CN103006645A - Application of 2-aminobenzothiazole derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor - Google Patents
Application of 2-aminobenzothiazole derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor Download PDFInfo
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Abstract
The invention relates to applications of 2-aminobenzothiazole derivatives in pharmaceutical chemistry and pharmacotherapy. Specifically, the invention relates to applications of a compound shown in formula I (described in the specification) and a medicinal composition of the compound in preparation of medicines used for treating diseases related to DHODH.
Description
Technical field
The present invention relates to the application of 2-amino-benzothiazole derivatives in pharmaceutical chemistry and pharmacotherapeutics field.Specifically, namely the 2-amino-benzothiazole derivatives is as dihydroorate dehydrogenase (DHODH) inhibitor, the application in the disease (such as tumor, inflammatory reaction) for the treatment of DHODH mediation.
Background technology
Dihydroorate dehydrogenase (Dihydroorotate dehydrogenase, DHODH) be that catalysis dihydrooratic acid dehydrogenation makes it be converted into a kind of enzyme of orotic acid, this process belongs to the four-step reaction of pyrimidine de novo synthesis, thereby DHODH is the synthetic key enzyme of nucleic acid pyrimidine.Suppress DHODH, can block the synthetic of de novo pyrimidine, cause DNA and RNA dyssynthesis.For most of biological, pyrimidine bases can obtain by de novo synthesis and salvage pathway, but the human cell who breaks up fast, the T-lymphocyte, B-lymphocyte and the tumor cell that for example activate, the de novo synthesis that need to depend on pyrimidine satisfies its growth demand.This is so that the DHODH inhibitor can be used as the treatment that cellular antiproliferative agent is used for tumor and some immunosuppressant reaction.Because the general mechanism of action that DHODH is synthetic to DNA and RNA, also so that its inhibition many other the signal paths in downstream are exerted an influence.Research (Proceedings of the National Academy of Sciences 2010,107 (29), 12828) shows that the inhibition of DHODH can cause the p53 stress in the mitochondrion, can be used for the treated tissue damage.Other has document (Annals of the Rheumatic Diseases 2006,65 (6), 728-735) report, the transcription factor NF-KB phosphorylation that the inhibition of DHODH can stop TNF to induce, suppress AP-1 and the kinase whose activation of c-jun N-terminal protein, finally suppress the apoptosis reaction that TNF induces.
Human dihydroorate dehydrogenase is positioned on the mitochondrial inner membrane, and its catalytic process needs the participation of other cofactor.On structure, DHODH mainly is divided into two parts, i.e. the α of the α-helixstructure of N-end zone and C-end/β barrel-like structure.DHODH is attached on the mitochondrial inner membrane by the unique texture of N-end, and the C-stub area then is the main site of catalytic action.The binding site that on DHODH, has simultaneously substrate and cofactor flavin mononucleotide (FMN) (Flavin mononucleotide, FMN) and ubiquinone (Coenzyme, CoQ).Its catalytic process is mainly finished by two-step reaction: at first dihydrooratic acid is reduced to orotic acid, and simultaneously FMN accepts the hydrogen atom that this process takes off and is oxidized to FMNH
2Afterwards under the effect of CoQ, FMNH
2Dehydrogenation occurs again be reduced to FMN.
Theoretically, any effect that can block with the chemical compound of substrate or cofactor competitive binding DHODH, thus blocking dna or RNA's is synthetic.(Biochemical pharmacology 1988,37 (20), and 3807-3816), such inhibitor competition is combined in the oxidoreduction site of C-end as the research of DHODH inhibitor report to be arranged once in early days with the dihydrooratic acid analog.Now the research of DHODH inhibitor is mainly carried out for the CoQ binding site, wherein Brequinar and Leflunomide have been applied to clinical.Brequinar is used for the host immune response that antitumor and organ transplantation cause, but Brequinar treatment window is narrow, and when combination with cisplatin or cyclosporin A oral administration, cause easily the side effect of thrombocytopenia, mucositis, limited its extensive use in clinical.Leflunomide was in listing in 1998, acute and chronic reaction and Xeno-rejection reaction that various autoimmune disease, organ transplantation are caused all have very strong inhibitory action, be used for the treatment of clinically lupus erythematosus, rheumatoid arthritis, and can be used for preventing and treating the graft rejection reaction.(Nature 2011 for current research, 471 (7339), show that 518-522) Leflunomide is as potent DHODH inhibitor, use separately or all can produce inhibitory action to the melanocyte oncocyte of external and experimental mouse with the other medicines coupling.Because side effect such as that the life-time service of Leflunomide also can produce is unusual such as the liver enzyme, hypertension or erythra, therefore seek the little efficient DHODH inhibitor of toxic and side effects and remain study hotspot in immune correlated disease and the oncotherapy.
