CN109400517A - 1- methyl-tryptophan class compound and its preparation method and application - Google Patents
1- methyl-tryptophan class compound and its preparation method and application Download PDFInfo
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- CN109400517A CN109400517A CN201710709533.0A CN201710709533A CN109400517A CN 109400517 A CN109400517 A CN 109400517A CN 201710709533 A CN201710709533 A CN 201710709533A CN 109400517 A CN109400517 A CN 109400517A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides a kind of 1- methyl-tryptophan class compound shown in formula I, preparation method, purposes and pharmaceutical composition.The deuterated 1- methyl-tryptophan compound, which has, inhibits indoles amine-(2,3)-dioxygenase, the effect of activating T cell.
Description
Technical field
The invention belongs to field of medicaments, and in particular, to a kind of 1- methyl-tryptophan class compound and preparation method thereof and
Purposes.
Background technique
T cell is the main component of lymphocyte, it has multiple biological function, wherein most important effect is immune
Effect attacks tumour cell to become in body, resists the important tool of disease infection.Tryptophan is to maintain T cell growth
One of with the important amino acid of proliferation.In the mammalian body, tryptophan can be in the work of indoleamine 2,3-dioxygenase (IDO) etc.
It is normally metabolized with the lower approach by based on kynurenin.However, many tumour cells have but over-expressed indoles amine
2,3- dioxygenases cause tryptophan to be consumed in large quantities rapidly, so that nutrient can not be provided for T cell, T cell are caused to stop
Growth and proliferation, or even apoptosis occurs and is removed.On the other hand, tryptophan follows the 3- hydroxyl that kynurenine pathway metabolism generates
The toxic products such as ortho-aminobenzoic acid, quinolinic acid, pyridine carboxylic acid inhibit the activation of T cell in turn again.These factors result in
Lack in human body enough T cells come to tumour cell specific antigen or tumor associated antigen identified and inhibited, from
And the continued growth, expansion and migration of tumour cell are resulted in, cause the immunologic escape of tumour.Therefore, suitable by developing
Drug inhibit the overexpression of indoleamine 2,3-dioxygenase, T cell can be activated, and then reach the work for inhibiting tumour
With.
Indoleamine 2,3-dioxygenase 1 (IDO1) was found in rabbit intestinal for the first time in 1967, people had been determined within 2006
The crystal structure of IDO1, biochemical function are clear in body.In addition, experiment shows that the mouse for being knocked IDO1 still can health
Ground life.Therefore, inhibit the safe coefficient of IDO1 high, the toxic side effect risk of IDO1 inhibitor on human body is also greatly diminished.
The exploitation of IDO inhibitor is divided into the small-molecule drug for directly acting on IDO1 and realizes that IDO inhibits simultaneously by a variety of collaboration approach
Activate the small-molecule drug two major classes of T cell.
Two compounds faster to IDO inhibitor clinical progress are respectively from Incyte company and NewLink
Company.Epacadostat under Incyte house flag has proceeded to clinical three phases at present, passes through the PD-1 antibody with Mo Shadong
Keytruda is used in combination, and early time data shows the total disease control rate (73%) that can significantly improve patients with terminal, to advanced stage
The response rate of melanoma is also increased to 57%, and when Keytruda is used alone, response rate only has 28% or so.In addition, number
Good according to the tolerance for also indicating that drug combination, 3 grades or more of adverse events incidence is lower.In the clinic of another second phase
In test, when the Keytruda and IDO inhibitor Indoximod of Newlink company is combined, 52% patient will appear tumour
It is obviously reduced or completely disappears, 73% conditions of patients is controlled.This combination mode is equally also demonstrated by resistance to well
By property and lower adverse reaction rate.
Available data shows that the exploitation of IDO inhibitor has boundless prospect, but there has been no in approval so far
The IDO inhibitor drug in city.Therefore there is the IDO inhibitor of more preferable pharmacodynamics performance and pharmacokinetics performance will have for exploitation
Powerful competitiveness.
