CN1168714C - Arylpiperazine derivatives useful as uroselective alpha-adrenoceptor blockers - Google Patents

Arylpiperazine derivatives useful as uroselective alpha-adrenoceptor blockers Download PDF

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CN1168714C
CN1168714C CNB998108421A CN99810842A CN1168714C CN 1168714 C CN1168714 C CN 1168714C CN B998108421 A CNB998108421 A CN B998108421A CN 99810842 A CN99810842 A CN 99810842A CN 1168714 C CN1168714 C CN 1168714C
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piperazine
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phenyl
propane
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CN1318052A (en
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N�����ϵ�
N·阿南德
N·辛哈
S·贾殷
A·梅达
A·K·萨克赛纳
J·B·古普塔
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Novel piperazine derivatives substituted on one nitrogen by an aromatic system and on the other nitrogen by (2,5-dioxopyrrolidin)-1-yl) alkanes or (2,6-dioxopiperidin-1-yl) alkanes have been found to exhibit selective alpha 1A adrenergic activity. The compounds are useful for treatment of disease conditions, such as peripheral vascular disease, congestive heart failure, hypertension and especially benign prostatic hypertrophy.

Description

Can be used for urinating the aryl piperazine derivative of selectivity alpha 1 adrenergic receptor retarding agent
1. invention field
The present invention relates to novel bridged piperazine derivatives, the urine-selectivity α of the prolongation that it had 1-adrenergic receptor antagonistic activity surpasses those previous compounds.Compound of the present invention is hopeful to be used for the treatment of benign prostatic hyperplasia (BPH).The method of the pharmaceutical composition that the invention still further relates to and make this novel cpd, contains this compound and with the method for this compounds for treating benign prostatic hyperplasia.
2. association area is described
J.Med.Chem.,1997, the 40 volumes, No.9, the summary in the 1292-1315 page or leaf has been narrated and has been treated feasible important pharmacology option in the benign prostatic hyperplasia now.Two kinds of methods of treatment the most successful are based on the male sex hormone level and the alpha-adrenergic receptor antagonistic action of being regulated by the 5 inhibitor.According to direct symptom and the alleviation of urinating, the validity of 5 alpha antagonists is limited.α 1-antagonist shows more effectively, can alleviate subjective symptom rapidly, therefore is preferred modality in the control treatment of benign prostate hyperplasia.α 1-adrenergic receptor also is present in the blood vessel, plays an important role in blood pressure regulation.Therefore, with regard to as being developed to antihypertensive drug at first, α 1Adrenergic receptor antagonist is a particularly important, and may beneficial effect (they are relevant with essential hypertension usually) also be arranged to lipid functional disorder and insulin resistant.
Below for being generally used for treating the important α of BPH 1-adrenergic receptor antagonist.
But most of these known drug are owing to lack prostatic and α blood vessel 1The selectivity that acts between-adrenergic receptor all has blood vessel side effect (as postural hypotension, faintness, dizziness, headache etc.).Obviously, to prostate gland α 1-adrenergic receptor has intrinsic more optionally α 1-adrenergic receptor antagonist can provide the benefit of urinating of potential increase.This has just emphasized optionally α of prostate gland 1The importance that-adrenergic receptor antagonist is found, they can improve and urinate and do not have the side effect that existing medicine exists.
Recently, existing people is by the α of low-affinity 1A-adrenergic receptor subclass proof is too high to the prostata tissue assessment of higher animal such as people and dog.This makes can develop selectively acting in the urinate medicine of symptom of these pathology.The present invention relates to develop a kind of novel α 1-antagonist, i.e. the diethylenediamine compound of new class is to α 1AAdrenergic receptor has bigger selectively acting, and therefore can provide selectivity to slow down hyperplasia of prostate and essential hypertension.
Existing many document descriptions the pharmacologically active relevant with phenylpiperazine.Eur.J.Med.Chem.-Chimica Therapeutica, 1977, the 12 volumes, No.2, the 173-176 page or leaf, the trifluoromethyl piperazine of replacement of having described band acylimino alkyl group side chain shown below does not have the CNS side effect as appetite-inhibiting agent.
Figure C9981084200091
As follows, existing people has reported some 2-[3-(4-aryl-1-piperazinyl) propyl group]-1H-benzo [de] isoquinoline 99.9-1,3-(2H)-diketone/2,5-pyrrolidine-diones (J.Indian Chem.Soc., 1986, V.LXIII, 529-530 page or leaf), N-(N 4-aryl-N 1-piperazinyl methyl)-and 4-(4 '-p-methoxy-phenyl) piperidines-2,6-diketone (J.Indian Chem.Soc., 1978, V.LV, 819-821 page or leaf) and N-N 4-arylpiperazinyl alkyl)-the synthetic and pharmacology of phthalic imidine (J.Indian Chem.Soc., 1979, V.LVI, 1002-1005 page or leaf).These shown compounds show hypertension in experimental animal and CNS suppresses active.
Figure C9981084200092
But these documents are not mentioned the adrenergic receptor retardation of these compounds, and therefore not mentioning them can be used for treating benign prostatic hyperplasia.
