CN1187332C - Tetrahydroisoquinoline hydroximic acid sulfamide compound, its synthesis method and its application - Google Patents

Tetrahydroisoquinoline hydroximic acid sulfamide compound, its synthesis method and its application Download PDF

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CN1187332C
CN1187332C CNB021115168A CN02111516A CN1187332C CN 1187332 C CN1187332 C CN 1187332C CN B021115168 A CNB021115168 A CN B021115168A CN 02111516 A CN02111516 A CN 02111516A CN 1187332 C CN1187332 C CN 1187332C
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tetrahydroisoquinoline
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acid
chirality
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CN1380288A (en
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马大为
丁克
吴问根
李佳
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention relates to a tetrahydroisoquinoline hydroximic acid sulfamide compound, a synthesis method and application of the tetrahydroisoquinoline hydroximic acid sulfamide compound used as an inhibitor for matrix proteinase and a drug, wherein R<1> and/or R<2> is H, OH, R or OR, R<3> and/or R<4> is H, OH, OR, Br, Cl, R, NO2 and NH2, and R is aliphatic alkyl or aryl of C<1-12>.

Description

Tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound, preparation method and use
Technical field;
The present invention relates to tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound, preparation method and use.This compound can be used as the inhibitor of stromatin enzyme, can be used for treating cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
Background technology
Matrix metalloproteinase (matrix metalloproteinases, MMPs) be the zinciferous endopeptidase of gang, all main components that can the degradation of cell epimatrix, thereby participate in renewal (the Ryoichi Hirayama of reticular tissue, Minoru Yamamota.Bioorg.Med.Chem.1997,5,765).Studies show that, some hypotype of MMP is that the human body normal physiological activity is necessary, the other hypotype is then being played the part of extremely important role in some pathology process, as transfer and (Schwartz, the M.A. such as diffusion, multiple arteriosclerosis of osteoarthritis, tumour; Van Eart, H.E.Prog.Med.Chem.1992,29,271).The overexpression meeting of these enzymes causes a large amount of disorders such as cancers, sacroiliitis, body ulcer, generations such as pulmonary emphysema, blood vessel scleratheroma.Therefore, as the target enzyme, it is one of problems of making earnest efforts of Pharmaceutical Chemists during the last ten years that development matrix metallo-proteinase inhibitor (MMPI) is treated these diseases with MMPs.
In the process of exploitation MMP selective depressant, Babine, (Babine, R.E. such as R.E; Bander, S.L., Chem.Rev., 1997,91,1395) research group's design synthesized piperidines sulphonyl Ammonia, thiazine sulphonyl ammoniac compounds, and find that they have the good restraining activity to MMP, and have good selectivity.Wherein the AG3340 of selective depressant MMP-2 and MMP-9 is used for clinical as the medicine of treatment cancer.Nearest Matter.H group (Matter, H.; Schwab, W., J.Med.Chem., 1999,42,4506-4523) a series of 2-aryl sulfonyls-1,2,3 have been synthesized in design, and 4-tetrahydroisoquinoline-3-carboxylate or 3-hydroxamic acid compound find that they have better inhibited activity to MMP.
Summary of the invention
The object of the invention provides a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound.
The object of the invention also provides a kind of synthetic method of above-mentioned tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound.
Another object of the present invention provides a kind of purposes of above-mentioned tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound.Show that through determination of activity great majority in them have wide spectrum, the ability of the different subunits of potent inhibition matrix metalloproteinase.Might be used to treat cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
The structural formula of related tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound is as described below among the present invention:
Figure C0211151600081
This compound also can be a chipal compounds.
Typical structural formula is as described below:
Or
Wherein: R 1And/or R 2Be to be positioned at 5-, 6-, H, OH or the OR of 7-or 8-position, R 3And/or R 4Be to be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ' H, OH, OR, Br, Cl, R, NO 2, NH 2Or R is C 1-12Aliphatic group or aryl.
Compound of the present invention can also following compound be an example:
Figure C0211151600084
Figure C0211151600091
Figure C0211151600101
Or
Deng.
The synthetic method of the above-mentioned tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound among the present invention can be a raw material with compound 34 or 36.
Compound 36 can be synthetic by two kinds of methods:
Figure C0211151600111
In the compound of the present invention, except that compound 1, all can R 1Or/and R 2For hydroxy benzaldehyde is a starting raw material, with phenolic hydroxyl group with after the benzyl oxide protection, with the Nitromethane 99Min. condensation, again through LiAlH 4Reduction, benzyl protection is sloughed in hydrogenation, obtains compound 34 m-hydroxyphenylacetamides, gets a-amino acid 35 with 34 with the oxoethanoic acid condensation, again with 35 in HCl (g)/MeOH esterification promptly obtain important intermediate 36 for raw material.
And compound 1 (R 1, R 2, R 3, R 4=H), can by phenyl aldehyde directly with the Nitromethane 99Min. condensation, restore, the compound 36 that obtains with esterification after the oxoethanoic acid condensation is a raw material.
The synthetic concrete operations reference of above compound 36 (Wayne K.Anderson, Howard L.Mcpherson.J.Med.Chem.1984,27,1321).
Method of the present invention can be made acid binding agent with the organic compound that contains lone-pair electron on the nitrogen, selectivity with 36 aminosulfonylization after, with azyloxy compound N H 2The OY reaction is the acid of the 6-hydroxy tetrahydro isoquinoline 99.9 hydroxyl trowel used for plastering among acidifying promptly obtains object sulfamide compound 37 again; With 6-hydroxy tetrahydro isoquinoline 99.9 hydroxyl trowel used for plastering acid sulphonamide 37 and C 1-12Fat or after the reaction of aromatic alcohol or its haloalkane generates ether, again with azyloxy compound N H 2The OY reaction then obtains the tetrahydroisoquinoline hydroxyl trowel used for plastering acid sulfamide compound of 6 ehter bond protections among the object; Compound 37 is made after the triflate and C 1-12Fat or replace or aromatic hydrocarbon that the end replaces obtains compound R with the coupling of Pd catalyzer 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzsulfamide that replaces is again with azyloxy compound N H 2Obtain the tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound of 6 alkyl after the OY reaction; R wherein 3Or/and R 4Just can obtain R behind the hydro-reduction during for the compound of nitro 3Or/and R 4Compound for amino.