Summary of the invention
The object of the present invention is to provide a kind of new compound with indoleamine 2,3-dioxygenase inhibiting effect and its
Purposes.It is an unexpected discovery of the invention that deuterated 1- methyl-tryptophan class compound provided by the present invention with it is corresponding non-deuterated
Compound is compared, and is had significantly superior different pharmacodynamics performance and pharmacokinetics performance, is specifically embodied in drug in animal
Intracorporal exposed amount has the raising of highly significant, therefore is more suitable for indoleamine 2,3-dioxygenase inhibitor, Jin Ergeng
It is applicable in the drug of preparation treatment indoleamine 2,3-dioxygenase inhibitor class related disease.
First aspect present invention provide a kind of 1- methyl-tryptophan class compound shown in formula I, its isomers, prodrug,
Crystal form, pharmaceutically acceptable salt, hydrate or solvate,
Wherein, RaFor hydrogen or carboxylic acid protecting group；
Rb、RcFor hydrogen or amido protecting group；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11It is to be each independently selected from hydrogen or deuterium, and at least one is
Deuterium.
In another preferred example, the compound is selected from the group:
Ra、Rb、RcFor hydrogen；
R1、R2、R3、R4、R5、R6、R7It is separately to be selected from hydrogen or deuterium, and at least one is deuterium.
In another preferred example, the compound is selected from the group:
Second aspect of the present invention provides a kind of preparation method of pharmaceutical composition, will be described in first aspect present invention
Compound, its isomers, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate and pharmaceutically acceptable
Carrier is mixed, to form pharmaceutical composition.
Third aspect present invention provides a kind of pharmaceutical composition, contains:
(1) compound described in first aspect present invention, its isomers, prodrug, crystal form, pharmaceutically acceptable salt, water
Close object or solvate；
(2) pharmaceutically acceptable carrier.
Fourth aspect present invention provides compound described in first aspect present invention, isomers, prodrug, crystal form, medicine
The purposes of acceptable salt, hydrate or solvate on, they are used as indoleamine 2,3-dioxygenase inhibitor, or use
Indoleamine 2,3-dioxygenase, which is treated and prevented, in preparation inhibits the drug for there are related disorders.
The purposes includes using with another or a variety of anti-cancer agent in conjunction, and the anticancer agent is selected from alkylating agent, platinum
Complex compound, metabolic antagonist, alkaloid, antibody drug, hormone anticancer agent, proteasome inhibitor, CDK kinase inhibitor,
VEGFR or EGFR inhibitor, m-TOR inhibitor, PI3K kinase inhibitor, B-Raf inhibitor, PARP inhibitor, c-Met kinases
Inhibitor, ALK kinase inhibitor, AKT inhibitor, ABL inhibitor, FLT3 inhibitor, PD-1 inhibitor, PD-L1 inhibitor etc..
The disease is selected from immunity disease, especially cancer, wherein the cancer include breast cancer, it is oophoroma, preceding
Column gland cancer, black cancer, the cancer of the brain, nasopharyngeal carcinoma, the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer, lung cancer, kidney, skin
Cancer, spongioblastoma, neuroblastoma, sarcoma, embryonal-cell lipoma, osteochondroma, osteocarcinoma, osteosarcoma, seminoma, testis
Ball tumour, hysteroma, H/N tumors, Huppert's disease, malignant lymphoma, polycythemia vera, leukaemia, thyroid gland
Tumour, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma or pediatric tumors.
In another preferred example, the pharmaceutical composition is injection, wafer, tablet, pill, powder or granule.
Fifth aspect present invention provides a kind for the treatment of method, comprising steps of object in need for the treatment of is given, the application present invention
Compound described in first aspect, its isomers, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, solvate or sheet
Pharmaceutical composition described in invention fourth aspect.
In another preferred example, the object is with the people for having related disorders with immunosupress.
