CN106749220A - A kind of substituent methyl indole derivatives of 6 ' substituted benzimidazole 4 and its preparation and application - Google Patents
A kind of substituent methyl indole derivatives of 6 ' substituted benzimidazole 4 and its preparation and application Download PDFInfo
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Abstract
The present invention relates to a kind of substituent methyl indole derivatives of 6 ' substituted benzimidazole 4 and its preparation and application, structural formula is：
Description
Technical field
The invention belongs to antagonist and its preparation and application field, more particularly to a kind of 6 '-substituted benzimidazole -4- substitutions
Methyl indole derivatives and its preparation and application.
Background technology
Marshall in 1970 et al. has synthesized first Angiotensin II (Angiotensin II, A II) receptor antagonist
Agent -- peptides Saralasin (Saralasin:Sarl-Ala8-Ang II), its split-phase of structure ten with Angiotensin II
Seemingly, it has specificity antagonism in vitro tissue.But in clinical practice application, due to it is oral it is invalid, be metabolized it is unstable and
Part A II can be made to produce agonism and be restricted.Nineteen eighty-two, Japanese Takeda Pharmaceutical Company Limited is in research imidazoleacetic acid class chemical combination
When the diuretic antihypertensive of thing is acted on, it is found that S-8307 can suppress the rabbit arterial of the inductions of A II and shrink and pressor effect, although activity compared with
It is weak, but belong to the acceptor specific antagonists of A II, and the stirring effect without Saralasin.The latter stage eighties, Dupont companies
(Med.Rev.1992,12:149-158) and Smithkline Beecham companies (Drugs of the fixture.1992,
17:Researcher 575-593), the C- stub areas of A II are compared with S-8307 arrangements, and series has been carried out to S-8307
Structural modification, has as a result respectively obtained two kinds of different types of structure, all compound Dup-753 with greater activity
(Losartan, Losartan) and SK＆F-108566 (Eprosartan, eprosartan), Losartan was listed in 1994 in Sweden
(Drugs of the Future.1997,22:1079-1085).Eprosartan listed (Drugs of in 1997 in Germany
the future.1996,21(8):794-798)。
The non-receptor antagonists of peptides A II with itself and the receptor affinities of A II it is strong, selectivity is high, it is oral effectively, long action time
The advantages of and be expected, be the up-and-coming depressor of a class.At present listing the non-receptor antagonists of peptides A II have Valsartan,
Losartan, eprosartan, Irb, Telmisartan etc..
Losartan (Losartan), in Sweden's listing, clinical ARB class medicines to be used for as first in 1994.To chlorine
The research of the structure-activity relationship of Sha Tan shows：1 extra phenyl ring is introduced in benzyl contraposition, biphenyl structural is constituted, bioactivity is carried
It is high；There is an acidic functionality at the phenyl ring ortho position for inducing one, and acid more strong affinity is bigger, for example：-CN、-COOMe、CF3、-CONH2
Deng can reach with carboxylic acid identical affinity, moreover, and 4 nitrogen-atoms can accommodate negative electrical charge distribution and receive tetrazole
Center of positive charge interacts on body, and effect is more preferable；Acidic substituent position on terminal phenyl rings is particularly significant, and 2 ', 6 ' double take
In generation, makes biphenyl on the same plane and increase spinning obstacle, and affinity can be caused to decline an order of magnitude；2 of imidazole ring
Substitution base is 3~4 lipophilic side chains of carbon atom of length, such as normal alkane；And branched paraffin, cycloalkane and aromatic substituent are equal
Reduce affinity；Imidazole ring 4 is preferably 1 lipophilic big functional group or group；The bit substituent of imidazole ring 5 is that can form hydrogen
The small group of key, such as alcohol, aldehyde, acid.
The research for being found to be the receptor antagonists of Ang II of Losartan provides molecular model, discloses the 3 of such compound
Most of structure：Imidazole ring structure, -1,1 '-biphenyl structural of 4- methylene, tetrazole structure.Many countries are all with this in recent years
It is template, carries out structural modification and transformation, obtains more good AT1Receptor antagonist.
Angiotensin Ⅱ receptor antagonist is mostly the transformation to Losartan structure, such as Candesartan
(J.Med.Chem.1993,36,15:2182-2195), Pomisartan (China Medicine University's journal, 2005,36,2:99-
101), TAK-536 (J.Med.Chem.1996,39,26:It is 5228-5235) etc. by the glyoxaline structure benzimidazole of Losartan
Structure replaces.Research to benzimidazoles compound, be concentrated mainly on to benzimidazole 6 (Pomisartan,
Telmisartan etc.) and 7 modifications of (such as Candesartan).