At the undocumented Indian patent application DEL 496/95 (1995 that inventor of the present invention showed, 3,3), DEL/500/95 (1995,3,21) and DEL/96/96 (1996, the initial synthetic method and they purposes as hypotensive and anti-schemic medicine of various 1-(4-aryl-piperazine-1-yl)-3-(2-oxygen-tetramethyleneimine-1-base/piperidines-1-yl) alkanes have been described 3,29).These compounds have low α 1(pKi～6 are with＞8 known α for-adrenergic block activity 1-antagonist such as Prazosin are compared), and to α 1ATo α 1BOr α 1DIn fact adrenergic receptor does not have adrenergic receptor subclass selectivity.Found these compounds are modified into dioxo compound from lactan, promptly be modified into 2 from 2-oxygen tetramethyleneimine, 5-dioxy tetramethyleneimine and 2, the 6-dioxopiperidin, can improve the adrenergic receptor blocking activity also can increase α greatly 1ASelectivity (with α 1B-adrenergic receptor blocking activity is compared), here as the basic demand for the treatment of the BPH candidate compound.
3. goal of the invention
An object of the present invention is to provide novel aryl piperazine derivative, compare with existing known compound, it can show obviously bigger α 1A-adrenergic block ability, thus specific treatment to benign prostatic hyperplasia is provided.
Another object of the present invention provides a kind of method of synthetic this novel cpd.
Another object of the present invention provides the composition that contains this novel cpd, can be used for the treatment of benign prostatic hyperplasia.
4. summary of the invention
Above-mentioned goal of the invention realizes by the new class bridged piperazine derivatives of following general formula 1
Y is O or S in the formula; Q, X, Z and Z ' respectively are CH or N; M=0-3; N=0-4; R 1, R 2Respectively be selected from: H, F, Cl, Br, OCH 3, OC 2H 5, OCH 2CF 3, SCF 3, CH 3, C 2H 5, CF 3, isopropoxy and cyclopropyl; R 3Be H, R 6, OH or OR 6R 6Be that replace or unsubstituted C1-C6 alkyl chain; And R 4, R 5Be H, C1-C3 alkyl, replacement or unsubstituted phenyl or five yuan of volutions.Preferably, when m=0 and n=1, R 1Be H, R 2Be H, Cl or CF 3, R 3, R 4And R 5=H, Y=O and Q=CH; But when m=0 and n=2, R 1Be H, R 2Be OCH 3, R 3, R 4And R 5=H, Y=O and Q=CH.
In formula I scope but structure is that the compound of Formula Il is because optionally and strong α 1A-adrenergic receptor antagonist is active (to compare α 1BAnd α 1DAdrenergic receptor) and by preferred,
N, X, Z, Z ', R in the formula 1', R 2And R 3Definition suc as formula I, and m '=1-4.In formula II, preferably when m '=1 and n=1, R 1Be H, R 2Be H, Cl or CF 3, and R 3Be H; When m '=1 and n=2, R 1Be H, R 2Be OCH 3And R 3Be H.
The present invention also provides the pharmaceutical composition that is used for the treatment of benign prostatic hyperplasia.These compositions comprise the compound of at least a above-mentioned formula I of effective dose, or preferably are the compound of formula II, and/or the acid addition salt of at least a pharmaceutically acceptable above-claimed cpd of effective dose, and pharmaceutically acceptable carrier.
Below for the explanation catalogue of specific compound of the present invention:
The compound chemistry title
No.
1. 1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
2. 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
3. 1-[4-(3-trifluoromethyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
4. 1-[4-(2-pyridyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
5. 1-[4-(3-chloro-phenyl-) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
6. 1-[4-(2-pyrimidyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
7. 1-[4-(3, the 4-3,5-dimethylphenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
8. 1-[4-(phenylpiperazine)-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
9. 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane
10. 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-2-(2,5-dioxy tetramethyleneimine-1-yl) ethane
11. 1-[4-(3-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
12. 1-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
13. 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
14. 1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
15. 1-[4-(4-chloro-phenyl-) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
16. 1-[4-(3-trifluoromethyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
17. 1-[4-(2-fluorophenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
18. 1-[4-(2-aminomethyl phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
19. 1-[4-(2-pyridyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
20. 1-[4-(3-chloro-phenyl-) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
21. 1-[4-(3, the 4-3,5-dimethylphenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
22. 1-[4-(2-pyrimidyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
23. 1-[4-(3-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
24. 1-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane
25. 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,6-dioxopiperidin-1-yl) butane
26. 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy-3-phenyl-tetramethyleneimine-1-yl) propane
27. 1-[4-(phenyl) piperidines-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane
5. detailed Description Of The Invention
5a. The compounds of this invention is synthetic
Available arbitrary following reaction sequence that shows prepares compound of the present invention, the compound of results formula II, R in the formula 1, R 2, R 3, R 4, R 5, R 6, m, n, Z, Z ', Q and Y group definition as above.The initiator that is used for flow process I, II and III can suitably be revised so that produce the compound of more formula I.
