阅读说明：本技术 抗癌密瘤杀内酰胺 (Anticancer lactam ) 是由 张宏杰 于 2017-09-30 设计创作，主要内容包括：提供了抗癌密瘤杀内酰胺化合物、其制备方法和治疗癌症的应用方法。(Anticancer oncolytic lactam compounds, methods of preparation thereof and methods of use for treating cancer are provided.)

1. A compound represented by formula (IX) or formula (X):

or a pharmaceutically acceptable salt, tautomer and/or prodrug thereof,

wherein

R¹Is an alkyl group; and is

R²Is an aryl group.

2. The compound of claim 1, wherein the compound is an optically pure stereoisomer.

3. The compound of claim 1, wherein the compound is of formula (IX).

4. The compound of claim 1, wherein the compound is of formula (X).

5. The compound of claim 3, wherein R¹Is C_1-6An alkyl group.

6. The compound of claim 4, wherein R²Is phenyl.

7. The compound of claim 1, wherein the compounds of formulae (IX) and (X) have relative stereochemistry as shown below:

8. the compound of claim 1, wherein the compound is selected from N- (N-butyl) -melenocidal alcohol lactams or N-phenyl-melenocidal alcohol lactams having the formula:

or a pharmaceutically acceptable salt and/or prodrug thereof.

9. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier.

10. A method of treating, preventing, or delaying progression of cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

11. The method of claim 10, wherein the cancer comprises colon cancer, breast cancer, prostate cancer, lung cancer, oral epidermoid cancer, or melanoma cancer.

12. The method of claim 10, wherein the subject is a human.

13. The method of claim 10, further comprising the step of administering a therapeutically effective amount of a second anti-cancer agent, wherein the compound of claim 1 and the second anti-cancer agent are administered sequentially or simultaneously.

Technical Field

The present invention belongs to the field of medicine and chemical industry. In particular, the invention relates to anticancer agents based on a melanoma-killing compound. The invention also includes methods of making and using the same for treating cancer.

Background

According to the compiled statistics of the WHO, different forms of cancer became the leading cause of death, taking over more than 880 million people worldwide in 2015 (WHO: http:// www.who.int/media/videos/fs 297/en/; 2017, 4-15 th day search). It is estimated that by 2036, there will be 2200 million cancer cases per year. While there are many cancer chemotherapies available today, they often have a very narrow therapeutic index and severe side effects. In addition, cancer may and often does develop resistance to many of these drugs. There is no drug that can cure cancer diseases at present, and thus there is a high necessity to discover and develop a new anticancer drug, and such research is imperative.

The millicide (miiusmane) is a group of compounds containing an oxospirodecane substructure. Several patents have been disclosed relating to compounds containing oxoor azaspirodecanes or thiaspirodecanes (thiaspirocane) substructures (US 2009/0318548a 1; US2011/021624a1 and WO2011098433a 1).

In US 2009/0318548a1, compounds of formula (VI) were synthesized. However, no anticancer data have been reported therein.

In US2011/021624a1, compounds of formula (VII) are synthesized. However, representative compounds were reported to exhibit weak cytotoxicity (IC) against MDA-MB-435, HCT116, A549 and Hela cancer cells₅₀Values in the range of 17-42 μ M).

In WO2011098433A1, compounds of the formula (VIII) are synthesized. The compound has a chemical structure containing a biphenyl group, which is reported to have tumor-inhibiting activity by inhibiting fatty acid synthesis.

Thus, there is a need for potent oncolytic compounds with more potent anti-cancer activity and low toxicity.

Citation or identification of any reference in this or any other section of this application shall not be construed as an admission that such reference is available as prior art to the present application.

Disclosure of Invention

The present invention relates to anticancer compounds synthesized based on melanoma. Specifically, the compounds of the present invention are derivatives of the basic structure of the melanoma. It is an object of the present invention to provide spinosyn derivatives having biological activity against cancers, particularly colon, breast, prostate, lung, melanoma, leukemia, brain, kidney, ovary and oral epidermoid cancers.

