CN1696127A - Analogue of thalidomide and preparation method - Google Patents
Analogue of thalidomide and preparation method Download PDFInfo
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- CN1696127A CN1696127A CN 200510016719 CN200510016719A CN1696127A CN 1696127 A CN1696127 A CN 1696127A CN 200510016719 CN200510016719 CN 200510016719 CN 200510016719 A CN200510016719 A CN 200510016719A CN 1696127 A CN1696127 A CN 1696127A
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Abstract
A novel analog of thalidomide and its preparing process are disclosed.
Description
Technical field
The present invention relates to the analogue of a series of Thalidomides and their preparation method.
Background technology
Thalidomide (Thalidomide) has another name called thalidomide, is a medicine of later stage the 1950's listing, is used for the conceived early stage antiemetic of calmness, hypnosis and women.But very fast this medicine of discovery has serious teratogenesis to fetus.So this medicine has been withdrawn from market in early 1960s.Nineteen sixty-five, (Sheskin, J.ClinPharmacol. Ther. 1965,6: 303-306) the report Thalidomide can effectively be treated erythema lepromatous leprosy disease (ENL) to Israel doctor Sheskin.1998, FDA (U.S. food and drug administration) approval Thalidomide was used for the treatment of ENL.In China, Thalidomide is the national essential drugs that the treatment leprosy is followed disease.Thalidomide is except treating ENL, and present known biological activity also comprises immunosuppression, anticancer, anti-HIV-1 virus etc.The research that Thalidomide is used for the treatment of multiple myeloma has entered the clinical II/III phase.But because Thalidomide also has the effect of tranquilizing soporific, and the dosage that uses clinically is bigger again, and the patient is had certain side effect.So designing and synthesizing the strong and side effect of specific activity Thalidomide is very significant than its weak compound treating leprosy and following following aspect disease and the immunosuppression of disease, cancer, rheumatic arthritis, HIV-1.
It is generally acknowledged Thalidomide work by suppressing tumour necrosis factor (TNF-α) (Moreira, A.L.et al.J.Exp.Med.1993,177,1675-1680).1999, Muller (Muller GW., Chen R., Huang S.Y.et al..Bioorg.Med.Chem.Lett.1999,9: the 1625-1630) ability of having synthesized the analogue that has amino Thalidomide on a series of phenyl ring and having tested they inhibition TNF-α.The inhibition ability that found that two compounds 1 with following structure and 2 couples of TNF-α of compound is stronger 19,000 and 2,000 times than Thalidomide respectively.Clinical study shows, 1 pair of compound
Prostate cancer has obvious curative effects, but constipation is arranged, feels sick, side effect such as fatigue.The research that compound 2 is used for the treatment of multiple myeloma entered the clinical III phase (Teo, S.K.DrugDiscov. Today, 2005,10,107-113).But all directly have amino on the phenyl ring of these two compounds, this amino is a toxophore.So it is stronger still to be necessary to seek biological activity, the analogue of side effect Thalidomide still less.
Summary of the invention
The purpose of this invention is to provide the analogue of a series of Thalidomides and their preparation method.The structure of these compounds is as follows:
Wherein, R is selected from (CH
3)
2N-;
R
1Be selected from O, H
2
X, Y, Z are selected from following combination: X=Y=CH, Z=N and X=Y=N, Z=CH;
R
2Be selected from H ,-CH
3,-CH
2CH
3
Ar
1Be selected from p-methylphenyl, rubigan, p-nitrophenyl, p-hydroxybenzene, p-methoxyphenyl, (, to)-Dimethoxyphenyl, benzyl and Alpha-Naphthyl; The analogue of ad hoc structure is as follows:
7：R＝3-N(CH
3)
2，R
1＝O
13：X＝Y＝CH，Z＝N
15：R
2＝H
8：R＝3-N(CH
3)
2，R
1＝H
2 14：X＝Y＝N，Z＝CH
16：R
2＝CH
3
9：R＝6-N(CH
3)
2，R
1＝H
2
17：R
2＝CH
2CH
3
10：R＝4-N(CH
3)
2，R
1＝O
11：R＝4-N(CH
3)
2，R
1＝H
2
12：R＝5-N(CH
3)
2，R
1＝H
2
18：Ar
1＝Ph-CH
3-p 26：Ar
2＝OCPh
19：Ar
1＝Ph-Cl-p 27：Ar
2＝OCPh-CH
3-p
20：Ar
1＝Ph-NO
2-p 28：Ar
2＝OCPh-OCH
3-p
21：Ar
1＝Ph-OH-p 29：Ar
2＝OCPh-NH
2-p
22：Ar
1＝Ph-OCH
3-p 30：Ar
2＝OCPh-OOCCH
3-o
23：Ar
1＝Ph-(OCH
3)
2-m，p 31：Ar
2＝3-pyridine?formyl
24：Ar
1＝CH
2Ph 32：Ar
2＝4-pyridine?formyl
25：Ar
1＝α-Naphthyl 33：Ar
2＝2-pyrazine?formyl
Wherein, o, m, p represent the neighbour of substituting group at phenyl ring respectively, and contraposition.
Technological process is as follows: the synthetic derivative that obtains the Thalidomide that 3-nitro or 4-nitro replace with 3-nitrophthalic acid acid anhydride or 4-nitrophthalic acid acid anhydride and glutamine at 130～180 ℃ of following direct reaction of vacuum condition of compound 7～12, then and formalin, 20～80 atmospheric hydrogen obtain 3-(N 60～120 ℃ of reactions, the N-dimethyl)-Thalidomide (7) or 4-(N, N-dimethyl)-Thalidomide (10).Compound 7 or 10 reacts in acetic acid with new activatory zinc powder and obtains compound 8 and 11.Use triethyl silicane again after compound 7 or the 10 usefulness aluminium mercury partial reductions, trifluoroacetic acid further reduction obtains compound 9 and 12.
Compound 13 and 14 synthetic employing 3,4-dinicotinic acid acid anhydrides or 2, the hydrochloride of 3-pyrazine dicarboxylic acid anhydride and glutamy imines, triethylamine reacts in dry DMF (N, dinethylformamide) or dioxane, removes the solvent of system after having reacted, in system, add diacetyl oxide and toluene, 60～110 ℃ were reacted 4～12 hours, removed dissolvant of reaction system then, obtained compound 13 and 14 by recrystallization or mistake chromatographic column.
The synthetic usefulness 2 of compound 15～17,3-imidazoles dioctyl phthalate and sulfur oxychloride reflux and obtain 2, the dimeric dimethyl chloride of 3-imidazoles dioctyl phthalate, after this acyl chlorides hydrolysis and the hydrochloride of glutamy imines, the triethylamine reaction obtains compound 15.2, behind the dimeric dimethyl chloride of 3-imidazoles dioctyl phthalate and methyl alcohol or the ethanol synthesis again with the hydrochloride of glutamy imines, the triethylamine reaction obtains compound 16 and 17.
The synthetic employing of compound 18～25 is to monomethylaniline, p-Chlorobenzoic acid amide, p-Nitroaniline, para hydroxybenzene amine, P-nethoxyaniline, right, m-dimethoxybenzene amine, benzylamine or αNai An and phthalyl glutamic acid anhydride reactant obtain corresponding amide acid, then with sulfur oxychloride, diacetyl oxide, N, N '-carbonyl dimidazoles or N, N '-dicyclohexylcarbodiimide reaction obtains compound 18～25.
The synthetic employing Benzoyl chloride of compound 26～33, to methyl benzoyl chloride, anisoyl chloride, the hydrochloride of acetyl bigcatkin willow acyl chlorides and glutamy imines, triethylamine react in methylene dichloride and obtain compound 26,27,28,30.Hydrochloride with paranitrobenzoyl chloride and glutamy imines, triethylamine reacts in methylene dichloride and obtains p-nitrophenyl formyl glutamy imines, and p-nitrophenyl formyl glutamy imines and tetrahydrobenzene obtain p-benzoyl glutamy imines (29) with palladium carbon catalytic transfer hydrogenation in methyl alcohol.The 3-pyridine carboxylic acid, 4-pyridine carboxylic acid or 2-pyrazine carboxylic acid and N, N '-carbonyl dimidazoles, the hydrochloride of glutamy imines, 4-(N, N-dimethyl)-pyridine refluxes in anhydrous tetrahydro furan and obtains compound 31,32,33.
The nuclear-magnetism of the analogue of the Thalidomide that the present invention makes, mass-spectrometric data prove that they are expected compound really.
Embodiment:
Embodiment 1:
Add 3-nitrophthalic acid acid anhydride 4.0g and glutamine 2.0g in 140 ± 10 ℃ the reactor toward being heated in advance, heated and stirred, react and after 40 minutes temperature is slowly risen to 180 ± 10 ℃, simultaneously system is connect vacuum pump, stopped reaction after 10 hours, add 24ml1,4-dioxane, heated and stirred make system become solution, and decompression steams dioxane, add 20ml methyl alcohol, the 20 minutes postcooling that reflux spend the night, and have precipitation to generate, and filter, methyl alcohol is washed, get shallow white solid, vacuum-drying obtains the Thalidomide 1.46g that 3 nitros replace, productive rate 35.2%, fusing point: 297-299 ℃.
1HNMR (DMSO-d
6): б 11.16 (s, 1H), 8.18-7.96 (m, 3H), 5.26-5.18 (dd, 1H), 2.96-2.87 (m, 1H), 2.68-2.56 (m, 2H), 2.15-2.08 (m, 1H);
13CNMR (DMSO-d
6): δ: 172.7,169.5,165.2,162.5,144.4,136.8,133.0,128.9,127.3,122.6,49.5,30.9,21.8. ultimate analysis (%, C
13H
9N
3O
6Calculated value): C 51.40 (51.49), and H 3.03 (2.99), and N 13.83 (13.86).
Embodiment 2:
Add the Thalidomide 1.1g that 3 nitros obtaining among the embodiment 1 replace in the autoclave, 40% formalin 3.3ml, methyl alcohol 100ml, 10% palladium carbon 0.5g feeds hydrogen, and the pressure that makes hydrogen is 30 normal atmosphere, system is heated to 80 ℃, stopped reaction after 40 hours.System adds flocculating aids filters, and filtrate adds silica gel adsorption, removes by rotary evaporation and desolvates, and uses CHCl
3: EtOAc=10: 1 crosses silicagel column for eluent, obtains yellow solid, and vacuum-drying obtains 3 N, Thalidomide (7) 0.83g that the N-dimethyl replaces, productive rate 82.5%, fusing point: 207-209 ℃.
1HNMR (DMSO-d
6): б 11.06 (s, 1H), 7.65-7.61 (dd, 1H), 7.28-7.22 (m, 2H), 5.10-5.06 (dd, 1H), 3.04 (s, 6H), 2.89-2.85 (m, 1H), 2.61-2.51 (m, 2H), 2.06-2.00 (m, 1H);
13CNMR (DMSO-d
6): δ: 172.8,170.0,167.1,166.3,149.8,135.1,133.9,122.5,113.4,112.9,48.8,42.9,31.0,22.1. ultimate analysis (%, C
15H
15N
3O
4Calculated value): C59.72 (59.79), H5.03 (5.02), N13.9 (13.95).
Embodiment 3
0.6g 3 N that obtain among the embodiment 2; the zinc powder that Thalidomide (7) that the N-dimethyl replaces and 5g cross with hydrochloric acid activation in the 50ml Glacial acetic acid 90 ℃ react filtered while hot behind the 40min; 50ml acetone divides to be washed for three times; mother liquor adds silica gel adsorption; chloroform: ethyl acetate=cross chromatographic column at 4: 1 obtains and N analogue (8) 0.20g of the Thalidomide that the formyl radical of position was reduced between the N-dimethyl was in; productive rate 34.9%, fusing point: 92-94 ℃.
1HNMR (DMSO-d
6), δ: 10.96 (s, 1H), 7.46-7.41 (m, 1H), and 7.00-6.97 (d, 1H), 6.88-6.86 (d, 1H), and 5.08-5.02 (dd, 1H), 4.38-4.18 (dd, 2H), 2.92 (s, 6H), 3.01-2.85 (m, 1H), and 2.65-2.51 (m, 1H), 2.40-2.36 (m, 1H), 2.16-1.95 (m, 1H).
13CNMR (DMSO-d
6), δ: 173.3,171.6,168.1,151.2,145.6,132.8,120.1,115.3,114.5,52.1,47.0,44.0,31.7,22.9. ultimate analysis (%, C
15H
17N
3O
3Calculated value): C62.549 (62.71), H 5.99 (5.96), and N 14.80 (14.63).
