CN1627946A - Carboximide derivatives as useful uro-selective alpha-1A adrenoceptor blockers - Google Patents

Carboximide derivatives as useful uro-selective alpha-1A adrenoceptor blockers Download PDF

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CN1627946A
CN1627946A CNA028290976A CN02829097A CN1627946A CN 1627946 A CN1627946 A CN 1627946A CN A028290976 A CNA028290976 A CN A028290976A CN 02829097 A CN02829097 A CN 02829097A CN 1627946 A CN1627946 A CN 1627946A
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rudimentary
alkyl
alkoxyl
replaces
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M·萨尔曼
G·C·亚达弗
S·沙马
G·S·卡普科蒂
A·楚格
J·B·古普塔
N·阿南德
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Ranbaxy Laboratories Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives

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Abstract

Novel carboximide derivatives, which selectively inhibit binding to the alpha >-1A< adrenergic receptor, a receptor which has been shown to be important in the treatment of benign prostatic hyperplasia. The compounds of the present invention are potentially useful in the treatment of benign prostatic hyperplasia.

Description

As urine-selectivity α 1AThe carboxylic imide derivative of adrenergic receptor blocker
Invention field
The present invention relates to some novel carboxylic acid imide (carboximide) derivants, its alternative inhibition and α 1AThe combination of adrenoreceptor, known this receptor is important in the treatment of benign prostatic hyperplasia.Chemical compound of the present invention is hopeful to be used for the treatment of benign prostatic hyperplasia.The invention still further relates to synthetic this new compound method, contain the pharmaceutical composition of described chemical compound and with the method for described compounds for treating benign prostatic hyperplasia.
Background of invention
Benign prostatic hyperplasia (BPH) is prostatic non-pernicious increase, and it is the modal benign tumor of male.Have approximately among all over-65s male 50% suffer to a certain degree BPH and these male in have 1/3rd to have and bladder outlet stops up such clinical symptoms (Hieble and Calne, Fed.Proc., 1986; 45:2601).In the world wide, the surgical operation that prostatic optimum and malignant disease causes among the male more than 50 years old is all more than the disease of any other organ.
It has been generally acknowledged that BPH has two kinds of ingredients, static and dynamic ingredient.Static ingredient (staticcomponent) is because due to the prostatic increase, this can cause compression of urethra and the constricted flow of urine from bladder.Dynamically ingredient (dynamic component) is that it is subjected to α because the smooth muscle tone of neck of bladder and prostate itself increases (this can hinder the emptying of bladder) 1Adrenoreceptor (α 1-AR) regulate.The therapeutic treatment that can be used for BPH can relate to the degree of these ingredients to some extent, and has expanded the selectivity of treatment.
Operative treatment comprises prostatic transurethral resection (TURP), open prostatectomy, balloon dilatation, hyperthermalgesia, fixed die graft and laser ablation at the static ingredient of BPH.Although TURP is treatment BPH patient's a gold medal method, there is the patient of 20-25% not have gratifying long-term effect (Lepor and Rigaud, J.Urol., 1990 approximately; 143:533).Some other risk comprises postoperative urinary tract infection (5-10%), urinary incontinence to a certain degree (2-4%) and operation (15-20%) (Wennberg etc., JAMA, 1987 once more; 257:933).
Except operative treatment, some pharmacotherapys also are conceived to the static ingredient of this disease.(Proscar Merck) is exactly a kind of method for the treatment of symptomatic BPH to finasteride.This medicine is the competitive inhibitor of 5, and this enzyme is responsible in prostate testosterone changed into dihydrotestosterone (Gormley etc., N.Engl.J.Med., 1992; 327:1185).The main mitogen of dihydrotestosterone prostate growth seemingly, the medicament that suppresses the 5-5 alpha-reductases can reduce prostatic size and promote urine flow to cross prostate-urethra.Although finasteride is effective 5 inhibitor and the serum of dihydrotestosterone and tissue concentration are significantly reduced that it is effect general (Oesterling, N.Engl.J.Med., 1995 when the symptomatic BPH of treatment; 332:99).The effect of finasteride needed just can manifest in 6-12 month, and is very little for many male's clinical improvementses.
Because 5 inhibitor effect aspect relief of symptoms and urodynamics alleviation in time is limited, clinically in other pharmacology method of consideration.
The dynamic ingredient of BPH can be used adrenergic receptor blocker (α 1-AR blocker) handle, it plays a role by reduce smooth muscle tone in prostate self.α 1-adrenergic aceptor antagonist seems much effective and can in time improve individual symptom, is the method for preferably controlling benign prostatauxe therefore.α 1-adrenoreceptor also is present in the blood vessel and in blood pressure regulation and plays a significant role.Therefore, α 1-adrenoceptor antagonists particular importance, they develop as antihypertensive at first, and might have beneficial effect to lipid dysfunction and development of insulin resistance, the lipid dysfunction is relevant with essential hypertension usually with development of insulin resistance.
