CN1726211A - Imidazole deriviatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase - Google Patents
Imidazole deriviatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase Download PDFInfo
- Publication number
- CN1726211A CN1726211A CNA2003801059426A CN200380105942A CN1726211A CN 1726211 A CN1726211 A CN 1726211A CN A2003801059426 A CNA2003801059426 A CN A2003801059426A CN 200380105942 A CN200380105942 A CN 200380105942A CN 1726211 A CN1726211 A CN 1726211A
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- CN
- China
- Prior art keywords
- glyoxalidine
- amino
- ethyl
- compound
- thioketones hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title 3
- 108010015720 Dopamine beta-Hydroxylase Proteins 0.000 title 1
- 102100033156 Dopamine beta-hydroxylase Human genes 0.000 title 1
- 229940124639 Selective inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 206010007558 Cardiac failure chronic Diseases 0.000 claims abstract description 5
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 76
- 239000002585 base Substances 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 34
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 24
- 229960002748 norepinephrine Drugs 0.000 claims description 24
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 24
- -1 nitro, amino Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
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- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
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- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 3
- 125000005544 phthalimido group Chemical group 0.000 claims description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
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- YZZVIKDAOTXDEB-JTQLQIEISA-N nepicastat Chemical compound NCC1=CNC(=S)N1[C@@H]1CC2=CC(F)=CC(F)=C2CC1 YZZVIKDAOTXDEB-JTQLQIEISA-N 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
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- 150000001412 amines Chemical class 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 11
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- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
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- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
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- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 206010019280 Heart failures Diseases 0.000 description 5
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
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Abstract
Compounds of formula (I) and a method for their preparation are described, where X is CH2, O or S, and n is 1, 2 or 3, with the proviso that if X is CH2, n is not 1. The compounds have potentially valuable pharmaceutical properties for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.
Description
The present invention relates to the selective depressant and their preparation method on every side of dopamine-.
In recent years, the interest of exploitation dopamine-(D β H) inhibitor is concentrated on such hypothesis, i.e. the inhibition of this kind of enzyme significantly clinical improvements suffers from the patient of cardiovascular disorder such as hypertension or chronic heart failure.The biosynthesizing of using the ultimate principle of D β H inhibitor to be based on them can to suppress the norepinephrine realized through the enzymatic hydroxylation of Dopamine HCL.The neurohumour system, the activation that mainly is sympathetic nervous system is the main clinical manifestation (Parmley W.W., Clinical Cardiology, 18:440-445,1995) of congestive heart failure.The rising of patients with congestive heart failure plasma norepinephrine concentration (Levine, people such as T.B., Am.J.Cardiol., 49:1659-1666,1982), the sympathetic outflow of maincenter increases (Leimbach, W.N. wait the people, Circulation, 73:913-919,1986) and heart kidney norepinephrine overflow increase (Hasking, G.J. wait the people, Circulation, 73:615-621,1966).Cardiac muscle exceedingly contacts norepinephrine for a long time can cause the adjusting of heart β1-Shen Shangxiansushouti decrement, left ventricle change, irregular pulse and necrosis, and all these all can weaken the functional completeness of heart.The patients with congestive heart failure that plasma norepinephrine concentration is high also has worst long-term prognosis (Cohn, people such as J.N., N.Engl.J.Med., 311:819-823,1984).In not having asymptomatic patient obviously in heart failure, existed this discovery that raises of plasma norepinephrine concentration to have prior meaning, it can predict death and morbidity (Benedict, people such as C.R., the Circulation of secondary, 94:690-697,1996).This shows that the sympathetic drive of activated is not only the clinical marker of congestive heart failure, also can cause running down of disease.
Suppress seemingly a kind of method likely of sympathetic nerve function with adrenoceptor antagonists, yet the patient of significant proportion is impatient at quick hemodynamics decline (Pfeffer, people such as M.A., N.Engl.J.Med. that the beta-Blocking agent treatment is followed, 334:1396-7,1996).The other method of directly regulating sympathetic nerve function is to reduce the biosynthesizing of norepinephrine by the enzyme D β H that in the inhibition sympathetic nerve Dopamine HCL is changed into norepinephrine.This method has several advantages, comprises on the contrary with the unexpected inhibition of sympathetic nervous system, and this method is to regulate gradually, and causes that Dopamine HCL discharges and increase, and this can improve renal function, as kidney vasorelaxation, diuresis and natriuresis.Therefore, D β H inhibitor can provide the remarkable advantage that is better than conventional beta blocker.
Therefore several D β H inhibitor obtain report in the literature.Find early stage first and second generation example such as abstinence from alcohol sulphur (Goldstein, people such as M., Life Sci., 3:763,1964) and N,N-Diethyldithiocarbamic Acid (Lippmann, people such as W., Biochem.Pharmacol., 18:2507,1969) or fusarinic acid (Hidaka, H.Nature, 231,1971) and fragrance or alkyl thiourea (Johnson, G.A. wait people, J.Pharmacol.Exp.Ther., 171:80,1970) effectiveness is low, to D β H poor selectivity, and causes toxic side effect.But, find that third generation D β H inhibitor has much higher effectiveness, for example nepicastat (RS-25560-197, IC
509nM) (Stanley, people such as W.C., Br.J.Pharmacol., 121:1803-1809,1997), it is developed to early studies in man.Though do not had and some relevant problems of the first and second generation D β H inhibitor, but an important discovery is, find that nepicastat penetrates hemato encephalic barrier (BBB), therefore can cause that maincenter reaches effect on every side, this situation may cause medicine central nervous system side effect undesirable and may be serious.Therefore, still have the unconsummated clinical demand to selective d β H inhibitor around effective, nontoxic, it can be used for treating some cardiovascular disorder.Have similar to nepicastat or more potent power, but do not have the D β H inhibitor of central nervous system effects (can not penetrate BBB) to provide to be better than the remarkable improvement of all D β H inhibitor compounds of describing so far in the prior art.
