CN1142916C - Dopamine D1 receptor agonist compounds - Google Patents

Dopamine D1 receptor agonist compounds Download PDF

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CN1142916C
CN1142916C CNB00803947XA CN00803947A CN1142916C CN 1142916 C CN1142916 C CN 1142916C CN B00803947X A CNB00803947X A CN B00803947XA CN 00803947 A CN00803947 A CN 00803947A CN 1142916 C CN1142916 C CN 1142916C
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hydrogen
thiophene
halogen
benzazepines
dopamine
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CN1341102A (en
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G���ٶ������
G·蒂尔布洛克
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Shire Pharmaceutical Development Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention provides 2,3,4,5-tetrahydro-1H-3-benzazepines of general formula (I) wherein: R<1> is hydrogen, halogen, C1-C4 alkyl, or CF3; R<2> is hydrogen, methyl, or lower alkenyl of 3-5 carbon atoms; R<3> and R<4> together form a furan, dihydrofuran, thiophene, dihydrothiophene, cyclopentane or cyclohexane ring and R<5> is hydrogen or R<4> and R<5> together form a furan, dihydrofuran, thiophene, dihydrothiophene, cyclopentane or cyclohexane ring and R<3> is hydrogen; R<6> is hydrogen, halogen, CF3, CN, NO2 or NH2; R<7> is hydrogen, halogen, CF3, CN, NO2 or NH2. The specific combination of substituents: R1 = H, R2 = H and R4 and R5 together forming a cyclohexane ring is excluded, namely 1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzol[d]azepine-7,8-diol. The compounds of the invention provide therapeutic agents that selectively interact positively with postsynaptic dopamine D1 receptors in the striatum, directly or in-directly (termed dopamine D1 agonists) and are particularly valuable as anti-Parkinsonian agents.

Description

Dopamine D 1 receptor agonist compounds
Technical field
The present invention relates to dopamine D 1 receptor agonist compounds, the preparation method and its usage of this compound.
Background technology
GB 1 599 705 discloses 1-thienyl and the 1-furyl-2,3,4 that is suitable for use as cardiovascular drug, 5-tetrahydrochysene-1H-3-benzazepines.Disclose some as the benzo a word used for translation degree of dopamine D 1 receptor agonist because of.For example, in EP 0 230 755-A, disclose 1-phenyl-3-benzazepines, and in EP 0 380 355-A, disclose 6-chloro-7,8-dihydroxyl-1-(4 '-hydroxy phenyl)-2,3,4, the carbamate of 5-tetrahydrochysene-1H-3-benzazepines.
The invention provides compound as the effective and selective ligands of d1 dopamine receptor.This compound can be used for treating neurodegenerative disease, particularly but be not limited to Parkinson's disease.Parkinson's disease is progressive neurodegenerative disease, it is characterized in that making carrying out property of postsynaptic dopamine neuron in the black substance that the postsynaptic striatal neuron innervates dead and cause striatal Dopamine HCL loss.Concentrate on the loss of Dopamine HCL in the compensation striatum for parkinsonian initial stage treatment.At present main alternative medicine is to use the Dopamine HCL metabolic precursor thereof, i.e. L-DOPA, and the latter is converted into Dopamine HCL in central nervous system.Yet L-DOPA can cause severe side effect, for example feels sick, vomiting, heart arrhythmias and ypotension.In addition, life-time service L-DOPA is relevant with psychotic generation with unusual unintentional motion (dyskinesia).Moreover the positive benefit relevant with accepting long-term L-DOPA treatment reduces because of undermined, particularly in several years behind initial begin treatment.Positively with striatum in the therapeutical agent (hereinafter being called the dopamine D 1 stimulant) of the direct or indirect selective reaction of postsynaptic d1 dopamine receptor be valuable especially Mirapexin thing.