Other can use disease that the DHODH inhibitor treats and pertinent literature also can referring to, comprise rheumatoid arthritis (Herrmann, M.L., Schleyerbach, R. and Kirschbaum, B.J., Leflunomide:an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases.Immunopharmacology 2000,47 (2-3), 273-289), colitis (Fitzpatrick, L.R., Deml, L, Hofmann, C.; Small, J.S., Groeppel, M., Hamm, S., Lemstra, S., Leban, J. and Ammendola, A., 4SC-101, a novel immunosuppressive drug, inhibits IL-17and attenuates colitis in two murine models of inflammatory bowel disease.Inflammatory bowel diseases 2010,16 (10), 1763-1777), systemic lupus erythematosus (sle) (Kulkarni, O.P., Sayyed, S.G., Kantner, C., Ryu, M., Schnurr, M., Sardy, M., Leban, J., Jankowsky, R., Ammendola, A. and Doblhofer, R., 4S C-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas) lpr Mice.Am.J.Pathol.2010,176 (6), 2840-2847), psoriatic arthritis (Kaltwasser, J.P., Nash, P., Gladman, D., Rosen, C.F., Behrens, F., Jones, P., Wollenhaupt, J., Falk, F.G. and Mease, P., Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis:A multinational, double-blind, randomized, placebo-controlled clinical trial.Arthritis ﹠amp; Rheumatism 2004,50 (6), 1939-1950), psoriasis (White, R.M., Cech, J., Ratanasirintrawoot, S., Lin, C.Y., Rahl, P.B., Burke, C.J., Langdon, E., Tomlinson, M.L., Mosher, J. and Kaufman, C., DHODH modulates transcriptional elongation in the neural crest and melanoma, Nature 2011,471 (7339), 518-522), transplant rejection (Makowka, L.; Sher, L.; Cramer, D.The development of Brequinar as an immunosuppressive drug for transplantation.Immunological reviews 1993,136,51), renal glomerular disease (Ceng Jianying, Zhang Jianlin, leflunomide is used for the clinical observation of renal glomerular disease, Chinese journals of practical medicine, 2006 (15)); Deng.
Among the present invention, we adopt the molecular docking method in the Computer-Aided Drug Design, screen for 230,000 molecular structures among the specs commercial chemicals data base, buy and test the inhibition activity to human DHODH, find that finally a class 2-amino-benzothiazole derivatives provided by the invention has good inhibitory action to the DHODH activity.Report first the Novel 2 Amino benzothiazole derivant among the present invention to the inhibitory action of human DHODH, about the purposes unprecedented relevant report of chemical compound of the present invention in the medicine of the disease (such as inflammatory reaction, autoimmune disease, tumor etc.) of preparation DHODH mediation.Therefore, the present invention has widened this compounds treatment field clinically.
Summary of the invention
An object of the present invention is to provide Novel 2 Amino benzothiazole derivant or the purposes of its pharmaceutically acceptable salt (general structure is shown in I) in the medicine of the disease (such as inflammatory reaction, autoimmune disease, tumor etc.) of preparation DHODH mediation with inhibition dihydroorate dehydrogenase (DHODH) effect.
Chemical compound involved in the present invention can be used as the micromolecular inhibitor of dihydroorate dehydrogenase (DHODH), and by blocking its biological activity, the biosynthesis of blocking dna or RNA is finally brought into play antiproliferative activity.Therefore chemical compound provided by the invention can be developed into and is new immunosuppressant or antitumor drug.
The invention provides by 2-amino-benzothiazole derivatives or its pharmaceutically acceptable salt shown in the following general formula (I):
Wherein,
A is aryl or 5 or 6 yuan of heterocyclic radicals, and 1-2 carbon atom replaced by X in the heterocyclic radical, and X is independently selected from following atom or group: N, O, S, SO
2And SO;
R
1, R
2, R
3, R
4For identical or different, be selected from independently of one another following group: hydrogen, C
1-C
3Alkyl, halogen, hydroxyl, C
1-C
4Alkoxyl, nitro, amino, phenyl formamido group, aniline formamido group, aniline sulfo-formamido group, CN, NCO, NCS, carboxyl, C
1-C
3Alkoxyl formyl, C
1-C
3Amide groups and the optional aniline formoxyl that replaces;
R
5Be hydrogen, C
1-C
6Alkyl or benzoyl;
Each R
6Can be independently selected from following group: hydrogen, the optional C that replaces
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6The optional C that replaces of alkynyl
1-C
6Alkoxyl, hydroxyl, the optional morpholinyl that replaces, the optional piperazinyl that replaces, the optional amino that replaces, halogen, the optional phenoxy group that replaces, C
1-C
6Alkoxy carbonyl, acetyl group, benzoyl, C
3-C
8Cycloalkyl, cyano group, nitro, benzyl, oxyl, carboxyl, ester group, sulfonic group, sulfydryl, C
1-C
3Amide groups, NCO, NCS, straight chain or ring-type C
1-C
6Saturated or unsaturated acyl-oxygen base, 2-oxo-2,3-indoline-3-methylene; With
N is the integer of 0-5.