The present invention provides a series of novel anti-cancer compounds belonging to a class of molecules referred to herein as "millikillers" isolated from the leaves, shoots and flowers of Angelica pubescens (Milius chinensis Fine and Gagnep.) (Annonaceae)) (Zhang HJ, Ma CY, Hung NV, Cuong NM, Tan GT, Santarsiero BD, Mesecar AD, Soejarto DD, Pezzuto JM, FoHHng S.Milius, a class of cytoxic agents from Milius chinensis.journal of Medicinal Chemistry 2006; 49: 693-. Representative anti-cancer, anti-tumor, fungicidal compounds are shown below:

these three oncocides (oncocidal alcohol, oncocidal ester, and oncocidal I) were evaluated in the NCI 60 cell line group. When using the NCI automatic COMPARE assay, it was observed that these three compounds showed different GI compared to the other compounds in the NCI database₅₀Response patterns, indicating a unique anti-cancer mechanism of the melanoma, warrant the use of these melanoma-killing compounds for cancer therapy.

U.S. patent applications US13/931,997 and US14/927,485 disclose a number of melanoma derivatives including N-methyl-2-pyrrolecarboxyl-melanoma, p-dimethylamino-benzoyl-melanoma, 4 β - (N-phenyl) melanoma, 4 α - (N-phenyl) melanoma, 4 β - (N-benzoyl-N-phenyl) melanoma, 4 α - (N-benzoyl-N-phenyl) melanoma, hexahydro-melanoma, 3, 4-dihydro-melanoma, 2', 3', 6', 7' -tetrahydro-melanoma, 2-hydroxy-3, 4-dihydro-melanoma, derivatives having the structural formula, 2-acetoxy-3, 4-dihydro-mevalonate, 8 '-oxo-mevalonate, 8' -hydroxy-mevalonate, 10 '-hydroxy-8' -oxo-mevalonate, 8', 10' -dihydroxy-mevalonate, 5 β - (p-trimethylammonio-benzoyl) mevalon iodide and 5 β - (p-dimethyl-allyl-ammonio-benzoyl) mevalon bromide:

a first aspect of the invention is a compound based on the basic structure of a melanoma for use in the treatment, prevention or delay of progression of cancer in a patient.

A second aspect of the invention is a pharmaceutically acceptable salt or prodrug based on the basic structure of melanoma for use in the treatment, prevention or delay of cancer progression in a patient.

A third aspect of the invention is a pharmaceutical formulation comprising a compound based on the basic structure of melanoma or a pharmaceutically acceptable salt or prodrug thereof for use in the treatment, prevention or delay of progression of cancer in a patient.

The fourth aspect of the present invention is a compound represented by formula (IX) or formula (X):

or a pharmaceutically acceptable salt, tautomer and/or prodrug thereof,

wherein

R¹Is an alkyl group; and

R²is an aryl group.

In a first embodiment of the fourth aspect of the present invention, there is provided a compound represented by formula (IX) or formula (X), wherein the compound is an optically pure stereoisomer.

In a second embodiment of the fourth aspect of the present invention, there is provided a compound represented by formula (IX) or formula (X), wherein the compound has formula (IX) or formula (X).

In a third embodiment of the fourth aspect of the invention, there is provided a compound represented by formula (IX), wherein R is¹Is C_1-6An alkyl group.

In a fourth embodiment of the fourth aspect of the invention, there is provided a compound represented by formula (IX) or formula (X), wherein the compounds of formulae (IX) and (X) have the relative stereochemistry shown below:

in a fifth embodiment of the fourth aspect of the present invention, there is provided a compound represented by formula (IX) or formula (X), wherein said compound is selected from N- (N-butyl) -melphalan lactam or N-phenyl-melphalan lactam, having the formula:

or a pharmaceutically acceptable salt and/or prodrug thereof.

In a sixth embodiment of the fourth aspect of the present invention, there is provided a compound represented by formula (X), wherein R is²Is phenyl.

