CN107312012A - Pyrimido phenodiazine * analog derivatives and its medical usage - Google Patents
Pyrimido phenodiazine * analog derivatives and its medical usage Download PDFInfo
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- CN107312012A CN107312012A CN201710514451.0A CN201710514451A CN107312012A CN 107312012 A CN107312012 A CN 107312012A CN 201710514451 A CN201710514451 A CN 201710514451A CN 107312012 A CN107312012 A CN 107312012A
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- 0 CSc(nc1-[n]2c(CN3*)c(*)nc2)nc(*)c1C3=O Chemical compound CSc(nc1-[n]2c(CN3*)c(*)nc2)nc(*)c1C3=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Abstract
The present invention relates to formula (I) pyrimido phenodiazineAnalog derivative and its in pharmaceutically acceptable salt, prodrug and pharmaceutical composition, such compound is benzene phenodiazineR is methyl, ethyl, trifluoroethyl, cyclopropyl, isopropyl and benzyl in receptor antagonist, formula, and X is hydrogen or chlorine.The application of medicine is prepared and its is used as the invention also discloses the compound.
Description
Technical field
The present invention relates to pyrimido phenodiazineAnalog derivative and its in pharmaceutically acceptable salt, prodrug and drug regimen
Thing, further relate to its prepare and its as medicine application, especially as benzene phenodiazineThe application of receptor antagonist.
Background technology
Flumazenil is first specific benzene phenodiazineReceptor selective antagonists, act on benzene phenodiazine in brainBy
Body, retardance this receptor is without producing benzene phenodiazineThe effect of class medicine, clinically for terminating by benzene phenodiazineClass is drug-induced
With the first aid of the general anesthesia of maintenance, and such drug poisoning, the Flumazenil of isotope marks can be also used for epileptics
The PET-CT imagings of stove etc..
The content of the invention
The compound of the present invention has the Flumazenil analog structure containing pyrimidine ring as described in claim 1, this
The characteristics of structure for the Flumazenil analog containing pyrimidine ring for planting new type is that pyrimidine ring 6 replaces by H or by halogen；Separately
Outside, diazaHydrocarbyl substituent is carried in ring on N atoms.It can be connect the invention provides the compound shown in formula I and its pharmacy
Salt, isomers, the solvate received.
Wherein：
R be methyl, ethyl, trifluoroethyl, cyclopropyl, isopropyl and benzyl,
X be hydrogen or chlorine,
Formula I can also be the form of its salt, be usually the salt formed with organic or inorganic alkali or acid.
The preferably acceptable salt of physiology of the invention.The acceptable salt of physiology of the compounds of this invention can be the present invention
The salt of material and inorganic acid, carboxylic acid or sulfonic acid, particularly preferably for example with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, high chlorine
Acid, fumaric acid, acetic acid, propionic acid, butanedioic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, flutter acid, the third two
Acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid, naphthalene-
2- sulfonic acid, benzene sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, the salt of tannic acid formation.Other acid, such as oxalic acid, although its
Body is not pharmaceutically acceptable, but can be used for preparing the salt as intermediate, to obtain the compounds of this invention and its pharmacy
Upper acceptable salt.
Physiologically acceptable salt equally can be the metal or ammonium salt of the compounds of this invention with free carboxy.It is special
You Xuanshi not be such as sodium, potassium, magnesium or calcium salt and inorganic ammonia or organic amine such as ethamine, diethylamine, triethylamine, N, N '-dibenzyl
Ethylenediamine, chloroprocaine, choline, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine, diethanol amine, triethanolamine, dicyclohexylamine,
Dimethylaminoethanol, arginine, the ammonium salt of lysine or ethylenediamine.
The compound of the present invention can also be its possible solvate.
The invention further relates to prepare the synthetic method of type I compound of the present invention, including:
1) by 4, the chloro- 2- first mercaptopyrimidine -5- formic acid (II) of 6- bis- obtain corresponding acyl chlorides (III) with oxalyl chloride reaction, so
Afterwards corresponding midbody acid amide (V) is obtained with substitution aminomethyl glyoxaline formic ether (IV) reaction.
Wherein, R, X definition are as claimed in claim 1.
2) thermal cyclization obtains target compound (I) to midbody acid amide (V) in the basic conditions
Wherein：R, X definition are as claimed in claim 1.