In technique scheme, according to R
1, R
2, R
3, R
4, R
5And R
6Represented substituent group or the difference of group, the chemical compound that general formula I provided by the invention represents comprises its enantiomer, diastereomer, racemic modification and combination thereof.
Herein, " alkyl " is often referred to saturated side chain and the straight chained alkyl that carbon chain lengths is 1-10 carbon atom, preferably a long 1-6 carbon atom, the more preferably alkyl of long 1-4 or 1-3 carbon atom." cycloalkyl " finger ring shape alkyl, its ring formation carbon number are generally 3-8.Exemplary cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, suberyl and cyclohexyl etc.
Herein, " alkenyl " refers to that straight or branched contains 2-10 carbon atom, wherein is the group that contains two keys between two carbon atoms in the chain at least.Preferred thiazolinyl is to contain 2-6, the more preferably thiazolinyl of 2-4 carbon atom.Typical alkenyl comprises vinyl, 1-acrylic, 2-methyl-1-propylene base, 1-butylene base and crotyl.
" alkynyl " used herein refers to that straight or branched contains 2-10 carbon atom, wherein is the group that contains three key between two carbon atoms in the chain at least.Preferred alkynyl is to contain 2-6, the more preferably alkynyl of 2-4 carbon atom.Typical alkynyl comprises acetenyl, 1-propinyl, 1-methyl-2-propynyl, 2-propynyl, ethyl acetylene base and 2-butyne base.
Term as used herein " aryl " refers to contain monocycle, dicyclo or the three cyclophane family groups of 6 to 14 carbon atoms, includes but not limited to phenyl, naphthyl or xenyl.Aryl optionally is selected from following substituent group by 1-4 (for example 1-3) and replaces: halogen, C
1-C
6The C that replaces of straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen
1-C
6The C that alkyl (for example trifluoromethyl, trichloromethyl), halogen replace
1-C
6Alkoxyl (for example trifluoromethoxy), carboxyl, C
1-C
4Alkoxyl, sulfydryl, C
1-C
10Alkylthio and C
1-C
4Acyl group.
Term as used herein " heterocyclic radical " refers to ring structure single or that condense, can be aromatics or non-aromatic in nature, and it preferably contains 3-20 and becomes annular atoms, more preferably contains 5-8 annular atoms, wherein at least 1 and preferably at most can to 4 be hetero atom.The example of heterocyclic radical comprises furyl, thienyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, triazolyl, thiazolyl, tetrazole radical, oxazolyl, isoxazolyl, pyrazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, quinolyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl and benzofuranyl.
Term as used herein " hetero atom " comprises O, S and N.When hetero atom was N, this N atom can be further by for example hydrogen or C
1-C
10The group of alkyl replaces.
Term as used herein " heteroaryl " refers to have as mentioned above those heterocyclic radicals of aromatic character, includes but not limited to furyl, thienyl, pyrrole radicals, pyridine radicals, oxazolyl, pyrazinyl, pyridazinyl, pyrimidine radicals etc.
Term as used herein " halogen " comprises fluorine, chlorine, bromine and iodine.
Term as used herein " optional replacement " refers to that its group of modifying optionally is selected from following substituent group by 1-3 and replaces: C
1-C
3Alkyl, carboxyl, halogen, C
1-C
3Alkoxyl, cyano group, nitro, amino, hydroxyl, aldehyde radical, C
1-C
6The C that acyl group, methylol, halogen replace
1-C
3The C that alkyl (for example trifluoromethyl), halogen replace
1-C
3Alkoxyl (for example trifluoromethoxy), sulfydryl, randomly by C
1-C
3Alkyl replaces De isoxazolyl, 5-methyl-isoxazole-3-amino and C
1-C
4Acyl group.
Herein, amide groups self or as the part of other group refers to " C
1-C
6Alkyl-CO-NH-" group, more preferably C
1-C
3Alkyl-CO-NH-.