A fifth aspect of the invention is a pharmaceutical composition comprising a compound of formula (IX) or formula (X) and at least one pharmaceutically acceptable carrier.

A sixth aspect of the invention is a method of treating, preventing or delaying progression of cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (IX) or formula (X).

A first embodiment of a sixth aspect of the invention provides a method of treating, preventing or delaying progression of cancer in a subject, wherein the cancer comprises colon cancer, breast cancer, prostate cancer, lung cancer, oral epidermoid cancer or melanoma cancer.

A second embodiment of a sixth aspect of the invention provides a method of treating, preventing or delaying the progression of cancer in a subject, wherein the subject is a human.

A third embodiment of a sixth aspect of the invention provides a method of treating, preventing or delaying the progression of cancer in a subject, further comprising the step of administering a therapeutically effective amount of a second anti-cancer agent, wherein the compound of claim 1 and the second anti-cancer agent are administered sequentially or simultaneously.

The compounds of the invention may exist in different forms such as free acids, free bases, enantiomers, racemates, diastereomers, esters and other prodrugs, salts and tautomers, and the disclosure includes all variant forms of these compounds.

The scope of protection includes counterfeit or fraudulent products containing or claiming to contain the compounds of the invention, whether or not they do contain such compounds and whether or not any such compounds are contained in therapeutically effective amounts.

Packages comprising a product description or instructions for use indicating that the package contains a formulation or pharmaceutical preparation of the invention and a product that is or contains or claims to be or contains such a formulation or formulation of the invention are included within the scope of protection. Such packages may be, but are not necessarily, counterfeit or fraudulent.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described.

The present invention includes all such variations and modifications. The invention also includes all of the steps and features referred to or indicated in the specification, individually or collectively, and any and all combinations of any two or more of the steps or features.

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It should also be noted that in this disclosure, particularly in the claims and/or paragraphs, terms such as "comprising", "comprises", "comprising", and the like, may have the meaning ascribed to it by united states patent law; for example, they may mean "include (included )" and the like; and terms such as "consisting essentially of" have the meaning attributed to them by U.S. patent law, e.g., they allow for elements not expressly recited, but exclude elements found in the prior art or that affect a basic or novel feature of the invention.

Furthermore, throughout the specification and claims, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Other definitions of selected terms used herein may be found in the detailed description of the invention, which applies to the entire text. Unless defined otherwise, all other technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Other aspects and advantages of the invention will be apparent to those skilled in the art from a reading of the following description.

Detailed Description

The scope of the present invention is not limited by any of the specific embodiments described herein. The following embodiments are provided for illustration only.

Definition of

Dense nodulation killing and basic structure

The term "melanoma" as used herein includes reference to a compound comprising the basic structure shown below:

as used herein, the carbon number of the melanoma molecule includes references to compounds comprising the numbering system shown below:

the term "basic structure of a hybridoma" as used herein includes reference to a compound comprising the basic structure shown below:

in one class of basic structures of the melanoma-killing compounds, the methyl and ethyl groups form tetrahydrofuran rings (1-oxa-spiro [4.5] decane and 2-oxa-spiro [4.5] decane).

In a second class of basic structures of the melanoma-killing compounds, methyl and ethyl groups form tetrahydro-thiophene rings (1-thia-spiro [4.5] decane and 2-thia-spiro [4.5] decane).

In a third class of basic structures of the melanoma-killing compounds, methyl and ethyl groups form pyrrolidine rings (1-aza-spiro [4.5] decane, 2-aza-spiro [4.5] decane, 1-aza-spiro [4.5] -1-decene, 2-aza-spiro [4.5] -1-decene, and 2-aza-spiro [4.5] -2-decene).

Hydrocarbyl radical

The term "hydrocarbyl" as used herein includes references to moieties composed of hydrogen and carbon atoms; such moieties may comprise aliphatic and/or aromatic moieties. The moiety may comprise 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Examples of hydrocarbyl groups include C_1-6Alkyl (e.g. C)₁、C₂、C₃Or C₄Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl); c substituted by aryl (e.g. benzyl) or cycloalkyl (e.g. cyclopropylmethyl)_1-6An alkyl group; cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); aryl (e.g., phenyl, naphthyl, or fluorenyl), and the like.