With α 1Thereby it is relevant with the ability of its reduction prostate smooth muscle tone alleviation obstructive symptom that-AR antagonist is used for the treatment of BPH.The adrenoreceptor that whole body all exists is brought into play main (Harrison etc., Trends Pharmacol.Sci., 1991 of acting in controlling blood pressure, nasal congestion, prostate function and other process; 12:62).The α that many clones are arranged 1-AR receptor subtype: α 1A-AR, α 1B-AR and α 1D-AR (Bruno etc., Biochem.Biophys.Res.Commun., 1991; 179:1485; Forray etc., Mol.Pharmacol., 1994; 45:703; Hirasawa etc., Biochem.Biophys.Res.Commun., 1993; 195:902; Ramarao etc., J.Biol.Chem., 1992; 267:21936; Schwinn etc., JPET, 1995; 272:134; Weinberg etc., Biochem.Biophys.Res.Commun., 1994; 201:1296).Many laboratorys have characterized the α in the human prostate by function, radioligand combination and Protocols in Molecular Biology 1-AR (Forray etc., Mol.Pharmacol.1994; 45:703; Hatano etc., Br.J.Pharmacol, 1994; 113:723; Marshal etc., Br.J.Pharmacol.1992; 112:59; Marshal etc., Br.J.Pharmacol., 1995; 115:781; Yamada etc., Life Sci., 1994; 54:1845).These are studied to supporting following notion that evidence is provided, i.e. α 1A-AR hypotype has constituted α in the human prostate smooth muscle 1The main part of-ARS and adjusting contraction in this tissue.These find prompting, exploitation hypotype-selectivity α 1A-AR antagonist may obtain that therapeutic effect is arranged and have the side effect of reduction in the treatment of BPH medicament.
The symptomatic bladder outlet that causes for treatment BPH has stopped up after deliberation many α 1-AR blocker (terazosin, prazosin and doxazosin), and terazosin (Hytrin Abbott) is studied the most widely.Although α 1-AR blocker can well be tolerated, but clinical adverse events takes place the patient of the 10-15% that has an appointment.Such all members' ill effect is similarly, is modal side effect with postural hypotension.
α 1-AR blocker can work quickly.Yet their curative effect is general, and this is to record by improvement and peak value urine flow velocity that symptom is kept the score.(Oesterling，N.Engl.J.Med.，1995；332：99)。The vascular side effect relevant with these medicines (for example position hypertension, dizziness, headache etc.) is because to prostate α 1-adrenoreceptor and blood vessel α 1-adrenoreceptor lacks selectively acting.Obviously, to prostate α 1-adrenoreceptor has the α of inherent more strong selectivity 1-adrenergic aceptor antagonist can more effectively improve the urine power effect.This concentrates on Prostato-selectivity α with research emphasis 1-adrenergic aceptor antagonist, this antagonist can improve the but not existing side effects of pharmaceutical drugs of urine power.
Have in the document many about with α, the description of the pharmacological activity that ω-dicarboxyl imide derivative is relevant.Eur.J.Med.Chem.Chemica?Therapeutica；1977；12(2)：173，J.Indian.Chem.Soc.，1978；LV：819；J。Indian Chem.Soc., 1979; LVI:1002 has discussed the synthetic of these derivants with CNS and antihypertensive active.Other reference material such as U.S. Patent number 4,524,206; 4,598,078; 4,567,180; 4,479,954; 5,183,819; 4,748,240; 4,892,943; 4,797,488; 4,804,751; 4,824,999; 4,957,913; 5,420,278; 5,330,762; 4,543,355 and PCT application number WO 98/37893; WO 93/21179 has also described the CNS and the antihypertensive active of these chemical compounds.Do not mention the adrenoreceptor blocking activity of these chemical compounds, therefore do not mention the application that they treat BPH yet.
J.Med.Chem., 1983; 26:203 has reported the dopamine and the α of some buspirone analog 1-adrenergic activity.EP 078800 has discussed the α of hybar X, pyrimidine threeway and triazinediones derivant 1-adrenoreceptor antagonistic activity.Yet with known α 1-antagonist is compared, the α of these chemical compounds 1-adrenergic block activity is low.
Be disclosed among Indian patent application 496/DEU95,500/DEU95 and the 96/DEU96 about the synthetic of various 1-(4-aryl piperazines-1-yl)-3-(2-oxo-pyrrolidine-1-base/piperidines-1-yl) alkane and their effects in early days as hypotensor and antischemic agent.These chemical compounds have low α 1-adrenergic block activity (pKi is about 6, and the known α of prazosin and so on 1The value of-antagonist＞8), and to adrenoreceptor α 1A/ α 1BOr α 1A/ α 1DIn fact there is not adrenoreceptor subclass selectivity.Further work shows, these chemical compounds are carried out structural modification, makes it become dioxo compound from lactams, promptly become 2,5-dioxo pyrrolidine and 2,6-dioxopiperidine from the 2-oxo-pyrrolidine, can strengthen the adrenoreceptor blocking activity, while and α 1BThe adrenal gland can not compare by blocking activity, can increase α greatly 1A/ α 1BThe selectivity of adrenoreceptor blocking activity is described in U.S. Patent number 6,083 to the basic demand as the chemical compound of treatment benign prostatic hyperplasia (BPH) outstanding material standed for, in 950 and 6,090,809, at this it is incorporated into for your guidance in full.
Goal of the invention
The prostata tissue that has confirmed senior species such as people and Canis familiaris L. recently contains the α that accounts for dominant trait's concentration 1A-adrenoceptor hypotype.This just makes and may develop the active medicament of these pathologic urine selective opposings of power situation.The present invention relates to novel α 1The exploitation of-adrenoreceptor, this receptor can be alleviated prostate hyperplasia and essential hypertension selectively, but not existing α 1AThe side effect of-AR antagonist.