Sixth aspect present invention provides a kind of preparation method of compound of formula I described in first aspect present invention, chemical combination
Methylation occurs under alkaline condition by such as Formula II compound represented by object I or methylenation is made,
Wherein, Ra、Rb、Rc、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11As defined in compound of formula I.
Wherein, compound II can according to document (Chem.Eur.J.2009,15,10397-10404；
J.Am.Chem.Soc.2000,122,1008-1014；J.Label Compd.Radiopharm 2010,53,406-489；
Org.Lett.2007,9,1513-1516；J.Am.Chem.Soc.1984,106,4286-4287；
Angew.Chem.Int.Ed.2015,54,9381-9385；Biochimica et Biophysica Acta, 1976,446,
479-485；Tetrahedron Lett.2002,43,2389-2392) it is made.
In yet other embodiments, comprise the following steps:
- 78 DEG C, alkali metal is added into the liquid ammonia solution of ferric nitrate, the organic solution of compound II is then added, continues
After stirring 30min at such a temperature, methylating reagent is added, 15min~6h is stirred in reaction at -78 DEG C~30 DEG C, and TLC is shown
Fully reacting, quenching, adjusting pH is 4~6, and filtering, mashing obtain compound I.
The preferred lithium of alkali metal described in the program, sodium, potassium；
The preferred ether of organic solvent described in the program, tetrahydrofuran, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE)；
The preferred iodomethane of methylating reagent described in the program, bromomethane, deuterated iodomethane, dimethyl suflfate.
The present invention also provides the preparation methods of another compound of formula I, which is characterized in that compound I passes through such as Formulas I A
Hydrogen/deuterium exchange reaction occurs under the action of deuterated reagent and is made for compound represented,
Wherein, Ra、Rb、Rc、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11As defined in compound of formula I.
In yet other embodiments, comprise the following steps:
Dissolved compound IA is in D2In O, deuterated reagent is added at 20 DEG C~110 DEG C in consersion unit, continues in the temperature
The lower stirring 30min of degree~for 24 hours, filtration drying obtains compound I.
The preferred deuterated hydrochloric acid of reaction reagent described in the program, sodium, acetic anhydride, thioacetic acid；
The preferably conventional organic reaction flask of consersion unit described in the program, oil bath pan, 400W high-pressure sodium lamp, vitreosil glass
Glass equipment.
In presently preferred embodiment, comprise the following steps:
1) compound IAa is in D2It is handled to obtain compound In with metallic sodium and acetic anhydride in O；
2) compound In obtains compound Io with hydrochloric acid water solution；
3) compound Io splits to obtain compound Ia and Ib with chirality HPLC；
If commercially available, it is possible to use Formulas I institute is made according to above-mentioned route in the deuterated compound as shown in Formula II of commercialization
Show compound；Such as it can be then made according to the step of offer in the above method by intermediate shown in purchase previously described formula II
Formulas I compound represented.
Term used in the present invention has following meaning in addition to having opposite statement:
Carboxylic acid protecting group of the invention is the group appropriate for carboxylic acid protection known in the art, referring to document
(" Protective Groups in Organic Synthesis ", 5ThEd.T.W.Greene&P.G.M.Wuts the carboxylic in)
Acid protecting group.As an example, preferably, the carboxylic acid protecting group can be C1-10Alkyl, such as: methyl, ethyl, tertiary fourth
Base etc.；
Amido protecting group of the invention is the group appropriate for amido protection known in the art, referring to document
(" Protective Groups in Organic Synthesis ", 5ThEd.T.W.Greene&P.G.M.Wuts the amine in)
Base blocking group.As an example, preferably, the amido protecting group can be amide blocking group, carbamate protection
Group etc..Such as: formoxyl, acetyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group etc.；
As used herein, " deuterated " refers to one or more hydrogen in compound or group replaced deuterium.It is deuterated to can be
One replaces, two replace, polysubstituted or full substitution.