The form of medication that the active component can be adapted to these methods of administration is administered.
There is the known administration shape that active component can be transmitted rapidly and/or in the way of change suitable for oral administration
Formula, such as tablet (uncoated tablets or coating tablet such as have enteric coating or the tablet not being coated), capsule, sugar coated tablet, particle, small medicine
Ball, pulvis, emulsion, suspension and aerosol.
Using parenteral be able to may avoid absorption step (in intravenous, intra-arterial, intracardiac, backbone or in waist marrow to
Medicine) or include absorb (intramuscular, subcutaneous, intracutaneous, percutaneous or Intraperitoneal medication).Form of medication suitable for parenteral is special
It is the preparation for the solution injected and inputted, suspension, emulsion, freeze-drying thing and aseptic powdery form.
Suitable for other administration route have for example the medicine of suction (particularly powder suction, spraying), nose drops/solution,
Spray；For tongue, the tablet or capsule, suppository, preparation, vaginal capsule, water for ear and eyes of the administration of sublingual or cheek
Property suspension (lotion, shaking mixture), lipophilicity suspension, ointment, emulsifiable paste, emulsion, paste, dusting or implant, like that
Rise special stent.
The active component can be changed into described form of medication with method known per se.It can use inert non-toxic
Suitable pharmaceutical excipient realize.It particularly includes carrier (such as microcrystalline cellulose), solvent (the poly- second two of such as liquid
Alcohol), emulsifying agent (such as lauryl sodium sulfate), dispersant (such as polyvinylpyrrolidone), synthesis and natural biological polymerization
Thing (such as protein), stabilizer (such as antioxidant and ascorbic acid), colouring agent (such as inorganic pigment such as iron oxide) are rectified
Taste agent and/or odor mask.In the case of suitable, described active component can be present in the form of microencapsulation it is a kind of or
In a variety of above-mentioned carriers.
Except the chemical combination beyond the region of objective existence of formula I, said medicine preparation can also include other drugs active component.
See embodiment on preparing the more detailed data of compound of Formula I, but the following examples are only of the invention preferred
Illustrative approach, the present invention is not limited in any way.
Embodiment 1：6- methyl -2- methyl mercaptos -5- oxos -6,7- dihydro -5H- imidazoles [1,5-a] pyrimidine [5,4-f] [1,
4] diaza- 8- Ethyl formates
The chloro- 2- methylthiopyrimidines -5- formic acid of 0.35g (1.71mmol) 4- is dissolved in 20mL dichloromethane solvents, added
0.37g (2.94mmol) oxalyl chloride, 1 drop DMF, is stirred at room temperature and removes solvent and excessive oxalyl chloride after 6h under reduced pressure, obtain yellow
Solid；It is dissolved in 20mL dichloromethane, then adds 0.22g (1.21mmol) 5- (methylamine methyl) -1H- imidazoles -4- first
Acetoacetic ester, 0.21g (2.05mmol) triethylamine is stirred at room temperature to being poured into 30mL saturated sodium bicarbonate solutions after completion of the reaction
In, extracted with dichloromethane (20mL × 2), merge organic phase, anhydrous sodium sulfate drying removes solvent under reduced pressure after filtering and obtains 5-
((4- chloro-n-methyl -2- methylthiopyrimidine -5- formamidos) methyl) -1H- imidazoles -4- Ethyl formates, are directly used in next step
Reaction.5- ((4- chloro-n-methyl -2- methylthiopyrimidine -5- formamidos) methyl) -1H- imidazoles -4- Ethyl formates are dissolved in
In 20mL acetonitriles, 0.58g (4.22mmol) Anhydrous potassium carbonate is added, is stirred at room temperature to removing solvent under reduced pressure after completion of the reaction.Will
It is dissolved with 20mL dichloromethane, and with 30mL saturated common salt water washings, anhydrous sodium sulfate drying removes solvent under reduced pressure after filtering,
Column chromatography for separation (CH2Cl2:CH3COCH3=10:1) white solid, is obtained, two step yields are 60%.Mp.192-194℃.1H
NMR(CDCl3,400MHz):δ 9.16 (s, 1H), 8.36 (s, 1H), 4.90 (s, 2H), 4.44 (q, J=7.1Hz, 2H), 3.27
(s, 3H), 2.64 (s, 3H), 1.45 (t, J=7.1Hz, 3H).HRMS(ESI)m/z:334.0967[M+H]+。
Embodiment 2:6- ethyls -2- methyl mercaptos -5- oxos -6,7- dihydro -5H- imidazoles [1,5-a] pyrimidine [5,4-f] [1,
4] diaza- 8- Ethyl formates
Method be the same as Example 1, by the chloro- 2- methylthiopyrimidines -5- formic acid of 0.35g (1.71mmol) 4- and 0.37g
The reaction of (2.94mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.24g (1.21mmol) 5- (second
Amine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((chloro- N- ethyls -2- (methyl mercapto) pyrimidine -5- formamidos of 4-)
Methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((chloro- N- ethyls -2- (methyl mercapto) pyrimidines of 4- -
5- formamidos) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.58g (4.22mmol) Anhydrous potassium carbonate,
Generation cyclization obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=10:1), two step yields are 66%.