Alkyl radical

As used herein, the terms "alkyl" and "C_1-6Alkyl "includes reference to a straight or branched alkyl moiety having 1,2, 3,4, 5, or 6 carbon atoms. The term includes references to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, the alkyl moiety may have 1,2, 3 or 4 carbon atoms.

Alkenyl radical

The terms "alkenyl" and "C" as used herein_2-6Alkenyl "includes reference to a straight or branched alkyl moiety having 2,3, 4,5 or 6 carbon atoms and, where applicable, additionally having at least one double bond of E or Z stereochemistry. The term includes references to groups such as vinyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

Alkynyl radical

As used hereinThe terms "alkynyl" and "C_2-6Alkynyl "includes reference to a straight or branched alkyl moiety having 2,3, 4,5 or 6 carbon atoms and additionally having at least one triple bond. The term includes references to groups such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

Alkoxy radical

As used herein, the terms "alkoxy" and "C_1-6Alkoxy "includes reference to-O-alkyl, wherein alkyl is straight or branched chain and contains 1,2, 3,4, 5, or 6 carbon atoms. In one class of embodiments, the alkoxy group has 1,2, 3, or 4 carbon atoms. The term includes references to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

Cycloalkyl radicals

The term "cycloalkyl" as used herein includes reference to an alicyclic moiety having 3,4, 5, 6, 7 or 8 carbon atoms. The groups may be bridged or polycyclic ring systems. More common cycloalkyl groups are monocyclic. The term includes references to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (norbomyl), bicyclo [2.2.2] octyl, and the like.

Aryl radicals

The term "aryl" as used herein includes reference to an aromatic ring system containing 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl is typically phenyl, but may be a polycyclic ring system having two or more rings (at least one of which is aromatic). The term includes references to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthracenyl and the like.

Cyclic group

A "cyclic group" is a ring or ring system, which may be unsaturated or partially unsaturated, but is usually saturated, typically containing 3-13 ring atoms, for example a 3-, 4-, 5-or 6-membered ring. The ring system may be a bridged or polycyclic ring system. The ring or ring system may be substituted with one or more hydrocarbyl groups. Cyclic groups include carbocyclyl (carbocyclyl) and heterocyclyl moieties.

Carbocyclic group

The term "carbocyclyl" as used herein includes reference to a saturated (e.g., cycloalkyl) or unsaturated (e.g., aryl) cyclic moiety having 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon ring atoms. In particular, carbocyclyl includes 3-to 10-membered rings or ring systems, which may be saturated or unsaturated, particularly 5-or 6-membered rings. The ring or ring system may be substituted with one or more hydrocarbyl groups. The carbocyclic moiety is for example selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo [2.2.2] octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthracenyl and the like.

Heterocyclic radical

The term "heterocyclyl" as used herein includes reference to a non-aromatic (e.g., heterocycloalkyl) or aromatic (e.g., heteroaryl) heterocyclic moiety having 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In particular, heterocyclyl includes 3-to 10-membered rings or ring systems, especially 5-or 6-membered rings, which may be saturated or unsaturated. The ring or ring system may be substituted with one or more hydrocarbyl groups.

The heterocyclic moiety is for example selected from the group consisting of oxiranyl, azirinyl, 1, 2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuryl, benzofuryl, benzopyranyl, 2H-pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidyl, pyrrolizidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl (especially thiomorpholinyl), indolizinyl, isoindolyl, 3H-indolyl, benzimidazolyl, coumaryl (cumaroyl), Indazolyl, triazolyl, tetrazolyl, purinyl, 4/V-quinolizyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothienyl, dibenzothienyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, pyridyl, phenanthrolinyl, furaronyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzopyranyl, isoindolinyl, dihydrobenzopyranyl (chromanyl), and the like.