In another preferred example, deuterium is greater than natural deuterium isotopic content in the deuterium isotopic content of deuterium the position of substitution
(0.015%), even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 97%, more preferably
Greater than 99%, even more preferably greater than 99.5%.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use
Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid
The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic
Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
The organic acids such as picric acid, methanesulfonic acid, toluenesulfonic acid, benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.It is another kind of
Preferred salt is the salt that the compounds of this invention and alkali are formed.The alkali for suitably forming salt includes but is not limited to: sodium hydroxide, hydrogen-oxygen
Change lithium, potassium hydroxide, triethylamine, diisopropyl ethyl amine, S- phenyl ethylamine, R- phenyl ethylamine, L- benzene glycine amide etc..
Abbreviations table:
Following table is the structural formula of compound involved in embodiment
Specific embodiment
The present invention is explained in detail below with reference to specific example, so that those of ordinary skill in the art are more fully understood
The present invention, specific example are only used to illustrate the technical scheme of the present invention, and do not limit the present invention in any way.
Embodiment 1: prepare compound In
At 20 DEG C, dissolved compound IAa (1.0g, 4.6mmol) is in D2In O (10mL), metallic sodium (0.6g) is sequentially added
With acetic anhydride (3mL), reaction continues stirring 18 hours, solid is collected by filtration, compound In is dried in vacuo to obtain after washing
(0.67g)。
MS (ESI) m/z:262 (M+H+)
1H-NMR (400MHz, DMSO) δ 8.15 (s, 1H), 7.54 (d, J=7.9Hz, 1H), 7.38 (d, J=8.2Hz,
1H), 7.10 (dd, J=24.2,21.4Hz, 3H), 3.73 (s, 3H), 3.13 (d, J=14.6Hz, 1H), 2.98 (d, J=
14.6Hz, 1H), 1.81 (s, 2H)
Embodiment 2: prepare compound Ia and Ib
For dissolved compound In (0.54g, 2mmol) in 2N hydrochloric acid (20mL), reaction stirring 6 under 100 degree is small at 20 DEG C
When, after TLC shows fully reacting, it is concentrated to give solid, is beaten to obtain racemic compound Io (350mg) with tetrahydrofuran.Pass through hand
Property HPLC preparative separation can respectively obtain compound Ia (96mg) and compound Ib (102mg).
MS (ESI) m/z:220 (M+H+)
1H-NMR (400MHz, MeOD) δ 7.61 (d, J=7.9Hz, 1H), 7.38 (d, J=8.3Hz, 1H), 7.25-7.17
(m, 1H), 7.15-7.06 (m, 2H), 3.79 (s, 3H), 3.48 (d, J=15.3Hz, 1H), 3.33 (d, J=13.3Hz, 1H)
Embodiment 3: prepare compound Ic
At -78 DEG C, metallic sodium (120mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Ether (5mL) solution of object IIc (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, and iodomethane is added
6h is stirred in (180mg), reaction under -78 °, and TLC shows fully reacting, quenched with water, is 5 or so with vinegar acid for adjusting pH, is stood
Solid is obtained, after filtering, mashing obtains compound Ic (181mg) in tetrahydrofuran.
MS (ESI) m/z:220 (M+H+)。
Embodiment 4: prepare compound Id
At -78 DEG C, lithium metal (100mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Tetrahydrofuran (5mL) solution of object IId (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, and sulphur is added
4h is stirred in dimethyl phthalate (260mg), reaction at -60 DEG C, and TLC shows fully reacting, quenched with water, is 5 with vinegar acid for adjusting pH
Left and right, stands to obtain solid, and after filtering, mashing obtains compound Id (172mg) in tetrahydrofuran.
MS (ESI) m/z:221 (M+H+)。
Embodiment 5: prepare compound Ie
Dissolved compound IAa (100mg, 0.49mmol) is in equipped with D2In the vitreosil reactor of O (50mL), at room temperature
After 400W high voltage mercury lamp radiation 30min, reaction solution is lyophilized on freeze dryer obtains compound Ie (100mg).