Summary of the invention
Figure C0080394700041
The invention provides 2,3,4 of general formula I, 5-tetrahydrochysene-1H-3-benzazepines, wherein: R 1Be hydrogen, halogen, C 1-C 4Alkyl or CF 3
R 2It is the low-grade alkenyl of hydrogen, a methyl or 3-5 carbon atom;
R 3And R 4Form furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring and R together 5Be hydrogen, perhaps R 4And R 5Form furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring and R together 3Be hydrogen;
R 6Be hydrogen, halogen, CF 3, CN, NO 2Or NH 2
R 7Be hydrogen, halogen, CF 3, CN, NO 2Or NH 2
Specific substituent combination: R 1=H, R 2=H and R 4And R 5Form cyclohexane ring together, i.e. 1-(5,6,7,8-naphthane-2-yl)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines-7, the 8-glycol is not included in the scope of the invention.
People such as K.S.Sugarnori (Journal of Neurochemistry, 1998,71,4,1685-93) the function difference of multiple dopamine D 1 sample acceptor has been described by compound N NC 01-0012. (compound N NC 01-0127) is the most approaching for disclosed this compound and The compounds of this invention, is that with difference of the present invention it is at R 1There is a hydrogen atom position.
US 4,265, and 889 disclose 6-low alkyl group-7,8-dihydroxyl-1-phenyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines.Disclosed this compound and difference of the present invention are that the substituting group on 1 of phenyl does not have furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring in this patent.
DE 2629887 disclose be used for the treatment of ephrosis, as diuretic(s) and the damaged periphery Dopamine Receptors stimulating drug of anti-Parkinson Cotard.Preferred compound is at R 1The position has hydrogen atom, and does not have furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring structure on phenyl.
GB 1599705 disclose because of its periphery dopaminergic activity have pharmaceutical activity, particularly as the compound 1-thienyl and the 1-furyl-2,3,4 of cardiovascular agent, 5-tetrahydrochysene-1H-3-benzazepines.These compounds do not have phenyl 1 of the ring of benzazepines.
EP 0380355 discloses the 6-chloro-7 as prodrug ,-dihydroxyl-1-(4 '-hydroxy phenyl)-2,3,3, the carbamate of 5-tetrahydrochysene-1H-3-benzazepines.Disclosed this compound does not have hydroxyl substituent 7 and 8 of benzazepines ring, and does not have ring substituents 1 of phenyl.
EP 0230755 discloses 1-phenyl-3-benzazepines.These compounds are at R 1The position has hydrogen atom, and does not have furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring structure on phenyl.
Formula I compound can exist with the form of mixture of enantiomers, and this mixture can split into one pure enantiomorph.This fractionation can be undertaken by the salt fractional crystallization from all kinds of SOLVENTS with formula I compound and optically active acid easily, perhaps can be undertaken by known method in other documents, for example the chiral column chromatogram.Therefore, the present invention includes all isomer, no matter be split or its mixture.
The valuable especially specific embodiments of the present invention is the nontoxic pharmaceutically acceptable acid additive salt of formula I benzazepines.This salt comprises those by mineral acid and organic acid deutero-salt, and described acid is for example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, acetate, lactic acid, toxilic acid, phthalic acid and tartrate.
The compounds of this invention is useful because of having pharmacological activity.Particularly, The compounds of this invention is effectively (height affinity) and the selective ligands (table 1) of central dopamine D1 acceptor, as according to the described method of Psychopharmacology 117:275-286 (1995), the competitiveness radiation-part substitutability analysis of carrying out with the rat striatum tissue homogenate measured like that.