Method of the present invention can also be with the oxoethanoic acid menthol ester reaction of compound 34 with chirality; the compound tetrahydroisoquinoline menthyl formate that R and two kinds of configurations of S are arranged that generates; above-mentioned two kinds of compounds reflux with hydrochloric acid, hydrochloric acid methanol respectively and obtain the tetrahydroisoquinoline methyl-formiate of two kinds of chiralitys respectively; again optionally with after the aminosulfonylization; at acidic conditions; NMM, HOBt effect are down; react the tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound that generates two kinds of chiralitys respectively with the compound of azyloxy, can be with above-mentioned method to R 1, R 2, R 3, R 4Substituting group is modified.
Concrete synthetic method is as follows:
1 contains in the presence of the acid binding agent of organic compound of lone-pair electron R in organic solvent and on the nitrogen 1, R 2, the tetrahydroisoquinoline that replaces Acid binding agent and R 3, R 4The mol ratio of the aryl sulfonyl halide that replaces is 1: 0.8-1.5: during 0.8-1.5, obtain R in reaction under-20 ℃-50 ℃ after 0.5-6 hour 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzsulfamide that replaces
Figure C0211151600122
In polar organic solvent, above-mentioned R 1, R 2, R 3, R 4The tetrahydroisoquinoline benzsulfamide and the molecular formula that replace are NH 2The reaction of the azyloxy compound of OY, mol ratio is followed successively by 1: 1-8, react 2-12 hour at normal temperatures after, acidifying obtains the R among the object 1, R 2, R 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound that replaces.
2 under solutions of weak acidity, and the oxoethanoic acid menthol ester of compound 34 with chirality reacted 3-24 hour in 0 ℃-60 ℃ organic polar solvent, and mol ratio is followed successively by 1: 1-2, the tetrahydroisoquinoline menthyl formate of generation have R and two kinds of configuration of compound of S; Above-mentioned two kinds of compounds more respectively with hydrochloric acid reflux 10-16 hour after, concentrate, add hydrochloric acid methanol backflow 10-16 hour, concentrate, obtain the R of R and two kinds of configuration chiralitys of S respectively 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl compound that replaces.
The R of R and two kinds of configuration chiralitys of S 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl compound that replaces and after hydrochloric acid reflux 8-12 hour, be dissolved under-10 ℃-room temperature of polar organic solvent neutralization, add N-methylmorpholine (NMM), dicyclohexylcarbodiimide (DCC), N-hydroxy benzo triazole (HOBt), splash into NH 2The mixed organic solvents solution of the NMM of OY and magnitude of recruitment slowly rises to room temperature after adding, react after 3-20 hour, and reaction generates the R of chirality 1, R 2, R 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound that replaces.The R of above-mentioned R and two kinds of configuration chiralitys of S 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl compound, N-methylmorpholine, dicyclohexylcarbodiimide, N-hydroxy benzo triazole, the NH that replace 2The mol ratio of OY is followed successively by 1: 0.5-5.0: 0.8-1.5: 1-2.0: 1-3.
If 3 with R 1Or/and R 2The R of=OH achiral or two kinds of R or S chirality 1, R 2, R 3, R 4The tetrahydroisoquinoline benzsulfamide that replaces is under alkaline condition and normal temperature and in the organic solution, respectively with C 1-12Fat or the reaction of fragrant haloalkane became ether in 5-24 hour, obtain corresponding R 1Or/and R 2Tetrahydroisoquinoline acid methyl esters benzenesulfonamides for alkoxyl group.Wherein sulfonamide compounds, C 1-12Fat or fragrant haloalkane, azyloxy compound N H 2The OY mol ratio is 1: 0.8-2: 1-8.Described organic solvent with alcohol for well.
4 at-78 ℃--20 ℃, the R of achiral or two kinds of R or S chirality 1, R 2, R 3, R 4The acid binding agent and the triflate Tf that contain the organic compound of lone-pair electron on the tetrahydroisoquinoline benzsulfamide that replaces, the nitrogen 2O reaction 0.1-1 hour generates R respectively 1Or/and R 2R for the achiral or chirality of fluoroform sulphur ester group 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzenesulfonamides that replaces.The above-claimed cpd mol ratio is followed successively by 1: 1-5: 1-5, and reaction is to carry out under the anhydrous and oxygen-free condition to good; Above-mentioned R 1Or/and R 2R for fluoroform sulphur ester group 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzenesulfonamides of the achiral or chirality that replaces is in alkali organic solvent and N 2Protection down, add fat or replace, aromatic hydrocarbon that the end replaces, contain the acid binding agent of lone-pair electron on the nitrogen, quaternary ammonium salt, reaction obtained R in 8-24 hour under CuI and palladium reagent catalyst action and 0-50 ℃ the time 1Or/and R 2R for fat base or substituted aryl 1, R 2, R 3, R 4The achirality that replaces or the tetrahydroisoquinoline of chirality acid methyl esters benzenesulfonamides, wherein R 1Or/and R 2R for fluoroform sulphur ester group 1, R 2, R 3, R 4The acid binding agent that contains lone-pair electron on tetrahydroisoquinoline acid methyl esters benzenesulfonamides, fat or the replacement of the achiral or chirality that replaces, the aromatic hydrocarbon that the end replaces, the nitrogen, quaternary ammonium salt, mol ratio is respectively 1: 1-10: 1-10: 1-10, and with respect to CuI and the palladium reagent catalyzer of the 0.2-2% of triflate weight.R 1Or/and R 2R for fat base or substituted aryl 1, R 2, R 3, R 4The achirality that replaces or the tetrahydroisoquinoline of chirality acid methyl esters benzenesulfonamides and NH 2The azyloxy compound reaction of OY obtains R equally 1Or/and R 2R for alkyl 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound of the achiral or chirality that replaces.
