CN107286057A - Resorcin compound and medical usage - Google Patents
Resorcin compound and medical usage Download PDFInfo
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- CN107286057A CN107286057A CN201610190950.4A CN201610190950A CN107286057A CN 107286057 A CN107286057 A CN 107286057A CN 201610190950 A CN201610190950 A CN 201610190950A CN 107286057 A CN107286057 A CN 107286057A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The present invention relates to compound shown in Formulas I, its pharmaceutically acceptable salt, solvate, hydrate, the pharmaceutical composition containing the compound, the preparation for treating the related malignant tumor medicines of PD 1.
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is related to novel cancer immunotherapy medicaments and its is preparing PD-1 associated malignancies
Purposes in medicine.
Background technology
Malignant tumour is exactly the cancer described in people, and it is the general designation of more than 100 kinds of relevant disease.When body inner cell is undergone mutation
Afterwards, uncontrolled multiple fission, will form cancer.Cancer cell can invade, destroy neighbouring tissue and organ, and can
To be passed from tumour, into blood or lymphatic system, here it is how new from primary position to other orga- nogenesis cancer is
Tumour, this process is cancer metastasis, and most of malignant tumour is organ or cell type according to their startings to name.Dislike
Property tumour be endanger human life and health serious disease, at present, it has also become the number one killer of human health.
Tumor therapeuticing method includes：Operation, radiotherapy, chemotherapy and immunization therapy.The traditional treatment method of first three is different from,
Immunotherapy of tumors (Tumor immunotherapy) is the immune system by transferring body, strengthens anti-tumor immunity, from
And suppress and killing tumor cell, the potentiality with treatment polytype tumour, it substantive can improve patients overall survival's phase, be to work as
The development trend of pre-neoplastic treatment.
Human body specific immunity can be divided into cellular immunity and humoral immunity, and T cell plays an important role in cellular immunity.T cell
Activation needs dual signal：First signal --- Antigenic Peptide-MHC compounds are combined with T cell surface receptor；Secondary signal --- it is anti-
The former combination in corresponding acceptor on costimulatory molecules on delivery cell and T cell surface.Secondary signal can be divided into by function：Excitement letter
Number and suppress signal.The CTLA-4 in T cell, PD-1 clearly it have been present in, BTLA is the co-suppression in costimulatory molecules
Signal, plays important negative immune adjustment effect, i.e., when tumor cell invasion body, the respective ligand that tumour cell is provided
After in combination, coinhibitory signals activation suppresses the activity of T cell, plays a part of similar immune brake.Therefore, suppress with
Upper path, can release T cell suppression, so as to activate T cell immunologic function.
Programmed death acceptor 1 (programmed death 1, PD-1, CD279) is CD28 superfamily members, PD-1 expression
In the T cell of activation, B cell and myeloid cell are by PDCD1 gene codes, the transmembrane protein of 288 amino acid compositions.PD-1
Structure mainly includes extracellular region-immune globulin variable region (IgV) spline structure domain, transmembrane region and intracellular region.Intracellular goes to include
C-terminal and N-terminal amino acid residue, contain 2 independent phosphorylation sites, respectively immunity receptor Tyrosine Inhibitory Motifs
(immunoreceptor tyrosine based inhibitorymotif, ITIM) and immunity receptor tyrosine change motif
(immunore-ceptor tyrosine based switch motif, ITSM).The extracellular IgV spline structures of PD-1 and its part
With reference to ITSM changes, and raises SHP2 signals, activates downstream passages, suppresses T cell activity.PD-1 native ligand have two-
PD-L1 and PD-L2.PD-L1 (Programmed death ligand 1, B7-H1)：It is 40kDa transmembrane protein, by CD274
Gene code, is expressed in macrophage subgroup, but in interferon and the tumor tissues of other inflammatory factor stimulation responses and other groups
It all may rapidly be raised in knitting, be PD-1 major ligand.PD-L2 (Programmed death ligand 1, B7-DC)
It is less with respect to PD-L1 expression quantity.
Tumour immunotherapy is the focus of whole pharmaceuticals industry maximum at present.It is anti-using monoclonal except cell therapies such as CAR-T
Body closes PD-1/PD-L1 paths, because it is to the substantial life cycle advantage of malignant tumour, 10% advanced melanoma cure rate
Deng the same Worth Expecting of performance.In July, 2014, Shi Guibao Opdivo takes the lead in granted for treating advanced melanoma in Japan,
PD-1 inhibitor as the first approval listing in the whole world.This is that PD-1 inhibitor shows that life cycle is treated in III phase clinical trials first
Effect, it compares 1 year survival rate with chemotherapeutic Dacarbazine：73% pair 42%, 40% pair 14% of response rate, and adverse reaction is
Reduction.Subsequent Opdivo in December is listed in the U.S..And the Keytruda (pembrolizumab) of Merck is then in 1
Year September with a unconventional large-scale 1 phase clinical trial for thering are 1000 patients to participate in, as a result with first PD-1 inhibitor identity into
Work(logs in American market, and it, which is approved for treatment, surgery excision or to have occurred shifting and the evening unresponsive to other drugs
Phase melanoma patients.In October, 2014, Opdivo is further approved for the evening of special mutation with Yervoy drug combinations
Phase melanoma, has reached 60% response rate, and the more mono- medicines of PFS extend 4.2 months.Compound combination, which is expected to substitution chemotherapy, turns into this
The new standard treatment of individual idicatio.The appearance of PD-1 inhibitor not only thoroughly changes the treatment of advanced melanoma, and it is non-small
Also high response is shown in the treatment of cell lung cancer.In March, 2015, U.S. FDA is used as two wires using 4 working day approval opdivo
Drug therapy squamous non-small cell lung cancer is listed.In a key name in Checkmate-017 III clinical trial phases, PD-1 suppresses
Agent shows than standard treatment docetaxel more preferably life cycle in an experiment first, patient's overall survival of 18 months up to 28%,
For twice of current standard therapy, and total response rate (ORR) 20%, also apparently higher than the 9% of standard treatment.In October, 2015,
FDA have approved Keytruda as the Second line Drug of the positive non-small cell lung cancers (squamous carcinoma and non-squamous carcinoma) of late period PD-L1 again.At one
In entitled Keynote 1 I phase clinical researches, it is to PD-L1 positive patients response rates up to 45%, and total response rate reaches 16%.