The purpose of this invention is to provide novel carboxylic imide derivative, it has the α apparently higher than known compound 1A-adrenergic block effect, thereby but particular treatment benign prostatic hyperplasia.
Purpose of the present invention also comprises the method that synthetic this new compound is provided.
Purpose of the present invention also comprises provides the compositions that contains described new compound, and said composition can be used for treating benign prostatic hyperplasia.
Summary of the invention
Purpose above-mentioned can realize by the novel carboxylic imide derivative that following formula I is represented:
Chemical compound with structure shown in the formula I
Formula I
Wherein, X is selected from
With
Wherein, junction point shows with the key table that turns back, and one of them junction point is bonded to the carbonyl of contiguous nitrogen, and second junction point is bonded to other carbonyl;
W is O, S, SO or SO 2
A is-(CH 2) m-,
Figure A0282909700124
Wherein, m is one of integer 2,3 or 4;
R 11Independently be selected from H, F, Cl, Br, I, OH, the rudimentary (C of straight or branched 1-6) alkyl, rudimentary (C 1-6) alkoxyl and rudimentary (C 1-6) perhaloalkyl radical and rudimentary (C 1-6) the perhalogeno alkoxyl;
Y is selected from
Figure A0282909700131
R 1And R 2Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I, OR 3, COR 3, OCOR 3, COOR 3, NH 2, N (R 4, R 5), rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, rudimentary (C 1-4) alkylthio group, rudimentary (C 1-4) perhaloalkyl radical, rudimentary (C 1-4) the perhalogeno alkoxyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkoxyl, being selected from the group of the optional replacement of aryl, aryloxy group, aralkyl, heterocyclic radical or heteroaryl, described substituent group is H, F, Cl, Br, I, OH, OR 3, rudimentary (C 1-4) alkyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkyl, wherein, R 3Be selected from H, straight or branched C 1-C 6Alkyl and perhaloalkyl radical; R 4And R 5Independently be selected from H, CHO replaces or unsubstituted rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, COR 3, COOR 3, CH 2CH (OR 3) 2, CH 2COOR 3, CH 2CHO and (CH 2) 2OR 3, wherein, R 3Identical with top definition; R 6, R 7, R 8, R 9And R 10Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I is by the optional rudimentary (C of straight or branched that replaces of one or more halogens 1-4) alkyl, by the optional rudimentary (C that replaces of one or more halogens 1-4) alkoxyl, (C 3-6) cycloalkyloxy, NH 2, the rudimentary (C of N- 1-4) alkyl amino, N, N-two-rudimentary (C 1-C 4) alkyl amino, N-low alkyl group (C 1-C 4) amino carbonyl, by aromatics or non-aromatics five or hexa-atomic cyclosubstituted hydroxyl, phenyl is by Cl, F, Br, I, NO 2, NH 2, (C 1-4) alkyl or (C 1-4) alkoxyl, (C 1-4) perhaloalkyl radical, (C 1-4) phenyl that replaces of perhalogeno alkoxyl, wherein, dotted line (... .) is singly-bound or does not have key.
The present invention also provides the pharmaceutical composition of treatment benign prostatic hyperplasia.These compositionss contain the chemical compound of at least a above-mentioned formula I of effective dose and/or at least a pharmaceutically acceptable its acid-addition salts of effective dose, and pharmaceutically acceptable carrier, and the optional excipient that contains.
Specific chemical compound of the present invention is as follows:
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-ethoxyl phenenyl) piperazine-1-yl }] propyl group)] carboxylic acid amides, (chemical compound 1)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl } propyl group] carboxylic acid amides, (chemical compound 2)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-methoxyphenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides, (chemical compound 3)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-hydroxyphenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides, (chemical compound 4)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides, (chemical compound 5)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-ethoxyl phenenyl) piperazine-1yl}-2-hydroxyphenyl] carboxylic acid amides, (chemical compound 6)
5-[N-{3-(2-hydroxyphenyl) piperazine-1-yl }]-1-aminopropyl-5-oxo-penta-1-acid, (chemical compound 7)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-hydroxyphenyl) piperazine-1-yl } propyl group] carboxylic acid amides, (chemical compound 8)
5-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-the 1-aminopropyl]-5-oxo-penta-1-acid, (chemical compound 9)
Methyl-5-[N-{3-(2-methoxyphenyl) piperazine-1-yl }-the 1-aminopropyl]-5-oxo-valerate hydrochlorate, (chemical compound 10)
1-carboxyl methyl cyclohexane-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-propyl group] carboxamide hydrochloride (chemical compound 11)
5-[N-{3-(2-methoxyphenyl) piperazine-1-yl }]-2-hydroxypropyl amino-5-oxo-penta-1-acid, (chemical compound 12)
The compounds of this invention pharmaceutically acceptable, nontoxic, acid-addition salts can be formed by mineral acid or organic acid with the method that this field is known, it have formula I free alkali effect and can replace above-mentioned free alkali to use.The typical example that is used to form the suitable acid of this acid-addition salts has malic acid, Fumaric acid, benzoic acid, ascorbic acid, 4,4 '-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-naphthoic acid), succinic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid, phenyl-sulfamic acid, phosphoric acid, bromic acid, sulphuric acid, cyclohexylsulfamic acid, hydrochloric acid and nitric acid.
The present invention also comprises the prodrug of the chemical compound of formula I.Usually, this prodrug is functional group's derivant of these chemical compounds, and it can change into described chemical compound in vivo easily.The conventional method of selecting and preparing suitable prodrug is known.