We are surprised to find, and the carbocyclic ring of some heteroatoms introducing nepicastat core texture and/or the aminoalkyl group side chain of prolongation nepicastat core texture are caused a series of compounds, and they suppress to have the potentially useful of highly significant for D β H.Have in these compounds manyly to have better effectiveness and significantly reduced brain enters, cause effectively around selective d β H inhibitor.Therefore, the present invention relates to the compound of general formula I, the mixture of (R) that it is independent and (S)-enantiomer or enantiomer, and pharmacologically acceptable salts:
R wherein
1, R
2And R
3Identical or different, and expression hydrogen, halogen, alkyl, alkylaryl, alkoxyl group, hydroxyl, nitro, amino, alkyl-carbonyl-amino, alkylamino or dialkyl amido; R
4Expression hydrogen, alkyl or alkylaryl; X represents CH
2, Sauerstoffatom or sulphur atom; N is 1,2 or 3, and collateral condition is when n is 1, and X is not CH
2
Unless stated otherwise, term alkyl in this specification sheets (no matter be independent use, still use with other group) means hydrocarbon chain, and it is a straight or branched, contain 1-6 carbon atom, optional by aryl, alkoxyl group, halogen, carbalkoxy or hydroxycarbonyl group replacement; Term aryl (no matter be independent use, still using with other group) means phenyl or naphthyl, and its optional alkoxy, halogen or nitro replace; And term halogen means fluorine, chlorine, bromine or iodine.
Another aspect of the present invention is the preparation method of the compound of formula I.Wherein X represents methylene radical (CH
2), some compounds of the formula II of oxygen or sulphur are known (Martinez, people such as G.R., United States Patent (USP) 5,538, on July 23rd, 988,1996 in the literature; Eriksson, M., PCT International Application No. WO 9959988A1, on November 25th, 1999; Napoletano, M., PCT International Application No. WO 9608489A1, on March 21st, 1996; Sarda, people such as N., Tetrahedron Lett., 17:271-272,1976; Neirabeyeh, people such as M.Al, Eur.J.Med.Chem., 26:497-504,1991), and other can prepare by those skilled in the art.The compound of formula II is a chirality, so formula II represents two optically pure independent (R)-and (S)-enantiomer or their mixture;
The compound of formula I is prepared as follows: in the presence of organic acid, the compound of formula II and the compound and the water-soluble thiocyanate-of formula III are reacted in inert organic solvents, wherein water miscible thiocyanate-is alkali metal thiocyanate or tetra-allkylammonium thiocyanate-,
Wherein X is CH
2, oxygen or sulphur; R
1, R
2And R
3Identical or different, and expression hydrogen, halogen, alkyl, alkylaryl, alkoxyl group, hydroxyl, nitro, alkyl-carbonyl-amino, alkylamino or dialkyl amido,
Wherein n represents 1,2 or 3; When n is 1 or 2, R
4Expression hydrogen, alkyl or alkylaryl; R
5Expression hydroxyl protecting group, and R
6The expression amino protecting group; When n is 3, R
5With above definition, but R
4And R
6Represent phthalimido together.
Suitable alkali metal thiocyanate comprises sodium, lithium and caesium thiocyanate-, but preferred potassium sulfocyanate.
Wherein n is that the compound of 1 formula III is known (Wolf, people such as E., Can.J.Chem., 75:942-948,1997), and wherein n is that the compound of 2 or 3 formula III is the new compound (referring to embodiment) that those skilled in the art can prepare.Preferred hydroxyl protecting group (R
5) comprise organic silyl compound such as trialkylsilkl, triphenyl silyl, phenyl dialkyl silyl or alkyl diphenyl base silyl.Preferred especially t-butyldimethylsilyl (TBDMS).Preferred amino protecting group (R
6) comprise carbamate, as alkyl carbamate, particularly tertiary butyl carbamate (Boc) group and alkyl aryl amino manthanoate.Can react with the compound and the potassium sulfocyanate (preferred 1.1-1.3 equivalent) of excessive a little formula III.
The present invention also provides the compound of formula II, wherein R
1, R
2And R
3In at least one is a fluorine.
Reaction can and be carried out under differing temps (preferred solvent reflux temperature) in inert solvent (ethyl acetate) basically.Preferred organic acid comprises acetic acid.When using n wherein to represent the compound of 1 formula III, then in suitable solvent with the intermediate of mineral acid treatment formula IV removing the Boc amino protecting group, and provide the compound (route 1) of formula I.Preferred mineral acid comprises hydrochloric acid, and preferred solvent comprises ethyl acetate.
When using wherein n to represent 2 and R
4During the compound of formula III of expression hydrogen, the mixture and the hydrochloric acid of the midbody product of formula V and VI are reacted, in ethyl acetate with the simplification compound (route 2) that obtains corresponding formula I; Work as R
4The expression alkyl reacts single midbody product and the hydrochloric acid of formula V when (comprising the alkyl that is replaced by aryl) in ethyl acetate, to obtain the compound of formula I.
When using n wherein to be the compound of 3 formula III; then in suitable solvent systems, handle the intermediate of formula VII with sodium borohydride; then as document (people such as Osby; Tetrahedron Lett.; 1984; 25 (20), 2093-2096) the middle adding acetic acid of describing is removed phenyl-diformyl imido amino protecting group, obtains the compound (route 3) of formula I.The compound purity of the formula I that obtains is very high, if but preferred words, it can be from suitable solvent recrystallization.
Be the pharmaceutical composition of the compound of preparation formula I, inertia pharmaceutically acceptable carrier and active compound are mixed.Pharmaceutically acceptable carrier can be solid or liquid.But the solid form preparation comprises powder, tablet dispersible granule and capsule.Solid carrier can be one or more materials, and it also can be used as thinner, seasonings, solubilizing agent, lubricant, suspending agent, tackiness agent or tablet disintegrant; It also can be an encapsulating material.
Preferably, this pharmaceutical preparation is a unit dosage, and as the preparation of packing, this packing contains the preparation of fractional dose, as tablet, capsule and the bottle of packing or the powder in the ampoule.
Dosage can change according to the specific compound of patient's needs, severity of disease and employing.For convenience's sake, the total dose of every day can be divided into administration several times in a whole day.The expection once a day or twice administration optimum.The medical field technician can determine proper dosage as the case may be.