As the series antineoplastic medicament with breakthrough mechanism, the potentiality of PD-1 inhibitor also have very big space, its response
Range, depth, persistence are very rare.In addition to melanoma, non-small cell lung cancer, kidney, in other solid tumors such as stomach
In the experiment such as cancer, carcinoma of urinary bladder, head and neck cancer, there is certain curative effect.At present, PD-1 inhibitor only has monoclonal antibody, small molecule
Inhibitor is rarely reported, and there is provided can treat PD-1 related neoplasms for small molecule PD-1/PD-L1 pathway inhibitors by the present invention
The preparation basis of medicine.
The content of the invention
Invention is related to compound shown in Formulas I, its raceme or optical isomer, its pharmaceutically acceptable salt, solvate, water
Compound,
Wherein,
X is O or S atom, substituted dimethyl carbamate meta or para position；
R1, R2 are each independently hydrogen or alkyl or isopropyl, the tert-butyl group or R1, R2 and N formation miscellaneous alkane of 4-8 rings N；
N is 2-5；
R3 be optionally present on phenyl ring 1,2 or 3 identical or different substituents, R is each independently selected from following group：
Hydrogen, alkyl, hydroxyl, nitro, amino, haloalkyl, alkoxy, amino, by alkyl is monosubstituted or disubstituted amino,
Carboxyl, amide groups, phenyl.
One of the present invention preferred embodiment in, compound of formula I, raceme or optical isomer, its is pharmaceutically acceptable
Salt, solvate, hydrate, its be selected from following compound：
M- (N- methyl amino ethoxies) benzene-N, N- dimethyl carbamate (compound 1)
M- (N, N- dimethylamino propoxy) benzene-N, N- dimethyl carbamate (compound 2)
M- (N, N- diethyl amino base oxethyl) benzene-N, N- dimethyl carbamate (compound 3)
M- (N, N- bis- (isopropyl) amino ethoxy) benzene-N, N- dimethyl carbamate (compound 4)
M- (N, N- bis- (normal-butyl) amino ethoxy) benzene-N, N- dimethyl carbamate (compound 5)
The 3- tert-butyl groups -5- (pyrrolidinyl -1- ethyoxyls) benzene-N, N- dimethyl carbamate (compound 6)
2- diethylamino methyl -5- (N, N- diethyl amino base oxethyl) benzene-N, N- dimethyl carbamate (compound 7)
The 3- tert-butyl groups -4- (N, N- dimethylamino propoxyl group) benzene-N, N- dimethyl carbamate (compound 8)
2- nitros -5- (N, N- Dimethylaminoethoxy) benzene-N, N- dimethyl carbamate (compound 9)
M- (N, N- dimethylaminoethyl sulfenyl) benzene-N, N- dimethyl carbamate (compound 10)
M- (N, N- lignocaine propyl group sulfenyl) benzene-N, N- dimethyl carbamate (compound 11)
M- (N, N- dipropylamino ethylsulfanyl) benzene-N, N- dimethyl carbamate (compound 12)
M- (3- piperidines propyl group -1- sulfenyls) benzene-N, N- dimethyl carbamate (compound 13)
Pharmaceutical composition, wherein at least includes compound, its raceme or the optical isomerism described in a kind of any one of claim 1
Body, its pharmaceutically acceptable salt, solvate, hydrate, and one or more pharmaceutically acceptable carriers or excipient.
Compound shown in Formulas I of the present invention can be prepared using conventional synthetic route as needed.
The present invention one preferred embodiment in, compound of formula I, its raceme or optical isomer, its pharmacy can
Salt, solvate, the hydrate of receiving can be prepared exemplarily by following reaction scheme：
For example, using the resorcinol of the substitutions of R shown in formula i as initiation material, in the pyridine solution for adding dimethylaminoethyl chloride,
Production iii compounds, formula iii compounds in the toluene solution containing sodium hydride with formula iv compound condensation productions I
Compound, formula i compounds is optionally by R is monosubstituted or polysubstituted resorcinol.
Compound of formula I of the present invention, raceme or optical isomer, its pharmaceutically acceptable salt, solvate, hydration
Thing and pharmaceutical composition are preparing the purposes in being used to treat and/or prevent the malignant tumor medicine related to PD-1.It is wherein described
Malignant tumour include but is not limited to：Melanoma, non-small cell lung cancer, kidney, stomach cancer, carcinoma of urinary bladder, head and neck cancer, pancreas
Cancer, celiothelioma, triple negative breast cancer etc..
The feature that any son aspect of either side or the either side of the present invention has is equally applicable to other either sides or should
Any son aspect of other either sides.In the present invention, for example, when referring to " first aspect present invention ", being somebody's turn to do " any son
Aspect " refers to any son aspect of first aspect present invention, when other side is referred in a similar manner, also with identical meanings.
It is further described to various aspects of the present invention with feature below.
All documents recited in the present invention, their full content is incorporated herein by reference, and if these document institute tables
The implication that reaches with it is of the invention inconsistent when, be defined by the statement of the present invention.In addition, various terms and the phrase tool that the present invention is used
General sense known to capable field technique personnel, nonetheless, the present invention remain desirable to make more these terms and phrase at this
Detailed description and interpretation, the implication that the term and phrase referred to is stated if any inconsistent with common art-recognized meanings, using the present invention as
It is accurate.
As described herein, term " pharmaceutically acceptable " for example describe " pharmaceutically acceptable salt " when, represent the salt its
It is not subjected in subject physiologic still, but also the synthetic for pharmaceutically having use value can be referred to.
When compound name used herein and inconsistent chemical structural formula, it is defined by chemical structural formula.
As described herein, term " effective dose " refer to can to realize treatment in subject and/or prevent disease of the present invention or
The dosage of illness.
As described herein, term " pharmaceutical composition ", it can also refer to " composition ", and it can be used for special in subject
It is not that treatment is realized in mammal and/or prevents disease of the present invention or illness.
As described herein, term " subject " can refer to patient or other receive formula I or its medicine group
Compound to treat and/or prevent the animal of disease of the present invention or illness, particularly mammal, for example people, dog, larynx, ox,
Horse etc..
As described herein, as do not specialized, " % " refers to the percentage of w/w, particularly in description solid matter
In the case of.Certainly, when describing liquid substance, the percentage that " % " can refer to weight/volume is (molten for solid
In the situation of liquid), or volume/volume percentage (situation that liquid is dissolved in for liquid) can be referred to.
In the present invention, described malignant tumour includes but is not limited to：Melanoma, non-small cell lung cancer, kidney, stomach cancer, wing
Guang cancer, head and neck cancer, cancer of pancreas, celiothelioma, triple negative breast cancer etc..In one embodiment of the invention, it is related to prevention
And/or treatment includes melanoma, non-small cell lung cancer, kidney, carcinoma of urinary bladder, head and neck cancer, cancer of pancreas, celiothelioma, three feminine genders
The medicine of breast cancer etc., it is included prevention and/or at least one compound of formula I or its pharmaceutical salts of therapeutically effective amount or its hydration
Thing gives needs and prevents and/or treat to include melanoma, non-small cell lung cancer, kidney, stomach cancer, carcinoma of urinary bladder, head and neck cancer, pancreas
The patient of the relevant disease such as gland cancer, celiothelioma, triple negative breast cancer.