Experimental compound Ki (nM) d1 dopamine receptor avidity Ki (nM) d2 dopamine receptor avidity
Embodiment 1 31 790
Embodiment 4 6.7 2500
Table 1
It is sick active that the benzazepines compound of formula I has Kang Pajinsenshi, can be active because it has central dopamine, as the standard pharmacological experiment method of using people's reports (Brain Research 24:485-493 (1970)) such as Ungerstedt proved.This method is based on drug-induced rotation (turn-taking) with the one-sided dopaminergic infringement of black substance rat of expansion.In brief, this experiment comprises the circling behavior of quantitative record rat, and these rats have produced the 6-hydroxydopamine infringement of nigrostriatum (nigrostriatal) dopamine system.One-sided substantia nigra infringement at a hemisphere causes the Dopamine Receptors system in this zone to become to the sex change allergy of nigral cell body.Make these super quick Dopamine Receptors activation causing asymmetric motions of animal with medicine, to sideway swivel (with respect to the brain of infringement one side).Speed and the perdurability to the sideway swivel that cause through administration are that this medicine central dopamine can active index.Known clinically to control Parkinson compounds effective, for example L-DOPA and apomorphine also are effective in this rat turn-takes model.For example, subcutaneous injection 0.438-5.79 μ mols/kg compound 1-indane-5-base-6-chloro-3-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines-7 during the 8-glycol, produces the strong behavior of turn-taking that dosage relies on form in the 6-of one-sided infringement hydroxydopamine rat model.Interior cumulative rotation of time limit (190 minutes) is as follows at a fixed time: 0.438 μ moles/kg=23,0.965 μ mole/kg=397 circle, 1.93 μ moles/kg=867 circle, 3.86 μ moles/kg=1078 circle, 5.79 μ moles/kg=1388 circle.
Embodiment
Only the invention will be further described by way of example.
Embodiment 1
A) 1-(cumarone-7-yl)-2-[2-(2-chloro-3,4 Dimethoxyphenyls) ethylamino] ethanol
With 2-chloro-3, (6.35g, 0.0296mol) (4.29g, 0.0268mol) solution in the 15ml acetonitrile refluxed 16 hours the 4-dimethoxyphenyl ethyl amine with (7-benzofuryl) oxyethane.Make reaction mixture be cooled to 0 ℃ (ice bath).Filter and, obtain title compound (3.52g, 35%), be white crystalline solid crude product recrystallization from hot acetonitrile. 1H-NMR (CDCl 3) [δ, ppm]: 2.86-3.16 (m, 6H); 3.85 (s, 6H); 5.26 (dd, 1H); 6.73-6.77 (m, 2H); 6.91 (d, 1H); 7.21-7.26 (m, 1H); 7.39 (d, 1H); 7.51 (d, 1H); 7.61 (d, 1H).
B) 1-(cumarone-7-yl)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With the vitriol oil (0.71ml 0.0135mol) handles 1-(cumarone-7-yl)-2-[2-(2-chloro-3,4-Dimethoxyphenyl) ethylamino in the 70ml trifluoroacetic acid] ethanol (2.20g, 5.85mmol), and stirring at room 90 minutes.This solution of vacuum-evaporation, and resistates is dissolved in the 30ml 4M sodium hydroxide, with methylene dichloride (4 * 50ml) extractions.Merge organic moiety, drying is filtered and evaporation, obtains crude product, is Huang/green glass shape.Through silica gel chromatography, make eluent then, obtain title compound, be sticking white solid (1.42g, 68%) with methylene chloride (9: 1).
1H-NMR(CDCl 3)[δ，ppm]：2.95-3.80(m，6H)；3.57(s，3H)；3.85(s，3H)；4.76(dd，1H)；6.30(s，1H)；6.80(d，1H)；6.95(d，1H)；7.21(t，1H)；7.54(d，1H)；7.62(d，1H)。
C) 1-(cumarone-7-yl)-6-chloro-7,8-hydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines hydrobromate
With 1-(cumarone-7-yl)-6-chloro-7,8-dimethoxy-2,3,4, (1.19g 3.32mm0l) is dissolved in the anhydrous methylene chloride (20ml) 5-tetrahydrochysene-1H-3-benzazepines.This solution is cooled to-78 ℃, and by syringe slowly add boron tribromide (133ml, 133mmol).This reaction mixture kept 30 minutes at-78 ℃, made it be warmed to 0 ℃, and stirred 2 hours.This reaction mixture is cooled to-78 ℃ then, slowly adds methyl alcohol (25ml), and stirred 30 minutes.This reaction mixture refluxed is after 1 hour, and solvent removed in vacuo obtains crude product.With the ether development, obtain title compound, be beige solid (1.26g, 92%).