The content of the invention
The technical problems to be solved by the invention are to provide a kind of 6 '-substituted benzimidazole -4- substituent methyls indoles and derive
Thing and its preparation and application, prepared by the present invention convenient, has obtained having more preferably AT1The new drug of receptor antagonist effect, the present invention exists
6 of benzimidazole are upper to introduce benzoxazole and pyrrole pyridine and oxazole group, then replaces sartans to join with 4- substituted indoles
Phenyl in benzene structure, and optimal bond distance is found by increasing and decreasing the length of the upper carbochain of benzimidazole 2, design has synthesized a class
New 6 '-substituted benzimidazole -4- substituent methyls indole derivatives (I), and there is provided the preparation method of the compound.
A kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses of the invention, its structural formula is：
R1It is ethyl, n-propyl, normal-butyl；X is C or N, Y are C or N；
Wherein, when X is C, R3It is H, methyl；When X is N, R3For unsubstituted；
When Y is C, R2It is H, methyl, when Y is N, R2For unsubstituted.
2- 4- [2- ethyl -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -
1H- indoles -1- bases } benzoic acid (compound Ia)
2- 4- [2- propyl group -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -
1H- indoles -1- bases } benzoic acid (compound Ib)
2- 4- [2- butyl -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -
1H- indoles -1- bases } benzoic acid (compound Ic)
2- 4- [2- ethyl -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Id)
2- 4- [2- propyl group -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Ie)
2- 4- [2- butyl -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound If)
2- 4- [2- ethyl -4- methyl -6- (7- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (Compound Ig per)
2- 4- [2- propyl group -4- methyl -6- (7- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Ih)
2- 4- [2- butyl -4- methyl -6- (7- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Ii)
2- 4- [2- ethyl -4- methyl -6- (4,7- dimethylbiphenyls [d] oxazoles) -2- bases] -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Ij)
2- 4- [2- propyl group -4- methyl -6- (4,7- dimethylbiphenyls [d] oxazoles) -2- bases] -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Ik)
2- 4- [2- butyl -4- methyl -6- (4,7- dimethylbiphenyls [d] oxazoles) -2- bases] -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Il)
2- { 4- { [2- ethyl -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Im)
2- { 4- { [2- propyl group -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound In)
2- { 4- { [2- butyl -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Io)
2- 4- [2- ethyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Ip)
2- 4- [2- propyl group -4- methyl -6- (7- Jia Ji oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Iq)
2- 4- [2- butyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Ir)
2- { 4- { [2- ethyl -4- methyl -6- (oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Is)
2- { 4- { [2- propyl group -4- methyl -6- (oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound It)
2- { 4- { [2- butyl -4- methyl -6- (oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid (compound Iu)
2- 4- [2- ethyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Iv)
2- 4- [2- propyl group -4- methyl -6- (7- Jia Ji oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Iw)
2- 4- [2- butyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -
1- yls] methyl } -1H- indoles -1- bases } benzoic acid (compound Ix)
A kind of preparation method of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses of the invention, including：
(1) be there is into condensation reaction with adjacent amino aromatic ring phenolic compounds in benzimidazole -6- carboxylic acid compounds and obtain 6- and take
For benzimidazole compound；Wherein benzimidazole -6- carboxylic acid compounds areAdjacent amino aromatic ring phenolate is closed
Thing is6- substituted benzimidazole compounds are
(2) by 6- substituted benzimidazoles compound withReact in organic solvent, react
After completely, aqueous slkali is added, hydrolyzed, post processing obtains 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses.
Organic solvent used is poly phosphoric acid solution in step (1).
Condensation reaction is 130-160 DEG C, -15h of reaction time 10 in the step (1).
Reacted in organic solvent in step (2), alkali is added wherein in organic solution.
The alkali is potassium carbonate, sodium carbonate, lithium carbonate, saleratus, sodium acid carbonate, triethylamine, diisopropylethylamine, pyrrole
Pyridine, sodium acetate, potassium acetate, potassium phosphate, sodium phosphate, NaOH, potassium hydroxide, lithium hydroxide, sodium hydrogen, potassium methoxide, sodium methoxide,
One kind in potassium ethoxide, caustic alcohol, normal propyl alcohol potassium, normal propyl alcohol sodium, potassium isopropoxide, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide or
It is several.