According to the present invention, the Pharmaceutical composition of the compounds of this invention can be applied with following any-mode：Orally, spraying suction,
Rectal application, nasal cavity applied medicine, cheek medication, vagina medicinal, local application, non-bowel medication as subcutaneous, vein, it is intramuscular,
In intraperitoneal, intrathecal, intra-ventricle, breastbone and intracranial injection or input or by a kind of explant reservoir medication.Wherein preferred mouth
Clothes, intraperitoneal or intravenous administration mode.In addition, to make the compounds of this invention effectively treat the neural decorum disorder disease of nerve center
Disease, preferable intraventricular route medication is to overcome the blood-brain barrier transmitance that compound may be low.
When oral medication, the compounds of this invention can be made into any oral acceptable dosage form, including but not limited to tablet,
Capsule, the aqueous solution or water slurry.Wherein, the carrier that tablet is typically used includes lactose and cornstarch, can also add in addition
Lubricant such as hard magnesium.The diluent that capsule preparations are typically used includes lactose and dried corn starch.Aqueous suspension preparation is then
Typically active component is used in mixed way with suitable emulsifying agent and suspending agent.If desired, may be used also in above oral dosage form
Add some sweeteners, aromatic or colouring agent.
When rectal application, the compounds of this invention typically can be made into the form of suppository, and it is by by medicine and a kind of suitable non-thorn
Swash the mixing of property excipient and be made.Solid state is presented in the excipient at room temperature, and fusing disengages medicine under rectal temperature.
Such excipient includes cocoa butter, beeswax and polyethylene glycol.
When local application, particularly treat Local out dressing easy to reach and suffer from face or organ, such as eyes, skin or lower intestinal tract god
During through property disease, the compounds of this invention can suffer from face or different topical preparations forms are made in organ according to different, specifically
It is bright as follows：
When eye local application, the compounds of this invention can be configured to the dosage form of a kind of micronized suspension or solution, be made
It is the Sterile Saline of isotonic certain pH with carrier, wherein also not adding preservative agent such as zephiran chloride alkoxide can be added.In addition it is right
In ophthalmically acceptable, compound can be also made to ointment such as petroleum jelly cream.
When topical application, the compounds of this invention can be made into appropriate ointment, lotion or cream formulation form, wherein activity
Composition is suspended or dissolved in one or more carriers.Here ointment is that workable carrier includes but is not limited to：Mineral oil, liquid
Body vaseline, albolene, propane diols, polyethylene glycol oxide, PPOX, emulsifying wax and water；Lotion or creme can be used
Carrier include but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene
Fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.
When lower intestinal tract local application, the compounds of this invention can be made into rectal suppository formulation as described above or suitable enema agent
Form, can also be used topical transdermal patch in addition.
The compounds of this invention can be with aseptic injection preparation form medication, including aseptic injection water or oil suspension, or aseptic injection
Solution.Wherein, workable carrier and solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing is non-
Volatile oil also is used as solvent or suspension media, such as monoglyceride or two glyceride.
Furthermore, it should be pointed out that the compounds of this invention for different patients specific dosage and application method be decided by it is many because
Element, includes the age of patient, body weight, sex, natural health situation, nutrition condition, the activity intensity of compound, when taking
Between, metabolic rate, the order of severity of illness and the subjective judgement of diagnosis and treatment doctor.Here preferably use dosage between
0.01-100mg/kg body weight/days.
Embodiment
The present invention can be further described by the following examples and test example.However, the scope of the present invention is not
It is limited to following embodiments or test example.One of skill in the art is it is understood that before without departing substantially from the spirit and scope of the present invention
Put, various change and modification can be carried out to the present invention.The present invention to used in experiment to material and test method enter
Row is general and/or specifically describes.Although to realize that many materials used in the object of the invention and operating method are that this area is public
Know, but the present invention is still described in detail as far as possible herein.
For following whole embodiments, standard operation well known by persons skilled in the art and purification process can be used.Unless otherwise
Illustrate, all temperature are represented with DEG C (degree Celsius).The structure of compound be by nuclear magnetic resonance (NMR) or mass spectrum (MS) come
Determine.Melting point compound m.p. is determined by RY-1 types melting point apparatus, and thermometer is calibrated, and m.p. is DEG C to provide.1H NMR
By JEOL JNM-ECA-400 type nmr determinations.Mass spectrum is determined by API3000 (ESI) types mass spectrograph.It is all anti-
The unreceipted all normalized pretreatment of solvent-applied.
In example below unless otherwise specified, % refers to mass percent.
The synthesis (compound 1) of m- (N- methyl amino ethoxies) benzene-N, the N- dimethyl carbamate of embodiment 1
By resorcinol (2.20g, 20mmol), dimethylaminoethyl chloride (2.8g, 26mmol), pyridine (2.4g, 30
Mmol) it is added in 30mL benzene, is heated to reflux 10 hours.After reaction terminates, room temperature is cooled to, solution is through saturation chlorination
Sodium water solution is washed three times, and anhydrous Na 2SO4 dries decompressions and is spin-dried for solvent, the washing of residue-petroleum ether, ethanol/water (5: 1, v: v)
Recrystallize to obtain product 3- hydroxy benzenes N, N- dimethyl carbamate (1-1), yield 50%.1-1 (7 is added in 30mL toluene
Mmol) and NaH (7mmol) are heated to reflux 1 hour, and 2- chloro-n-methyls ethylamine hydrochloride (10mmol, first is added dropwise
Benzole soln), flow back 5 hours.Decompression is spin-dried for toluene, and residue is dissolved in (20%) ether in the 50ml NaOH aqueous solution and extracted.Water
Layer is acidified to pH-6 with HCl solution (20%).Solution ether is extracted, and ether layer is dried with anhydrous Na 2SO4.Ether decompression rotation
It is dry, residue with ethanol/ethyl acetate (1: 1, v: v) recrystallize white solid be compound 1 hydrochloride, yield 40%, m.p.