MS (ESI) m/z:220 (M+H+)。
Embodiment 6: prepare compound If
At -78 DEG C, metallic potassium (150mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
2- methyltetrahydrofuran (5mL) solution of object IIf (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature,
It is added bromomethane (150mg), 3h is stirred in reaction at -50 DEG C, and TLC shows fully reacting, quenched with water, be with vinegar acid for adjusting pH
5 or so, solid is stood to obtain, after filtering, mashing obtains compound If (163mg) in tetrahydrofuran.
MS (ESI) m/z:220 (M+H+)
Embodiment 7: prepare compound Ig
At -78 DEG C, metallic sodium (150mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Methyl tertiary butyl ether(MTBE) (5mL) solution of object IIg (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, add
Enter iodomethane (180mg), it is 5 with vinegar acid for adjusting pH that 2h is stirred in reaction at -40 DEG C, and TLC shows fully reacting, quenched with water
Left and right, stands to obtain solid, and after filtering, mashing obtains Compound Ig per (156mg) in tetrahydrofuran.
MS (ESI) m/z:220 (M+H+)
Embodiment 8: prepare compound Ih
At -78 DEG C, metallic sodium (150mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Ether (5mL) solution of object IIh (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, and iodomethane is added
2h is stirred in (180mg), reaction at -30 DEG C, and TLC shows fully reacting, quenched with water, is 5 or so with vinegar acid for adjusting pH, is stood
Solid is obtained, after filtering, mashing obtains compound Ih (177mg) in tetrahydrofuran.
MS (ESI) m/z:220 (M+H+)。
Embodiment 9: prepare compound Ii
At -78 DEG C, metallic sodium (150mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Ether (5mL) solution of object IIi (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, and iodomethane is added
1h is stirred in (180mg), reaction at -10 DEG C, and TLC shows fully reacting, quenched with water, is 5 or so with vinegar acid for adjusting pH, is stood
Solid is obtained, after filtering, mashing obtains compound Ii (177mg) in tetrahydrofuran.
MS (ESI) m/z:220 (M+H+)。
Embodiment 10: prepare compound Ij
Dissolved compound IAa (300mg, 1.38mmol) is in D2In O (2mL) and deuterated hydrochloric acid (0.4mL), sulfydryl second is added
Sour (0.1mL), reaction stir 8h at 110 DEG C.After reaction solution is extracted with ethyl acetate, water phase freeze-dryingization on freeze dryer
It closes object Ij (290mg).
MS (ESI) m/z:224 (M+H+)
Embodiment 11: prepare compound Ik
At -78 DEG C, metallic sodium (150mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Ether (5mL) solution of object IIk (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, and iodomethane is added
15min is stirred in (180mg), reaction at 30 DEG C, and TLC shows fully reacting, quenched with water, is 5 or so with vinegar acid for adjusting pH, quiet
Solid is set to obtain, after filtering, mashing obtains compound Ik (149mg) in tetrahydrofuran.
MS (ESI) m/z:222 (M+H+)。
Embodiment 12: prepare compound Im
At -78 DEG C, metallic sodium (150mg) is added into liquefied ammonia (10mL) solution of ferric nitrate (5mg), chemical combination is then added
Ether (5mL) solution of object IIm (200mg, 0.98mmol), reaction continue after stirring 30min at such a temperature, and deuterated iodine is added
3h is stirred in methane (180mg), reaction at -78 DEG C, and TLC shows fully reacting, quenched with water, is 5 or so with vinegar acid for adjusting pH,
Solid is stood to obtain, after filtering, mashing obtains compound Im (178mg) in tetrahydrofuran.
MS (ESI) m/z:222 (M+H+)。
Embodiment 13: the Pharmacokinetic Evaluation of rat
From Shanghai, western Poole-Bi Kai experimental animal Co., Ltd buys male SPF grades of medical fitness, healthy SD without exception
Rat.Compound IAa, Ia, Ib, Id, Im pass through intravenous injection administration (dosage 12.5mg/kg).It takes a blood sample through jugular puncture, often
A sample acquires about 0.2mL, and heparin sodium is anticoagulant, and blood sampling time point is as follows:
Before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h after administration, for 24 hours and 48h.