5 R 3Or/and R 4R for the achiral or chirality of nitro 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzsulfamide that replaces, in methanol solution, adding weight percentage is the Pd/C of 8-15%, under the normal temperature and pressure hydrogenation 5-10 hour, obtains R 3Or/and R 4For amino, R 1, R 2The tetrahydroisoquinoline acid methyl esters benzenesulfonamides of the achiral or chirality that replaces.
Then, in methylene dichloride, methyl alcohol, chloroform isopolarity organic solvent, R 3Or/and R 4For amino, R 1, R 2The tetrahydroisoquinoline acid methyl esters benzenesulfonamides of the achiral or chirality that replaces and the compound reaction of azyloxy, mol ratio is 1: 1-8, to react after 2-12 hour, acidifying obtains target product R 3Or/and R 4R for amino 1, R 2, R 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound of the achiral or chirality that replaces.
Following reaction formula can be used as above-mentioned examples of reactions, but is not whole:
Figure C0211151600141
R 1And R 2Can exchange, also can be identical; R 5Be H, OH.
R described in the inventive method 1, R 2, R 3And/or R 4As previously mentioned, i.e. R 1And/or R 2Be H, OH or OR, R 3And/or R 4Be H, OH, OR, Br, Cl, R, NO 2, NH 2Or R is C 1-12Aliphatic group or aryl, R in the compound of the present invention that is generated 1And/or R 2Be to be positioned at 5-, 6-, 7-or 8-position, R 3And/or R 4Be to be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ' justice.The organic compound acid binding agent that contains lone-pair electron on the described nitrogen can be pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine (DMAP), N, N-diisopropyl ethyl amine (DIEA), bipyridine etc.Described polar organic solvent can be methylene dichloride, methyl alcohol, chloroform etc.Described azyloxy compound N H 2Y=comprises the monovalence metal or the C of potassium, sodium etc. among the OY 1-5Alkyl, as NH 2OK, NH 2ONa, NH 2OBn etc.Described alkali organic solvent can be N, dinethylformamide (DMF), triethylamine, N,N-dimethylacetamide etc.Described palladium reagent can be Pd (PPh 3) 4, Pd (OAc) 2, Pd (dppf) Cl 2, Pd 2(dba) 3Or Pd (PPh 3) 2Cl 2Wherein Bn is a benzyl, PPh 3For triphenylphosphinyl, dppf are 1,1 '-two (diphenylphosphino) ferrocene, dba is to benzyl acetone.
Related tetrahydroisoquinoline hydroxyl trowel used for plastering acid sulfamide compound novel structure among the present invention, simple synthetic method not only, and this compound shows that through determination of activity great majority in them have wide spectrum, the ability of the different subunits of potent inhibition matrix metalloproteinase.Might be used to treat cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
N-benzenesulfonyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid (2) synthetic:
1) 1-methoxycarbonyl-6-hydroxyl-1,2,3, (0.6g 2.9mmol) is dissolved in 20ml CH to the 4-tetrahydroisoquinoline 2Cl 2In, (0.24ml, 2.9mmol), (0.36ml, 2.9mmol), equality of temperature stirred after 1 hour 0 ℃ of following dropping benzene sulfonyl chloride, aq.NaHCO to add pyridine 3, H 2O, HCl, aq.NaCl respectively wash once, and purification by silica gel column chromatography (PE: EA, 3: 2) gets N-benzenesulfonyl-1-methoxycarbonyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline 0.84g (83%); 1H NMR (300MHz, CDCl 3) δ 2.75～2.83 (m, 2H), 3.54 (s, 3H), 3.74～3.83 (m, 2H), 5.49 (s, 1H), 6.54 (d, J=2Hz, 1H), 6.68 (dd, J=8,3Hz, 1H), 7.18 (d, J=8Hz), 7.49～7.59 (m, 3H), 7.78 (dd, J=8,1Hz, 2H).
2) get compound N-benzenesulfonyl-1-methoxycarbonyl-6-hydroxyl-1,2,3, (109mg 0.31mmol) is dissolved among the MeOH 2ml 4-tetrahydroisoquinoline, adds KONH 2Methanol solution 1.5ml (1M is by HONH 2HCl and KOH reaction makes), stirring at room transferred to acidity with 1N HCl after 4 hours, be evaporated to dried, purification by silica gel column chromatography (PE: EA, 2: 3), N-benzenesulfonyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid 0.9g (83%); 1H NMR (300MHz, acetone-d 6) δ 2.49～2.73 (m, 1H), 2.83～2.95 (m, 1H), 3.50～3.58 (m, 1H), 3.95～4.06 (m, 1H), 5.29 (s, 1H), 6.55 (s, 1H), 6.64 (dd, J=8,2Hz, 1H), 7.14 (d, J=8Hz, 1H), 7.49～7.55 (m, 3H), 7.88 (dd, J=8,1Hz, 2H); EI-MS (m/z): 719 (2M ++ Na), 543 ((3M ++ K+H)/2,100%), 371 (M ++ Na), 349 (M ++ H); HRMS (EI, m/z), calculated value C 15H 13NO 3S (M +-CONHOH): 287.06161, measured value 287.06144.
Embodiment 2
N-(to the anisole alkylsulfonyl)-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid (8) synthetic:
1) with compound N-benzenesulfonyl-1-methoxycarbonyl-6-hydroxyl-1,2,3; 4-tetrahydroisoquinoline (380mg; 1.1mmol) be dissolved among the anhydrous MeOH 3ml, add 2M MeONa 0.6ml, 0 ℃ adds bromobenzyl (0.3ml down; 1.6mmol); after stirring is spent the night under the room temperature, concentrate, resistates is dissolved in ethyl acetate; with 1N HCl, H 2O, aq.NaHCO 3Washing, purification by silica gel column chromatography (PE: EA, 4: 1) gets N-benzenesulfonyl-1-methoxycarbonyl-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline 0.69g (86%); 1H NMR (300MHz, CDCl 3) δ 2.83～2.95 (m, 2H), 3.55 (s, 3H), 3.84 (dd, J=6,1Hz, 2H), 5.02 (s, 2H), 5.52 (s, 1H), 6.70 (d, J=2Hz, 1H), 6.85 (dd, J=8,2Hz, 1H), 7.25～7.85 (m, 11H).
2) get compound N-to anisole alkylsulfonyl-1-methoxycarbonyl-6-benzyloxy-1,2,3, (145mg 0.31mmol) is dissolved among the MeOH 2ml 4-tetrahydroisoquinoline, adds KONH 2Methanol solution 1.5ml (1M is by HONH 2HCl and KOH reaction make), stirring at room transferred to acidity with 1N HCl after 4 hours, was evaporated to dried, purification by silica gel column chromatography (PE: EA, 2: 3) gets N-(to the anisole alkylsulfonyl)-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid 0.12g (83%); 1H NMR (600MHz, CDCl 3) δ 2.61～2.66 (m, 1H), 2.74～2.77 (m, 1H), 3.39 ~ 3.41 (t, J=5Hz, 1H), 3.69 (s, 1H), 3.82 (s, 3H), 4.98 (s, 2H), 5.29 (s, 1H), 6.62 (d, J=2Hz, 1H), 6.81 (d, J=5Hz, 1H), 6.90 (d, J=2Hz, 2H), 7.21～7.37 (m, 5H), 7.71 (d, J=8Hz, 2H), 9.30 (brs, 1H); EI-MS (m/z): 468 (M +), 408 (M +-CONHOH), 357,119,91 (PhCH 2 +, 100%); HRMS (EI, m/z), calculated value C 23H 22NO 4S (M +-CONHOH): 408.12696, measured value: 408.12352.
Embodiment 3
N-(2,5-dichlorobenzene alkylsulfonyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid (6) synthetic:
1) 1-methoxycarbonyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline and 2,5-dichloro benzosulfonic acid are raw material, method obtains product N-(2,5-dichlorobenzene alkylsulfonyl)-1-methoxycarbonyl-6-hydroxyl-1,2,3, the 4-tetrahydroisoquinoline with example 1 (1) 1H NMR (300MHz, CDCl 3) δ 2.74～2.95 (m, 2H), 3.60 (s, 3H), 3.92～4.07 (m, 2H), 5.30 (brs, 1H), 5.57 (s, 1H), 6.63 (d, J=2Hz, 1H), 6.73 (dd, J=8,2Hz, 1H), 7.30～7.53 (m, 3H), 8.17 (d, J=2Hz, 1H).
2) method obtains product N-(2,5-dichlorobenzene alkylsulfonyl)-1-methoxycarbonyl-6-benzyloxy-1,2,3, the 4-tetrahydroisoquinoline with example 2 (1) 1H NMR (300MHz, CDCl 3) δ 2.72～2.95 (m, 2H), 3.63 (s, 3H), 3.85～4.01 (m, 2H), 5.03 (s, 2H), 5.57 (s, 1H), 6.67 (d, J=2Hz, 1H), 6.87 (dd, J=8,2Hz, 1H), 7.26～7.45 (m, 8H), 8.13 (d, J=2Hz, 1H).
3) method obtains product N-(2,5-dichlorobenzene alkylsulfonyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid with example 1 (2). 1H NMR (300MHz, acetone-d 6) δ 2.57～2.71 (m, 1H), 2.71～2.85 (m, 1H), 3.71～3.80 (m, 1H), 4.05～4.16 (m, 1H), 5.31 (s, 1H), 6.53～6.65 (m, 2H), 7.07 (d, J=8Hz, 1H), 7.48～7.53 (m, 2H), 8.05 (d, J=2Hz, 1H); EI-MS (m/z): 355 (M +-CONHOH), measured value: 54.97924.
Embodiment 4
N-(p-nitrophenyl alkylsulfonyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid (5) synthetic:
1) 1-methoxycarbonyl-6-hydroxyl-1,2,3, (0.6g 2.9mmol) is dissolved in 20ml CH to the 4-tetrahydroisoquinoline 2Cl 2In, (0.24ml, 2.9mmol), (0.36ml, 2.9mmol), equality of temperature stirred after 1 hour 0 ℃ of following dropping p-nitrophenyl SULPHURYL CHLORIDE, aq.NaHCO to add pyridine 3, H 2O, 1NH 4Cl, each washs aq.NaCl once, and purification by silica gel column chromatography (PE: EA, 3: 2) gets N-p-nitrophenyl alkylsulfonyl-1-methoxycarbonyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline 0.91g (86%); 1H NMR (300MHz, CDCl 3) δ 2.84～2.96 (m, 2H), 3.57 (s, 3H), 3.79～3.91 (m, 2H), 5.40 (brs, 1H), 5.55 (s, 1H), 6.58 (d, J=2Hz, 1H), 6.71 (dd, J=8,2Hz, 1H), 7.35 (d, J=2Hz, 1H), 8.03～8.09 (m, 2H), 8.35～8.43 (m, 2H).
2) get compound N-p-nitrophenyl alkylsulfonyl-1-methoxycarbonyl-6-hydroxyl-1,2,3, (123mg 0.31mmol) is dissolved among the MeOH 2ml 4-tetrahydroisoquinoline, adds KONH 2Methanol solution 1.5ml (1M is by HONH 2HCl and KOH reaction make), stirring at room transferred to acidity with 1N HCl after 4 hours, was evaporated to dried, purification by silica gel column chromatography (PE: EA, 2: 3) gets N-p-nitrophenyl alkylsulfonyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid 1.05g (86%); 1H NMR (300MHz, acetone-d 6) δ 2.75～2.88 (m, 1H) .88～2.96 (m, 1H), 3.73～3.82 (m, 1H), 3.96～4.09 (m, 1H), 5.33 (s, 1H), 6.55 (s, 1H), 6.64 (dd, J=8,2Hz, 1H), 7.13 (d, J=8Hz, 1H), 8.14 (d, J=8Hz, 2H), 8.36 (d, J=8Hz, 2H); EI-MS (m/z): 332 (M +-CONHOH), 146 (100%); HRMS (EI, m/z), calculated value C 15H 13N 2O 5S (M +-CONHOH): 333.05452, measured value: 333.05314.