Mp.159-161℃。1H NMR(CDCl3,400MHz):δ 9.16 (s, 1H), 8.37 (s, 1H), 4.88 (s, 2H), 4.44 (q, J=
7.1Hz, 2H), 3.70 (q, J=7.1Hz, 2H), 2.63 (s, 3H), 1.44 (t, J=7.1Hz, 3H), 1.25 (t, J=7.1Hz,
3H)。HRMS(ESI)m/z:348.1123[M+H]+。
Embodiment 3:2- methyl mercapto -5- oxos -6- (2,2,2- trifluoroethyls) -6,7- dihydro -5H- imidazoles [1,5-a] is phonetic
Pyridine [5,4-f] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 1, by the chloro- 2- methylthiopyrimidines -5- formic acid of 0.35g (1.71mmol) 4- and 0.37g
The reaction of (2.94mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.30g (1.21mmol) 5-
The reaction of ((2,2,2- trifluoroethylamines) methyl) -1H- imidazoles -4- Ethyl formates obtains 5- ((the chloro- 2- methyl mercaptos-N- (2,2,2- of 4-
Trifluoroethyl) pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((4-
Chloro- 2- methyl mercaptos-N- (2,2,2- trifluoroethyls) pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile
0.58g (4.22mmol) Anhydrous potassium carbonate is added in solution, occurs cyclization and obtains white solid, column chromatography for separation
(CH2Cl2:CH3COCH3=10:1), two step yields are 59%.Mp.160-162℃.1H NMR(CDCl3,400MHz):δ9.17
(s, 1H), 8.40 (s, 1H), 5.07 (s, 2H), 4.45 (q, J=7.1Hz, 2H), 4.25 (q, J=8.6Hz, 2H), 2.66 (s,
3H), 1.45 (t, J=7.1Hz, 3H).HRMS(ESI)m/z:402.0844[M+H]+。
Embodiment 4:6- cyclopropyl -2- methyl mercaptos -5- oxos -6,7- dihydro -5H- imidazoles [1,5-a] pyrimidine [5,4-f]
[1,4] diaza- 8- Ethyl formates
Method be the same as Example 1, by the chloro- 2- methylthiopyrimidines -5- formic acid of 0.35g (1.71mmol) 4- and 0.37g
The reaction of (2.94mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.25g (1.21mmol) 5- (rings
Propylamine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- cyclopropyl -2- methylthiopyrimidines -5- formamides of 4-
Base) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5-, ((the chloro- N- cyclopropyl -2- methyl mercaptos of 4- are phonetic
Pyridine -5- formamidos) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.58g (4.22mmol) Carbon Dioxide
Potassium, occurs cyclization and obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=10:1), two step yields are 95%.