Heterocycloalkyl radicals

The term "heterocycloalkyl" as used herein includes reference to a heterocyclic moiety having 3,4, 5, 6, or 7 ring carbon atoms and having 1,2, 3,4, or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. The heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds, so long as the ring is not aromatic. The group may be a polycyclic ring system, but more commonly is a monocyclic ring system. The term includes references to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl, and the like. The ring or ring system may be substituted with one or more hydrocarbyl groups.

Heteroaryl radical

The term "heteroaryl" as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, wherein at least one ring atom is selected from nitrogen, oxygen and sulfur. The group may be a polycyclic ring system having two or more rings, at least one of which is aromatic, but more typically the group is monocyclic. The ring or ring system may be substituted with one or more hydrocarbyl groups. The term includes references to groups such as pyrimidinyl, furanyl, benzo [ b ] thienyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridyl, benzo [ b ] furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-benzopyranyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl, and the like.

Halogen element

The term "halogen" as used herein includes references to F, Cl, Br or I.

Halogen containing moieties

As used herein, the expression "halogen-containing moiety" includes reference to a moiety comprising from 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur, said moiety comprising at least one halogen. The moiety may be a hydrocarbyl group, e.g. C_1-6Alkyl or C_1-6Alkoxy, or carbocyclyl such as aryl.

Substituted by

The term "substituted" as used herein in reference to a moiety means that one or more hydrogen atoms, especially up to 5 hydrogen atoms, more specifically 1,2 or 3 hydrogen atoms in the moiety are substituted independently of each other by a corresponding number of the described substituents. The term "optionally substituted" as used herein means substituted or unsubstituted. It will, of course, be understood that the substituents are only at their chemically possible positions and that the skilled person will be able to determine (whether experimentally or theoretically) whether a particular substitution is possible without undue effort.

Enantiomers

The term "enantiomer" as used herein refers to one of two stereoisomers having mirror images of each other.

Racemic modification

The term "racemate" as used herein refers to a mixture of equal amounts of enantiomers of a chiral molecule.

Diastereoisomers

The term "diastereomer" as used herein refers to one of a class of stereoisomers which are not enantiomers but have different configurations at one or more equivalent chiral centers. Examples of diastereomers are epimers that differ only in the configuration of one chiral center.

Stereoisomers

The term "stereoisomer" as used herein refers to one of a class of isomeric molecules having the same molecular formula and bonded atomic order, but differing in the three-dimensional orientation of its atoms in space.

Tautomers

The term "tautomer" refers to isomeric molecules that are susceptible to interconversion by chemical reaction. The reaction typically results in the migration of hydrogen atoms, which results in the conversion of single bonds and adjacent double bonds.

Prodrugs

A prodrug is a drug that is administered as an inactive (or less than fully active) chemical derivative and is subsequently converted in vivo to an active pharmacological agent, usually by normal metabolic processes.

Independently of each other

When two or more moieties are described as "each independently" selected from a series of atoms or groups, this means that the moieties may be the same or different. Thus, the authentication of each portion is independent of the authentication of one or more other portions.

Embodiments of the present invention are described below. Preferred features of each aspect of the invention are as for each of the other aspects, mutatis mutandis. Furthermore, it is to be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments.

Compounds of the invention

In exemplary embodiments, the present invention provides compounds of formula (I) or (II):

