CN112237576A - Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use - Google Patents
Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use Download PDFInfo
- Publication number
- CN112237576A CN112237576A CN201910641816.5A CN201910641816A CN112237576A CN 112237576 A CN112237576 A CN 112237576A CN 201910641816 A CN201910641816 A CN 201910641816A CN 112237576 A CN112237576 A CN 112237576A
- Authority
- CN
- China
- Prior art keywords
- dihydroxy
- dimethylisochroman
- formyl
- preparation
- ischemic stroke
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- General Chemical & Material Sciences (AREA)
Abstract
The invention discloses 6 (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (wherein AA is L-His, L-Lys, L-Pro, L-Arg, L-Thr and L-Trp residue) with the following formula, a preparation method thereof and a treatment effect thereof on resisting ischemic stroke attack for 24 hours. The invention thus discloses their use in the manufacture of a medicament which is effective against ischemic stroke attacks for 24 hours.
Description
Technical Field
The present invention relates to 6 (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is L-His, L-Lys, L-Pro, L-Arg, L-Thr and L-Trp residue) of the following formula, to a process for their preparation, and to their therapeutic effect against ischemic stroke attacks for 24 hours. The invention thus relates to their use in the manufacture of a medicament which is effective against ischemic stroke attacks for 24 hours. The invention belongs to the field of biological medicine.
Technical Field
Ischemic stroke is a common, severely damaging cerebrovascular disease. Ischemic stroke is characterized by high morbidity, high disability rate, high recurrence rate and high mortality rate, and is one of the most serious fatal diseases for human beings. Currently, rtPA is the only clinically accepted effective drug for the treatment of ischemic stroke. However, rtPA has two difficult problems to overcome in treating ischemic stroke. The first problem is that rtPA is not effective in patients with ischemic stroke that has occurred for more than 4 hours. The second problem is that continued use of rtPA can cause bleeding in the brain, thorax and abdominal cavities. The invention is a hot spot and a leading edge of research on cerebrovascular drugs, and the drugs are effective on patients with ischemic stroke of more than 4 hours, especially patients with ischemic stroke of 24 hours, and have no bleeding side effect. The inventors have focused on the development of a drug that is effective in ischemic stroke for more than 4 hours, especially in patients with ischemic stroke for 24 hours, without bleeding side effects. After 3 years of exploration, the inventor finds that the following 6 (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is L-His, L-Lys, L-Pro, L-Arg, L-Thr and L-Trp residues) is effective to rats with 24 hours of ischemic stroke attack and has no bleeding side effect. Based on this finding, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is a residue of L-His, L-Lys, L-Pro, L-Arg, L-Thr or L-Trp).
The second aspect of the present invention is to provide a method for synthesizing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is a residue of L-His, L-Lys, L-Pro, L-Arg, L-Thr, or L-Trp), which comprises:
1) preparing D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate by a standard method under the catalysis of thionyl chloride;
2) converting D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate into (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid benzyl ester under the catalytic action of boron trifluoride diethyl ether;
3) preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid by Pd/C catalytic hydrogenation of benzyl (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate by a standard method;
4) preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA-OBzl by a standard method under the catalytic action of diphenyl phosphorazide and N-methylmorpholine;
5) (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA-OBzl is catalytically hydrogenated to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA.
The third aspect of the present invention is to evaluate the activity of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA against ischemic stroke.