1H-NMR(CD 3OD)[δ，ppm]：3.15(m，1H)；3.30-3.99(m，5H)；5.00(m，1H)；6.10(s，1H)；6.93(d，1H)；7.07(d，1H)；7.30(t，1H)；7.64(m，1H)；7.79(d，1H)。
Embodiment 2
A) 1-(benzo [b] thiophene-7-yl)-2-[2-(2-chloro-3,4-Dimethoxyphenyl) ethylamino] ethanol
With 2-chloro-3, (7.00g, 32.5mmol) (5.30g, 30.1mmol) solution in the 20ml acetonitrile refluxed 72 hours the 4-dimethoxyphenyl ethyl amine with 7-benzo [b] thienyl oxyethane.Make this reaction mixture be cooled to 0 ℃ (ice bath), filter and, obtain title compound (5.57g, 47%), be white crystalline solid crude product recrystallization from hot acetonitrile. 1H-NMR(CDCl 3)[δ，ppm]：2.83-3.08(m，6H)；3.84(s，3H)；3.85(s，3H)；5.06(m，1H)；6.73(d，1H)；6.88(d，1H)；7.35(m，3H)；7.43(d，1H)；7.73(m，1H)。
B) 1-(benzo [b] thiophene-7-yl)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
Under nitrogen atmosphere, with methylsulfonic acid (0.7ml 10.7mmol) handles 1-(benzo [b] thiophene-7-yl)-2-[2-(2-chloro-3,4-Dimethoxyphenyl) ethylamino in the 30ml trifluoroacetic acid] ethanol (3.90g, 10mmol), and with this vlil 18 hours.This solution of vacuum-evaporation, and resistates is dissolved in the methylene dichloride (100ml), gained solution is with strong aqua (2 * 50ml, 0.880), the washing of water (100ml) and saturated sodium-chloride water solution (100ml), drying is filtered also evaporation, obtain crude product, be Huang/green glass shape.Through silica gel chromatography, make eluent then, obtain title compound, be light brown jelly (3.01g, 81%) with methylene chloride (9: 1).
1H-NMR(CDCl 3)[δ，ppm]：2.82-2.92(m，2H)；3.13-3.23(m，2H)；3.41-3.55(m，2H)；3.49(s，3H)；3.83(s，3H)；4.66(d，1H)；6.21(s，1H)；7.11(d，1H)；7.37-7.41(m，3H)；7.76(d，1H)。
C) 1-(benzo [b] thiophene-7-yl)-6-chloro-7,8-hydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 1-(benzo [b] thiophene-7-yl)-6-chloro-7,8-dimethoxy-2,3,4, (1.31g 3.5mmol) is dissolved in the anhydrous methylene chloride (20ml) 5-tetrahydrochysene-1H-3-benzazepines.This solution is cooled to-78 ℃, and by syringe slowly add boron tribromide (14ml, 14mmol).This reaction mixture kept 30 minutes at-78 ℃, made it be warmed to 0 ℃, and stirred 2 hours.This reaction mixture is cooled to-78 ℃ then, slowly adds methyl alcohol (10ml), and stirred 30 minutes.This reaction mixture refluxed is after 1 hour, and solvent removed in vacuo obtains crude product.Recrystallization carries out purifying from methyl alcohol, obtains title compound, is beige solid (0.68g, 45%).Fusing point 185-188 ℃.C 18H 16ClNO 2S.HBr.H 2The analysis of O (calculated value): C 48.61 (48.61), H 4.27 (4.30), and N 2.98 (3.15). 1H-NMR(CD 3OD)[δ，ppm]：3.02(t，1H)；3.30-3.38(m，1H)；3.60-3.74(m，3H)；3.89(d，1H)；4.91(d，1*H)；5.97(s，1H)；7.23(d，1H)；7.41(d，1H)；7.45-7.52(m，2H)；7.84(d，1H)。
Embodiment 3
A) 2-(2-chloro-3,4-Dimethoxyphenyl) ethylamino]-1-indane-5-base-ethanol
(3.38g, (2.0g 23.2mmol), and refluxes this solution 20 hours 21.1mmol) to add 2-(2-chloro-3,4-Dimethoxyphenyl) ethamine in the solution in anhydrous acetonitrile (20ml) to 2-indane-5-basic ring oxidative ethane.In case cooling promptly forms white precipitate, filter and collect, and, obtain title compound with the ether washing, be white solid (2.85g, 36%).