The present invention also comprises enantiomer, diastereomer, N-oxide, polymorph, pharmaceutically acceptable salt and the pharmaceutically acceptable solvate of these chemical compounds, and has homovital metabolite.The present invention also comprises and contains pharmaceutical composition, it contains the molecule shown in the formula I or its prodrug, metabolite, enantiomer, diastereomer, N-oxide, polymorph, solvate or pharmaceutically acceptable salt and pharmaceutically acceptable carrier, and the optional excipient that contains.
On the other hand, the present invention relates to selectivity retardance α 1AThe method of receptor, this method are that the chemical compound of the present invention with effective dose is transported in the described receptor environment, for example are transported in the outer medium of born of the same parents the mammal of described receptor (or contain).
Detailed Description Of The Invention
For realizing above-mentioned target, and, provide the method for the chemical compound of synthesis type I, shown in flow process 1 here according to the purpose of the present invention of mentioning and describing roughly
Flow process I
Formula I
Wherein, X is selected from
Figure A0282909700152
With
Figure A0282909700153
Wherein, junction point shows with the key table that turns back, and one of them junction point is bonded to the carbonyl of contiguous nitrogen, and second junction point is bonded to other carbonyl;
W is O, S, SO or SO 2
A is-(CH 2) m-,
Wherein, m is one of integer 2,3 or 4;
R 11Independently be selected from H, F, Cl, Br, I, OH, the rudimentary (C of straight or branched 1-6) alkyl, rudimentary (C 1-6) alkoxyl and rudimentary (C 1-6) perhaloalkyl radical and rudimentary (C 1-6) the perhalogeno alkoxyl;
Y is selected from
R 1And R 2Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I, OR 3, COR 3, OCOR 3, COOR 3, NH 2, N (R 4, R 5), rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, rudimentary (C 1-4) alkylthio group, rudimentary (C 1-4) perhaloalkyl radical, rudimentary (C 1-4) the perhalogeno alkoxyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkoxyl, being selected from the group of the optional replacement of aryl, aryloxy group, aralkyl, heterocyclic radical or heteroaryl, described substituent group is H, F, Cl, Br, I, OH, OR 3, rudimentary (C 1-4) alkyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkyl, wherein, R 3Be selected from H, straight or branched C 1-C 6Alkyl and perhaloalkyl radical; R 4And R 5Independently be selected from H, CHO replaces or unsubstituted rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, COR 3, COOR 3, CH 2CH (OR 3) 2, CH 2COOR 3, CH 2CHO and (CH 2) 2OR 3, wherein, R 3Identical with top definition; R 6, R 7, R 8, R 9And R 10Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I is by the optional rudimentary (C of straight or branched that replaces of one or more halogens 1-4) alkyl, by the optional rudimentary (C that replaces of one or more halogens 1-4) alkoxyl, (C 3-6) cycloalkyloxy, NH 2, the rudimentary (C of N- 1-4) alkyl amino, N, N-two-rudimentary (C 1-C 4) alkyl amino, N-low alkyl group (C 1-C 4) amino carbonyl, by aromatics or non-aromatics five or hexa-atomic cyclosubstituted hydroxyl, phenyl is by Cl, F, Br, I, NO 2, NH 2, (C 1-4) alkyl or (C 1-4) alkoxyl, (C 1-4) perhaloalkyl radical, (C 1-4) phenyl that replaces of perhalogeno alkoxyl, wherein, dotted line (---) is singly-bound or does not have key.
But the initial substance appropriate reconstruction of flow process I is so that produce the specific compound of more formula I.
Flow process I
Flow process I has shown chemical compound synthetic of formula I, wherein, and X, Y, A, R 6, R 7, R 8, R 9And R 10As top definition.Preparation process comprises the α that makes formula II, and ω-dicarboximide and suitable highly basic react a period of time under the temperature between 20-100 ℃, and this time can change between a few hours one, to obtain the chemical compound of corresponding formula I.Suitable alkali is selected from sodium hydroxide and potassium hydroxide.More specifically, the hydrolysis of the chemical compound of formula II is carried out in aqueous slkali, and this aqueous slkali makes in being selected from water, methanol and alcoholic acid polar solvent.The preferred temperature conditions of reaction is 90-100 ℃.The initial compounds of formula II can be used on the method manufacturing that discloses among our the international application no RLL-236WO, and this application and the application submit to simultaneously.
Explained the present invention among the embodiment that provides below in detail, these embodiment only are for example, therefore can not be as limitation of the scope of the invention.
Embodiment
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-ethoxyl phenenyl) piperazine-1-yl } propyl group] preparation of carboxylic acid amides (chemical compound 1).