Material and method
In vitro study
As previously described (Kojima, K., Parvez, S. with Nagatsu enzymes in catecholamine biosynthesis.In Methods inNeurotransmitter and Neuropeptide Research T.1993.Analysisof, pp.349-380:ElsieverScience Publishers), by Dopamine HCL β-hydroxylation being become the merit rating D β H activity of norepinephrine.Use SK-N-SH cell (ATCC HTB-11), human neuroblastoma deutero-clone is as people D β H source.The SK-N-SH cell of cultivating in 24 orifice plates is containing pre-the cultivation 20 minutes in the reaction medium of 200mM sodium-acetate, 30mM N-ethyl maleimide, 5 μ M copper sulfate, 0.5mg/mL hydrogen peroxide enzyme aqueous solution, 1mM Supirdyl, 10mM fumaric acid sodium and 20mM xitix.After this, increase in the reaction medium of (0.5-100mM) further cell cultures 45 minutes at dopamine concentration.Pre-cultivate and incubation period between, the sustained oscillation cell and with temperature maintenance at 37 ℃.Cross the chloric acid termination reaction by adding 0.2M.The acidifying sample carries out being stored in 4 ℃ before norepinephrine is measured in the injection high pressure liquid chromatography.In of the experiment of the new D β H inhibitor of research, target test compounds (0.3-10000nM) is joined in pre-cultivation and the culture solution the influence of enzymic activity; Cultivate in the presence of finite concentration (50mM) Dopamine HCL, this concentration is the corresponding K of measuring in the saturation experiments
mThe value 2.5 times.
Research in the body
Male NMRI mouse or Wistar mouse derive from Harlan-Interfauna (Spain), and they with the density of 10 and 5/cage, are raised down in the condition of controling environment (12h illumination/dark cycle, 22 ± 1 ℃ of room temperatures) respectively.Allow arbitrarily to obtain food and tap water, and experiment is carried out by day.
Time=during 0h, give the test compounds or the vehicle (water) of animal given dose by oral gavage.After after the administration 2,6,9,12,18 and 24 hours, put to death animal, and isolating cardiac (left atrium and left ventricle) and brain (volume cortex and wall cortex), weigh and crossed in the chloric acid under 4 ℃ of dark storage 12 hours at 0.2M by detruncation.After the cultivation, by the gained supernatant liquor is collected in culture centrifuging (0.2 μ M/10min/～5000rpm, 4 ℃).With the supernatant liquor refrigerated storage in-80 ℃ up to analyzing.Dopamine HCL in the supernatant liquor and norepinephrine carry out quantitatively with Electrochemical Detection by high pressure liquid chromatography.
The result
In vitro study
Cultivating the SK-N-SH cell in the presence of the Dopamine HCL that concentration increases causes the concentration dependent of norepinephrine to form gained K
m(μ M) and V
Max(nmol mg albumen
-1h
-1) value is respectively 20.6 ± 1.6 and 153.8 ± 4.4.By these kinetic parameters, select to be used for suppressing research near saturated dopamine concentration (50mM).As shown in table 1, find that compound 2,3,4,5,6,7,8,10,12,16,19,24,26,28 and 29 significantly suppresses D β H activity.The concentration dependent that compound 2,3,4 and nepicastat 1 (reference substance) produce the β-hydroxylation of Dopamine HCL reduces, and it is to the active IC of people D β H
50Value (sees Table 2) in low nM scope.In order to prove conclusively as a part of the present invention, it is the reason that observed biological property is significantly improved that molecule is carried out structural modification, selects to carry out studying in the further body near the compound 4 of nepicastat 1.
Table 1. is selected compound (5 μ M) to the active influence of D β H in the SK-N-SH cell.Value is represented with the per-cent of contrast.
| Sequence number | Mean value ± SEM | Sequence number | On average ± |
| 1 | 0.0±0.3 | 24 | 0.0±1.9 |
| 2 | 1.6±0.3 | 25 | 66.0±4.5 |
| 3 | 4.1±0.6 | 26 | 4.5±1.9 |
| 4 | 3.3±0.3 | 27 | 15.5±5.8 |
| 5 | 8.1±0.3 | 28 | 2.6±1.6 |
| 6 | 6.9±0.6 | 29 | 2.2±2.5 |
| 7 | 8.0±0.1 | 30 | 99.4±2.8 |
| 8 | 9.4±0.7 | 31 | 27.3±0.4 |
| 9 | 50.2±1.9 | ||
| 10 | 8.2±0.7 | ||
| 11 | 36.7±4.4 | ||
| 12 | 3.0±0.5 | ||
| 13 | 94.0±3.1 | ||
| 14 | 77.9±2.2 | ||
| 15 | 86.1±2.7 | ||
| 16 | 0.0±0.6 | ||
| 17 | 53.2±3.9 | ||
| 18 | 94.8±1.2 | ||
| 19 | 6.9±0.5 | ||
| 20 | 16.8±4.8 | ||
| 21 | 124.8±6.5 | ||
| 22 | 17.8±2.1 | ||
| 23 | 54.5±9.9 |
The IC that D β H suppresses in the table 2.SK-N-SH cell
50Value (nM)
| Compound | IC 50(nM) |
| 2 | 60(14，250) |
| 3 | 91(56，147) |
| 4 | 105(69，161) |
| Nepicastat 1 | 36(28，46) |
Research in the body
Mouse
The compound 4 of 100mg/kg and the time dependent experiment of nepicastat (1) show that two kinds of compounds are long-acting in heart.4 and 1 reduces the maximum effect time (T that organizes norepinephrine
Max) after the administration seemingly 9 hours (Fig. 1).After this, norepinephrine organizes level to recover, and reaches at 24 hours and initially organizes 50% of level.
At T
Max(after the administration 9 hours), 4 and 1 all reduces noradrenaline levels in the left ventricle in the dose-dependently mode.4 and 1 all obtains maximum restraining effect under the dosage of 100mg/kg.Opposite with the discovery in the heart, 4 norepinephrines that do not influence in the brain wall cortex are organized level, and 1 reduces this regional noradrenaline levels (Fig. 2) of brain in the dose-dependently mode.
Rat
As shown in the mouse, the influence of 4 and 1 pairs of norepinephrines all depends on dosage, and reaches its maximum effect at 9 hours (data do not show).Yet as shown in Figure 3,4 (100mg/kg) are equal more remarkable than 1 (100mg/kg) to the restraining effect of the noradrenaline levels in left atrium and the left ventricle.As viewed in mouse, 4 do not influence in brain wall cortex and the brain volume cortex norepinephrine organizes level, and 1 significantly reduce these regional noradrenaline levels of brain.