Mp.138-140℃。1H NMR(CDCl3,400MHz):δ 9.22 (s, 1H), 8.41 (s, 1H), 4.96 (s, 2H), 4.47 (q, J=
7.1Hz, 2H), 3.04-3.01 (m, 1H), 2.65 (s, 3H), 1.47 (t, J=7.1Hz, 3H), 0.99-0.83 (m, 4H).HRMS
(ESI)m/z:360.1127[M+H]+。
Embodiment 5:6- isopropyls -2- methyl mercaptos -5- oxos -6,7- dihydro -5H- imidazoles [1,5-a] pyrimidine [5,4-f]
[1,4] diaza- 8- Ethyl formates
Method be the same as Example 1, by the chloro- 2- methylthiopyrimidines -5- formic acid of 0.35g (1.71mmol) 4- and 0.37g
The reaction of (2.94mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine it is (different with 0.26g (1.21mmol) 5-
Propylamine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- isopropyls -2- methylthiopyrimidines -5- formamides of 4-
Base) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5-, ((the chloro- N- isopropyls -2- methyl mercaptos of 4- are phonetic
Pyridine -5- formamidos) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.58g (4.22mmol) Carbon Dioxide
Potassium, occurs cyclization and obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=10:1), two step yields are 98%.
Mp.136-138℃。1H NMR(CDCl3,400MHz):δ9.19(s,1H),8.40(s,1H),5.00-4.92(m,1H),4.80
(br, 2H), 4.46 (q, J=7.1Hz, 2H), 2.65 (s, 3H), 1.46 (t, J=7.1Hz, 3H), 1.27 (d, J=6.7Hz,
6H)。HRMS(ESI)m/z:362.1281[M+H]+。
Embodiment 6:6- benzyls -2- methyl mercaptos -5- oxos -6,7- dihydro -5H- imidazoles [1,5-a] pyrimidine [5,4-f] [1,
4] diaza- 8- Ethyl formates
Method be the same as Example 1, by the chloro- 2- methylthiopyrimidines -5- formic acid of 0.35g (1.71mmol) 4- and 0.37g
The reaction of (2.94mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.31g (1.21mmol) 5- (benzyls
Amine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- benzyls -2- methylthiopyrimidines -5- formamidos of 4-) first
Base) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((the chloro- N- benzyls -2- methylthiopyrimidines -5- first of 4-
Amide groups) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.58g (4.22mmol) Anhydrous potassium carbonate, occur
Cyclization obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=10:1), two step yields are 89%.Mp.144-
146℃。1H NMR(CDCl3,400MHz):δ9.24(s,1H),8.38(s,1H),7.38-7.29(m,5H),4.84(s,2H),
4.81 (s, 2H), 4.38 (q, J=7.1Hz, 2H), 2.65 (s, 3H), 1.41 (t, J=7.1Hz, 3H).HRMS(ESI)m/z:
410.1281[M+H]+。
Embodiment 7:Chloro- 6- methyl -2- methyl mercaptos -5- oxos -6,7- dihydros -5H- imidazoles [1,5-a] pyrimidine [5,4- of 4-
F] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 1,20mL bis- is dissolved in by the chloro- 2- first mercaptopyrimidine -5- formic acid of 0.49g (2.03mmol) 4,6- bis-
In chloromethane alkane solvents, 0.52g (4.06mmol) oxalyl chloride is added, 1 drop DMF is stirred at room temperature after 5h and removes solvent and excess under reduced pressure
Oxalyl chloride, obtain yellow solid；It is dissolved in 20mL dichloromethane, then adds 0.37g (2.03mmol) 5- (methylamine first
Base) -1H- imidazoles -4- Ethyl formates, 0.35g (3.45mmol) triethylamine is stirred at room temperature to being poured into 30mL after completion of the reaction
In saturated sodium bicarbonate solution, extracted with dichloromethane (20mL × 2), merge organic phase, anhydrous sodium sulfate drying subtracts after filtering
Pressure is evaporated off solvent and obtains 5- ((4,6- Dichloro-N-methyl -2- methylthiopyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- first
Acetoacetic ester, is directly used in next step reaction.By 5- ((4,6- Dichloro-N-methyl -2- methylthiopyrimidine -5- formamido groups) first