Organic solvent is 1,4- dioxane, tetrahydrofuran, toluene, dimethylbenzene, n-hexane, hexamethylene in the step (2)
Alkane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), HMPA, carbon tetrachloride, acetone, benzene, chlorobenzene,
2- methyltetrahydrofurans, dichloromethane, chloroform, dichloroethanes, ether, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, second two
One or more in alcohol di-n-butyl ether；Adding aqueous slkali is：The sodium hydroxide solution of 0.1-10M, the lithium hydroxide of 0.1-10M
One or more in solution, the potassium hydroxide solution of 0.1-10M.Step (2) reaction temperature in organic solvent be 10-
100 DEG C, the reaction time is 2-8h, and 10-100 DEG C of hydrolysis, the reaction time is 2-10h.
The step (2) post-processes：After reaction terminates, to water is added in reactant mixture, 2-4 is extracted with ethyl acetate
It is secondary, merge organic phase, afterwards with saturated common salt water washing 2-4 time, organic phase is dried with anhydrous magnesium sulfate, concentrated under reduced pressure after filtering,
Concentrate is recrystallized.
The present invention prepares equation：
Wherein, the mol ratio of compound II, III is 1:0.8-1:2, IV, the mol ratio of V is 1:0.8–1:2.
Beneficial effect
A kind of application of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses of the invention, 6 '-substitution benzo miaow
Azoles -4- substituent methyls indole derivatives is preparing prevention and treatment hypertension, coronary heart disease, heart brain and kidney blood vessel diseases, antimigraine, lung
Application in arterial hypertension disease medicament；
The compounds of this invention is a kind of novel hypertension II receptor antagonist, can be used for prevent and treat hypertension,
The diseases such as heart brain and kidney blood vessel diseases, pulmonary hypertension.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.In addition, it is to be understood that after the content for having read instruction of the present invention, people in the art
Member can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Scope.
Embodiment 1
2- 4- [2- propyl group -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -
1H- indoles -1- bases } benzoic acid (compound Ib) preparation method：
Step 1：The synthesis of 4- methyl-2-propyls -6- (4- benzoxazole -2- bases) benzimidazole IVb：
Compound IIc (534mg, 2.45mmol) is slowly added to be heated in 80 DEG C of polyphosphoric acids (15mL),
It is stirred and heated to 150 DEG C.The polyphosphoric acids that compound IIIb (320mg, 2.94mmol) is slowly added into the former several times is molten
In liquid, after adding completely, in stirring reaction 12h at 150 DEG C.After question response is finished, reaction solution is poured into the frozen water of 100mL,
And pH is adjusted to 8-10 with concentrated ammonia liquor, and having a large amount of precipitations and occur, filtering, filter cake is washed three times with 5% ethanol solution.It is to be filtered
After biscuit is dry, gained filter cake column chromatography is purified, obtain faint yellow solid compound IVb about 357mg (yield is 58.7%).1H
NMR(400MHz,CDCl3)δ:8.29 (s, 1H), 8.02 (s, 1H), 7.40 (d, J=8.0Hz, 1H), 7.23 (t, J=7.8Hz,
1H), 7.14 (d, J=7.5Hz, 1H), 2.95 (t, J=7.7Hz, 2H), 2.67 (s, 6H), 1.94-1.84 (m, 2H), 1.00
(t, J=7.4Hz, 3H) .MS (ESI) m/z:306.2[M+H]+.