1H NMR (400 MHz, DMSO-d6): δ (ppm) 1.96-2.03 (2H, m, CH 2-CH 2-CH 2), 2.50-2.84 (10H, m, 5xCH 2), 3.72 (3H, s, CH 3O), 3.80 (3H, s, CH 3O), 4.56 (J 6.04 for 1H, t, H-1), 5.14 (1H, wide, NH) and 6.94-7.14 (5H, m, Ar-H).This material need not to be further purified and promptly is used for next step reaction.
B) 1-indane-5-base-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 2-[(2-chloro-3,4-Dimethoxyphenyl) ethylamino]-1-indane-5-base-ethanol (2.7g 7.18mmol) is dissolved in the trifluoroacetic acid (50ml), to wherein add methylsulfonic acid (0.76g, 7.90mmol).With this reaction mixture stirring and refluxing 20 hours, make it be cooled to room temperature then.Remove and to desolvate, obtain the oily resistates, this resistates is dissolved in the methylene dichloride (200ml), with ammonia solution (0.88M, 150ml), water (2 * 150ml), salt solution (100ml) washing, and dry.Remove and desolvate, obtain crude product, be white solid. 1HNMR (400MHz, CDCl 3): δ (ppm) 2.04-3.52 (12H, m, 6xCH 2), 2.55 (1H, wide, NH), 3.70 (3H, s, CH 3O), 3.86 (3H, s, CH 3O), 4.27 (1H, d, H-1), 6.43 (1H, s, H-9), 6.88-7.20 (3H, m, other Ar-H).This material need not to be further purified and promptly is used for next step reaction.
C) 1-indane-5-base-6-chloro-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 1-indane-5-base-6-chloro-7,8-dimethoxy-2,3,4, (1.3g 3.63mmol) is dissolved in the methyl alcohol (20ml) 5-tetrahydrochysene-1H-3-benzazepines, and (37%, 1.87ml 23.2mmol), forms white precipitate to wherein dripping formaldehyde solution.(97%, 0.92g 14.9mmol), makes most of solid form solution to add sodium cyanoborohydride.Then this reaction mixture of stirring at room 3 hours.Remove and desolvate, obtain containing the resistates (3.8g) of water white oil and white solid.This resistates is through column chromatography purifying (petrol ether/ethyl acetate, 1: 1, R f0.25), obtain required product, be water white oil (1.16g, 86%). 1H NMR (400 MHz, CDCl 3): δ (ppm) 2.08 (2H, t, J7.5,1xCH 2), 2.37 (3H, s, N-CH 3), 2.86-3.54 (10H, m, other 5xCH 2), 3.61 (3H, s, OCH 3), 3.83 (3H, s, OCH 3), 4.32 (1H, d, 1-H), 6.26 (1H, s, 9-H), 6.92-7.22 (3H, m, other Ar-H).