Embodiment 4
0.23g 3 N that obtain among the embodiment 2, the Thalidomide (7) that the N-dimethyl replaces is dissolved in 10ml ethanol, 1ml water, in the solution that the 1ml Glacial acetic acid is made into, once add the aluminium foil that is cut into fragment that the 0.06g ether was washed, 0.002g mercury chloride, heating, system is refluxed, react stopped reaction after 3 hours, add flocculating aids and filter, acetone is washed, mother liquor concentrates evaporate to dryness, vacuum-drying.The compound that obtains is transferred in the reaction flask of 5ml; add the 1.5ml Glacial acetic acid; 0.75ml trifluoroacetic acid, the 0.4ml triethyl silicane, with system be warming up to 70 ℃ the reaction 3 hours after stopped reaction; add silica gel adsorption; chloroform: ethyl acetate=5: 1 is crossed chromatographic column, obtains and N, and the N-dimethyl is in analogue (9) 0.09g of the Thalidomide that the adjacent formyl radical is reduced; productive rate 41.0%, fusing point: 250-254 ℃ (dec.).
1HNMR (DMSO-d
6), δ: 10.98 (s, 1H), 7.39-7.35 (m, 1H), 7.17-7.15 (d, 1H), 6.98-6.96 (d, 1H), 5.13-5.08 (dd, 1H), 4.57-4.38 (dd, 2H), 2.95-2.77 (m, 7H), 2.62-2.57 (m, 1H), 2.49-2.46 (m, 1H), 2.01-1.98 (m, 1H).
13CNMR (DMSO-d
6), δ: 172.9,171.0,168.2,147.7,133.2,129.7,129.1,117.3,113.4,51.5,47.7,41.9,31.2,22.4. ultimate analysis (%, C
15H
17N
3O
3Calculated value): C62.65 (62.71), H 5.93 (5.96), and N 14.70 (14.63).
Embodiment 5:
With reference to the method for embodiment 1, the Tetra hydro Phthalic anhydride 4.0g and the glutamine 2.0g that replace with the 4-nitro react, and obtain the Thalidomide 1.98g that the 4-nitro replaces, productive rate 47.6%, fusing point: 230-231 ℃.
1HNMR (DMSO-D
6), δ: 11.19 (s, 1H), 8.70-8.67 (d, 1H), 8.58-8.57 (d, 1H), 8.22-8.19 (d, 1H), 5.28-5.22 (dd, 1H), 2.98-2.85 (m, 1H), 2.65-2.53 (m, 2H), 2.12-2.09 (m, 1H).
13CNMR (DMSO-D
6), δ: 173.5,170.3,166.4,166.1,152.6,136.6,133.4,130.9,125.8,119.2,50.4,31.7,22.7. ultimate analysis (%, C
13H
9N
3O
6Calculated value): C 51.44 (51.49), and H 3.00 (2.99), and N 13.90 (13.86).
Embodiment 6:
With reference to the method for embodiment 2, with Thalidomide and formalin that the 4-nitro that obtains among the embodiment 5 replaces, hydrogen reaction obtains 4-(N, N-dimethyl)-Thalidomide (10).Productive rate 75.0%, fusing point: 258-259 ℃.
1HNMR (DMSO-d
6): б 11.06 (s, 1H), 7.66-7.64 (d, 1H), 7.07-7.06 (d, 1H), 6.98-6.96 (dd, 1H), 5.08-5.03 (dd, 1H), 3.10 (s, 6H), 2.89-2.84 (m, 1H), 2.60-2.51 (m, 2H), 2.02-1.99 (m, 1H);
13CNMR (DMSO-d
6): δ: 172.8,170.1,167.7,167.2,154.4,133.9,124.7,115.9,115.1,105.3,48.7,40.1,31.0,22.2. ultimate analysis (%, C
15H
15N
3O
4Calculated value): C 59.75 (59.79), H5.00 (5.02), and N 13.94 (13.95).
Embodiment 7:
Method with reference to embodiment 3; with the 4-(N that obtains among the embodiment 6; the N-dimethyl)-Thalidomide (10) and activated zinc powder react in Glacial acetic acid; obtain being in N by crossing chromatographic column; the analogue (11) of the Thalidomide that the formyl radical of position is reduced between the N-dimethyl; productive rate 55.9%, fusing point: 240-244 ℃ (dec.).
1HNMR (DMSO-d
6): б 10.95 (s, 1H), 7.40-7.38 (d, 1H), 7.03-7.00 (dd, 1H), 6.94 (s, 1H), 5.1-5.07 (dd, 1H), 4.33-4.16 (dd, 2H), 2.92 (s, 6H), 2.91-2.86 (m, 1H), 2.61-2.57 (m, 1H), 2.40-2.33 (m, 1H), and 2.00-1.97 (m, 1H);
13CNMR (DMSO-d
6): δ: 173.3,171.5,169.2,151.0,133.0,129.9,117.0,112.8,105.7,52.1,47.0,31.7,23.0. ultimate analysis (%, C
15H
17N
3O
3Calculated value): C 62.72 (62.71), and H 5.83 (5.96), and N 14.70 (14.63).
Embodiment 8:
With reference to the method among the embodiment 4, with 4 N that obtain among the embodiment 6, the Thalidomide (10) that the N-dimethyl replaces is in ethanol, in the solution that water, Glacial acetic acid are made into and the aluminium foil that is cut into fragment washed of ether, the mercury chloride back flow reaction, stopped reaction after 3 hours adds flocculating aids and filters, and acetone is washed, mother liquor concentrates evaporate to dryness, vacuum-drying.With the compound that obtains in Glacial acetic acid and trifluoroacetic acid; 70 ℃ of reactions of triethyl silicane; crude product adds silica gel adsorption; chloroform: ethyl acetate=2: 1 mistake chromatographic columns; obtain and N; the N-dimethyl is in the analogue (12) of the Thalidomide that the formyl radical of contraposition is reduced, productive rate 71.0%, fusing point: 275-277 ℃ (dec.).
1HNMR (DMSO-d
6), δ: 10.92 (s, 1H), 7.50-7.48 (m, 1H), 6.81-6.79 (m, 2H), 5.06-5.01 (dd, 1H), 4.33-4.17 (dd, 2H), 3.00 (s, 6H), 2.95-2.87 (m, 1H), 2.60-2.52 (m, 1H), 2.38-2.33 (m, 1H), 1.97-1.93 (m, 1H).
13CNMR (DMSO-d
6), δ: 172.9,171.4,168.6,152.9,144.1,123.8,119.0,111.7,105.2,51.3,46.9,40.0,31.3,22.6. ultimate analysis (%, C
15H
17N
3O
3Calculated value): C 62.69 (62.71), H5.95 (5.96), and N 14.74 (14.63).
Embodiment 9:
0.91g 3; 4-dinicotinic acid acid anhydride is dissolved in the anhydrous dioxane of 35ml; the hydrochloride that adds 1.02g glutamy imines; 1.68ml anhydrous triethylamine; system connects drying tube, and the evaporated under reduced pressure solvent is spent the night in 50 ℃ of following reactions; vacuum-drying; in system, add 25ml toluene again, 25ml diacetyl oxide and 2ml trifluoroacetic acid, system connects 110 ℃ of reactions of drying tube and adds silica gel adsorption after 5 hours; chloroform: ethyl acetate=2: 1 mistake chromatographic columns; obtain phthaloyl by 3, analogue (13) 1.39g of the Thalidomide that 4-pyridine diformyl replaces, productive rate 88%; fusing point: 229-230 ℃
1HNMR (DMSO-d
6), δ: 11.09 (s, 1H), 9.12-9.07 (m, 2H), 7.89-7.87 (dd, 1H), 5.16-5.10 (dd, 1H), 2.82-2.56 (m, 1H), 2.49-2.26 (m, 2H), 2.00-1.96 (m, 1H).
13CNMR (DMSO-d
6), δ: 173.5,170.4,167.3,166.9,157.2,145.2,139.7,126.2,118.0,50.1,31.7,22.7. ultimate analysis (%, C
12H
9N
3O
4Calculated value): C55.53 (55.60), H 3.53 (3.50), and N 16.18 (16.21).
Embodiment 10:
1.0g 2; 3-pyrazine dicarboxylic acid anhydride; 1.10g the hydrochloride of glutamy imines is dissolved in the anhydrous dioxane of 30ml; add, the 1.9ml anhydrous triethylamine, system connects drying tube; reaction is spent the night under 50 ℃; the evaporated under reduced pressure solvent, vacuum-drying adds 25ml toluene again in system; 25ml diacetyl oxide and 2ml trifluoroacetic acid; system connects 100 ℃ of reactions of drying tube and adds silica gel adsorption, chloroform after 15 hours: ethyl acetate=cross chromatographic column at 2: 1 obtains phthaloyl by 2; analogue (14) 1.40g of the Thalidomide that 3-pyrazine diformyl replaces; productive rate 80.7%, fusing point:＞300 ℃
1HNMR (DMSO-d
6), δ: 11.20 (s, 1H), 9.08 (s, 2H), 5.34-5.29 (dd, 1H), 2.95-2.80 (m, 1H), 2.65-2.47 (m, 2H), 2.15-2.06 (m, 1H).
13CNMR (DMSO-d
6), δ: 172.6,169.3,163.7,149.3,146.4,49.2,30.8,21.9. ultimate analysis (%, C
11H
8N
4O
4Calculated value): C 50.70 (50.77), and H 3.15 (3.10), N21.50 (21.53).
Embodiment 11:
Toward the 30ml sulfur oxychloride, the N of 0.2ml adds 5.0g 2 in the toluene system of dinethylformamide and 50ml, 3-imidazoles dioctyl phthalate stirs reflux, steam solvent after 5 hours, obtain yellow solid, in system, add 15ml benzene, stir 20 minutes after-filtration, the solid that obtains divides with 30ml benzene to be washed for three times, and vacuum-drying obtains 2, the dimeric dimethyl chloride 4.57g of 3-imidazoles dioctyl phthalate, productive rate 91.1%.1.5g 2, the dimeric dimethyl chloride of 3-imidazoles dioctyl phthalate stirs in 15ml water and spends the night, and filters, vacuum-drying, obtain 2, the hydrochloride of the dimeric dioctyl phthalate of 3-imidazoles dioctyl phthalate and 1.58g glutamy imines, 2.7ml triethylamine stirs in the 40ml methylene dichloride and spends the night, and obtains white solid, filter, methylene dichloride is washed repeatedly, vacuum-drying, obtain analogue (15) 2.1g of Thalidomide, productive rate 81%, fusing point: 278-280 ℃ (dec.)
1HNMR (DMSO-d
6), δ: 13.40 (s, 1H), 13.1 (s, 1H), 10.86 (s, 1H), 10.11-10.09 (d, 1H), 7.78 (s, 1H), 4.76-4.69 (m, 1H), 2.71-2.67 (m, 1H), 2.48-2.41 (m, 1H), 2.06-1.94 (m, 2H).
13CNMR (DMSO-d
6), δ: 174.6,172.3,164.3,158.2,137.5,134.2,132.3,50.7,31.8,25.0. ultimate analysis (%, C
10H
10N
4O
5Calculated value): C 45.04 (45.12), H3.72 (3.79), and N 21.10 (21.05).
Embodiment 12:
According to the method among the embodiment 11, replace 2 with absolute methyl alcohol, the water of the dimeric dimethyl chloride hydrolysing step of 3-imidazoles dioctyl phthalate reacts, and obtains analogue (16) 1.9g of Thalidomide, productive rate 71%, fusing point: 165-167 ℃,
1HNMR (DMSO-d
6), δ: 13.42 (s, 1H), 10.86 (s, 1H), 10.16-10.10 (d, 1H), 7.74 (s, 1H), 4.72-4.65 (m, 1H), 3.56 (s, 3H), 2.76-2.69 (m, 1H), 2.49-2.46 (m, 1H), 2.00-1.91 (m, 2H).
13CNMR (DMSO-d
6), δ: 173.7,172.6,166.1,157.8,134.7,134.0,131.7,51.4,50.0,31.3,22.8. ultimate analysis (%, C
11H
12N
4O
5Calculated value): C 47.08 (47.15), and H 4.39 (4.32), and N 20.02 (19.99).
Embodiment 13:
According to the method among the embodiment 11, replace 2 with absolute ethanol, the water of the dimeric diacid chloride hydrolysing step of 3-imidazoles dioctyl phthalate reacts, and obtains analogue (17) 2.2g of Thalidomide, productive rate 78%, mp 139-140 ℃,
1HNMR (DMSO-d
6), δ: 13.40 (s, 1H), 10.86 (s, 1H), 10.11-10.09 (d, 1H), 7.78 (s, 1H), 4.76-4.69 (m, 1H), 4.26-4.22 (t, 2H), 2.71-2.67 (m, 1H), 2.48-2.41 (m, 1H), 2.06-1.94 (m, 2H), 1.25-1.20 (t, 3H).
13CNMR (DMSO-d
6), δ: 173.6,172.6,165.3,158.8,138.1,131.9,130.8,62.1,50.7,31.8,25.0,14.9. ultimate analysis (%, C
12H
14N
4O
5Calculated value): C48.90 (48.98), H 4.83 (4.80), and N 19.00 (19.04).
Embodiment 14:
In the 350ml anhydrous pyridine, add the 50.0g Tetra hydro Phthalic anhydride; 50g L-L-glutamic acid; nitrogen protection; reflux reduces pressure after 6 hours and steams pyridine, adds the 200ml acetic anhydride, and reflux reduces pressure after 25 minutes and steams acetic anhydride; add the 100ml anhydrous diethyl ether after reducing to room temperature; stir 20 minutes after-filtration, the 100ml anhydrous diethyl ether divides to be washed for three times, and solid that obtains and 150ml anhydrous ethyl acetate reflux together; cool overnight; filtration, 100ml ethyl acetate divide washes for three times, obtains the pure white solid; vacuum-drying; obtain phthalyl glutamic acid acid anhydride 66.5g, productive rate 76%, fusing point: 195-196 ℃ (literature value: 195-196 ℃).
Embodiment 15:
2.5g stirring in the 30ml anhydrous diethyl ether monomethylaniline, phthalyl glutamic acid acid anhydride and 1ml spend the night, steam ether, add the 100ml chloroform and make the system dissolving, transfer in the separating funnel of 500ml, after washing organic phase at twice with the hydrochloric acid 200ml of 2N, again with 50ml saturated nacl aqueous solution washing organic phase, tell organic phase, spend the night with anhydrous magnesium sulfate drying, filter evaporate to dryness filtrate, vacuum-drying, obtain the phthalyl glutamy to monomethylaniline 2.96g, productive rate 84%, fusing point: 178-179 ℃.
2.96g the phthalyl glutamy is to monomethylaniline; 1.38g N, N-carbonyl dimidazoles, 0.03g 4-N; the N-lutidine is in the 40ml anhydrous tetrahydro furan; night is flow through in nitrogen protection next time, adds silica gel adsorption, chloroform: ethyl acetate=2: 1 mistake chromatographic columns; obtain phthalyl-N-p-methylphenyl-glutamy imines (18) 2.33g; productive rate 83%, fusing point: 100-103 ℃
1HNMR (dmso-d
6): б 7.95-7.88 (m, 4H), 7.25-7.23 (d, 2H), 7.01-6.99 (d, 2H), 5.40-5.36 (dd, 1H), 3.11-3.08 (m, 1H), 2.88-2.69 (m, 2H), 2.33 (s, 3H), 2.22-2.18 (m, 1H);
13CNMR (dmso-d
6): δ 170.9,169.3,167.4,134.3,134.5,133.2,129.7,129.2,128.5,122.4,49.8,31.5,21.4,20.1. ultimate analysis (%, C
20H
16N
2O
4Calculated value): C 68.90 (68.96), and H 4.70 (4.63), and N 8.00 (8.04).
Embodiment 16:
Replace monomethylaniline is reacted among the embodiment 15 with p-Chlorobenzoic acid amide, obtain phthalyl-N-(4-chloro-phenyl)-glutamy imines (19), productive rate 89%, fusing point: 270-271 ℃,
1HNMR (dmso-d
6): б 7.97-7.89 (m, 4H), 7.55-7.53 (d, 2H), 7.20-7.17 (d, 2H), 5.43-5.37 (dd, 1H), 3.17-3.07 (m, 1H), 2.91-2.68 (m, 2H), 2.28-2.20 (m, 1H);
13CNMR (dmso-d
6): δ 172.4,170.4,168.0,135.8,135.3,133.7,132.1,131.3,129.8,124.3,50.7,32.4,22.2. ultimate analysis (%, C
19H
13N
2O
4Calculated value): C 61.85 (61.88), and H 3.56 (3.55), and Cl 9.65 (9.61), and N 7.56 (7.60).
Embodiment 17:
Replace the p-methylphenyl among the embodiment 15 to react with p-Nitroaniline, obtain phthalyl-N-(4-nitro-phenyl)-glutamy imines (20), productive rate 79%, fusing point: 226-227 ℃,
1HNMR (dmso-d
6): б 9.63 (s, 1H), 7.96-7.89 (m, 4H), 6.92-6.89 (d, 2H), 6.81-6.78 (d, 2H), 5.40-5.34 (dd, 1H), 3.10-3.04 (m, 1H), 2.88-2.67 (m, 2H), 2.21-2.17 (m, 1H);
13CNMR (dmso-d
6): δ 172.7,170.6,168.0,157.9,135.8,132.0,130.2,127.4,124.3,116.2,50.8,32.4,22.3. ultimate analysis (%, C
19H
13N
3O
6Calculated value): C 60.18 (60.16), and H 4.40 (3.45), and N 11.05 (11.08).
Embodiment 18:
Replace monomethylaniline is reacted among the embodiment 15 with para hydroxybenzene amine, obtain phthalyl-N-(4-hydroxyl-phenyl)-glutamy imines (21), productive rate 83%, fusing point: 253-254 ℃,
1HNMR (dmso-d
6): б 7.94-7.89 (m, 4H), 7.04-7.02 (d, 2H), 6.99-6.98 (d, 2H), 5.39-5.36 (dd, 1H), 3.77 (s, 3H), 3.10-3.08 (m, 1H), 2.88-2.70 (m, 2H), 2.21-2.19 (m, 1H);
13CNMR (dmso-d
6): δ 171.7,169.6,167.1,158.7,134.9,131.2,129.4,128.0,123.4,114.0,55.2,49.9,31.5,21.3. ultimate analysis (%, C
19H
14N
2O
5Calculated value): C 65.19 (65.14), and H 4.01 (4.03), and N 8.05 (8.00).
Embodiment 19:
Replace monomethylaniline is reacted among the embodiment 15 with P-nethoxyaniline, obtain phthalyl-N-(4-methoxyl group-phenyl)-glutamy imines (22), productive rate 90%, fusing point: 209-210 ℃,
1HNMR (dmso-d
6): б 7.93-7.77 (m, 4H), 7.29 (s, 1H), 6.96-6.93 (d, 1H), 6.70-6.69 (d, 1H), 5.21-5.15 (dd, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.18-3.12 (m, 1H), 3.00-2.94 (m, 2H), 2.32-2.26 (m, 1H);
13CNMR (dmso-d
6): δ 171.1,168.7,167.4,149.3,134.4,131.7,127.4,123.7,120.4,111.2,55.9,50.3,32.2,22.1. ultimate analysis (%, C
20H
16N
2O
5Calculated value): C 65.90 (65.93), and H 4.49 (4.43), and N 7.65 (7.69).
Embodiment 20:
With 3, the 4-dimethoxyaniline replaces monomethylaniline is reacted among the embodiment 15, obtains phthalyl-N-(3,4-dimethoxy-phenyl)-glutamy imines (23), productive rate 79%, and fusing point: 117-118 ℃,
1HNMR (dmso-d
6): б 7.95-7.89 (m, 4H), 7.31-7.24 (m, 5H), 5.40-5.37 (dd, 1H), 4.94-4.92 (d, 1H), 4.82-4.80 (d, 1H), 3.10-3.07 (m, 1H), 2.84-2.62 (m, 2H), 2.15-2.12 (m, 1H);
13CNMR (dmso-d
6): δ 171.5,169.5,167.1,137.0,134.8,131.2,128.2,127.1,126.9,123.4,49.6,42.8,31.1,21.2. ultimate analysis (%, C
21H
18N
2O
6Calculated value): C 63.90 (63.96), H4.62 (4.60), and N 7.22 (7.10).
Embodiment 21:
Replace monomethylaniline is reacted among the embodiment 15 with benzylamine, obtain phthalyl-N-benzyl-glutamy imines (24), productive rate 85%, fusing point: 178-179 ℃,
1HNMR (dmso-d
6): б 8.36-8.33 (d, 2H), 7.97-7.90 (m, 4H), 7.50-7.47 (d, 2H), 5.46-5.40 (dd, 1H), 3.18-3.09 (m, 1H), 3.07-2.73 (m, 2H), 2.27-2.22 (m, 1H);
13CNMR (dmso-d
6): δ 172.3,170.3,167.9,148.0,142.5,135.8,132.1,131.2,125.1,124.4,50.7,32.4,22.1. ultimate analysis (%, C
20H
16N
2O
4Calculated value): C 68.89 (68.96), and H 4.59 (4.63), N8.09 (8.04).
Embodiment 22:
Replace monomethylaniline is reacted among the embodiment 15 with αNai An, obtain phthalyl-N-α naphthyl-glutamy imines (25), productive rate 76%, fusing point: 240-242 ℃,
1HNMR (dmso-d
6): б 8.01-7.31 (m, 11H), 5.79-5.75 (dd, 1H), 3.25-3.21 (m, 1H), 3.11-2.92 (m, 2H), 2.40-2.29 (m, 1H),
13CNMR (dmso-d
6): δ 171.9,171.5,168.4,135.2,134.7,134.4,132.2,129.4,128.2,126.9,126.7,126.2,125.8,124.5,123.5,122.4,50.6,31.1,21.7. ultimate analysis (%, C
23H
16N
2O
4Calculated value): C 71.98 (71.87), and H 4.30 (4.20), and N 7.24 (7.29).
Embodiment 23:
0.46ml Benzoyl chloride is dissolved in the 15ml methylene dichloride, be added dropwise in the methylene dichloride system of the hydrochloride that contains 0.66g glutamy imines and 1.68ml anhydrous triethylamine, stirring is spent the night, and separates out solid, filters, the 20ml methylene dichloride is washed at twice, the solid that obtains Virahol recrystallization obtains benzoyl glutamy imines (26) 0.85g, productive rate 92%, fusing point: 208-211 ℃ (dec.)
1HNMR (dmso-d
6): б 10.86 (s, 1H), 8.77-8.75 (d, 1H), 7.86-7.86 (m, 2H), 7.58-7.47 (m, 3H), 4.82-4.75 (m, 1H), 2.85-2.77 (m, 1H), 2.57-2.51 (m, 1H), 2.15-2.11 (m, 1H), 2.00-1.98 (m, 1H);
13CNMR (dmso-d
6): δ 173.1,172.2,166.1,133.9,131.5,128.4,127.3,49.5,31.0,24.2. ultimate analysis (%, C
12H
12N
2O
3Calculated value): C 62.01 (62.06), and H 5.30 (5.21), and N 12.10 (12.06).
Embodiment 24:
With replacing the methyl benzoyl chloride among the embodiment 23 to react to methyl benzoyl chloride, obtain toluyl glutamy imines (27), productive rate 84%, fusing point: 218-220 ℃ (dec.),
1HNMR (dmso-d
6): б 10.85 (s, 1H), 8.70-8.68 (d, 1H), 7.79-7.78 (d, 2H), 7.30-7.29 (d, 2H), 4.79-4.75 (m, 1H), 2.83-2.77 (m, 1H), 2.62-2.54 (m, 1H), 2.14-2.11 (m, 1H), 1.98-1.96 (m, 1H);
13CNMR (dmso-d
6): δ 173.0,172.2,165.9,141.3,131.1,128.8,127.3,49.4,31.0,24.2,20.9. ultimate analysis (%, C
13H
14N
2O
3Calculated value): C 63.35 (63.40), and H 5.77 (5.73), and N 11.30 (11.38).
Embodiment 25:
The Benzoyl chloride that replaces among the embodiment 23 with anisoyl chloride reacts, obtains toluyl glutamy imines (28), and productive rate 94%, fusing point: 215-218 ℃ (dec.),
1HNMR (dmso-d
6): б 10.85 (s, 1H), 8.63-8.60 (d, 1H), 7.86-7.84 (d, 2H), 7.03-7.01 (d, 2H), 4.79-4.73 (m, 1H), 2.83-2.75 (m, 1H), 2.56-2.51 (m, 1H), 2.14-2.09 (m, 1H), 1.98-1.94 (m, 1H);
13CNMR (dmso-d
6): δ 173.1,172.4,165.6,161.8,129.2,126.1,113.6,55.4,49.8,31.0,24.3. ultimate analysis (%, C
13H
14N
2O
4Calculated value): C59.48 (59.54), H 5.42 (5.38), and N 10.60 (10.68).
Embodiment 26:
The methyl benzoyl chloride that replaces among the embodiment 23 with paranitrobenzoyl chloride reacts; obtain p-nitrophenyl formyl glutamy imines; yield 95%; p-nitrophenyl formyl glutamy imines and molar weight are the tetrahydrobenzene of 10 times of amounts, weight ratio be 1 10% palladium carbon in methyl alcohol, under nitrogen protection, refluxed 4 hours; the product that obtains obtains p-benzoyl glutamy imines (29) with the Virahol recrystallization; productive rate 87%, fusing point: 230-233 ℃ (dec.)
1HNMR (dmso-d
6): б 10.78 (s, 1H), 8.29-8.27 (d, 1H), 7.60-7.58 (d, 2H), 6.56-6.54 (d, 2H), 5.66 (s, 1H), 4.74-4.67 (m, 1H), 2.81-2.72 (m, 1H), 2.56-2.54 (m, 1H), 2.12-2.06 (m, 1H), 1.94-1.91 (m, 1H);
13CNMR (dmso-d
6): δ 173.2,172.7,166.2,151.9,129.0,120.5,112.6,49.4,31.1,24.4. ultimate analysis (%, C
12H
13N
3O
3Calculated value): C58.20 (58.29), H 5.35 (5.30), and N 17.12 (17.00).
Embodiment 27:
The Benzoyl chloride that replaces among the embodiment 23 with acetyl bigcatkin willow acyl chlorides reacts, and obtains acetyl salicylyl glutamy imines (30), productive rate 87%, fusing point: 179-182 ℃ (dec.),
1HNMR (dmso-d
6): б 10.84 (s, 1H), 8.50-8.48 (d, 1H), 7.65-7.63 (m, 1H), 7.54-7.52 (m, 1H), and 7.38-7.34 (m, 1H), 7.22-7.39 (m, 1H), 4.75-4.72 (m, 1H), 2.78-2.75 (m, 1H), 2.55-2.51 (m, 1H), 2.08-1.98 (m, 2H);
13CNMR (dmso-d
6): δ 173.0,172.0,168.9,165.0,147.9,131.6,129.2,128.7,125.9,123.4,49.4,30.9,24.1,20.8. ultimate analysis (%, C
14H
14N
2O
5Calculated value): C 57.99 (57.93), and H 4.81 (4.86), and N 9.58 (9.65).
Embodiment 28:
1.0g the 3-pyridine carboxylic acid, 1.42g N, N '-carbonyl dimidazoles and 0.03g 4-N, the hydrochloride that adds 1.34g glutamy imines in the 60ml anhydrous tetrahydro furan after the N-lutidine refluxed 20 minutes connects drying tube and then refluxes and spend the night solvent evaporated, add the 50ml chloroform in system, the 30 minutes postcooling that reflux spend the night, and separate out solid, filter, the 30ml chloroform divides to be washed for three times, obtains 3-pyridine formyl glutamy imines (31) 1.56g, productive rate 82%, fusing point: 226-227 ℃ (dec.)
1HNMR (dmso-d
6): б 10.88 (s, 1H), 9.02-9.03 (d, 1H), 8.99-8.96 (d, 1H), 8.74-8.73 (m, 1H), 8.23-8.20 (m, 1H), 7.55-7.52 (m, 1H), 4.84-4.78 (m, 1H), 3.28-2.76 (m, 1H), 2.59-2.53 (m, 1H), 2.15-2.11 (m, 1H), and 2.03-2.01 (m, 1H);
13CNMR (dmso-d
6): δ 173.0,172.0,164.8,152.1,148.4,135.0,129.4,123.5,49.6,30.9,24.1. ultimate analysis (%, C
11H
11N
3O
3Calculated value): C56.60 (56.65), H 4.72 (4.75), and N 18.00 (18.02).
Embodiment 29:
Replace 3-pyridine carboxylic acid among the embodiment 28 with the 4-pyridine carboxylic acid and react and obtain 4-pyridine formyl glutamy imines (32), productive rate 79%, fusing point: 249-252 ℃ (dec.),
1HNMR (dmso-d
6): б 10.90 (s, 1H), 9.07-9.05 (d, 1H), 8.76-8.75 (dd, 2H), 7.78-8.77 (dd, 2H), 4.84-4.78 (m, 1H), 2.81-2.78 (m, 1H), 2.58-2.51 (m, 1H), 2.16-2.11 (m, 1H), 2.02-1.96 (m, 1H);
13CNMR (dmso-d
6): δ 173.2,172.1,165.0,150.4,141.0,121.4,49.9,31.1,24.2. ultimate analysis (%, C
11H
11N
3O
3Calculated value): C56.58 (56.65), H 4.79 (4.75), and N 17.90 (18.02).
Embodiment 30:
Replace 3-pyridine carboxylic acid among the embodiment 28 to react with the 2-pyrazine carboxylic acid and obtain 2-pyrazine formyl glutamy imines (33), productive rate 88%, fusing point: 206-207 ℃ (dec.),
1HNMR (dmso-d
6): б 10.81 (s, 1H), 9.14-9.09 (d, 2H), 8.83-8.82 (d, 1H), 8.70-8.68 (m, 1H), 4.78-4.73 (m, 1H), 2.74-2.68 (m, 1H), 2.53-2.51 (m, 1H), 2.18-2.12 (m, 1H), 2.00-1.90 (m, 1H);
13CNMR (dmso-d
6): δ. ultimate analysis (%, C
10H
10N
4O
3Calculated value): C 51.33 (51.28), H4.26 (4.30) N 23.79 (23.92).
Claims (3)
1. thalidomide analogs is selected from the compound of following formula representative:
Wherein, R is selected from (CH
3)
2N-;
R
1Be selected from O, H
2
X, Y, Z are selected from following combination: X=Y=CH, Z=N and X=Y=N, Z=CH;
R
2Be selected from H ,-CH
3,-CH
2CH
3
Ar
1Be selected from p-methylphenyl, rubigan, p-nitrophenyl, p-hydroxybenzene, p-methoxyphenyl, (, to)-Dimethoxyphenyl, benzyl and Alpha-Naphthyl;
Ar
2Be selected from benzoyl, to methyl benzoyl, to anisoyl, p-benzoyl base, acetyl salicyloyl, 3-pyridine formyl radical, 4-pyridine formyl radical and 2-pyrazine formyl radical; The structure of particular analog compound is as follows:
7：R＝3-N(CH
3)
2，R
1＝O 13：X＝Y＝CH，Z＝N 15：R
2＝H
8：R＝3-N(CH
3)
2，R
1＝H
2 14：X＝Y＝N，Z＝CH 16：R
2＝CH
3
9：R＝6-N(CH
3)
2，R
1＝H
2 17：R
2＝CH
2CH
3
10：R＝4-N(CH
3)
2，R
1＝O
11：R＝4-N(CH
3)
2，R
1＝H
2
12：R＝5-N(CH
3)
2，R
1＝H
2
18：Ar
1＝Ph-CH
3-p 26：Ar
2＝OCPh
19：Ar
1＝Ph-Cl-p 27：Ar
2＝OCPh-CH
3-p
20：Ar
1＝Ph-NO
2-p 28：Ar
2＝OCPh-OCH
3-p
21：Ar
1＝Ph-OH-p 29：Ar
2＝OCPh-NH
2-p
22：Ar
1＝Ph-OCH
3-p 30：Ar
2＝OCPh-OOCCH
3-o
23：Ar
1＝Ph-(OCH
3)
2-m，p 31：Ar
2＝3-pyridine?formyl
24：Ar
1＝CH
2Ph 32：Ar
2＝4-pyridine?formyl
25：Ar
1＝α-Naphthyl 33：Ar
2＝2-pyrazine?formyl
Wherein, o, m, p represent the neighbour of substituting group at phenyl ring respectively, and contraposition.
2. the method for structural compounds shown in the synthetic claim 1 is characterized in that:
(1) synthetic have shown in the compound of structure 7-12: 3-nitrophthalic acid acid anhydride or 4-nitrophthalic acid acid anhydride and L-glutaminate obtain the derivative of the Thalidomide that 3-nitro or 4-nitro replace at 130～180 ℃ of following direct reaction of vacuum condition, then and formalin, 20～80 atmospheric hydrogen obtain 3-(N, N-dimethyl)-Thalidomide 60～120 ℃ of reactions
7：R＝3-N(CH
3)
2，R
1＝O； 8：R＝3-N(CH
3)
2，R
1＝H
2；
9：R＝6-N(CH
3)
2，R
1＝H
2； 10：R＝4-N(CH
3)
2，R
1＝O；
11：R＝4-N(CH
3)
2，R
1＝H
2；?12：R＝5-N(CH
3)
2，R
1＝H
2
(7) or 4-(N, N-dimethyl)-Thalidomide (10); The new activatory zinc powder of compound 7 or compound 10 and 5～40 times of molar weights reacts in acetic acid and obtains compound 8 and 11; Use triethyl silicane again after compound 7 or the 10 usefulness aluminium mercury partial reductions, trifluoroacetic acid further reduction obtains compound 9 and 12;
(2) structure 13 shown in synthetic and 14 compound:
13：X＝Y＝CH，Z＝N
14：X＝Y＝N，?Z＝CH
With 3,4-dinicotinic acid acid anhydrides or 2, the hydrochloride of 3-pyrazine dicarboxylic acid anhydride and glutamy imines, triethylamine reacts in dry DMF (N, dinethylformamide) or dioxane, removes the solvent of system after having reacted, in system, add diacetyl oxide and toluene, 60～110 ℃ were reacted 4～12 hours, removed dissolvant of reaction system then, obtained compound 13 and 14 by recrystallization or mistake chromatographic column;
(3) compound of structure 15-17 shown in synthetic: with 2,3-imidazoles dioctyl phthalate and sulfur oxychloride reflux and obtain 2, the dimeric dimethyl chloride of 3-imidazoles dioctyl phthalate, and after this acyl chlorides hydrolysis and the hydrochloride of glutamy imines, triethylamine reacts and obtains compound 15; 2, behind the dimeric dimethyl chloride of 3-imidazoles dioctyl phthalate and methyl alcohol or the ethanol synthesis again with the salt of glutamy imines
15：R
2＝H
16：R
2＝CH
3
17：R
2＝CH
2CH
3
Hydrochlorate, the triethylamine reaction obtains compound 16 and 17;
(4) compound of structure 18-25 shown in synthetic:
18：Ar
1＝Ph-CH
3-p； 19：Ar
1＝Ph-Cl-p；
20：Ar
1＝Ph-NO
2-p； 21：Ar
1＝Ph-OH-p；
22：Ar
1＝Ph-OCH
3-p； 23：Ar
1＝Ph-(OCH
3)
2-m，?p；
24：Ar
1＝CH
2Ph； 25：Ar
1＝α-Naphthyl
With to monomethylaniline, p-Chlorobenzoic acid amide, p-Nitroaniline, para hydroxybenzene amine, P-nethoxyaniline, right, m-dimethoxybenzene amine, benzylamine or αNai An and phthalyl glutamic acid anhydride reactant obtain corresponding amide acid, then with sulfur oxychloride, diacetyl oxide, N, N '-carbonyl dimidazoles or N, N '-dicyclohexylcarbodiimide reaction obtains compound 18～25;
(5) compound of structure 26-33 shown in synthetic:
26：Ar
2＝OCPh； 27：Ar
2＝OCPh-CH
3-p；
28：Ar
2＝OCPh-OCH
3-p； 29：Ar
2＝OCPh-NH
2-p；
30：Ar
2＝OCPh-OOCCH
3-o； 31：Ar
2＝3-pyridine?formyl；
32：Ar
2＝4-pyridine?formyl； 33：Ar
2＝2-pyrazine?formyl
Adopt Benzoyl chloride, to methyl benzoyl chloride, anisoyl chloride, the hydrochloride of acetyl bigcatkin willow acyl chlorides and glutamy imines, triethylamine react in methylene dichloride and obtain compound 26,27,28,30; Hydrochloride with paranitrobenzoyl chloride and glutamy imines, triethylamine reacts in methylene dichloride and obtains p-nitrophenyl formyl glutamy imines, and p-nitrophenyl formyl glutamy imines and tetrahydrobenzene obtain p-benzoyl glutamy imines (29) with palladium carbon catalytic transfer hydrogenation in methyl alcohol; The 3-pyridine carboxylic acid, 4-pyridine carboxylic acid or 2-pyrazine carboxylic acid and N, N '-carbonyl dimidazoles, the hydrochloride of glutamy imines, 4-(N, N-dimethyl)-pyridine refluxes in anhydrous tetrahydro furan and obtains compound 31,32,33.
3. medicinal compositions, it contains compound of claims 1 and acceptable carrier pharmaceutically.
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| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
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| CN102576023B (en) * | 2009-10-20 | 2014-07-09 | 国立大学法人东京工业大学 | Screening method utilizing thalidomide-targeting factor |
| CN102827022A (en) * | 2012-09-21 | 2012-12-19 | 西华大学 | 2-acetoxy-N-(4-methoxyphenyl) benzamide and preparation method and application thereof |
| WO2019043214A1 (en) | 2017-09-04 | 2019-03-07 | F. Hoffmann-La Roche Ag | Glutarimide |
| US11802131B2 (en) | 2017-09-04 | 2023-10-31 | C4 Therapeutics, Inc. | Glutarimides for medical treatment |
| CN107556311A (en) * | 2017-10-31 | 2018-01-09 | 无锡福祈制药有限公司 | A kind of lenalidomide analog |
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| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
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