Step 2：2- 4- [2- propyl group -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound Ib) synthesis：
By 2- n-propyl -4- methyl -6- (benzoxazole -2- bases) benzimidazole (compound IVb, 349mg, 1.20mmol)
It is dissolved in 20mL DMFs, adds sodium hydrogen (86.4mg, 3.6mmol) to stir 30min at room temperature afterwards.Slowly
The DMF of neighbour's methoxycarbonyl group phenyl -4- chloromethyls indoles containing N- (compound V, 395mg, 1.32mmol) is added dropwise
In solution (10mL).After completion of dropping, mixed liquor continues stirring reaction about 2h, TLC and monitors complete to reaction at room temperature.Add
The sodium hydroxide solution 2mL of 2M, at room temperature stirring reaction about 2h.After question response is complete, pH value to 5- is adjusted with 2M watery hydrochloric acid
6, to 200mL dichloromethane and 200mL water is added in reaction solution, take organic phase.With dichloromethane (150mL × 3) aqueous phase extracted
Three times, merge organic phase.Organic phase is washed with saturated aqueous common salt (300mL × 4) four times.Anhydrous magnesium sulfate dries organic phase, mistake
Filter, filtrate decompression is concentrated, and obtains Tan solid.The solid is recrystallized to give into pale solid Ib about 400mg, and (yield is
61.7%).1H NMR(400MHz,DMSO)δ12.89(s,1H),8.14(s,1H),7.93(m,2H),7.74-7.70(m,
3H), 7.66-7.45 (m, 3H), 7.44-7.32 (m, 2H), 7.05-6.98 (m, 2H), 6.75 (s, 1H), 6.33 (d, J=
6.3Hz, 1H), 5.95 (s, 2H), 2.88 (t, J=7.5Hz, 2H), 2.68 (s, 3H), 1.85-1.71 (m, 2H), 0.96 (t, J
=7.2Hz, 3H)13C NMR(101MHz,DMSO)δ167.73,163.88,158.18,150.64,145.04,142.21,
137.60,137.19,135.89,132.79,131.17,131.04,130.56,129.49,128.88,128.83,128.43,
126.45,125.42,125.15,122.48,121.53,120.09,119.81,116.57,111.13,109.83,107.96,
101.13,45.24,29.27,20.93,16.90,14.28.MS(ESI)m/z:541.2[M+H]+。
Embodiment 2
2- 4- [2- ethyl -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -
1H- indoles -1- bases } benzoic acid (compound Ia) preparation method：
As described in Example 1, yield is 56.3% to experimental procedure.1H NMR(400MHz,DMSO)δ12.93(s,1H),
8.17(s,1H),7.93(m,2H),7.80-7.69(m,3H),7.64-7.48(m,3H),7.39-7.37(m,2H),7.04-
7.00 (m, 2H), 6.73 (d, J=3.2Hz, 1H), 6.33 (d, J=5.8Hz, 1H), 5.95 (s, 2H), 2.91 (q, J=
7.5Hz, 2H), 2.69 (s, 3H), 1.31 (t, J=7.5Hz, 3H)13C NMR(101MHz,DMSO)δ167.66,163.89,
159.24,150.64,144.97,142.21,137.66,137.20,136.04,132.94,131.09,130.55,130.55,
129.54,128.89,128.89,128.48,126.45,125.44,125.16,122.52,121.51,120.12,119.82,
116.61,111.14,109.79,107.92,101.14,45.18,20.87,16.93,12.04.MS(ESI)m/z：527.2[M
+H]+。
Embodiment 3
2- 4- [2- butyl -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -
1H- indoles -1- bases } benzoic acid (compound Ic) preparation method：
As described in Example 1, yield is 48.6% to experimental procedure.1H NMR(400MHz,DMSO)δ12.90(s,1H),
8.15(s,1H),7.98-7.88(m,2H),7.79-7.68(m,3H),7.62-7.52(m,3H),7.43-7.33(m,2H),
7.09-6.95 (m, 2H), 6.74 (d, J=3.3Hz, 1H), 6.34 (dd, J=5.6,2.3Hz, 1H), 5.95 (s, 2H), 2.89
(t, 2H), 2.67 (s, 3H), 1.76-1.68 (m, 2H), 1.41-1.31 (m, 2H), 0.85 (t, J=7.3Hz, 3H)13C NMR
(101MHz,DMSO)δ167.56,163.88,158.34,150.63,145.02,142.20,137.77,137.20,135.91,
133.17,131.18,130.53,130.34,129.48,128.96,128.96,128.52,126.48,125.44,125.16,
122.54,121.52,120.07,119.82,116.67,111.14,109.75,107.95,101.22,45.23,29.57,
27.09,22.38,16.92,14.15.MS(ESI)m/z:555.2[M+H]+。
Embodiment 4
2- 4- [2- ethyl -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound Id) preparation method：
As described in Example 1, yield is 46.1% to experimental procedure.1H NMR (400MHz, CDCl3) δ 8.15 (d, J=
7.7Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.71 (t, J=7.7Hz, 1H), 7.60 (t, J=7.7Hz, 1H), 7.50