145-147℃.1H NMR (400MHz, DMSO-d6) δ：9.29 (s, 2H), 7.31 (t, J=8.12Hz, J=7.88
Hz, 1H), 6.85 (d, J=8.40Hz, 1H), 6.78 (d, J=7.84Hz, 1H), 4.26 (t, J=5.04Hz,
2H), 3.29 (s, 2H), 3.03 (s, 3H), 2.90 (s, 3H), 2.59 (s, 3H) .13C NMR (100MHz, DMSO-d6) δ：
159.4,153.8,152.3,129.7,114.8,111.7,108.7,63.5,47.1,36.3,36.1,32.7.HRMS
(ESI)[M+H]+：m/z calcd for C12H18N203 238.1317；Found 239.1391.IR (γ cm-1, KBr,
Figure 1S.4)：3002 (Ph-H), 2947 (- CH3), 1720 (C=0), 1271 (C-O-C), 1084 (0=C-O), 891
(C6H4).
The synthesis (compound 2) of m- (N, N- dimethylamino propoxy) benzene-N, the N- dimethyl carbamate of embodiment 2
1-1 is prepared by method in above-described embodiment 1, and the reaction of the chloro- 1- of 3- (N, N- dimethyl) propylamine obtains compound 2.1-1
(7mmol) and NaH (7mmol) are added in 30ml toluene, are heated to reflux 1 hour, then 3- chloro- 1- (N, N- is added dropwise
Dimethyl) propylamine (10mmol is dissolved in toluene) is heated to reflux 5 hours.Decompression is spin-dried for after toluene, and residue is dissolved in 50ml
(20%) ether is extracted in the NaOH aqueous solution.Water layer is acidified to pH-6, the extraction of solution ether, ether layer with HCl solution (20%)
Dried with anhydrous Na 2SO4.Ether decompression be spin-dried for, residue with ethanol/ether (1: 1, v: v) recrystallize white solid be chemical combination
The hydrochloride of thing 2, yield 70%, m.p.120-123 DEG C.1H NMR (400MHz, DMSO-d6) δ：11.08 (s, 1H),
7.28 (t, J=8.12Hz, 1H), 6.82 (d, J=8.40Hz, 1H), 6.71 (s, 1H), 6.70 (d, J=1.40
Hz, 1H), 4.05 (t, J=5.88Hz, 2H), 3.18 (t, J=7.56Hz, 2H), 3.03 (s, 3H), 2.90 (s,
3H), 2.75 (s, 6H), 2.12-2.19 (m, 2H) .13C NMR (100MHz, DMSO-d6) δ：159.5,154.4,152.8,
130.2,114.8,112.0,109.0,65.7,54.3,42.4,36.8,36.6,24.3.HRMS (ESI) [M+H]+：
m/z calcd for C14H22N203 266.1630；Found 267.1702.IR (γ cm-1, KBr, Figure 2S.4)：
3015 (Ph-H), 2954 (- CH3), 1705 (C=0), 1182 (C-O-C), 1056 (0=C-O), 864 (C6H4)
The synthesis (compound 3) of m- (N, N- diethyl amino base oxethyl) benzene-N, the N- dimethyl carbamate of embodiment 3
1-1 is prepared by method in above-described embodiment 1, and chloro- (N, N- diethyl) the ethamine reactions of 2- obtain compound 3.Specifically
Operating method be the same as Example 2.Obtain the hydrochloride that product as white solid is compound 3, yield 65%, m.p.157-159 DEG C.1H
NMR (400MHz, DMSO-d6) δ：10.98 (s, 1H), 7.31 (t, J=8.12Hz, 1H), 6.85 (dd, J=
8.12Hz, J=2.24Hz 1H), 6.79 (t, J=2.24Hz, 1H), 6.75 (dd, J=8.12Hz, J=1.96
Hz, 1H), 4.39 (t, J=5.04Hz, 2H), 3.47 (q, J=5.04Hz, J=4.76Hz, 2H), 3.19 (m,
(t, J=7.28Hz, 6H) the .13C NMR of 4H), 3.03 (s, 3H), 2.91 (s, 3H), 1.26 (100MHz,
DMSO-d6)δ：158.7,154.4,152.9,130.3,115.4,112.1,109.2,63.0,49.9,47.3,36.8,
36.6,9.0.HRMS (ESI) [M+H]+：m/z calcd for C15H24N203 280.1787；found 281.1861.IR
(γ cm-1, KBr, Figure 3S.4)：3030 (Ph-H), 2941 (- CH3), 1707 (C=0), 1185 (C-O-C), 1074
(0=C-O), 861 (C6H4)
The synthesis (compound 4) of m- (N, N- bis- (isopropyl) amino ethoxy) benzene-N, the N- dimethyl carbamate of embodiment 4
1-1 is prepared by method in above-described embodiment 1, and the chloro- DIPEA hydrochloric acid reactant salts of 2- obtain compound 4.
Concrete operation method be the same as Example 2.Obtain the hydrochloride that product as white solid is compound 4, yield 55%, m.p.112-114 DEG C.
1H NMR (400MHz, DMSO-d6) δ：10.10 (s, 1H), 7.31 (t, J=8.68Hz, 1H), 6.82 (m, 1H),
6.73-6.76 (m, 2H), 4.37 (t, J=5.04Hz, 2H), 3.65-3.73 (m, 2H), 3.51 (q, J=4.52
Hz, 2H), 3.04 (s, 3H), 2.90 (s, 3H), 1.34 (dd, J=6.44Hz, J=10.96Hz, 12H) .13C NMR
(100MHz, DMSO-d6) δ：158.2,153.8,152.3,129.7,114.8,111.5,108.5,64.0,54.5,
45.8,36.3,36.1,18.1,16.7.HRMS (ESI) [M+H]+：m/zcalcd for C17H28N203 308.2100；
Found 309.2173.IR (γ cm-1, KBr, Figure 4S.4)：3087 (Ph-H), 2991 (- CH3), 1709 (C=0),
(C6H4) of 1287 (C-O-C), 1074 (0=C-O), 882
The synthesis (compound 5) of m- (N, N- bis- (normal-butyl) amino ethoxy) benzene-N, the N- dimethyl carbamate of embodiment 5
1-1 is prepared by method in above-described embodiment 1, and the reaction of 2- chloro- N, N- bis- (normal-butyl) ethylamine hydrochloride obtains chemical combination
Thing 5.Concrete operation method be the same as Example 2. obtains the hydrochloride that product as white solid is compound 5, yield 65%, m.p.