Blood specimen collection is placed on ice, and centrifugal separation plasma (centrifugal condition: 8000 revs/min, 6 minutes, 2-8
℃).- 80 DEG C are deposited in front of the plasma analysis of collection.
Blood sample is analyzed by experiment mechanism analysis department using LC-MS/MS.
According to the plasma drug concentration data of drug, the non-compartment model of pharmacokinetics software for calculation WinNonlin5.2 point is used
Not Ji Suan test sample pharmacokinetic parameter AUC0-t、AUC0-∞、MRT0-∞、CL、T1/2With parameters and its average value and mark such as Vd
It is quasi- poor.
The pharmacokinetic parameter of deuterated compound and non-deuterated compound is as shown above.According to experimental result it is found that
Deuterated compound Ia, Id, Im of the invention, compared with corresponding non-deuterated compound IAa, the exposed amount of drug in animal body
(AUC) it is significantly improved.Wherein exposed amount (AUC) improves 70% or more to compound Ia in animal body.
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are general for this field
Logical technical staff is obvious and is included within the scope of the invention.
Claims (13)
1. a kind of 1- methyl-tryptophan class compound shown in formula I, its isomers, prodrug, crystal form, pharmaceutically acceptable
Salt, hydrate or solvate,
Wherein, RaFor hydrogen or carboxylic acid protecting group；
Rb、RcFor hydrogen or amido protecting group；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
2. 1- methyl-tryptophan class compound as described in claim 1, its isomers, prodrug, crystal form, pharmaceutically acceptable
Salt, hydrate or solvate, which is characterized in that
Wherein, RaFor hydrogen or carboxylic acid protecting group；
Rb、RcFor hydrogen or amido protecting group；
R1、R2、R3、R4、R5、R6、R7It is separately to be selected from hydrogen or deuterium, and at least one is deuterium.
3. 1- methyl-tryptophan class compound as described in claim 1, its isomers, prodrug, crystal form, pharmaceutically acceptable
Salt, hydrate or solvate, which is characterized in that
Wherein, Ra、Rb、RcFor hydrogen；
R1、R2、R3、R4、R5、R6、R7It is separately to be selected from hydrogen or deuterium, and at least one is deuterium.
4. 1- methyl-tryptophan class compound as claimed in claim 1 or 3, prodrug, crystal form, can pharmaceutically connect its isomers
Salt, hydrate or the solvate received, which is characterized in that the absolute configuration of the compound is R configuration or S configuration.
5. 1- methyl-tryptophan class compound as claimed in claim 1 or 3, prodrug, crystal form, can pharmaceutically connect its isomers
Salt, hydrate or the solvate received, which is characterized in that the absolute configuration of the compound is R configuration.
6. 1- methyl-tryptophan class compound as described in claim 1, its isomers, prodrug, crystal form, pharmaceutically acceptable
Salt, hydrate or solvate, which is characterized in that the compound is selected from the group:
7. a kind of preparation method of pharmaceutical composition, which is characterized in that by compound of any of claims 1-6,
Its isomers, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate and pharmaceutically acceptable carrier carry out
Mixing, to form pharmaceutical composition.
8. a kind of pharmaceutical composition, which is characterized in that contain:
(1) compound described in any one of claims 1-6, its isomers, prodrug, crystal form, pharmaceutically acceptable salt, hydration
Object or solvate；
(2) pharmaceutically acceptable carrier.
9. a kind of method by inhibiting indoles amine-(2,3)-dioxygenase to realize treating cancer, it includes to needs, this is treated
Patient apply any one of claim the 1-6 compound, its isomers, prodrug, crystal form, pharmaceutically acceptable salt, water
Close object or solvate or pharmaceutical composition according to any one of claims 8.