or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵And R¹⁶Each of which isIndependently selected from: hydrogen, halogen or a moiety comprising 1-30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur; or these groups may form, together with the carbon atom to which they are attached, one or more cyclic groups optionally substituted with halogen or a moiety comprising 1-30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur; r¹And R²、R³And R⁴、R⁵And R⁶、R⁷And R⁸、R⁹And R¹⁰、R¹¹And R¹²、R¹³And R¹⁴Or R¹⁵And R¹⁶May form, together with the carbon atom to which they are attached, one or more carbonyl groups (C ═ O); or, when R is¹And R²、R³And R⁴、R⁵And R⁶、R⁷And R⁸、R⁹And R¹⁰、R¹¹And R¹²、R¹³And R¹⁴Or R¹⁵And R¹⁶When one of them is hydrogen, halogen, hydrocarbyl or alkoxy, R¹And R²、R³And R⁴、R⁵And R⁶、R⁷And R⁸、R⁹And R¹⁰、R¹¹And R¹²、R¹³And R¹⁴Or R¹⁵And R¹⁶The other of which is selected from: r¹⁷、-OR¹⁷、-C(O)R¹⁷and-C (O) OR¹⁷；R¹⁷Independently selected from: hydrogen, halogen, trifluoromethyl, cyano, nitro, optionally substituted by 1,2, 3,4 or 5R¹⁸Substituted hydrocarbyl, optionally substituted with 1,2, 3,4 or 5R¹⁸Substituted heterocyclyl, optionally substituted with 1,2, 3,4 or 5R¹⁸Substituted- (CH)₂)_k-heterocyclyl, -OR¹⁹、-C(O)R²⁰、-C(O)N(R¹⁹)R²⁰、-C(O)OR¹⁹、-OC(O)R¹⁹、-S(O)₂R¹⁹、-S(O)₂N(R¹⁹)R²⁰、-N(R¹⁹)R²⁰、-N(R¹⁹)N(R¹⁹)R²⁰、-N(R¹⁹)C(O)R²⁰and-N (R)¹⁹)S(O)₂R²⁰(ii) a Wherein k is between 1 and 6An integer of (e.g., 1,2, or 3); r¹⁸Independently selected from: halogen, trifluoromethyl, cyano, nitro, oxo, ═ NR¹⁹、-OR¹⁹、-C(O)R²⁰、-C(O)N(R¹⁹)R²⁰、-C(O)OR¹⁹、-OC(O)R²⁰、-S(O)₂R¹⁹、-S(O)₂N(R¹⁹)R²⁰、-N(R¹⁹)R²⁰、-N(R¹⁹)N(R¹⁹)R²⁰、-N(R¹⁹)C(O)R²⁰and-N (R)¹⁹)S(O)₂R²⁰；R¹⁹And R²⁰Each independently hydrogen, or is selected from: hydrocarbyl, heterocyclyl or- (CH)₂)_k-heterocyclyl, said hydrocarbyl, heterocyclyl or- (CH)₂)_k-heterocyclyl is optionally selected from 1,2, 3,4 or 5 independently from halogen, cyano, amino, hydroxy, C_1-6Alkyl and C_1-6Substituent substitution of alkoxy; wherein k is an integer between 1 and 6 (e.g., 1,2, or 3); x is oxygen or sulfur; r is hydrogen or is selected from: hydrocarbyl, heterocyclyl or- (CH)₂)_k-heterocyclyl, said hydrocarbyl, heterocyclyl or- (CH)₂)_k-heterocyclyl is optionally selected from 1,2, 3,4 or 5 independently from halogen, cyano, amino, hydroxy, C_1-6Alkyl and C_1-6Substituent substitution of alkoxy; wherein k is an integer between 1 and 6 (e.g., 1,2, or 3); the dotted line "- - -" represents a single bond or a double bond.

In certain embodiments, the compounds of the invention are represented by formula (IX) or formula (X):

or a pharmaceutically acceptable salt, tautomer and/or prodrug thereof, wherein R¹Is an alkyl group; and R²Is an aryl group.

In certain embodiments, the compounds are optically pure stereoisomers.

In certain embodiments, the compound has formula (X).

In certain embodiments, the compounds of formula (X) have the relative stereochemistry shown below:

in certain embodiments, the compounds of formula (X) have the absolute stereochemistry shown below:

in certain embodiments, R²Is phenyl.

In certain embodiments, the compound has formula (IX).