Can reach a conclusion, fully opposite with nepicastat 1,4 restraining effect that show it to D β H around, and in brain, do not have restraining effect.
With reference now to accompanying drawing,, wherein:
Fig. 1 shows that the time-dependent manner with noradrenaline levels in the mouse left ventricle of 100mg/kg 4 or nepicastat 1 oral administration reduces.Symbol is the mean value of every group of 5 mensuration, and vertical line is represented S.E.M..
Fig. 2 shows orally give 4 or nepicastat 1 back 9 hours, two width of cloth figure of the noradrenaline levels in mouse left ventricle and the brain wall cortex.Symbol is the mean value of every group of 5 mensuration, and vertical line is represented S.E.M..
Fig. 3 shows orally give 4 or nepicastat 1 back 9 hours, four width of cloth figure of the noradrenaline levels in rat heart (left atrium and left ventricle) and the brain (volume and wall cortex).Post is the mean value of every group of 5 mensuration, and vertical line is represented S.E.M..
Conclusion
Some compounds of general formula I are very powerful dopamine-B-hydroxylase inhibitors, and dopamine enzymatic hydroxylation becomes the decline of norepinephrine may have some angiocardiopathies for the treatment of benefit treating wherein, as having potential valuable pharmaceutical properties in hypertension and the chronic heart failure. Use the D β H inhibitor that seldom enters brain (CNS), opened up new prospect with selective for treating hypertension and chronic heart failure by the potential that improves D β H inhibition on every side such as the possibility of compound 4.
Invention disclosed herein is carried out illustration by following preparation embodiment, and they should not be interpreted as limiting the scope of content disclosed herein.Those skilled in the art know that other approach and similar structures.
Embodiment
(R)-and 5-aminomethyl-1,2-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride, compound 3, table 1)
Will be in (R)-6 in the ethyl acetate (3mL), 8-difluoro chroman-3-base amine hydrochlorate (0.22g, 1.0mmol), [3-(tertiary butyl dimethyl-silicon alcoxyl base)-2-oxopropyl] t-butyl carbamate (0.33g, 1.1mmol), potassium sulfocyanate (0.11g, 1.1mmol) and acetic acid (0.3mL, stirring the mixture 5.0mmol) refluxed 2 hours, be cooled to room temperature, then, use anhydrous magnesium sulfate drying with the sodium hydrogen carbonate solution washing, and vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.23g) is dissolved in the ethyl acetate (2mL), and (2mL 4mmol), at room temperature stirred mixture 2 hours to be incorporated in 2MHCl solution in the ethyl acetate thereon.Shift precipitation by filtering, with the ethyl acetate washing, obtaining fusing point is the crystal of 192 ℃ (decomposition).
Embodiment 2-3
By using above-mentioned technology and methods involving well known by persons skilled in the art, use suitable chroman-following compound of 3-base amine hydrochlorate preparation:
(R)-and 5-aminomethyl-1,2-chroman-3-base-1,3-glyoxalidine-2-thioketones hydrochloride (compound 24, table 1)
(R)-and 5-aminomethyl-1,2-(6-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 22, table 1)
Embodiment 4
(R, S)-5-aminomethyl-1,2-(6-hydroxyl thiochroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride
Will be at the 6-hydroxyl thiochroman in the ethyl acetate (3mL)-3-base amine hydrochlorate (0.22g, 1.0mmol), [3-(tertiary butyl dimethyl-silicon alcoxyl base)-2-oxopropyl] t-butyl carbamate (0.33g, 1.1mmol), potassium sulfocyanate (0.11g, 1.1mmol) and acetic acid (0.3mL, 5.0mmol) stir the mixture and refluxed 2 hours, then be cooled to room temperature, wash with sodium hydrogen carbonate solution, use anhydrous magnesium sulfate drying, and vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.25g) is dissolved in the ethyl acetate (2mL), and (2mL 4mmol), at room temperature stirred mixture 2 hours to be incorporated in 2MHCl solution in the ethyl acetate thereon.By filter shifting precipitation,, obtain not fuse and the crystal that decomposes with the ethyl acetate washing.
Embodiment 5
(3,4-dihydroxyl butyl) t-butyl carbamate
At room temperature, to 4-amino-1, the 2-propylene glycol (2.1g, 20mmol) once add in the stirred solution in ethanol (50mL) two-tertiary butyl, two carbonic ethers (4.80g, 22mmol).The gained mixture was at room temperature stirred 2 hours, then vacuum-evaporation, and, use ethyl acetate-sherwood oil mixture to carry out purifying as elutriant by silica gel column chromatography, obtain colorless oil.
Embodiment 6-7
By using above-mentioned technology and methods involving well known by persons skilled in the art, the 4-amino-1 that uses suitable N-to replace, the following compound of 2-propylene glycol preparation:
(3,4-dihydroxyl butyl) methyl carbamic acid tert-butyl ester
(3,4-dihydroxyl butyl) benzylamino t-butyl formate
[4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-hydroxybutyl] t-butyl carbamate
At room temperature, to (3,4-dihydroxyl butyl) t-butyl carbamate (2.60g, 12.7mmol), triethylamine (2.03mL, 14.50mmol) and 4-(dimethylamino) pyridine (0.05g, 0.4mmol) once add in the stirred solution in anhydrous methylene chloride (40mL) TERT-BUTYL DIMETHYL CHLORO SILANE (2.0g, 13.17mmol).The gained mixture was at room temperature stirred 18 hours, and anhydrous magnesium sulfate drying is used in water, salt water washing.Filter and vacuum concentration, obtain oily matter,, use ethyl acetate-sherwood oil to carry out purifying, obtain colorless oil as elutriant by silica gel column chromatography.
Embodiment 9-10
By using above-mentioned technology and methods involving well known by persons skilled in the art, use the following compound of compound of embodiment 6 and 7:
[4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-hydroxybutyl] methyl carbamic acid tert-butyl ester
[4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-hydroxybutyl] benzylamino t-butyl formate
Embodiment 11
[4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-oxo butyl] t-butyl carbamate
At room temperature, to Dess-Martin periodinane (5.0g, 11.8mmol) add [4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-hydroxybutyl] t-butyl carbamate (3.77g, 11.8mmol) solution in anhydrous methylene chloride in the solution in anhydrous methylene chloride (35mL).The gained mixture was at room temperature stirred 1 hour, and 1/3 of original volume is arrived in vacuum-evaporation, and is applied on the unmodified packed column.With ethyl acetate-petroleum ether solvent mixture wash-out, obtain colorless oil.