(d, J=7.7Hz, 1H), 7.44-7.35 (m, 2H), 7.23 (t, J=7.6Hz, 1H), 7.15 (t, J=8.6Hz, 2H), 7.04
(d, J=8.2Hz, 1H), 6.60 (s, 1H), 6.45 (s, 1H), 5.75 (s, 2H), 3.00-2.71 (m, 5H), 2.64 (s, 3H),
1.28(t,3H).13C NMR (101MHz, DMSO) δ 166.4,162.7,159.68,156.35,146.70,145.57,
143.15,137.63,137.20,136.06,132.88,131.06,130.61,130.58,129.68,128.89,128.81,
128.47,126.48,126.7,122.51,121.81,120.70,119.48,119.06,116.68,109.83,108.52,
101.10,45.22,20.90,16.91,12.00.MS(ESI)m/z:541.3[M+H]+。
Embodiment 5
2- 5- [2- propyl group -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound Ie) preparation method：
As described in Example 1, yield is 46.3% to experimental procedure.1H NMR (400MHz, CDCl3) δ 8.15 (d, J=
7.7Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.71 (t, J=7.7Hz, 1H), 7.60 (t, J=7.7Hz, 1H), 7.50
(d, J=7.7Hz, 1H), 7.44-7.35 (m, 2H), 7.23 (t, J=7.6Hz, 1H), 7.15 (t, J=8.6Hz, 2H), 7.04
(d, J=8.2Hz, 1H), 6.60 (s, 1H), 6.45 (s, 1H), 5.75 (s, 2H), 3.07-2.82 (m, 5H), 2.63 (s, 3H),
1.86–1.74(m,2H),0.90(t,3H).13C NMR (101MHz, DMSO) δ 162.70,159.68,156.35,154.35,
146.70,145.57,143.15,137.63,137.20,136.06,132.88,131.06,130.61,130.58,129.68,
128.89,128.81,128.47,126.48,126.70,122.51,121.81,120.70,119.48,119.06,116.68,
109.83,108.52,101.10,45.22,24.19,20.90,16.91,13.70.MS(ESI)m/z:555.3[M+H]+。
Embodiment 6
2- 5- [2- butyl -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound If) preparation method：
As described in Example 1, yield is 47.2% to experimental procedure.1H NMR (400MHz, CDCl3) δ 8.12 (d, J=
7.7Hz, 1H), 8.02 (d, J=13.1Hz, 2H), 7.69 (t, J=7.6Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.50
(d, J=7.8Hz, 1H), 7.41-7.33 (m, 2H), 7.20 (dd, J=17.0,8.3Hz, 2H), 7.12 (d, J=7.4Hz,
1H), 7.04 (t, J=7.7Hz, 1H), 6.59-6.49 (m, 2H), 5.72 (s, 2H), 2.74 (s, 3H), 2.70-2.57 (m,
5H), (t, J=7.3Hz, the 3H) of 1.54-1.42 (m, 2H), 1.21-1.12 (m, 2H), 0.7413C NMR(101MHz,DMSO)δ
162.70,159.68,156.35,154.35,146.70,145.57,143.15,137.63,137.20,136.06,132.88,
131.06,130.61,130.58,129.68,128.89,128.81,128.47,126.48,126.70,122.51,121.81,
120.70,119.48,119.06,116.68,109.83,108.52,101.10,45.22,24.19,20.90,16.81,
16.53 14.10.MS(ESI)m/z:569.3[M+H]+。
Embodiment 7
2- { 4- { [2- ethyl -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound Im) preparation method：
As described in Example 1, yield is 53.3% to experimental procedure.1H NMR(400MHz,DMSO)δ12.97(s,1H),
8.50(m,1H),8.24(s,1H),8.17(m,1H),7.97(s,1H),7.92(m,1H),7.73(m,1H),7.55(m,3H),
7.45-7.36 (m, 1H), 7.02 (m, 2H), 6.72 (d, J=3.3Hz, 1H), 6.39-6.29 (m, 1H), 5.96 (s, 2H),
(t, J=7.5Hz, the 3H) of 2.92 (q, J=7.5Hz, 2H), 2.70 (s, 3H), 1.3113C NMR(101MHz,DMSO)δ
167.69,166.48,159.68,156.35,146.70,145.57,143.15,137.63,137.20,136.06,132.88,
131.06,130.61,130.58,129.68,128.89,128.81,128.47,126.48,122.51,121.81,120.70,
119.48,119.06,116.68,109.83,108.52,101.10,45.22,20.90,16.91,12.00.MS(ESI)m/z:
528.2[M+H]+。
Embodiment 8
2- { 4- { [2- propyl group -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound In) preparation method：
As described in Example 1, yield is 56.3% to experimental procedure.1H NMR(400MHz,DMSO)δ12.97(s,1H),
8.50 (dd, J=4.9,1.3Hz, 1H), 8.22-8.15 (m, 2H), 7.96 (s, 1H), 7.89 (m, 1H), 7.69 (m, 1H),
7.58-7.49 (m, 3H), 7.41 (m, 1H), 7.05-7.00 (m, 2H), 6.73 (d, J=3.3Hz, 1H), 6.32 (d, J=
6.5Hz, 1H), 5.96 (s, 2H), 2.89 (t, J=7.6Hz, 2H), 2.69 (s, 3H), 1.79-1.74 (m, 2H), 0.95 (t, J
=7.3Hz, 3H)13C NMR(101MHz,DMSO)δ167.61,166.48,158.63,156.35,146.69,145.65,
143.15,137.45,137.18,135.91,132.54,130.93,130.62,130.59,129.64,128.85,128.78,
128.35,126.48,122.43,121.83,120.68,119.45,119.05,116.61,109.93,108.55,101.00,
45.31,29.29,20.90,16.87,14.27.MS(ESI)m/z:542.2[M+H]+。
Embodiment 9