Flow process I
What flow process I showed is the synthetic of formula II compound, R in the formula 1, R 2, R 3, R 4, R 5, R 6, m ', n, Z, Z ', Q, X and Y definition as above.This preparation is included in alkali and organic solvent when existing, α with 1-(4-aryl piperazines-1-yl)-ω-chlorine alkane condensation formula III of formula IV, ω-dicarboximide, temperature range is 80-150 ℃, reaction times is between 8-24 hour, produce 1-(4-aryl-piperazine-1-yl)-ω-[N-(α, ω-dicarboxylic dihydrazides imino-)] alkane of corresponding formula II, R in the formula 1And R 2Definition as above.Phase-transfer catalyst (preferably being the bromination tetrabutylammonium) is particularly useful in the catalysis of this reaction.
Figure C9981084200121
Flow process I
Flow process II
Also the piperazine of the acid anhydrides shrinking type V of available formula VI comes the compound of preparation formula II, R in the formula 1, R 2, R 3, Y, Z, Z ' and m ' definition as above.
Flow process II
Flow process III
The preparation of formula II compound also can be passed through to use α, ω-saturated dihalide alkanisation α, and ω-dicarboximide makes 1-(ω-alkylhalide group) dicarboximide (formula VII) and 1-aryl piperazines (formula VIII) condensation that obtain thus, R in the formula then 1, R 2, R 3, Y, Z, Z ' m ' and n definition as above.Preferably reaction is carried out when having alkali and organic solvent, and temperature range is 60-100 ℃, carries out 10-24 hour, produces 1-(4-aryl piperazines-1-yl)-ω-[N-(α, ω-dicarboxylic dihydrazides imino-)] alkane of corresponding formula II.Phase-transfer catalyst (preferably being bromination tetrabutylammonium and potassiumiodide) is particularly useful in the catalysis of this reaction.
Figure C9981084200132
Flow process III
In above-mentioned flow process, mention specific alkali, acid, solvent, phase-transfer catalyst etc., it will be understood by those skilled in the art that also available other acid, alkali, solvent, phase-transfer catalyst etc.Similarly, also can be by actual needs conditioned reaction temperature and duration of the reaction.
The initial piperazine of formula IV, V and VIII is known in the art, and disclosed method preparation: Kiritzy in the available following document, people such as J.A., J.Med.Chem., 1978, the 21 volumes, the 1301st page; U.S. Patent No. 3,637,705 (Abbott, 1972); FR 2,179, and 491 (1973); People such as Aggarwal S.K, Ind.J.Chem., 1982, the 21B volume, 435-439 page or leaf; With U.S. Patent No. 2,922,788 (Parcell, 1960).
5b. pharmacology test result
The receptor binding assay of available following case description (RBA) assessment The compounds of this invention is to the avidity of the various subclass of alpha-adrenergic receptor.It is pointed out that the identification of above-mentioned acceptor and identify still to be in conceptual phase, their kind and subclass also will be examined or check and refine.
Receptors bind of the following stated and external functional analysis studies show that compound of the present invention has selectivity and strong α 1AThe adrenergic receptor antagonistic activity (is better than α 1BAnd α 1DAdrenergic receptor).Also the witness method of the affine prostata tissue of this compound selective (being better than vascular tissue) of the present invention.In addition, following example has also been described the method for treatment Mammals BPH, and wherein Ce Shi compound eases off the pressure at the dosage of not obvious change blood pressure.Compare with compound known (as terazosin, Doxazosin etc.), proved that compounds more of the present invention have obvious selectivity to prostata tissue.Compound of the present invention also brings high blood pressure down, and effect is lasting.Proved that compound of the present invention can be used for treating warm-blooded animal and Mammals.But these compounds of orally give, or in suitable pharmaceutical composition, absorb with parenteral road approach.
The preferred compound of the present invention is 1-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane (compound N is o.2), 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane (compound N is o.9) and 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane (compound N is o.13).
The pharmacy of The compounds of this invention can accept, nontoxic, acid salt is with the free alkali of formula I and II, and is synthetic with methods known in the art with organic or inorganic acid, and alternative free alkali uses.The representative example that is applicable to the acid that forms these acid salt is oxysuccinic acid, fumaric acid, phenylformic acid, xitix, pamoic, Succinic Acid, dimethylene Whitfield's ointment, methylsulfonic acid, ethane disulfonic acid, acetate, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, aspartic acid, stearic acid, Palmiticacid, methylene-succinic acid, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, phenyl-sulfamic acid, phosphoric acid, Hydrogen bromide, sulfuric acid, cyclohexyl thionamic acid, hydrochloric acid and nitric acid.
The present invention also is included in the formula I in its scope and the prodrug of II compound.Usually, these prodrugs are these compound functions derivatives, change into defined compound in vivo easily.The step of selecting and preparing suitable prodrug is known.