Herein, acyl group self or as the part of other group can contain 1-6 carbon atom, preferred 1-3 carbon atom.Exemplary acyl group includes but not limited to formoxyl, acetyl group etc.
Herein, " ester group " refers to " C (O) OR " group, and wherein R can be C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aryl, heterocyclic radical etc.
A preferred embodiment of the present invention is that described chemical compound has structural formula shown in the general formula (II):
Wherein,
R
1, R
2, R
3, R
4For identical or different, be selected from independently of one another following group: hydrogen, C
1-C
3Alkyl, halogen, C
1-C
4Alkoxyl, nitro, amino, C
1-C
3Amide groups, phenyl formamido group, aniline formyl ammonia, aniline sulfo-formamido group, CN, NCO, NCS, carboxyl, C
1-C
3Alkoxyl formyl;
R
5Be hydrogen or C
1-C
3Alkyl;
R
6, R
7, R
8, R
9, R
10Identical or different, be selected from independently of one another following group: hydrogen, the optional C that replaces
1-C
6Alkyl, the optional C that replaces
2-C
6Alkenyl, the optional C that replaces
2-C
6Alkynyl, halogen, the optional amino that replaces, morpholinyl, the optional piperazinyl that replaces, acetyl group, benzoyl, nitro, hydroxyl, carboxyl, cyano group, sulfonic group, the optional sulfonyl that replaces, sulfydryl, the optional C that replaces
1-C
6Alkoxyl, phenoxy group, straight chain or ring-type C
1-C
6Saturated or unsaturated acyl-oxygen base, C
1-C
6Alkoxy carbonyl.
In a preferred embodiment, R
9Be trichloromethyl, R
1-R
8And R
10-R
11Be hydrogen atom.
In a preferred embodiment, R
8And R
10Be chlorine atom, R
1-R
7, R
9And R
11Be hydrogen atom.
In a preferred embodiment, R
3Be methyl, R
9Be methoxyl group, R
1-R
2, R
4-R
8And R
10-R
11Be hydrogen atom.
The preferred formula II chemical compound of the present invention is selected from:
The present invention also comprises pharmaceutically acceptable salt, prodrug or the solvate of formula I, II chemical compound.
" pharmaceutically acceptable salt " refers to the pharmaceutically acceptable salt of any compound of Formula I in this article.Can comprise that inorganic and organic bronsted lowry acids and bases bronsted lowry prepares salt by pharmaceutically acceptable avirulent bronsted lowry acids and bases bronsted lowry.Acid comprises: acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, dichloroacetic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, bar be acid, pantothenic acid, phosphonic acids, succinic acid, sulphuric acid, tartaric acid, oxalic acid, p-methyl benzenesulfonic acid etc. not.Especially preferred hydrochloric acid, hydrobromic acid, phosphonic acids, sulphuric acid and methanesulfonic acid, most preferably mesylate.Acceptable alkali salt comprises alkali metal (such as sodium, potassium), alkaline-earth metal (such as calcium, magnesium) and aluminum salt.
" prodrug " comprises the derivant of the compounds of this invention in this article, and it passes through enzyme or non-enzyme process in vivo such as hydrolysis, carries out metabolism biological and transforms, and forms the compounds of this invention.Can utilize prodrug to improve medicine or biological nature, for example, dissolubility, fusing point, stability and relevant physicochemical properties, trap, pharmacokinetics character are sent relevant characteristic with other.For example, form that can prodrug prepares compound of Formula I, wherein, derivatization (for example with suitable group (this group can comprise such as alkyl, aryl, phosphate ester, sugar, amine, ethylene glycol, sulphonic acid ester or acid functional group), by ester bond, amido link or phosphoric acid ester bond) for example dissociate-the OH preparation, group behind the derivatization is unstable, after the administration certain time or contact required biotic environment after can be removed/rupture (for example hydrolysis), to expose compound of Formula I.
In addition, the salt that allows in the compounds of this invention or its pharmacopedics can form hydrate, ethanol equal solvent compound or polymorph.
Second aspect present invention comprises a kind of pharmaceutical composition, and said composition contains the chemical compound of the formula I of the present invention, the II that treat effective dose or its pharmaceutically acceptable salt, prodrug, solvate, and pharmaceutically acceptable carrier or excipient.
" treatment effective dose " refers to when needing the mammal of this treatment, and the amount of this medicine is enough to treat the disease of DHODH mediation.
Although everyone demand is different, those skilled in the art can determine the optimal dose of every kind of active component in the pharmaceutical composition of the present invention.Generally speaking, chemical compound of the present invention or its pharmaceutically acceptable salt, to mammal oral administration every day, dose is according to about 0.0025 to 50 mg/kg of body weight.But preferably the per kilogram oral administration is about 0.01 to 10 milligram.For example, the unit oral dose can comprise about 0.01 to 50 milligram, preferably about 0.1 to 10 milligram the compounds of this invention.Unit dose can give one or many, and be one or more pieces every day, and every contains and has an appointment 0.1 to 50 milligram, eligibly about 0.25 to 10 milligram the compounds of this invention or its solvate.
Pharmaceutical composition of the present invention can be formulated into the dosage form that is fit to various route of administration, includes but not limited to be formulated into for outside the intestinal, and is subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, in the sheath, intracranial, the form of nasal cavity or external administration is used for the treatment of tumor and other diseases.Dosage is effectively to improve or eliminate the dose of one or more diseases.For the treatment of specified disease, effective dose is the dose that is enough to improve or alleviate in some mode the symptom relevant with disease.Such dose can be used as single dose and uses, perhaps can be according to effective therapeutic scheme administration.Dosage is also permitted cure diseases, but administration is normally in order to improve the symptom of disease.Generally need repetitively administered to realize required doing well,improving.The dosage of medicine will be according to patient's age, health and body weight, and the kind of concurrent treatment, the frequency for the treatment of, and required treatment benefit decides.
Pharmaceutical preparation of the present invention can give any mammal, as long as they can obtain the therapeutic effect of the compounds of this invention.Of paramount importance in these mammals is human.
Chemical compound of the present invention or its drug regimen can be used for treating and the disease of preventing various DHODH mediations, especially relevant with the inhibition of DHODH disease.Herein, the disease of DHODH mediation mainly is various because the disease that certain class cell fast breeding causes, such as cancer, and inflammatory reaction and by host's rejection of the same race or that xenotransplant causes.The disease of DHODH mediation also comprises various autoimmune diseases.Specifically, the disease of DHODH mediation includes but not limited to rheumatoid arthritis, colitis, lupus erythematosus (comprising systemic lupus erythematosus (sle)), renal glomerular disease (comprising multiple Secondary cases and primary glomerulopathy), anti-organ graft rejection, melanoma, psoriatic arthritis and psoriasis etc.
Pharmaceutical preparation of the present invention can be made in a known manner.For example, by traditional mixing, granulate ingot processed, dissolving, or freezing dry process manufacturing.When making oral formulations, can be in conjunction with solid adjuvant material and reactive compound, the selectivity milled mixtures.If after need to or adding appropriate amount of addition agent in case of necessity, the processing granular mixture obtains tablet or lozenge core.
Suitable adjuvant is filler particularly, for example saccharide such as lactose or sucrose, mannitol or sorbitol; Cellulose preparation or calcium phosphate, for example tricalcium phosphate or calcium hydrogen phosphate; And binding agent, for example gelatinized corn starch comprises corn starch, wheaten starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.If necessary, can increase disintegrating agent, such as starch above-mentioned, and carboxymethyl starch, crospolyvinylpyrrolidone, agar, or alginic acid or its salt are such as sodium alginate; Adjuvant is flowing regulator and lubricant particularly, for example, Silicon stone, Talcum, stearates, such as the magnesium calcium stearate, stearic acid or Polyethylene Glycol.If necessary, Ke Yi Give lozenge nuclear core provides the suitable coating that can resist gastric juice.For this reason, can use concentrated saccharide solution.This solution can contain Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, Polyethylene Glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to prepare the coating of resistant to gastric juice, can use suitable cellulose solution, for example cellulose acetate phthalic acid or hydroxypropyl emthylcellulose phthalic acid.Can add dyestuff or pigment to the coating of tablet or lozenge nuclear core.For example, for identification or in order to characterize the combination of active component dosage.
Therefore, third aspect present invention provides the method for the disease of a kind for the treatment of or prevention DHODH mediation, and the method comprises that the object that needs is with chemical compound of the present invention or pharmaceutical composition.
Medication includes but not limited to the various medications that this area is known, can be determined according to patient's practical situation.These methods include but not limited to outside the intestinal, and are subcutaneous, vein, and muscle, intraperitoneal, transdermal, the oral cavity, in the sheath, intracranial, nasal cavity or external administration.
The present invention also comprises the purposes of the compounds of this invention in the medicine that the disease of preparation treatment or prevention DHODH mediation is used.
The present invention also relates to formula I of the present invention, the purposes of II chemical compound in the medicine of the active usefulness of preparation inhibition DHODH.
The invention still further relates to formula I of the present invention or the II chemical compound purposes in the medicine that preparation inhibition helicobacter pylori is used, and the purposes in the preparation antifungal.
The specific embodiment
In following embodiment, will further illustrate the present invention.These embodiment only are used for explanation the present invention, but do not limit the present invention in any way.Employed reagent, treatment conditions etc. among the embodiment except as otherwise noted, otherwise use the reagent of buying on conventional or the market to implement under the condition of routine.
Embodiment 1
Carry out virtual screening by the Computer-Aided Drug Design method and obtain chemical compound provided by the invention.
The present invention is comprehensively based on the molecular docking method of receptor, and the SPECS compound database (230,000 chemical molecular structures) of Dutch SPECS chemical company is carried out virtual screening, and final screening obtains the instantiation 1 to 19 of chemical compound provided by the invention.
With the compound crystal structure (the PDB data base numbers 1D3G) of DHODH and its micromolecular inhibitor Brequinar analog as receptor, adopt Glide docking software that 230,000 compound structures in the SPECS compound database are docked in the receptor, joint mode successively adopts Glide's " standard accurate model " (SP mode) and " extremely accurate model " (XP mode), then according to the give a mark ordering of GlideGscore to each chemical compound joint mode, examine and analyze docking of each chemical compound and DHODH and finally pick out the testing in vitro that 19 compound structures suppress the DHODH activity behind the binding pattern and test, all chemical compounds all buy from Dutch SPECS company (
Www.specs.net).
Embodiment 2
Chemical compound provided by the invention is to the active extracorporeal extracorporeal suppression of dihydroorate dehydrogenase (DHODH)
Material: the plasmid that contains people DHODH full length gene have Prof.Jon Clardy (Harvard Medical School) be so kind as to give (J.Bio.Chem.2008,283 (50), 35078-35085) or can buy from Aureal Dongyuan County bio tech ltd.The pET-19b carrier is available from Novagen company.E.coli DH5 and E.coli BL21 (DE3) bacterial strain are preserved for this laboratory.Restricted enzyme Nde I and Bam HI are available from NEB company.Primer is synthetic by Shanghai Ying Jun Bioisystech Co., Ltd.Other reagent are all available from sigma.
According to people DHODH gene order design primer among the GenBank, forward primer is Fw:5 '-TGAACTACATATGGCCACGGGAGATGAG-3 '; Reverse primer Rv:5 '-ATATGGATCCTCACCTCCGATGATCTGC-3 '.Take the plasmid that contains the DHODH gene as template amplification, amplification condition: 95 ℃ of denaturation 2min; 94 ℃ of degeneration 30s; 60 ℃ of annealing 45s; 72 ℃ are extended 1min50s; 29 circulations, 72 ℃ are extended 10min fully.Reaction is carried out 1% agarose gel electrophoresis after finishing, and take 2000bp DNA standard as the relative molecular weight reference, checking amplified production relative molecular weight size is cut glue, reclaims amplified production with test kit.
Respectively PCR product and carrier pET-19b are carried out double digestion with Nde I and Bam HI, reclaim the genes of interest and the carrier segments that digested, spend the night with 16 ℃ of connections of T4DNA ligase, make up recombinant expression carrier pET-19b-DHODH.Recombinant plasmid transformed E.coli DH5a competence is inoculated on the LB flat board that contains ammonia benzyl penicillium sp and cultivates, and the positive bacterium colony of picking at random is inoculated in respectively in the little centrifuge tube that 2mL contains ammonia benzyl penicillium sp and spreads cultivation.Get bacterium liquid after spreading cultivation and extract in a small amount plasmid and carry out that enzyme action is identified and bacterium liquid PCR evaluation, and carry out determined dna sequence by Shanghai Ying Jun Bioisystech Co., Ltd.
Recombiant plasmid pET-19b-DHODH Transformed E .coli BL21 (DE3) competence that order-checking is correct, coat on the LB flat board that contains ampicillin and cultivate, the picking monoclonal is inoculated in 37 ℃, 230rpm shaking table overnight incubation in the LB culture medium that contains 100 μ M ampicillin.Be inoculated in 37 ℃, 230rpm amplification culture in the LB culture medium that 500mL contains 100 μ M ampicillin in 1: 200 ratio.When treating that thalline OD value reaches 0.8-1, add IPTG in culture medium, making the IPTG final concentration is 0.5mM.25 ℃ of abduction deliverings that spend the night.4 ℃, the centrifugal collection of 4000rpm are induced rear thalline, collect bacterial sediment with recentrifuge behind the deionized water wash, are put in-80 ℃ of preservations.
Use the resuspended thalline of lysate during protein purification.Lysate contains 50mM HEPES (pH 8.0), 0.15MNaCl, and the 10mM imidazoles, 10% glycerol, 0.1%Triton X-100 adds a little STI, ultrasonication thalline behind the resuspended mixing.4 ℃ of broken liquid, the centrifugal 30min of 10000rpm.Getting cleer and peaceful precipitation carries out protein electrophoresis and determines the albumen existence form.Supernatant is added combination in the ready Ni-NTA chromatographic column, collect and pass liquid.Wash resin 3-5 time with the lysate that contains the 20mM imidazoles again, at last with the lysate eluted protein that contains the 300mM imidazoles, protein liquid behind the collection eluting.Get the above 10 μ L albumen samples that respectively go on foot and carry out the SDS-PAGE electrophoresis, the testing goal protein content.Protein liquid is dialysed in dialysis solution and is gone imidazoles, dialysis solution to contain 50mM HEPES (pH 8.0), 0.15M NaCl, 10% glycerol, 0.1%Triton X-100 behind the eluting.
DHODH is active to be determined by the method for measuring the DCIP minimizing, under the condition that coenzyme Q-10 exists, and DHODH catalytic substrate DHO, and two H are transferred on the prothetic group FMN of DHODH, and then pass to coenzyme Q-10, and pass to DCIP by coenzyme Q-10 at last, DCIP is reduced.Determine that by the amount of measuring the DCIP that per minute reduces enzyme lives.Assay method adopts 96 orifice plates to be read by the BioTek microplate reader.Every hole contains surveys the liquid 199 μ L (50mM HEPES (pH 8.0), 0.15M KCl, 100 μ M coenzyme Q-10s, 100 μ M DCIP) that live.Add 0.2 μ M inhibitor (being dissolved in DMSO), making the inhibitor final concentration is 10 μ M, and incubated at room 10min adds 1 μ L substrate DHO at last, and making the DHO final concentration is 500 μ M.Read 6min with microplate reader under the 600nm wavelength behind the mixing, interval 30s reads a secondary data.Each the experiment establish at least 3 parallel.Suppression ratio by the chemical compound variable concentrations calculates half effective inhibition concentration (IC at last
50).
Acquired results is as shown in the table:
The employing said method records, the half-inhibition concentration (IC of chemical compound 1
50) be 6.83 μ M, the IC of chemical compound 4
50Value is 0.35 μ M, the IC of chemical compound 5
50Value is 3.10 μ M, the IC of chemical compound 7
50Value is 5.94 μ M, the IC of chemical compound 9
50Value is 1.84 μ M, the IC of chemical compound 14
50Value is 3.18 μ M, the IC of chemical compound 15
50Value is 2.89 μ M.
Claims (10)
1. the 2-amino-benzothiazole derivatives shown in the following general formula I, its pharmaceutically acceptable salt, prodrug or the solvated compounds purposes in the medicine that the disease of preparation treatment or prevention DHODH mediation is used:
Wherein,
A is aryl or 5 or 6 yuan of heterocyclic radicals, and 1-2 carbon atom replaced by X in the heterocyclic radical, and X is independently selected from following atom or group: N, O, S, SO
2And SO;
R
1, R
2, R
3, R
4For identical or different, be selected from independently of one another following group: hydrogen, C
1-C
3Alkyl, halogen, hydroxyl, C
1-C
4Alkoxyl, nitro, amino, phenyl formamido group, aniline formamido group, aniline sulfo-formamido group, CN, NCO, NCS, carboxyl, C
1-C
3Alkoxyl formyl, C
1-C
3Amide groups and the optional aniline formoxyl that replaces;
R
5Be hydrogen, C
1-C
6Alkyl or benzoyl;
Each R
6Can be independently selected from following group: hydrogen, the optional C that replaces
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6The optional C that replaces of alkynyl
1-C
6Alkoxyl, hydroxyl, the optional morpholinyl that replaces, the optional piperazinyl that replaces, the optional amino that replaces, halogen, the optional phenoxy group that replaces, C
1-C
6Alkoxy carbonyl, acetyl group, benzoyl, C
3-C
8Cycloalkyl, cyano group, nitro, benzyl, oxyl, carboxyl, ester group, sulfonic group, sulfydryl, C
1-C
3Amide groups, NCO, NCS, straight chain or ring-type C
1-C
6Saturated or unsaturated acyl-oxygen base, 2-oxo-2,3-indoline-3-methylene; With
N is the integer of 0-5.
