CN106146338A - Naphthaquinone derivatives containing adamantyl, its preparation method and application - Google Patents

Naphthaquinone derivatives containing adamantyl, its preparation method and application Download PDF

Info

Publication number
CN106146338A
CN106146338A CN201510199108.2A CN201510199108A CN106146338A CN 106146338 A CN106146338 A CN 106146338A CN 201510199108 A CN201510199108 A CN 201510199108A CN 106146338 A CN106146338 A CN 106146338A
Authority
CN
China
Prior art keywords
alkyl
unsubstituted
group
amino
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201510199108.2A
Other languages
Chinese (zh)
Other versions
CN106146338B (en
Inventor
张翱
杨财广
王美凝
倪腾凤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN201510199108.2A priority Critical patent/CN106146338B/en
Publication of CN106146338A publication Critical patent/CN106146338A/en
Application granted granted Critical
Publication of CN106146338B publication Critical patent/CN106146338B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention provides a kind of naphthaquinone derivatives containing adamantyl, its preparation method and application, specifically, the invention provides a kind of naphthaquinone derivatives containing adamantyl as shown in following formula (I).Wherein, the definition of each group is as noted in the discussion.The compounds of this invention has Sortase A enzyme inhibition activity and cytotoxic activity, and may be used for treating the related disease of Sortase A enzymatic activity and various malignant tumour.

Description

Naphthaquinone derivatives containing adamantyl, its preparation method and application
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of naphthaquinone derivatives containing adamantyl, its Preparation method, pharmaceutical composition, its as Sortase A inhibitor in preparation antibacterials and cell toxicant thereof Application in preparing cancer therapy drug for the activity.
Background technology
1,4-naphthoquinone structure fragment is widely present in various structures and the different natural products of biologically active, its Derivative is in the news the diversified biologically active having including antibacterial, antitumor, neuroprotective. The features such as the unique rigid caged multiring structure of adamantane structure Duan Yinqi, highly lipophilic property, are optimizing guide Physico character and druggability aspect also have important application.
Sortase A is a kind of mediation gram-positive bacteria cell membrane and the covalently bound protease of surface protein, It is primarily present in Grain-positive cause of disease bacterium.The surface protein of Grain-positive cause of disease bacterium rises in its pathogenic course Multiple key effect, study these albumen and understanding bacterium course of infection and the new therapeutic target of screening are indicated Significance.Therefore, Sortase A be considered as treatment bacterium infect a class is new, preferable target spot. On the other hand, although molecular targeted agents develops rapidly in recent years, cytotoxic drug is still antitumor at present The extremely important treatment means of class in treatment.
In sum, this area is in the urgent need to developing the novel medicine for Sortase A target spot.
Content of the invention
It is an object of the invention to provide a kind of Sortase A target spot inhibitor.
A first aspect of the present invention, provides a kind of naphthoquinones class containing adamantyl as shown in following formula (I) and derives Thing:
Wherein,
R1, R2, R3, R4, R5Be each independently selected from lower group: hydrogen, halogen atom, nitro, itrile group, Hydroxyl, amino, carboxyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C1-C6Alkoxy-carbonyl, C1-C6 Amide groups, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, replacement or do not take Five yuan of generation or six membered heteroaryl；
It is preferred that R1, R2, R3, R4, R5Be each independently selected from lower group: H, halogen atom, nitro, Itrile group, hydroxyl, amino, carboxyl, C1-C6Alkoxy carbonyl, C1-C6Amide groups, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl or C1-C6Alkyl-amino；
A is the substituted or unsubstituted adamantyl being selected from the group:
Wherein, R6、R7、R8、R12、R13、R14Be each independently selected from lower group: hydrogen, halogen, hydroxyl, Carboxyl, amino, nitro, cyano group, C1-C6Alkoxyl, C1-C6Alkyl-amino, C1-C6Alkoxy carbonyl, C1-C6Amide groups, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, replacement Or unsubstituted five yuan or six membered heteroaryl；
It is preferred that R6、R7、R8、R12、R13、R14Be each independently selected from lower group: H, hydroxyl, carboxylic Base, amino, C1-C6Alkoxy carbonyl, C1-C6Amide groups, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6 Alkoxyl, or C1-C6Alkyl-amino；
R9、R10、R11Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, Cyano group, C1-C6Alkoxyl, C1-C6Alkyl-amino, C2-C6Alkoxy carbonyl (ROC=O-), C2-C6Thiazolinyl Carbonyl (RC=O-), C2-C6Alkyl-carbonyl (RC=O-), substituted or unsubstituted C1-C6Acyloxy (RC=OO-), Substituted or unsubstituted C1-C6Amine acyloxy (RNC=OO-), C1-C6Aminoacyl (RNC=O-), C1-C6Acid amides Base (RC=ON-), substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, or take Generation or unsubstituted five yuan or six membered heteroaryl；
It is preferred that R9、R10、R11It is each independently selected from lower group: H, C1-C6Alkyl, replacement or do not take The C in generation1-C6Acyloxy (RC=OO-), substituted or unsubstituted C1-C6Amine acyloxy (RNC=OO-), hydroxyl, Carboxyl, amino, C1-C6Alkoxy carbonyl (ROC=O-), C1-C6Aminoacyl (RNC=O-), C1-C6Acid amides Base (RC=ON-), halo C1-C6Alkyl, C1-C6Alkoxyl or C1-C6Alkyl-amino；
-L-is the divalent linker being selected from the group:
Wherein, R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、 R28It is each independently selected from lower group: hydrogen, the C of unsubstituted or halo1-C6Alkyl, halogen, cyano group, nitro, C2-C10Alkynyl, C2-C10Thiazolinyl, C6-C10Aryl, hydroxyl, C1-C6Alkoxyl, C1-C6Amido；Or, R16And R17Or R18、R23And R20Or R21It is collectively forming replacement or unsubstituted with the carbon atom being connected or nitrogen-atoms Five yuan or hexa-member heterocycle；
It is preferred that R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、 R27、R28It is each independently selected from lower group: hydrogen, C1-C6Alkyl, C6-C10Aryl, hydroxyl, C1-C6Alcoxyl Base, C1-C6Amino；Or, R16And R17Or R18、R23And R20Or R21With the carbon atom being connected or nitrogen-atoms It is collectively forming substituted or unsubstituted five yuan or hexatomic ring；
N is 1,2,3,4,5,6 or 7；
Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituent of lower group and take Generation: halogen, hydroxyl, carboxyl, benzyl, C1-C6Alkoxy carbonyl, amino, C1-C6Amide groups, nitro, Cyano group, the C of unsubstituted or halo1-C6Alkyl, C2-C10Thiazolinyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C6-C10Aryl, five yuan or six membered heteroaryl, preferably halogen, C1-C6Alkoxy carbonyl, unsubstituted or halogen The C in generation1-C6Alkyl.
In another preference, R1, R2, R3, R4, R5Be each independently selected from lower group: hydrogen, halogen, Hydroxyl, carboxyl, amino, nitro, cyano group, C1-C6Alkoxyl, substituted or unsubstituted C1-C10Alkyl, Substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five yuan or six membered heteroaryl；
R6、R7、R8、R12、R13、R14Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, Amino, nitro, cyano group, C1-C6Alkoxyl, substituted or unsubstituted C1-C10Alkyl, replacement or unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl, preferably H, hydroxyl, carboxyl, amino, C1-C6Alkyl, Halo C1-C6Alkyl, C1-C6Alkoxyl, or C1-C6Alkyl-amino；Wherein, described on finger group one Individual or multiple hydrogen atoms be selected from lower group substituent replace: halogen, hydroxyl, carboxyl, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl；It is preferably halogen, C1-C6Alkyl.
In another preference, R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、 R26、R27、R28It is each independently selected from lower group: hydrogen, C1-C6Alkyl；
Or, R16And R17Or R18、R23And R20Or R21It is collectively forming with the carbon atom being connected or nitrogen-atoms and take Generation or unsubstituted five yuan or hexa-member heterocycle, it is therefore preferable to five-ring heterocycles.
In another preference, in described compound, R1、R2、R3、R4、R5、R6、R7、R8、 R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、 R24、R25、R26、R27、R28In any one is respectively described in the embodiment of the present invention institute in particular compound Corresponding group.
In another preference, the described naphthaquinone derivatives containing adamantyl is the chemical combination being selected from the group Thing:
A second aspect of the present invention, provides the preparation of a kind of formula (I) derivative as described in the first aspect of the invention Method, described method includes step (b):
B (), in atent solvent, carries out oxidation reaction with Formula II compound, obtains compound of formula I；Wherein, each base The definition of group is as described in first aspect present invention.
In another preference, described oxidation reaction is carried out in the presence of ammonium ceric nitrate.
In another preference, described Formula II compound is through the following steps that prepared by (a1) or (a2):
(a1) in atent solvent, with formula III compound and A-NH2Or A-CH (R) NH2Reaction, obtains Formula II Compound；
Wherein,For L；
(a2) in atent solvent, react with A-COOH with formula III ' compound, obtain Formula II compound；
Wherein,For L；
The definition of remaining each group is as described in first aspect present invention.
In another preference, described step (a1) or (a2) are carried out in the presence of an organic base, it is preferred that described Organic base be selected from the group: DIPEA (DIPEA) and/or triethylamine.
In another preference, described step (a1) or (a2) are carried out in the presence of condensing agent；It is preferred that substantive examination Condensing agent be selected from the group: 2-(7-azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU).
Third aspect present invention, provides a kind of pharmaceutical composition, and described pharmaceutical composition includes: treatment has Effect amount as described in the first aspect of the invention containing the naphthaquinone derivatives of adamantyl, its optical isomer, its Pharmaceutically acceptable salt or its prodrug；And pharmaceutically acceptable carrier.
In another preference, described pharmaceutical composition is lived with Sortase A enzyme for (i) treatment or prevention Property related disease；(ii) kill bacterium, be preferably selected from the bacterium of lower group: Sa.Newman, Sa.RN4220, Sa.8325-4, Se.1457, Bs.681, and/or Ec.DH5 α；(iii) treatment or pre-anti-cancer, it is preferred that Described cancer is selected from the group: lung cancer, colon cancer, oral epithelium cancer, cancer of the stomach, leukaemia.
In another preference, the described disease related to Sortase A enzymatic activity is and Sortase A enzyme table The amount of reaching raises, or Sortase A enzymatic activity strengthens related disease.
A fourth aspect of the present invention, provides a kind of naphthalene containing adamantyl as described in the first aspect of the invention The purposes of naphthoquinone derivatives, for (a) for preparing treatment or preventing the disease related to Sortase A enzymatic activity Sick pharmaceutical composition；(ii) kill bacterium for external non-therapeutic, be preferably selected from the bacterium of lower group: Sa.Newman, Sa.RN4220, Sa.8325-4, Se.1457, Bs.681, and/or Ec.DH5 α；(iii) For preparing the pharmaceutical composition for the treatment of or pre-anti-cancer, it is preferable that described cancer is selected from the group: lung cancer, Colon cancer, oral epithelium cancer, cancer of the stomach, leukaemia；(iv) for external non-therapeutic ground suppression Sortase A Enzymatic activity.
A fifth aspect of the present invention, provides a kind of method for disinfection, comprising: for object administration to be sterilized The naphthaquinone derivatives containing adamantyl as described in the first aspect of the invention of antimicrobial effective amount.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (such as embodiment) Can be combined with each other between each technical characteristic of middle specific descriptions, thus constitute new or preferred technical side Case.As space is limited, at this no longer one by one tire out state.
Detailed description of the invention
The present inventor on the basis of existing technology, designed and synthesized a class new while there is naphthoquinones and gold The derivative of firm alkane two class dominance structure fragment, through in vitro living to Sortase A albumen and various bacteria Property screening, result shows that it has Sortase A inhibitory activity in various degree and antibacterial, bactericidal activity； Through in vitro carrying out antitumor activity screening to kinds of tumor cells, what result showed that it has in various degree anti-swells Tumor activity.
Term
As used herein, term " halogen " refers to it is F, Cl, Br or I.
Term " C1-C10Alkyl " refers to the straight or branched alkyl on main chain with 1 to 10 carbon atom, term “C1-C6Alkyl " has a similar implication, representational example such as methyl, ethyl, propyl group, isopropyl, Butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, base etc..
Term " C1-C10Alkoxyl " refers to the straight or branched alkoxyl on main chain with 1 to 10 carbon atom, Term " C1-C6Alkoxyl " has similar implication, representational example such as methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy etc..
Term " the C of halo1-C10Alkyl " refers to that the one or more hydrogen atoms on group are substituted with halogen atoms C1-C10Alkyl, term " halo C1-C6Alkyl " has similar implication, representational example such as trifluoro Methyl etc..
Term " C3-C10Cycloalkyl " refers to the fatty carbocylic radical with 3 to 10 carbon atoms, including monocyclic and Ring, bridged ring, volution etc., representational example such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, gold Firm alkyl etc..
Term " C2-C6Alkoxy carbonyl " refers to the alkoxy carbonyl with 2 to 6 carbon atoms, representational example Son such as methoxycarbonyl, ethoxy carbonyl etc..
Term " C2-C6Alkyl carbonyl epoxide " refers to the alkyl carbonyl epoxide with 2 to 6 carbon atoms, representational example Son such as acetoxyl group etc..
Term " C2-C6Amide groups " refers to the carbonylamino with 2 to 6 carbon atoms, and representational example is for example Acetamido, propionamido-, amide-based small etc..
Term " C6-C10There is on aryl " finger ring the armaticity carbocylic radical of 6 to 10 carbon atoms, representational Example such as phenyl, naphthyl etc..
Described five yuan or hexatomic ring refer to have 5 or 6 atoms on ring, including carbon atom or choosing From carbocyclic ring or heterocycle, such as cyclopropane, cyclobutane, the ring penta of the hetero atom (preferably 1-4) of N, O and S Alkane, the cycloaliphatic ring such as hexamethylene, or nafoxidine, morpholine, piperazine, oxa-or the azepine cycloaliphatic ring such as piperidines.
Described five yuan or six membered heteroaryl refer to have at least one (preferably 1-4) on ring and are selected from N, O Heteroatomic five yuan or hexa-atomic armaticity ring group, such as thienyl, thiazolyl, pyrazolyl, imidazoles with S Base, pyridine radicals, pyrazinyl, pyrimidine radicals etc..
Described acyloxy is the group with RC=OO-structure；Described amine acyloxy is for having The group of RNC=OO-structure；Described alkoxy carbonyl is the group with ROC=O-structure；Described Aminoacyl is the group with RNC=O-structure；Described amide groups is the group with RC=ON-structure； In above-mentioned each group, each R is each independently hydrogen, has aliphatic alkyl, the tool of 1-10 carbon atom There is the unsaturated group of aliphatic series of 1-10 carbon atom or there is the aromatic radical of 1-10 carbon atom；Especially, R in described amine acyloxy (RNC=OO-), aminoacyl (RNC=O-), can also collectively form ring-type with N Amine, such as piperazine, piperidines, morpholine, nafoxidine etc..
In the present invention, term " prodrug " refers to compound of formula I, its optical isomer or it is pharmaceutically acceptable The derivative of salt, themselves may only have more weak activity or there is no activity, but upon administration at physiology Under the conditions of can be converted into corresponding biologically active form.
Naphthaquinone derivatives containing adamantyl
It is an aspect of the invention to provide a kind of naphthaquinone derivatives containing adamantyl, which is logical formula (I) institute Compound, its optical isomer, its pharmaceutically acceptable salt and the prodrug thereof showing,
Wherein,
R1, R2, R3, R4, R5Be each independently selected from lower group: hydrogen, halogen atom, nitro, itrile group, Hydroxyl, amino, carboxyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C1-C6Alkoxy-carbonyl, C1-C6 Amide groups, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, replacement or do not take Five yuan of generation or six membered heteroaryl；
It is preferred that R1, R2, R3, R4, R5Be each independently selected from lower group: H, halogen atom, nitro, Itrile group, hydroxyl, amino, carboxyl, C1-C6Alkoxy carbonyl, C1-C6Amide groups, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl or C1-C6Alkyl-amino；
A is the substituted or unsubstituted adamantyl being selected from the group:
Wherein, R6、R7、R8、R12、R13、R14Be each independently selected from lower group: hydrogen, halogen, hydroxyl, Carboxyl, amino, nitro, cyano group, C1-C6Alkoxyl, C1-C6Alkyl-amino, C1-C6Alkoxy carbonyl, C1-C6Amide groups, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, replacement Or unsubstituted five yuan or six membered heteroaryl；
It is preferred that R6、R7、R8、R12、R13、R14Be each independently selected from lower group: H, hydroxyl, carboxylic Base, amino, C1-C6Alkoxy carbonyl, C1-C6Amide groups, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6 Alkoxyl, or C1-C6Alkyl-amino；Wherein, substituent selected from halogen atom, hydroxyl, carboxyl, nitro, Cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl, preferably halogen atom, C1-C6Alkyl.
R9、R10、R11Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, Cyano group, C1-C6Alkoxyl, C1-C6Alkyl-amino, C2-C6Alkoxy carbonyl (ROC=O-), C2-C6Thiazolinyl Carbonyl (RC=O-), C2-C6Alkyl-carbonyl (RC=O-), substituted or unsubstituted C1-C6Acyloxy (RC=OO-), Substituted or unsubstituted C1-C6Amine acyloxy (RNC=OO-), C1-C6Aminoacyl (RNC=O-), C1-C6Acid amides Base (RC=ON-), substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, or take Generation or unsubstituted five yuan or six membered heteroaryl；
It is preferred that R9、R10、R11It is each independently selected from lower group: H, C1-C6Alkyl, replacement or do not take The C in generation1-C6Acyloxy (RC=OO-), substituted or unsubstituted C1-C6Amine acyloxy (RNC=OO-), hydroxyl, Carboxyl, amino, C1-C6Alkoxy carbonyl (ROC=O-), C1-C6Aminoacyl (RNC=O-), C1-C6Acid amides Base (RC=ON-), halo C1-C6Alkyl, C1-C6Alkoxyl or C1-C6Alkyl-amino；Wherein, substituent Selected from halogen atom, hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, amino, C1-C6Amide groups, nitro, Cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C6-C10Aryl Or five yuan or six membered heteroaryl, preferably halogen atom, C1-C6Alkoxy carbonyl, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl or phenyl.
-L-is the divalent linker being selected from the group:
Wherein, R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、 R28It is each independently selected from lower group: hydrogen, the C of unsubstituted or halo1-C6Alkyl, halogen, cyano group, nitro, C2-C10Alkynyl, C2-C10Thiazolinyl, C6-C10Aryl, hydroxyl, C1-C6Alkoxyl, C1-C6Amido；Or, R16And R17Or R18、R23And R20Or R21It is collectively forming replacement or unsubstituted with the carbon atom being connected or nitrogen-atoms Five yuan or hexa-member heterocycle；
It is preferred that R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、 R27、R28It is each independently selected from lower group: hydrogen, C1-C6Alkyl, C6-C10Aryl, hydroxyl, C1-C6Alcoxyl Base, C1-C6Amino；Or, R16And R17Or R18、R23And R20Or R21With the carbon atom being connected or nitrogen-atoms It is collectively forming substituted or unsubstituted five yuan or hexatomic ring；
N is 1,2,3,4,5,6 or 7；
Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituent of lower group and take Generation: halogen, hydroxyl, carboxyl, benzyl, C1-C6Alkoxy carbonyl, amino, C1-C6Amide groups, nitro, Cyano group, the C of unsubstituted or halo1-C6Alkyl, C2-C10Thiazolinyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C6-C10Aryl, five yuan or six membered heteroaryl, preferably halogen, C1-C6Alkoxy carbonyl, unsubstituted or halogen The C in generation1-C6Alkyl.
In another preference, R1, R2, R3, R4, R5Be each independently selected from lower group: hydrogen, halogen, Hydroxyl, carboxyl, amino, nitro, cyano group, C1-C6Alkoxyl, substituted or unsubstituted C1-C10Alkyl, Substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five yuan or six membered heteroaryl；
R6、R7、R8、R12、R13、R14Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, Amino, nitro, cyano group, C1-C6Alkoxyl, substituted or unsubstituted C1-C10Alkyl, replacement or unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl, preferably H, hydroxyl, carboxyl, amino, C1-C6Alkyl, Halo C1-C6Alkyl, C1-C6Alkoxyl, or C1-C6Alkyl-amino；Wherein, described on finger group one Individual or multiple hydrogen atoms be selected from lower group substituent replace: halogen, hydroxyl, carboxyl, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl；It is preferably halogen, C1-C6Alkyl.
In another preference, R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、 R26、R27、R28It is each independently selected from lower group: hydrogen, C1-C6Alkyl；
Or, R16And R17Or R18、R23And R20Or R21It is collectively forming with the carbon atom being connected or nitrogen-atoms and take Generation or unsubstituted five yuan or hexa-member heterocycle, it is therefore preferable to five-ring heterocycles.
In another preference, in described compound, R1、R2、R3、R4、R5、R6、R7、R8、 R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、 R24、R25、R26、R27、R28In any one is respectively described in the embodiment of the present invention institute in particular compound Corresponding group.
In another preference, described derivative is the compound being selected from the group:
The preparation of the naphthaquinone derivatives containing adamantyl
Present invention also offers the preparation method of the compound shown in a kind of formula I, the method is following method:
By naphthoquinones carboxylic acid derivates and corresponding amantadine compound, or by naphthoquinones aminoderivative with accordingly Adamantine carboxyl compound, is condensed in the presence of condensing agent, reoxidizes and obtain target compound.
Under a kind of preferable case of the present invention, described preparation method is shown below:
The concrete reaction condition of described condensation reaction and oxidation reaction is the conventional selection of those skilled in the art, For example, it is possible in the presence of the alkali of such as DIPEA (DIPEA), triethylamine etc., in example Such as 2-(7-azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU) BTA- N, N, N ', carry out under the condensing agent effect of N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) etc.；Oxidation can be at nitre Carry out under conditions of acid cerium ammonium；Wherein, R1、R2、R3、R4、R5, L, A be defined as above.
The purposes of the naphthaquinone derivatives containing adamantyl
Present invention also offers the naphthoquinone derivatives such as the present invention, compound, its optics that i.e. formula is (I) are different One or more in structure body, its pharmaceutically acceptable salt and prodrug thereof are at preparation antibacterials, anticarcinogen Application in thing.
Screened by external activity, it has been found that the compounds of this invention has Sortase A enzyme inhibition activity, and Having antibacterial activity, therefore the compounds of this invention may be used for preparation treatment and/or prevents various bacterium to infect Medicine.
Screened by external activity, it has been found that the compounds of this invention has antitumor activity, therefore the present invention Compound may be used for preparation treatment and/or the medicine preventing various cancer, on lung cancer, colon cancer, oral cavity The various cancers such as skin cancer, cancer of the stomach, leukaemia.
Present invention also offers a kind of pharmaceutical composition, it comprises selected from the naphthoquinone derivatives according to the present invention, I.e. formula be the one in the compound of I, its optical isomer, its pharmaceutically acceptable salt and prodrug thereof or Multiple.Naphthoquinone derivatives according to the present invention is included in described pharmaceutical composition with therapeutically effective amount.Additionally, Described pharmaceutical composition optionally can also comprise pharmaceutically acceptable auxiliary material, for example excipient, adhesive, Colouring agent, antioxidant, preservative, disintegrant, sweetener, diluent, solvent etc., but it is not limited to this A bit.
Described pharmaceutical composition may be used for treatment and/or prevents various bacterium to infect, various cancers such as lung cancer, Colon cancer, oral epithelium cancer, cancer of the stomach, leukaemia etc., but it is not limited to these.
Present invention also offers a kind of method treating bacterium infection and cancer, it includes to this treatment of needs Patient's drug treatment effective dose selected from according to the naphthaquinone derivatives of the present invention, i.e. formula be I compound, In its optical isomer, its pharmaceutically acceptable salt and prodrug thereof one or more or according to the present invention Pharmaceutical composition.Described cancer for example, lung cancer, colon cancer, cancer of the stomach, leukaemia etc., but be not limited to These.
Pharmaceutical composition and application process
Owing to the compounds of this invention has the excellent inhibitory activity to Sortase A enzyme, and to bacterium Kill activity, therefore the compounds of this invention and various crystal formation thereof, pharmaceutically acceptable inorganic or organic salt, Hydrate or solvate, and can use containing the pharmaceutical composition that the compounds of this invention is main active In treatment, prevention and alleviate by the disease related to Sortase A enzymatic activity or expression, or with bacterium sense The related disease of dye.According to prior art, the compounds of this invention can be used for treating following disease: lung cancer, knot Intestinal cancer, oral epithelium cancer, cancer of the stomach, leukaemia etc..
The pharmaceutical composition of the present invention comprise safe and effective amount in the range of the compounds of this invention or its pharmacologically Acceptable salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: The amount of compound be enough to be obviously improved the state of an illness, and is unlikely to produce serious side effect.Generally, drug regimen Thing contains 1-2000mg the compounds of this invention/agent, more preferably, containing 5-200mg the compounds of this invention/agent. It is preferred that described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or Gelatinous mass, they are suitable for people and use and it is necessary to have enough purity and of a sufficiently low toxicity." phase Capacitive " referred to herein as the compound of each component energy and the present invention in composition and they between mutually mix With, and significantly reduce the drug effect of compound.Pharmaceutically acceptable carrier part example have cellulose and Its derivative (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, Kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil are (such as soya-bean oil, sesame oil, peanut Oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite etc.), emulsifying agent (such as tell Temperature), wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, anti- Rotten agent, apirogen water etc..
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, representational method of application Including (but being not limited to): in oral, knurl, rectum, parenteral (in intravenous, muscle or subcutaneous) and Topical.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.At this In a little solid dosage forms, reactive compound mixes with at least one conventional inert excipients (or carrier), such as lemon Acid sodium or Dicalcium Phosphate, or mix with following compositions: (a) filler or bulking agent, for example, starch, lactose, Sucrose, glucose, mannitol and silicic acid；(b) adhesive, for example, hydroxymethyl cellulose, alginates, Gelatin, PVP, sucrose and Arabic gum；(c) NMF, for example, glycerine；D () collapses Solve agent, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicate, And sodium carbonate；(e) retarding solvent, such as paraffin；F () absorbs accelerator, for example, quaternary ammonium compound；(g) Wetting agent, such as cetanol and glycerin monostearate；(h) adsorbent, for example, kaolin；(i) moisten Lubrication prescription, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate, Or its mixture.In capsule, tablet and pill, formulation also can comprise buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can use coating and shell material to prepare, Such as casing and other materials well known in the art.They can comprise opacifying agent, and, in this composition The release of reactive compound or compound can release in certain part in alimentary canal in a delayed fashion.Can The example of the embedding component using is polymeric material and Wax.If desired, reactive compound also can with upper State one or more in excipient and form microencapsulation form.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup Or tincture.Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent using in this area, Such as water or other solvents, solubilizer and emulsifying agent, example is known, ethanol, isopropanol, ethyl carbonate, acetic acid second Ester, propane diols, 1,3-BDO, dimethylformamide and oil, particularly cottonseed oil, peanut oil, jade Rice embryo oil, olive oil, castor oil and sesame oil or the mixture etc. of these materials.
In addition to these inert diluents, composition also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspension Agent, sweetener, tender taste agent and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspending agent, for example, ethoxylation isooctadecane alcohol, Polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials mixed Compound etc..
Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, divide Dissipate liquid, suspension or emulsion, and for being again dissolved into the aseptic powder of aseptic Injectable solution or dispersion liquid End.Suitable aqueous and nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and Its suitable mixture.
For the formulation of the compounds of this invention of topical include ointment, powder, patch, propellant and Inhalant.Active component aseptically with physiologically acceptable carrier and any preservative, buffer, Or the propellant that may need if desired is mixed together.
The compounds of this invention can be individually dosed, or combine with other pharmaceutically acceptable compounds to Medicine.
It when making pharmaceutical composition, is the food in one's mouth that the compounds of this invention of safe and effective amount is applicable to treatment Breast animal (such as people), when wherein applying, dosage is the effective dosage pharmaceutically thought, for 60kg body weight People for, day dosage be usually 1～2000mg, preferably 5～500mg.Certainly, concrete dosage also should Consider the factor such as method of administration, patient health situation, within the scope of these are all skilled practitioners technical ability.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate The present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example Method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise Percentage and number are calculated by weight.Unless otherwise stated, in the present invention use preparation and method of testing with And equipment etc. is method and apparatus conventional in the art.Agents useful for same is the pure or chemical pure of analysis.
Embodiment 1
The Isosorbide-5-Nitrae of 232mg-dimethoxy-2-naphthoic acid is dissolved in the dichloromethane that 5ml is dried, adds 151mg Amantadine and 0.5ml DIPEA, be cooled to 0～5 DEG C, adds 570mg condensing agent HATU It with 136mg HOAt, is naturally warmed to room temperature reaction 3h.After TLC detection raw material point disappears substantially, add 8ml Saturated sodium bicarbonate solution, layering, water layer 5ml dichloromethane extracts, and merges organic phase, uses saturated food Salt solution washs, and anhydrous sodium sulfate is dried.Decompression boils off solvent, and the product obtaining directly is dissolved in 10ml second In nitrile, ammonium ceric nitrate 986mg is dissolved in 6ml water, then slowly drips to it in reactant liquor, reaction After 10min, TLC detection raw material point disappears substantially, adding 20ml ethyl acetate, layering, by organic layer With saturated aqueous common salt washing, anhydrous sodium sulfate is dried.Decompression boils off solvent, column chromatography for separation, obtains 262mg Yellow solid.
1H NMR (300MHz, CDCl3) δ 8.57 (s, 1H), 8.11 (m, 2H), 7.86 (3,1H), 7.80 (m, 2H), 2.15 (s, 6H), 1.74 (s, 4H), 1.59 (m, 5H).
Embodiment 2
In addition to replacing amantadine with 2-amantadine, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 9.25 (s, 1H), 8.26-8.04 (m, 2H), 7.93 (s, 1H), 7.86 -7.75 (m, 2H), 4.28 (m, 1H), 2.07-1.87 (m, 10H), 1.82-1.69 (m, 4H).
Embodiment 3
In addition to replacing amantadine with adamantane methylamine, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.84 (s, 1H), 8.16 (m, 2H), 7.95 (s, 1H), 7.88-7.80 (m, 2H), 3.22 (d, J=6.1Hz, 2H), 2.05 (s, 3H), 1.74 (m, 8H), 1.62 (s, 4H).
Embodiment 4
In addition to replacing amantadine with (R)-1-(1-adamantyl) ethylamine hydrochloride, according to embodiment 1 Method prepares target compound.
1H NMR (300MHz, CDCl3) δ 8.71 (s, 1H), 8.14-7.98 (m, 2H), 7.85 (s, 1H), 7.80 -7.70 (m, 2H), 3.85 (m, 1H), 1.98 (s, 4H), 1.69 (m, 4H), 1.57 (m, 7H), 1.11 (d, J=6.8 Hz, 3H).
Embodiment 5
Beyond replacing amantadine with (R)-1-(3,5-dimethyladamantane base) ethamine, according to embodiment 1 Method prepare target compound.
1H NMR (300MHz, CDCl3) δ 8.58 (s, 1H), 8.07 (m, 2H), 7.82 (s, 1H), 7.77 (m, 2H), 2.17 (m, 1H), 1.95 (s, 2H), 1.75 (m, 4H), 1.42 (m, 2H), 1.30 (m, 2H), 1.18 (m, 2H), 0.86 (s, 6H).
Embodiment 6
In addition to replacing amantadine with 3-hydroxyadamantaneamine, prepare target according to the method for embodiment 1 Compound.
1H NMR (300MHz, CDCl3) δ 8.65 (s, 1H), 8.08 (m, 2H), 7.82 (s, 1H), 7.78 (m, 2H), 2.31 (s, 3H), 2.07 (m, 8H), 1.72 (s, 3H).
Embodiment 7
In addition to replacing amantadine with 4-hydroxyadamantaneamine, prepare target according to the method for embodiment 1 Compound.
1H NMR (300MHz, CDCl3) δ 9.19 (s, 1H), 8.22-8.03 (m, 2H), 7.92 (s, 1H), 7.85 -7.76 (m, 2H), 4.23 (s, 1H), 2.25 (s, 3H), 1.91 (m, 4H), 1.82 (m, 4H), 1.68 (m, 2H), 1.59 (s, 1H).
The synthesis of intermediate 8-1 and 9-1
It is dissolved in 8-2 (167mg, 1mmol) in 2ml THF, under ice bath, add two dimethyl dicarbonates of 164mg Butyl ester, then slowly drips the triethylamine of 0.14ml, is slowly increased to room temperature, and reaction is overnight.THF is revolved Dry, by the extraction of 10ml ethyl acetate, saturated common salt washing, anhydrous Na2SO4It is dried, remove solvent under reduced pressure, Obtain white crude 8-3 (230mg, 86%).It is dissolved in intermediate 8-3 (1eq) in 3ml dichloroethanes, add DMAP (0.1eq), the lower dropping butyl chloride of stirring, it after reaction 2h, is spin-dried for solvent, add water, use dichloromethane Alkane extracts, and dichloromethane layer saturated common salt is washed, and is dried, removes solvent under reduced pressure, and column chromatography obtains intermediate 8-4.Directly being dissolved in the intermediate 8-4 obtaining in dichloromethane, stirring is lower adds trifluoroacetic acid, will after 1h Reactant liquor is spin-dried for obtaining intermediate 8-1.
Obtain intermediate 9-1 by same method, simply butyl chloride is melted into acryloyl chloride.
Embodiment 8
In addition to replacing amantadine with intermediate 8-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.65 (s, 1H), 8.13-8.00 (m, 2H), 7.81 (s, 1H), 7.79 -7.73 (m, 2H), 2.48 (s, 2H), 2.31 (s, 2H), 2.20-2.03 (m, 12H), 1.61 (s, 2H), 0.90 (t, J= 7.4Hz, 3H).
Embodiment 9
In addition to replacing amantadine with intermediate 9-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.69 (s, 1H), 8.08 (m, 2H), 7.82 (s, 1H), 7.78 (m, 2H), 6.29 (d, J=17.3Hz, 1H), 6.00 (dd, J=17.3,10.3Hz, 1H), 5.77-5.68 (m, 1H), 2.53 (s, 2H), 2.34 (s, 2H), 2.13 (m, 8H), 1.64 (s, 2H).
The synthesis of intermediate 10-1,11-1,12-1
It is dissolved in 8-2 (1.67g, 10mmol) in 20ml THF, under ice bath, be dividedly in some parts the potassium carbonate of 2g, Then slowly drip benzyl chloroformate 1.7ml again, be warmed to room temperature reaction 2h.Being spin-dried for THF, dichloromethane extracts Taking, dichloromethane layer saturated common salt is washed, and is dried, removes solvent under reduced pressure, obtain crude product 10-2 (2g, 62%). By intermediate 10-2 (1eq), ethyl isocyanate (1eq) is dissolved in dry DCM, adds under nitrogen protection Enter TMSCl (0.05eq), under room temperature, stir 18h.Being spin-dried for DCM, column chromatography obtains intermediate 10-3.Will Intermediate 5 (1eq) is molten in ethanol, adds palladium carbon (0.1eq), reacts 12h under hydrogen atmosphere.By palladium carbon Leaching out, filtrate is spin-dried for obtaining intermediate 10-1.
Obtain intermediate 11-1 and 12-1 by same method, simply change ethyl isocyanate into the tert-butyl group Isocyanates and benzyl isocyanate ester.
Embodiment 10
In addition to replacing amantadine with intermediate 10-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.66 (s, 1H), 8.13-8.05 (m, 2H), 7.83 (s, 1H), 7.81 -7.75 (m, 2H), 4.50 (s, 1H), 3.14 (m, 2H), 2.49 (s, 2H), 2.32 (s, 2H), 2.09 (s, 8H), 1.62 (s, 2H), 1.10 (t, J=7.2Hz, 3H).
Embodiment 11
In addition to replacing amantadine with intermediate 11-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.63 (s, 1H), 8.11-8.02 (m, 2H), 7.80 (s, 1H), 7.78 -7.73 (m, 2H), 4.50 (s, 1H), 2.47 (s, 2H), 2.29 (s, 2H), 2.08 (m, 8H), 1.60 (s, 2H), 1.26 (s, 9H).
Embodiment 12
In addition to replacing amantadine with intermediate 12-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.65 (s, 1H), 8.11-8.01 (m, 2H), 7.80 (s, 1H), 7.79 -7.72 (m, 2H), 7.22 (m, 5H), 4.63 (s, 1H), 3.34 (m, 2H), 2.77 (t, J=6.8Hz, 2H), 2.46 (s, 2H), 2.31 (s, 2H), 2.08 (s, 8H), 1.61 (s, 2H).
Embodiment 13
100mg 2-amino naphthoquinones is dissolved in the dichloromethane that 5ml is dried, adds 104mg adamantanecarboxylic acid It with 0.3ml DIPEA, is cooled to 0～5 DEG C, add 330mg condensing agent HATU and 80mg HOAt, is warmed to room temperature reaction 3h naturally.After TLC detection raw material point disappears substantially, add 8ml saturated carbon Acid hydrogen sodium solution, layering, water layer 5ml dichloromethane extracts, and merges organic phase, is washed by saturated common salt Washing, anhydrous sodium sulfate is dried.Decompression boils off solvent, and column chromatography obtains yellow product 13 (155mg, 80%).
1H NMR (300MHz, CDCl3) δ 8.74 (s, 1H), 8.11 (m, 2H), 7.87 (s, 1H), 7.75 (m, 2H), 2.13 (s, 3H), 1.97 (m, 6H), 1.76 (m, 7H).
The synthesis of intermediate 14-1 and 15-1
N-tert-butoxycarbonyl-l-alanine (94mg, 0.46mmol) is dissolved in the dichloromethane that 5ml is dried, adds 84mg 3,5-dimethyladamantane amine and 0.3mlN, N-diisopropylethylamine, it is cooled to 0～5 DEG C, add 268mg Condensing agent HATU and 64mg HOAt, is warmed to room temperature reaction 3h naturally.After TLC detection raw material point disappears substantially, Adding 5ml saturated sodium bicarbonate solution, layering, water layer 5ml dichloromethane extracts, and merges organic phase, uses Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried.Decompression boil off solvent, column chromatography obtain intermediate 14-2 (133mg, 80%).It is directly dissolved in the intermediate 6 obtaining in DCM, drip trifluoroacetic acid solution, after reaction 1h, will Solvent is spin-dried for obtaining intermediate 14-1.
Obtain intermediate 15-1 by same method, simply N-tert-butoxycarbonyl-l-alanine is changed into N-tertiary fourth oxygen Carbonyl-L-PROLINE.
Embodiment 14
In addition to replacing amantadine with intermediate 14-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 9.35 (s, 1H), 8.18-8.00 (m, 2H), 7.80 (s, 1H), 7.79 -7.72 (m, 2H), 6.12 (s, 1H), 4.65-4.48 (m, 1H), 2.11 (s, 1H), 1.84 (s, 2H), 1.64 (s, 3H), 1.46 (m, 3H), 1.30 (m, 5H), 1.12 (m, 2H), 0.81 (s, 6H).
Embodiment 15
In addition to replacing amantadine with intermediate 15-1, prepare target chemical combination according to the method for embodiment 1 Thing.
1H NMR (300MHz, CDCl3) δ 8.11 (dd, J=8.6,4.3Hz, 2H), 7.84-7.75 (m, 2H), 6.98 (s, 1H), 6.76 (s, 1H), 4.77-4.54 (m, 1H), 3.36 (dd, J=13.8,7.3Hz, 2H), 2.33 (s, 1H), 2.14 (d, J=3.1Hz, 1H), 2.10-1.96 (m, 2H), 1.90 (s, 2H), 1.80-1.66 (m, 4H), 1.47-1.36 (m, 2H), 1.29-1.05 (m, 5H), 0.85 (s, 6H).
Embodiment 16
It is dissolved in naphthoquinones (158mg, 1mmol) and glutaric acid 0.3ml (3mmol) in 3ml water and 7ml acetonitrile, Reactant liquor is heated to 65 DEG C, slowly drips silver nitrate after stirring 10min and the acetonitrile-water of ammonium persulfate is molten Liquid, reaction is overnight.Being spin-dried for acetonitrile, being extracted with ethyl acetate, organic layer saturated aqueous common salt washs, nothing Aqueous sodium persulfate is dried.Decompression boil off solvent, column chromatography for separation obtain intermediate 4-(2-naphthoquinones)-butyric acid (120mg, 50%).The acid and 3 that will obtain, 5-dimethyladamantane amine reacts, obtains target according to the method for embodiment 1 Compound 16.
1H NMR (400MHz, CDCl3) δ 8.13-8.04 (m, 2H), 7.78-7.71 (m, 2H), 6.83 (s, 1H), 2.61 (t, J=7.2Hz, 2H), 2.19 (t, J=7.2Hz, 2H), 2.15-2.10 (m, 1H), 1.97-1.86 (m, 2H), 1.83-1.76 (m, 3H), 1.62 (m, 4H), 1.38 (m, 2H), 1.28 (m, 4H), 1.14 (m, 2H), 0.84 (s, 6H).
Embodiment 17
Except replacing glutaric acid with suberic acid, obtain outside intermediate 7-(2-naphthoquinones)-enanthic acid, according to embodiment 16 Method obtain target compound 17.
1H NMR (400MHz, CDCl3) δ 8.12-8.03 (m, 2H), 7.78-7.70 (m, 2H), 6.79 (s, 1H), 5.18 (s, 1H), 2.56 (t, J=7.7Hz, 2H), 2.13 (m, 1H), 2.08 (t, J=7.5Hz, 2H), 1.83 (s, 3H), 1.64 (m, 4H), 1.43-1.34 (m, 6H), 1.28 (m, 4H), 1.15m, 3H), 0.84 (s, 6H).
The synthesis of intermediate 18-1
It is dissolved in naphthoquinones (2g, 12.6mmol) in 50ml THF, adds palladium carbon, under hydrogen shield, react 12h, By reacting liquid filtering, filtrate is slowly added into sodium hydrogen under nitrogen protection, after stirring 10min at 0 DEG C, slowly Slow dropping dimethyl suflfate, continues reaction 4h.THF is spin-dried for, is extracted with ethyl acetate, saturated common salt Washing, anhydrous sodium sulfate is dried, and removes solvent under reduced pressure and obtains Isosorbide-5-Nitrae-dimethoxy-naphthalene (1.31g).By obtain Isosorbide-5-Nitrae- Dimethoxy-naphthalene (1eq) is dissolved in 5ml dichloromethane, under ice bath, slowly drips butter of tin (1.2eq), stirs After mixing 10min, then drip 1,1-dichlormethyl ether (1.2eq), reacts 3h at 0 DEG C.Add in reactant liquor Frozen water, with DCM extraction, saturated common salt wash, anhydrous sodium sulfate is dried, and removes solvent under reduced pressure, obtain Isosorbide-5-Nitrae- Dimethoxy-2-naphthaldehyde.NaH is joined in 50ml flask, under nitrogen protection, adds 5ml toluene, And triethyl group 2-phosphono propyl ester, then reaction is heated to 110 DEG C backflow 30min, by obtain Isosorbide-5-Nitrae- Dimethoxy-2-naphthaldehyde is dissolved in 2ml toluene, is slowly added drop-wise in reactant liquor, continues backflow 12h.With 2M HCl is acidified, and is then extracted with ethyl acetate, and saturated common salt is washed, and anhydrous sodium sulfate is dried, decompression Solvent is evaporated off, and column chromatography obtains intermediate 18-2.Add potassium hydroxide by molten for intermediate 18-2 in ethanol, 1h is reacted in reaction under reflux.It is spin-dried for solvent, obtain intermediate 18-1.
Embodiment 18
The intermediate 18-1 and 3 that will obtain, 5-dimethyladamantane amine reacts, and obtains according to the method for embodiment 1 To target compound 18.
1H NMR (300MHz, CDCl3) δ 8.13-8.01 (m, 2H), 7.78-7.68 (m, 2H), 7.08 (s, 1H), 6.89 (s, 1H), 5.67 (s, 1H), 2.07 (s, 3H), 1.89 (s, 2H), 1.75-1.65 (m, 4H), 1.32 (m, 5H), 1.16 (m, 2H), 0.85 (s, 6H).
The pharmaceutical research of embodiment 19 the compounds of this invention
(1) the Sortase A inhibitory activity test of embodiment compound
The cDNA sequence of surface protein SasX and IsdA of staphylococcus aureus is building up to expression vector In pET28b, obtained purity be more than by Ni-NTA post and Superdex Hiload 75 post two-step purifying The albumen of 95%.Transpeptidation reaction buffer solution is 50mM Tris-HCl, 150mM NaCl, 5mM CaCl2, PH is 7.5.The reaction system of 50 μ l adds final concentration of 200 μ g/ μ l transpeptidase Sa-SrtA or Transpeptidase Sp-SrtA, compound, be subsequently added final concentration of 300 μ g/ μ l surface protein SasX and Another enzyme reaction substrate of IsdA and final concentration of 3mM, hatches 10min, is supervised continuously by ELIASA The change of fluorescence intensity during survey enzyme reaction obtains enzyme kinetics curve, takes enzyme kinetics curve Linear segment obtain different reaction first rate Vi corresponding to compound.When V0 is for being not added with compound required The reaction first rate obtaining.Inhibiting rate (%)=(1-Vi/V0) × 100%.Each compound does three simultaneously to be repeated to take Mean value calculation inhibiting rate.Experimental result is shown in Table one.
Table one compound is in the inhibitory action to Sortase A enzymatic activity for the molecular level
(2) the antibacterial activity test of embodiment compound
Picking S.aureus Newman, S.aureus RN4220, S.epidermidis the 145th, B.subtilis is the 168th, P.aeruginosa PAO1, E.coli DH5 alpha monoclonal are placed in TSB or LB culture medium 37 DEG C and cultivated Night.Secondary daily fresh TSB or LB culture medium dilution A600 to 0.01, cultivates 2h in 37 DEG C of shaking tables Rear dilution A600 to 0.005.Take 180 μ l bacterium solution to be inoculated in 96 orifice plates, be subsequently adding 20 μ l TSB Or the SD compound of a series of concentration that LB has diluted, make final concentration of 6.25 μM-200 of compound μM (compound from 200 μM start equimultiples dilution).96 orifice plates are placed in 37 DEG C of incubators cultivation 16 H, visually observes the growing state of bacterium in each hole next day, with each compound not bacteria growing inhibiting Least concentration is as the MIC value of this compound.Each sample does three parallel holes.
Table two compound bactericidal activity
The bactericidal activity to Sa.Newman for table three compound
From above-mentioned result of the test it can be seen that the naphthoquinone compound that the present invention is protected has excellent antibacterial Activity, therefore has preferable application prospect.
(3) the antitumor activity test of embodiment compound
Anti tumor activity in vitro test has been carried out to the naphthoquinone derivatives of the above embodiment of the present invention 1-12.Adopt It with KB, KB/VCR and A549 cell, is separately added into each compound treatment 72h, detects with srb assay The propagation growth inhibition effect of compound and degree thereof.In experiment, compound uses the highest final concentration 100 μM, Downward 4 times of dilutions, 6 concentration gradients (respectively 100 μM, 25 μM, 6.25 μM, 1.563 μM, 0.391 μM With 0.098 μM), process cell 72 hours.Being repeated twice, experimental result is shown in Table four.
The anti tumor activity in vitro of table the 4th, embodiment compound
From above-mentioned result of the test it can be seen that the naphthoquinone compound that the present invention is protected has excellent anti-swollen Tumor activity.Therefore there is preferable application prospect.
The all documents mentioned in the present invention are incorporated as reference all in this application, just as each document It is individually recited as with reference to like that.In addition, it is to be understood that after the above-mentioned instruction content having read the present invention, The present invention can be made various changes or modifications by those skilled in the art, and these equivalent form of values fall within this Shen equally Please appended claims limited range.

Claims (10)

1. the naphthaquinone derivatives containing adamantyl as shown in following formula (I):
Wherein,
R1, R2, R3, R4, R5Be each independently selected from lower group: hydrogen, halogen atom, nitro, itrile group, Hydroxyl, amino, carboxyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C1-C6Alkoxy-carbonyl, C1-C6 Amide groups, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, replacement or do not take Five yuan of generation or six membered heteroaryl；
It is preferred that R1, R2, R3, R4, R5Be each independently selected from lower group: H, halogen atom, nitro, Itrile group, hydroxyl, amino, carboxyl, C1-C6Alkoxy carbonyl, C1-C6Amide groups, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl or C1-C6Alkyl-amino；
A is the substituted or unsubstituted adamantyl being selected from the group:
Wherein, R6、R7、R8、R12、R13、R14Be each independently selected from lower group: hydrogen, halogen, hydroxyl, Carboxyl, amino, nitro, cyano group, C1-C6Alkoxyl, C1-C6Alkyl-amino, C1-C6Alkoxy carbonyl, C1-C6Amide groups, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, replacement Or unsubstituted five yuan or six membered heteroaryl；
It is preferred that R6、R7、R8、R12、R13、R14Be each independently selected from lower group: H, hydroxyl, carboxylic Base, amino, C1-C6Alkoxy carbonyl, C1-C6Amide groups, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6 Alkoxyl, or C1-C6Alkyl-amino；
R9、R10、R11Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, Cyano group, C1-C6Alkoxyl, C1-C6Alkyl-amino, C2-C6Alkoxy carbonyl (ROC=O-), C2-C6Thiazolinyl Carbonyl (RC=O-), C2-C6Alkyl-carbonyl (RC=O-), substituted or unsubstituted C1-C6Acyloxy (RC=OO-), Substituted or unsubstituted C1-C6Amine acyloxy (RNC=OO-), C1-C6Aminoacyl (RNC=O-), C1-C6Acid amides Base (RC=ON-), substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl, or take Generation or unsubstituted five yuan or six membered heteroaryl；
It is preferred that R9、R10、R11It is each independently selected from lower group: H, C1-C6Alkyl, replacement or do not take The C in generation1-C6Acyloxy (RC=OO-), substituted or unsubstituted C1-C6Amine acyloxy (RNC=OO-), hydroxyl, Carboxyl, amino, C1-C6Alkoxy carbonyl (ROC=O-), C1-C6Aminoacyl (RNC=O-), C1-C6Acid amides Base (RC=ON-), halo C1-C6Alkyl, C1-C6Alkoxyl or C1-C6Alkyl-amino；
-L-is the divalent linker being selected from the group:
Wherein, R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、 R28It is each independently selected from lower group: hydrogen, the C of unsubstituted or halo1-C6Alkyl, halogen, cyano group, nitro, C2-C10Alkynyl, C2-C10Thiazolinyl, C6-C10Aryl, hydroxyl, C1-C6Alkoxyl, C1-C6Amido；Or, R16And R17Or R18、R23And R20Or R21It is collectively forming replacement or unsubstituted with the carbon atom being connected or nitrogen-atoms Five yuan or hexa-member heterocycle；
It is preferred that R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、 R27、R28It is each independently selected from lower group: hydrogen, C1-C6Alkyl, C6-C10Aryl, hydroxyl, C1-C6Alcoxyl Base, C1-C6Amino；Or, R16And R17Or R18、R23And R20Or R21With the carbon atom being connected or nitrogen-atoms It is collectively forming substituted or unsubstituted five yuan or hexatomic ring；
N is 1,2,3,4,5,6 or 7；
Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituent of lower group and take Generation: halogen, hydroxyl, carboxyl, benzyl, C1-C6Alkoxy carbonyl, amino, C1-C6Amide groups, nitro, Cyano group, the C of unsubstituted or halo1-C6Alkyl, C2-C10Thiazolinyl, C1-C6Alkoxyl, C1-C6Alkyl-amino, C6-C10Aryl, five yuan or six membered heteroaryl, preferably halogen, C1-C6Alkoxy carbonyl, unsubstituted or halogen The C in generation1-C6Alkyl.
2. the naphthaquinone derivatives containing adamantyl as claimed in claim 1, it is characterised in that
R1, R2, R3, R4, R5Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, amino, Nitro, cyano group, C1-C6Alkoxyl, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted five yuan or six membered heteroaryl；
R6、R7、R8、R12、R13、R14Be each independently selected from lower group: hydrogen, halogen, hydroxyl, carboxyl, Amino, nitro, cyano group, C1-C6Alkoxyl, substituted or unsubstituted C1-C10Alkyl, replacement or unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl, preferably H, hydroxyl, carboxyl, amino, C1-C6Alkyl, Halo C1-C6Alkyl, C1-C6Alkoxyl, or C1-C6Alkyl-amino；Wherein, described on finger group one Individual or multiple hydrogen atoms be selected from lower group substituent replace: halogen, hydroxyl, carboxyl, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl；It is preferably halogen, C1-C6Alkyl.
3. the naphthaquinone derivatives containing adamantyl as claimed in claim 1, it is characterised in that R15、 R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28Independently of one another It is selected from the group: hydrogen, C1-C6Alkyl；
Or, R16And R17Or R18、R23And R20Or R21It is collectively forming with the carbon atom being connected or nitrogen-atoms and take Generation or unsubstituted five yuan or hexa-member heterocycle, it is therefore preferable to five-ring heterocycles.
4. the naphthaquinone derivatives containing adamantyl as claimed in claim 1, it is characterised in that described Derivative is the compound being selected from the group:
5. the preparation method of formula (I) derivative as claimed in claim 1, it is characterised in that include step (b):
B (), in atent solvent, carries out oxidation reaction with Formula II compound, obtains compound of formula I；Wherein, each base The definition of group is as described in the appended claim 1.
6. method as claimed in claim 5, it is characterised in that described Formula II compound through the following steps that Or prepared by (a2) (a1):
(a1) in atent solvent, with formula III compound and A-NH2Or A-CH (R) NH2Reaction, obtains Formula II Compound；
Wherein,For L；
(a2) in atent solvent, with formula III ' compound reacts with A-COOH, obtains Formula II compound；
Wherein,For L；
The definition of remaining each group is as described in the appended claim 1.
7. a pharmaceutical composition, it is characterised in that described pharmaceutical composition includes: therapeutically effective amount as Described in claim 1 containing the naphthaquinone derivatives of adamantyl, its optical isomer, it is pharmaceutically acceptable Salt or its prodrug；And pharmaceutically acceptable carrier.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that described pharmaceutical composition is used for The disease that i () treats or prevention is related to Sortase A enzymatic activity；(ii) kill bacterium, be preferably selected from lower group Bacterium: Sa.Newman, Sa.RN4220, Sa.8325-4, Se.1457, Bs.681, and/or Ec.DH5 α； (iii) treatment or pre-anti-cancer, it is preferred that described cancer is selected from the group: lung cancer, colon cancer, on oral cavity Skin cancer, cancer of the stomach, leukaemia.
9. the purposes of the naphthaquinone derivatives containing adamantyl as claimed in claim 1, it is characterised in that A () is for the pharmaceutical composition preparing treatment or prevent the disease related to Sortase A enzymatic activity；(ii) it is used for Kill bacterium external non-therapeutic, be preferably selected from the bacterium of lower group: Sa.Newman, Sa.RN4220, Sa.8325-4, Se.1457, Bs.681, and/or Ec.DH5 α；(iii) for preparing treatment or pre-anti-cancer Pharmaceutical composition, it is preferable that described cancer is selected from the group: lung cancer, colon cancer, oral epithelium cancer, stomach Cancer, leukaemia；(iv) for external non-therapeutic ground suppression Sortase A enzymatic activity.
10. a method for disinfection, it is characterised in that for object administration antimicrobial effective amount to be sterilized as The naphthaquinone derivatives containing adamantyl described in claim 1.
CN201510199108.2A 2015-04-23 2015-04-23 Naphthaquinone derivative containing adamantyl, preparation method and application thereof Active CN106146338B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510199108.2A CN106146338B (en) 2015-04-23 2015-04-23 Naphthaquinone derivative containing adamantyl, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510199108.2A CN106146338B (en) 2015-04-23 2015-04-23 Naphthaquinone derivative containing adamantyl, preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN106146338A true CN106146338A (en) 2016-11-23
CN106146338B CN106146338B (en) 2020-09-08

Family

ID=57346693

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510199108.2A Active CN106146338B (en) 2015-04-23 2015-04-23 Naphthaquinone derivative containing adamantyl, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN106146338B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11217361A (en) * 1998-01-29 1999-08-10 Fuji Photo Film Co Ltd Naphthoquinone compound and medicine composed of the same
CN103122002A (en) * 2011-11-17 2013-05-29 北京韩美药品有限公司 Naphthoquinone compound with antitumor activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11217361A (en) * 1998-01-29 1999-08-10 Fuji Photo Film Co Ltd Naphthoquinone compound and medicine composed of the same
CN103122002A (en) * 2011-11-17 2013-05-29 北京韩美药品有限公司 Naphthoquinone compound with antitumor activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ROBERT B. SMITH等: "Molecular anchors—mimicking metabolic processes in thiol analysis", 《NEW JOURNAL OF CHEMISTRY》 *

Also Published As

Publication number Publication date
CN106146338B (en) 2020-09-08

Similar Documents

Publication Publication Date Title
He et al. 1, 2, 3-Triazole-containing derivatives of rupestonic acid: click-chemical synthesis and antiviral activities against influenza viruses
WO2017114509A1 (en) Aldehyde and preparation and application thereof
CN111135171A (en) Diseases and treatments associated with toxic aldehydes
UA122205C2 (en) Cyclopropanamine compound and use thereof
JP6873221B2 (en) Benzamide and nicotinamide compounds and methods of using them
JP6043361B2 (en) Oleanolic acid amidated derivatives, their preparation and use
CN103044395B (en) Desloratadine-containing amino acid derivative as well as preparation method and application thereof
US20090275585A1 (en) Novel Compounds and Therapeutic Use Thereof for Protein Kinase Inhibition
CN108524482A (en) The purposes of 2- (substitution phenylamino) benzoic acids FTO inhibitor for treating leukaemia
DE112012004878T5 (en) Heterocyclic dihydro five-membered ketone derivatives as DHODH inhibitor and their use
CN107257789A (en) It is used as the new N acyl groups aryl sulfamide derivatives of aminoacyl TRNA synthetase inhibitors
WO2011131135A1 (en) Heteroaryl (alkyl) dithiocarbamate compounds, preparation methods and uses thereof
JP2020511542A (en) Substituted [5,6] cyclo-4 (3H) -pyrimidinones as anticancer agents
CN106831662B (en) A kind of amido polyol is for fumidil and its synthetic method and application
CN103183682A (en) C-10 site carbamido substituted artemisinin derivative, preparation method and application
CN103864765B (en) Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use
CN106146338A (en) Naphthaquinone derivatives containing adamantyl, its preparation method and application
CN101287712B (en) Heterocyclic compounds
CN103304573B (en) Narcissine compounds is preparing the application of antitumor drug
CA2729052A1 (en) Salts of methyl 2-((r)-(3-chlorophenyl)((r)-1-((s)-2-(methylamino)-3((r)-tetrahydro-2h-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate
CN110981888B (en) N-aryl dithiopyrryl ketonuria and amino ester derivatives, preparation and application thereof
CN101062925B (en) Paclitaxel derivatives, preparation method and medicinal composition and usage thereof
CN104292211A (en) Desloratadine nitric oxide donor, and preparation method and application thereof
ES2402060T3 (en) Quinazoline derivative and pharmaceutical product
CN104926804A (en) Compounds with anti-tumor effect, and preparation method and application of compounds

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant