CN1265107A - Indole and 2,3-dihydronindole derivatives, their prepn. and use - Google Patents
Indole and 2,3-dihydronindole derivatives, their prepn. and use Download PDFInfo
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- CN1265107A CN1265107A CN 98807554 CN98807554A CN1265107A CN 1265107 A CN1265107 A CN 1265107A CN 98807554 CN98807554 CN 98807554 CN 98807554 A CN98807554 A CN 98807554A CN 1265107 A CN1265107 A CN 1265107A
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Abstract
The present invention relates to indole and 2,3-dihydroindole derivatives having formula (I) any of its enantiometers or any mixture thereof, or an acid addition salt thereof, wherein A, R<1>, R<2>, R<3>, W, X, Y and Z are as described in the description. The compounds are potent serotonin reuptake inhibitors and have 5-HT1A receptor antagonistic activity.
Description
The present invention relates to new indoles and 2,3-indolin derivatives, this compound be effective serotonin reuptake inhibitor, contain the pharmaceutical composition of these compounds and their treatment to serotonin reuptake transporter restraining effect or 5-HT
1AThe functional disorder of receptor antagonism sensitivity or the purposes of disease.The compounds of this invention is also to 5-HT
1AAcceptor has antagonistic activity, and is considered to be specially adapted to the treatment of dysthymia disorders.
Background technology
Compare with first-generation antidepressant drug (tricyclic compound and nonselective MAO inhibitor), selective serotonin (or 5-TH) reuptake inhibitor (SSRI) is showing bigger progress in treatment aspect the dysthymia disorders as fluoxetine, paroxetine, Sertraline, fluvoxamine and citalopram because the side effect that they have still less and severe degree less.The side effect that first-generation antidepressant drug causes is so serious, makes some patients withdraw from treatment.
Used SSRI and all other antidepressant drugs all have a serious defective, promptly must could produce result of treatment through the treatment of several weeks.The hysteresis of drug effect starting is a serious problem, especially to treatment intensive patients with depression and the patient that introgression is arranged.In addition, there is 1/3rd patient insensitive to SSRI.
The electrophysiology experiment of mouse shows, the acute administration of SSRI can reduce the neuronic excitement of 5-HT of dorsal suture core in the rodent brain, can make the neuronic agonist activity normalizing of 5-HT (Arborelius with the SSRI continued treatment, L. wait the people, Naunyn-Schmiedeberg ' s Arch.Pharmacol.1995,352,157; Gartside, people such as S.E., Br.J.Pharmacol.1995,115,1064; Chaput, people such as Y., Naunyn-Schmiedeberg ' s Arch.Pharmacol.1986,33,342).Show (somatodendritic) 5-HT that the recovery of 5-HT neurone agonist activity and body are tree-shaped in addition
1AThe mistake of autoreceptor quick relevant (Le Poul, people such as E., Naunyn-Schmiedeberg ' s Arch.Pharmacol.1995,352,141; Invernizzi, people such as R., Eur.J.Pharmacol.1994,260,243).
Therefore there is the people to propose, SSRI and a kind ofly can cause 5-HT
1AQuick or the medicament administration simultaneously that suppresses of the rapid mistake of acceptor under Feedback mechanism running, quick startup (Artigas, people such as F., Trends Neurosci.1996,19,387 that will cause antidepressant effect; De Vry, J.DrugNews Perspec.1996,9,270).
A kind of compound and 5-HT that suppresses serotonin reuptake transporter
1AThe effect of receptor antagonist Combined Preparation has carried out estimating (Innis, people such as R.B., Eur.J.Pharmacol.1987,143, p195-204 and Gartside, S.E., Br.J.Pharmacol.1995,115, p1064-1070 in some researchs; Blier, people such as P., Trends Pharmacol.Sci.1994,15,220), in these researchs, find 5-HT
1AReceptor antagonist can stop the reduction by the caused agonist activity of acute administration of serotonin reuptake inhibitor.
In addition, unite use pindolol (a kind of well-known 5-HT
1AAcceptor and beta-adrenoceptor antagonists) and the treatment of SSRI in clinical trial, obtained evaluation, it is reported that patient's mental state obtains significant the improvement within a week.In addition, to the insensitive patient of used anti depressant medication, pindolol and SSRI Combined Preparation also demonstrate good effect (people such as Artigas F., Arch.Gen.Psychiary, 1994,51, p248-251 and Blier, people such as P., J.Clin.Phychopharmacol.1995,15, p217-222).