Embodiment 12-13
By using above-mentioned technology and methods involving well known by persons skilled in the art, use the following compound of compound of embodiment 9 and 10:
[4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-oxo butyl] methyl carbamic acid tert-butyl ester
[4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-oxo butyl] benzylamino t-butyl formate
Embodiment 14
(S)-and 5-(2-amino-ethyl)-1-(5,7-two fluoro-1,2,3,4-naphthane-2-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 2, table 1)
Will be in (S)-5 in the ethyl acetate (2mL), 7-two fluoro-1,2,3,4-naphthane-2-base amine hydrochlorate (0.17g, 0.79mmol), [4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-oxo butyl] t-butyl carbamate (0.28g, 0.87mmol), potassium sulfocyanate (0.085g, 0.85mmol), water (0.014mL, 0.80mmol) and acetic acid (0.2mL, stirring the mixture 3.3mmol) refluxed 7 hours, be cooled to room temperature, with the sodium hydrogen carbonate solution washing, and use anhydrous magnesium sulfate drying, vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.24g) is dissolved in the ethyl acetate (2mL), and (2mL 4mmol), at room temperature stirred mixture 2 hours to be incorporated in 2M HCl solution in the ethyl acetate.Shift precipitation by filtering, with the ethyl acetate washing, obtain crystal, this crystal does not fuse and decomposes.
Embodiment 15
By using above-mentioned technology and methods involving well known by persons skilled in the art, it is suitable 1,2,3 to use, the 4-naphthane-following compound of 2-base amine hydrochlorate preparation:
(S)-and 5-(2-amino-ethyl)-1-(1,2,3,4-naphthane-2-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 20, table 1)
Embodiment 16
(R)-and 5-(2-amino-ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 4, table 1)
Will be in (R)-6 in the ethyl acetate (30mL), 8-difluoro chroman-3-base amine hydrochlorate (1.68g, 7.58mmol), [4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-oxo butyl] t-butyl carbamate (3.13g, 9.85mmol), potassium sulfocyanate (0.96g, 9.85mmol), water (0.18mL, 10mmol) and acetic acid (3.0mL, stirring the mixture 50mmol) refluxed 7 hours, was cooled to room temperature, washed with sodium hydrogen carbonate solution, and use anhydrous magnesium sulfate drying, vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (2.15g) is dissolved in the ethyl acetate (20mL), and (20mL 40mmol), at room temperature stirred mixture 2 hours to be incorporated in 2M HCl solution in the ethyl acetate.Shift precipitation by filtering, with the ethyl acetate washing, obtain crystal, this crystal does not fuse and decomposes.
Embodiment 17-37
By using above-mentioned technology and methods involving well known by persons skilled in the art, use suitable chroman-3-base amine hydrochlorate and the following compound of [4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-oxo butyl] t-butyl carbamate preparation:
(R)-and 5-(2-amino-ethyl)-1-chroman-3-base-1,3-glyoxalidine-2-thioketones hydrochloride (compound 12, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 16, table 1)
(R)-and 5-(2-amino-ethyl)-1-(8-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 21, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 23, table 1)
(R)-and 5-(2-amino-ethyl)-1-(8-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 19, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-fluorobenzene and dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 7, table 1)
(R)-and 5-(2-amino-ethyl)-1-(8-fluorobenzene and dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 6, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6,7-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 8, table 1)
(S)-and 5-(2-amino-ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 9, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6,7,8-trifluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 10, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-chloro-8-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 11, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-methoxyl group-8-chlorobenzene and dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 13, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-nitro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 18, table 1)
(R)-and 5-(2-amino-ethyl)-1-(8-nitro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 17, table 1)
(R)-and 5-(2-amino-ethyl)-1-[6-(kharophen) chroman-3-yl]-1,3-glyoxalidine-2-thioketones hydrochloride (compound 14, table 1)
(R)-and 5-(2-amino-ethyl)-1-(6-hydroxyl-7-benzyl chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 15, table 1)
(R)-and 5-(2-benzyl amino-ethyl)-1-(6-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 25, table 1)
(R)-and 5-(2-benzyl amino-ethyl)-1-(6-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 26, table 1)
(R)-and 1-(6-hydroxychroman-3-yl)-5-(2-methylamino-ethyl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 27, table 1)
(R)-and 1-(6,8-difluoro chroman-3-yl)-5-(2-methylamino-ethyl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 28, table 1)
(R)-and 1-chroman-3-base-5-(2-methylamino-ethyl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 29, table 1)
Embodiment 38
(R, S)-5-(2-amino-ethyl)-1-(6-melonia benzo thiapyran-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 30, table 1)
Will be at the 6-melonia benzo thiapyran in the ethyl acetate (2mL)-3-base amine hydrochlorate (0.12g, 0.50mmol), [3-(tertiary butyl dimethyl-silicon alcoxyl base)-2-oxopropyl] t-butyl carbamate (0.17g, 0.55mmol), potassium sulfocyanate (0.055g, 0.55mmol), water (0.009g, 0.50mmol) and acetic acid (0.2mL, stirring the mixture 3.3mmol) refluxed 7 hours, be cooled to room temperature, with the sodium hydrogen carbonate solution washing, and use anhydrous magnesium sulfate drying, vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.12g) is dissolved in the ethyl acetate (1mL), and (1mL 2mmol), at room temperature stirred mixture 2 hours to be incorporated in 2M HCl solution in the ethyl acetate.Shift precipitation by filtering, with the ethyl acetate washing, obtain crystal, this crystal does not fuse and decomposes.