With 2-[3-{4-(2-ethoxyl phenenyl) piperazine-1-yl } propyl group-3a, 4,7,7a-tetrahydrochysene-1H-iso-indoles-1,3 (2H)-dione hydrochloride (0.5g, 1.15mmol) be dissolved in sodium hydrate aqueous solution (11.5ml, 0.2N) and about 2 hours of reflux.After reaction finishes, the pH of reactant is transferred to about 7 and with chloroform extraction (2 * 15ml) with glacial acetic acid.With the solvent concentrating under reduced pressure and from chloroform and diethyl ether the crystallization crude product to obtain 0.13g title compound (25%), m.pt.128-131 ℃
MS?m/z?430.5(MH +)
IR(KBR?cm -1)：1645.8(C＝O)
1H?NMR(300MHZ，TFA)δ：1.72-1.74(3H，d)，2.59(2H，br?s)，2.80(3H，br?s)，2.93-2.99(1H，d)，3.53(1H，BR?S)，3.69(1H，BR?S)，3.86-3.98(m，4H)，4.47-4.50(6H，m)，4.75-4.79(2H，m)，5.11-5.19(1H，m)，6.00-6.13(2H，BRD)，7.39-7.49(2H，m)，7.82-7.88(2H，m)
Following chemical compound prepares with similar method:
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl } propyl group] carboxylic acid amides; M.p.186-188 ℃., (chemical compound 2)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-methoxyphenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides; M.p.140-143 ℃, (chemical compound 3)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-hydroxyphenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides; M.p.124-127 ℃, (chemical compound 4)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides; M.p.159-162 ℃, (chemical compound 5)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-ethoxyl phenenyl) piperazine-IYL}-2-hydroxyphenyl] carboxylic acid amides; M.p.118-121 ℃, (chemical compound 6)
5-[N-3-(2-hydroxyphenyl) piperazine-1-yl]]-1-aminopropyl-5-oxo-penta-1-acid; M.p.200-202 ℃, (chemical compound 7)
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-hydroxyphenyl) piperazine-1-yl } propyl group] carboxylic acid amides; M.p.165-170 ℃, (chemical compound 8)
5-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-the 1-aminopropyl]-5-oxo-penta-1-acid; M.p.121-125 ℃, (chemical compound 9)
Methyl-5-[N-{3-(2-methoxyphenyl) piperazine-1-yl }-the 1-aminopropyl]-5-oxo-valerate hydrochlorate; M.p.191-194 ℃, (chemical compound 10)
1-carboxyl methyl cyclohexane-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-propyl group] carboxamide hydrochloride, (chemical compound 11)
5-[N-{3-(2-methoxyphenyl) piperazine-1-yl }]-2-hydroxypropyl amino-5-oxo-penta-1-acid; M.p.140-144 ℃, (chemical compound 12)
Pharmacology's measurement result
Receptors bind is measured
Receptors bind is measured and is carried out with natural alpha-adrenergic receptor.Different chemical compounds are to α 1AAnd α 1BThey replace the specific bonded merit rating of [3H] prazosin (Michel etc., Br J Pharmacol. from the film of rat lower jaw and liver respectively to the affinity of adrenoreceptor hypotype by research; 1989; 98:883).In conjunction with method (Eur J Pharmacol., 1978 measured according to U ' Prichard etc.; 50:87) and carry out little modification.
After butchering, separate submaxillary gland immediately.Liver pours into buffer (Tris HCl 50mM, NaCl 100MM, 10mM EDTA pH 7.4).Tissue is made homogenate with 10 volume buffer (Tris HCl 50mM, NaCl 100MM, 10mMEDTA pH 7.4).With homogenate by two-layer wet filter paper filtering and with filtrate centrifugal 10 minutes at 500g.Supernatant is subsequently with 40, centrifugal 45 minutes of 000g.The gained filter cake is resuspended in the mensuration buffer (TrisHCl 50mM, 5mM EDTA pH 7.4) of equal volume and is stored in-70 ℃ up to mensuration.
Film homogenate (150-250 μ g protein) is measured in the buffer (pH 7.4 for Tris HCl 50.mM, EDTA 5mM) at 250 μ l and was cultivated 1 hour in 24-25 ℃.When having the 300nM prazosin, measure non-specific binding.Stop cultivating by GF/B fibrous filters vacuum filtration.Filter is used ice-cold 50mM Tris HCl buffer (pH7.4) washing then.Count with the filtrate drying and to the binding radioactivity of staying on the filter.Adopt G Pad Prism software, estimate by the nonlinear fitting program IC50And Kd.Use Cheng ﹠amp; The formula of Prusoff (Cheng ﹠amp; Prusoff, Biochem Pharmacol, 1973,22:3099), Ki=IC 50/ (1+L/Kd), calculate the value that suppresses constant K i in conjunction with research by competitive, wherein L be used for particular experiment [ 3H] concentration (Table I) of prazosin.
External functional study
For studying the selection of these chemical compounds, studied these chemical compound antagonism aortas (α to different alpha-adrenergic receptor hypotypes 1D), prostate (α 1A) and spleen (α 1B) ability.(1.5g/kg) male wister rat of the personal urethane anesthesia of aorta, prostate and spleen separate tissue.In the organ bath that contains the KrebsHenseleit buffer, this buffer contains following component (mM): NaCl 118 with isolating fixation of tissue; KCl 4.7; CaCl 22.5; MgSO 47H 2O 1.2; NaHCO 325; KH 2PO 41.2; Glucose 11.5.Buffer is maintained 37 ℃ and feed 95%O 2And 5%CO 2Mixture.Tissue is applied 2g (aorta) or 1g (spleen and prostate) static pressure.Firmly on displacement transducer monitoring contractile response and the recorder chart recorder chart.Allow structural equation 2 hours.At the balance period terminal point, do not had and when containing test compound (concentration is 0.1,1 and 10 μ M) to the contractile response curve of norepinephrine (aorta) and phyenlephrinium (spleen and prostate).Calculate the antagonist affinity and be expressed as pK in the Table II BValue.
Urine selectivity research in the body
For urine selectivity in disintegrating, with the method for Brune etc. (Pharmacol., 1996,53:356) studied in conscious beagle these chemical compounds to the effect of average artery pressure (MAP) and intraurethral pressure (IUP).In brief, (St.Paul MN.USA) implants the femoral artery of dog with long-term continuous measurement arteriotony for TL11 M2-D70-PCT, Data Sci.International with telemetering pickup before two weeks of research beginning.At recovery stage, make animal adapt to suspension strap (sling restraint).In test that day, the animal at one night of fasting is placed suspension strap.Swan-Ganz. pommel catheter (Balloon tipped catheter) is placed the urethra of prostate level and make ball expansion (Brune etc., 1996).Behind the record baseline reading, write down of the effect of 16 μ g/kg phyenlephriniums (i.v.) to MAP and IUP.Orally administered carrier or the experiment medicine after in of the reaction of 0.5,1,2,3,4,6,9 and 24 hour record phenyl epinephrines to MAP and IUP.With Dataquest software (DataSci.International.St.Paul, MN.USA) variation of online record MAP.Test phyenlephrinium behind the medicine to the variation of MAP and IUP reaction percentage change calculations with control value.Area also calculates the urine selectivity with the ratio of MAP and IUP value under the calculated curve.
Table 1: radioligand is in conjunction with research:
Chemical compound is to the affinity of α-1 adrenoceptor hypotype
????S?No Compound number ????α 1A(rat lower jaw) ????α 1B(rat liver) ????α 1B/α 1A
????1 ????1 ????20 ????＞1000 ????＞50
????2 ????2 ????19 ????＞1000 ????＞53
????3 ????3 ????＞1000 ????＞1000
????4 ????4 ????1892 ????9743 ????5
????5 ????5 ????21 ????1759 ????84
????6 ????6 ????398 ????1239 ????3
????7 ????7 ????12640 ????12970 ????1
????8 ????8 ????593 ????5082 ????9
????9 ????9 ????777 ????2097 ????3
????10 ????10 ????139 ????＞1000 ????＞7
????11 ????11 ????3.15 ????99 ????31
????12 ????12 ????＞1000 ????＞1000 ????1
Table II: external functional examination
????S.No. Compound number Alpha-adrenoceptor subtype (pK B) Selectivity
????α 1A ????α 1B ????α 1D ????α 1B/α 1A ????α 1D/α 1A
????1 ??1 ????8.22 ????8.16 ????7.24 ????1.15 ????9.5
Although described the present invention by particular, modification and equivalent variations are obvious for the technical staff who is proficient in this field, and they are included within the scope of the invention.

Claims (10)

1. chemical compound with structure shown in the formula I
Formula I
And pharmaceutically acceptable salt, enantiomer, diastereomer, N-oxide, prodrug, metabolite, polymorph or pharmaceutically acceptable solvate, wherein, X is selected from
With
Wherein, junction point shows with the key table that turns back, and one of them junction point is bonded to the carbonyl of contiguous nitrogen, and second junction point is bonded to other carbonyl;
W is O, S, SO or SO 2
A is-(CH 2) m-,
Figure A028290970002C4
Wherein, m is one of integer 2,3 or 4;
R 11Independently be selected from H, F, Cl, Br, I, OH, the rudimentary (C of straight or branched 1-6) alkyl, rudimentary (C 1-6) alkoxyl and rudimentary (C 1-6) perhaloalkyl radical;
Y is selected from
Figure A028290970002C5
R 1And R 2Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I, OR 3, COR 3, OCOR 3, COOR 3, NH 2, N (R 4, R 5), rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, rudimentary (C 1-4) alkylthio group, rudimentary (C 1-4) perhaloalkyl radical, rudimentary (C 1-4) the perhalogeno alkoxyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkoxyl, being selected from the group of the optional replacement of aryl, aryloxy group, aralkyl, heterocyclic radical or heteroaryl, described substituent group is H, F, Cl, Br, I, OH, OR 3, rudimentary (C 1-4) alkyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkyl, wherein, R 3Be selected from H, straight or branched C 1-C 6Alkyl and perhaloalkyl radical; R 4And R 5Independently be selected from H, CHO replaces or unsubstituted rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, COR 3, COOR 3, CH 2CH (OR 3) 2, CH 2COOR 3, CH 2CHO and (CH 2) 2OR 3, wherein, R 3Identical with top definition; R 6, R 7, R 8, R 9And R 10Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I is by the optional rudimentary (C of straight or branched that replaces of one or more halogens 1-4) alkyl, by the optional rudimentary (C that replaces of one or more halogens 1-4) alkoxyl, (C 3-6) cycloalkyloxy, NH 2, the rudimentary (C of N- 1-4) alkyl amino, N, N-two-rudimentary (C 1-C 4) alkyl amino, N-low alkyl group (C 1-C 4) amino carbonyl, by aromatics or non-aromatics five or hexa-atomic cyclosubstituted hydroxyl, phenyl is by Cl, F, Br, I, NO 2, NH 2, (C 1-4) alkyl or (C 1-4) alkoxyl, (C 1-4) perhaloalkyl radical, (C 1-4) phenyl that replaces of perhalogeno alkoxyl, wherein, dotted line (... .) is singly-bound or does not have key.