In certain embodiments, the compounds of formula (IX) have the relative stereochemistry shown below:

in certain embodiments, the compound of formula (IX) has the absolute stereochemistry shown below:

in certain embodiments, R¹Is C_1-6Alkyl radical, C_2-6Alkyl radical, C_3-6Alkyl or C_3-5An alkyl group. In certain embodiments, R¹Is C₄An alkyl group. In certain embodiments, R¹Is n-butyl.

In certain embodiments, the compound is a tautomer of a compound of formula (IX) or (X).

In certain embodiments, the compounds have the same relative stereochemistry at the C-1, C-1' and C-5 carbons as the melanoma.

In certain embodiments, the compound has the same absolute stereochemistry at the C-1, C-1' and C-5 carbons as the melanoma.

In certain embodiments, the compounds are enantiomers.

In certain embodiments, the compound is a racemate.

In certain embodiments, the compounds are diastereomers.

In certain embodiments, the compound is a tautomer.

The invention also provides a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier.

It should be noted that a compound having one of the following formulae should not be a compound of the present invention and should therefore be removed from a compound of the present invention:

wherein Ac is acetyl (CH)₃C ═ O), Me is methyl (CH)₃)。

Compounds having the following formula (V) are not included in the present invention:

wherein R is¹＝R²＝R³＝R⁴＝R⁵H; or R¹＝R²＝R³＝R⁴＝H，R⁵＝OCH₃(ii) a Or R¹＝R³＝R⁴＝R⁵＝H，R²＝OCH₃(ii) a Or R¹＝R²＝R⁴＝R⁵＝H，R³＝OCH₃(ii) a Or R¹＝R²＝R⁴＝H，R³＝R⁵＝OCH₃(ii) a Or R¹＝R⁵＝OCH₃，R²＝R³＝R⁴H; or R¹＝R⁴＝R⁵＝H，R²＝R³＝OCH₃(ii) a Or R¹＝R³＝R⁵＝H，R²＝R⁴＝OCH₃(ii) a Or R¹＝R⁵＝H，R²＝R³＝R⁴＝OCH₃(ii) a Or R¹＝R⁴＝R⁵＝H，R²And R³Together with the carbon atom to which they are attached form a cyclic [1,3 ]]Dioxolyl; or R¹＝R²＝R³＝R⁴＝H，R⁵＝CH₃(ii) a Or R¹＝R³＝R⁴＝R⁵＝H，R²＝CH₃(ii) a Or R¹＝R²＝R⁴＝R⁵＝H，R³＝CH₃(ii) a Or R¹＝R²＝R³＝R⁴＝H，R⁵F; or R¹＝R³＝R⁴＝R⁵＝H，R²F; or R¹＝R²＝R⁴＝R⁵＝H，R³F; or R¹＝R²＝R³＝H，R⁴＝R⁵F; or R¹＝R²＝R⁴＝H，R³＝R⁵F; or R¹＝R³＝R⁴＝H，R²＝R⁵F; or R¹＝R⁵＝F，R²＝R³＝R⁴H; or R¹＝R⁴＝R⁵＝H，R²＝R³F; or R¹＝R³＝R⁵＝H，R²＝R⁴F; or R¹＝R²＝R³＝R⁴＝H，R⁵Cl; or R¹＝R³＝R⁴＝R⁵＝H，R²Cl; or R¹＝R²＝R⁴＝R⁵＝H，R³Cl; or R¹＝R²＝R⁴＝H，R³＝R⁵Cl; or R¹＝R⁵＝Cl，R²＝R³＝R⁴H; or R¹＝R⁴＝R⁵＝H，R²＝R³Cl; or R¹＝R³＝R⁵＝H，R²＝R⁴Cl; or R¹＝R²＝R³＝R⁴＝H，R⁵Br; or R¹＝R³＝R⁴＝R⁵＝H，R²Br; or R¹＝R²＝R⁴＝R⁵＝H，R³Br; or R¹＝R²＝R³＝R⁴＝H，R⁵I ═ I; or R¹＝R²＝R⁴＝R⁵＝H，R³＝I。