2. the 2-amino-benzothiazole derivatives shown in the general formula I of claim 1, its pharmaceutically acceptable salt, prodrug or solvated compounds suppress purposes in the medicine of the active usefulness of DHODH in preparation.
3. the 2-amino-benzothiazole derivatives shown in the general formula I of claim 1, its pharmaceutically acceptable salt, prodrug or solvated compounds suppress medicine that helicobacter pylori uses or the purposes in the preparation antifungal in preparation.
4. purposes as claimed in claim 1 is characterized in that, described disease is selected from: inflammatory reaction, cancer and because host's rejection of the same race or that xenotransplant causes.
5. purposes as claimed in claim 4 is characterized in that, described disease is selected from: autoimmune disease, colitis, renal glomerular disease (comprising multiple Secondary cases and primary glomerulopathy), anti-organ graft rejection and melanoma.
6. purposes as claimed in claim 4 is characterized in that, described disease is selected from rheumatoid arthritis, psoriatic arthritis, lupus erythematosus (comprising systemic lupus erythematosus (sle)) and psoriasis.
7. such as each described purposes among the claim 1-6, it is characterized in that described A is phenyl or furyl.
8. such as each described purposes among the claim 1-6, it is characterized in that described formula I chemical compound is the Formula Il chemical compound:
Wherein,
R
1, R
2, R
3, R
4For identical or different, be selected from independently of one another following group: hydrogen, C
1-C
3Alkyl, halogen, C
1-C
4Alkoxyl, nitro, amino, C
1-C
3Amide groups, phenyl formamido group, aniline formyl ammonia, aniline sulfo-formamido group, CN, NCO, NCS, carboxyl, C
1-C
3Alkoxyl formyl;
R
5Be hydrogen or C
1-C
3Alkyl;
R
6, R
7, R
8, R
9, R
10Identical or different, be selected from independently of one another following group: hydrogen, the optional C that replaces
1-C
6Alkyl, the optional C that replaces
2-C
6Alkenyl, the optional C that replaces
2-C
6Alkynyl, halogen, the optional amino that replaces, morpholinyl, the optional piperazinyl that replaces, acetyl group, benzoyl, nitro, hydroxyl, carboxyl, cyano group, sulfonic group, the optional sulfonyl that replaces, sulfydryl, the optional C that replaces
1-C
6Alkoxyl, phenoxy group, straight chain or ring-type C
1-C
6Saturated or unsaturated acyl-oxygen base, C
1-C
6Alkoxy carbonyl.
9. such as each described purposes among the claim 1-3, it is characterized in that described chemical compound is selected from:
10. a pharmaceutical composition is characterized in that, described compositions contains the 2-amino-benzothiazole derivatives shown in the following general formula I, its pharmaceutically acceptable salt, prodrug or solvated compounds, and pharmaceutically acceptable carrier or excipient:
Wherein,
A is aryl or 5 or 6 yuan of heterocyclic radicals, and 1-2 carbon atom replaced by X in the heterocyclic radical, and X is independently selected from following atom or group: N, O, S, SO
2And SO;
R
1, R
2, R
3, R
4For identical or different, be selected from independently of one another following group: hydrogen, C
1-C
3Alkyl, halogen, hydroxyl, C
1-C
4Alkoxyl, nitro, amino, phenyl formamido group, aniline formamido group, aniline sulfo-formamido group, CN, NCO, NCS, carboxyl, C
1-C
3Alkoxyl formyl, C
1-C
3Amide groups and the optional aniline formoxyl that replaces;
R
5Be hydrogen, C
1-C
6Alkyl or benzoyl;
Each R
6Can be independently selected from following group: hydrogen, the optional C that replaces
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6The optional C that replaces of alkynyl
1-C
6Alkoxyl, hydroxyl, the optional morpholinyl that replaces, the optional piperazinyl that replaces, the optional amino that replaces, halogen, the optional phenoxy group that replaces, C
1-C
6Alkoxy carbonyl, acetyl group, benzoyl, C
3-C
8Cycloalkyl, cyano group, nitro, benzyl, oxyl, carboxyl, ester group, sulfonic group, sulfydryl, C
1-C
3Amide groups, NCO, NCS, straight chain or ring-type C
1-C
6Saturated or unsaturated acyl-oxygen base, 2-oxo-2,3-indoline-3-methylene; With
N is the integer of 0-5.
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| CN 201110297601 CN103006645A (en) | 2011-09-27 | 2011-09-27 | Application of 2-aminobenzothiazole derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor |
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