D) 1-indane-5-base-6-chloro-3-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines-7,8-glycol
With 1-indane-5-base-6-chloro-7,8-dimethoxy-3-methyl-2,3,4, (1.03g 2.77mmol) is dissolved in the anhydrous methylene chloride (15ml) 5-tetrahydrochysene-1H-3-benzazepines, it is cooled to-78 ℃.With 25 minutes, in this solution, drip BBr 3(the 1.0M dichloromethane solution, 13.8ml, 13.8mmol).This reaction mixture stirred 1 hour at-78 ℃, stirred 3 hours at 0 ℃, and stirring at room 1 hour.This reaction mixture is cooled to-78 ℃ again, and handles, then in stirred overnight at room temperature with methyl alcohol (20ml).Remove and desolvate, obtain brown resistates.Add methyl alcohol (10ml), and methyl alcohol is removed in decompression.This process repeats four times, obtains crude product, is brown resistates, and this resistates recrystallization from methanol obtains pale solid (0.87g, 74%).This material recrystallization from methanol obtains title compound, is pale solid (0.53g, 45%), fusing point 255-257 ℃ (decomposition); Measured value: %C, 56.42; %H, 5.58; %N, 3.14.C 20H 23BrClNO 2Theoretical value %C, 56.55; %H, 5.46; %N, 3.30.Mass spectrum 354 (m-81).
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.05-3.79 (m, 6xCH 2), 4.60 (1H, d, H-1), 6.16 (1H, wide, H-9), 6.97-7.28 (3H, m, other Ar-H).
Embodiment 4
A) 1-(benzo [b] thiophene-5-yl)-2-[2-(2-chloro-3,4-Dimethoxyphenyl) ethylamino] ethanol
With 2-chloro-3, (7.00g, 32.5mmol) (5.30g, 30mmol) solution in the 30ml acetonitrile refluxed 48 hours the 4-dimethoxyphenyl ethyl amine with (5-benzo [b] thienyl) oxyethane.Reaction mixture is cooled to 0 ℃ (ice bath), filters, and, obtain title compound (4.40g, 37%), be white crystalline solid crude product recrystallization from hot acetonitrile.Fusing point 137-9 ℃. 1H NMR(CDCl 3)[δ，ppm]：2.75(m，6H)；3.72(s，3H)；3.79(s，3H)；4.76(m，1H)；6.90(d，1H)；6.99(d，1H)；7.35(d，1H)；7.43(d，1H)；7.73(d，1H)；7.83(s，1H)；7.91(d，1H)。
B) 1-(benzo [b] thiophene-5-yl)-3-methyl-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
Under nitrogen atmosphere, with methylsulfonic acid (0.36ml 5.5mmol) handles 1-(benzo [b] thiophene-5-yl)-2-[2-(2-chloro-3,4-Dimethoxyphenyl) ethylamino in the 40ml trifluoroacetic acid] ethanol (2.00g, 5.1mmol), and reflux 18 hours.With the evaporation of this solution for vacuum, resistates is dissolved in the methylene dichloride (100ml), and with strong aqua (100mol, 0.880), (2 * 100ml) and saturated sodium-chloride water solution (100ml) washing, drying is filtered also evaporation to water, obtain crude product, be Huang/green glass shape.Crude product is dissolved in the methyl alcohol (40ml), and (37mmol), (1.35g 21mmol), and stirred gained solution 18 hours to add sodium cyanoborohydride then for 2.8ml, 37% weight to add formalin.Solvent removed in vacuo, and resistates is dissolved in the hydrochloric acid (100ml, 1M).(2 * 100ml) wash this solution, and alkalize with strong aqua (100ml, 0.880), and (2 * 100ml) extract this mixture with methylene dichloride with ether.(2 * 100ml) and saturated sodium-chloride water solution (150ml) washing, drying is filtered also vacuum concentration to the extracting solution water that merges.Through silica gel chromatography, make eluent then, obtain title compound, be white solid (640mg, 34%) with ether.