2. chemical compound, described chemical compound is selected from
1-carboxyl-hexamethylene-4-alkene-2-[N-{3-(2-ethoxyl phenenyl) piperazine-1-yl } propyl group] carboxylic acid amides;
1-carboxyl-hexamethylene-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl } propyl group] carboxylic acid amides;
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-methoxyphenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides;
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-hydroxyphenyl) piperazine-1-yl }-the 2-hydroxypropyl] carboxylic acid amides;
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-the 2-hydroxypropyl] Carboxylamide;
1-carboxyl hexamethylene-4-alkene-2-[N-{3-(2-ethoxyl phenenyl) piperazine-1-yl }-the 2-hydroxyphenyl] Carboxylamide;
5-[N-{3-(2-hydroxyphenyl) piperazine-1-yl }]-1-aminopropyl-5-oxo-penta-1-acid;
1-carboxyl-hexamethylene-4-alkene-2-[N-{3-(2-hydroxyphenyl) piperazine-1-yl } propyl group] carboxylic acid amides;
5-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-the 1-aminopropyl]-5-oxo-penta-1-acid;
Methyl-5-[N-{3-(2-methoxyphenyl) piperazine-1-yl }-the 1-aminopropyl]-5-oxo-valerate hydrochlorate;
1-carboxyl methyl cyclohexane-4-alkene-2-[N-{3-(2-isopropyl phenyl) piperazine-1-yl }-propyl group] carboxamide hydrochloride;
5-[N-{3-(2-methoxyphenyl) piperazine-1-base L}-2-hydroxypropyl amino-5-oxo-penta-1-acid.
3. selectivity antagonism α in mammal 1The method of-adrenoreceptor, described method comprise the chemical compound with structure shown in the formula I that gives described mammal treatment effective dose:
Formula I
And pharmaceutically acceptable salt, enantiomer, diastereomer, N-oxide, prodrug, metabolite, polymorph or pharmaceutically acceptable solvate, wherein, X is selected from
With
Figure A028290970004C3
Wherein, junction point shows with the key table that turns back, and one of them junction point is bonded to the carbonyl of contiguous nitrogen, and second junction point is bonded to other carbonyl;
W is O, S, SO or SO 2
A is-(CH 2) m-,
Wherein, m is one of integer 2,3 or 4;
R 11Independently be selected from H, F, Cl, Br, I, OH, the rudimentary (C of straight or branched 1-6) alkyl, rudimentary (C 1-6) alkoxyl and rudimentary (C 1-6) perhaloalkyl radical;
Y is selected from
R 1And R 2Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I, OR 3, COR 3, OCOR 3, COOR 3, NH 2, N (R 4, R 5), rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, rudimentary (C 1-4) alkylthio group, rudimentary (C 1-4) perhaloalkyl radical, rudimentary (C 1-4) the perhalogeno alkoxyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkoxyl, being selected from the group of the optional replacement of aryl, aryloxy group, aralkyl, heterocyclic radical or heteroaryl, described substituent group is H, F, Cl, Br, I, OH, OR 3, rudimentary (C 1-4) alkyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkyl, wherein, R 3Be selected from H, straight or branched C 1-C 6Alkyl and perhaloalkyl radical; R 4And R 5Independently be selected from H, CHO replaces or unsubstituted rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, COR 3, COOR 3, CH 2CH (OR 3) 2, CH 2COOR 3, CH 2CHO and (CH 2) 2OR 3, wherein, R 3Identical with top definition; R 6, R 7, R 8, R 9And R 10Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I is by the optional rudimentary (C of straight or branched that replaces of one or more halogens 1-4) alkyl, by the optional rudimentary (C that replaces of one or more halogens 1-4) alkoxyl, (C 3-6) cycloalkyloxy, NH 2, the rudimentary (C of N- 1-4) alkyl amino, N, N-two-rudimentary (C 1-C 4) alkyl amino, N-low alkyl group (C 1-C 4) amino carbonyl, by aromatics or non-aromatics five or hexa-atomic cyclosubstituted hydroxyl, phenyl is by Cl, F, Br, I, NO 2, NH 2, (C 1-4) alkyl or (C 1-4) alkoxyl, (C 1-4) perhaloalkyl radical, (C 1-4) phenyl that replaces of perhalogeno alkoxyl, wherein, dotted line (... .) is singly-bound or does not have key.
4. the method for a treatment benign prostatic hyperplasia in mammal, described method comprises the chemical compound with structure shown in the formula I that gives described mammal treatment effective dose:
Formula I
And pharmaceutically acceptable salt, enantiomer, diastereomer, N-oxide, prodrug, metabolite, polymorph or pharmaceutically acceptable solvate, wherein, X is selected from
With
Wherein, junction point shows with the key table that turns back, and one of them junction point is bonded to the carbonyl of contiguous nitrogen, and second junction point is bonded to other carbonyl;
W is O, S, SO or SO 2
A is-(CH 2) m-,
Wherein, m is one of integer 2,3 or 4;
R 11Independently be selected from H, F, Cl, Br, I, OH, the rudimentary (C of straight or branched 1-6) alkyl, rudimentary (C 1-6) alkoxyl and rudimentary (C 1-6) perhaloalkyl radical;
Y is selected from
Figure A028290970006C1
R 1And R 2Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I, OR 3, COR 3, OCOR 3, COOR 3, NH 2, N (R 4, R 5), rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, rudimentary (C 1-4) alkylthio group, rudimentary (C 1-4) perhaloalkyl radical, rudimentary (C 1-4) the perhalogeno alkoxyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkoxyl, being selected from the group of the optional replacement of aryl, aryloxy group, aralkyl, heterocyclic radical or heteroaryl, described substituent group is H, F, Cl, Br, I, OH, OR 3, rudimentary (C 1-4) alkyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkyl, wherein, R 3Be selected from H, straight or branched C 1-C 6Alkyl and perhaloalkyl radical; R 4And R 5Independently be selected from H, CHO replaces or unsubstituted rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, COR 3, COOR 3, CH 2CH (OR 3) 2, CH 2COOR 3, CH 2CHO and (CH 2) 2OR 3, wherein, R 3Identical with top definition; R 6, R 7, R 8, R 9And R 10Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I is by the optional rudimentary (C of straight or branched that replaces of one or more halogens 1-4) alkyl, by the optional rudimentary (C that replaces of one or more halogens 1-4) alkoxyl, (C 3-6) cycloalkyloxy, NH 2, the rudimentary (C of N- 1-4) alkyl amino, N, N-two-rudimentary (C 1-C 4) alkyl amino, N-low alkyl group (C 1-C 4) amino carbonyl, by aromatics or non-aromatics five or hexa-atomic cyclosubstituted hydroxyl, phenyl is by Cl, F, Br, I, NO 2, NH 2, (C 1-4) alkyl or (C 1-4) alkoxyl, (C 1-4) perhaloalkyl radical, (C 1-4) phenyl that replaces of perhalogeno alkoxyl, wherein, dotted line (... .) is singly-bound or does not have key.
5. pharmaceutical composition, described pharmaceutical composition contain the treatment effective dose as claim 1 or 2 defined chemical compounds and pharmaceutically acceptable carrier.
6. selectivity antagonism α in mammal 1The method of-adrenoreceptor, described method comprise the step as pharmaceutical composition as described in the claim 5 that gives described mammal treatment effective dose.
7. the method for a treatment benign prostatic hyperplasia in mammal, described method comprise the step as pharmaceutical composition as described in the claim 5 that gives described mammal treatment effective dose.
8. method, described method is used for the chemical compound of preparation formula I
Formula I
Or its pharmaceutically acceptable salt, enantiomer, diastereomer, N-oxide, prodrug, metabolite, polymorph or pharmaceutically acceptable solvate, wherein, X is selected from
With
Figure A028290970007C2
Wherein, junction point shows with the key table that turns back, and one of them junction point is bonded to the carbonyl of contiguous nitrogen, and second junction point is bonded to other carbonyl;
W is O, S, SO or SO 2
A is-(CH 2) m-,
Figure A028290970007C3
Wherein, m is one of integer 2,3 or 4;
R 11Independently be selected from H, F, Cl, Br, I, OH, the rudimentary (C of straight or branched 1-6) alkyl, rudimentary (C 1-6) alkoxyl and rudimentary (C 1-6) perhaloalkyl radical;
Y is selected from
Figure A028290970007C4
R 1And R 2Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I, OR 3, COR 3, OCOR 3, COOR 3, NH 2, N (R 4, R 5), rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, rudimentary (C 1-4) alkylthio group, rudimentary (C 1-4) perhaloalkyl radical, rudimentary (C 1-4) the perhalogeno alkoxyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkoxyl, being selected from the group of the optional replacement of aryl, aryloxy group, aralkyl, heterocyclic radical or heteroaryl, described substituent group is H, F, Cl, Br, I, OH, OR 3, rudimentary (C 1-4) alkyl, by F, Cl, Br, I, OH or OR 3Rudimentary (the C of one or more replacement 1-4) alkyl, wherein, R 3Be selected from H, straight or branched C 1-C 6Alkyl and perhaloalkyl radical; R 4And R 5Independently be selected from H, CHO replaces or unsubstituted rudimentary (C 1-4) alkyl, rudimentary (C 1-4) alkoxyl, COR 3, COOR 3, CH 2CH (OR 3) 2, CH 2COOR 3, CH 2CHO and (CH 2) 2OR 3, wherein, R 3Identical with top definition; R 6, R 7, R 8, R 9And R 10Independently be selected from H, OH, CN, NO 2, Cl, F, Br, I is by the optional rudimentary (C of straight or branched that replaces of one or more halogens 1-4) alkyl, by the optional rudimentary (C that replaces of one or more halogens 1-4) alkoxyl, (C 3-6) cycloalkyloxy, NH 2, the rudimentary (C of N- 1-4) alkyl amino, N, N-two-rudimentary (C 1-C 4) alkyl amino, N-low alkyl group (C 1-C 4) amino carbonyl, by aromatics or non-aromatics five or hexa-atomic cyclosubstituted hydroxyl, phenyl is by Cl, F, Br, I, NO 2, NH 2, (C 1-4) alkyl or (C 1-4) alkoxyl, (C 1-4) perhaloalkyl radical, (C 1-4) phenyl that replaces of perhalogeno alkoxyl, wherein, dotted line (... .) is singly-bound or does not have key; Described method is included in the chemical compound that makes formula II in the suitable solvent and suitable alkali reaction obtaining the chemical compound of formula I, and is as described below:
Figure A028290970008C1
All symbols as above define.
9. method as claimed in claim 8, wherein, described alkali is selected from potassium hydroxide and sodium hydroxide.
10. method as claimed in claim 8, wherein, described suitable solvent is selected from water, methanol and ethanol.
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