109-111 DEG C of .1H NMR (400MHz, DMSO-d6) δ：10.92 (s, 1H), 7.31 (t, J=8.40Hz, 1H),
6.82 (dd, J=8.40Hz, 1H), 6.74-6.77 (m, 2H), 4.41 (t, J=4.76Hz, 2H), 3.49 (q,
J=4.76Hz, 2H), 3.10 (m, 4H), 3.03 (s, 3H), 2.91 (s, 3H), 1.69 (m, J=7.56Hz,
4H), 1.32 (m, J=7.56Hz, J=7.28Hz, 4H), 0.91 (t, J=7.28Hz, 6H) .13C NMR (100
MHz, DMSO-d6) δ：158.1,153.8,152.3,129.8,114.9,111.6,108.4,62.4,52.3,50.4,
36.3,36.1,24.8,19.5,13.6.HRMS (ESI) [M+H]+：m/z calcd for C19H32N203 336.2413；
Found 337.2486.IR (γ cm-1, KBr, Figure 5S.4)：3050 (Ph-H), 2963 (- CH3), 1726 (C=0),
(C6H4) of 1278 (C-O-C), 1055 (0=C-O), 862
The synthesis (compound 6) of embodiment 6 the 3- tert-butyl groups -5- (pyrrolidinyl -1- ethyoxyls) benzene-N, N- dimethyl carbamate
3- tert-butyl resorcins (3.33g, 20mmol), dimethylaminoethyl chloride (2.8g, 26mmol), pyridine (2.4
G, 30mmol) it is added in 30ml toluene, it is heated to reflux 10 hours.After reaction terminates, room temperature is cooled to, solution is through saturation
Sodium-chloride water solution is washed three times, and anhydrous Na 2SO4 is dried.Decompression is spin-dried for solvent, and residue-petroleum ether is washed, ethanol/water (5: 1,
V: product 3- tert-butyl group 5- hydroxy benzenes-N, N- dimethyl carbamates (6-1), yield 45% v) are recrystallized to obtain.In 30mL first
6-1 (7mmol) and NaH (7mmol) are added in benzene to be heated to reflux 1 hour, and 1- (2- chloroethyls) nitrogen is added dropwise
Penta ring hydrochloride (10mmol, toluene solution), flows back 5 hours.Decompression is spin-dried for toluene, and residue is dissolved in 50ml NaOH water
(20%) ether is extracted in solution.Water layer is acidified to pH-6 with HCl solution (20%).Solution ether is extracted, and ether layer is with anhydrous
Na2SO4 is dried.Ether decompression is spin-dried for, and residue obtains the hydrochloride that white solid is compound 6 with ethyl alcohol recrystallization, yield 52%,
M.p.177-178 DEG C of .1H NMR (400MHz, DMSO-d6) δ：11.22 (s, 1H), 6.84 (s, 1H), 6.73 (s,
1H), 6.62 (s, 1H), 4.34 (t, J=4.76Hz, 2H), 3.55 (s, 4H), 3.09 (s, 2H), 3.03 (s,
3H), 2.90 (s, 3H), 1.88-2.00 (m, 4H), 1.26 (s, 9H) .13C NMR (100MHz, DMSO-d6) δ：
157.9,154.0,153.2,152.0,111.9,109.2,105.6,63.4,53.5,52.5,36.3,36.1,34.6,
30.9,22.6.HRMS (ESI) [M+H]+：m/z calcd for C19H30N203 334.2256；found 335.2329.IR
(γ cm-1, KBr, Figure 6S.4)：2960 (- CH3), 1719 (C=0), 1326 (C-O-C), 1082 (0=C-O),
869(C6H4).
Embodiment 7 2- diethylamino methyl -5- (N, N- diethyl amino base oxethyl) benzene-N, N- dimethyl carbamate
Synthesize (compound 7)
Synthesized by method in above-described embodiment 1,4- diethylamino methyl resorcinols (3.91g, 20mmol), diformazan ammonia
Base formyl chloride (2.8g, 26mmol), pyridine (2.4g, 30mmol) is added in 30ml toluene, is heated to reflux 10 hours.
After reaction terminates, room temperature is cooled to, solution is washed three times through saturated sodium-chloride water solution, and anhydrous Na 2SO4 is dried.Decompression is spin-dried for
Solvent, residue-petroleum ether washing, ethyl alcohol recrystallization obtains product 2- Diethylaminomethyl -5- hydroxy benzenes-N, N- dimethyl carbamates
(7-1), yield 49%.7-1 (7mmol) and NaH (7mmol) are added in 30mL toluene to be heated to reflux 1 hour,
2- chlorine diethylin ethylcarbodiimide hydrochloride (10mmol, toluene solution) is added dropwise, flows back 5 hours.Decompression is spin-dried for toluene, residual
Slag is dissolved in (20%) ether in the 50ml NaOH aqueous solution and extracted.Water layer is acidified to pH-6 with HCl solution (20%).Solution
Ether is extracted, and ether layer is dried with anhydrous Na 2SO4.Ether decompression is spin-dried for, and it is compound that residue, which obtains white solid with ethyl alcohol recrystallization,
7 hydrochloride, yield 52%, m.p.178-179 DEG C.1H NMR (400MHz, DMSO-d6) δ：11.16 (s, 1H),
10.90 (s, 1H), 7.85 (d, J=8.40Hz, 1H), 6.96 (dd, J=8.40Hz, J=2.24Hz, 1H),
6.88 (d, J=2.24Hz, 1H), 4.43 (t, J=4.76Hz, 2H), 4.13 (d, J=5.32Hz, 2H), 3.48 (d,
J=4.76Hz, 2H), 3.19 (m, 4H), 3.10 (s, 3H), 2.97-3.07 (m, 4H), 2.94 (s, 3H), 1.24-1.28
(m, 12H) .13C NMR (100MHz, DMSO-d6) δ：158.8,153.4,151.6,133.7,115.4,112.3,
109.04,62.7,49.2,48.2,46.8,45.5,36.6,36.3,8.4,8.2.HRMS (ESI) [M+H]+：m/z
calcd for C20H35N303 365.2678；Found 366.2751.IR (γ cm-1, KBr, Figure 7S.4)：3034
(Ph-H) (C6H4) of, 2935 (- CH3), 1718 (C=0), 1265 (C-O-C), 1101 (0=C-O), 824
The synthesis (compound 8) of embodiment 8 the 3- tert-butyl groups -4- (dimethylamino propoxyl group) benzene-N, N- dimethyl carbamate
2- isopropyls hydroquinones (3.0g, 20mmol), dimethylaminoethyl chloride (2.8g, 25mmol), pyridine (2.4
G, 30mmol) it is added in 30ml toluene, it is heated to reflux 10 hours.After reaction terminates, room temperature is cooled to, solution is through saturation