Drawings
FIG. 1 is a scheme for the synthesis of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA in which AA is selected from the group consisting of L-His, L-Lys, L-Pro, L-Arg, L-Thr and L-Trp residues. (i) Benzyl alcohol, SOCl2(ii) a (ii) Acetone, BF3-Et2O;(iii)H2Pd/C, MeOH; (iv) AA-OBzl, diphenyl phosphorazide, N-methylmorpholine and anhydrous tetrahydrofuran; (v) h2,Pd/C,MeOH。
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of benzyl D (+) -beta- (3, 4-dihydroxyphenyl) lactate (1)
91.0mL of thionyl chloride was slowly added dropwise to 150mL of benzyl alcohol stirred at 0 ℃. After dropping, stirring for 1h at room temperature, adding 55.0g (250mmol) of salvianic acid A sodium, stirring for 48h at room temperature, and completely reacting. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate and saturated NaClWashed with aqueous solution (30 mL. times.3) and dried over anhydrous Na2SO4Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 20.1g (35%) of the title compound as a yellow oil.1HNMR(300M Hz,DMSO-d6):δ/ppm=8.75(s,1H),8.67(s,1H),7.31(m,5H),6.61(s,1H),6.58(s,1H),6.42(dd,J1=1.8Hz,J2=2.1Hz,1H),5.55(d,J=6.0Hz,1H),5.12(s,2H),4.19(q,J1=6.9Hz,J2=6.0Hz,1H),2.73(qd,J1=8.1Hz,J2=5.4Hz,2H);ESI-MS(m/e):287[M-H]-。
EXAMPLE 2 preparation of benzyl (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate (2)
10.0g (30.6mmol) of benzyl D (+) -beta- (3, 4-dihydroxyphenyl) lactate (1) was dissolved in 104mL of acetone. 4.4mL of boron trifluoride diethyl ether were slowly added dropwise with stirring at 0 ℃. After dropping, the mixture was stirred at room temperature for 4 hours, and the compound 1 completely disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate. The resulting solution was washed with saturated aqueous NaCl (30 mL. times.3), and then with anhydrous Na2SO4Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 11.4g (80%) of the title compound as a yellow oil.1H NMR(300MHz,DMSO-d6):δ/ppm=1.58(s,1H),1.54(s,1H),7.39(m,5H),6.52(s,1H),6.47(s,1H),1.93(s,1H),4.47(m,1H),2.71(m,2H),1.40(m,6H);ESI-MS(m/e):327[M-H]-。
EXAMPLE 3 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3)
11.4g (34.8mmol) of benzyl (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate (2) were dissolved in 60mL of methanol. Then 1.14g Pd/C is added, the mixture is stirred evenly, hydrogen is introduced, the mixture reacts for 24 hours at room temperature, and the compound 2 completely disappears. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 10.5g (95%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6):δ/ppm=12.60(s,1H),8.82(d,J=6.9Hz,2H),8.66(d,J=5.4Hz,2H),6.52(s,1H),6.46(s,1H),4.34(m,1H),2.68(d,J=7.2Hz,2H),1.37(d,J=3.8Hz,6H);ESI-MS(m/e):237[M-H]-。
EXAMPLE 4 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-His-OBzl (4a)
476mg (2.0mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) was dissolved in 12mL of anhydrous tetrahydrofuran, and 1mL of diphenylphosphoryl azide (DPPA) was added and stirred for 30 min. 700mg (2.2mmol) His-OBzl was added at 0 ℃ with stirring. The pH of the reaction solution is adjusted to 8-9 by N-methylmorpholine. After stirring at room temperature for 24h, compound 3 completely disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate and successively treated with 1N CH3COONa aqueous solution (30 mL. times.3), saturated NaCl aqueous solution (30 mL. times.3), and saturated KHSO4Washing with an aqueous solution (30 mL. times.3), washing with a saturated aqueous NaCl solution (30 mL. times.3), and washing with anhydrous Na2SO4Dried for 12h, filtered, the filtrate concentrated under reduced pressure and the residue purified by silica gel column chromatography to give 335mg (36%) of the title compound as a colorless solid.1HNMR(300MHz,DMSO-d6):δ/ppm=11.89(s,1H),8.83(s,1H),8.67(s,1H),8.33(s,1H),7.57(s,1H),7.34(s,1H),6.79(s,1H),6.78(s,1H),6.53(s,1H),5.10(q,J1=12.6Hz,J2=14.1Hz,2H),4.57(m,1H),4.17(d,J=8.40Hz,1H),2.90(s,2H),2.68(m,1H),1.43(d,J=16.2Hz,2H);ESI-MS(m/e):464[M-H]-。