In several patents of having applied for, comprised uniting and used 5-HT
1AAntagonist and serotonin reuptake inhibitor are treated dysthymia disorders (seeing EP-A2-687472 and EP-A2-714663).
In EP-A1-529462, disclose some have below general formula 1,4-benzodioxan derivative:
Wherein, B is the optional indol-3-yl that replaces, and Q is C
nH
2n, wherein n is 1,2,3,4,5 or 6.It is said that these compounds have serotonin agonist activity and serotonin antagonistic action and serotonin reuptake transporter and suppress active, can be used as anxiolytic, thymoleptic, antihypertensive drug and cerebral protective agent.
In patent US 5200948, people such as Perregaard disclose 2 of relevant indoles with following formula, indazole, 2-indolone and they, the 3-dihydro derivative:
Wherein X be-CH-,-CH
2-,-NH-or-CO-; Ar is
Wherein Y is O or S, Z be O, S or-CH-, and n is 1,2 or 3.These compounds are valuable 5-HT
1AReceptors ligand.Goal of the invention
The purpose of this invention is to provide and have effective serotonin reuptake transporter and suppress active and 5-HT
1AAcceptor has the compound of antagonism performance, and this compound can be used as the medicine of fast-acting, and treatment emotionality mental disorder is as dysthymia disorders.
Another object of the present invention provides a kind of pharmaceutical composition that contains above-claimed cpd as activeconstituents.
Brief summary of the invention
The present invention makes up independently of one another or mutually particularly including following content.
Indoles or 2 with following formula, 3-indolin derivatives, its enantiomer or its mixture or their acid salt,
Wherein:
X is-O-,-S-or-CR
4R
5-; With
Y is-CR
6R
7-,-CR
6R
7-CR
8R
9-or-CR
6=CR
7-; Perhaps
X and Y form group-CR together
4=CR
5-or-CR
4=CR
5-CR
6R
7
Z is-O-or-S-;
W is N, C or CH;
A is the group that is selected from formula (II), (III) and (IV) represents
Dotted line wherein is meant an optional key; R
1, R
2, R
3, R
12, R
13, R
14, R
15, R
16And R
17Wherein aryl can be by halogen, trifluoromethyl to be selected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxyl group, hydroxyl, formyl radical, acyl group, amino, alkylamino, dialkyl amido, amido, alkoxycarbonyl amido, amino carbonyl amino, alkyl amino-carbonyl amino, dialkyl amino carbonyl amino, nitro and cyano group and aryl or aralkyl independently of one another, alkoxyl group, hydroxyl, amino, alkylamino, nitro and cyano group replace; R
4, R
5, R
6, R
7, R
8And R
9Be selected from hydrogen and alkyl independently of one another; And R
11Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, acyl group and formyl radical.
In one embodiment of the invention, Z is-O-that other substituting group as defined above.
In another embodiment of the invention, Z is-S-that other substituting group as defined above.
In the 3rd embodiment of the present invention, A is formula (II) group, and other substituting group as defined above.
In the 4th embodiment of the present invention, A is formula (III) group, and other substituting group as defined above.
In the 5th embodiment of the present invention, A is formula (IV) group, and other substituting group as defined above.
In a specific embodiments of the present invention, A is that formula (II) group and Z are-O-, and A is that formula (III) group and Z are-O-, and A is that formula (IV) group and Z are-O-; A is that formula (II) group and Z are-S-, and A is that formula (III) group and Z are-S-, and A is that formula (IV) group and Z are-S-;
In the further embodiment of the present invention, R
4, R
5, R
6, R
7, R
8And R
9Be selected from hydrogen or methyl.
Examples of compounds according to the present invention is 3-[2-[4-(1, a 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-bromo-1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 2-Methyl-1H-indole; 6-chloro-3-[2-[4-(2,2,5-trimethylammonium-2; 3-Dihydrobenzofuranes-7-yl) piperidines-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-4-chloro-1H-indoles; 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperidines-1-yl] ethyl]-the 1H-indoles; 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl)-1; 2,3,6-tetrahydrochysene-1-pyridyl] ethyl]-the 1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-methoxyl group-1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 5-Methyl-1H-indole; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 6-Methyl-1H-indole, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(5-chloro-2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 6-chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 6-chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-chromene-8-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 4-Methyl-1H-indole, 3-[2-[4-(7-chloro-1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 2-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-2,3-indoline, 6-chloro-3-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl)-1; 2,3,6-tetrahydrochysene-1-pyridyl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-6-chloro-1H-indoles, 3-[2-[4-(1; 4-Ben Bing dioxin (Benzodioxin)-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 3-[2-[4-(cumarone-7-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 3-[2-[4-(1; 3-Ben Bing dioxolane (Benzodioxolan)-4-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 6-chloro-3-[2-[4-(6-chloro-1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 5-chloro-3-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(thionaphthene-7-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-5-bromo-1H-indoles, 3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl)-1; 2,3,6-tetrahydrochysene-1-pyridyl-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(1; 4-benzodioxan-5-yl)-1,2,3; 6-tetrahydrochysene-1-pyridyl-1-yl] ethyl]-5-fluoro-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-6-chloro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-5-fluoro-1H-indoles, 6-chloro-3-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(cumarone-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(cumarone-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-5-bromo-1H-indoles; 3-[2-[4-(cumarone-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-5-fluoro-1H-indoles; 3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-5-bromo-1H-indoles, 1-ethanoyl-3-[2-[4-(1; 4-benzodioxan-4-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles, 1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles; 1-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 1-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-5-fluoro-1H-indoles; 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-2,3-dihydro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-butyl-1H-indoles; 1-allyl group-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-propargyl-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-1-Methyl-1H-indole; 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-benzyl-2,3-dihydro-1H-indoles, 1-allyl group-3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles, 1-ethanoyl-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(phendioxin; 4-dithiane-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(phendioxin, 4-dithiane-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(phendioxin; 4-dithiane-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(phendioxin-thia-4-oxa--cyclohexane (oxan)-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(phendioxin-thia-4-oxa--hexanaphthene (oxan)-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(phendioxin-thia-4-oxa--hexanaphthene (oxan)-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, or their acid salt.
The invention still further relates to a kind of pharmaceutical composition, comprise formula (I) compound or its pharmaceutically-acceptable acid addition, and at least a pharmaceutically acceptable carrier or thinner.
In further embodiment, the present invention relates to the purposes that formula (I) compound or its pharmaceutically-acceptable acid addition are used to prepare medicine, described medicine is suitable for treatment to serotonin reuptake transporter restraining effect or 5-HT
1AThe functional disorder of receptor antagonism sensitivity or disease.
The present invention be more particularly directed to The compounds of this invention or its use of a compound or its pharmaceutically-acceptable acid addition and be used to prepare the purposes of medicine, described medicine is suitable for treating the emotionality mental disease, as depression, psychosis, anxiety disorder comprises general anxiety disease, Phobias and mandatory symptom.
In another embodiment, the present invention relates to the functional disorder or the methods for the treatment of diseases of a kind of people's of comprising living animal, described disease is to serotonin reuptake transporter restraining effect or 5-HT
1AReceptor antagonism sensitivity, this method comprise, the described people's of comprising living animal are imposed formula (I) compound or its pharmaceutically-acceptable acid addition of treatment significant quantity.
The present invention be more particularly directed to a kind of emotionality mental disease, as dysthymia disorders, psychosis, anxiety disorder comprises the methods of treatment of general anxiety disease, Phobias and mandatory symptom, this method comprises, the living animal that comprises the people of needs treatment is imposed formula (I) compound or its pharmaceutically-acceptable acid addition of treatment significant quantity.
Because they have made up 5-HT
1AThe antagonistic action of acceptor and the restraining effect of serotonin reuptake transporter, The compounds of this invention is considered to be specially adapted to the medicine that the fast-acting of dysthymia disorders is treated in conduct, and this compound also can be owing to treating the insensitive patients with depression of used anti depressant medication.
Claimed compound is specially adapted to treat the dysthymia disorders that needs the antidepressant drug fast-acting, perhaps other antidepressant drug is had the dysthymia disorders of tolerance.
Halogen is meant fluorine, chlorine, bromine or iodine.
Alkyl is meant the straight or branched alkyl of 1-4 carbon atom, comprise as, methyl, ethyl, propyl group, sec.-propyl and butyl.
Alkenyl is meant that 2-4 carbon atom contains the chain base of two keys, comprise as, vinyl, 1-, 2-propenyl, 2-, 3-propenyl or the like.
Alkynyl is meant that 2-4 carbon atom contains the chain base of one three key, comprise as, ethynyl, 1-, 2-propynyl, 2-, 3-proyl or the like.
Cycloalkyl is meant the cyclic alkyl of 3-7 carbon atom, comprises cyclopropyl, cyclobutyl or the like.
Alkoxyl group is meant-the O-alkyl that wherein alkyl as defined above.
Acyl group is meant-the CO-alkyl that wherein alkyl as defined above.
Alkylamino is meant-the NH-alkyl that dialkyl amido is meant-N-(alkyl)
2, wherein alkyl as defined above.
Amido is meant-the NH-acyl group that wherein acyl group as defined above.
Alkoxycarbonyl amido is meant alkyl-O-CO-NH-, and wherein alkyl as defined above.
Alkyl amino-carbonyl amino is meant alkyl-NH-CO-NH-, and wherein alkyl as defined above.
Dialkyl amino carbonyl amino is meant (alkyl)
2-NH-CO-NH-, wherein alkyl as defined above.
Aryl is meant aromatic ring, as phenyl or naphthyl.
Aralkyl is meant aryl-alkyl, and wherein aryl and alkyl are as defined above.
According to the present invention, typical organic acid addition salt is the additive salt with following acid: toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, oxalic acid, dimethylene Whitfield's ointment, methylsulfonic acid, ethane disulfonic acid, acetate, propionic acid, tartrate, Whitfield's ointment, citric acid, gluconic acid, lactic acid, oxysuccinic acid, amygdalic acid, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, glyconic acid (glycolic), p-benzaminic acid, L-glutamic acid, Phenylsulfonic acid, theophylline acetate, and 8-halo theophylline, as 8-bromine theophylline.Typical inorganic acid addition salt is and the additive salt of spirit of salt, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid.The pharmacy acceptable salt that acid salt of the present invention preferably forms with non-toxic acid.
Compound of the present invention can exist with the form of non-solventization, also can form the existence of solvation form with pharmaceutically acceptable solvent such as water, ethanol etc.With regard to purpose of the present invention, it is generally acknowledged that the solvation form is equal to the non-solvent form.
Some compound of the present invention contains chiral centre, and the centralization compound exists with the form of isomer (being enantiomer), the present invention includes all these isomer and their mixture such as racemic mixture.
Racemic form can be split as optical antipode by currently known methods, for example, separates the non-mapping salt that they and optically active acid form, and discharges optically active amine compound with alkaline purification.Another kind is according to the chromatography on optical activity matrix with the method that racemic form is split as optical antipode.Racemic compound of the present invention thus can be split as their optical antipode, for example, and by the gradation crystallization of d-or l-salt (as tartrate, amygdalate or camsilate).Compound of the present invention also can split by forming non-mapping derivative.
Can also adopt other method well known to those skilled in the art, resolve optical isomer.These methods comprise J.Jaques, the method that ACollet and S.Wilen are discussed in " enantiomer, racemic modification and fractionation " (John Wiley and Sons, New York, (1981)).
Optically active compound can also have optically active initiator preparation.
The compounds of this invention can be prepared according to one of following method, comprising:
A) carbonyl in the reduction formula V compound,
R wherein
1-R
3, R
12, R
14-R
17, X, Y, Z, W and dotted line as defined above;
B) with the amine of formula (VI)
R wherein
1-R
3, X, Y, Z, W and dotted line as defined above, use formula G-CH
2CH
2The reagent of-A carries out alkylation, wherein A as defined above, G is suitable leavings group such as halogen, methanesulfonates or tosylate;
C) amine of formula (VI)
R wherein
1-R
3, X, Y, Z, W and dotted line as defined above, with formula B-CH
2CH
2The reductive alkylation of the reagent of-A, wherein A as defined above, B is aldehyde or hydroxy-acid group;
D) the two keys of the indoles of reduction-type (VII) are corresponding 2 to obtain, the 3-indolin derivatives
R wherein
1-R
3, X, Y, Z, W and dotted line as defined above, A ' is above-mentioned formula (II), (III) or group (IV), and its its dotted portion is represented singly-bound;
E) the two keys of the tetrahydropyrans of reduction-type (VIII) are to obtain corresponding piperidine derivative
R wherein
1-R
3, A, X, Y and Z such as front define;
F) handle general formula (I) compound with reductive agent, the Y in the general formula is-CR
6=CR
7-, perhaps X wherein and Y form group-CR together
4=CR
5-or-CR
4=CR
5-CR
6R
7-, to reduce two keys, reduce ring system thus accordingly;
G) with general formula (I) compound substituent R
1-R
3Or R
12-R
17In one or more reduction remove, in general formula, one or more in these substituting groups are to be selected from chlorine, bromine or iodine;
H) with the amine of formula (IX)
R wherein
1-R
3, X, Y and Z as defined above, carry out dialkyl groupization with the reagent of formula (X) expression,
Wherein A as defined above, G is suitable leavings group such as halogen, methanesulfonates or tosylate;
I) with the amine of formula (XI)
Wherein A carry out dialkyl groupization with the reagent of formula (XII) expression as defined above,
R wherein
1-R
3, X, Y, Z and W as defined above, G is suitable leavings group such as halogen, methanesulfonates or tosylate; Perhaps
J) with the indole nitrogen atom alkylization or the acidylate of formula (XIII) compound
R wherein
1-R
3, X, Y, Z, W and dotted line as defined above, A " is selected from above-mentioned formula (III) or (IV) group, the R in the formula
11Be hydrogen, that used is formula R
11Alkylation that-G represents or acylating reagent, wherein G is suitable leavings group such as halogen, methanesulfonates or tosylate, R
11As defined above but be not hydrogen.
Therefore, formula (I) compound is to come out with free alkali or with the isolated in form of its acid salt.
Method reduction reaction a) preferably in organic inert solvent (as ether or tetrahydrofuran (THF)), lithium aluminum hydride exist and the reflux temperature condition under carry out, generally from the reagent, 1 of formula (IV) expression, unsubstituted indoles in 3-position or oxalyl chloride are by the described preparation of following embodiment for the initial compounds formula V.
Method b) alkylated reaction is implemented in inert organic solvents (as boiling point suitable alcohol or ketone) easily, preferably alkali (as salt of wormwood or triethylamine) exist and reflux temperature under carry out.
The aryl piperazine derivative of formula (IV) expression is according to people such as Martin, J.Med.Chem., 1989,32,1052, described in method or people such as Kruse, Rec Trav.Chim.PaysBas, 1988, method described in 107,303 prepares easily from corresponding arylamine; The initiator arylamine is commercially available, or existing description fully in the document.
The aryl 5,6-tetrahydropyridine derivative of formula (IV) expression is known in the document, referring to U.S. Pat 2891066; People such as McElvain, J.Amer.Chem.Soc., 1959,72,3134.With butyllithium corresponding arylamine is carried out lithiumation very simply, add 1-benzyl-4-piperidone again, obtain N-benzyl-aryl tetrahydrochysene pyrrole with acid treatment subsequently; Sloughing of benzyl can be passed through catalytic hydrogenation, or earlier with the agent treated as Vinyl chloroformate, obtains corresponding urethanum, carries out acid hydrolysis or basic hydrolysis then.The initiator aromatic bromide is commercially available, or existing description fully in the document.
Formula G-CH
2CH
2The reagent of-A is commercially available, perhaps can prepare according to literature method, for example, is reduced into the 2-hydroxyethyl derivative from corresponding acetogenin, according to usual way hydroxyl is converted into group G again.
Method c) reductive alkylation reaction is implemented according to conventional literature method, and reaction can be divided into for two steps to be carried out, and is about to (VI) and formula B-CH
2The reagent that-A represents is according to ordinary method, by acyl chlorides or use coupling reagent such as dicyclohexylcarbodiimide to be coupled, then with regard to the acid amides lithium aluminium hydride reduction of gained.Reaction also can be carried out formula G-CH according to one pot of method of routine
2Carboxylic acid that-A represents or aldehyde be commercially available or document in existing the description.
Method d) indoles double bond reduction reaction is easy to implement, earlier at inert solvent, in tetrahydrofuran (THF) Huo diox, 0 ℃ to the reflux temperature with diborane or diborane precursor as three second ammoniums or methyl-sulfide title complex, then intermediate product diborane derivative is carried out acid-catalyzed hydrolysis; The enforcement of reduction reaction also can be chosen in the trifluoroacetic acid and handle with sodium cyanoborohydride.
Method e) and f) enforcement of double bond reduction reaction is the easiest, at noble metal catalyst, has down hydrogenation in alcohol as platinum or palladium.
Method g) removing of halogenic substituent can be implemented easily, carries out catalytic hydrogenation in the presence of palladium catalyst in alcohol, perhaps handles with ammonium formiate in alcohol with under the temperature that improves in the presence of palladium catalyst.
Method h) and i) dialkyl groupization of amine is reflected at and is easy under the comparatively high temps implement in inert solvent (as chlorobenzene, toluene, N-Methyl pyrrolidone, dimethyl formamide or acetonitrile), and reaction also can be carried out in the presence of alkali (as salt of wormwood or triethylamine).Method h) and initiator i) be commercially available, perhaps can prepare with usual way by commercially available material.
Method j) N-alkylated reaction is in inert solvent (as alcohol or ketone), under the temperature that improves and carry out under reflux temperature in the presence of the alkali (as salt of wormwood or triethylamine).In addition, can also use phase transfer reagent.
Following examples are to further specify of the present invention, but they should be interpreted as limitation of the invention.Embodiment
The indoles that used halogen, methyl or methoxy replace among the described embodiment 1 is commercially available.
The 2-of used replacement (1-indyl) acetate is prepared according to usual way by corresponding substituted indole and ethyl bromoacetate among the described embodiment 3.
The 3-of used replacement (2-bromotrifluoromethane) indoles is used lithium aluminium hydride reduction by corresponding 2-(1-indyl) acetic ester among the described embodiment 2 in alcohol, handles being prepared subsequently with tetrabromomethane/triphenylphosphine according to conventional literature method.
Among the described embodiment 1,2 and 3 used aryl piperazines by corresponding arylamine according to people such as Martin, J.Med.Chem., 32 (1989), 1052, described in method, or people such as Kruse, Rec Trav.Chim.PaysBas, 107 (1988), the method described in 303 is prepared.
The initiator arylamine is commercially available or has described in following document:
5-amino-1,4-benzodioxan synthetic as people such as Dauksas, Zh.Org.Khim.3 (1967) 1121 is described.Corresponding chlorinated derivative prepares according to similar methods.
7-amino-2,3-Dihydrobenzofuranes synthetic as described in the U.S. Patent application US 4302592.
Synthesizing as people such as Van Wijingaarden of 7-amino-cumarone, J.Med.Chem.31 (1988) 1934 is described.
Synthesizing as people such as Boswell of 7-amino-benzo [b] thiophene, J.Heterocycl.Chem.5 (1968) 69 is described.
7-amino-2,3-dimethyl benzofuran and corresponding 5-chlorine and 5-methyl-derivatives are according to German patent DE 3526510 preparations.
4-amino-benzo thiapyran is according to European patent application EP 79683 preparations.
8-amino-6-chloro-2, the preparation of 2-dimethylbiphenyl pyrans is with 6-chloro-2, and (according to people such as Bolzoni, Angew.Chem.90 (1978) 727-preparation) is nitrated according to usual way for 2-dimethylbiphenyl pyrans, and the 8-nitro-derivative with gained reduces subsequently.According to similar methods, by 5-chloro-3,3-dimethyl benzofuran (according to European patent application EP 7,719 800206 preparations) preparation 7-amino-5-chloro-3,3-dimethyl benzofuran.Corresponding dechlorination derivative obtains with hydrogen treat in the presence of noble metal catalyst according to ordinary method.
The aryl 5,6-tetrahydropyridine derivative is known on the document (referring to U.S. Pat 2891066; Or people such as McElvain, J.Amer.Chem.Soc., 1959,72,3134).Very simple, with butyllithium corresponding arylamine is carried out lithiumation, add 1-benzyl-4-piperidone again, handle obtaining N-benzyl-aryl tetrahydropyridine subsequently with mineral acid or trifluoroacetic acid; Sloughing of benzyl can be passed through catalytic hydrogenation, or earlier with the agent treated as Vinyl chloroformate, obtains corresponding urethanum, carries out acid hydrolysis or basic hydrolysis then.Corresponding piperidine derivative can obtain by two keys that reduction is removed in the tetrahydro pyridine ring.All these methods all are well known to those skilled in the art.The bromide of initial aryl has sufficient description on document.Obtain 4-(1,4-benzodioxan-5-yl)-1,2 according to this method, 3, and 6-tetrahydropyridine, 4-(2,3-dihydro-2,2-dimethyl benzofuran-7-yl)-1,2,3,6-tetrahydropyridine, 4-(2,3-dihydro-cumarone-7-yl)-1,2,3,6-tetrahydropyridine, 4-(cumarone-7-yl)-1,2,3,6-tetrahydropyridine and corresponding piperidine derivative.
Fusing point is measured and not correction up on Buchi SMP-20 instrument.Mass spectrum obtains in the Ouattro MS-MS system that Fisons Instruments provides at VGBiotech.The MS-MS system is connected with the HPLC system of HP 1050 standard packages.With volume be sample (the 10 μ g/mL) solvent of 20-50 μ L in 1: 1 the mixture of acetonitrile solution/water of 1% acetate, import electrospray ionization source by the active sampling thief with the flow velocity of 30 μ L.Under the two standard sets operational condition, obtain spectrogram.One group obtains molecular weight information (MH+) (21ev), and another group derives fragmentation pattern (70ev).Background correction obtains the ionic relative intensity according to fragmentation pattern, if do not demonstrate the intensity (MH+) of molion, then this ion only exists under first group of operational condition.The 1H NMR of all new compounds spectrum is at record on Brucker AC 250 spectrometers, under the 250MHz or on Brucker DRX 500 spectrometers, under the 500MHz.Deuterochloroform (99.8% D) or deuterated dimethyl sulfoxide (99.9% D) are as solvent, and TMS is as interior mark.Chemical displacement value is represented with ppm, below abbreviation is used for representing the multiplicity of NMR signal: s=is unimodal, d=doublet, t=triplet, the q=quartet, the qui=quintet, h=septet, two times of doublets of dd=, two times of triplets of dt=, two times of quartets of dq=, three times of triplets of tt=, m=multiplet.The NMR signal of general slightly disacidify proton correspondence.The water-content of crystalline compounds Karl Fischer titration measuring.General isolation of purified program is that the dry organic extract liquid (anhydrous magnesium sulfate or sodium sulfate) that merges filters and vacuum boils off solvent with the specific aqueous solution of appointment organic solvent extraction.The column chromatography used silica gel is Kieselgel 60 types, 230-400 order ASTM (ASTM (American society for testing materials)).Embodiment 13-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles oxalate, 1a.
Under nitrogen atmosphere, ether (130mL) solution of 5-chloro-indoles (5.0g) is chilled to 0 ℃, drips ether (20mL) solution of oxalyl chloride (4.6g) subsequently, behind the stirring 16h, filter and collect crystallized product, 2-(5-chloro-1H-indol-3-yl)-2-oxo Acetyl Chloride 98Min. (7.2g).
Under the room temperature, dry tetrahydrofuran (25mL) drips of solution of this product (2.0g) is added to 1-(1,4-benzodioxan-5-yl) piperazine (1.2g) and triethylamine (7.5mL) are in the mixture of tetrahydrofuran (THF) (75mL), this mixture stirs 16h, subsequent filtration, solvent removed in vacuo obtains 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl]-1,2-dioxo ethyl]-5-chloro-1H-indoles solid crude product.Under room temperature and nitrogen atmosphere, this product is dissolved in tetrahydrofuran (THF) (25mL), be added drop-wise to the tetrahydrofuran (THF) suspension of lithium aluminum hydride (2.1g), behind the backflow 3.5h, add the aqueous sodium hydroxide solution termination reaction, carry out general isolation of purified with ethyl acetate.The oily matter of gained is by flash chromatography purifying (eluent: heptane/ethanol/ethyl acetate/triethylamine 15: 2: 2: 1), oxalate adds oxalic acid by acetone soln and makes and recrystallization in methyl alcohol/tetrahydrofuran (THF) (1: 5), obtain 0.8g 1a, m.p.224-28 ℃
1HNMR (DMSO-d
6): 3.05 (t, 2H); 3.10-3.50 (m, 10H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.10 (d, 1H); 7.30 (s, 1H); 7.40 (d, 1H); 7.65 (s, 1H); 11.15 (s, 1H) .MS m/z (%): 398 (MH+, 9%), 233 (100%), 221 (29%), 218 (19%), 178 (59%).
Be prepared like the following compounds: 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-bromo-1H-indoles oxalate, 1b, m.p.236-40 ℃.
1H NMR (DMSO-d
6): 3.10 (t, 2H); 3.15-3.45 (m, 10H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 7.35 (d, 1H); 7.80 (s, 1H); 11.20 (s, 1H) .MS m/z (%): 444 (MH+, 5%), 442 (5%), 233 (80%), 224 (21%), 222 (22%), 221 (25%), 218 (23%), 190 (19%), 70 (100%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2-Methyl-1H-indole oxalate, 1c, m.p.205-8 ℃.