1H-NMR(CDCl 3)[δ，ppm]：2.35(m，1H)；2.39(s，3H)；2.85-2.98(m，2H)；3.13(m，2H)；3.31(m，1H)；3.56(s，3H)；3.83(s，3H)；4.47(d，1H)；6.25(s，1H)；7.11(d，1H)；7.37-7.41(m，3H)；7.76(d，1H)。
C) 1-(benzo [b] thiophene-5-yl)-3-methyl-6-chloro-7,8-dihydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 1-(benzo [b] thiophene-5-yl)-3-methyl-6-chloro-7,8-dimethoxy-2,3,4, (470mg 1.2mmol) is dissolved in the methylene dichloride (15ml) 5-tetrahydrochysene-1H-3-benzazepines.This solution is cooled to-78 ℃, and by syringe slowly add boron tribromide (6ml, 6mmol).Reaction mixture was kept 60 minutes at-78 ℃, make it be warmed to 0 ℃, and stirred 2 hours.This reaction mixture is cooled to-78 ℃ then, slowly adds methyl alcohol (40ml), and stirred 30 minutes.After the solvent removed in vacuo,, make eluent, obtain title compound, be yellow solid (127mg, 30%) with ethanol/methylene (1: 9) through silica gel chromatography. 1H-NMR((CD 3) 2SO)[δ，ppm]：2.29(s，3H)；2.4(m，1H)；2.95-3.12(m，4H)；3.30-3.4(m，3H)；3.89(d，1H)；4.38(d，1*H)；6.09(s，1H)；7.21(dd，1H)；7.44(d，1H)；7.68(s，1H)；7.74(d，1H)；7.96(d，1H)。
D) 1-(benzo [b] thiophene-5-yl)-3-methyl-6-chloro-7,8-dihydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines one hydrochloride
With 1-(benzo [b] thiophene-5-yl)-3-methyl-6-chloro-7,8-dihydroxyl-2,3,4, (111mg 0.31mmol) is dissolved in the mixture of anhydrous diethyl ether (30ml) and anhydrous chloroform (6ml) 5-tetrahydrochysene-1H-3-benzazepines.This solution is used in anhydrous diethyl ether (12ml, 24mml) the 2N salt acid treatment in, and stirring 5 hours.This reaction mixture is filtered, and crude product is recrystallization from methanol, obtains title compound, is faint yellow solid (95mg, 78%).Fusing point＞220 ℃ (decomposition), 1H-NMR ((CD 3) 2SO) [δ, ppm]: 2.82 (s, 3H); 2.9-3.0 (m, 2H); 3.5-3.6 (m, 2H); 3.7 (m, 1H); 3.84 (d, 1H); 4.87 (d, 1H); 5.89 (s, 1H); 7.23 (dd, 1H); 7.52 (d, 1H); 7.77 (s, 1H); 7.84 (d, 1H); 8.10 (d, 1H); 9.04 (s, OH); 9.40 (s, OH); 11.15 (wide unimodal, HCl).
C 19H 18NO 2The calculated value of ClS.HCl: C, 57.71; H, 4.85; N, 3.54; Cl, 17.70.Measured value: C, 55.51; H, 5.18; N, 3.08; Cl, 17.66.
Embodiment 5
A) 1-(benzo [b] furans-7-yl)-3-methyl-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 1-(benzo [b] furans-7-yl)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzazepines (0.96g, 2.7mmol) be dissolved in the methyl alcohol (25ml), add formalin (1.6ml, 37% weight, 21mmol), add then sodium cyanoborohydride (0.75g, 12mmol), and with gained solution stirring 24 hours.With this solution for vacuum concentration, and resistates is dissolved in the methylene dichloride (100ml), and this solution with water (2 * 100ml) and saturated nacl aqueous solution (100ml) washing, drying is filtered and vacuum concentration.Through silica gel chromatography, make eluent with methylene chloride (9: 1), obtain title compound, be light orange jelly (0.88g, 88%). 1H-NMR(CDCl 3)[δ，ppm]：2.34(m，1H)；2.37(s，3H)；2.96(m，1H)；3.07(m，1H)；3.18(m，1H)；3.45(s，3H)；3.81(s，3H)；4.84(d，1*H)；6.10(s，1H)；6.78(d，1H)；7.06(d，1H)；7.23(m，1H)；7.53(dd，1H)；7.58(d，1H)。
B) 1-(benzo [b] furans-7-yl)-3-methyl-6-chloro-7,8-hydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 1-(benzo [b] furans-7-yl)-3-methyl-6-chloro-7,8-dimethoxy-2,3,4, (0.52g 1.4mmol) is dissolved in the anhydrous methylene chloride (15ml) 5-tetrahydrochysene-1H-3-benzazepines.This solution is cooled to-78 ℃, and by syringe slowly add boron tribromide (6ml, 6mmol).This reaction mixture kept 1 hour at-78 ℃, made it be warmed to 0 ℃, and stirred 2 hours.This reaction mixture is cooled to-78 ℃ then, slowly adds methyl alcohol (10ml), and stirred 1 hour, then stirring at room 18 hours.Solvent removed in vacuo obtains crude product.Through silica gel chromatography, make eluent with methylene chloride (9: 1), and from propan-2-ol/ether recrystallization, obtain title compound, be dark yellow solid (100mg, 17%).C 19H 18ClNO 3.HBr.1.5H 2The analysis of O (calculated value): C 50.58 (50.51) H 4.78 (4.90) N 2.78 (3.10). 1H-NMR((CD 3) 2SO)[δ，ppm]：2.51(s，3H)3.02(t，1H)；3.30-3.38(m，1H)；3.60-3.74(m，3H)；3.89(d，1H)；5.03(d，1*H)；5.82(s，1H)；7.05(d，1H)；7.20(d，1H)；7.36(m，1H)；7.72(m，1H)；8.00(d，1H)。
Embodiment 6
A) 1-(benzo [b] thiophene-7-yl)-3-methyl-6-chloro-7,8-dihydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines
With 1-(benzo [b] thiophene-7-yl)-6-chloro-7,8-dihydroxyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepines hydrobromate (180mg, 0.4mmol) be suspended in the anhydrous methanol (5ml), add formalin (0.2ml, 37% weight, 2.7mmol), (0.10g 1.6mmol), obtains clarifying colourless solution to add sodium cyanoborohydride then.Stir this solution 18 hours, and obtained white suspension.Make this suspension be cooled to 0 ℃, add Hydrogen bromide (1ml, 48% weight), obtain clear soln, stirred 90 minutes.With this solution for vacuum evaporation, resistates is made eluent through silica gel chromatography with chloroform/methanol (9/1), obtains title compound, is yellow solid (170mg, 94%). 1H-NMR((CD 3) 2SO)[δ，ppm]：2.11(t，1H)；2.29(s，3H)；2.80(dd，1H)；2.95(m，2H)；3.18(d，1H)；3.35(m，3H)；4.53(d，1*H)；5.88(s，1H)；7.23(d，1H)；7.46(m，2H)；7.66(d，2H)；7.83(d，1H)。

Claims (7)

1. the dopamine D 1 receptor agonist compounds of general formula I:
Figure C0080394700021
Wherein:
R 1Be halogen, C 1-C 4Alkyl or CF 3
R 2It is the low-grade alkenyl of hydrogen, a methyl or 3-5 carbon atom;
R 3And R 4Form furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring and R together 5Be hydrogen, perhaps R 4And R 5Form furans, dihydrofuran, thiophene, dihydro-thiophene, pentamethylene or cyclohexane ring and R together 3Be hydrogen;
R 6Be hydrogen, halogen, CF 3, CN, NO 2Or NH 2
R 7Be hydrogen, halogen, CF 3, CN, NO 2Or NH 2
2. the compound of claim 1, wherein R 1It is halogen.
3. the compound of claim 2, wherein R 1Be chlorine.
4. be used for the treatment of and prevent the pharmaceutical composition of neurodegenerative disease, the compound or its salt that contains claim 1 is as activeconstituents, and randomly contains physiology acceptable carrier, vehicle or thinner.
The purposes of the compound of claim 1 in the medicine of preparation treatment neurodegenerative disease,
6. the purposes of claim 5, the R among its Chinese style I 1The expression halogen.
7. the purposes of claim 5, the R among its Chinese style I 1Expression chlorine.
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