2- { 4- { [2- butyl -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases benzoic acid (compound Io) preparation method：
As described in Example 1, yield is 48.6% to experimental procedure.1H NMR(400MHz,DMSO)δ13.00(s,1H),
8.50(m,1H),8.23(s,1H),8.17(m,1H),7.96(s,1H),7.91(m,1H),7.71(m,1H),7.63-7.47
(m, 3H), 7.46-7.37 (m, 1H), 7.05-7.00 (m, 2H), 6.73 (d, J=3.2Hz, 1H), 6.35 (d, J=6.7Hz,
1H), 5.96 (s, 2H), 2.90 (t, 2H), 2.69 (s, 3H), 1.72 (m, 2H), 1.36 (m, 2H), 0.85 (t, J=4.5Hz,
3H).13CNMR(101MHz,DMSO)δ167.73,166.48,158.79,156.35,146.70,145.63,143.15,
137.54,137.18,135.94,132.86,131.01,130.59,130.59,129.62,128.83,128.78,128.41,
126.51,122.48,121.82,120.69,119.44,119.06,116.70,109.87,108.55,101.08,45.30,
29.55,27.12,22.37,16.89,14.15.MS(ESI)m/z:556.2[M+H]+。
Embodiment 10
Compound receptors binding activity is tested
Subject cell is rat smooth muscle cells (VSMCs), and medicine is the compound and positive control of embodiment 1-9
Medicine Losartan, is divided into saturability experiment and competitive trials.
Saturability is tested：Will be quantitative125I-Ang II are dissolved in 1mL PBS solutions, then the solution for being diluted to various concentrations.
Take vascular smooth muscle 3-7 alternative in experiment, be laid on 24 orifice plates (1 × 105/ hole), it is adherent rear for testing.Association reaction：It is overall
Product is 500 μ L, and it is gradually increased that cell plates sequentially add concentration per hole125I-Ang II solution, makes its final concentration of 0-1.5nM,
4 DEG C of reaction 150min, in order to deduct non-specific binding, unlabelled Ang II (final concentration of 1 × 10 are added per hole-6M) and
Increasing concen-trations125I-Ang II solution (final concentration of 0-1.5nM), 4 DEG C of reaction 150min, it is unnecessary that reaction is removed after terminating
Reaction solution, is washed 3 times with PBS, adds 0.1mol/L NaOH solution vitellophag 10min, and cell dissociation buffer is moved into plastics
Pipe, the γ that solution in often managing is measured with gamma counter is counted.Processed through the saturation curve fit procedures of GraphPad Prism 5
Arrive125I-Ang II acceptor combination saturation curves.Each concentration uses 3 multiple holes.
Competitive trials：Drug solution：Take a certain amount of testing compound and be dissolved in 1mL DMSO solutions, make final concentration of
10-2M, successively 10 times of solution (1 × 10 for being diluted to various concentrations-10M~1 × 10-4M).Plating cells (1 × 105/ hole) after, often
Hole adds 0.1nM125Noval chemical compound (the final concentration 1 × 10 of I-Ang II and various concentrations-6~1 × 10-11Mol/L), it is overall
Product is 500 μ L, 4 DEG C of reaction 150min, and reaction removes free after terminating125I-Ang II, are washed 3 times with PBS, are added
0.1mol/L NaOH solutions digest 10min, and cell liquid is moved into plastic tube, and the γ that solution in often managing is measured with gamma counter is counted
Number.Being processed through the competition binding curve fitting procedures of GraphPad Prism 5 can show that new compound suppresses and memebrane protein knot
The semi-inhibit constant and IC of conjunction50Value.
Experimental result：Tested compound and VSMC film AT1Acceptor have compared with compatibility (such as the institute of table 1
Show), compare IC50Value finds that, except compound Ic, Im, outside Io, remaining compound has compared with Losartan to AngII with Ki values
More preferable inhibitory action, wherein the compatibility highest of compound Id, can well suppress Ang II and VSMC film
AT1The combination of acceptor, highly further research.