Sodium-chloride water solution is washed three times, and anhydrous Na 2SO4 dries decompressions and is spin-dried for solvent, and residue-petroleum ether is washed, ethanol/water (5: 1,
V: product 3- tert-butyl group 4- hydroxy benzenes-N, N- dimethyl carbamates (8-1), yield 45% v) are recrystallized to obtain.In 30mL first
8-1 (7mmol) and NaH (7mmol) are added in benzene to be heated to reflux 1 hour, and 3- chlorine dimethylamino-propyls are added dropwise
Hydrochloride (10mmol, toluene solution), flows back 5 hours.Decompression is spin-dried for toluene, and residue is dissolved in the 50ml NaOH aqueous solution
In (20%) ether extract.Water layer is acidified to the extraction of pH-6. solution ether, ether layer anhydrous Na 2SO4 with HCl solution (20%)
Dry.Ether decompression is spin-dried for, and residue obtains the hydrochloride that white solid is compound 8, yield 66%, m.p. with ethyl alcohol recrystallization
164-167℃.1H NMR (400MHz, DMSO-d6) δ：10.84 (s, 1H), 6.96 (d, J=8.68Hz, 1H),
6.92 (d, J=2.52Hz, 1H), 6.89 (d, J=2.80Hz, 1H), 4.07 (t, J=6.16Hz, 2H), 3.20
(t, J=7.84Hz, 2H), 3.02 (s, 3H), 2.89 (s, 3H), 2.77 (s, 6H), 2.18-2.26 (m, J=6.16
Hz, J=7.84Hz, 2H), 1.30 (s, 9H) .13C NMR (100MHz, DMSO-d6) δ：155.0,154.7,
145.0,138.5,120.6,113.3,65.9,54.7,42.5,36.8,36.6,35.0,30.1,24.6.HRMS (ESI)
[M+H]+：m/zcalcd for C18H30N203 322.2256；Found 323.2329.IR (γ cm-1, KBr, Figure
8S.4)：3002 (Ph-H), 2947 (- CH3), 1720 (C=0), 1271 (C-O-C), 1084 (0=C-O), 891 (C6H4)
The synthesis (compound 9) of 2- nitros -5- (Dimethylaminoethoxy) benzene-N, the N- dimethyl carbamates of embodiment 9
4- nitros -1,3- resorcinol (2.5g, 20mmol), dimethylaminoethyl chloride (2.8g, 25mmol), pyridine (2.4
G, 30mmol) it is added in 30ml toluene, it is heated to reflux 10 hours.After reaction terminates, room temperature is cooled to, solution is through saturation
Sodium-chloride water solution is washed three times, and anhydrous Na 2SO4 dries decompressions and is spin-dried for solvent, and residue-petroleum ether washing, ethyl alcohol recrystallization is obtained
Product 2- nitro -5- hydroxy benzenes-N, N- dimethyl carbamates (9-1), yield 62%.9-1 (7 is added in 30mL toluene
Mmol) and NaH (7mmol) are heated to reflux 1 hour, and 2- chlorine dimethylaminoethyl hydrochlorides (10mmol, first is added dropwise
Benzole soln), flow back 5 hours.Decompression is spin-dried for toluene, and residue is dissolved in (20%) ether in the 50ml NaOH aqueous solution and extracted.
Water layer is acidified to the extraction of pH-6. solution ether with HCl solution (20%), and ether layer is dried with anhydrous Na 2SO4.Ether decompression rotation
Dry, residue obtains the hydrochloride that white solid is compound 9, yield 73%, m.p.118-121 DEG C with ethyl alcohol recrystallization.1H NMR
(400MHz, DMSO-d6) δ：11.12 (s, 1H), 8.17 (d, J=8.96Hz, 1H), 7.07-7.11 (m, 2H), 4.53
(t, J=5.04Hz, 2H), 3.54 (t, J=5.04Hz, 2H), 3.09 (s, 3H), 2.93 (s, 3H), 2.82
(s, 6H) .13C NMR (100MHz, DMSO-d6) δ：162.5,152.5,146.6,135.5,127.5,112.7,111.0,
63.5,54.7,42.8,36.5,36.3.HRMS (ESI) [M+H]+：m/z calcd for C13H19N305 297.1325；
Found 298.1397.IR (γ cm-1, KBr, Figure 9S.4)：3006 (Ph-H), 2940 (- CH3), 1735 (C=0),
(C6H4) of 1589 (- NO2), 1291 (C-O-C), 1097 (0=C-O), 838
The synthesis (compound 10) of m- (N, N- dimethylaminoethyl sulfenyl) benzene-N, the N- dimethyl carbamate of embodiment 10
3- hydroxythiophenols (6.30g, 50mmol) are dissolved in ethanol, and adding caustic alcohol, (1.15g metallic sodiums are dissolved in
In 35mL ethanol solutions) it is heated to reflux 30 minutes, the chloro- N of 2-, N- dimethylaminoethyls (8.0g, 80mmol) is added dropwise
It is heated to reflux 4 hours.Decompression is spin-dried for solvent, and residue is dissolved in (10%) ether in the 50ml NaOH aqueous solution and extracted.Water layer is used
HCl solution (20%) is acidified, ether washing, and water layer adds ammoniacal liquor and neutralizes to obtain solid product, ether/petroleum ether (1: 1, v: v) weight
The product 3- sulfydryls benzene of crystallization-dimethyl carbamate (10-1), yield 32%.10-1 (26 is added in 100ml toluene
Mmol), NaH (30mmol) is heated to reflux 1.5 hours, and dimethylaminoethyl chloride (3.5g, 33mmol) is added dropwise and adds
Heat backflow 3 hours, next operation such as embodiment 6.Through ethanol/ether (1: 1, v: v) recrystallize white solid product be 10
Hydrochloride, yield 79%, m.p.132-134 DEG C of .1H NMR (400MHz, DMSO-d6) δ：11.22 (s, 1H), 7.36
(t, J=7.84Hz, 1H), 7.27 (m, J=7.84Hz, 1H), 7.21 (t, J=1.96Hz, 1H), 6.97
(m, J=8.12Hz, J=2.24Hz, 1H), 3.41-3.45 (m, 2H), 3.19-3.23 (m, 2H), 3.04 (s,
3H), 2.91 (s, 3H), 2.76 (s, 6H) .13C NMR (100MHz, DMSO-d6) δ：154.4,152.4,135.8,
130.5,125.1,121.8,120.4,55.5,42.3,36.9,36.7,26.0.HRMS (ESI) [M+H]+：m/z calcd
for C13H20N202S 268.1245；Found 269.1318.IR (γ cm-1, KBr, Figure 10S.4)：3009 (Ph-H),
(C6H4) of 2952 (- CH3), 1712 (C=0), 1215 (C-S-C), 891
The synthesis (compound 11) of m- (N, N- lignocaine propyl group sulfenyl) benzene-N, the N- dimethyl carbamate of embodiment 11
11-1 is synthesized by method in above-described embodiment 10,3- hydroxythiophenols, the chloro- N of 3-, N- lignocaines propyl group reaction is obtained
11-1, yield 37%, following operation also be the same as Example 10, ethanol/ether (1: 1, v: v) recrystallize 11 hydrochloric acid,
Yield 58%, m.p.117-119 DEG C of .1H NMR (400MHz, DMSO-d6) δ：10.82 (s, 1H), 7.33 (t, J
=7.84Hz, J=8.12Hz, 1H), 7.20 (m, J=7.84Hz, 1H), 7.13 (t, J=1.96Hz, 1H),
6.95 (m, J=8.12Hz, J=2.24Hz, 1H), 3.11 (m, J=7.28Hz, 2H), 3.01-3.06 (m, J
=8.12Hz, 4H), 3.04 (s, 3H), 2.91 (s, 3H), 1.92-2.00 (m, 4H), 1.19 (t, J=7.28Hz,
6H) .13C NMR (100MHz, DMSO-d6) δ：154.4,152.3,137.2,130.3,125.1,121.8,120.0,
49.4,46.6,36.8,29.3,22.9,8.9.HRMS (ESI) [M+H]+：m/z calcd for C16H26N202S
310.1715；Found 311.1787.IR (γ cm-1, KBr, Figure 11S.4)：3081 (Ph-H), 2934 (- CH3),
(C6H4) of 1735 (C=0), 1203 (C-S-C), 879
The synthesis (compound 12) of m- (N, N- dipropylamino ethylsulfanyl) benzene-N, the N- dimethyl carbamate of embodiment 12
12-1 is synthesized by method in above-described embodiment 10,3- hydroxythiophenols, the chloro- N of 2-, N- dipropyls amino-ethyl reaction is obtained
Next 12-1, yield 51% operates also be the same as Example 10, and ethanol/Diethyl ether recrystallization obtains 12 hydrochloric acid, yield 55%.m.p.
116-118 DEG C of .1H NMR (400MHz, DMSO-d6) δ：11.09 (s, 1H), 7.36 (t, J=7.84Hz, 1H),
7.28 (m, J=7.84Hz, 1H), 7.25 (t, J=1.96Hz, 1H), 6.99 (m, J=8.12Hz, J=2.24
Hz, 1H), 3.47-3.51 (m, 2H), 3.14-3.19 (m, 2H), 3.04 (s, 3H), 2.97-3.03 (m, 4H), 2.91
(s, 3H), 1.56-1.78 (m, 4H), 0.89 (t, J=7.44Hz, 6H) .13C NMR (100MHz, DMSO-d6) δ：
154.4,152.5,135.8,130.5,125.3,121.9,120.4,55.6,51.1,36.8,25.5,16.9,11.4.
HRMS(ESI)[M+H]+：m/z calcd for C17H28N202S 324.1871；Found 325.1944.IR (γ cm-1,
KBr, Figure 12S.4)：(C6H4) of 2970 (- CH3), 1732 (C=0), 1208 (C-S-C), 888
The synthesis (compound 13) of m- (3- piperidines propyl group -1- sulfenyls) benzene-N, the N- dimethyl carbamate of embodiment 13
13-1 is synthesized by method in above-described embodiment 10,3- hydroxythiophenols, 1- (3- chloropropyls) piperidine hydrochlorate reacts
To 13-1, yield 83%, following operation also be the same as Example 10, acetone/diethyl ether recrystallize 13 hydrochloride, yield 78%.
M.p.90-93 DEG C of .1H NMR (400MHz, DMSO-d6) δ：10.51 (s, 1H), 7.36 (t, J=8.12Hz, J
=7.88Hz, 1H), 7.23 (d, J=7.84Hz, 1H), 7.15 (t, J=1.68Hz, 1H), 6.97 (dd, J
=8.12Hz, J=1.68Hz, 1H), 3.39 (s, 2H), 3.08-3.14 (m, 4H), 3.06 (s, 3H), 2.93 (s,
3H), 2.79-2.88 (m, 2H), 2.00-2.08 (m, 2H), 1.68-1.86 (m, 5H), 1.33-1.42 (m, 1H) .13C
NMR (100MHz, CDCl3) δ：153.9,151.8,136.7,129.8,124.7,121.4,119.5,54.7,51.9,
36.3,36.1,29.1,22.7,22.3,21.4.HRMS (ESI) [M+H]+：m/z calcd for C17H26N202S
322.1715；Found 323.1788.IR (γ cm-1, KBr, Figure 13S.4)：3027 (Ph-H), 2999 (- CH3),
(C6H4) of 1727 (C=0), 1165 (C-S-C), 887
Compound 1-13 prepared by embodiment 1-13 chemical name and structural formula is as shown in the table.
The compounds of this invention of embodiment 14 suppresses the activity that PD-1/PD-L1 is combined on model in vitro
14.1 test events：Compound HTRF is screened
1. test philosophy：
Recombinant protein PD-1 and PD-L1 are combined with antibody anti-Tag1-EuK, anti-Tag2-XL665 respectively, work as PD-1
When being combined with PD-L1, energy transmission reads light absorption value 665/620, if small molecule is combined with interference, energy to PD-1/PD-L1
Amount transmission weakens.Light absorption value 665/620 is also corresponding to be weakened.HTRF kits are purchased from Cisbio companies.
2. method of testing：
Antibody anti-Tag1-EuK and anti-Tag2-XL665 are diluted to 1.83nM and 66.7nM, people source PD-1 respectively
Recombinant protein and people source PD-L1 recombinant proteins are diluted to final concentration of 100nM and2nM respectively.In 384 orifice plates, add per hole
Enter 4 μ L PD-1,4 μ L PD-L1 solution.After room temperature is coated with 30 minutes, 2 microlitres of testing compound (DMSO is separately added into per hole
Dissolving, coating buffer dilution) and 5 μ L anti-Tag1-EuK and 5 μ L anti-Tag2-XL665 mixed liquors, incubation at room temperature 1
Hour, ELIASA reads light absorption value at 665nm and 620nm respectively, and the two ratio AU665/AU620 is whether to evaluate compound
The foundation for disturbing PD-1/PD-L1 to combine.
3. test result：
The target compound of table 1 suppresses PD-1/PD-L1 combination HTRF measurement results
| Compound number | 500uM inhibiting rates (%) |
| 1 | 18.5 |
| 2 | 16.0 |
| 3 | 15.5 |
| 4 | 17.5 |
| 5 | 41.9 |
| 6 | 13.0 |
| 7 | 12.8 |
| 8 | 22.2 |
| 9 | 43.0 |
| 10 | 14.9 |
| 11 | 17.9 |
| 12 | 15.9 |
| 13 | 17.4 |
15.2 test events：PD-1 recombinant proteins and small molecule effect, small molecule NMR Influence of Displacement
1. test philosophy：
PD-1 recombinant proteins and small molecule mixing, if small molecule has interaction with PD-1 recombinant proteins, may interfere with small point
Sub indivedual hydrogen atom (there may be the hydrogen atom on the atom of interaction) spins, and then chemical shift is changed.
2. method of testing：
PD-1 recombinant proteins (being purchased from Sino Biological Inc., 10377-HO8H) are dissolved in phosphate buffer
(PBS, NaCl 137mM, KCl 2.7mM, Na2HPO4,10.0mM, KH2PO4,2.0mM, pH=7.4) compound
It is dissolved in DMSO-d6.PD-1 recombinant proteins and testing compound concentration ratio are 1: 1000 mixing (PBS: DMSO=9: 1, common 0.5ml).
Bruker Avance III 600MHz spectrometer are detected.
3. test result：
Compound 9 is after the effect of PD-1 recombinant proteins is added, and change is maximum, it is unconverted at other peaks in the case of, chemistry
Displacement to low field is moved to 2.681 at 2.674 peak, and the hydrogen is the methyl hydrogen on tertiary N, and the peak is moved to low field, electrical screen
The effect of covering reduces, and illustrates that with albumen certain effect occurs for the N being attached thereto.Compound 5 add PD-1 recombinant proteins after, its
His peak is unchanged, and the triplet of chemical shift 3.029 is moved to 3.031 to low field.Compound 1 is adding PD-1 restructuring eggs
Bai Hou, other peaks are unchanged, and the peak of chemical shift 2.597 is moved to 2.599 to low field.
The compound of table 2 nmr chemical change in displacement under the effect of PD-1 recombinant proteins
| Compound number | 500uM inhibiting rates | Chemical shift | Plus chemical shift after PD-1 |
| 9 | 43.0 | 2.674 | 2.681 |
| 5 | 41.9 | 3.029 | 3.031 |
| 1 | 18.5 | 2.597 | 2.599 |
Claims (5)
1. compound shown in Formulas I, its raceme or optical isomer, its pharmaceutically acceptable salt, solvate, hydrate
Wherein,
X is O or S atom, substituted dimethyl carbamate meta or para position；
R1、R2It is each independently hydrogen or alkyl or isopropyl, the tert-butyl group or R1、R2With the N formation miscellaneous alkane of 4-8 rings N；
N is 2-5；
R3For be optionally present on phenyl ring 1,2 or 3 identical or different substituents, R is each independently selected from following group：Hydrogen, alkyl, hydroxyl, nitro, amino, haloalkyl, alkoxy, amino, by alkyl is monosubstituted or disubstituted amino, carboxyl, amide groups, phenyl.
2. compound, its raceme or the optical isomer of any one of claim 1, its pharmaceutically acceptable salt, solvate, hydrate, it is selected from：
M- (N- methyl amino ethoxies) benzene-N, N- dimethyl carbamate (compound 1)
M- (N, N- dimethylamino propoxy) benzene-N, N- dimethyl carbamate (compound 2)
M- (N, N- diethyl amino base oxethyl) benzene-N, N- dimethyl carbamate (compound 3)
M- (N, N- bis- (isopropyl) amino ethoxy) benzene-N, N- dimethyl carbamate (compound 4)
M- (N, N- bis- (normal-butyl) amino ethoxy) benzene-N, N- dimethyl carbamate (compound 5)
The 3- tert-butyl groups -5- (pyrrolidinyl -1- ethyoxyls) benzene-N, N- dimethyl carbamate (compound 6)
2- diethylamino methyl -5- (N, N- diethyl amino base oxethyl) benzene-N, N- dimethyl carbamate (compound 7)
The 3- tert-butyl groups -4- (N, N- dimethylamino propoxyl group) benzene-N, N- dimethyl carbamate (compound 8)
2- nitros -5- (N, N- Dimethylaminoethoxy) benzene-N, N- dimethyl carbamate (compound 9)
M- (N, N- dimethylaminoethyl sulfenyl) benzene-N, N- dimethyl carbamate (compound 10)
M- (N, N- lignocaine propyl group sulfenyl) benzene-N, N- dimethyl carbamate (compound 11)
M- (N, N- dipropylamino ethylsulfanyl) benzene-N, N- dimethyl carbamate (compound 12)
M- (3- piperidines propyl group -1- sulfenyls) benzene-N, N- dimethyl carbamate (compound 13).
3. pharmaceutical composition, wherein at least includes compound, its raceme or optical isomer, its pharmaceutically acceptable salt, solvate, hydrate described in a kind of any one of claim 1, and one or more pharmaceutically acceptable carriers or excipient.
4. the pharmaceutical composition described in compound, its raceme or optical isomer, its pharmaceutically acceptable salt, solvate, hydrate or claim 2 described in claim any one of 1-3 is preparing the purposes in being used to treat and/or prevent the malignant tumor medicine relevant with PD-1 paths.
5. the purposes of claim 4, wherein described malignant tumour (includes but is not limited to：Melanoma, non-small cell lung cancer, kidney, stomach cancer, carcinoma of urinary bladder, head and neck cancer, cancer of pancreas, celiothelioma, triple negative breast cancer etc..
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019167814A1 (en) * | 2018-02-27 | 2019-09-06 | クミアイ化学工業株式会社 | Method for producing mercaptophenol compound and intermediate of said compound |
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2016
- 2016-03-31 CN CN201610190950.4A patent/CN107286057A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019167814A1 (en) * | 2018-02-27 | 2019-09-06 | クミアイ化学工業株式会社 | Method for producing mercaptophenol compound and intermediate of said compound |
| KR20200124227A (en) * | 2018-02-27 | 2020-11-02 | 구미아이 가가쿠 고교 가부시키가이샤 | Method for producing a mercaptophenol compound and its intermediate |
| US10851052B2 (en) | 2018-02-27 | 2020-12-01 | Kumiai Chemical Industry Co., Ltd. | Method for producing mercaptophenol compound and intermediate of said compound |
| TWI730297B (en) * | 2018-02-27 | 2021-06-11 | 日商組合化學工業股份有限公司 | Method for manufacturing mercaptophenol compound and intermediate thereof |
| KR102279795B1 (en) | 2018-02-27 | 2021-07-21 | 구미아이 가가쿠 고교 가부시키가이샤 | Method for producing mercaptophenol compound and intermediates thereof |
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