10. compound according to claim 1 to 6, its isomers, prodrug, crystal form, pharmaceutically acceptable
The drug of salt, hydrate or solvate or pharmaceutical composition according to any one of claims 8 in preparation treatment immunity disease is used
On the way, the medicinal usage especially in preparation treating cancer, wherein the cancer include breast cancer, oophoroma, prostate cancer,
Black cancer, the cancer of the brain, nasopharyngeal carcinoma, the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer, lung cancer, kidney, cutaneum carcinoma, plastic
Cell plastid tumor, neuroblastoma, sarcoma, embryonal-cell lipoma, osteochondroma, osteocarcinoma, osteosarcoma, seminoma, orchioncus,
It is hysteroma, H/N tumors, Huppert's disease, malignant lymphoma, polycythemia vera, leukaemia, thyroid tumors, defeated
Urinary catheter tumour, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma or pediatric tumors.
11. purposes according to claim 10, wherein compound of any of claims 1-6, its isomers,
Prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate and another or a variety of anti-cancer agent in conjunction use, institute
The anticancer agent stated is selected from alkylating agent, platinum complex, metabolic antagonist, alkaloid, antibody drug, hormone anticancer agent, proteasome
Inhibitor, CDK kinase inhibitor, VEGFR or EGFR inhibitor, m-TOR inhibitor, PI3K kinase inhibitor, B-Raf inhibit
Agent, PARP inhibitor, c-Met kinase inhibitor, ALK kinase inhibitor, AKT inhibitor, ABL inhibitor, FLT3 inhibitor,
PD-1 inhibitor, PD-L1 inhibitor.
12. a kind of preparation method of 1- methyl-tryptophan class compound shown in formula I, which is characterized in that pass through such as Formula II institute
The tryptophan compound shown carries out methyl or deuterium methylation reaction is made,
Wherein, Ra、Rb、Rc、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11Definition it is as described in claim 1.
13. a kind of preparation method of 1- methyl-tryptophan class compound shown in formula I, which is characterized in that pass through such as Formulas I A institute
The compound shown occurs hydrogen/deuterium exchange system and obtains,
Wherein, Ra、Rb、Rc、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11Definition it is as described in claim 1.
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| CN201710709533.0A CN109400517A (en) | 2017-08-17 | 2017-08-17 | 1- methyl-tryptophan class compound and its preparation method and application |
| PCT/CN2018/101082 WO2019034147A1 (en) | 2017-08-17 | 2018-08-17 | 1-methyl-tryptophan compound and preparation method and use thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105367477A (en) * | 2014-08-11 | 2016-03-02 | 中国科学技术大学 | 1-methyl tryptophan synthesis method |
| WO2017019175A1 (en) * | 2015-07-24 | 2017-02-02 | Newlink Genetics Corporation | Salts and prodrugs of 1-methyl-d-tryptophan |
-
2017
- 2017-08-17 CN CN201710709533.0A patent/CN109400517A/en active Pending
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2018
- 2018-08-17 WO PCT/CN2018/101082 patent/WO2019034147A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105367477A (en) * | 2014-08-11 | 2016-03-02 | 中国科学技术大学 | 1-methyl tryptophan synthesis method |
| WO2017019175A1 (en) * | 2015-07-24 | 2017-02-02 | Newlink Genetics Corporation | Salts and prodrugs of 1-methyl-d-tryptophan |
Non-Patent Citations (3)
| Title |
|---|
| BHANDARI, DHANANJAY M. ET AL.,: ""Tryptophan Lyase (NosL): Mechanistic Insights from Substrate Analogues and Mutagenesis"", 《BIOCHEMISTRY》 * |
| STN REGISTRY数据库: ""105201-57-8/rn"", 《STN REGISTRY数据库》 * |
| 盛怀禹等: "《同位素有机化学》", 31 October 1994, 浙江教育出版社 * |
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