The series of compounds of table 1. and AT1The compatibility of acceptor compares
| Compound | IC50±SEM(nM) | Ki(nM) |
| Ia | 9.07±4.67 | 6.57±3.38 |
| Ib | 6.40±6.67 | 4.63±4.83 |
| Ic | 30.63±5.88 | 22.18±4.26 |
| Id | 3.67±2.00 | 2.65±1.45 |
| Ie | 15.78±2.05 | 11.43±1.48 |
| If | 7.11±2.18 | 5.15±1.58 |
| Im | 61.24±5.27 | 44.35±3.82 |
| In | 5.20±6.70 | 3.77±4.85 |
| Io | 30.63±6.52 | 22.18±5.23 |
| Losartan | 18.18±1.32 | 13.16±1.25 |
Embodiment 11
Antihypertensive activity experiment in compound animals body
Experimental animal：Spontaneous hypertensive rat (SHR) 18,220-250g, ♂, SPF grade, purchased from Beijing dimension tonneau China
Experimental animal Technology Co., Ltd., credit number：SCXK (capital) 2012-0001.
By test product：Antihypertensive activity compound Id, positive control drug Losartan.The quantity of Losartan is 50-100mg/
People, if people's body weight is 60kg, after being scaled rat dosage, the dosage of Losartan is 5-10mg/kg, this experiment selection 10mg/kg
As test dose.
Experimental technique：Spontaneous hypertensive rat, is randomly divided into blank group, Losartan group, and compound Id administration groups are used
Hurtless measure blood pressure transducer is connected to the clear-headed free moving animals blood pressure recording analysis system of MPA-HBBS types after amplifying through carrier wave
(Shanghai, Alcott), four limbs are subcutaneously inserted needle electrode, are connected to AC amplifier for the lead electrocardio of monitoring standard two
Figure.Femoral arteriography method measures Conscious Rat sustainer mean arterial pressure (MAP), systolic pressure (SAP), diastolic pressure (DAP), heart rate
And electrocardiogram (ECG) (HR).
Testing compound and positive control drug Losartan are configured to the suspension that concentration is 10mg/kg during experiment.Experiment
Preceding SHR takes femoral arteriography to perform the operation, and overnight recovers.Second day SHRs connects multi-path physiology signal system, on-line continuous detection
Blood pressure, record is administered blood pressure after preceding and administration.
Data processing：All experimental datas represent with mean ± standard deviation (x_ ± SD), blood pressure ratio between each group after medication
Relatively with the variance analysis of completely randomized design, such as each group population mean not, then with the Multiple range test between multiple sample averages, i.e.,
Q inspections are processed.
Experimental result：Blood pressure decreasing value finds that compound Id is by oral administration compared with blank group as variable before and after treating
After in into rat body, rat serum be pressed with conspicuousness reduction, and compound enter in vivo after step-down it is rapid-action, by flatten surely hold
Long, 4h reaches maximum reducing value upon administration, and the maximum reducing value of 10mg/kg dosages for Compound Id and Losartan is respectively
43.22 ± 6.86mmHg and 39.17 ± 6.26 (is shown in Table 2), and the antihypertensive effect of these three compounds is better than the chlorine under same dose
Sha Tan, (compared with blank * p ＜ 0.05, * * p are less than still notable antihypertensive effect with lasting step-down trend, at 24 hours
0.01)。
Compound Id antihypertensive effects and duration are superior to marketed drug Losartan, be new tool it is efficient, long-acting,
The compound of steady antihypertensive activity, highly further research and development.
Table 2. test after each group blood pressure decreasing value compare (N=6)
Claims (10)
1. one kind 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses, its structural formula is：
R1It is ethyl, n-propyl, normal-butyl；X is C or N, Y are C or N；
Wherein, when X is C, R3It is H, methyl；When X is N, R3For unsubstituted；
When Y is C, R2It is H, methyl, when Y is N, R2For unsubstituted.
2. a kind of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses as claimed in claim 1, its feature exists
In：6 '-substituted benzimidazole -4- substituent methyl indole derivativeses are：
2- 4- [2- ethyl -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -1H- Yin
Diindyl -1- bases } benzoic acid；
2- 4- [2- propyl group -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -1H- Yin
Diindyl -1- bases } benzoic acid；
2- 4- [2- butyl -4- methyl -6- (benzo [d] oxazole -2- bases) -1H- benzos [d] imidazoles -1- bases] methyl } -1H- Yin
Diindyl -1- bases } benzoic acid；
2- 4- [2- ethyl -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- propyl group -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- butyl -4- methyl -6- (4- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- ethyl -4- methyl -6- (7- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- propyl group -4- methyl -6- (7- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- butyl -4- methyl -6- (7- methyl benzo [d] oxazole) -2- bases] -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- ethyl -4- methyl -6- (4,7- dimethylbiphenyls [d] oxazoles) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- propyl group -4- methyl -6- (4,7- dimethylbiphenyls [d] oxazoles) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid；
2- 4- [2- butyl -4- methyl -6- (4,7- dimethylbiphenyls [d] oxazoles) -2- bases] -1H- benzos [d] imidazoles -1- bases]
Methyl } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- ethyl -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- propyl group -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- butyl -4- methyl -6- (oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- ethyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1-
Base] methyl } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- propyl group -4- methyl -6- (7- Jia Ji oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1-
Base] methyl } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- butyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [4,5-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1-
Base] methyl } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- ethyl -4- methyl -6- (oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- propyl group -4- methyl -6- (oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- butyl -4- methyl -6- (oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1- bases] first
Base } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- ethyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1-
Base] methyl } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- propyl group -4- methyl -6- (7- Jia Ji oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1-
Base] methyl } -1H- indoles -1- bases } benzoic acid；
2- { 4- { [2- butyl -4- methyl -6- (7- Jia Ji oxazoles simultaneously [5,4-b] pyridine -2- bases) -1H- benzos [d] imidazoles -1-
Base] methyl } -1H- indoles -1- bases } benzoic acid.
3. a kind of preparation method of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses as claimed in claim 1, wraps
Include：
(1) be there is into condensation reaction with adjacent amino aromatic ring phenolic compounds in benzimidazole -6- carboxylic acid compounds and obtain 6- substituted benzenes
Benzimidazole compounds；Wherein benzimidazole -6- carboxylic acid compounds areAdjacent amino aromatic ring phenolic compounds
For6- substituted benzimidazole compounds are
(2) by 6- substituted benzimidazoles compound withReact in organic solvent, reaction is complete
Afterwards, aqueous slkali is added, is hydrolyzed, post processing obtains 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses.
4. the preparation method of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses according to claim 3,
It is characterized in that：Organic solvent used is poly phosphoric acid solution in step (1).
5. the preparation method of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses according to claim 3,
It is characterized in that：Condensation reaction is 130-160 DEG C, -15h of reaction time 10 in the step (1).
6. the preparation method of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses according to claim 3,
It is characterized in that：Reacted in organic solvent in step (2), alkali is added wherein in organic solution.
7. the preparation method of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses according to claim 6,
It is characterized in that：The alkali is potassium carbonate, sodium carbonate, lithium carbonate, saleratus, sodium acid carbonate, triethylamine, diisopropyl second
Amine, pyridine, sodium acetate, potassium acetate, potassium phosphate, sodium phosphate, NaOH, potassium hydroxide, lithium hydroxide, sodium hydrogen, potassium methoxide, first
In sodium alkoxide, potassium ethoxide, caustic alcohol, normal propyl alcohol potassium, normal propyl alcohol sodium, potassium isopropoxide, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide
One or more.
8. the preparation method of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses according to claim 3,
It is characterized in that：Organic solvent is 1,4- dioxane, tetrahydrofuran, toluene, dimethylbenzene, n-hexane, ring in the step (2)
Hexane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), HMPA, carbon tetrachloride, acetone, benzene, chlorine
Benzene, 2- methyltetrahydrofurans, dichloromethane, chloroform, dichloroethanes, ether, methyl tertiary butyl ether(MTBE), glycol dimethyl ether,
One or more in ethylene glycol di-n-butyl ether；Adding aqueous slkali is：The sodium hydroxide solution of 0.1-10M, the hydrogen-oxygen of 0.1-10M
Change one or more in lithium solution, the potassium hydroxide solution of 0.1-10M.
9. the preparation method of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses according to claim 3,
It is characterized in that：Reaction temperature of the step (2) in machine solvent is 10-100 DEG C, and the reaction time is 2-8h, hydrolysis 10-
100 DEG C, the reaction time is 2-10h.
10. the application of a kind of 6 '-substituted benzimidazole -4- substituent methyl indole derivativeses as described in claim 1-2 is any,
It is characterized in that：6 '-substituted benzimidazole -4- substituent methyls indole derivatives prepare prevention and treatment hypertension, coronary heart disease,
Application in heart brain and kidney blood vessel diseases, antimigraine, pulmonary hypertension disease medicament.
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