EXAMPLE 5 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Lys (Cbz) -OBzl (4b)
By the method of example 4, from 830mg (3.48mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 2.27g (4.19mmol) of Lys (Cbz) -OBzl 780mg (30%) of the title compound were obtained as a colorless solid.1H NMR(300MHz,DMSO-d6):δ/ppm=8.83(s,1H),8.68(s,1H),7.88(d,J=7.80Hz,1H),7.36(m,12H),6.60(s,1H),6.52(s,1H),5.15(m,4H),4.34(d,J=6.90Hz,1H),4.23(d,J=11.1Hz,1H),2.62(m,2H),1.28(m,10H),1.44(m,4H);FT-MS(m/e):590[M-H]-。
EXAMPLE 6 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Pro-OBzl (4c)
From 476mg (2.00mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 491.7mg (2.20mmol) of Pro-OBzl 374mg (46%) of the title compound are obtained as a colorless solid according to the method of example 4.1H NMR(300MHz,DMSO-d6):δ/ppm=8.82(s,1H),8.65(s,1H),7.35(m,5H),6.52(s,1H),6.45(s,1H),5.13(s,1H),4.49(d,J=2.4Hz,1H),4.39(m,1H),3.71(m,1H),3.46(m,1H),2.83(m,1H),2.42(m,1H),2.13(m,1H),1.86(m,3H),1.37(dd,J1=21.6Hz,J2=18.0Hz,6H);ESI-MS(m/e):424[M-H]-。
EXAMPLE 7 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Arg (NO)2)-OBzl(4d)
The procedure of example 4 was followed starting from 1.9g (8.00mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 4.2g (8.80mmol) of Arg (NO)2) OBzl gave 805mg (19%) of the title compound as a colourless solid.1H NMR(300MHz,DMSO-d6):δ/ppm=8.87(s,1H),8.71(s,1H),8.50(s,1H),7.98(d,J=7.50Hz,1H),7.35(d,J=7.80Hz,1H),6.53(s,1H),6.46(s,1H),5.14(d,J=1.80Hz,2H),4.38(d,J=5.40Hz,1H),4.23(d,J=6.60Hz,1H),2.68(m,2H),1.82(m,2H),1.62(m,1H),1.44(d,J=12.6Hz,6H),1.23(m,3H);ESI-MS(m/e):529[M-H]-。
EXAMPLE 8 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Thr-OBzl (4e)
From 512mg (2.15mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 902mg (2.37mmol) of Thr-OBzl, 624mg (26.0%) of the title compound are obtained as colorless solid according to the method of example 4.1H NMR(300MHz,DMSO-d6):δ/ppm=8.77(s,2H),7.50(d,J=8.70Hz,1H),7.37(m,5H),6.54(s,1H),6.47(s,1H),5.16(q,J1=12.9Hz,J2=7.80Hz,2H),4.36(m,3H),2.74(m,2H),1.45(d,J=6.00Hz,6H),1.10(d,J=6.00Hz,3H);ESI-MS(m/e):428[M-H]-。
EXAMPLE 9 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Trp-OBzl (4f)
From 1.20g (5.00mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 2.80g (6.00mmol) of Trp-OBzl, 437mg (17%) of the title compound are obtained as colorless solid according to the method of example 4.1H NMR(300MHz,DMSO-d6):δ/ppm=11.0(s,1H),8.83(s,1H),8.67(s,1H),7.64(d,J=7.80Hz,1H),7.52(d,J=7.50Hz,1H),7.34(m,6H),7.11(m,2H),6.97(m,1H),6.49(s,1H),6.42(s,1H),5.11(s,2H),4.66(d,J=7.50Hz,1H),4.15(d,J=2.40Hz,1H),3.17(d,J=5.10Hz,2H),2.64(m,1H),2.47(m,1H),1.24(s,6H);ESI-MS(m/e):513[M-H]-。
EXAMPLE 10 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-His (5a)
Following the procedure of example 3, from 335mg (0.72mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-His-OBzl (4a) was obtained 246mg (91%) of the title compound as a colorless solid. Mp is 172.0-175.2 ℃;=165.0(c=0.1,MeOH);IR(cm-1):3130,2850,1580,1516,1384,1260,1189,1149,1092,835;1HNMR(300MHz,DMSO-d6):δ/ppm=8.06(d,J=7.50Hz,1H),7.64(s,1H),6.87(s,1H),4.50(d,J=19.5Hz,2H),4.42(q,J1=6.90Hz,J2=6.00Hz,1H),4.16(m,1H),3.39(q,J1=6.90Hz,J2=7.20Hz,1H),2.98(m,2H),2.67(m,2H),1.43(d,J=16.2Hz,6H);FT-MS(m/e):374.13678[M-H]-(theoretical value: 374.13521).
EXAMPLE 11 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Lys (5b)
Following the procedure of example 3, 203mg (56%) of the title compound was obtained as a colorless solid from (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Lys (Cbz) -OBzl (4 b). Mp is 202.1-204.3 ℃;=225.8(c=0.1,MeOH);IR(cm-1):3081,2929,1573,1510,1382,1290,1226,1148,1095,1037,960,869,836;1H NMR(300MHz,DMSO-d6):δ/ppm=8.61(s,1H),7.61(s,J=6.00Hz,1H),6.54(s,1H),6.47(s,1H),4.16(m,1H),3.86(m,1H),2.73(m,3H),1.69(m,2H),1.53(m,2H),1.42(d,J=6.90Hz,5H),1.28(m,2H);FT-MS(m/e):368.17814[M+H]+(theoretical value: 368.17907).
EXAMPLE 12 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Pro (5c)
By the method of example 3, starting from 374mg (0.92mmol) ((0.92 mmol))R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Pro-OBzl (4c) gave 270mg (93%) of the title compound as a colorless solid. Mp is 147.2-149.6 ℃;=64.6(c=0.1,MeOH);IR(cm-1):2971,1721,1603,1519,1448,1363,1183,1145,1100,958,870,829;1H NMR(300MHz,DMSO-d6):δ/ppm=8.76(s,1H),6.48(m,2H),4.78(d,J=7.50Hz,1H),4.45(d,J=8.70Hz,1H),4.25(m,1H),3.69(m,2H),3.37(m,5H),2.85(m,1H),2.43(m,1H),2.20(m,2H),1.88(m,2H),1.47(s,3H),1.33(s,3H);FT-MS(m/e):334.12422[M-H]-(theoretical value: 334.12906).
EXAMPLE 13 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Arg (5d)
The procedure is as in example 3 from 805mg (1.50mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Arg (NO)2) OBzl (4d) gave 236mg (53%) of the title compound as a yellow solid. Mp is 191.3-194.2 ℃;=198.8(c=0.1,MeOH);IR(cm-1):3385,3165,2983,1661,1602,1517,1502,1406,1287,1257,1195,1143,956,833,665;1H NMR(300MHz,DMSO-d6):δ/ppm=9.14(s,1H),8.84(s,2H),7.55(d,J=6.60Hz,4H),6.54(s,1H),6.47(s,1H),4.16(d,J=9.30Hz,1H),3.92(d,J=6.00Hz,1H),3.06(s,2H),2.74(d,J=13.8Hz,1H),1.66(s,2H),1.43(d,J=8.40Hz,6H);FT-MS(m/e):393.18102[M-H]-(theoretical value: 396.18523).
EXAMPLE 14 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Thr (5e)
453mg (92.0%) of the title compound were obtained as colorless powder from 624mg (1.05mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Thr-OBzl (4e) according to the method of example 3. Mp is 132.2-134.0 ℃;=151.0(c=0.1,MeOH);IR(cm-1):2976,2895,1729,1650,1520,1446,1382,1289,1146,1102,962,868,830,786;1H NMR(300MHz,DMSO-d6):δ/ppm=8.85(s,1H),8.70(s,1H),7.37(d,J=8.70Hz,1H),6.54(s,1H),6.48(s,1H),4.27(m,3H),2.74(d,J=13.5Hz,1H),2.59(d,J=11.4Hz,1H),1.42(d,J=12.1Hz,6H),1.08(d,J=6.90Hz,3H);FT-MS(m/e):338.12678[M-H]-(theoretical value: 338.12398).
EXAMPLE 15 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Trp (5f)
235mg (65.0%) of the title compound are obtained as a colorless solid by the method of example 3 from 437mg (0.85mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Trp-OBzl (4 f). Mp is 185.6-187.0 ℃;=79.8(c=0.1,MeOH);IR(cm-1):3383,2975,1724,1659,1520,1456,1362,1280,1186,1147,1096,740;1H NMR(300MHz,DMSO-d6):δ/ppm=12.9(s,1H),11.0(s,1H),8.83(s,1H),8.67(s,1H),7.55(d,J=7.80Hz,1H),7.44(d,J=8.10Hz,1H),7.34(d,J=7.80Hz,1H),7.14(s,1H),7.05(t,J=7.50Hz,1H),6.99(t,J=12.3Hz,1H),6.50(s,1H),6.44(s,1H),4.57(q,J1=17.7Hz,J2=7.20Hz,1H),4.14(d,J=9.00Hz,1H),3.23(d,J=5.10Hz,2H),2.66(d,J=13.8Hz,1H),2.42(m,1H),1.35(s,1H);FT-MS(m/e):423.15973[M-H]-(theoretical value: 423.15561).
EXAMPLE 16 evaluation of the therapeutic Effect of Compounds 5a-f on rats with ischemic stroke attacks of 24 hours
Male SD rats (280. + -.20 g) were anesthetized with a 10% chloral hydrate (4mL/kg) by intraperitoneal injection. A2 cm long incision was made vertically in the middle of the neck of the rat, and the right common carotid artery, external carotid artery and internal carotid artery were isolated along the intramuscular side of the sternocleidomastoid. Respectively clamping an opening of an internal carotid artery and a proximal end of a common carotid artery by using a noninvasive artery clamp, ligating a distal end of an external carotid artery, cutting a small opening on the external carotid artery, loosening the artery clamp at the proximal end of the common carotid artery, and taking 10 mu L of blood to enter a 1mL centrifuge tube. Thereafter, the proximal end of the common carotid artery is clamped with a non-invasive artery clamp. The blood in the tube was allowed to clot at ambient temperature for 30 minutes and then allowed to clot at-20 ℃ overnight to convert to a firm clot. The clot is removed, 1mL of normal saline is added, and the clot is smashed into a uniform suspension of fine thrombus mass and normal saline by a steel shovel. The thrombus mass suspension was transferred to a 1mL syringe. The artery clamp at the proximal end of the common carotid artery of the rat is loosened, and 1mL of thrombus mass suspension is slowly injected into the brain of the rat from the external carotid artery of the rat to the proximal end through the internal carotid artery. Then the external carotid artery is ligated to the proximal end, and the artery clamp at the internal carotid artery and common carotid artery is opened to restore blood flow. The degree of neurological deficit was assessed by the Zealonga method 24 hours after the rats were awakened. 0 point indicates no sign of neurological deficit, 1 point indicates that the front limb on the uninjured side cannot stretch, 2 points indicates walking to the uninjured side, 3 points indicates turning to the uninjured side to form rear-end walking, 4 points indicates that the disorder is identified without autonomous walking, and 5 points indicates death. Rats were evenly grouped according to score. Each group of rats was orally administered 1 time saline (3mL/kg/d) or a physiological saline solution of compounds 5a-f (dose of 100 nmol/kg/day) per day. Oral administration was continued for 3 days, and scored daily. Calculating the death rate of each group of rats to be 5 points/total number multiplied by 100 percent according to the scores; number of cases/total cases with a score on the last day lower than the score before dosing but not 0 x 100%; the cure rate is 0 counts/total counts on the last day x 100%. The data are shown in Table 1. The results show that the mortality rate of the rats treated with the compounds 5a-f is not zero but is lower than that of the rats treated with physiological saline, and the cure rate of the rats treated with the compounds 5a-f is higher than that of the rats treated with physiological saline. Therefore, the invention has outstanding technical effects.
TABLE 1 neurobiological score of stroke 24-hour rats treated with Compounds 5a-f
Claims (3)
2. A process for preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA of claim 1, comprising:
2.1 preparing D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate by a standard method under the catalysis of thionyl chloride;
2, converting 2D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate into (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid benzyl ester under the catalytic action of boron trifluoride diethyl etherate;
preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid by Pd/C catalytic hydrogenation with benzyl 3 (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate according to a standard method;
2.4 preparing (R) -6, 7-dihydroxy-1, 1-dimethyl isochroman-3-formyl-AA-OBzl by a standard method under the catalysis of diphenyl phosphorazide and N-methylmorpholine;
catalytic hydrogenation of 5(R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA-OBzl to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA.
3. Use of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA according to claim 1 for the preparation of a medicament for the treatment of ischemic stroke.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910641816.5A CN112237576A (en) | 2019-07-16 | 2019-07-16 | Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910641816.5A CN112237576A (en) | 2019-07-16 | 2019-07-16 | Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112237576A true CN112237576A (en) | 2021-01-19 |
Family
ID=74167384
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910641816.5A Withdrawn CN112237576A (en) | 2019-07-16 | 2019-07-16 | Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112237576A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5238939A (en) * | 1990-05-25 | 1993-08-24 | Akzo N.V. | Isochromane derivatives |
CN103450330A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Dihydroxyltetrahydroisoquinoline-3-formyl amino acids as well as synthesis, antithrombotic effect and application thereof |
CN106608901A (en) * | 2015-10-22 | 2017-05-03 | 彭莉 | Dihydroxy dimethyl tetrahydroisoquinoline-3-formyl-Lys (Ala-Lys) and synthesis, activity and application thereof |
CN106608902A (en) * | 2015-10-22 | 2017-05-03 | 彭莉 | Dihydroxydimethyltetrahydroisoquinolin-3-formyl-Lys(Lys) and its synthesis method, activity and use |
CN112010830A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, thrombolytic activity and use |
-
2019
- 2019-07-16 CN CN201910641816.5A patent/CN112237576A/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5238939A (en) * | 1990-05-25 | 1993-08-24 | Akzo N.V. | Isochromane derivatives |
CN103450330A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Dihydroxyltetrahydroisoquinoline-3-formyl amino acids as well as synthesis, antithrombotic effect and application thereof |
CN106608901A (en) * | 2015-10-22 | 2017-05-03 | 彭莉 | Dihydroxy dimethyl tetrahydroisoquinoline-3-formyl-Lys (Ala-Lys) and synthesis, activity and application thereof |
CN106608902A (en) * | 2015-10-22 | 2017-05-03 | 彭莉 | Dihydroxydimethyltetrahydroisoquinolin-3-formyl-Lys(Lys) and its synthesis method, activity and use |
CN112010830A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, thrombolytic activity and use |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP3009573B2 (en) | Separation of aminoarginine and uses to block nitric oxide production in the body | |
SU1225481A3 (en) | Method of producing mixture of glyceryl-1,2 and 1,3-bis-(di-h-propylacetates) showing properties of central nervous system depressant | |
US9890193B2 (en) | Compounds having triple activities of thrombolysis, antithrombosis, and radical scavenging, synthesis, and use thereof | |
CN112010830B (en) | Dihydroxydimethylisochroman-3-formyl aromatic amino acid, preparation, thrombolytic activity and application thereof | |
CN114315585B (en) | Hydroxypentyl benzoic acid diester compound, and preparation method and pharmaceutical application thereof | |
CN112239442A (en) | Dihydroxydimethylisochroman-3-formyl-Phe, preparation thereof, and anti-ischemic stroke effect and application thereof | |
CN112237576A (en) | Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use | |
CN108948146B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (ARPAK) -RGDV, and synthesis, activity and application thereof | |
CN112239445A (en) | Dihydroxydimethylisochroman-3-formyl-AA, preparation thereof, and anti-ischemic stroke effect and application thereof | |
CN109912588B (en) | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof | |
CN108948155B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (QRPAK) -RGDV, and synthesis, activity and application thereof | |
CN111848726B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl aromatic amino acid | |
CN112175041B (en) | Ethyl QRPAK modified bis-carbolino piperazine diketone and preparation, activity and application thereof | |
CN111848730B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl polar amino acid | |
CN111848724B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl acidic amino acid | |
CN112239448A (en) | Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, antithrombotic activity and use | |
CN111848606B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formylglycine and alanine | |
CN110577575B (en) | 1S-methyl-beta-tetrahydrocarboline acyl-K (ARPAK) -RGDV, and synthesis, activity and application thereof | |
CN112010936B (en) | Ethyl GRPAK modified bis-carbolino piperazine diketone and preparation, activity and application thereof | |
CN111848729B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl asparagine and glutamine | |
CN111848725B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl basic amino acid | |
CN106432414B (en) | Pentamethoxytryptophane-KAPKAP, its preparation, activity and use | |
CN110577574B (en) | 1S-methyl-beta-tetrahydrocarboline acyl-K (PAK) -RGDV, and synthesis, activity and application thereof | |
JP3112754B2 (en) | Cycloalkenone compound and brain function improving agent containing the compound as active ingredient | |
CN106432418B (en) | Pentamethoxychromoamino carbonyl propionyl-PAKPAK, its preparation, activity and application |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210119 |
|
WW01 | Invention patent application withdrawn after publication |