Embodiment 5
N-benzenesulfonyl-6-(1-certain herbaceous plants with big flowers alkynyl)-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid (12) synthetic:
1) compound N-benzenesulfonyl-1-methoxycarbonyl-6-hydroxyl-1,2,3, (175mg 0.5mmol) is dissolved in CH to the 4-tetrahydroisoquinoline 2Cl 2Among the 4ml, add NEt 3(0.21ml), in-78 ℃, N 2Be added dropwise to Tf under the protection 2O (0.12ml) adds the shrend reaction of going out behind the 10min, rise to room temperature, CH 2Cl 2Dilution after the organic phase washing, behind the purification by silica gel column chromatography (PE: EA, 4: 1), is dissolved in it among DMF 5ml N 2Protection adds 1-certain herbaceous plants with big flowers alkynes (0.44ml), NEt down 3(0.34ml), Bu 4NI (0.5g), the CuI of catalytic amount and Pd (PPh 3) 2Cl 2, stirred overnight at room temperature concentrates, after the ethyl acetate dilution, and water, the aq.NaCl washing, purification by silica gel column chromatography (PE: EA, 7: 1) gets N-benzenesulfonyl-1-methoxycarbonyl-6-(1-certain herbaceous plants with big flowers alkynyl)-1,2,3,4-tetrahydroisoquinoline 0.19g (76%); 1H NMR (300MHz, CDCl 3) δ 0.89 (t, J=7Hz, 3H), 1.20～1.70 (m, 12H), 2.47 (t, J=7Hz, 2H); 2.81～2.88 (m, 2H), 3.35 (s, 3H), 3.78～3.85 (m, 2H), 5.55 (s, 1H), 7.12～7.35 (m, 3H), 7.47～7.58 (m, 3H), 7. (d, J=7Hz, 2H); EI-MS (m/z): 408 (M +-CO 2CH 3, 100%); ESI-MS (m/z): 490 (M ++ Na), 408 (M +-CO 2CH 3)
2) get compound N-benzenesulfonyl-1-methoxycarbonyl-6-(1-certain herbaceous plants with big flowers alkynyl)-1,2,3, (155mg 0.31mmol) is dissolved among the MeOH 2ml 4-tetrahydroisoquinoline, adds KONH 2Methanol solution 1.5ml (1M is by HONH 2HCl and KOH reaction make), stirred after 4 hours the chamber, transfers to acidity with 1N HCl, is evaporated to dried; purification by silica gel column chromatography (PE: EA, 2: 3) gets N-benzenesulfonyl-6-(1-certain herbaceous plants with big flowers alkynyl)-1; 2,3,4-tetrahydroisoquinoline-1-hydroxamic acid 0.126g (81%) 1H NMR (300MHz, CDCl 3) δ 0.86 (t, J=8Hz, 3H), 1.15～1.67 (m, 12H), 2.38 (t, J=7Hz, 2H), 2.50～2.64 (m, 1H), 2.64～2.78 (m, 1H), 3.44～3.53 (m, 1H), 3.66～3.78 (m, 1H), 5.47 (s, 1H), 7.03 (s, 1H), 7.18 (s, 2H), 7.31～7.55 (m, 3H), 7.77 (d, J=7Hz, 2H); EI-MS (m/z): 408 (M +-CONHOH), 267.
Embodiment 6
(S)-and 6-hydroxyl-7-methoxyl group-2-(tolysulfonyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-1-hydroxamic acid (21) and (R)-6-hydroxyl-7-methoxyl group-2-(tolysulfonyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-1-hydroxamic acid (22) synthetic:
1) 15.22g (0.1mol) 3-hydroxyl-4-methoxybenzaldehyde is dissolved in 120ml methyl alcohol, add sodium hydroxide 4.00g (0.1mol), after the stirring and dissolving, add bromobenzyl 11.9ml (0.1mol), room temperature reaction, TLC track to the raw material completely dissolve, drain methyl alcohol, add less water, hydrochloric acid transfers pH value to being approximately 7, and ethyl acetate extraction three times merges organic phase, water, saturated nacl aqueous solution washing successively, anhydrous sodium sulfate drying filters, and concentrates, column chromatography gets 23.02g compound 3-benzyloxy-4-methoxybenzaldehyde, productive rate 95%. 1H-NMR(300MHz，CDCl 3)δ9.82(s，1H)，7.45～6.98(m，8H)，5.19(s，2H)，3.96(s，3H).EI-MS(m/z)242(M +)，243，92，91，77，65，63，51。
2) 16.7g (0.069mol) 3-benzyloxy-4-methoxybenzaldehyde (1eq) is dissolved in the 60ml Glacial acetic acid, adds 5.852g (0.076mol) ammonium acetate, 7.25ml (0.138mol) CH 3NO 2, stirring heating backflow (110 ℃) is blackish green to solution, and cooling with frozen water, is filtered filter cake CHCl 3-Hexane (1/1) recrystallization gets 18.95g2-benzyloxy-1-methoxyl group-4-(2-nitro allyl group) benzene, productive rate 96.3%. 1H-NMR(300MHz，CDCl 3)δ7.91(d，J＝13.6Hz，1H)，7.47～6.91(m，9H)，5.17(s，2H)，3.94(s，3H).EI-MS(m/z)285(M +)，92，91，77，65，63，50。
3) under the room temperature, 11.20g (0.039mol) 2-benzyloxy-1-methoxyl group-4-(2-nitro allyl group) benzene is dissolved in the 60ml anhydrous methylene chloride, stirs and dropwise splash into LiAlH down 4(4.71g, anhydrous Et 0.122mol) 2In O (150ml) suspension liquid, react half an hour, slowly add water 4.2ml, 15%NaOH (4.2ml), H 2O (12.6ml) filters, and filtrate is used anhydrous sodium sulfate drying.Filter, concentrate, get 9.1g3-benzyloxy-4-orthoxine, productive rate 90.1%, underpressure distillation: 148～152 ℃/5Pa. 1H-NMR (300MHz, CDCl 3) δ 7.47～6.76 (m, 8H), 5.17 (s, 2H), 3.89 (s, 3H), 2.89 (t, J=6.7Hz, 2H), 2.65 (t, J=6.7Hz, 2H), 1.38 (br, 2H) .EI-MS (m/z) 257 (M +), 229,228,167,137,92,91,65.
4) 3-benzyloxy-4-orthoxine is dissolved in methyl alcohol, adds Pd-C (10%), normal temperature, normal pressure hydrogenation 6 hours filter, concentrate product 3-hydroxyl-4-orthoxine, productive rate 98.2%. 1H-NMR (300MHz, CDCl 3) δ 6.93～6.64 (m, 3H), 3.83 (s, 3H), 3.22 (br, 1H), 2.94 (t, J=6.8Hz, 2H), 2.66 (t, J=6.8Hz, 2H) .EI-MS (m/z) 167 (M +), 151,139,138,137,123,122,94.
5) the 3-hydroxyl-4-orthoxine hydrochloride with 2.11g (10.3mmol) is dissolved in the ethanol, transfer to slightly acidic with 4N hydrochloric acid after, add 2.77g (13mmol) oxoethanoic acid menthol ester 56, slowly be heated to 50 ℃, TLC tracks to and reacts completely.Concentrate and remove ethanol, add less water, ethyl acetate extraction 3 times, merge organic phase, water successively, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrate, column chromatography gets 1.68g (S) type 6-benzyloxy-7-methoxyl group-1,2,3,4-tetrahydroisoquinoline menthyl formate 57 (a) and 1.05g (R) type compound 58 (a).The overall yield 73.2% of diastereomer 57 (a) and 58 (a), ratio is 1.6: 1,57 (a) [α] D 24=+4.1 (c=1.0, CHCl 3). 1H-NMR (300MHz, CDCl 3) δ 6.86 (s, 1H), 6.66 (s, 1H), 4.80 (td, J=10.9,4.4Hz, 1H), 4.64 (s, 1H), 3.85 (s, 3H), 3.29 (m, 1H), 3.00 (m, 1H), 2.69 (m, 2H), 2.05～0.75 (m, 18H) .EI-MS (m/z) 178 (M-183, C 11H 19O 2), 179,163,135,134,107,55,41.ESI-MS 362.3 (M+1) .X-ray diffraction .58 (a) [α] D 24=-72.2 (c=1.0, CHCl 3). 1H-NMR (300MHz, CDCl 3) δ 6.85 (s, 1H), 6.62 (s, 1H), 4.79 (td, J=10.9,4.4Hz, 1H), 4.61 (s, 1H), 3.84 (s, 3H), 3.25 (m, 1H), 3.01 (m, 1H), 2.69 (m, 2H), 2.00～0.67 (m, 18H) .EI-MS (m/z) 178 (M-183, C 11H 19O 2), 179,163,135,134,107,55,41.
6) with 0.67g (1.86mmol) S type compound 57 (a), join 6N hydrochloric acid, reflux after 14 hours, be cooled to room temperature, with dichloromethane extraction three times, water layer concentrates, and oil pump is drained, and adds hydrochloric acid methanol and refluxes 12 hours, concentrate, transfer to alkalescence with sodium hydrogen carbonate solution, CHCl 3Extract three times, merge organic phase, water successively, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and concentrates, and column chromatography gets 0.25g compound (S)-6-hydroxyl-7-methoxyl group-1,2,3,4-tetrahydroisoquinoline-1-methyl-formiate, productive rate 56.5%.
[α] D 22＝+9.58(c＝1.0，CHCl 3)。
1H-NMR(300MHz，CDCl 3)δ6.84(s，1H)，6.65(s，H)，4.68(s，1H)，3.86(s，3H)，3.77(s，3H)，3.23(m，1H)，3.03(m，1H)，2.79(m，2H)。
EI-MS(m/z)237(M +)，179，178，165，164，163，135，134。
HRMS calculated value C 12H 15NO 4(M +): 37.10011, measured value: 237.10029.
7) compound (S)-6-hydroxyl-7-methoxyl group-1,2,3,4-tetrahydroisoquinoline-1-methyl-formiate (1eq) is dissolved in methylene dichloride, at the dichloromethane solution of-10 ℃ of following agitation and dropping aryl sulfonyl chlorides (1eq), and the dichloromethane solution of pyridine (1eq), after adding, temperature slowly rises to-5 ℃, after TLC tracks to the raw material complete reaction, uses the dilute hydrochloric acid cancellation.Add less water, transfer pH about 5, dichloromethane extraction three times merges organic phase, water successively, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and concentrates, column chromatography gets (S)-6-hydroxyl-7-methoxyl group-2-tolysulfonyl-1,2,3,4-tetrahydroisoquinoline-1-methyl-formiate.Productive rate 76.9%.
[α] D 24＝-21.5(c＝1.0，CHCl 3)。
IR(KBr，cm -1)3439，2959，1730，1598，1519，1329，838，806。
1H-NMR(300MHz，CDCl 3)δ7.75(d，J＝9.0Hz，2H)，6.95(d，J＝9.0Hz，2H)，6.84(s，1H)，6.63(s，1H)，5.64(s，1H)，5.42(s，1H)，3.86(s，3H)，3.85(s，3H)，3.77(m，2H)，3.59(s，3H)，2.73(m，2H)。
EI-MS(m/z)348(M-59，C 2H 3O 2)，349，177，176，171，107，92，77。
HRMS calculated value C 17H 18NO 5S (M-59, C 2H 3O 2): 48.08938, measured value: 348.08419
8) compound (S)-6-hydroxyl-7-methoxyl group-2-tolysulfonyl-1,2,3,4-tetrahydroisoquinoline-1-methyl-formiate (1eq) joins 4N hydrochloric acid, refluxes after 8～12 hours, be cooled to room temperature, concentrating under reduced pressure, oil pump is drained, be dissolved in methylene dichloride, add NMM (1eq), stir after 10 minutes, under ice-water bath, add DCC (1.1eq), add HOBt (1.3eq) after 5 minutes, continue to stir 10 minutes, splash into the mixing dichloromethane solution of BnONH2 HCl (2eq) and NMM (2eq), slowly rise to room temperature after adding, after TLC tracks to the raw material complete reaction, filter, filtrate is dissolved in ethyl acetate after concentrating, use dilute hydrochloric acid successively, saturated sodium bicarbonate, water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, concentrate, column chromatography gets compound (S)-6-hydroxyl-7-methoxyl group-2-tolysulfonyl-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid, productive rate 62.5%.
[α] D 22＝-7.6(c＝1.0，CH 3OH)。
IR(KBr，cm -1)3283，2939，1641，1597，1499，1347，835，805。
1H-NMR(300MHz，DMSO-d 6)δ10.99(s，1H)，9.02(s，1H)，8.98(s，1H)，7.69(d，J＝8.8Hz，2H)，7.05(d，J＝8.8Hz，2H)，6.80(s，1H)，6.48(s，1H)，5.05(s，1H)，3.92(m，1H)，3.87(s，3H)，3.80(s，3H)，3.41(m，1H)，2.68(m，1H)，2.46(m，1H)。
EI-MS(m/z)348(M-60，CH 2NO 2)，347，177，176，171，161，107，77。
HRMS calculated value C 17H 18NO 5S (M-60, CH 2NO 2): 348.09057, measured value: 348.08852.
9) 58 same 6), 7), 8), obtaining R type product, productive rate is 50.3%.
[α] D 22＝-4.3(c＝1.0，CHCl 3)。
1H-NMR(300MHz，CDCl 3)δ6.85(s，1H)，6.67(s，H)，4.68(s，1H)，3.88(s，3H)，3.79(s，3H)，3.25(m，1H)，3.05(m，1H)，2.71(m，2H)。
EI-MS(m/z)238(M+1)，179，178，176，164，163，135，134。
Embodiment 7
Through Chinese Academy of Sciences's Shanghai medicine Ye Qizhuan researcher seminar part target compound of the present invention has been carried out biological activity test, the MMP-1 (collagenase-1) of these compounds to being tested, MMP-3 (matrix lytic enzyme-1), MMP-9 (gelatinase-B), MMP-12 (scavenger cell elastoser), MMP-13 (collagenase-3), MMP-15 (membranous type 2-MMPs), the inhibition of MMP-16 (membranous type 3-MMPs) is active in table 1.
The biological activity test of table 1 new medium proteinase inhibitor
Compound IC50(μM)
MMP-1 MMP-3 MMP-9 MMP-12 MMP-13 MMP-15 MMP-16
2 ＞6.25 1.962 0.430 0.278 0.389 0.385 0.289
3 ＞6.25 ＞6.25 1.942 ＞6.25 ＞6.25 ＞6.25 ＞6.25
4 0.252 0.083 0.061 0.013 0.048 0.055 0.033
5 0.198 0.710 0.481 0.064 0.194 0.441 0.273
6 ＞83.25 ＞83.25 ＞83.25 22.301 ＞83.25 ＞83.25 361.767
7 1.010 0.218 0.125 0.099 0.182 0.178 0.121
8 0.423 0.292 0.159 0.110 0.207 0.075 0.108
9 1.104 0.22 0.200 0.073 0.162 0.264 0.193
10 ＞83.25 26.990 16.073 0.425 42.060 59.356 15.681
11 0.586 0.18 0.031 0.039 0.068 0.042 0.029
12 ＞83.25 ＞83.25 39.926 11.854 36.115 ＞83.25 71.143
13 ＞6.25 0.347 0.125 0.060 0.294 0.308 0.141
21(S) 0.852 * 0.150 0.135 0.129 0.117 0.085
22(R) 1.946 * 0.221 0.179 0.278 0.295 0.147
23(S) 0.111 0.114 0.042 0.051 0.051 0.009 0.015
24(R) 0.127 * 0.037 0.038 0.050 0.012 0.017
25(S) 0.566 * 0.086 0.097 0.129 0.097 0.067
26(R) 0.767 * 0.033 0.083 0.137 0.058 0.046
28(R) ＞83.25 ＞83.25 8.613 10.939 46.694 49.518 15.200
29(S) ＞6.25 * 2.872 ＞6.25 5.485 0.861 0.373
30(R) ＞83.25 ＞83.25 29.090 10.750 40.181 52.053 34.132
31(S) 1.198 * 0.117 0.142 0.225 0.101 0.082
32(R) ＞83.25 ＞83.25 17.903 11.684 47.174 30.228 26.102
The result shows that tetrahydroisoquinoline hydroxamic acid compound of the present invention has the obvious suppression effect to matrix metalloproteinase, can be developed to medicines such as novel anticancer, sacroiliitis.

Claims (10)

1. tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound, its structural formula is as follows:
Figure C021115160002C1
Wherein, R 1And/or R 2Be to be positioned at 5-, 6-, H, OH or the OR of 7-or 8-position, R 3And/or R 4Be to be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ' H, OH, OR, Br, Cl, R, NO 2, NH 2Or R is C 1-12Aliphatic group or aryl.
2. a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 1 is characterized in that structural formula is as follows: Or
Figure C021115160002C3
Wherein, R 1, R 2, R 3Or R 4According to claim 1.
3. a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 1 is characterized in that structural formula is as follows:
Figure C021115160003C2
Or
Figure C021115160003C3
4. the preparation method of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 1, it is characterized in that following (! ), the method for (2), (3), (4), (5), (6) prepares respectively:
(! ) in organic solvent and on the nitrogen, contain in the presence of the acid binding agent of organic compound of lone-pair electron R 1, R 2The tetrahydroisoquinoline that replaces
Figure C021115160004C1
Acid binding agent and R 3, R 4The mol ratio of the aryl sulfonyl halide that replaces is 1: 0.8-1.5: during 0.8-1.5, obtain R in reaction under-20 ℃-50 ℃ after 0.5-6 hour 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzsulfamide that replaces
Figure C021115160004C2
In polar organic solvent, above-mentioned R 1, R 2, R 3, R 4The tetrahydroisoquinoline benzsulfamide and the molecular formula that replace are NH 2The azyloxy compound reaction of OY, mol ratio is followed successively by 1: 1-8, to react at normal temperatures 2-12 hour, acidifying obtains R 1, R 2, R 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound that replaces;
(2) under solutions of weak acidity, the oxoethanoic acid menthol ester of compound 34 with chirality to be reacted 3-24 hour in 0 ℃-60 ℃ organic polar solvent, mol ratio is followed successively by 1: 1-2, the tetrahydroisoquinoline menthyl formate of generation have R and two kinds of configuration of compound of S; Above-mentioned two kinds of compounds more respectively with hydrochloric acid reflux 10-16 hour after, add hydrochloric acid methanol backflow 10-16 hour, obtain the R of R and two kinds of configuration chiralitys of S respectively 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl compound that replaces;
The R of R and two kinds of configuration chiralitys of S 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl compound that replaces is dissolved under-10 ℃-room temperature of polar organic solvent neutralization adding N-methylmorpholine, dicyclohexylcarbodiimide, N-hydroxy benzo triazole, NH with after hydrochloric acid reflux 8-12 hour 2The mixed organic solvents solution of OY reacted 3-20 hour, generated the R of chirality 1, R 2, R 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound that replaces, the R of above-mentioned R and two kinds of configuration chiralitys of S 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl compound, N-methylmorpholine, dicyclohexylcarbodiimide, N-hydroxy benzo triazole, the NH that replace 2The mol ratio of OY is followed successively by 1: 0.5-5.0: 0.8-1.5: 1-2.0: 1-3;
(3) if with R 1Or/and R 2The R of=OH achiral or two kinds of R or S chirality 1, R 2, R 3, R 4The tetrahydroisoquinoline benzsulfamide that replaces is under alkaline condition and normal temperature and in the organic solution, respectively with C 1-12Fat or fragrant haloalkane reaction 5-24 hour, obtain corresponding R 1Or/and R 2Be the tetrahydroisoquinoline acid methyl esters benzenesulfonamides of alkoxyl group, wherein sulfonamide compounds, C 1-12Fat or fragrant haloalkane, azyloxy compound N H 2The OY mol ratio is 1: 0.8-2: 1-8;
(4) at-78 ℃--20 ℃, RU, the R of achiral or two kinds of R or S chirality 2, R 3, R 4The acid binding agent and the triflate that contain the organic compound of lone-pair electron on the tetrahydroisoquinoline benzsulfamide that replaces, the nitrogen were reacted 0.1-1 hour, generated R respectively 1Or/and R 2R for the achiral or chirality of fluoroform sulphur ester group 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzenesulfonamides that replaces, the above-claimed cpd mol ratio is followed successively by 1: 1-5: 1-5; Above-mentioned R 1Or/and R 2R for fluoroform sulphur ester group 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzenesulfonamides of the achiral or chirality that replaces is in alkali organic solvent and N 2Protection down, add fat or replace, aromatic hydrocarbon that the end replaces, contain the acid binding agent of lone-pair electron on the nitrogen, quaternary ammonium salt, reaction obtained R in 8-24 hour under CuI and palladium reagent catalyst action and 0-50 ℃ the time 1Or/and R 2R for fat base or substituted aryl 1, R 2, R 3, R 4The achirality that replaces or the tetrahydroisoquinoline of chirality acid methyl esters benzenesulfonamides, wherein R 1Or/and R 2R for fluoroform sulphur ester group 1, R 2, R 3, R 4The acid binding agent that contains lone-pair electron on tetrahydroisoquinoline acid methyl esters benzenesulfonamides, fat or the replacement of the achiral or chirality that replaces, the aromatic hydrocarbon that the end replaces, the nitrogen, quaternary ammonium salt, mol ratio is respectively 1: 1-10: 1-10: 1-10, and with respect to CuI and the palladium reagent catalyzer of the 0.2-2% of triflate weight; R 1Or/and R 2R for fat base or substituted aryl 1, R 2, R 3, R 4The achirality that replaces or the tetrahydroisoquinoline of chirality acid methyl esters benzenesulfonamides and NH 2The azyloxy compound reaction of OY obtains R with (1) method 1Or/and R 2R for alkyl 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound of the achiral or chirality that replaces;
(5) R 3Or/and R 4R for the achiral or chirality of nitro 1, R 2, R 3, R 4The tetrahydroisoquinoline acid methyl esters benzsulfamide that replaces, in methanol solution, adding weight percentage is 8-15%'s Pd/ C under the normal temperature and pressure hydrogenation 5-10 hour, obtains R 3Or/and R 4For amino, R 1, R 2The tetrahydroisoquinoline acid methyl esters benzenesulfonamides of the achiral or chirality that replaces;
Then, in polar organic solvent methylene dichloride, methyl alcohol or chloroform, R 3Or/and R 4For amino, R 1, R 2The tetrahydroisoquinoline acid methyl esters benzenesulfonamides of the achiral or chirality that replaces and the compound reaction of azyloxy, mol ratio is 1: 1-8, to react after 2-12 hour, acidifying obtains R 3Or/and R 4R for amino 1, R 2, R 3, R 4The tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound of the achiral or chirality that replaces;
R wherein 1, R 2, R 3, R 4According to claim 1.
5. the preparation method of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 4, the organic compound acid binding agent that it is characterized in that containing on the described nitrogen lone-pair electron is pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine, N, N-diisopropyl ethyl amine or bipyridine.
6. the preparation method of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 4 is characterized in that described azyloxy compound N H 2Y=comprises the monovalence metal or the C of potassium, sodium among the OY 1-5Alkyl.
7. the preparation method of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 4 is characterized in that described alkali organic solvent can be N, dinethylformamide, triethylamine or N,N-dimethylacetamide.
8. the preparation method of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 4 is characterized in that described palladium reagent is Pd (PPh 3) 4, Pd (OAc) 2, Pd (dppf) C 12, Pd 2(dba) 3Or Pd (PPh 3) 2Cl 2
9. the purposes of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 1 is characterized in that being used to prepare the inhibitor of stromatin enzyme.
10. the purposes of a kind of tetrahydroisoquinolihydroximic hydroximic acid sulfamide compound as claimed in claim 1 is characterized in that being used for preparation treatment cancer, sacroiliitis, body ulcer, the medicine of pulmonary emphysema, blood vessel scleratheroma disease.
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