Base) -1H- imidazoles -4- Ethyl formates are dissolved in 20mL acetonitriles, add 0.98g (7.10mmol) Anhydrous potassium carbonate, be stirred at room temperature to
Remove solvent under reduced pressure after completion of the reaction.It is dissolved with 20mL dichloromethane, with 30mL saturated common salt water washings, anhydrous sodium sulfate
Dry, remove solvent, column chromatography for separation (CH after filtering under reduced pressure2Cl2:CH3COCH3=60:1) white solid, the production of two steps, are obtained
Rate is 27%.Mp.174-176℃.1H NMR(CDCl3,400MHz):δ8.31(s,1H),5.26(br,1H),4.49(br,
1H), 4.43 (br, 2H), 3.21 (s, 3H), 2.62 (s, 3H), 1.43 (t, J=7.1Hz, 3H).HRMS(ESI)m/z:
368.0580[M+H]+。
Embodiment 8:Chloro- 6- ethyls -2- methyl mercaptos -5- oxos -6,7- dihydros -5H- imidazoles [1,5-a] pyrimidine [5,4- of 4-
F] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 7, by the chloro- 2- first mercaptopyrimidine -5- formic acid of 0.49g (2.03mmol) 4,6- bis- and 0.52g
The reaction of (4.06mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.24g (1.21mmol) 5- (second
Amine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- ethyls -2- methylthiopyrimidines -5- formyl ammonia of 4,6- bis-
Base) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((the chloro- N- ethyls -2- methyl mercaptos of 4,6- bis-
Pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.98g (7.10mmol) anhydrous carbon
Sour potassium, occurs cyclization and obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=60:1), two step yields are
43%.Mp.152-154℃.1H NMR(CDCl3,400MHz):δ 8.34 (s, 1H), 5.37 (d, J=16.2Hz, 1H), 4.47-
4.42 (m, 2H), 4.38 (br, 1H), 3.68 (q, J=7.0Hz, 2H), 2.64 (s, 3H), 1.45 (t, J=7.1Hz, 3H),
1.24 (t, J=7.0Hz, 3H).HRMS(ESI)m/z:382.0735[M+H]+。
Embodiment 9:4- chloro- 2- methyl mercaptos -5- oxos -6- (2,2,2- trifluoroethyls) -6,7- dihydro -5H- imidazoles [1,5-
A] pyrimidine [5,4-f] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 7, by the chloro- 2- first mercaptopyrimidine -5- formic acid of 0.49g (2.03mmol) 4,6- bis- and 0.52g
The reaction of (4.06mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.30g (1.21mmol) 5-
((2,2,2- trifluoroethylamines) methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- 2- methyl mercaptos-N- of 4,6- bis- (2,
2,2- trifluoroethyls) pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- carboxylic acid, ethyl esters, it is directly used in next step reaction.To 5-
((chloro- 2- methyl mercaptos-N- (2,2,2- trifluoroethyls) pyrimidine -5- of 4,6- bis- formamido groups) methyl) -1H- imidazoles -4- carboxylic acid second
0.98g (7.10mmol) Anhydrous potassium carbonate is added in the acetonitrile solution of ester, occurs cyclization and obtains white solid, column chromatography point
From (CH2Cl2:CH3COCH3=60:1), two step yields are 41%.Mp.163-165℃.1H NMR(CDCl3,400MHz):δ
8.34 (s, 1H), 5.11 (s, 2H), 4.54 (q, J=8.3Hz, 2H), 4.43 (q, J=7.1Hz, 2H), 2.54 (s, 3H), 1.44
(t, J=7.1Hz, 3H).HRMS(ESI)m/z:436.0453[M+H]+。
Embodiment 10:Chloro- 6- cyclopropyl -2- methyl mercaptos -5- oxos -6,7- dihydros -5H- imidazoles [1,5-a] pyrimidines of 4- [5,
4-f] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 7, by the chloro- 2- first mercaptopyrimidine -5- formic acid of 0.49g (2.03mmol) 4,6- bis- and 0.52g
The reaction of (4.06mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.25g (1.21mmol) 5- (rings
Propylamine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- cyclopropyl -2- methylthiopyrimidines -5- formyls of 4,6- bis-