Compounds having the following formula (VI) are not included in the present invention:

wherein X¹And X²Are carbon atoms connected by a double bond or by a single bond component of an epoxy ring or a hydroxyethylene moiety; x³And X⁴Are carbon atoms connected by a double bond or by a single bond component of an epoxy ring or a hydroxyethylene moiety; r¹Selected from the group consisting of: branched alkyl chains, unbranched alkyl chains, cycloalkyl groups, aromatic groups, alcohols, ethers, amines, and substituted or unsubstituted ureas, esters, aldehydes, and carboxylic acids; r²Selected from the group consisting of: H. OH and NHR³Wherein R is³Is a nitrogen protecting group.

Compounds having the following formula (VII) are not included in the present invention:

wherein R is¹、R³And R⁴Selected from the group consisting of: branched alkyl chains, unbranched alkyl chains, cycloalkyl groups, aromatic groups, alcohols, ethers, amines, and substituted or unsubstituted ureas, esters, aldehydes, and carboxylic acids; m is an integer of 0 to 5.

Compounds having the following formula (VIII) are not included in the present invention:

wherein Z is oxygen or sulfur or nitrogen, substituted with a D group; d represents hydrogen or represents C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl or represents C₃-C₇-cycloalkyl or 4-to 7-membered monocyclic heterocyclyl, wherein said groups may optionally be mono-or polysubstituted by identical or different substituents, selected from the group consisting of: halogen and hydroxy and C₁-C₃-alkyl, halo-C₁-C₃-alkyl or C₁-C₃-an alkoxy group; x represents halogen, nitro or cyano or represents optionally mono-or polyhalogen-substituted C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy, C₃-C₇-cycloalkyl or C₃-C₇-cycloalkyl-C₁-C₆-an alkoxy group; and W and Y independently of one another represent hydrogen, nitro, cyano or halogen or represent optionally mono-or polyhalogen-substituted C₁-C₆Alkyl radical, C₁-C₆-alkoxy or C₃-C₇-a cycloalkyl group; and V¹、V²And V³Independently of one another, represents hydrogen, halogen, nitro or cyano or represents C₁-C₆-alkyl, halo-C₁-C₆Alkyl radical, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆Alkyl thio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxy-C₁-C₆Alkyl radical, C₃-C₁₀-cycloalkyl or represents monocyclic heterocycloalkyl, and/or V¹And V²Together with the carbon atom to which they are attached form a saturated or unsaturated ring T¹Optionally containing at least one further heteroatom and having 4-to 7-ring atoms, and whose ring atoms may be mono-or polysubstituted by identical or different substituents selected from the group consisting of: halogen and C₁-C₆-an alkyl group.

Examples of the compounds of the present invention include those shown below. It will of course be appreciated that each compound may, where appropriate, be in the form of the free compound, an enantiomer, an acid or base addition salt or a prodrug.

The present invention provides 17 compounds with effective anticancer activity and their synthesis. Compounds of the present invention, namely 4 beta- (N-phenyl) melphalan, 4 alpha- (N-phenyl) melphalan, 4 beta- (N-benzoyl-N-phenyl) melphalan, 4 alpha- (N-benzoyl-N-phenyl) melphalan, hexahydro-melphalan, 3, 4-dihydro-melphalan, 2', 3', 6', 7' -tetrahydro-melphalan, 2-hydroxy-3, 4-dihydro-melphalan, 2-acetoxy-3, 4-dihydro-melphalan, 8 '-oxo-melphalan, 8' -hydroxy-melphalan, 10 '-hydroxy-8' -oxo-melphalan, and evaluating their anti-cancer activity, were synthesized and evaluated, 8', 10' -dihydroxy-melphalan, 5 β - (p-trimethylammonium-benzoyl) melphalan alcohol iodide, 5 β - (p-dimethyl-allyl-ammonium-benzoyl) melphalan alcohol bromide, N- (N-butyl) -melphalan alcohol lactam and N-phenyl-melphalan alcohol lactam. The compounds of the invention have the following chemical formula: