CN104327097B - Triazole derivatives of rapamycin and application - Google Patents
Triazole derivatives of rapamycin and application Download PDFInfo
- Publication number
- CN104327097B CN104327097B CN201410534717.4A CN201410534717A CN104327097B CN 104327097 B CN104327097 B CN 104327097B CN 201410534717 A CN201410534717 A CN 201410534717A CN 104327097 B CN104327097 B CN 104327097B
- Authority
- CN
- China
- Prior art keywords
- compound
- rapamycin
- alkyl
- present
- cancer
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Abstract
The invention relates to triazole derivatives of rapamycin and application. Concretely, the triazole derivatives of rapamycin comprises compounds of the following formula I, or pharmaceutically acceptable salts, solvates, isomers, esters and prodrugs thereof. In the formula I, n is 1, 2 or 3, X is carbonyl or chemical bonds, R is hydrogen or C1-C4 alkyl, R1 is hydrogen, hydroxyl, hydroxymethyl, halogens, trifluoromethyl, trifluoromethoxyl, amino, carboxyl, cyan, N-(C1-C4)alkylamino, N,N-di(C1-C4)alkylamino, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkoxylethyl, (C1-C4)alkylacyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di(C1-C4)alkylcarbamoyl or (C1-C3)alkylenedioxyl. The compounds have excellent biological activity.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to new rapamycin type derivative, its optically active body and its pharmacy
Upper acceptable salt, the more particularly to triazole derivatives of rapamycin.The invention still further relates to their preparation method
And the pharmaceutical composition containing described compound.The invention still further relates to this derivative is used for preparation treatment and/or pre- anti-cancer
Medicine in purposes.
Technical background
Cancer/malignant tumour serious harm human health, it has also become a global health problem, seriously threatens the mankind
Life.2009, WHO explicitly pointed out, and cancer is just becoming the mankind " killer " the most fatal, and more than 90% malignant tumour there is no
Gratifying medicine and measure.Annual whole world cancer patient about 10,000,000 at present, has 7,600,000 people dead；China's cancer
Disease number of the infected about 2,000,000,1,500,000 people are dead, it has also become the second largest fatal disease of China.The World Health Organization predicts, arrives
The year two thousand twenty cancer public health problem maximum by becoming the whole world.Anti-tumor drug has become world's second largest medication field,
Anti-tumor drug market reaches 523.72 hundred million dollars within 2009, is only second to the medication of angiocardiopathy.The tradition of clinical practice at present
Cancer therapy drug mainly has plant bases, alkylating agents, antibioticses and steroids, mostly cell toxicity medicament, selectively
Low, toxic and side effect is very big, and is also easy to produce drug resistance, and curative effect is significantly affected.Therefore develop the anticancer target of new high-efficiency low-toxicity
Become the trend of antineoplastic research and development to medicine.In recent years, molecular targeted agents because have with strong points, effective and
The low advantage of toxicity, it has also become the focus of therapeutic field of tumor research and development both at home and abroad.Wherein mammal rapamycin target position
(mammalian target of rapamycin, mTOR) is the treatment of cancer target position of latest find.
Rapamycin (Rapamycin, RPM), is also called sirolimus (Sirolimus), and its chemical structural formula is as follows
(FDA)：
Analog CCI-779 (Temsirolimus) chemical structural formula that it has clinically used is following (FDA)：
Known rapamycin CAS registration number 53123-88-9, molecular formula C51H79NO13, molecular weight 914.17, from ether
In obtain is colorless crystalline solid, 183-185 ° of mp, D25-58.2 ° of [α] (methyl alcohol), be dissolved in ether, chloroform, acetone, first
Alcohol and DMF, are slightly soluble in hexane and petroleum ether, water insoluble, mouse LD50 (mg/kg)》600 (i.p.),>2,500 (being administered orally) (V é
zina).
The report in 1975 such as Vezina obtains hypotoxicity antifungal antibiotic rapamycin from streptomyces hygroscopicus zymotic fluid, after
Effort through more than 20 years, successfully develops as novel potent immunodepressant.The immunosuppressive activity of rapamycin compares cyclosporine
Strong decades of times, toxic and side effect is less than cyclosporine and FK506.It is applied not only to the acute rejection of organ transplant, and can also
Reverse ongoing graft-rejection；Various autoimmune diseases can be treated.
Rapamycin is the big ring triene antibiotic being obtained by streptomyces hygroscopicus, and it is found in vivo and in vitro equal
There is antifungal activity, especially anti-candida albicanses [C.Vein et al.；J.Antibiot.28,721(1975)；S.N.Sega
Et al.；J.Antibiot.28,727(1975)；H.A.Baker et al.；J.Antibiot.31,539(1978)；United States Patent (USP) 3,
929,992；With United States Patent (USP) 3,993,749].In addition, rapamycin individually (United States Patent (USP) 4,885,171) or with Sapylin group
Close and use (United States Patent (USP) 4,401,653) to have shown with antitumor activity.
The immunosuppressive action of rapamycin has been observed that, Ciclosporin A and FK-506 (other kind of macrocycle molecule) also table
Reveal the validity as immunodepressant, therefore can be used for preventing graft rejection [R.Y.Calne et al., Lancet 1183
(1978)；With United States Patent (USP) 5,100,899].R.Martel et al. [Can, J.Physiol.Pharmacol.55,48 (1977)]
It is found that rapamycin in experimental allergic encephalomyelitis model, Multiple Sclerosis Model, adjuvant arthritis model, rheumatoid
All effective in property arthritis model；And effectively suppress the formation of class IgE antibody.
Rapamycin may also be used for preventing or treat systemic lupus erythematosus [United States Patent (USP) 5,078,999], pneumonia [U.S.
State's patent 5,080,899], IDD [United States Patent (USP) 5,321,009], the skin disease such as psoriasis [U.S.
Patent 5,286,730], enteropathy [United States Patent (USP) 5,286,731], the intimal thickening after smooth muscle cell proliferation and injury of blood vessel
[United States Patent (USP) 5,288,711 and 5,516,781], adult T-cell leukemia/lymthoma [european patent application 525,
960Al], ophthalmia disease [United States Patent (USP) 5,387,589], pernicious carninomatosis [United States Patent (USP) 5,206,018], heart diseases associated with inflammation [beautiful
State's patent 5,496,832] and anaemia [United States Patent (USP) 5,561,138].
In recent years, with deepening continuously that rapamycin derivative is studied, find that rapamycin and its derivative have
The effect of suppression kinds of tumors growth, shows to its study on mechanism, rapamycin and its derivative be all by with
FKBP212 albumen generates compound, and this compound is combined with the FRB region of mTOR, and the function of suppression mTOR, thus suppress downstream
The expression of correlation factor, promotes Apoptosis, plays its unique targeting anti-tumor activity.
In recent years, the molecular design derivative successively having multiple rapamycins is applied to cancer by FDA approval
Treat or be used for clinical testing, the everolimus that Novartis Co., Ltd (Novartis) researches and develops was ratified for late period by FDA in 2009
Kidney is treated.The CCI-779 (CCI-779) that Hui Shi pharmacy (Wyeth) is developed, is ratified treatment advanced renal cell cancer by FDA；
Deferolimus researches and develops for Ariad company, and no immunosuppressive activity is now in clinical testing.
MTOR is the center of intracellular complicated signal transduction path, cell growth, propagation, cell metabolism, phagocytosis and
Play a crucial role in vascularization.MTOR inhibitors and FKBP12 protein combination form compound suppression mTOR overactivity, hold back
Make ribosomal biosynthesis and protein translation, thus playing the effect for the treatment of tumour.MTOR inhibitors are as important
Efficiently non-cytotoxicity class Targeted cancer therapy medicine, currently as mTOR inhibitors carry out anticancer research have sirolimus and its
Three derivatives：CCI-779 (temsirolimus, CCI-779), everolimus (everolimus, RAD001) and
AP23573(ridaforolimus).Wherein CCI-779 is first antineoplastic mTOR being approved by the FDA in the United States listing
Inhibitor, for the Orphan drug of the treatment of advanced renal cell carcinoma.
Although people in terms of the studies and clinical application of rapamycin and its derivative achieved with great achievement, but this
Skilled person still expects there is the product of more clinical value to provide one kind more preferably to select for clinical.
Content of the invention
It is an object of the invention to for a kind of more medicine particularly rapamycin of using value of clinical offer and its spreading out
Biological.The inventors discovered that the triazole derivatives of a series of rapamycin, show and various tumor cell strains are had by force
Big antitumor activity and/or other beat all advantage.The present invention is based on this and finds and be accomplished.
For this reason, first aspect present invention provides with compounds of Formula I：
Or its pharmaceutically acceptable salt, solvate, isomers, ester, prodrug, wherein,
N is 1,2 or 3；
X is or " "；
R is hydrogen or (C1-C4) alkyl；
R1For hydrogen, hydroxyl, methylol, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, N- (C1-C4) alkane
Base amino, N, N- bis- (C1-C4) alkyl amino, (C1-C4) alkyl sulfenyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkoxyl second
Base, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N, N- bis- (C1-C4) alkyl carbamoyl
Base or (C1-C3) alkylenedioxy group.
The compound of any embodiment according to a first aspect of the present invention, wherein n is 1,2 or 3.
The compound of any embodiment according to a first aspect of the present invention, wherein X is or " ".
The compound of any embodiment according to a first aspect of the present invention, wherein R is hydrogen or (C1-C4) alkyl.
The compound of any embodiment, wherein R according to a first aspect of the present invention1For hydrogen, hydroxyl, methylol, halogen, three
Methyl fluoride, trifluoromethoxy, amino, carboxyl, cyano group, N- (C1-C4) alkyl amino, N, N- bis- (C1-C4) alkyl amino, (C1-
C4) alkyl sulfenyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkoxyethyl, (C1-C4) alkyl acyl, carbamoyl, N-
(C1-C4) alkyl-carbamoyl, N, N- bis- (C1-C4) alkyl-carbamoyl or (C1-C3) alkylenedioxy group.
The compound of any embodiment according to a first aspect of the present invention, wherein,
N is 1,2 or 3；
X is or " "；
R is hydrogen or methyl；
R1For hydrogen, hydroxyl, methylol, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, N- (C1-C4) alkane
Base amino, N, N- bis- (C1-C4) alkyl amino, (C1-C4) alkyl sulfenyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkoxyl second
Base, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N, N- bis- (C1-C4) alkyl carbamoyl
Base or (C1-C3) alkylenedioxy group.
The compound of any embodiment according to a first aspect of the present invention, wherein,
N is 1；
X is；
R is hydrogen or methyl；
R1For hydrogen, hydroxyl, methylol, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, N- (C1-C4) alkane
Base amino, N, N- bis- (C1-C4) alkyl amino, (C1-C4) alkyl sulfenyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkoxyl second
Base, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N, N- bis- (C1-C4) alkyl carbamoyl
Base or (C1-C3) alkylenedioxy group.
The compound of any embodiment according to a first aspect of the present invention, wherein,
N is 2；
X is " "；
R1For hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C1-C4) alkyl, (C1-C4)
Alkoxyl, (C1-C4) thiazolinyl, (C1-C4) alkynyl, N- (C1-C4) alkyl amino, N, N- bis- (C1-C4) alkyl amino, (C1-C4) alkane
Base sulfenyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkoxyl second
Base, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N, N- bis- (C1-C4) alkyl carbamoyl
Base or (C1-C3) alkylenedioxy group.
The compound of any embodiment according to a first aspect of the present invention, wherein,
N is 3；
X is " "；
R1For hydrogen, hydroxyl, methylol, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, N- (C1-C4) alkane
Base amino, N, N- bis- (C1-C4) alkyl amino, (C1-C4) alkyl sulfenyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkoxyl second
Base, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N, N- bis- (C1-C4) alkyl carbamoyl
Base or (C1-C3) alkylenedioxy group.
The compound of any embodiment according to a first aspect of the present invention, it is selected from：
(it is in the present invention for oxygen rapamycin for 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) acetyl group)
In can be abbreviated as X-42), or its chemical constitution is
(it is at this for oxygen rapamycin for 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) iso-propionyl)
X-60 can be abbreviated as in bright), or its chemical constitution is
40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) ethyl) oxygen rapamycin (its in the present invention
X-51 can be abbreviated as), or its chemical constitution is
(3- (4- (methylol) -1H-1,2,3- triazole -1- base) is just for 40-O-
Propyl group) oxygen rapamycin (it can be abbreviated as X-33 in the present invention), or its chemical constitution is
Or its pharmaceutically acceptable salt, solvate, isomers, ester, prodrug.
The compounds of this invention is substantially the derivative of 40 hydroxyls replacements of rapamycin, and therefore its title can be still
It is defined by rapamycin nucleus, stated with the substituent on 40 hydroxyls, as described above.
Further, second aspect present invention provides a kind of pharmaceutical composition, appoints including first aspect present invention
Compound described in one embodiment, and optional pharmaceutically acceptable carrier or auxiliary material.According in this respect, the invention still further relates to
Described pharmaceutical composition is as preventing or treating the application in the medicine of the diseases such as tumour and/or cancer.
Further, third aspect present invention provides compound described in first aspect present invention any embodiment in system
It is ready for use on the purposes in prevention or the medicine for the treatment of tumour and/or cancer.In accordance with the purpose of the invention, wherein said tumour and/
Or cancer is selected from：Lung cancer, cancer of the esophagus, cancer of the stomach, prostate cancer, leukaemia, kidney.
Further, the method that fourth aspect present invention provides prevention and/or treatment tumour and/or cancer, the method
Compound of formula I including the first aspect present invention giving prevention and/or from therapeutically effective amount to subject in need.
Further, fifth aspect present invention provides compound described in preparation first aspect present invention any embodiment
Method, it comprises the following steps：
From following compound A-1：
Prepare with following formula A-2 compound：
Then make the alkynyl alcohol compound that A-2 compound is replaced with R1Through five water sulfuric acid ketone and Vitamin C
Sour sodium reaction obtains compound of formula I：
Compound of formula I is optionally made to form its pharmaceutically acceptable salt, solvate, isomers, ester, prodrug.Wherein
Each substituent is as described in first aspect present invention any embodiment.
Method according to a fifth aspect of the present invention, wherein, when X is " ", and R is hydrogen, the preparation method of A-2 compound
For：
With A-1 compound as raw material, with triflate shown in B-1Compounds in side chain reaction obtains B-2 chemical combination
Thing：
Then B-2 compound and reaction of sodium azide is made to obtain A-2 compound.
Method according to a fifth aspect of the present invention, wherein, when X for when, the preparation method of A-2 compound is：
Reacted with trim,ethylchlorosilane for raw material with A-1 compound, obtain with following formula C-1 compound：
Then C-1 compound and formula are madeC-2 compound esterification, obtain with following formula C-3 compound：
Then C-3 compound and reaction of sodium azide is made to obtain C-4 compound：
C-4 compound deprotection is finally made to obtain A-2 compound.
The feature that any one of either side of the present invention or this either side has is equally applicable to other either sides
Or any one of this other either side, as long as they will not be conflicting, certainly in where applicable each other, if necessary may be used
Individual features are made suitably modify.In the present invention, for example, when referring to " any one of first aspect present invention ", it is somebody's turn to do " any one "
Refer to the arbitrary sub- aspect of first aspect present invention；When other side refers in a similar manner, also there are identical meanings.
It is further described with feature to various aspects of the present invention below.
All documents recited in the present invention, their full content is incorporated herein by, and if these are civilian
When implication expressed by offering is inconsistent with the present invention, it is defined by the statement of the present invention.Additionally, the present invention use various terms and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term referring to and phrase if any inconsistent with common art-recognized meanings, with institute of the present invention table
The implication stated is defined.
In the present invention, when X is " ", refer to not exist group herein, that is, represent that X is chemical bond.
In the present invention, group " C1-C4Alkyl ", " C1-4Alkyl ", " (C1-C4) alkyl " etc., they have identical meanings,
All represent the straight or branched alkyl with 1-4 carbon atom.Other situations also can make similar understanding.
In the present invention, group " C1-4Alkyl ", including its individually statement and exist with other moiety combinations, example
As C can be selected from1-3Alkyl, C1-2Alkyl.Similarly, C1-4Alkoxy is as being selected from C1-3Alkoxyl, C1-2Alkoxyl.
In the method for synthetic compound of formula i of the present invention, reaction various raw material used are those skilled in the art's roots
Can prepare according to existing knowledge, or can be by what method known to document was obtained, or can be by business
Industry is buied.In above reaction scheme, intermediate used, raw material, reagent, reaction condition etc. all can be according to this area skills
The existing knowledge of art personnel can be made suitably to change.Or, those skilled in the art can also be square according to a second aspect of the present invention
Method synthesizes the not specifically enumerated other compound of formula I of the present invention.
According to the present invention, the pharmaceutical salts of compound of formula I can be acid-addition salts or the salt being formed with alkali.Acid-addition salts are illustrated
Say it can is that inorganic acid salt is such as, but not limited to hydrochloride, sulfate, phosphate, hydrobromate；Or acylate is for example but not
Be limited to acetate, oxalates, sal limonis, gluconate, succinate, tartrate, tosilate, mesylate,
Benzoate, lactate and maleate；Compound of formula I says it can is that alkali metal salt is such as, but not limited to the citing of alkali forming salt
Lithium, sodium and sylvite；Alkali salt is such as, but not limited to calcium and magnesium salts；Organic alkali salt is such as, but not limited to diethanolamine salt and courage
Alkali salt etc.；Or chirality alkali salt is such as, but not limited to alkyl phenyl amine salt.
The solvate of the compound of the present invention can be hydrate or comprise other recrystallisation solvents such as alcohols such as second
Alcohol.
According to the present invention, compound of formula I there may be cis/trans isomers, the present invention relates to cis form and trans forms
And the mixture of these forms.If necessary, the preparation of single stereoisomers can split mixture according to conventional methods, or
Prepared by such as Stereo-selective synthesis.If there is motor-driven hydrogen atom, the present invention also relates to the tautomerism of compound of formula I
Form.
The present invention therefore further relates at least one compound of formula I containing the effective dose as active ingredient, or its medicine
Pharmaceutical composition with salt and/or its stereoisomer and customary pharmaceutical excipients or assistant agent.Generally drug regimen of the present invention
Thing contains compound of formula I and/or its physiologically acceptable salt of 0.1-90 weight %.Pharmaceutical composition can according to this area
The method preparation known.When for this purpose, if it is desired, compound of formula I and/or stereoisomer and one or more can be consolidated
Body or liquid pharmaceutical excipients and/or assistant agent combine, and making can be used as the suitable administration form of people or dosage form.
The compound of formula I of the present invention or can be administered in a unit containing its pharmaceutical composition, method of administration can
For enteron aisle or non-bowel, in such as oral, muscle, subcutaneous, knurl, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc..Form of administration
For example tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent, emulsion, granule, liposome, transdermal agent,
Buccal tablet, suppository, freeze drying powder injection, injection etc..Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate to
Medicine system.In order to unit dosage forms for administration is made tablet, various carrier well known in the art can be widely used.With regard to carrier
Example is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose,
Urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, polyethylene glycol, second
Alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, purple
Glue, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, for example, be dried starch, alginate, agar powder, brown
Algae starch, sodium acid carbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methyl are fine
Dimension element, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；Absorption enhancement
Agent, such as quaternary ammonium salt, lauryl sodium sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, stearate,
Boric acid, atoleine, polyethylene glycol etc..Tablet can also be made further coating tablet, such as sugar coated tablet, film coating
Piece, ECT, or double-layer tablets and multilayer tablet.In order to administration unit is made pill, can widely use known in this field
Various carriers.Example with regard to carrier is, such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenation
Vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive for example Arabic gum, bassora gum, gelatin,
Ethanol, honey, liquid sugar, rice paste or batter etc.；Disintegrant, such as agar powder, be dried starch, alginate, dodecyl sodium sulfate,
Methylcellulose, ethyl cellulose etc..In order to administration unit is made suppository, various load well known in the art can be widely used
Body.Example with regard to carrier is, for example polyethylene glycol, lecithin, cocoa butter, higher alcohol, the ester of higher alcohol, gelatin, semi-synthetic
Glyceride etc..In order to administration unit is made capsule, active ingredient compound of formula I or its stereoisomer is various with above-mentioned
Carrier mixes, and thus obtained mixture is placed in hard obviously capsule or soft capsule.Also can be by active ingredient Formulas I chemical combination
Thing or its stereoisomer make microcapsules, are suspended in aqueous medium and form supensoid agent, also can load in hard shell capsules or make
Injection is applied.In order to administration unit is made injection preparation, such as solution, emulsion, freeze drying powder injection and supensoid agent, permissible
Using all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1,3-PD, the different tristearin of ethoxylation
Alcohol, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic parenteral solution, can be to note
Penetrate with adding appropriate sodium chloride, glucose or glycerine in preparation, further, it is also possible to add conventional cosolvent, buffer, pH
Conditioning agent etc..
Additionally, if desired, can also add in pharmaceutical preparation colouring agent, preservative, spices, flavouring, sweetener or
Other materials.
Formula I, or the dosage of its isomers depend on many factors, for example to prevent or treat
The sex of the property of disease and the order of severity, patient or animal, age, body weight and individual reaction, particular compound used, give
Medicine approach and administration number of times etc..Above-mentioned dosage with ingle dose form or can be divided into several, such as two, three or four dosage forms
Administration.
Term " composition " used herein means the product including each specified composition comprising specified amount, and directly or
Any product indirectly producing from the combination of each specified composition of specified amount.
The actual dose level of each active component in pharmaceutical composition of the present invention can be changed, so that the reactive compound of gained
Amount can effectively be directed to concrete patient, composition and administering mode and obtain required therapeutic response.Dosage level must be according to materialization
The activity of compound, the patient's condition of method of administration, the order of severity of the treated patient's condition and patient to be treated and medical history are selecting.
But, the way of this area is, the dosage of compound from the beginning of less than the level obtaining required therapeutic effect and requiring, gradually
Increasing dosage, until obtaining required effect.
The compound of the present invention can be used for preparing antineoplastic.Described tumour includes but is not limited to melanoma, stomach
Cancer, lung cancer, breast cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical carcinoma, oophoroma, cancer of pancreas, prostate cancer, colon cancer, bladder
The malignant tumours such as cancer, head and neck neoplasm, nasopharyngeal carcinoma, cutaneum carcinoma and leukaemia.Described cancer of the stomach includes sdenocarcinoma of stomach；Described lung cancer
Including adenocarcinoma of lung；Described colon cancer includes adenocarcinoma of colon；Described oophoroma includes adenocarcinoma ovaries；Described kidney includes kidney
Clear cell adenocarcinoma；Leukaemia includes ALL, chronic leukemia, specific type leukaemia.
When for above-mentioned treatment and/or prevention or other treatment and/or prevention, the one for the treatment of and/or prevention effective dose
Plant the compounds of this invention can apply in a pure form, or these forms (are had with pharmaceutically acceptable ester or prodrug forms
In the case of) application.Or, described compound can be to be subjected to figuration containing this purpose compound and one or more medicine
The pharmaceutical composition administration of agent.The compounds of this invention of word " prevention and/or therapeutically effective amount " refers to be applied to any medical science
The reasonable effect of prevention and/or treatment/Hazard ratio treats the compound of the q.s of obstacle.It is to be understood that chemical combination of the present invention
Total consumption per day of thing and composition must be maked decision in reliable medical judgment scope by attending physician.For any specific
Patient, depending on specific treatment effective dose level must be according to many factors, described factor includes treated obstacle and this barrier
The order of severity hindering；The activity of the particular compound being adopted；The concrete composition being adopted；The age of patient, body weight, general
Health status, sex and diet；The administration time of the particular compound being adopted, method of administration and excretion rate；When treatment continues
Between；The medicine being applied in combination with the particular compound being adopted or using simultaneously；And similar factor known to medical field.Example
If the way of this area is that the dosage of compound, from the beginning of less than the level obtaining required therapeutic effect and requiring, gradually increases
Plus dosage, until obtaining required effect.It is, in general, that formula I is used for the dosage of mammal particularly people
Can between 0.001～1000mg/kg body weight/day, such as between 0.01～100mg/kg body weight/day, such as between 0.01～
10mg/kg body weight/day.
Unless otherwise noted, term used herein " alkyl " and " alkyl " and the bag that comprise carbon number modification
Include the alkyl that " alkyl " in the moiety combinations of these " alkyl " refers to straight or branched, such as (C1-C4) alkyl includes but do not limit
In methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl group etc.；" alkylidene " refers to the alkylidene of straight or branched；" ring
Alkyl " refers to substituted or unsubstituted cycloalkyl.
The present invention includes pharmaceutical composition, and said composition contains the rapamycin class compound of formula I, its optical isomerism
Body and its pharmaceutically acceptable salt are as active component, and pharmaceutically acceptable excipients.Described pharmaceutically acceptable
Excipients refer to any diluent that can be used for pharmaceutical field, adjuvant and/or carrier.The derivative of the present invention can be with it
He uses, as long as they do not produce other unfavorable effects, such as allergic reaction active ingredient combinations.
The pharmaceutical composition of the present invention can be configured to several formulation, wherein containing some figurations in pharmaceutical field conventional
Agent；For example, oral formulations (such as tablet, capsule, solution or suspension)；Injectable preparation is (as injectable solution or mixed
Suspension, or injectable dried powder, add water for injection can use immediately before the injection)；Topical formulations (such as ointment
Or solution).
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, including：Oral formulations
Adhesive, lubricant, disintegrant, cosolvent, diluent, stabilizer, suspending agent, non-pigment, flavouring etc.；Injectable system
The preservative of agent, solubilizer, stabilizer etc.；The matrix of topical formulations, diluent, lubricant, preservative etc..Pharmaceutical preparation
Can by oral administration or parenteral (for example intravenous, subcutaneous, intraperitoneal or local) administration, if some drugses are in stomach bar
It is unstable under part, enteric coated tablets can be configured to.
It has been found that the compounds of this invention has suppression tumor cell growth activity in vitro, therefore, it can serve as making
Standby treatment and/or the medicine of pre- anti-cancer.Especially treatment breast cancer, prostate cancer, kidney and leukemia.The compounds of this invention also by
Expect to can be used for treating other cell proliferative diseases such as psoriasis, benign prostatauxe, atherosclerotic and ISR.
It is also contemplated that the rapamycin class compound of the present invention will have anti-leukocythemia, malignant lymphoma and solid tumor as in tissue such as
Cancer in liver, kidney, prostate and pancreas and the activity of sarcoma scope.
Derivative according to the present invention can be used for preparation treatment as active component and/or prevent various cancers, the present invention
The method also providing for treating or preventing above-mentioned disease, including the basis giving with or being susceptible to this sick Case treatment effective dose
The derivative of the present invention.The rapamycin class compound of formula I be used for patient clinical dosage must rely on treated main body,
Administration concrete ways, the seriousness of disease being treated and change, and optimal dose by treat concrete patient doctor determine.
Reactive compound of the present invention can use as unique cancer therapy drug, or can be other with one or more anti-swollen
Tumor medicine is used in combination.Therapeutic alliance by by each therapeutic component simultaneously, order or separate administration and realize.
Examples provided hereinafter and preparation example are further elucidated with and illustrate the compounds of this invention and its preparation side
Method.It should be appreciated that the scope of following embodiments and preparation example never in any form restriction the scope of the present invention.
Schematically synthetic route A describes the preparation of the generalformula-compound of the present invention below, and all of raw material all passes through
These illustrate synthetic routes described in method, by organic chemistry filed well-known to the ordinarily skilled artisan method preparation or
Commercially available.Whole final compounds of the present invention are all by the method described in these signal formulas or to pass through similar side
Method preparation, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.In these signal formulas, application is whole variable
Definition in the definition of factor following article or such as claim.
According to formula I derivative of the present invention, in route A, R, R1, X and n such as content of the invention defined.
Route A：The synthetic route of generalformula-compound
Compound A-1 is walked reaction through 2-4, generates azido compound A-2.By compound A-2 and alkynyl alcohol compound
Obtaining formula through five water sulfuric acid ketone and sodium ascorbate reaction is the derivative shown in I.
Wherein, when X is " ", and R is hydrogen, A-2 is prepared according to the method that step 1 describes：With A-1 as raw material, with B-1 tri-
The reaction of fluorine methanesulfonates side chain obtains B-2, then through obtaining A-2 with reaction of sodium azide.
Step 1 (route B)
When X for when, prepared by the method that A-2 describes according to step 2：With A-1 as raw material, through the protection of silicon ether, esterification, Azide
Obtain A-2 with deprotection, (TMSCl Chinese full name：Trim,ethylchlorosilane).
Step 2 (route C)
Preparation method of the present invention is simple, and the compound of preparation is respectively provided with stronger antitumor activity.
In above-mentioned route, raw material A -1, compound shown in B-1, B-2, C-1 and C-2 can be common by organic chemistry filed
Method known to technical staff is prepared or commercially available.Preparation method of the present invention is simple, and the compound of preparation has preferably anti-
Tumor promotion.
Specific embodiment
Following specific embodiment is intended to illustrate rather than limits the scope of the present invention.
In the present invention, the proton nmr spectra of prepared compound is measured with BrukerARX-300, mass spectrum Agilent
1100LC/MSD measures；It is pure or chemical pure that agents useful for same is analysis.
It is prepared for the typical compound of some present invention, they are represented with below formula I in some embodiments below,
The exemplary title of each substituent and these compounds is shown in Table 1 respectively,
Table 1：The structural formula of embodiment 1-4
| Embodiment | X | R | n | R1 | The exemplary title of compound |
| 1 | H | 1 | H | 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) acetyl group) oxygen rapamycin (X-42) | |
| 2 | CH3 | 1 | H | 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) iso-propionyl) oxygen rapamycin (X-60) | |
| 3 | — | H | 2 | H | 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) ethyl) oxygen rapamycin (X-51) |
| 4 | — | H | 3 | H | 40-O- (3- (4- (methylol) -1H-1,2,3- triazole -1- base) n-propyl) oxygen rapamycin (X-33) |
Embodiment 1：40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) acetyl group) oxygen rapamycin (X-
42) preparation
(preparing according to synthetic route A and C)
Step A：The preparation of 28- epoxide TMS-rapamycin
Respectively rapamycin (5.5mmol, 5.0g) and imidazoles (1.5g) are added in ethyl acetate (80mL) solution, plus
Material is cooled to 0-5 DEG C after finishing, dropping trim,ethylchlorosilane (mmol, 4.3g), insulation reaction 2 hours.Protect when forming double silicon ethers
After shield product, incline to reactant liquor and add dilute sulfuric acid (15mL, 1N H2SO4), continue stirring reaction about 16h, after completion of the reaction, reaction
Liquid respectively through saturated sodium bicarbonate, saturated common salt water washing, organic layer through anhydrous sodium sulfate drying, be evaporated white foam is solid
Body 5.1g, yield 47%, MS (ESI) m/z:1008.5(M+Na)+..
Step B：The preparation of 28- epoxide TMS -43-O- (2- chloracetyl)-oxygen rapamycin
28-OTMS- rapamycin (2.6g, 2.6mmol) and anhydrous methylene chloride (40mL) are added in three-necked bottle, plus
Enter triethylamine (3mL), be added dropwise over chloracetyl chloride (0.54g, 4.8mmol) at 0-5 DEG C, finish, 0-5 DEG C of reaction 6h.React
Bi Hou, reactant liquor is poured in 300mL water, and dichloromethane extracts, and merges extract, washing, anhydrous sodium sulfate drying.It is evaporated
White solid 2.1g, yield：82.6%MS (ESI) m/z:1084.6(M+Na)+.
Step C：The preparation of 43-O- (2- chloracetyl)-oxygen rapamycin
By that 28-OTMS-43-O- (2- chloracetyl)-oxygen rapamycin (2mmol, 2.1g) is added to acetone (36mL) is molten
In liquid, charging is cooled to 0-5 DEG C after finishing, and adds dilute sulfuric acid (10mL, 1N H to reactant liquor2SO4), continue stirring reaction about 2h,
After completion of the reaction, respectively through saturated sodium bicarbonate, saturated common salt water washing, organic layer, through anhydrous sodium sulfate drying, steams reactant liquor
Do to obtain white foam solid 1.8g, yield 47%, MS (ESI) m/z:1012.5(M+Na)+.
Step D：The preparation of 43-O- (2- acetyl azide)-oxygen rapamycin
Respectively by 43-O- (2- chloracetyl)-oxygen rapamycin (1.8g, 1.8mmol) and sodium azide (0.3g,
4.6mmol) it is added in (300mL) DMF solution, charging is warmed up to 50 DEG C after finishing, after reaction completely, reactant liquor is poured into
In 100mL water, ethyl acetate extracts 2 times, merges extract, washing, anhydrous sodium sulfate drying.It is evaporated to obtain grease, through post layer
Analysis respectively obtains 1.0g, and yield is 48%, MS (ESI) m/z:1019.5(M+Na)+.
Step E：The system of 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) acetyl group) oxygen rapamycin
Standby
By 43-O- (2- acetyl azide)-oxygen rapamycin (0.35mmoL, 0.35g) and propilolic alcohol (1.78mmoL,
0.1g) it is added in DMF (10mL) solution, in reactant liquor, add sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g),
2h is stirred at room temperature, after completion of the reaction, reaction is fallen to add in 30mL water, separate out faint yellow solid, suction filtration, wash, lightly dry
Yellow solid, obtains sterling 0.13g, yield through silica gel column chromatography and C18 preparative separation：35.3%.
MS(ESI)m/z:1075.6(M+Na)+.
1H NMR(500MHz,DMSO)δ7.96(s,1H),6.44(s,1H),6.43-6.31(m,1H),6.27-6.20
(m, 1H), 6.15 (m, 1H), 6.14-6.05 (m, 1H), 5.47 (dd, J=14.7,9.7Hz, 1H), 5.37 (s, 2H), 5.27
(d, J=4.2Hz, 1H), 5.19 (t, J=5.6Hz, 1H), 5.10 (d, J=10.2Hz, 1H), 5.01-4.96 (m, 1H),
4.95-4.92 (m, 1H), 4.66-4.58 (m, 1H), 4.53 (d, J=5.2Hz, 2H), 4.05-3.97 (m, 2H), 3.95 (d, J
=3.9Hz, 1H), 3.63 (d, J=12.4Hz, 1H), 3.44 (d, J=15.7Hz, 1H), 3.27 (s, 3H), 3.16 (s, 3H),
3.05 (s, 3H), δ 2.85-2.77 (m, 1H), 2.74 (d, J=16.0Hz, 1H), 2.44-2.34 (m, 2H), 2.27-2.18 (m,
1H), 2.16-1.80 (m, 4H), 1.74 (s, 1H), 1.63 (s, 2H), 1.61-1.03 (m, 11H), 0.98 (d, J=6.3Hz,
3H), 0.87 (d, J=6.3Hz, 3H), 0.82 (d, J=6.1Hz, 3H), 0.79 (d, J=6.6Hz, 3H), 0.73 (d, J=
6.2Hz,3H).
13C NMR(126MHz,DMSO)δ210.39,207.52,198.84,169.21,166.99,166.81,147.98,
139.31,137.85,137.14,132.34,130.40,126.99,126.98,124.84,124.09,99.00,85.49,
82.23,79.86,77.59,75.73,73.67,66.19,56.91,56.75,55.44,54.95,50.79,50.33,
45.22,43.48,37.99,35.29,35.15,34.79,33.33,31.90,30.45,29.66,29.15,26.40,
26.22,24.44,21.62,20.36,15.54,15.52,14.63,13.47,13.32,10.45.
Embodiment 2：40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) iso-propionyl) oxygen rapamycin
(X-60)
(preparing according to synthetic route A and C)
Step A：The preparation of 28- epoxide TMS -43-O- (2- bromine iso-propionyl)-oxygen rapamycin
28-OTMS- rapamycin (2.5g, 2.5mmol) and anhydrous methylene chloride (40mL) are added in three-necked bottle, plus
Enter triethylamine (3mL), be added dropwise over 2- isopropyl acyl chlorides (1.1g, 5mmol) at 0-5 DEG C, finish, 0-5 DEG C of reaction 8h.Reaction finishes
Afterwards, reactant liquor is poured in 300mL water, dichloromethane extracts, merges extract, washing, anhydrous sodium sulfate drying.It is evaporated in vain
Color solid 1.9g, yield：77.2%MS (ESI) m/z:1142.5(M+Na)+.
Step B：The preparation of 43-O- (2- bromine iso-propionyl)-oxygen rapamycin
28-OTMS-43-O- (2- bromine iso-propionyl)-oxygen rapamycin (1.9g, 1.7mmol) is added to acetone
(40mL) in solution, charging is cooled to 0-5 DEG C after finishing, and adds dilute sulfuric acid (10mL, 1N H to reactant liquor2SO4), continue stirring
Reaction about 2h, after completion of the reaction, respectively through saturated sodium bicarbonate, saturated common salt water washing, organic layer is through anhydrous slufuric acid for reactant liquor
Sodium is dried, and is evaporated to obtain white foam solid 1.6g, yield 47%, MS (ESI) m/z:1070.5(M+Na)+.
Step C：The preparation of 43-O- (2- nitrine iso-propionyl)-oxygen rapamycin
Respectively by 43-O- (2- bromine iso-propionyl)-oxygen rapamycin (1.6g, 1.5mmol) and sodium azide (0.2g,
3mmol) it is added in (30mL) DMF solution, charging is warmed up to 50 DEG C after finishing, after reaction completely, reactant liquor is poured into 90mL
In water, ethyl acetate extracts 2 times, merges extract, washing, anhydrous sodium sulfate drying.It is evaporated to obtain grease, through column chromatography for separation
Obtain 0.8g, yield is 46%, MS (ESI) m/z:1033.6(M+Na)+.
Step D：40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) iso-propionyl) oxygen rapamycin (X-
60) preparation
By 43-O- (2- nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL, 0.2g) and propine (1.25mmoL,
0.07g) alcohol is added in DMF (10mL) solution, adds sodium ascorbate (0.08g) and cupric sulfate pentahydrate in reactant liquor
(0.09g) 2h, is stirred at room temperature, after completion of the reaction, reaction is fallen to add in 30mL water, separate out faint yellow solid, suction filtration, wash,
Dry faint yellow solid, obtains sterling 0.11g, yield through column chromatography for separation：51.6%.
MS(ESI)m/z:1089.5(M+Na)+.
1H NMR(500MHz,DMSO)δ8.05(s,1H),6.44(s,1H),6.44–6.33(m,1H),6.28–6.19
(m, 1H), 6.14 (m, 1H), 6.13 6.06 (m, 1H), 5.59 (dd, J=14.1,6.9Hz, 1H), 5.46 (dd, J=14.7,
9.7Hz, 1H), 5.26 (s, 1H), 5.10 (d, J=9.7Hz, 1H), 5.00 4.95 (m, 1H), 4.94 (m, 1H), 4.64 4.56
(m, 1H), 4.53 (s, 2H), 4.06 3.97 (m, 2H), 3.95 (d, J=3.7Hz, 1H), 3.63 (d, J=11.7Hz, 1H),
3.44 (d, J=13.5Hz, 1H), 3.25 (s, 3H), 3.16 (s, 3H), 3.05 (s, 3H), 2.87 2.69 (m, 2H), 2.44
2.34 (m, 2H), 2.27 2.17 (m, 1H), 2.15 1.79 (m, 6H), 1.75 (d, J=8.9Hz, 3H), 1.74 (s, 3H),
1.63 (s, 3H), 1.61 1.02 (m, 12H), 0.98 (d, J=6.2Hz, 3H), 0.87 (d, J=6.3Hz, 3H), 0.82 (d, J
=6.2Hz, 3H), 0.78 (d, J=6.4Hz, 3H), 0.73 (d, J=6.3Hz, 3H).
13C NMR(126MHz,DMSO)δ210.38,207.52,198.83,169.21,169.02,166.98,147.81,
139.31,137.85,137.12,132.35,130.40,126.99,126.98,124.81,122.37,98.99,85.47,
82.22,80.10,77.38,75.72,73.66,66.19,57.37,56.90,56.70,55.44,54.97,50.78,
45.22,43.49,37.97,35.33,35.15,34.79,33.34,31.90,30.44,29.66,28.99,26.40,
26.22,24.44,21.61,20.36,17.14,15.54,15.52,14.64,13.49,13.30,10.45.
Embodiment 3：40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) ethyl) oxygen rapamycin (X-
51)
(preparing according to synthetic route A and B)
Step A：The preparation of 43-O- (2- bromoethyl)-oxygen rapamycin
Rapamycin (6g, 6.6mmol), diisopropylethylamine (4.2g, 33mmol) are added to the toluene solution of 50mL
In, add 2- bromoethyl sulfonic acid ester side chain (5g, 19.6mmol), finish, be warming up to 60 DEG C of reaction 3h.After completion of the reaction, will be anti-
Liquid is answered to be cooled to room temperature, respectively through, in watery hydrochloric acid, saturated sodium bicarbonate and saturated aqueous common salt, organic layer is done through anhydrous sodium sulfate
Dry, be evaporated to obtain faint yellow solid, after obtain 2.9g white solid, yield through column chromatography for separation：82.6%, 1042.5 (M+Na)+.
Step B：The preparation of 43-O- (2- azidoethyl)-oxygen rapamycin
Respectively by 43-O- (2- bromoethyl)-oxygen rapamycin (5.9g, 5.7mmol) and sodium azide (1.1g, 17mmol)
It is added in (30mL) DMF solution, adds catalyst KI (0.1g), charging is warmed up to 50 DEG C after finishing, after reaction completely, will be anti-
Answer liquid to be poured in 90mL water, ethyl acetate extracts 2 times, merge extract, washing, anhydrous sodium sulfate drying.It is evaporated to obtain grease,
Respectively obtain 3.1g through column chromatography for separation, yield is 47%, MS (ESI) m/z:1005.5(M+Na)+.
Step C：The preparation of 40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- base) ethyl) oxygen rapamycin
43-O- (2- azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) and propilolic alcohol (1.78mmoL, 0.1g) are added
Enter in DMF (10mL) solution, add sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) in reactant liquor, room temperature is stirred
Mix 2h, after completion of the reaction, reaction is fallen to add in 40mL water, separates out faint yellow solid, suction filtration, washing, dry pale yellow colored solid
Body, obtains sterling 0.23g, yield through silica gel column chromatography and C18 preparative separation：72.3%.
MS(ESI)m/z:1061.5(M+Na)+.
1H NMR(400MHz,DMSO)δ7.95(s,1H),6.47(s,1H),6.44–6.35(m,1H),6.27–6.21
(m, 1H), 6.20 6.12 (m, 1H), 6.11 (m, 1H), 5.46 (dd, J=14.6,9.8Hz, 1H), 5.28 (d, J=4.2Hz,
1H), 5.15 (t, J=5.5Hz, 1H), 5.09 (d, J=10.1Hz, 1H), 5.01 4.87 (m, 2H), 4.50 (d, J=5.3Hz,
2H), 4.45 (m, 2H), 4.01 (m, 2H), 3.96 (m, 1H), 3.89 (m, 2H), 3.63 (d, J=12.1Hz, 1H), 3.44 (d, J
=14.8Hz, 1H), 3.23 (s, 3H), 3.15 (s, 3H), 3.05 (s, 3H), 3.03 2.88 (m, 2H), 2.87 2.60 (m,
2H),2.43–2.30(m,2H),2.26–2.15(m,1H),2.15–1.78(m,5H),1.59–1.02(m,10H),0.98(d,J
=6.3Hz, 3H), 0.86 (d, J=6.5Hz, 3H), 0.82 (d, J=6.0Hz, 3H), 0.77 (d, J=6.6Hz, 3H), 0.73
(d, J=6.4Hz, 3H).
13C NMR(101MHz,DMSO)δ210.95,208.01,199.38,169.71,167.47,148.24,139.80,
138.34,137.62,132.84,130.92,127.49,125.37,123.44,99.50,86.00,82.90,82.74,
82.55,76.24,74.11,68.25,66.70,57.42,57.17,55.96,55.55,51.27,50.32,45.70,
43.99,38.68,36.16,35.66,35.29,33.86,32.65,31.32,30.12,30.02,26.91,26.73,
24.95,22.13,20.86,16.03,15.19,13.95,13.85,10.96.
Embodiment 4：40-O- (3- (4- (methylol) -1H-1,2,3- triazole -1- base) n-propyl) oxygen rapamycin (X-
33)
(preparing according to synthetic route A and B)
Step A：The preparation of 43-O- (3- bromopropyl)-oxygen rapamycin
Will be molten for toluene that rapamycin (8.0g, 8.7mmol), diisopropylethylamine (5.6g, 44mmol) are added to 50mL
In liquid, add 3- bromopropyl sulfonic acid ester side chain (11.8g, 28.5mmol), finish, be warming up to 60 DEG C of reaction 3h.After completion of the reaction,
Reactant liquor is cooled to room temperature, respectively through, in watery hydrochloric acid, saturated sodium bicarbonate and saturated aqueous common salt, organic layer is through anhydrous sodium sulfate
It is dried, be evaporated to obtain faint yellow solid, obtain 4.8g white solid, yield through column chromatography for separation：82.6%, 1056.5 (M+Na)+.
Step B：The preparation of 43-O- (3- nitrine propyl group)-oxygen rapamycin
Respectively by 43-O- (3- bromopropyl)-oxygen rapamycin (6.8g, 6.5mmol) and sodium azide (1.3g,
19.5mmol) it is added in (30mL) DMF solution, adds catalyst KI (0.1g), charging is warmed up to 50 DEG C after finishing, has reacted
Quan Hou, reactant liquor is poured in 100mL water, and ethyl acetate extracts 2 times, merges extract, washing, anhydrous sodium sulfate drying.Steam
Do to obtain grease, respectively obtain 3.8g through column chromatography for separation, yield is 46%, MS (ESI) m/z:1019.6(M+Na)+.
Step C：The system of 40-O- (3- (4- (methylol) -1H-1,2,3- triazole -1- base) n-propyl) oxygen rapamycin
Standby
By 43-O- (3- nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) and propilolic alcohol (1.78mmoL, 0.1g)
It is added in DMF (10mL) solution, add sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g), room temperature in reactant liquor
Stirring 2h, after completion of the reaction, reaction is fallen to add in 60mL water, precipitation faint yellow solid, suction filtration, washing, faint yellowly dry
Solid, obtains sterling 0.19g, yield through silica gel column chromatography and C18 preparative separation：43.4%.
MS(ESI)m/z:1075.6(M+Na)+.
1H NMR(400MHz,DMSO)δ7.95(s,1H),6.47(s,1H),6.45–6.35(m,1H),6.28–6.19
(m, 1H), 6.22 6.14 (m, 1H), 6.15 6.07 (m, 1H), 5.47 (dd, J=13.9,10.3Hz, 1H), 5.29 (s, 1H),
5.19 5.12 (m, 1H), 5.09 (d, J=9.9Hz, 1H), 5.03 4.90 (m, 2H), 4.50 (d, J=4.7Hz, 2H), 4.39
(m, 2H), 3.99 (m, 3H), 3.63 (d, J=11.3Hz, 1H), 3.57 3.40 (m, 4H), 3.16 (s, 3H), 3.05 (s,
3H),3.01(s,3H),2.88–2.65(m,2H),2.38(m,2H),2.29–2.15(m,1H),1.96(m,6H),1.75(s,
3H), 1.63 (s, 3H), 1.60 1.02 (m, 10H), 0.98 (d, J=5.4Hz, 3H), 0.87 (d, J=5.8Hz, 3H), 0.82
(d, J=5.5Hz, 3H), 0.78 (d, J=5.9Hz, 3H), 0.73 (d, J=5.7Hz, 3H).
13C NMR(101MHz,DMSO)δ210.95,208.02,199.37,169.71,167.48,148.38,139.80,
138.34,137.62,132.83,130.93,127.49,125.37,123.15,99.50,86.00,82.93,82.74,
82.45,76.24,74.12,66.70,66.04,57.42,55.96,55.53,51.27,47.00,45.70,43.98,
38.73,36.34,35.66,35.30,33.86,32.75,31.35,31.06,30.14,30.07,26.92,26.72,
24.95,22.13,20.87,16.07,16.03,15.22,13.96,13.84,10.96.
Mensure embodiment 1 solubility at room temperature, in water to each compound of embodiment 4, with Rapa for comparison, eachization
The solubility ratio (i.e. the solubility of each compound is the multiple of Rapa solubility) of compound, all in the range of 13.5～22.4, shows
The compounds of this invention has excellent physicochemical property, and higher solubility is extremely advantageous for preparation shaping, drug absorption etc.
's.
Test example 1：Antitumor activity is tested
(1) by Leukemia K562 cell, human leukemia cell line HL-60, Human Prostate Cancer Cells PC-3, human prostata cancer
Cell DU-145, kidney cancer cell 22RV1 and kidney cancer cell SK-N-BE cell line are recovered and are passed on 2-3 time, make cell viability stable
For cell in vitro active testing.Suspension cell is not required to digest, and attached cell trypsase (0.25%) is digested, and adds
Cell culture fluid containing serum terminates digestion, with pipette transfer cell liquid to centrifuge tube, is centrifuged 3min, gently under 1500r/min
Add 5mL nutrient solution after light abandoning supernatant, piping and druming mixes cell, counts, attached cell 5000-10000/hole, suspend thin
20000/hole of born of the same parents, adds 96 orifice plates, and in 37 DEG C, 5%CO2 culture, cell culture added testing drug after 24 hours.
(2) test the BA of the compounds of this invention, and compared with rapamycin (Rapa), use dimethyl sulfoxide (DMSO)
Dissolving given the test agent, as mother liquor, then dilutes given the test agent with cell culture fluid：Take 10ul sample mother liquor, add 990ul thin
Born of the same parents' nutrient solution, dilute sample is to test concentrations.Sample diluting liquid is added the cell culture fluid cultivating 24h in 96 orifice plates
In, each concentration adds 3 holes, if blank (not plus drug-treated).By 96 orifice plates in 37 DEG C, 5%CO2 continuation culture 96h,
Add MTT (tetrazole) (5mg/mL) 20 μ L in every hole, after putting into 8h in incubator, suspension cell is centrifuged in 4000r/min
10min, abandoning supernatant, add dimethyl sulfoxide (DMSO) 150 μ L, so that survivaling cell is fully dissolved with MTT product first, put into
Measurement result in ELIASA, can obtain medicine IC by Bliss method50Value (μm ol/L).Result shows the compound pair of the present invention
Various cancer cells are respectively provided with the significantly superior good BA than rapamycin, for example：To K562 cell, the IC of Rapa50Value
(μm ol/L) is 42, and the IC of each compound of embodiment 1～450Value (μm ol/L) all in the range of 1～9, for example change by embodiment 4
Compound IC50Value (μm ol/L) is 6；To HL-60 cell, the IC of Rapa50Value (μm ol/L) is 32, and each chemical combination of embodiment 1～4
The IC of thing50It is worth (μm ol/L) all in the range of 0.5～6, such as embodiment 3 compound IC50Value (μm ol/L) is 4.
Industrial applicability：The invention belongs to pharmaceutical technology field, it is related to new rapamycin type derivative, its optical activity
The triazole derivatives of body and its pharmaceutically acceptable salt, more particularly to rapamycin.The invention still further relates to they
Preparation method and containing described compound pharmaceutical composition.The invention still further relates to this derivative be used for preparation treatment and/
Or the purposes in the medicine of pre- anti-cancer.The compounds of this invention has excellent active anticancer, can be prepared into cancer therapy drug to control
Treat and/or pre- anti-cancer.
Claims (3)
1. it is selected from following compound or its pharmaceutically acceptable salt：
40-O- (2- (4- (methylol) -1H-1,2,3- triazole -1- bases) ethyl) oxygen rapamycin, its chemical constitution is
40-O- (3- (4- (methylol) -1H-1,2,3- triazole -1- bases) n-propyl) oxygen rapamycin, its chemical constitution is
2. a kind of pharmaceutical composition, including compound described in claim 1, and optional pharmaceutically acceptable auxiliary material.
3. compound described in claim 1 is used for preventing in preparation or treats the purposes in leukemic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410534717.4A CN104327097B (en) | 2014-10-11 | 2014-10-11 | Triazole derivatives of rapamycin and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410534717.4A CN104327097B (en) | 2014-10-11 | 2014-10-11 | Triazole derivatives of rapamycin and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104327097A CN104327097A (en) | 2015-02-04 |
| CN104327097B true CN104327097B (en) | 2017-02-08 |
Family
ID=52401914
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410534717.4A Active CN104327097B (en) | 2014-10-11 | 2014-10-11 | Triazole derivatives of rapamycin and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104327097B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501294B (en) * | 2017-05-17 | 2019-09-10 | 福建省微生物研究所 | Rapamycin guanidine derivative and purposes |
| CN108484637A (en) * | 2018-03-13 | 2018-09-04 | 福建省微生物研究所 | Target anticancer new drug X-76 salt-forming compounds and application thereof, preparation method |
| CN115068477B (en) * | 2022-06-09 | 2024-02-09 | 福建省微生物研究所 | Application of rapamycin derivatives in preparation of antitumor drugs |
| CN115160343B (en) * | 2022-06-09 | 2023-11-14 | 福建省微生物研究所 | Rapamycin derivative, and preparation method and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5527907A (en) * | 1993-11-19 | 1996-06-18 | Abbott Laboratories | Macrolide immunomodulators |
| US5385909A (en) * | 1993-11-22 | 1995-01-31 | American Home Products Corporation | Heterocyclic esters of rapamycin |
| AU4246197A (en) * | 1996-09-09 | 1998-03-26 | American Home Products Corporation | Rapamycin derivatives with unnatural stereochemistries |
| US20110098241A1 (en) * | 2008-04-14 | 2011-04-28 | Poniard Pharmaceuticals, Inc. | Rapamycin analogs as anti-cancer agents |
| EP2809675A4 (en) * | 2012-11-30 | 2015-08-12 | Hangzhou Zylox Pharma Co Ltd | Rafamycin analogs and methods for making same |
-
2014
- 2014-10-11 CN CN201410534717.4A patent/CN104327097B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| 含 1， 2， 3 －三氮唑哌啶衍生物的合成;郑晓瑞;《广州化工》;20120531;第40卷(第10期);第87页 * |
| 鬼臼毒素三氮唑衍生物的合成及其抗肿瘤活性;赵明等;《武警后勤学院学报（医学版）》;20130731;第22卷(第7期);第607页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104327097A (en) | 2015-02-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107213466B (en) | A kind of column aromatic hydrocarbons compound, preparation method, pharmaceutical composition and purposes | |
| RU2591823C2 (en) | Novel methods for targeting cancer stem cells | |
| US10765660B2 (en) | Agent containing flavonoid derivatives for treating cancer and inflammation | |
| CN104341434B (en) | The rapamycin triazole derivatives replaced and purposes | |
| CN106580987B (en) | The purposes of dihydro palmatine anti-ulcerative colitis | |
| CN104327097B (en) | Triazole derivatives of rapamycin and application | |
| RU2657750C1 (en) | Novel methods for targeting cancer stem cells | |
| CN102731517A (en) | Camptothecin derivative, and preparation method and application thereof to preparation of medicament for treating tumor | |
| CN103502219A (en) | Novel small-molecules as therapeutics | |
| WO2020177748A1 (en) | Quaternized modified taxane derivative, and pharmaceutical composition and use thereof | |
| CN101735276A (en) | Water-soluble phosphate monoester derivatives and application thereof | |
| CN104530081B (en) | The azacyclo-derivant of rapamycin and purposes | |
| CN105566305B (en) | The polymorph and its preparation method and application of 4- (substituted anilinic) quinazoline derivant xylenesulfonate | |
| RU2411244C2 (en) | Camptotecin derivatives and application thereof | |
| CN101402667B (en) | Glycosylation modified nitric oxide donor type oleaolic acid compounds, preparation and uses thereof | |
| CN101845051A (en) | Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof | |
| CN104603133A (en) | Combination therapy for the treatment of cancer and immunosuppression | |
| CN108017656A (en) | Camptothecin derivative and its application in antitumor drug is prepared | |
| CN105377838A (en) | New anti-malarial agents | |
| CN113214097B (en) | Compounds for the treatment of alzheimer's disease | |
| CN106188094B (en) | Isoxazole ring analog derivative and its preparation method and application | |
| CN102827124A (en) | Coumarins derivate and medicine composition thereof and application | |
| JP2012532150A (en) | 13a- (S) Deacidified Tyrophorinine Salt, Pharmaceutical Composition and Use | |
| CN101845052B (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
| CN101016329A (en) | Method of preparing cyclopamine from jervine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |