development or worsening of those symptoms, or preventing or preventing the disease or condition.

The term "pharmaceutically effective amount," "therapeutically effective amount," or "therapeutically effective amount" refers to a subject compound that is being sought by a researcher, veterinarian, physician, or other clinical technician to cause a biological or medical response to a tissue, system, animal, or human. the amount.

The term "therapeutically effective amount" includes an amount of a compound which, after administration, is sufficient to prevent the development or alleviation of one or more symptoms of the disease or condition being treated to some extent. The therapeutically effective amount will vary with the compound, condition or condition and its severity, as well as the age, weight, etc. of the mammal being treated.

A "patient" as defined herein includes animals, such as mammals, including but not limited to primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In a preferred embodiment, the patient is a human. An effective amount of a compound of the present invention can be determined by one of ordinary skill in the art. For an adult dose of 0.0001-100 mg of active compound per kg body weight per day, it can be administered in a single dose or in divided doses, for example, 1 per day. -4 times. It should be clear that the specific dosage level and number of administrations may vary for any particular subject, depending on a number of factors, including the activity of the particular compound employed, the metabolic stability of the compound, and the length of action, the subject's Species, age, weight, health profile, gender and eating habits, manner and timing of medication, rate of excretion, combination of medications, and severity of specific conditions.

The free compound of the present invention has a markedly improved solubility relative to the antitumor platinum compound of the prior art, and has a solubility in water of 50 mg/ml or more, particularly those of the preferred embodiments of the present invention, each having 90 mg/ml or even 100 mg/ Solubility above ml. Moreover, the prior art platinum compound cannot form a salt, and the compound of the present invention can be formed into a salt form, which is more advantageous for its preparation into a stable preparation form.

Any of the above dosage forms containing an effective amount of the compound are within the scope of routine experimentation and within the scope of the invention. The therapeutically effective dose can be adjusted depending on the route of administration and the dosage form. Representative compounds of the invention are those which exhibit a high therapeutic index. The therapeutic index is the dose ratio between toxicity and efficacy, which can be LD ₅ . The index is expressed as the ratio of in vivo antitumor activity (ED ₅ .) or in vitro cytotoxicity (IC ₅ .). LD ₅ . To make a 50% population lethal dose, ED ₅ . To achieve a therapeutically effective dose in 50% of the population. LD ₅ is determined in animal cell culture media or experimental animals by standard pharmaceutical methods. And ED ₅ . . Since the compound of the present invention represents a toxic LD ₅₀ (a dose of mmol/kg causing half of animal death) is much higher than the platinum compounds of the prior art, such as cisplatin and carboplatin, and an effective dose of antitumor activity in vivo and an inhibitory cytotoxic concentration in vitro. IC ₅ . The value is comparable to or lower than carboplatin, so it can be used for patients who cannot tolerate treatment with existing platinum compounds such as carboplatin and cisplatin, and achieve good technical results. The compounds of the invention may be used alone or in combination with each other, and/or in combination with other suitable therapeutic agents useful in the treatment of proliferative diseases. BEST MODE FOR CARRYING OUT THE INVENTION The following examples and test examples illustrate the exemplification of the present invention in more detail, but do not limit the invention in any way. It will be understood by those skilled in the art that modifications or substitutions of the corresponding technical features are still within the scope of the claimed invention. The purity of the raw materials used in the present invention may be as long as it is chemically pure or higher, and the sources are commercially available. The compounds obtained in the following examples are all in the form of a salt. The compounds in the form of these salts can be adjusted to pH by adding a base to obtain a free base compound, and can be easily converted into other kinds of organic or by adding the corresponding acid. Inorganic salts; compounds in the form of these salts can also be obtained as a free base compound by an anion exchange resin, and can be easily converted into other kinds of organic or inorganic salts by the addition of the corresponding acid. May be, but not limited to, nitrates, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, sulfates, hydrogen sulfates, phosphites, acetates, propionates, isobutyric acid Salt, malonate, benzoate, succinate, suberate, fumarate, mandelate, phthalate, besylate, p-toluenesulfonate, citrate Tartrate, methanesulfonate, arginine salt, glucuronate or galactate, etc., will not be described in the following examples.

[Example 1] : 2-(3-(1-piperidinyl)-propanyl)-malonic acid · cis-( 1, 2 trans-cyclohexanediamine) platinum (II) phosphate

Step 1: 2-( 3-Bromopropanyl)-malonic acid diethyl ester

Take 15.15 g (0. lmol) of diethyl malonate and 50. 5 g (0.25 mol) of 1, 3-dibromopropene in a 150 ml three-necked flask, and add K ₂ C0 ₃ 15.12 g (0. llmol). 153mg of tetrabutylammonium bromide was stirred, heated in an oil bath to 65~85 ° C for 16~24h, filtered, filtered, washed with diethyl ether (30ml X 3 times), the filtrate was combined, washed with water (40ml X 3 times) The organic layer was dried over Mg~0 _{4 for} 4 to 8 h, and the solvent was evaporated under reduced pressure, and then distilled under reduced pressure using an oil pump to obtain a vacuum of 7 mmHg and a fraction of 9.36 g of 135 ° C - 147 ° C, yield 33.31%.

Step 2: 2-(3-(ipiperidinyl)-propanyl)-malonic acid diethyl ester

113.6 g (0.4 mol) of diethyl 2-bromoethyl-malonate was placed in a three-necked flask, and 55.7 g (0.4 mol) of anhydrous K ₂ CO _{3 3 was} added thereto, and 500 ml of acetonitrile was stirred. Another 85.0g (1.0mol) of piperidine solution was added to the reaction solution, and the reaction was heated to 40-60 ° C for 2-6 hours in an oil bath. The insoluble matter was filtered off, and the filtrate was drained, and then dissolved in 1000 ml of ethyl acetate to dissolve. The aqueous solution was washed with aq. NaCl (250 ml X 3 times), and the organic layer was dried over anhydrous MgSO ₄ overnight. The solvent was evaporated under reduced pressure to give 99.5 g of pale yellowish red transparent material, purified by column chromatography to yield 34.9 g of pure product. 27.88%.

Step 3: 2-(3-(1-piperidinyl)-propenyl)-malonic acid disodium salt

Take NaOH 212mg (5mmol) and add 2.5m L of water to dissolve, then obtain 2M NaOH solution, and take 2-(3-(1-piperidinyl)-propenyl)-malonate 570m _g (2mraol) The above NaOH solution was added to a 20 mL three-necked flask, and stirred at room temperature for 45 to 60 hours to obtain a solution of 2-(3-(1-piperidinyl)-propanyl)-malonic acid disodium salt.

Step 4: trans-cyclohexanediamine-diiodoplatinum(II)

Take potassium chloroplatinate (K ₂ PtCl ₄ ) 2.075g (5 round ol), add 50ml of water, stir and dissolve at room temperature, take KI6.64g (40mmol) dissolved in 50ml of water, add to the reaction solution, protect with N ₂ , the water bath is heated to 40~60 °C for 0.5~2h. Further, 571 mg (5 mmol) of trans-cyclohexanediamine was dissolved in 50 ml of water, and then added to the reaction solution, and the reaction was continued for 0.5 to 2 hours under the conditions. Filtration afforded the product as a yellow solid, which was washed with water (10 ml, EtOAc) Elemental analysis: C12.66% (theoretical 12.80%); H2.65% (theoretical 2.51%); N4.94% (theoretical 4.98%).

Step 5: trans-cyclohexanediamine* platinum (ruthenium) sulfate dihydrate

A _g2 S0 ₄ 625 mg (2 mmol) was placed in a 100 ml three-necked flask, stirred with water at 30 rpm, and trans-cyclohexanediamine*diiodomolybdenum (11) 1.12 g (2 mmol) was added to the reaction solution, and 40 ml was further added. Water reaction, N ₂ protection, protection from light, water bath 40~60 °C reaction 4~8h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 6: 2-(3-(1-piperidinyl)-propanyl)-malonic acid*cis-(1,2-trans-cyclohexanediamine)platinum(II) phosphate;

Take 2-(3-(1-piperidinyl)-propanyl)-malonic acid disodium salt solution and adjust the pH to 5~7 with P0 ₄ (1M), then trans-cyclohexanediamine·diiodine The platinum (Π) sulphate aqueous solution is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40-75 ° C for 4-6 hours, and the reaction solution is suction filtered, concentrated to a certain volume, and quenched to obtain a crystalline product, crystallized. The product was dissolved in water, the pH was adjusted to 10-11 with EtOAc and then ethyl acetate (10 ml X 3 times), and the organic layer was combined, and the mixture was adjusted to pH 5-7 by adding H ₃ P0 ₄ (1M) to give the final product 131 mg.

The compound is easily soluble in water and has a solubility of more than 100 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by being free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, B. Acid salts, decanoates, p-toluenesulfonates, fumarates, and the like. Analysis of free alkali elements: C38.24% (theoretical 38.06%); H5.93% (theoretical 5.78%); N7.72% (theoretical 7.84%).

'HNMR(D ₂ 0) (ppm): δ 3.62 (t, 1H) , δ 2.90 (m, 2Η), δ 2.43(t, 2H) , δ 2.33(t, 4H) , δ 1.85(m, 2H) , δ 1.77(m, 2Η), δ 1.62(m, 2Η) , δ 1.54(m, 4H) , δ 1.46(m, 2Η) , δ 1.37(m, 2Η), δ 1.28 (m, 2Η) , δ 1.21 (m, 2H).

[Example 2]: 2-(3-(1-tetrahydropyrroleyl)-propanyl)-malonic acid·cis-(1,2-trans-cyclohexanediamine)platinum (ruthenium)phosphoric acid Salt

Step 1: Same as [Example 3] Step 1.

Step 2: 2-(3- (1-tetrahydropyrrolidinyl)-propenyl)-malonic acid diethyl ester

113.5 g (0.4 mol) of diethyl 2-bromoethyl-malonate was placed in a three-necked flask, and 55.7 g (0.4 raol) of anhydrous K ₂ C0 _{3 was added} , and 500 ml of acetonitrile was stirred. Another 71.2 g (1.0 mol) of tetrahydropyrrole solution was added to the reaction solution, and the oil bath was heated to The reaction was carried out at 40-60 ° C for 2-6 h, and the insoluble material was filtered. The filtrate was evaporated, and then ethyl acetate (100 ml) was dissolved, washed with saturated aqueous NaCI (250 ml X 3 times). The pump was depressurized to remove the solvent, and 97.8 g of pale yellowish red transparent material was obtained. The pure product was purified by column chromatography to obtain 31.85 g of a pure yield of 26.63%.

Step 3: 2-(3- (1-tetrahydropyrrole)-propanyl)-malonic acid disodium salt

Take NaOH 205mg (5 1) and add 2.5m L of water to dissolve, then obtain 2M NaOH solution, and take 2-(3-(1-tetrahydropyrrole)-propionyl)-malonate 542mg (2mmol) The solution was placed in a 20 mL three-necked flask, and the above NaOH solution was added thereto, and stirred at room temperature for 45 to 60 hours to obtain a solution of 2-(3-(1-tetrahydropyrrole)-propionyl)-malonic acid disodium salt.

Step 4 5: Same as [Example 1] Step 4 5

Step 6: 2-(3-(1-tetrahydropyrrole)-propionyl)-malonic acid ·cis-(1 2 trans-cyclohexanediamine) platinum (ruthenium) phosphate;

Take 2-(3-(1-tetrahydropyrrole)-propionyl)-malonic acid disodium salt solution and adjust the pH to 5~7 with P0 ₄ (1M) and then trans-cyclohexanediamine. The diiodoplatinum (ruthenium) sulphate aqueous solution is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40-75 ° C for 4-6 h, and the reaction solution is suction filtered, concentrated to a certain volume, and quenched to obtain a crystalline product. The crystallized product is dissolved in water, adjusted to pH 10-11 with NaOH, extracted with ethyl acetate (10 ml×3 times), and the organic layer is combined. P0 ₄ (1M) is added to adjust the pH to 5-7 to obtain the final product 123 mg.

The compound is easily soluble in water and has a solubility of more than 100 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C36.73% (theoretical 36.78%) H5.39% (theoretical 5.56%) N8.18% (theory 8.05%).

'HNMR (D ₂ 0) (ppm): δ 3.61 (t, 1H), δ 2.91 (m, 2H), δ 2.42 (t, 2H), δ 2.34 (t, 4H), δ 1.83 (m, 2H) , δ 1.78 (m, 2H) , δ 1.61 (m, 2H) , δ 1.55 (m, 4H) , δ 1.38 (ra, 2H) , δ 1.29 (m, 2H) δ 1.20 (m, 2H

[Example 3] _: 2-methyl-2-(2-methylaminoethyl)-malonic acid. cis-diaminoplatinum (II) phosphate;

Step 1: 2-(2-Bromoethyl)-2-methyl-propionic acid ethyl ester

Take 11.8 g (0.1 mol) of 2-methyl-malonate and 47 g (0.25 mol) of 1,2-dibromoacetate in a 150 ml three-necked flask, and add K ₂ C0 ₃ 15.2 g (0 Llmol), tetrabutylammonium bromide 155mg stirred, heated in oil bath to 65~85 ° C reaction for 16~24h, suction filtration, solids were removed and washed with ether (30ml X 3 times), the filtrate was combined with water (40ml X 3 The organic layer was washed, dried with MgS0 _{4 for} 4-8 h, and the solvent was evaporated under reduced pressure, and then evaporated to dryness with a vacuum pump, and a vacuum of 7 mmHg and a fraction of 7.31 g of a fraction of 132 ° C to 142 ° C was collected. The yield was 26.01%. Step 2: 2-Methyl-2-(2-methylaminoethane)-malonic acid diethyl ester

112.4 g (0.4 mol) of 2-(2-bromoethyl)-malonic acid diethyl ester was placed in a three-necked flask, and 55.2 g (0.12 g) of anhydrous K ₂ C0 _{3 was added} , and 500 ml of acetonitrile was stirred. In addition, 31.0 g (1.0 raol) of the methylamine solution stored under freezing was added to the reaction solution, and the mixture was heated to 40-60 ° C for 2-6 hours in an oil bath. The insoluble matter was filtered off, and the filtrate was drained and then added with ethyl acetate 1000 ml. Dissolve, wash with saturated aqueous NaCl solution (250 ml×3 times), dry the organic layer with anhydrous MgSO ₄ overnight, and remove the solvent by vacuum pump to obtain 81.3 g of pale yellowish red transparent substance. Purify by column chromatography to obtain pure product 25.6 g. The yield was 27.71%. Step 3: 2-Methyl-2-(2-methylaminoethane)-malonic acid disodium salt

Take 215 mg (5 瞧ol) of NaOH and add 2.5 liters of water to dissolve, then obtain 2M NaOH solution, and take 2-methyl-2-(2-methylaminoethenyl)-malonate 462mg (2 legs ol) The mixture was placed in a 20 mL three-necked flask, and the above NaOH solution was added thereto, and stirred at room temperature for 45 to 60 hours to obtain a solution of 2-methyl-2-(2-methylaminoethane)-malonic acid disodium salt.

Step 4: Diamine · Diiodoplatinum (Π)

|々",. ,,,,,,1

Pt,

HH^, NH ₃

Take potassium chloroplatinate (K ₂ PtCl ₄ ) 2. 075g ( 5mmol ), add water 50ml, stir and dissolve at room temperature, take KI6. 640g (40mraol) dissolved in 50ml of water, added to the reaction solution, N ₂ protection, protected from light, 5~2小时。 The water bath was heated to 40 ~ 60 ° C reaction 0. 5 ~ 2h. 5〜2小时。 Then, the reaction was carried out under the conditions of 0. 5~2h. The product was 2.29 g, the yield was 95. 1%. The product was washed with water (10 ml of EtOAc). Elemental analysis: HI. 24% (theory 1.21%); N5. 56% (theory 5.797%).

Step 5: Diamine · Platinum (II) sulfate dihydrate

NH ₂

H ₂ 0,

S04

H ₂ 0-NH ₂ takes Ag ₂ S0 ₄ 625 mg (2 sec ol ) in a 100 ml three-necked flask, and 30 ml of water is added to stir, and diammine·diiodoplatinum (11) 0. 96 g (2 mmol) is added to the reaction solution. Then add 40ml of water to react, N ₂ protection, protected from light, water bath 40~6 (4~8h reaction under TC). The Agl precipitate is removed by suction filtration to obtain the filtrate, which is the aqueous solution of the product.

Step 6: 2-Methyl-2-(2-methylaminoethenyl)-malonic acid*cis-diammineplatinum (ruthenium) phosphate

Take 2mmol of 2-methyl-2-(2-methylaminoethane)-malonic acid disodium salt solution and adjust the pH to 5~7 with P0 ₄ ( 1M), then cis-diamine·II The hydrated platinum (II) sulfate aqueous solution is poured into the reaction solution, protected by N ₂ , heated to a water bath. 40~75°C reaction for 4-6h, the reaction solution is filtered and concentrated to a certain volume, static crystallized, the product is dissolved in water, adjusted to pH 10-11 with NaOH, extracted with ethyl acetate (10ml×3 times), combined organic The layer was added with P0 ₄ (1M) to adjust the pH to 5-7 to obtain 115 mg of 2-(2-methylaminoethylhydrazinyl)-3-hydroxy-propionic acid·cis diaminoplatinum(II) phosphate.

The compound is easily soluble in water and has a solubility of more than 100 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by being free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, phosphate. , citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C20.45% (theory 20.90%); H4.43% (theoretical 4.23%); N10.58% (theoretical 10.45%).

'HNMR (D ₂ 0) (ppm): 52.81 (t, 2H), 52.66 (s, 3H), δ 1.96 (t, 2H), Sl.45 (s, 3H).

[Example 4] _: 2-methyl-2-(2-triethylaminoethane)-malonic acid*cis-diaminoplatinum(II) methanesulfonate; Step 1: Same as [Example 3 ]step 1.

Step 2: 2-Methyl-2-(2-triethylaminoethenyl)-malonic acid ethyl ester hydroxide

112.4 g (0.4 raol) of 2-methyl-2-bromoethyl-malonate was placed in a three-necked flask, and 55.2 g (0.4 mol) of anhydrous K ₂ CO _{3 3 was added} , and 500 ml of acetonitrile was stirred. Another 40.4g (0.4mol) of triethylamine was added to the reaction solution, and the reaction was heated to 45-60 ° C for 2-6 h in an oil bath. 46.4 g of silver oxide was added, stirring was continued for 1 h, and the pH was adjusted to 10-11. The organic layer was washed with ethyl acetate (100 ml×3×), and the solvent was evaporated to give a pale yellow crystalline solid (35.27 g).

Step 3: 2-Methyl-2-(2-triethylethenyl)-malonic acid disodium salt

Take NaOH 215mg (5mmol) and add 2.5mL of water to dissolve, then obtain 2M NaOH solution, and take 2-methyl-2-(2-triethylaminoethenyl)-malonate hydroxide 764mg (2mmol) The above NaOH solution was added to a 20 mL three-necked flask, and stirred at room temperature for 45 to 60 hours to obtain a solution of 2-methyl-2-(2-triethylaminoethenyl)-malonic acid disodium salt.

Step 4: Same as [Example 3] Step 4. Step 5: Same as [Example 3] Step 5.

Step 6: 2-methyl-2-(-triethylaminoethane)-malonic acid, cis-diaminoplatinum(II) methanesulfonate;

Take 2-methyl-2-(2-triethylaminoethenyl)-malonate solution with methanesulfonic acid (1M) to adjust the pH to 5~7, then cis-diamine·dihydrate platinum (II) The methanesulfonate aqueous solution is poured into the reaction solution, protected with N ₂ , heated in a water bath to 45-75 ° C for 4-6 h, and the reaction solution is suction filtered, concentrated to a certain volume, and quenched to obtain a crystalline product, crystallized. The product was dissolved in water, the pH was adjusted to 10-11 with NaOH, and then extracted with ethyl acetate (10 ml X 3 times). The organic layer was combined, methanesulfonic acid (1M) was added to adjust the pH to 5~7 to give the product 127mg. Soluble in water, solubility 386mg / ml, can be converted into various organic or inorganic salts by ion exchange, which can be, but not limited to, sulfate, phosphate, tartrate, succinate, acetate, strontium Acid salt, p-toluenesulfonate, fumarate, and the like. Elemental analysis: 28.79% (theory 28.97%); H5.25% (theoretical 5.35%) _; N7.15% (theoretical 7.24%); S5.36% (theoretical 5.52%).

'HNMR(D ₂ 0) (ppm): δ 3.38(s, 3Η), δ 2.78(q, 6Η), δ 2.65(t, 2H), δ 1.85(t, 2Η), δ 1.30(s, 3Η) , δ 1.08 (t, 9H).

[Example 5]: 3-piperidinyl-1,1-cyclobutane-dicarboxylic acid diethyl ester, cis-diamino-platinum (ruthenium) phosphate

Step 1: 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid diethyl ester

93.8 g (0.4 raol) of 3-chloro-1,1-cyclobutane-dicarboxylic acid diethyl ester was placed in a three-necked flask, and 55.2 g (0.4 mol) of anhydrous K ₂ CO _{3 3 was} added thereto, and 500 ml of acetonitrile was stirred. Another 85.0 g (1.0 mol) of piperidine solution was added to the reaction solution, and the mixture was heated to 40-60 ° C for 2 - 6 h, and the insoluble matter was filtered off. The filtrate was drained, and then dissolved in 1000 ml of ethyl acetate to dissolve. The aqueous solution was washed with aq. NaCl (250 ml X 3 times), and the organic layer was dried over anhydrous MgSO ₄ overnight. The solvent was evaporated under reduced pressure to give 101.5 g of pale yellowish red transparent material and purified by column chromatography to yield 32.5 g of pure product, yield 29.76. %.

Step 2: 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid disodium salt

Take 212.3mg (5mmol) of NaOH and dissolve it in water 2.5m L to obtain 2M NaOH solution, and take 546mg (2mmol) of 3-piperidinyl-1,1-cyclobutane-dicarboxylate in 20mL three-necked flask.屮, the above NaOH solution was added, and stirred at room temperature for 45-60 h to obtain a 3-piperidinyl-1,1-cyclobutane-dicarboxylic acid disodium salt solution.

Step 3: Same as [Example 3] Step 4.

Step 4: Same as [Example 3] Step 5.

Step 5: 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid, cis-diaminoplatinum (ruthenium) phosphate;

Take 3-piperidinyl-1,1-cyclobutane-dicarboxylic acid disodium salt solution with 3⁄4P0 ₄ (1M) to adjust the pH to 5-7, then cis-diamine·dihydrate platinum (Π) sulfuric acid The salt solution is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40-75 ° C for 4-6 h, and the reaction solution is suction filtered, concentrated to a certain volume, and still, to obtain a crystalline product, the crystal product is dissolved in water, and NaOH is used. After adjusting the pH to 10-11, it was extracted with ethyl acetate (10 ml of X 3 times), and the organic layer was combined. H ₃ P0, (1M) was added to adjust the pH to 5 to 7 to obtain 143 mg of the final product.

The compound is easily soluble in water and has a solubility of 219 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by liberation, and may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C29.18% (theoretical 29.01%); H4.73% (theoretical 4.84%); N9.52% (theoretical 9.23%).

'HN R(D ₂ 0) (ppm): δ 2.92(m, 1H) , δ 2.72 (m, 2Η) , δ 2.42 (d, 2Η), δ 2.25(t, 4H), δ 1.51(m, 4Η ), δ 1.31 (m, 2H).

[Example 6]: 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid·cis-(1,2 trans-cyclohexanediamine)platinum (ruthenium) phosphate; Step 1. 2: Same as [Example 5] Steps 1, 2.

Step 3: Same as [Example 1] Step 4.

Step 4: Same as Step 5 of [Example 1].

Step 5: 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid * cis diaminoplatinum (ruthenium) phosphate;

Take 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid disodium salt solution with H ₃ P0, (1M) to adjust the pH to 5-7, then trans-cyclohexanediamine, diiodide The platinum (II) sulfate aqueous solution is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40 to 75 ° C for 4-6 hours, and the reaction solution is suction filtered, concentrated to a certain volume, and quenched to obtain a crystalline product, a crystalline product. Dissolved in water, adjusted to pH 10-11 with NaOH, extracted with ethyl acetate (10 ml X 3 times), combined organic layer, and added to H ₃ P0 ₄ (1M) to adjust pH to 5~7 to give 133 mg of the final product.

The compound is easily soluble in water and has a solubility of 309 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C38.25% (theoretical 38.20%); H5.48% (theoretical 5.43%); N7.88% (theoretical 7.87%).

'HNMR(D ₂ 0) (ppm): δ 2.98 (m, 1H), δ 2.85 (ra, 2H), δ 2.72 (m, 2Η), δ 2.42 (d, 2H), δ 2.25(t, 4H) , δ 1.78(m,2H), δ 1.62 (m, 2Η) , δ 1.51(m,4H), δ 1.42(m,2H), δ 1.36(m,2H) δ 1.28 (m, 2Η

[Example 7] _: 2-(4-piperidinyl)-propionic acid·cis-(1,2-trans-cyclopentanediamine) platinum (ruthenium) phosphate;

Step 1: 2-(4-piperidinyl)-malonic acid diethyl ester

64 g (0.4 mol) of diethyl malonate was placed in a three-necked flask, and 55.2 g (0.4 mol) of anhydrous K ₂ CO _{3 3 was added} , and 500 ml of acetonitrile was stirred. Another 4-bromopiperidine hydrobromic acid solution (containing 4-bromopiperidine 160.0g) was added to the reaction solution, and heated in an oil bath to 40-60 ° C for 2-6 h, the insoluble matter was filtered off, and the filtrate was drained. After adding 1000 ml of ethyl acetate, it was dissolved, washed with a saturated aqueous solution of NaCl (250 ml of X 3 times), and the organic layer was dried overnight with anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure to obtain pale yellowish red transparent 101.5 g. The purity of the product was 32. lg, and the yield was 33.03%.

Step 2: 2-(4-piperidinyl)-malonic acid disodium salt

Take NaOH 200mg (5mmol) and add 2.5m L of water to dissolve, then obtain 2M NaOH solution, and take 246mg (2mmol) of 2-(4-piperidinyl)-malonate in 20mL three-necked flask, add the above NaOH The solution was stirred at room temperature for 45-60 h to obtain a solution of 2-(4-piperidinyl)-malonic acid disodium salt.

Step 3: 1, 2-trans-cyclopentanediamine

6.8 g (100 mmol) of cyclopentene was placed in a 100 ml three-necked flask, and 30 ml of dichloromethane was added to stir and dissolve. Br ₂ 16 g (100 mmol) was slowly added dropwise at -5 to 10, and stirred for 1 to 3 hours with saturated carbonic acid. The sodium hydride solution (10 ml X 3 times) was washed, and the organic layer was dried over anhydrous MgSO _{4 for} 2 to 3 h. The solvent was evaporated under reduced pressure to give a pale yellow transparent material, 2-, 2-di-bromocyclopentane. Llg, yield 88.2%. Elemental analysis: C26.45% (theoretical 26.32%); H3.72% (theoretical 3.51%).

Take 11.5 g (50 诵ol) of 1,2-trans-dibromocyclopentanyl, place it in a 100 ml autoclave, add 30 ml of 30% ammonia in ethanol, heat to 40-60 ° C, and react for 6-8 hours. The solvent was evaporated to give a pale-yellow transparent material, <RTIgt;</RTI> Elemental analysis: C60.11% (theoretical 59.95%); H12.17% (theory 12.08%); N28.09% (theories 27.97%).

Step 4: 1, 2-trans-cyclopentadiamine*diiodoplatinum (ruthenium)

Take potassium tetrachloroplatinate (K ₂ PtCl ₄ ) 2.07g (5 solid ol), add water 50ml, stir and dissolve at room temperature, take KI6.64g (40mmol) dissolved in 50ml of water, add to the reaction solution, N ₂ protection, protected from light , the water bath is heated to 40~60 °C for 0.5~2h. Further, 500 mg (5 mmol) of 1,2-trans-cyclopentanediamine was dissolved in 50 ml of water, and then added to the reaction solution, and the reaction was continued under the conditions of 0.5 to 2 h. The product was obtained as a yellow solid, which was washed with water (10 EtOAc, EtOAc) Elemental analysis: C10.75% (theoretical 10.93%); H2.34% (theory 2.19%); N5.28% (theory 5.10%).

Step 5: 1, 2-trans-cyclopentanediamine·platinum(II) sulfate dihydrate

Take A _g2 S0 ₄ 625 mg (2 mmol ) in a 100 ml three-necked flask, add 30 ml of water and stir, and take 1,2-trans-cyclopentanediamine·diiodoplatinum (11) 1.10 g (2 mmol) into the reaction solution. , and then add 40ml of water to react, N ₂ protection, protected from light, and the reaction in water bath at 40~60 °C for 4~8h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 6: 2-(4-Piperidinyl)-malonic acid · cis-(1,2-trans-cyclopentanediamine) Platinum (II) phosphate

Take 2-(4-dipropionate sodium salt solution with H ₃ P0 ₄ ( 1M) to adjust the pH to 5~7, then 1,2-trans-cyclohexanediamine·platinum(II) sulfate dihydrate the reaction mixture was poured into an aqueous solution, N ₂ protection, the water bath was heated to 40 ~ 60 ° C the reaction 4 ~ 8h, the reaction solution was added 2. 5g column chromatography on silica gel (200-300 mesh) was stirred for 15min drained, column chromatography After treatment, the product is obtained, the crystal product is dissolved in water, the pH is adjusted to 10-11 with NaOH, and then extracted with ethyl acetate (10 ml X 3 times), the organic layer is combined, and H ₃ P0 ₄ (1 M) is added to adjust the pH to 5-7 , the final product is 139mg.

The compound is easily soluble in water and has a solubility of 322 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C32. 58% (theoretical 32. 5%); H4. 57% (theory 4. 79%); N8. 61% (theory 8. 75%)

¹匪R (D ₂ 0) (ppra): δ 3. 65 (d, 1H), δ 2. 97 (ra, 2Η), δ 2. 90 (m, 2H) , δ 2. 80 (m, 1Η) ), δ 2. 69 (m, 2Η) , δ 1. 86 (m, 2Η), δ 1. 71 (ra, 2Η) , δ 1. 58 (m, 2Η) , δ 1. 50 (m, 1Η) ), δ 1. 42 (m, 1Η) , δ 1. 32 (m, 2Η) ο

[Example 8] : 2-methyl-(4-piperidyl)-propionic acid·cis-(1,2-trans-cyclopentadiamine)-platinum (II) phosphate; Step 1: 2 -methyl-(4-piperidinyl)-dipropyl malonate

6 g (0. 4 mol) of 2-methyl-malonate diethyl ester was placed in a three-necked flask, and 55.2 g (0.4 mol) of anhydrous K ₂ C0 _{3 was added} , and 500 ml of acetonitrile was stirred. Another 4-bromopiperidine hydrobromic acid solution (containing 4-bromopiperidine 160. 0g) was added to the reaction solution, and heated in an oil bath to 40 to 60 ° C for 2-6 hours, the insoluble matter was filtered off, and the filtrate was pumped. After drying, ethyl acetate (100 ml) was added, and the mixture was washed with a saturated aqueous solution of sodium chloride (250 ml X 3 times). The organic layer was dried over anhydrous MgSO. The yield was 33.78%, the yield was 32.78%.

Step 2: 2-Methyl-(4-piperidinyl)-malonic acid disodium salt

Take NaOH 200mg (5 sec ol) and add water 2. 5m L to dissolve, that is, 2M NaOH solution is obtained, and another 2-methyl-(4-piperidinyl)-malonate 514mg (2mmol) is placed in 20mL three mouths. In the flask, the above NaOH solution was added, and the mixture was stirred at room temperature for 45 to 60 hours to obtain a solution of 2-methyl-(4-piperidinyl)-malonic acid disodium salt.

Steps 3, 4, and 5: Same as [Example 7] Steps 3, 4, and 5.

Step 6: 2-((4-piperidinyl)-malonic acid · cis-(1,2-trans-cyclopentanediamine) platinum (II) phosphate

Take 2-methyl-(4-piperidinyl)-malonate solution and adjust the pH to 5~7 with H ₃ P0, ( 1M), then 1, 2 trans-cyclohexanediamine· hydrated platinum ([pi) sulfate solution was poured into the reaction mixture, N ₂ protection, the water bath was heated to 40 ~ 60 ° C the reaction 4 ~ 8h, the reaction solution was added 2. 5g column chromatography on silica gel (200-300 mesh) was stirred 15min After draining and column chromatography, the product was obtained. The crystal product was dissolved in water. The pH was adjusted to 10-11 with NaOH and then extracted with ethyl acetate (lOral X 3 times). The organic layer was combined and H ₃ P0 ₄ (1M) was added. Adjust the pH to 5~7 to obtain 143mg of the final product.

The compound is easily soluble in water and has a solubility of 307 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Free base element analysis: C34. 18% (theoretical 34. 01%); H5. 16% (theoretical 5.06%); N8. 62% (theoretical 8.50%). 'HNMR (D ₂ 0) (ppm) δ 2.96 (m, 2H), δ 2.89 (m 2H) δ 2.81 (m, 1H) , δ 2.70 (ra, 2H), δ 1.86 (m 2H), δ 1.71 ( _m 2H), 51.59 (m, 2H), δ 1.51 (ra, 1H), δ 1.44 (ra, 1H), δ 1.36 (s, 3H), δ 1.30 (ra, 2H).

[Example 9] 2-methyl-(4-piperidyl)-malonic acid·cis.cis- 1 2-ethylenediamine platinum (II) p-toluenesulfonate; Step 1 2: same [Embodiment 8] Step 1 2

Step 3: 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid disodium salt

Take NaOH 240mg (6mmol) and add 2.5m L of water to dissolve, then obtain 2M NaOH solution, and take 2-methyl-(4-piperidinyl)-malonate 514mg (2ramol) in 20mL three-necked flask, add 218 mg (2 mmol) of ethyl bromide, 20 mg of tetrabutyl bromide and the above NaOH solution were stirred at room temperature for 45-60 h to obtain 2-methyl-(N-ethyl-4-piperidinyl)-malonic acid. Disodium salt solution.

Step 4: 1, 2-Ethylenediamine, Diiodoplatinum (II)

Take potassium chloroplatinate (K ₂ PtCl ₄ ) 2.076g (5mmol), add 50ml of water, stir to dissolve at room temperature, take KI6.64g (40mmol) dissolved in 50ml of water, add to the reaction solution, protect with N _{2 ,} protect from light, water bath Heat to 40~60 °C for 0.5~2h and then freeze-preserved 1 2-ethylenediamine (commercially available) 301mg (5ramol) Dissolve in 50ml of water, then add to the reaction solution, continue to maintain the reaction under these conditions 0.5~ 2h. The product was obtained as a yellow solid, which was washed with water (10 ml, EtOAc) Elemental analysis: C4.77% (theoretical 4.72%) HI.41% (theoretical 1.57%) N5.41% (theoretical 5.50%)

Step 5: 1 2-Ethylenediamine·Dihydrate

Take Ag ₂ S0 ₄ 625mg (2 1) in a 100ml three-necked flask, add 30ml of water and stir, and take 1 2-ethylenediamine·two Platinum iodide (n) 1.020g (2mmol) was put into the reaction solution, and further reacted with 40 ml of water, protected by N _{2 ,} protected from light, and reacted in a water bath at 40-60 ° C for 4-8 h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 6: 2-methyl-(N-ethyl-4-piperidyl)-malonic acid 'cis- 1,2-ethylenediamine platinum (ruthenium) phosphate;

Take 2-methyl-(N-ethyl-4-piperidyl)-malonic acid disodium salt solution with ?0, (1M) to adjust the pH to 5~7, then ethylenediamine·dihydrate platinum ( II) The aqueous solution of sulphate is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40~60 ° C for 4-8 h, the reaction solution is filtered and concentrated to a certain volume, and the pH is adjusted to 10-11 with NaOH. Ethyl ester (10ml X3 times) is extracted, combined with extract, adjusted to pH 5~7 with 1^0 ₄ (1M), static, crystallized product, crystal product dissolved in water, pH adjusted to 10-11 with NaOH It was extracted with ethyl acetate (10 ml×3×), and the organic layer was combined, and the mixture was adjusted to pH 5 to 7 by adding H ₃ P0 ₄ (1M) to obtain 135 mg of the final product.

The compound is readily soluble in water and has a solubility of 290 mg/ral and can be converted into various organic or inorganic salts, which may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citric acid. Salt, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C32.51% (theoretical 32.37%); H5.33% (theoretical 5.19%); N8.56% (theoretical 8.71%).

'HNMR (D ₂ 0) (ppm): δ 2.92 (t, 4H), δ 2.79 (ra, 1 Η), δ 2.45 (ra, 2H) ₎ δ 2.29 (m, 2H), δ 2.19 (m, 2 Η) , δ 1.59 (m, 3Η), δ 1.42 (s, 3Η), δ 1.34 (ra, 2Η), δ 1.05 (t, 3Η).

[Example 10] 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid 'cis-1, 3-propanediamine-platinum(II) phosphate; Steps 1, 2: Same as [Example 8] steps 1, 2.

Step 3: Same as [Example 9] Step 3.

Step 4: 1, 3-propanediamine, diiodoplatinum (ruthenium)

Take potassium chloroplatinate (K ₂ PtCl ₄ ) 2.073g (5mmol), add 50ml of water, stir and dissolve at room temperature, take KI6.63g (40mmol) dissolved in 50ml of water, add to the reaction solution, protect with N _{2 ,} protect from light, water bath Heat to 40~60 °C for 0.5~2h. The cryopreserved 1,3-propanediamine (commercially available) 372 mg (5 mmol) was dissolved in 50 ml of water, and then added to the reaction solution, and the reaction was continued for 0.5 to 2 hours under the conditions. The product was obtained as a yellow solid, which was washed with water (10 ml, EtOAc, EtOAc) Elemental analysis: C6.77% (theoretical 6.88%); HI.79% (theory 1.91%); N5. 43% (theory 5.35%).

Step 5: 1, 3-propanediamine·two

Take Ag ₂ S0 ₄ 625mg C2mmol ) in a 100ml three-necked flask, add 30ml of water and stir, and take 1,2-ethylenediamine. Diiodoplatinum(II) 1. 043g (2 oz) into the reaction solution, and then Add 40ml water to react, protect with N _{2 ,} protect from light, and react in water bath for 40~60 Ό under 4~8h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 6: 2-((N-Ethyl-4-piperidinyl)-malonic acid 'cis-1,3-1,3-diamine-platinum(II) phosphate

Take 2-methyl-(N-ethyl-4-piperidinyl)-malonic acid disodium salt solution with H ₃ P0 ₄ ( 1M) to adjust the pH to 5~7, then 1,3 -propylenediamine Pb (Π) sulfate aqueous solution of dihydrate is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40~60 ° C for 4-8 h, the reaction solution is filtered and concentrated to a certain volume, and the pH is adjusted to 10 with NaOH. -11, extracted with ethyl acetate (10 ml of X 3 times), and the extracts were combined, and the pH was adjusted to 5 to 7 with H ₃ P0 ₄ (1M).

The compound is readily soluble in water and has a solubility of 276 mg/ml and can be converted into various organic or inorganic salts, which may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citric acid. Salt, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C33. 63% (theoretical 33. 87%); H5. 51% (theory 5. 44%); N8. 36% (theory 8. 47%).

'HNMR (D ₂ 0) (ppm) : δ 2. 78 (m, 1H) , δ 2. 65 (t, 4Η), δ 2. 46 (m, 2H) , δ 2. 29 (m, 2Η) , δ 2. 19 (m, 2H) , δ 1. 82 (m, 2H) , δ 1. 59 (ra, 3Η) , δ 1. 43 (s, 3H) , δ 1. 35 (m, 2Η) , δ 1. 06 (t, 3Η).

[Example 11] 2-Methyl-(N-ethyl-4-piperidyl)-malonic acid 'cis-1,4-butanediamine platinum (II) phosphate; Steps 1, 2: Same as [Example 8] steps 1, 2.

Step 3: Same as [Example 9] Step 3.

Step 4: 1, 4-butanediamine, diiodoplatinum (II)

Take potassium chloroplatinate (K ₂ PtCl ₄ ) 2. 071g (5ramol ), add 50ml of water, stir and dissolve at room temperature, take KI6. 635g (40 countries ol) dissolved in 50 ml of water, added to the reaction solution, protected with N _{2 ,} protected from light, heated in a water bath to 40 ~ 60 ° C for 0.5 ~ 2h. The frozen 1,4-butanediamine (commercially available) 431 mg (5ramol) was dissolved in 50 ml of water, and then added to the reaction solution, and the reaction was continued for 0.5 to 2 hours under the conditions. The product was obtained as a yellow solid, which was washed with water (10 ml, EtOAc, EtOAc) Elemental analysis: C8.69% (theoretical 8.94%); H2.39% (theoretical 2.23%); N5.44% (theoretical 5.21%).

Step 5: 1, 4-butanediamine, platinum (II) sulfate dihydrate

Take Ag ₂ S0 ₄ 624 mg ( ₂ mmol) in a 100 ml three-necked flask, add 30 ml of water and stir, and take 1, 4-butylenediamine diiodoplatinum (II) 1.072 g (2 mmol) into the reaction solution, and then add 40 ral. Water reaction, N ₂ protection, protection from light, water bath 40~60 underarm reaction 4~8h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 6: 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid · cis- 1, 3-propanediamine platinum (II) phosphate

Take 2-methyl-(N-ethyl-4-piperidinyl)-malonic acid disodium salt solution with P0 ₄ (1M) to adjust the pH to 5~7, then 1,4-butanediamine, two The hydrated platinum (Π) sulfate aqueous solution is poured into the reaction solution, protected, heated in a water bath to 40~60 ° C for 4-8 hours, the reaction solution is filtered and concentrated to a certain volume, and the pH is adjusted to 10-11 with NaOH. Ethyl acetate (10 ml X 3 times) was extracted, and the extracts were combined, and the pH was adjusted to 5 to 7 with H ₃ P0 ₄ (1M) to give a final product of 142 mg.

The compound is readily soluble in water and has a solubility of 279 mg/ml and can be converted into various organic or inorganic salts, which may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citric acid. Salt, p-toluenesulfonate, fumarate, and the like. Free base element analysis: . 35.43% (theoretical 35.29%); H5.57% (theoretical 5.69%); N8.39% (theory 8.24%).

'HNMR(D ₂ 0) (ppm): δ 2.79 (m, 1H) , δ 2.66 (t, 4Η), δ 2.45 (m, 2Η), δ 2.28 (m, 2Η), δ 2.18(m, 2Η) , δ 1.62 (m, 3H) , δ 1.54 (m, 4H), δ 1.42 (s, 3Η), δ 1.35 (m, 2Η), δ 1.05 (t, 3Η).

[Example 12] 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid 'cis-1, 3-(2,2-hydroxymethyl)-propylenediamine platinum ( Π) phosphate;

Steps 1, 2: Same as [Example 8] Steps 1, 2.

Step 3: Same as [Example 9] Step 3. Step 4: 1 3- (2 2-Hydroxymethyl-propylenediamine' Iodine Platinum (II)

Take potassium chloroplatinate (K ₂ PtCl ₄ ) 2.074g (5mmol), add 50ml of water, stir to dissolve at room temperature, take KI6.636g (40mmol) dissolved in 50ml of water, add to the reaction solution, protect with N _{2 ,} protect from light, water bath Heat to 40~60 °C for 0.5~2h and then take 1 3-(2,2-hydroxymethyl)-propylenediamine 671mg (5ramol) dissolved in 50ml water, then added to the reaction solution, continue to maintain this condition. The reaction is 0.5~2h. The product was obtained as a yellow solid, which was washed with water (10 ml X 3 times) and diethyl ether (10 ml X 3 times) to give the product 2.163 g. Elemental analysis: C10.37% (theory 10.29°/.) H2.49% (theoretical 2.40%) N5.01% (theoretical 4.80%).

Step 5: 1 3- (2-hydroxymethyl)-propylenediamine · Platinum (Π) sulfate dihydrate

3⁄4Ag ₂ S0 ₄ 624mg (2 1) Put in a 100ml three-necked flask, add 30ml of water and stir, and take 1 3-(2 2-hydroxymethyl)-propanediamine*diiodoplatinum (11) 1.162g (2mmol) In the reaction solution, add 40 ml of water to react, protect with N _{2 ,} protect from light, and react in water bath at 40-60 ° C for 4-8 h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 6: 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid·cis- 1 3-(2,2-hydroxymethyl)-propanediamine-platinum (phosphonium) phosphate Salt

Take 2-methyl-(N-ethyl-4-piperidinyl)-malonic acid disodium salt solution with H ₃ P0 ₄ (1M) to adjust the pH to 5~7, then 1 3- (2 2- Hydroxymethyl)-propylenediamine*Pb (Π) sulfate aqueous solution is poured into the reaction solution, protected by N ₂ , heated in a water bath to 40~60 ° C for 4-8 h, and the reaction solution is filtered and concentrated to a certain concentration. Volume, adjust the pH to 10-11 with NaOH, extract with ethyl acetate (10 ml×3 times), combine the extracts, adjust the pH to 5~7 with H ₃ P0 ₄ (1M), stand still, and obtain 142mg of crystalline product. Soluble in water, solubility 389mg/ml, can be converted into various organic or inorganic salts, which can be, but are not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citrate, Tosylate, fumarate, and the like. Analysis of free alkali elements: C34.48% (theoretical 34.53%); H5.47% (theoretical 5.58%) N7.36% (theoretical 7.55%)

3⁄4 NMR (D ₂ 0) (ppm) δ 3.45 (s, 4H), δ 2.78 (m, 1Η), δ 2.60 (s, 4H), δ 2.43 (m, 2Η), δ 2. 26 (m, 2H) , 2. 16 (m, 2H) , δ 1. 58 (m, 2H) , δ 1· 42 (s, 3H) , 1. 34 (m, 2H) , δ 1. 06 (t, 3H).

[Example 13] : 2-(2-Dimethylaminoethane)-3-hydroxy-propionic acid 'cis- 1, 4-(trans-2, 3-cyclobutyl)-butanediamine Platinum (phosphonium) phosphate;

Steps 1, 2: Same as [Example 5] steps 1, 2.

Step 3: 1, 4- (trans -2, 3-cyclobutyl) - butanediamine - diiodoplatinum (II)

Take potassium tetrachloroplatinate (PtClJ 2. 075g (5mmol), add water 50ml, stir and dissolve at room temperature, take KI6. 64g (40mraol) dissolved in 50ml of water, add to the reaction solution, protect with N _{2 ,} protect from light, heat to 40 in water bath The reaction was carried out at ~60 ° C for 0.5 to 2 h. Further, 1,4-mg (trans-2, 3-cyclobutyl)-butanediamine 571 mg (5 诵ol) was dissolved in 50 ml of water, and then added to the reaction solution. , 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。 Elemental analysis: C12. 61% (theoretical 12.79%); H2. 45% (theory 2.49%); N5. 11% (theory 4.97%) „

Step 4: 1, 4- (trans-2, 3-cyclobutyl)-butanediamine* platinum (II) sulfate dihydrate

Take Ag ₂ S0 ₄ 625 mg (2 ol ) in a 100 ml three-necked flask, add 30 ml of water and stir, and take 1, 4- (trans-2, 3-cyclobutyl)-butanediamine·diiodoplatinum (11 1. 126g (2mmol) was put into the reaction solution, and then added with 40ml of water to react, protected by N _{2 ,} protected from light, and reacted in a water bath at 40~60°C for 4~8h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 5: 3-piperidinyl-1,1-cyclobutane-dicarboxylic acid·cis-1,4-(trans-2, 3-cyclobutyl)-butanediamine platinum (II) phosphate Salt

Take 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid disodium salt solution with H ₃ P0 ₄ (1M) to adjust the pH to 5~7, then 1, 4- (trans-2, 3 -cyclobutyl)-butylenediamine*diiodoplatinum(II) sulfate aqueous solution is poured into the reaction solution, protected with N ₂ , heated in a water bath to 40-75 ° C for 4-6 h, and the reaction solution is filtered and concentrated to a certain concentration. Volume, static, crystallized product, crystallized product is dissolved in water, pH is adjusted to 10-11 with NaOH, extracted with ethyl acetate (10 ml X 3 times), the organic layer is combined, and methanesulfonic acid (1M) is added to adjust the pH to 5~7, the final product is 145mg.

The compound is easily soluble in water and has a solubility of 278 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C38.29% (theoretical 38.20%); H5.39% (theoretical 5.43%); N7.65% (theory 7.87%).

'HNMR (D ₂ 0) (ppm): δ 3.19 (m, 1H) , δ 2.82 (m, 2Η), δ 2.73 (m, 2Η), δ 2.55 (m, 2Η), δ 2.45 (m, 2Η) , δ 2.33(t, 2Η), δ 2.22 (m, 2Η), δ 2.09 (ra, 2Η), 1.85 (m, 2Η), δ 1.51 (ra, 4H), δ 1.32 (ιη, 2Η).

[Example 14] 2-(2-diethylaminoethenyl)-3-hydroxy-propionic acid·cis-1, 3-(2,2-(4-oxopentyl))-propanediamine Platinum (Π) phosphate;

Steps 1, 2: Same as [Example 5] steps 1, 2.

Step 3: 1, 3- (2, 2- (4- ) ) - propanediamine diiodoplatinum (II)

Take potassium chloroplatinate ( ₂ PtCl ₄ ) 2.071g (5mmol), add 50ml of water, stir to dissolve at room temperature, take KI6.64g (40mmol) dissolved in 50ml of water, add to the reaction solution, protect with N ₂ , avoid light, heat in water bath The reaction was carried out at 40 to 60 ° C for 0.5 to 2 hours. Then take 1, 3-(2-(2-oxocyclohexyl))-propanediamine 722mg (5诵ol) dissolved in 50ml of water, then add to the reaction solution, continue to maintain the reaction for 0.5~2h under these conditions. . The product was obtained as a yellow solid, which was washed with water (10 ml X 3 times) and diethyl ether (10 ml X 3 times) to give the product 2.547 g. Elemental analysis: C14.35% (theory 14.17%); H2.75% (theoretical 2.70%); N4.72% (theoretical 4.72%).

Step 4: 1, 3- (2, 2- (4- ) - Propanediamine · Platinum (Π) sulfate dihydrate

Take Ag ₂ S0 ₄ 623mg (2 excitation 1) in a 100ml three-necked flask, add 30ml of water and stir, take 1, 3- (2, 2- (4- Oxyhexyl))-propanediamine, diiodoplatinum (Π) 1.185g (2mmol) was put into the reaction solution, and then added with 40ml of water to react, protected by N _{2 ,} protected from light, and reacted in a water bath at 40-60 ° C 4~8h. The Agl precipitate was removed by suction filtration to obtain a filtrate which was an aqueous solution of the product.

Step 5: 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid·cis-1, 3-(2,2-(4-oxocyclohexyl))-propanediamine platinum (II Phosphate

Take 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid disodium salt solution with H ₃ P0 ₄ (1M) to adjust the pH to 5~7, then 1, 3- (2, 2- (4) -oxohexyl))-propanediamine-diiodoplatinum(II) sulfate aqueous solution is poured into the reaction solution, protected with N ₂ , heated in a water bath to 40-75 ° C for 4-6 hours, and the reaction solution is filtered. After concentration to a certain volume, static, to obtain a crystalline product, the crystalline product is dissolved in water, the pH is adjusted to 10-11 with NaOH, and then extracted with ethyl acetate (10 ml X 3 times), the organic layer is combined, and methanesulfonic acid (1M) is added. The pH was adjusted to 5-7 to give a final product of 151 mg.

The compound is easily soluble in water and has a solubility of 311 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by liberation, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C37.12% (theoretical 37.09%); H5.45% (theoretical 5.31%); N7.81% (theoretical 7.63%).

'HNMR(D ₂ 0) ( pm): δ 3.61(t,4H), δ 3.18 (m, 1Η), δ 2.81(m,2H), δ 2.65(s,4H), δ 2.45 (m, 2Η) , δ 2.32(t, 4H), 1.65(t, 2H), δ 1.52 (ra, 4Η), δ ΐ.39 (m, 2Η).

[Experimental Example 1]: Acute Toxicity of Platinum Complexes to Normal Mice

Take Kunming mice with body weight of 18~22g and 4~6 weeks old, male and female. The platinum compounds in the example are dissolved in 5% dextrose solution, and the single dose of intravenous administration (control drug is carboplatin and cisplatin). The mortality and toxicity were observed after the drug, and a total of 14 days were observed. The Bliss method was used to calculate LD ₅ according to the mortality rate. value. See Table 1: Table 1. Intravenous injection of cisplatin, carboplatin and the example platinum compound LD _{5 in} mice. result:

Compound LDoiKmmol/kg) Target compound LD ₅₀ value (face ol/kg) Cisplatin 0.044 Compound 7 0.752 Carboplatin 0. 336 Compound 8 0. 697 Compound 1 0. 637 Compound 9 0. 688 Compound 2 0. 702 Compound 10 0. 693 Compound 3 0. 776 Compound 11 0. 569 Compound 4 0. 687 Compound 12 0. 646 Compound 5 0. 676 Compound 13 0. 755 Compound 6 0. 741 Compound 14 0. 871 Conclusion: The molar concentration of the compound of the example compound is much less acute toxicity than cisplatin and carboplatin.

[Experimental Example 2] _: Cytotoxic effect of platinum compounds on tumor cell cells

The toxic effects of the platinum compounds of the examples on tumor cells were observed by applying the MTT colorimetric method. Several tumor cells in the exponential growth phase were prepared as single cell suspensions, seeded in 96-well plates at a density of 4 X 107 wells, and cultured in 1640 medium (complete medium) containing 10% fetal bovine serum at 37 °C. The cells were allowed to adhere for 24 hours, and the final volume was 100 μl. After 24 hours of culture, the morphology of the cells was observed. For the amount of platinum compound, the following concentrations were determined by preliminary tests due to different IC50 of various cells: cisplatin 200, 60, 20, 6, 2, 0.64 g/ml, carboplatin 200, 60, 20, 6, 2, 0.6 g/ml, the platinum compounds of the examples were appropriately adjusted according to their sensitivity to each cell, and the results are shown in Table 2-5 below:

Table 2. Cytotoxicity IC ₅₀ of different platinum compounds for different cells

IC _{5 of} different cell lines for chemotherapy drugs. (n = 6)

ICa (mM)

Cell line compound compound chemical compound carboplatin cisplatin

Substance 1 substance 2 substance 3 substance 4 substance 5 lung epithelial cells

0. 037 0. 0033 0. 003 0. 004 0. 003 0. 005 0. 006

BEAS-2B

Lunar cancer Lewis

0. 038 0. 045 0. 025 0. 040 0. 032 0. 024 0. 022 Colon cancer SW480

0. 087 0. 015 0. 012 0. 014 0. 017 0. 020 0. 026 Lung cancer H292

0. 055 0. 0053 0. 005 0. 003 0. 006 0. 011 0. 006 Table 3. Cytotoxicity IC ₅₀ of different platinum compounds tested on different cells

IC _{5 of} different cell lines for chemotherapy drugs. (n = 6)

IC ( mM)

^卡销~" ~~ Ϊ ~~ ϊ1⁄2 ~~ ϊϊ¥ i ^lAW 6 things 7 things 8 things 9 things 10 lung epithelial cells _{0 037}

0. 0033 0. 004 0. 004 0. 005 0. 009 0. 002

BEAS-2B '

Lung cancer Lewis Q ₀₃ g 0. 045 0. 037 0. 035 0. 037 0. 053 0. 013 Intestinal cancer SW480 _{0 087} o ₀₁₅ 0.013 0.015 0.011 0.012 0.013 Lung cancer H292 _Q . _{055 0} . ₀₀₅₃ 0.005 0.003 0. 007 0.005 0.004 Table 4. Cytotoxicity ICs of different platinum compounds for different cells

IC _{5 of} different cell lines for chemotherapy drugs. (n = 6)

IC ₅ „ (mM)

Cell line compound compound compound compound carboplatin cisplatin

11 12 13 14

Testicular cells ST

0.195 0.009 0.011 0.0052 0.014 0.0081 冃 s 0.625 0.0025 0.0017 0.0032 0.0021 0.0096

MGC803

Colon cancer SW480

0.087 0.015 0.019 0.012 0.0082 0.033 Lung cancer H292

0.055 0.0053 0.0051 0.0046 0.0062 0.009 It can be seen from Tables 2-4 that the compounds of Examples 1-14 have a stronger in vitro cytotoxic effect than cisplatin. In addition, the present invention also synthesizes the phosphate of the compound:

Table 5. Other compounds synthesized by the present invention, melting point of compound, solubility in water, and IC ₅ mM for H292 in vitro)

In addition, the present invention also provides phosphates of the following compounds:

Table 6: in vitro as well as their structure and melting point of the H292 pair of IC _5. The values are as follows:

In vitro

Compound structure H292 in water solubility

IC ₅₀ (mM)

[Formulation Example 1] _: Preparation of Injection

Prescription 1

Example 1 Compound Phosphate 10g

Glucose 50g

Add water to 1000ml

Made of 1000

Process: 10 g of the compound phosphate of Example 2 and 50 g of glucose were added to a 2000 ml glassware, and dissolved in 1000 ml of water for injection at room temperature to dissolve, and filtered through a 0.22 Wn microporous membrane, and then dispensed into a lml ampule. , the specification is 10mg/ml.

Prescription 2

Example 4 Compound Mesylate 10g

Glucose 50g

Add water to 1000ml

Made of 1000 Process: The compound of the compound of Example 4, 10 g of methanesulfonate and 50 g of glucose, was added to a 1000 ml glassware, and dissolved in 1000 ml of water for injection at room temperature, and filtered with a 0.22 Wn microporous membrane, and then placed in a 2 ml vial. , that is, the specification is 10mg / bottle.

[Formulation Example 2] _: Preparation of lyophilized powder for injection

Prescription 1

Example 8 Compound Phosphate 10g

Mannitol 50g

Add water to 1000ml

Made of 1000

Process: 10 g of the compound of Example 8 and 50 g of mannitol were added to a 1000 ml glassware, dissolved in 1000 ml of water for injection at room temperature, and filtered through a 0.22 m microporous membrane, and then placed in a 2 ml vial. Each bottle is filled with 1ml solution, freeze-dried, that is, the specification is 10m _g / bottle.

Prescription 2

Example 12 Compound Phosphate 20g

Mannitol 50g

Add water to 1000ml

Made of 1000

Process: 20 g of the compound phosphate of Example 12 and 50 g of mannitol were added to a 1000 ml glassware, dissolved in 1000 ml of water for injection at room temperature, and filtered through a 0.22 Mm microporous membrane, and then placed in a 2 ml vial. Each bottle is filled with 1 ml of solution and lyophilized to obtain a specification of 20 mg/bottle.

Prescription 3

Example 13 Compound Phosphate 50g

Add water to 1000ml

Made of 1000

Process: 50 g of the compound of Example 13 was added to a 1000 ml glassware, and dissolved in 1000 ml of water for injection at room temperature to dissolve, and filtered through a 0.22 Mm microporous membrane, and then filled into a 2 ml vial, each bottle was filled. Lml solution, freeze-dried, that is, the specification is 50m _g / bottle.

Claims

claims

1. The compound represented by formula A, its pharmaceutically acceptable salt, solvate, isomer or precursor,

A

Among them: R includes but is not limited to hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocycle, alkenyl, alkynyl, the above alkyl, cycloalkyl, alkenyl, Alkynyl, alkoxyalkyl, alkylaminoalkyl and heterocycle may be unsubstituted or optionally substituted, preferably by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, Cycloalkyl, alkylamino, amino, heterocyclic substitution;

R. May exist or not exist when R. When present, R. It can be, but is not limited to, alkyl, cycloalkyl, alkyloxyalkyl, alkylaminoalkyl, heterocycle, alkenyl, alkynyl, the above alkyl, cycloalkyl, alkenyl, alkynyl, Alkoxyalkyl, alkylaminoalkyl and heterocycle may be unsubstituted or optionally substituted, preferably by halogen, hydroxyl, alkyloxy, alkyl, alkoxyalkyl, cycloalkyl, Ethylamino, amino, heterocyclic substitution, the condition is R. If it contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;

R, and R ₂ may be the same or different, including but not limited to hydrogen, alkyl, cycloalkyl, alkyloxyalkyl, alkylaminoalkyl, heterocycle, alkenyl, alkynyl, the above alkyl, ring Alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylaminoalkyl and heterocycle may be unsubstituted or optionally substituted, preferably by halogen, hydroxyl, alkyloxy, alkyl , alkoxyalkyl, cycloalkyl, alkylamino, amino, heterocyclic substitution, the condition is R. , or if it contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;

R and R ₂ and the nitrogen atom to which they are connected can also form a closed saturated or unsaturated heterocyclic ring. The above ring can also be optionally fused with other rings, and can be optionally replaced by halogen, hydroxyl, alkane, etc. Oxygen, alkyl, alkoxyalkyl, cycloalkyl, heterocycle, aryl substitution, provided that or if R ₂ contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;

R ₃ can be, but is not limited to, alkyl, cycloalkyl, - R _3l -0-R ₃₂ -, R ₃₁ and R are independently selected from bonds or hydrocarbon groups, R ₃₁ is connected to the nitrogen atom in the formula, provided that If R ₃₁ contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom; the above-mentioned alkyl or cycloalkyl group may be unsubstituted or optionally substituted. Substituted, preferably substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, acrylamino, amino, heterocycle, etc.;

1¾ ₃ with ^ R. , R,, R ₂ and the atoms they are connected together can also form a closed saturated or unsaturated ring. This ring can also be optionally fused with other rings, and can be optionally replaced by halogen, hydroxyl, Alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocycle, aryl substitution;

R ₄ and R ₅ may be the same or different, and may be but are not limited to: hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycle, alkenyl, alkynyl, the above alkyl Base, alkenyl, alkynyl, cycloalkyl, alkyloxyalkyl, alkylaminoalkyl and heterocycle may be unsubstituted or optionally substituted, preferably by halogen, hydroxyl, alkoxy , straight chain or branched alkyl group, alkoxyalkyl group, cycloalkyl group, alkylamino group, amino group, heterocyclic substitution;

R ₄ and R ₅ and the atoms to which they are connected can also form a closed ring together, for example, it can be a five-membered, six-membered, seven-membered or eight-membered ring. The above ring can also be optionally fused with other rings, and can be optionally substituted; where, when R is H, ! ^and! ^ and the nitrogen atoms to which it is connected together form a closed saturated or unsaturated heterocyclic ring, or I ^R, and the atoms to which it is connected together form a closed saturated or unsaturated ring, or R ₃ and R ₂ together form a closed saturated or unsaturated ring. The atoms that are connected together form a closed saturated or unsaturated ring; or! ^ and ^, and the atoms to which they are connected together form a closed saturated or unsaturated ring; the above ring can optionally be replaced by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl , heterocyclic, aryl-substituted and the compound of formula A is not the following and two compounds:

B2

2. The compound according to claim 1, R is selected from hydrogen, C alkyl, cycloalkyl; RR, and R ₂ are selected from hydrogen, C _alkyl , cycloalkyl, alkyloxyalkyl, amino, and alkylamino Alkyl, heterocycle; R can be but not limited to: C ₈ alkyl, cycloalkyl; R nR ₅ is selected from hydrogen, hydroxyl, d _-8 alkyl, cycloalkyl, alkoxy, alkoxy alkyl Base, heterocycle.

3. The compound according to claim 1 or 2, its structure is shown in formula C:

H ₂ N..

Among them, ^ is preferred but not limited to:

R ₅ may be but is not limited to (C) _n , where _n = 1-6, preferably 3-5, most preferably 4, and some of -CH ₂ - may be substituted by -0-. One or more hydrogens of (C) can be halogen, alkyl, hydroxyl or Substituted with alkoxy groups, etc., the preferred compound is (±) trans 1,2-hexane, pentyl, butyl and propylenediamine platinum (11). R ₇ can be but is not limited to (CH ₂ ) _n , where n=0-3, preferably n = 0-2, some of which - (: - can be replaced by -0-, one or more of (CH ₂ ) Each hydrogen can be replaced by halogen, alkyl, hydroxyl, hydroxyalkyl or alkyloxy;

and 1¾ can be but are not limited to: hydrogen, halogen, hydroxyl, hydroxyalkyl, alkyl, alkoxy, heterocycle, etc., and can be the same or different, preferably hydroxymethyl;

. And Ru can be but not limited to: hydrogen, halogen, hydroxyalkyl, alkyl, alkoxy, heterocycle, etc., preferably hydroxymethyl;

R ₁₂ may be, but is not limited to, (CH ₂ )„, where n=2-4, some of -CH ₂ - may be substituted by -O-, and one or more hydrogens of (CH ₂ )„ may be replaced by halogen, alkane Substituted by hydroxyl group, hydroxyl group or alkyloxy group;

R ₁₃ can be -CH ₂ - or - 0-, preferably -CH ₂ -;

RH can be hydrogen, halogen, alkyl, alkoxy, hydroxyalkyl or hydroxyl, R ₁₃ is preferably hydrogen;

R ₁₅ may be but is not limited to (CH ₂ ) _n , where n = 1-3, -CH ₂ - 0- or - 0-, and one or more hydrogens of (CH ₂ ) can be alkyl, alkoxy , hydroxyl, or hydroxyalkyl substituted, preferably -CH ₂ -0-CH ₂ -;

4. The compound according to claim 3, having the following structure:

T90000/M0ZN3/X3d I/OZ OAV

(J), a compound according to claim 1, having the following structure:

6ξ

T90000/M0ZN3/X3d I/OZ OAV

09

T90000/M0ZN3/X3d I/ OZ OAV 61

WO 2014/114183

£9

T90000/M0ZN3/X3d I/ OZ OAV

6. The compound according to any one of claims 1 to 5, which is in the form of a pharmaceutically acceptable salt. Preferred pharmaceutically acceptable salts are nitrates, carbonates, sulfates, phosphates, methanesulfonates, and trisulfates. Fluomethanesulfonate, p-toluenesulfonate, benzenesulfonate, acetate, fumarate, tartrate, oxalate, maleate, malate, succinate, lactate, Citrate, glutamate, aspartate.

7. A pharmaceutical composition containing a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. The composition may be in any suitable dosage form, preferably in the form of an injection; and the composition may or may not contain Contains one or more other medicines used to treat cancer.

8. The method for preparing the compound of claim 1, comprising the following steps:

(1): Take potassium chloroplatinite and add water, stir and dissolve at room temperature, take potassium iodide, add water to dissolve, then put it into the above-mentioned potassium chloroplatinite solution, and perform the reaction under nitrogen-filled conditions in a water bath, protected from light;

(2): Dissolve R ₄ NH ₂ in water and add it dropwise to the reaction solution in (1), and carry out the reaction under water bath conditions;

(3): Cool the reaction solution to below room temperature, dissolve 1^¾ in water and add dropwise to the reaction solution in (2). React in a water bath. A large amount of yellow precipitate will be generated. Cool the temperature in the reaction solution to below room temperature and filter with suction. , wash Polyester, to obtain diiododiamine platinum (II);

(4): Take Ag ₂ S0j]n and stir it into water. Take the above-mentioned diiododiamine platinum (Π) and put it into the reaction solution, then add water, react under nitrogen-filled water bath conditions in the dark, and suction filtrate to obtain dihydrate Amine platinum (II) · sulfate;

(5): Take diethyl malonate, and Br-R ₃ -Br in a flask, add K ₂ CO ₃ , stir with tetrabutylammonium bromide, heat the reaction, filter with suction, remove the solid and wash, and combine filtrate, wash the organic layer, dry, distill the solvent under reduced pressure, and collect the distillate;

(6): Put 2-Br-R ₃ -diethyl malonate into a flask, add anhydrous 1«:0 ₃ and stir with acetonitrile.

Add to the reaction solution, heat the reaction, filter out the insoluble matter, drain the filtrate, add an organic solvent to dissolve, wash with the aqueous solution, dry the organic layer, remove the solvent under reduced pressure, and obtain the product, which is purified;

(7): Put the product of (6) into a flask, add NaOH solution, and stir at room temperature;

(8): Take the product of (7), adjust the pH with an acid solution, then add the product of the above (4), and heat the reaction to obtain it;

Or include the following steps:

(1): Take potassium chloroplatinite and add water, stir and dissolve at room temperature, take potassium iodide, add water and dissolve it, then put it into the above potassium chloroplatinite solution, and carry out the reaction in a dark water bath under nitrogen filling;

(2): Dissolve the bidentate ammonia NH ₂ -X-NH ₂ in water and add it dropwise to the reaction solution in (1). After the water bath reaction, a large amount of yellow precipitate will be generated. Cool the temperature of the reaction solution below room temperature and filter with suction. After washing, bidentate diiododiamine platinum (II) is obtained;

(3): Take A _g2 S0jJD and stir it in water. Take the above diiododiamine platinum (II) and put it into the reaction solution. Then add water, react in a nitrogen-filled water bath in the dark, and filter it to obtain dihydrate diamine platinum (II). Platinum (II) sulfate;

(4): Take ethyl malonate, and Br-R ₃ - Br in a flask, add K ₂ CO ₃ , stir with tetrabutylammonium bromide, heat the reaction, filter with suction, remove the solid and wash, and combine the filtrate , wash the organic layer, dry, distill the solvent under reduced pressure, and collect the distillate;

(5): Take 2-Br-R ₃ -ethyl malonate and place it in a flask, add anhydrous 1 ₂ (: 0 _{3 )} , and stir with acetonitrile. Add another ^^- to the reaction solution, heat the reaction, and filter. Remove the insoluble matter, drain the filtrate, add ethyl acetate to dissolve, wash with saturated NaCl aqueous solution, dry the organic layer, remove the solvent under reduced pressure with a water pump, and purify; (6): Put the product of (5) into a flask, add NaOH solution, and stir at room temperature;

(7): Take the product of (6), adjust it with an acid solution, add the product of the above (3), and heat the reaction to obtain it.

9. The use of the compound of claims 1-6, its pharmaceutically acceptable salt, solvate, isomer or precursor or the pharmaceutical composition of claim 8 in the preparation of drugs for the treatment of cell proliferative diseases, wherein the cells The proliferative disease is preferably cancer, and particularly preferred cancers are breast cancer, lung cancer, colon cancer, gastric cancer, esophageal cancer, ovarian cancer, osteosarcoma, cervical cancer, bladder cancer, liver cancer, brain tumors, prostate cancer, and melanoma.

10. A kit, including the pharmaceutical composition of claim 7 and instructions for use, and may also include one or more other drugs for treating cancer.

11. A method of treating a cell proliferative disease, preferably cancer, comprising administering to a patient a medicament according to any one of the preceding claims.