The present invention also comprises enantiomorph, diastereomer, N-oxide compound and the pharmacy acceptable salt of these compounds, and the metabolite with identical active type.The present invention also comprises pharmaceutical composition, and it contains formula I and II molecule or its prodrug, metabolite, enantiomorph, diastereomer, N-oxide compound or pharmacy acceptable salt, with pharmaceutically acceptable carrier combinations, and the optional vehicle that comprises.
On the other hand, the present invention relates to the The compounds of this invention of effective dose is sent in the environment that is delivered to described acceptor, for example (or by delivering medicine to the Mammals with described acceptor) in the extracellular medium optionally blocks α to reach 1AThe method of acceptor.
Now with following non-restrictive example explanation the present invention.
Preparation 1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane (compound N is o.1)
Flow process I:80 ℃, will be in acetone (25ml) 2,5-dioxy tetramethyleneimine (0.500g, 5mmol), 1-[4-(4-fluorophenyl)-piperazine-1-yl]-3-chloropropane (1.28g, 5mmol), salt of wormwood (0.502g, 3.75mmo) and the bromination tetrabutylammonium (0.322g, 1mmol) the mixture stirring and refluxing is 16 hours.Solvent is fallen in vacuum-evaporation, and residue is suspended in the water (80ml).(3 * 50ml) extract the aqueous solution, mix organic layer, water (2 * 50ml) washings, Na with chloroform 2SO 4Drying, vacuum-evaporation obtains title compound.Chloroform-methanol (98: 2) is an elutriant, using the column chromatography purification product on the silica gel fast, obtains 1.00g (65%), oil.
Flow process II: in pyridine (10ml) with 1-amino-3-[4-(4-fluorophenyl) piperazine-1-yl] propane (and 0.700g, 2.95mmol) and succinyl oxide (0.295g 2.95mmol) refluxed 10 hours.Add diacetyl oxide, mixture was refluxed 5 hours again.Solvent removed in vacuo is suspended in residue in the water, and (2 * 25ml) extract with chloroform.Merge organic layer, water (2 * 25ml) washings, Na 2SO 4Drying concentrates.Chloroform-methanol (98: 2) is an elutriant, using the column chromatography purification compound on the silica gel fast, obtains 0.436g (46%), oil.
Flow process III: will be at N, 1-chloro-3-(2 in the dinethylformamide (25ml), 5-dioxy tetramethyleneimine-1-yl) propane (1.54g, 8.80mmol), 1-(4-fluorophenyl) piperazine (1.58g, 8.80mmol), salt of wormwood (1.21g, 8.80mmol) and potassiumiodide (0.146g, 0.88mmol) 100 ℃ the heating 18 hours.Decompression removes down and desolvates.Water vibration residue, (2 * 25ml) extract, and mix organic layer, water (2 * 20ml) washings, Na with chloroform 2SO 4Drying concentrates the oil that obtains and is elutriant with chloroform-methanol (98: 2), using column chromatography purification on the silica gel fast, obtains 2.00g (71%), oil.
By in the free alkali methanol solution, adding the ether hydrogen chloride solution, with quantitative results 1-[4-(4-fluorophenyl) piperazine-1-yl]-hydrochloride of 3-(2,5-dioxy tetramethyleneimine-1-yl) propane (compound N is o.1), filter the precipitation of formation, m.p246-247 ℃.
Preparation 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane (compound N is o.2)
Flow process I:80 ℃, will be in acetone (100ml) 2,5-dioxy tetramethyleneimine (3.68g, 37.24mmol), 1-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-3-chloropropane (10.0g, 37.24mmol), salt of wormwood (7.70g, 55.8mmo) and the bromination tetrabutylammonium (2.38g, 7.4mmol) the mixture stirring and refluxing is 12 hours.Solvent is fallen in vacuum-evaporation, and residue is placed water (80ml).(3 * 50ml) extract the aqueous solution, mix organic layer, water (2 * 50ml) washings, Na with chloroform 2SO 4Drying, vacuum-evaporation obtains title compound.Chloroform-methanol (99: 1) is an elutriant, using the column chromatography purification product on the silica gel fast, obtains 8.00g (65%), oil.Use the method for preparing hydrochloride; Mp199-202 ℃.
Flow process II: will be at N, 1-chloro-3-(2 in the dinethylformamide (115ml), 5-dioxy tetramethyleneimine-1-yl) propane (28.00g, 159.5mmol), 1-(2-p-methoxy-phenyl) piperazine hydrochloride (36.45g, 159.5mmol), salt of wormwood (44.03g, 319.0mmol) and potassiumiodide (1.58g, 9.57mmol) 80 ℃ of heating 17 hours, decompression removes down and desolvates.Residue is suspended in the ethyl acetate (600ml) water (5 * 100ml) washings, Na 2SO 4Drying concentrates the oil that obtains and is elutriant with chloroform-methanol (99: 2), goes up at silica gel (100-200 sieve mesh) and uses column chromatography purification, obtains 55.1g (80%), oil.Use the method for preparing hydrochloride; Mp199-202 ℃.
In acetone, in the presence of salt of wormwood and bromination tetrabutylammonium, by 2,5-dioxy tetramethyleneimine and 1-bromo-2 cbloropropane isopropyl chloride prepared in reaction 1-chloro-3-(2,5-dioxy tetramethyleneimine-1-yl) propane.
Preparation 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane (compound N is o.9)
Flow process III: will be at N, 1-chloro-4-(2 in the dinethylformamide (45ml), 5-dioxy tetramethyleneimine-1-yl) butane (11.0g, 58.04mmol), 1-(2-p-methoxy-phenyl) piperazine hydrochloride (12.99g, 56.85mmol), salt of wormwood (16.02g, 116.09mmol) and potassiumiodide (0.577g, 3.48mmol) 100 ℃ the heating 18 hours.N is removed in decompression, and dinethylformamide places water (100ml) with residue, and (2 * 100ml) extract with chloroform.Extract Na 2SO 4Drying, decompression concentrate down and obtain oily 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane, is elutriant with it with chloroform-methanol (98: 2), upward use column chromatography purification at silica gel (230-400 sieve mesh), obtain 18.00g (92%), oil.Use the method for preparing hydrochloride; Mp218-220 ℃.
In acetone, in the presence of salt of wormwood and bromination tetrabutylammonium, by 2,5-dioxy tetramethyleneimine and 1-bromo-3-chlorobutane prepared in reaction 1-chloro-4-(2,5-dioxy tetramethyleneimine-1-yl) butane.
Preparation 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-]-3-(2,6-dioxopiperidin-1-yl) propane (compound N is o.13)
Flow process I:80 ℃, will be in acetone (80ml) 2,6-dioxy tetramethyleneimine (2.60g, 23.02mmol), 1-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-3-chloropropane (6.18g, 23.02mmol), salt of wormwood (2.38g, 17.27mmo) and the bromination tetrabutylammonium (1.48g, 4.60mmol) the mixture stirring and refluxing is 16 hours.Solvent is fallen in vacuum-evaporation, and residue is placed water (60ml).(3 * 40ml) extract, and mix organic layer, water (2 * 40ml) washings, anhydrous Na with chloroform 2SO 4Drying, vacuum-evaporation obtains title compound.Chloroform-methanol (98: 1) is an elutriant, goes up at quick silica gel (230-400 sieve mesh) and uses the column chromatography purification product, obtains 3.58g (45%), oil.
Quantitatively prepare hydrochloride with aforesaid method; Mp206-210 ℃.
Flow process III: will be at N, 1-chloro-3-(2 in the dinethylformamide (90ml), 6-dioxopiperidin-1-yl) propane (22.06g, 116.40mmol), 1-(2-p-methoxy-phenyl) piperazine (21.90g, 114.06mmol), salt of wormwood (16.06g, 116.40mmol) and potassiumiodide (1.16g, 6.98mmol) 80 ℃ of heating 17 hours, decompression removes down and desolvates.Residue is dissolved water (5 * 100ml) washings, Na in ethyl acetate (400ml) 2SO 4Drying concentrates the oil that obtains and is elutriant with chloroform-methanol (99: 1), goes up at silica gel (100-200 sieve mesh) and uses column chromatography purification, obtains 33.8g (86%), oil.By quantitatively preparing hydrochloride in the methanol solution that excessive ether hydrogen chloride solution is joined free alkali, filter and collect the precipitation that forms; Mp206-210 ℃.
What below provide is catalogue by above-mentioned one or more method synthetic The compounds of this invention.
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.246-247 ℃.
1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.199-202 ℃.
1-[4-(3-trifluoromethyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.218-220 ℃.
1-[4-(2-pyridyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.261-262 ℃.
1-[4-(3-chloro-phenyl-) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.230-231 ℃.
1-[4-(2-pyrimidyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.196-198 ℃.
1-[4-(3, the 4-3,5-dimethylphenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.244-246 ℃.
1-[4-(phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.258-259 ℃.
1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane hydrochloride; M.p.218-220 ℃.
1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-2-(2,5-dioxy tetramethyleneimine-1-yl) ethane hydrochloride; M.p.232-234 ℃.
1-[4-(3-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.199-201 ℃.
1-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.240-242 ℃.
1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.206-210 ℃.
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane; M.p.200-202 ℃.
1-[4-(4-chloro-phenyl-) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.206-208 ℃.
1-[4-(3-trifluoromethyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.228-229 ℃.
1-[4-(2-fluorophenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.215-216 ℃.
1-[4-(2-aminomethyl phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.206-207 ℃.
1-[4-(2-pyridyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.244-245 ℃.
1-[4-(3-chloro-phenyl-) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.214-215 ℃.
1-[4-(3, the 4-3,5-dimethylphenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; The low melting point moisture absorption.
1-[4-(2-pyrimidyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.195-196 ℃.
1-[4-(3-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.196-197 ℃.
1-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride salt; M.p.218-220 ℃.
1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,6-dioxopiperidin-1-yl) butane hydrochloride; M.p.190-192 ℃.
1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.171-172 ℃.
1-[4-(phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane hydrochloride salt; M.p.208-209 ℃.
Above-mentioned all fusing points are not all proofreaded, and the open capillaries method of available Buchi 535 is measured.
Receptor binding assay
The extracorporeal receptor combination
To natural α 1-adrenergic receptor carries out receptor binding assay (RBA).With the rat jaw down and the rats'liver film preparation assess α respectively 1AAnd α 1The avidity of hypotype.28 ℃ is that (50mM Tris, 0.5mM EDTA use 0.5nM[in pH7.4) for the analysis buffer of 250ml in final volume 3H] Prazosin cultivated every part of membranin (100-200mg) 60 minutes.On the Milipore filter, filter termination reaction rapidly.Dried filtrate, statistics bonded radioactivity.In the presence of the 0.3mM Prazosin, measure non-specific binding.Press Lowry, people J.Biol.Chem. such as O.H, the 193rd volume, the albumen appraisal procedure analyzing proteins of 265-275 page or leaf (1951).Table 1 has been listed the result.
Table 1
Compound number RBA (KinM) External functional analysis (pK B) BP in the body
α1A α1B α1A α1B α1D Descend (mmHg) Time length (minute)
Compound 1 ＞2500 1000 7.1 7.0 6.8 5.0 15.0
Compound 2 19 244 8.7 7.6 7.3 25 120.0
Compound 3 1500 1000 - 7.2 5.0 - -
Compound 4 1660 2100 - - 5.6 - -
Compound 5 106 175 5.3 5.3 7.0 - -
Compound 6 1140 ＞2500 4.7 5.3 6.5 - -
Compound 7 450 282 6.4 6.7 6.5 - -
Compound 8 57 590 7.5 - 6.6 - -
Compound 9 1 35 9.0 8.0 8.3 46 ＞180
Compound 10 1600 2350 6.9 6.7 6.9 - -
Compound 11 ＞2500 ＞2500 - - - - -
Compound 12 ＞2500 ＞2500 - - - - -
Compound 13 3 168 8.6 8.0 7.9 50.0 ＞180
Compound 14 67 192 8.4 7.4 7.1 20.0 60.0
Compound 15 520 201 6.7 6.0 6.2 - -
Compound 16 345 765 6.5 - 6.9 - -
Compound 17 21 396 8.0 7.1 7.9 50.0 120.0
Compound 18 9 267 8.2 5.5 8.5 40.0 ＞150
Compound 19 164 ＞2500 6.4 - 6.7 - -
Compound 20 22 113 7.5 - 7.6 - -
Compound 21 2130 176 6.5 6.7 6.5 - -
Compound 22 ＞2500 ＞2500 6.4 - 7.0 - -
Compound 23 2170 940 - - - - -
Compound 24 ＞2500 ＞2500 - - - - -
Compound 25 1.6 7.5 - - - - -
Compound 26 30 600 - - - - -
Compound 27 1300 2000 - - - - -
External functional study
External α 1-adrenergic receptor selectivity
In order to study the selectivity of The compounds of this invention, these compound opposings have been studied by α to the effect of different alpha-adrenergic receptor hypotype 1-3 adrenergic receptor agonists inductive aorta (α 10), prostate gland (α 1A) and spleen (α 1B) the contraction ability of replying.From isolating aorta, prostate gland and spleen tissue with the male Wistar rat of urethanum anesthesia.Isolated being organized in the organ bath that contains Krebs Henseleit damping fluid fixed, and this damping fluid contains following composition (mM): NaCl 118; KCl 4.7; CaCl 22.5; MgSO 47H 2O 1.2; NaHCO 325; KH 2PO 41.2; Glucose 11.5.Buffering is maintained 37 ℃, use 95%O 2And 5%CO 2Mixture ventilation.Tissue is applied resting tension 2g (aorta) or 1g (spleen and prostate gland).Firmly the movable sensor monitoring is shunk and is replied, and on chart recorder record.Made structural equation 2 hours.At the terminal point of balance period, when having and do not have test compounds (concentration is 0.1,1 and 10 μ M), obtain concentration response curve to norepinephrine (aorta) and phenylephrine (spleen and prostate gland).Calculate the affinity of antagonist, and in table 1 with pK BExpress.
The extracorporeal receptor selectivity
Tested the selectivity of The compounds of this invention, as β to different receptor actings 1-and α 2-Adrenergic, muscarine is cholinergic, serotoninergic (5-HT 2A), histamine can (H 1), Angiotensin II, endothelin (endothelin) (ET AWith B) and calcium and potassium channel.Study compound to 5-HT with rat aorta 2A,-ET A, calcium and potassium channel effect.In rabbit aorta, studied the angiotensin-ii receptor antagonistic activity.Muscarine cholinergic receptor and ET have been studied with the rat tracheae BReceptor antagonist activity is studied H with guinea pig trachea 1Receptor antagonist activity.The vascular of electricity consumption stimulation in rats transports research α 2The effect of-adrenergic receptor, and study β with the rat ventricle band of electricity irritation 1-adrenergic receptor antagonistic activity.Table 2 has been listed the result of selectivity research.
Table 2
Selectivity research
Acceptor type pK B
Compound 2 Compound 9 Compound 13
α 2--Adrenergic NE NE NE
Beta-adrenergic 4.2 - 5.1
Muscarine is cholinergic 5.0 5.0 5.5
H 1-histamine energy 5.3 5.4 5.5
5-HT 2A 7.6 7.9 8.0
ET A - 4.3 4.3
ET B - 5.4 4.9
Angiotensin II - 5.6 5.3
Calcium channel NE NE NE
Potassium channel NE NE 5
NE: not effect
(-): not test
Antihypertensive function in the body
Studied the antihypertensive function of the compound that the present invention selectes, by intravenously, oral and intraduodenal route, their reduce the ability of dopey and conscious normotensive and original hypertensive rat blood pressure.Table 1 and 3 has been listed the result.
Dopey ensive rat
Intravenous route
With urethanum (2.5g/kg) anesthesia male Wistar rat.In femoral vein and carotid artery, insert conduit.With Statham pressure transmitter recording blood pressure and heart rate.With Grass polygraph and on-line data acquisition system (Buxco AT) record data.Give the effect (3 hour) of The compounds of this invention test to blood pressure with the 0.3mg/kg intravenously at first, table 1 has been listed the result.With 0.03,0.1,0.3 and the selected compound of 1mg/kg dose study give effect by intravenously to bringing high blood pressure down.
Intraduodenal route
Allow male Wistar rat fasting 18 hours.Use the urethanum anesthetized rat.In femoral vein and carotid artery, insert conduit.After cutting open the belly, conduit is placed duodenum.In duodenum, give compound of the present invention (with 0.3,1,3 and 10mg/kg dosage), monitoring blood pressure 3 hours.The result of table 3 displayed record.
Table 3
Effect to the mean arterial pressure of anesthetized normotensive rat
Compound number Dosage (mg/kg) Mean arterial pressure (% is from the change on basis) Acting duration
Compound 2 1 -19 ＞2.5 hours
3 -43 ＞2.5 hours
10 -42 ＞2.5 hours
Compound 9 1 -19 ＞3.0 hours
3 -53 ＞3.0 hours
10 -57 ＞3.0 hours
Compound 13 1 -32 ＜3.0 hours
3 -40 ＞3.0 hours
10 -42 ＞3.0 hours
Conscious normal arterial pressure rat
Under Sodital anesthesia (35mg/kg), in the femoral artery of normotensive male Wistar rat (spending the night), insert conduit with digestible food nursing.By neck region that femoral catheter is external, with recording blood pressure.Performed the operation back 24 hours, with the rat of the present invention compound of gavage by the orally give overnight fasting (with 0.1,0.3 and 1mg/kg dosage).With Statham pressure transmitter recording blood pressure and heart rate on the Grass polygraph, the results are shown in table 4.
Table 4
Effect to the systolic blood pressure of conscious original hypertensive rat
Compound number Dosage (mg/kg) Systolic pressure (% from basis change amount) (6 hours time)
Compound 2 1 -7.0
3 -12.0
10 -13.0
30 -17.0
Compound 9 1 -0.4
3 -7.0
10 -24.0
30 -25.0
Compound 13 1 -7.0
3 -18.0
10 -19.0
30 -14.0
Conscious original hypertensive rat
This research original hypertensive rat of weight at 250-300g.The fasting rat spends the night.Monitor blood pressure with semi-automatic non-invasi monitoring of blood pressure device from caudal artery.Orally give compound of the present invention (with 1,3,10 and 30mg/kg dosage).1.5,4,6 and 24 hours monitoring blood pressures before administration and after the administration.Table 5 has shown the result.
Table 5
Effect to the mean arterial blood pressure of conscious free active ensive rat
Compound number Dosage (mg/kg) Mean arterial blood pressure (change amount) from the basis
Compound 2 3 -14
10 -10
Compound 9 1 -4
10 -11
Compound 13 1 -5
3 -10
Selectivity research in the body
(35mg/kg iv) anaesthetizes the male hybrid dog with vetanarcol.Inserting conduit in tracheae practices artificial respiration.Insert conduit in femoral artery and the femoral vein, be respectively applied for the administration of recording blood pressure and drug solution.With pressure transmitter recording blood pressure on polygraph.Make a paramedian incision in the side to penis, expose bladder.Conduit by direct insertion bladder drains urine, and it is incorporated into urethra gently, places prostate-urethra.Make airbag inflation with the 2cc air, and prove its position (swell increment) with digital pressure.On polygraph, write down endo-urethral pressure by pressure transmitter.Before giving The compounds of this invention, (1-16 μ g/kg iv) presses prostate gland and the fractionated dose response relation of blood pressure to obtain phenylephrine.Obtaining the phenylephrine dose response curve preceding 10 minutes, intravenously give compound 2,9 and 13 (with 0.01,0.03,0.1 and the dosage of 0.3mg/kg).As analytical results as described in the people such as Kenny (1996) and calculate counterfeit pK BValue.Table 6 has shown the result.
Table 6
To the effect of pressing in the anesthesia blood pressure of dog and the urethra
Counterfeit pK B
Blood pressure Press in the urethra
Compound 2 6.9 7.60
Compound 9 7.4 7.9
Compound 13 7.1 8.1
Described the present invention with the reference certain embodiments, but this only plays illustrative purposes.Other multiple example will be apparent to those skilled in the art, and is considered as belonging to scope of the present invention.

Claims (35)

1. the compound of a formula I structure or its pharmacy acceptable salt,
Figure C998108420002C1
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from:
H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H; Condition is not comprise:
When m=0 and n=1, R 1Be H, R 2Be H, Cl or CF 3, R 3, R 4And R 5=H, Y=O and Q=CH; When m=0 and n=2, R 1Be H, R 2Be OCH 3, R 3, R 4And R 5=H, Y=O and Q=CH; Work as R 1, R 2When being H simultaneously, m is 1; Work as R 1, R 2When forming the phenyl ring of trifluoromethyl replacement with phenyl ring, n is 0; Work as R 1, R 2When forming methyl substituted phenyl with phenyl ring, m is 0.
2. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
3. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
4. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(3, a 4-3,5-dimethylphenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
5. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-2-(2,5-dioxy tetramethyleneimine-1-yl) ethane or its hydrochloride.
6. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(3-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
7. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
8. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
9. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
10. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(4-chloro-phenyl-) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
11. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(3-trifluoromethyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
12. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(2-fluorophenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
13. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(2-aminomethyl phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
14. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(3-chloro-phenyl-) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
15. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(3, a 4-3,5-dimethylphenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
16. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(3-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
17. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
18. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,6-dioxopiperidin-1-yl) butane or its hydrochloride.
19. compound as claimed in claim 1 is characterized in that, described compound is 1-[4-(phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
20. a pharmaceutical composition that is used for the treatment of benign prostatic hyperplasia is characterized in that, contains described compound of claim 1 and pharmaceutically acceptable carrier.
21. the compound of following formula I or the purposes of its pharmacy acceptable salt,
Figure C998108420003C1
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from: H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H, it is characterized in that, be used to prepare selectivity antagonism Mammals α 1The medicine of-adrenergic receptor.
22. purposes as claimed in claim 21 is characterized in that, described compound is 1-[4-(2-methoxyl group-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
23. purposes as claimed in claim 21 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane or its hydrochloride.
24. purposes as claimed in claim 21 is characterized in that, described compound is 1-[4-(2-methoxyl group-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
25. the compound of following formula I or the purposes of its pharmacy acceptable salt,
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from: H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H, it is characterized in that, be used to prepare the medicine that treatment Mammals benign prostatic hyperplasia is used.
26. purposes as claimed in claim 25 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
27. purposes as claimed in claim 25 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane or its hydrochloride.
28. purposes as claimed in claim 25 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
29. the compound of following formula I or the purposes of its pharmacy acceptable salt,
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from: H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H, it is characterized in that, be used to prepare the medicine that treatment Mammals blood vessel disease, congestive heart failure or hypertension are used.
30. purposes as claimed in claim 29 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,5-dioxy tetramethyleneimine-1-yl) propane or its hydrochloride.
31. purposes as claimed in claim 29 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-4-(2,5-dioxy tetramethyleneimine-1-yl) butane or its hydrochloride.
32. purposes as claimed in claim 29 is characterized in that, described compound is 1-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane or its hydrochloride.
33. a manufacturing structure is the method for formula I compound or its pharmacy acceptable salt,
Figure C998108420005C1
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from: H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H;
It is characterized in that, comprise that with structure be formula III ' compound
With structure be the compound reaction of formula IV
Figure C998108420005C3
Producing structure is the compound of formula I, wherein, formula III ' with formula IV in R 1-R 5And the definition of m, n, Q, X, Y, Z and Z ' is identical with the definition of formula I.
34. a manufacturing structure is the method for formula I compound or its pharmacy acceptable salt,
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from: H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H;
It is characterized in that comprise with structure being the compound of formula VI '
With structure be the compound reaction of formula V
Producing structure is the compound of formula I, the R among its Chinese style VI ' and the formula V 1-R 5And the definition of m, n, Q, X, Y, Z and Z ' is identical with the definition of formula I.
35. a manufacturing structure is the method for formula I compound or its pharmacy acceptable salt,
Y is O in the formula; Q, Z and Z ' respectively are CH; X is N; M=0 or 1; N=0,1 or 2; R 1, R 2Respectively be selected from: H, F, Cl, OCH 3, CH 3, CF 3R 3, R 4And R 5Be H; It is characterized in that comprise with structure being the compound of formula VII '
Figure C998108420006C4
With structure be the compound reaction of formula VIII
Figure C998108420006C5
Producing structure is the compound of formula I, wherein, and the R among formula VII ' and the formula VIII 1-R 5And the definition of m, n, Q, X, Y, Z and Z ' is identical with the definition of formula I.
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PCT/IB1999/000140 WO2000005206A1 (en) 1998-07-21 1999-01-26 Arylpiperazine derivatives useful as uro-selective alpha-1-adrenoceptor blockers
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