Amino) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((the chloro- N- cyclopropyl -2- first of 4,6- bis-
Sulfenyl pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.98g (7.10mmol) nothing
Aqueous carbonate potassium, occurs cyclization and obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=60:1), two step yields are
45%.Mp.152-154℃.1H NMR(CDCl3,400MHz):δ 8.34 (s, 1H), 5.42 (br, 1H), 4.45 (q, J=
7.0Hz, 2H), 4.35 (br, 1H), 2.99-2.94 (m, 1H), 2.63 (s, 3H), 1.48 (t, J=7.1Hz, 3H), 0.99 (br,
1H),0.80(br,1H)。HRMS(ESI)m/z:394.0735[M+H]+。
Embodiment 11:Chloro- 6- isopropyls -2- methyl mercaptos -5- oxos -6,7- dihydros -5H- imidazoles [1,5-a] pyrimidines of 4- [5,
4-f] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 7, by the chloro- 2- first mercaptopyrimidine -5- formic acid of 0.49g (2.03mmol) 4,6- bis- and 0.52g
The reaction of (4.06mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine it is (different with 0.26g (1.21mmol) 5-
Propylamine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- isopropyls -2- methylthiopyrimidines -5- formyls of 4,6- bis-
Amino) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((the chloro- N- isopropyls -2- first of 4,6- bis-
Sulfenyl pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.98g (7.10mmol) nothing
Aqueous carbonate potassium, occurs cyclization and obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=60:1), two step yields are
32%.Mp.140-142℃.1H NMR(CDCl3,400MHz):δ 8.37 (s, 1H), 5.49 (d, J=16.5Hz, 1H), 4.95-
4.88 (m, 1H), 4.46 (q, J=7.1Hz, 2H), 4.15 (q, J=16.5Hz, 1H), 2.64 (s, 3H), 1.46 (t, J=
7.1Hz, 3H), 1.37 (d, J=6.8Hz, 3H), 1.15 (d, J=6.8Hz, 3H).HRMS(ESI)m/z:396.0895[M+H
]+。
Embodiment 12:Chloro- 6- benzyls -2- methyl mercaptos -5- oxos -6,7- dihydros -5H- imidazoles [1,5-a] pyrimidine [5,4- of 4-
F] [1,4] diaza- 8- Ethyl formates
Method be the same as Example 7, by the chloro- 2- first mercaptopyrimidine -5- formic acid of 0.49g (2.03mmol) 4,6- bis- and 0.52g
The reaction of (4.06mmol) oxalyl chloride obtains yellow solid；Then by its under the conditions of triethylamine with 0.31g (1.21mmol) 5- (benzyls
Amine methyl) -1H- imidazoles -4- Ethyl formates reaction obtain 5- ((the chloro- N- benzyls -2- methylthiopyrimidines -5- formyl ammonia of 4,6- bis-
Base) methyl) -1H- imidazoles -4- Ethyl formates, it is directly used in next step reaction.To 5- ((the chloro- N- benzyls -2- methyl mercaptos of 4,6- bis-
Pyrimidine -5- formamido groups) methyl) -1H- imidazoles -4- Ethyl formates acetonitrile solution in add 0.98g (7.10mmol) anhydrous carbon
Sour potassium, occurs cyclization and obtains white solid, column chromatography for separation (CH2Cl2:CH3COCH3=60:1), two step yields are
47%.Mp.167-169℃.1H NMR(CDCl3,400MHz):δ 8.34 (s, 1H), 7.36-7.31 (m, 5H), 5.33 (d, J=
16.2Hz, 1H), 5.11 (d, J=14.5Hz, 1H), 4.45 (br, 1H), 4.39 (q, J=7.1Hz, 2H), 4.27 (d, J=
16.2Hz, 1H), 2.64 (s, 3H), 1.41 (t, J=7.1Hz, 3H).HRMS(ESI)m/z:444.0894[M+H]+。
Embodiment 13：Antagonism of the compound to diazepam sedation and hypnosis
1) preparation of drug solution
Diazepam (DZP) is dissolved in DMSO/TW-80 (2:1) in the mixed solvent, is made 50mg/ml liquid storages.Flumazenil
(FLU) 10mg/ml liquid storages and noval chemical compound is dissolved in DMSO, are made.All drug stocks are configured in experimental day.Experiment starts
Before, each liquid storage is diluted to working concentration with deionized water.Diazepam final concentration of 3mg/ml, FLU and noval chemical compound final concentration
For 1mg/ml, control solvent is 15%DSMO solution.
2) mouse righting reflex behavior model
Take and adapted to the experimental situation kunming mice of 3 days (SPF grades), weigh and be placed in after numbering in clean rearging cage,
Per 1, cage.By each mouse administered volume of 10ml/kg criterion calculations.First FLU or noval chemical compound are given using tail vein injection mode
Working solution, then gives DZP working solutions using intraperitoneal injection mode, and dosing interval is no more than 1min twice.After second is administered
Mouse is put back in rearging cage, the time point is calculated as zero point (T0).Mouse active situation is observed, will when mouse is stopped action
It is turned into dorsal position posture.If mouse can not independently right explanation in 2min, its righting reflex behavior disappears, and records mouse
Start the time (T for righting disappearance occur1).If mouse can independently right in righting reflex loss after for a period of time in 1min
Then illustrate that its righting reflex behavior recovers for 3 times, the time (T that record mouse righting reflex behavior recovers2)。T1With T0Difference be
For the incubation period of righting reflex loss；T2With T1Difference be righting reflex loss duration.
3) different compounds induce diazepam the influence of righting reflex loss
The influence of FLU and noval chemical compound to DZP sedation and hypnosis is studied using mouse righting reflex behavior model.If
Control groups, FLU groups and noval chemical compound group, wherein Control groups first give control solvent (15%DMSO solution), and FLU groups are first
FLU working solutions (10mg/kg) are given, noval chemical compound group first gives noval chemical compound working solution (10mg/kg), then gives each group small
Mouse DZP working solutions (30mg/kg).Observe the situation of change of each group mouse righting reflex behavior in 120min.
4) data analysis
The softwares of experimental data application GraphPad Prism 5.0 carry out statistical analysis, as a result with average ± standard errorRepresent.The comparison of each experimental group and Control groups is tested using t-test, P<0.05 represents have significantly
Significant difference.
5) result of the test
Note：The size of animal of Control and FLU groups is 18, and the size of animal of other groups is 6.
Claims (6)
1. compound and its pharmaceutically acceptable salt, solvate shown in formula I.
Wherein：
R be methyl, ethyl, trifluoroethyl, cyclopropyl, isopropyl and benzyl,
X is hydrogen or chlorine.
2. compound as claimed in claim 1 and its pharmaceutically acceptable salt, solvate.
3. compound as claimed in claim 2 and its pharmaceutically acceptable salt, solvate, wherein the compound preferably has
There is following structure.
4. preparing the method for any one of the claims 1 to 3 compound, it includes：
1) the chloro- 2- methylthiopyrimidines -5- formic acid (II) of 4- are obtained into corresponding acyl chlorides (III) with oxalyl chloride reaction, then with substitution
Aminomethyl glyoxaline formic ether (IV) reaction obtains corresponding midbody acid amide (V).
Wherein, R, X definition are as claimed in claim 1.
2) thermal cyclization obtains target compound (I) to midbody acid amide (V) in the basic conditions
Wherein：R, X definition are as claimed in claim 1.
5. a kind of medicine, its comprising at least one compound of formula I as defined in claim 1 or its pharmaceutically acceptable salt,
Solvate and at least one other excipient.
6. compound of formula I or its pharmaceutically acceptable salt, isomers, solvate are used to prepare as defined in claim 1
GABAAAcceptor benzene phenodiazineRelationship of Antagonists, is mainly used in diagnosis and the rescue of benzodiazepine poisoning, is also applied for azoles
The rescue of toxic reaction caused by the related drugs such as pyrrole is smooth, zopiclone, alcohol are excessive；Other potential uses also include being used as maincenter
Excitant be used for it is postoperative waken, and the stupor and drowsiness caused by treatment hepatic encephalopathy and other causes of disease.
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Citations (1)
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Non-Patent Citations (4)
| Title |
|---|
| A. TERLETSKAYA等: "Computer-aided investigation of the structure–activity relationships of benzodiazepine derivatives at diazepam-sensitive receptors", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
| ALEXANDER JACKSON等: "Evaluation of a novel series of fluorine-18-labeled imidazobenzodiazepines as potential new positron emission tomography radioligands for the GABAA receptor", 《NUCLEAR MEDICINE AND BIOLOGY》 * |
| ALEXANDER JACKSON等: "The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| GARRY WONG等: "Synthetic and Computer-Assisted Analysis of the Structural Requirements for Selective, High-Affinity Ligand Binding to Diazepam-Insensitive Benzodiazepine Receptors", 《J. MED. CHEM.》 * |
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