Embodiment 39
By using above-mentioned technology and methods involving well known by persons skilled in the art, use suitable chroman-following compound of 3-base amine hydrochlorate preparation:
(R, S)-5-(2-amino-ethyl)-1-(6-hydroxyl thiochroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 31, table 1)
Embodiment 40
2-[3-(2,2-dimethyl [1,3] dioxolane-4-yl) propyl group] isoindole-1, the 3-diketone
To the 3-(2 in acetonitrile (10mL), 2-dimethyl-[1,3] propylamine (1.05g dioxolane-4-yl), 6.60mmol) and ethoxycarbonyl phthalic imidine (1.45g, 6.60mmol) stirred solution in once add triethylamine (0.92mL 6.60mmol), at room temperature stirred the gained mixture 18 hours, vacuum-evaporation, and resistates is dissolved in the ethyl acetate (50mL).With salt solution, 10% citric acid solution and salt solution washing soln, then use anhydrous magnesium sulfate drying.Filter and vacuum concentration, obtain oily matter,, use ethyl acetate-sherwood oil mixture to carry out purifying, obtain colorless oil as elutriant by silica gel column chromatography.
Embodiment 41
2-(4,5-dihydroxyl amyl group) isoindole-1, the 3-diketone
At room temperature, to the 2-[3-(2 in tetrahydrofuran (THF) (20mL), 2-dimethyl [1,3] propyl group dioxolane-4-yl)] isoindole-1, the 3-diketone (1.65g, once add in stirred solution 5.70mmol) 2N HCl solution (15mL, 30mmol), the gained mixture was at room temperature stirred 2 hours, and then half of original volume arrived in vacuum-evaporation.With the saturated resistates of sodium-chlor, and use ethyl acetate extraction.Use the anhydrous magnesium sulfate drying organic phase.Filter and vacuum concentration, obtain colorless oil.
Embodiment 42
The technology of describing in the Application Example 8 is used 2-(4,5-dihydroxyl amyl group) isoindole-1, the following compound of 3-diketone preparation:
2-[5-(tertiary butyl dimethyl-silicon alcoxyl base)-4-hydroxyl amyl group] isoindole-1, the 3-diketone
Embodiment 43
The technology of describing in the Application Example 11 is used 2-[5-(tertiary butyl dimethyl-silicon alcoxyl base)-4-hydroxyl amyl group] isoindole-1, the following compound of 3-diketone preparation:
2-[5-(tertiary butyl dimethyl-silicon alcoxyl base)-4-oxo amyl group] isoindole-1, the 3-diketone
Embodiment 44
(S)-and 5-(3-aminopropyl)-1-(5,7-two fluoro-1,2,3,4-naphthane-2-yl)-1,3-glyoxalidine-2-thioketones hydrochloride (compound 5, table 1)
Will be in (S)-5 in the ethyl acetate (3mL), 7-two fluoro-1,2,3,4-naphthane-2-base amine hydrochlorate (0.22g, 1.0mmol), 2-[5-(tertiary butyl dimethyl-silicon alcoxyl base)-4-oxo amyl group] isoindole-1, the 3-diketone (0.38g, 1.05mmol), sulphur hydracid potassium (0.11g, 1.10mmol), water (0.18g, 1.0mmol) and acetic acid (0.3mL, 5.0mmol) stir the mixture and refluxed 7 hours, be cooled to room temperature, wash with sodium hydrogen carbonate solution, use anhydrous magnesium sulfate drying, and vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.18g) is dissolved in the mixture of Virahol (5mL) and tetrahydrofuran (THF) (2mL).(0.066g 1.74mmol), stirs mixture 1.5 hours at room temperature to add entry (0.8mL) and sodium borohydride.(0.6mL 10mmol), refluxes solution 2 hours, and then vacuum-evaporation is to doing to add acetic acid.Resistates is put into acetone, and the elimination solid is used for the 2N HCl solution acidifying filtrate of ethyl acetate.Collecting precipitation is used washing with acetone, obtains crystal, and this crystal does not fuse and decomposes.
Embodiment 45
(R)-and 5-(3-aminopropyl)-1-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride
Will be in (R)-6 in the ethyl acetate (1.5mL), 8-difluoro chroman-3-base amine hydrochlorate (0.11g, 0.50mmol), 2-[5-(tertiary butyl dimethyl-silicon alcoxyl base)-4-oxo amyl group] isoindole-1,3-diketone (0.19g, 0.55mmol), sulphur hydracid potassium (0.055g, 0.55mmol), water (0.009g, 0.50mmol) and acetic acid (0.15mL, 2.5mmol) stir the mixture and refluxed 7 hours, be cooled to room temperature, with the sodium hydrogen carbonate solution washing, use anhydrous magnesium sulfate drying, and vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.10g) is dissolved in the mixture of Virahol (2.5mL) and tetrahydrofuran (THF) (1mL).(0.038g 1.0mmol), stirs mixture 1.5 hours at room temperature to add entry (0.4mL) and sodium borohydride.(0.3mL 5mmol), refluxes solution 2 hours, and then vacuum-evaporation is to doing to add acetic acid.Resistates is put into acetone, and the elimination solid is used for the 2N HCl solution acidifying filtrate of ethyl acetate.Collecting precipitation is used washing with acetone, obtains crystal, and this crystal does not fuse and decomposes.
Embodiment 46
(R, S)-5-(3-aminopropyl)-1-(6-hydroxyl thiochroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride
Will be at the 6-hydroxyl thiochroman in the ethyl acetate (3mL)-3-base amine hydrochlorate (0.22g, 1.0mmol), 2-[5-(tertiary butyl dimethyl-silicon alcoxyl base)-4-oxo amyl group] isoindole-1, the 3-diketone (0.38g, 1.05mmol), sulphur hydracid potassium (0.11g, 1.10mmol), water (0.18g, 1.0mmol) and acetic acid (0.3mL, 5.0mmol) stirred solution refluxed 7 hours, be cooled to room temperature, wash with sodium hydrogen carbonate solution, use anhydrous magnesium sulfate drying, and vacuum-evaporation.With silica gel column chromatography purifying resistates, use ethyl acetate-sherwood oil mixture as elutriant.Gained oily matter (0.17g) is dissolved in the mixture of Virahol (5mL) and tetrahydrofuran (THF) (2mL), (0.066g 1.74mmol), stirs mixture 1.5 hours at room temperature to add sodium borohydride.(0.6mL 10mmol), refluxes solution 2 hours, and vacuum-evaporation is to doing to add acetic acid.Resistates is put into acetone, and the elimination solid is used for the 2NHCl solution acidifying filtrate of ethyl acetate.Collecting precipitation is used washing with acetone, obtains crystal, and this crystal does not fuse and decomposes.
Claims (13)
1. the mixture and the pharmacologically acceptable salts of the compound of formula I and independent (R) thereof and (S)-enantiomer or enantiomer:
R wherein
1, R
2And R
3Identical or different, and expression hydrogen, halogen, alkyl, alkoxyl group, hydroxyl, nitro, amino, alkyl-carbonyl-amino, alkylamino or dialkyl amido; R
4Expression hydrogen, alkyl or alkylaryl; X represents CH
2, Sauerstoffatom or sulphur atom; N is 1,2 or 3, and collateral condition is when n is 1, and X is not CH
2Wherein the term alkyl means the straight or branched hydrocarbon chain, and it contains 1-6 carbon atom, and is optional by aryl, alkoxyl group, halogen, carbalkoxy or hydroxycarbonyl group replacement; Term aryl means phenyl or naphthyl, and its optional alkoxy, halogen or nitro replace; Term halogen means fluorine, chlorine, bromine or iodine.
2. according to the compound of claim 1, it comprises: (S)-5-(2-amino-ethyl)-1-(1,2,3,4-tetralin-2-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (S)-and 5-(2-amino-ethyl)-1-(5,7-two fluoro-1,2,3,4-tetralin-2-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-chroman-3-base-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(8-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(8-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-fluorobenzene and dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(8-fluorobenzene and dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6,7-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (S)-and 5-(2-amino-ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6,7,8-trifluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-chloro-8-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-methoxyl group-8-chlorobenzene and dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-nitro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(8-nitro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-[6-(kharophen) and dihydropyrane-3-yl]-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-aminomethyl-1,2-chroman-3-base-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-aminomethyl-1,2-(6-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-amino-ethyl)-1-(6-hydroxyl-7-benzyl chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-aminomethyl-1,2-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(3-aminopropyl)-1-(6,8-difluoro chroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (S)-and 5-(3-aminopropyl)-1-(5,7-two fluoro-1,2,3,4-tetralin-2-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R, S)-5-(2-amino-ethyl)-1-(6-hydroxyl thiochroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R, S)-5-(2-amino-ethyl)-1-(6-melonia benzo thiapyran-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-benzyl amino-ethyl)-1-(6-methoxyl group benzo dihydropyrane-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 5-(2-benzyl amino-ethyl)-1-(6-hydroxychroman-3-yl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 1-(6-hydroxychroman-3-yl)-5-(2-methylamino-ethyl)-1,3-glyoxalidine-2-thioketones hydrochloride; (R)-and 1-(6,8-difluoro chroman-3-yl)-5-(2-methylamino-ethyl)-1,3-glyoxalidine-2-thioketones hydrochloride or (R)-1-chroman-3-base-5-(2-methylamino-ethyl)-1,3-glyoxalidine-2-thioketones hydrochloride.
3. independent (R) of the compound of the formula I of claim 1-and (S)-enantiomer or the mixture of enantiomer and the preparation method of pharmacologically acceptable salts; it is included in organic acid and exists down; make independent (R) of the compound of formula II-or (S)-mixture of enantiomer or enantiomer and the compound of formula III and water-soluble thiocyanate-be in reacting in the inert solvent basically; then carry out the deprotection of intermediate product IV-VII
Wherein X is CH
2, oxygen or sulphur; R
1, R
2And R
3Identical or different, and expression hydrogen, halogen, alkyl, alkoxyl group, hydroxyl, nitro, alkyl-carbonyl-amino, alkylamino or dialkyl amido;
Wherein n represents 1,2 or 3; When n is 1 or 2, R
4Expression hydrogen, alkyl; R
5Expression hydroxyl protecting group, and R
6The expression amino protecting group; When n represents 3, R
5With above definition, but R
4And R
6Represent phthalimido together;
Wherein this water-soluble thiocyanate-is alkali metal thiocyanate or tetra-allkylammonium thiocyanate-, and wherein the term alkyl means the straight or branched hydrocarbon chain, and it contains 1-6 carbon atom, and is optional by aryl, alkoxyl group, halogen, carbalkoxy or hydroxycarbonyl group replacement; Term aryl means phenyl or naphthyl, and its optional alkoxy, halogen or nitro replace; Term halogen means fluorine, chlorine, bromine or iodine.
4. pharmaceutical composition, it comprises the claim 1 for the treatment of significant quantity or 2 compound and the effective carrier of pharmacy.
5. according to the compound of claim 1 or 2, it is as medicine.
6. claim 1 or 2 the compound purposes in producing medicine, described medicine are used for the treatment of wherein at the Dopamine HCL hydroxyl and turn to the disease that reduction in the norepinephrine has the treatment benefit.
7. claim 1 or 2 the compound purposes in producing medicine, described medicine is used for the treatment of the patient who suffers from cardiovascular disorder.
8. claim 1 or 2 the compound purposes in producing medicine, described medicine is used for the treatment of hypertension or chronic heart failure.
9. claim 1 or 2 the compound purposes in producing medicine, described medicine is used to suppress dopamine-.
10. the compound of formula III:
Wherein n represents 2, R
4The expression hydrogen or alkyl; R
5Expression hydroxyl protecting group, and R
6The expression amino protecting group, wherein this hydroxyl protecting group is trialkylsilkl, triphenyl silyl, phenyl dialkyl silyl or alkyl diphenyl base silyl; And amino protecting group is alkyl carbamate or carboxylamine alkyl aryl ester, and wherein the term alkyl means the straight or branched hydrocarbon chain, and it contains 1-6 carbon atom, and is optional by aryl, alkoxyl group, halogen, carbalkoxy or hydroxycarbonyl group replacement; Term aryl means phenyl or naphthyl, and its optional alkoxy, halogen or nitro replace; Term halogen means fluorine, chlorine, bromine or iodine.
11. the compound of formula III:
Wherein n represents 3, R
5The expression hydroxyl protecting group; And R
4And R
6Represent phthalimido together, wherein this hydroxyl protecting group is trialkylsilkl, triphenyl silyl, phenyl dialkyl silyl or alkyl diphenyl base silyl.
12. the compound of formula II:
R wherein
1, R
2And R
3Identical or different, and expression fluorine or hydrogen, collateral condition is R
1, R
2And R
3One of at least expression fluorine wherein defines identical in X and the claim 1.
13. (R)-6,8-two fluoro-3,4-dihydro-2H-1-chromene-3-amine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0223719.6 | 2002-10-11 | ||
| GB0223719A GB2393958A (en) | 2002-10-11 | 2002-10-11 | Peripherally-selective imidazole inhibitors of dopamine-beta-hydroxylase |
| GB0224306.1 | 2002-10-18 |
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| Publication Number | Publication Date |
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| CN1726211A true CN1726211A (en) | 2006-01-25 |
| CN100393715C CN100393715C (en) | 2008-06-11 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2003801059426A Expired - Fee Related CN100393715C (en) | 2002-10-11 | 2003-10-10 | Imidazole deriviatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase |
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| KR (1) | KR101350741B1 (en) |
| CN (1) | CN100393715C (en) |
| AR (2) | AR041589A1 (en) |
| AT (5) | ATE505465T1 (en) |
| CY (2) | CY1108452T1 (en) |
| DE (4) | DE60336276D1 (en) |
| DK (2) | DK1908760T3 (en) |
| ES (5) | ES2384118T3 (en) |
| GB (2) | GB2393958A (en) |
| HK (1) | HK1116188A1 (en) |
| SI (2) | SI1408038T1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101687858B (en) * | 2007-05-08 | 2012-12-26 | 比亚尔-珀特拉和Ca股份公司 | 1, 3-dihydroimidazole- 2 -thione derivatives as inhibitors of dopamine-beta-hydroxylase |
| CN103380128A (en) * | 2010-12-22 | 2013-10-30 | 拜欧波尔特拉及正大有限公司 | Crystalline forms and processes for their preparation |
| CN105555775A (en) * | 2013-09-13 | 2016-05-04 | 比亚尔-波特拉&Ca有限公司 | Processes for preparing medicaments for the treatment of cardiovascular diseases and intermediates for use therein |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL82401A0 (en) * | 1986-05-06 | 1987-11-30 | Merrell Dow Pharma | Dopamine beta hydroxy-lase inhibiting imidazole derivatives and pharmaceutical compositions containing them |
| US4868210A (en) | 1988-03-30 | 1989-09-19 | Warner-Lambert Company | Antihyperlipidemic and antiatherosclerotic compounds and compositions |
| CZ290082B6 (en) * | 1994-04-26 | 2002-05-15 | Syntex (U. S. A.) Inc. | Benzocycloalkylazolethione derivatives, pharmaceutical preparation containing thereof, process of their preparation and intermediates of the preparation process |
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- 2002-10-11 GB GB0223719A patent/GB2393958A/en not_active Withdrawn
- 2002-10-18 GB GB0224306A patent/GB2394223B/en not_active Expired - Lifetime
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- 2003-10-10 KR KR1020127005102A patent/KR101350741B1/en active IP Right Grant
- 2003-10-10 AT AT07076125T patent/ATE505465T1/en active
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- 2003-10-10 SI SI200331309T patent/SI1408038T1/en unknown
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- 2003-10-10 DK DK03256420T patent/DK1408038T3/en active
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- 2003-10-10 DE DE60336772T patent/DE60336772D1/en not_active Expired - Lifetime
- 2003-10-10 CN CNB2003801059426A patent/CN100393715C/en not_active Expired - Fee Related
- 2003-10-10 AR ARP030103711A patent/AR041589A1/en active IP Right Grant
- 2003-10-10 SI SI200331986T patent/SI1908760T1/en unknown
- 2003-10-10 AT AT07076123T patent/ATE550335T1/en active
- 2003-10-10 DE DE60322642T patent/DE60322642D1/en not_active Expired - Lifetime
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101687858B (en) * | 2007-05-08 | 2012-12-26 | 比亚尔-珀特拉和Ca股份公司 | 1, 3-dihydroimidazole- 2 -thione derivatives as inhibitors of dopamine-beta-hydroxylase |
| CN103380128A (en) * | 2010-12-22 | 2013-10-30 | 拜欧波尔特拉及正大有限公司 | Crystalline forms and processes for their preparation |
| CN103380128B (en) * | 2010-12-22 | 2017-03-01 | 拜欧波尔特拉及正大有限公司 | Crystal formation and preparation method thereof |
| CN105555775A (en) * | 2013-09-13 | 2016-05-04 | 比亚尔-波特拉&Ca有限公司 | Processes for preparing medicaments for the treatment of cardiovascular diseases and intermediates for use therein |
| US10329268B2 (en) | 2013-09-13 | 2019-06-25 | Bial-Portela & Ca, S.A. | Processes for preparing medicaments for the treatment of cardiovascular diseases and intermediates for use therein |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2394223B (en) | 2007-05-16 |
| CY1108452T1 (en) | 2014-04-09 |
| AR095674A2 (en) | 2015-11-04 |
| DK1908760T3 (en) | 2011-07-25 |
| ES2384118T3 (en) | 2012-06-29 |
| DE60336276D1 (en) | 2011-04-14 |
| DE60336772D1 (en) | 2011-05-26 |
| DE60336275D1 (en) | 2011-04-14 |
| GB0224306D0 (en) | 2002-11-27 |
| CY1112457T1 (en) | 2015-12-09 |
| SI1908760T1 (en) | 2011-05-31 |
| AR041589A1 (en) | 2005-05-26 |
| CN100393715C (en) | 2008-06-11 |
| ATE500248T1 (en) | 2011-03-15 |
| KR20120038014A (en) | 2012-04-20 |
| ATE550335T1 (en) | 2012-04-15 |
| DK1408038T3 (en) | 2008-11-24 |
| ATE505465T1 (en) | 2011-04-15 |
| GB2394223A (en) | 2004-04-21 |
| HK1116188A1 (en) | 2008-12-19 |
| ATE403652T1 (en) | 2008-08-15 |
| ES2361939T3 (en) | 2011-06-24 |
| ATE500247T1 (en) | 2011-03-15 |
| GB2393958A (en) | 2004-04-14 |
| GB0223719D0 (en) | 2002-11-20 |
| KR101350741B1 (en) | 2014-01-10 |
| SI1408038T1 (en) | 2008-10-31 |
| ES2309279T3 (en) | 2008-12-16 |
| DE60322642D1 (en) | 2008-09-18 |
| ES2364919T3 (en) | 2011-09-16 |
| ES2361938T3 (en) | 2011-06-24 |
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