1H NMR (DMSO-d
6): 2.35 (s, 3H); 2.95-3.15 (m, 4H); 3.15-3.45 (m, 8H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H), 6.95 (t, 1H); 7.00 (t, 1H); 7.25 (d, 1H); 7.50 (d, 1H); 10.85 (s, 1H) .MS m/z (%): 378 (MH+, 5%), 233 (9%), 221 (7%), 218 (5%), 158 (100%) .6-chloro-3-[2-[4-(2,2,5-trimethylammonium-2,3-Dihydrobenzofuranes-7-yl) piperidines-1-yl] ethyl]-1H-indoles fumarate, 1d, m.p.232-37 ℃
1H NMR (DMSO-d
6): 1.40 (s, 6H); 1.65-1.85 (m, 4H); 2.20 (s, 3H); 2.30 (t, 2H); 2.60 (t, 2H); 2.70-2.85 (m, 3H); 2.90 (s, 3H); 3.1 0-3.30 (m, 2H); 6.60 (s, 2H); 6.70 (s, 1H); 6.80 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H) .MS m/z (%): 423 (MH+, 11%), 258 (100%), 178 (14%), 70 (41%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-4-chloro-1H-indoles oxalate, 1e, m.p.210-18 ℃.
1H NMR (DMSO-d
6): 3.10-3.50 (m, 12H); 4.10-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.00 (d, 1H); 7.05 (t, 1H); 7.30-7.40 (m, 2H); 11.40 (s, 1H) .MS m/z (%): 398 (MH+, 10%), 233 (100%), 221 (47%), 218 (18%), 180 (25%), 178 (84%) .6-chloro-3-[2-[4-(2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperidines-1-yl] ethyl]-1H-indoles oxalate, 1f, m.p.190-93 ℃
1H NMR (DMSO-d
6): 1.40 (s, 6H); 1.75-.1.95 (m, 4H), 2.50-2.70 (m, 2H); (2.70-2.80 m, 1 H); 2.85-3.05 (m, 6H); 3.25-3.40 (m, 2H); 6.75 (t, 1H); 6.95 (d, 1H); 6.95-7.10 (m, 2H); 7.25 (s, 1H); 7.40 (s, 1H); 7.55 (d, 1H); 11.00 (s, 1H) .) .MSm/z (%): 409 (MH+, 6%), 244 (100%), 232 (9%), 178 (16%) .6-chloro-3-[2-[4-(2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl)-1,2,3,6-tetrahydrochysene-1-pyridyl] ethyl]-1H-indoles oxalate, 1g, m.p.200-4 ℃
1H NMR (DMSO-d
6): 1.40 (s, 6H); 2.70-2.80 (m, 2H); 3.00 (s, 2H); 3.15 (t, 2H); 3.30 (t, 2H); 3.35-3.50 (m, 2H); 3.85-4.00 (m, 2H); 6.35 (s, 1H); 6.85 (t, 1H); 7.00 (d, 1H); 7.05-7.15 (m, 2H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.15 (s, 1H) .MS m/z (%): 407 (MH+, 2%), 207 (8%), 180 (33%), 178 (100%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles oxalate, 1c, m.p.224-26 ℃.
1H NMR (DMSO-d
6): 3.10 (t, 2H); 3.10-3.50 (m, 10H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 6.95 (t, 1H); 7.30 (s, 1H); 7.30-7.50 (m, 2H); 11.10 (s, 1H) .MS m/z (%): 382 (MH+, 9%), 233 (78%), 221 (30%), 218 (22%), 190 (20%), 162 (97%), 70 (100%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-methoxyl group-1H-indoles half oxalate, li, mp 189-96 ℃.
1H NMR (DMSO-d
6): 3.00 (t, 2H); 3.05-3.30 (m, 10H); 3.80 (s, 3H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.70-6.80 (m, 2H); 7.10 (s, 1H); 7.15 (s, 1H); 7.25 (d, 1H); 10.70 (s, 1H) .MS m/z (%): 394 (MH+, 7%), 233 (79%), 218 (21%), 190 (21%), 174 (61%), 70 (100%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-Methyl-1H-indole hemifumarate, 1j, mp 147-54 ℃.
1H NMR (DMSO-d
6): 2.40 (s, 3H); 2.60-2.80 (m, 6H); 2.85 (t, 2H); 2.95-3.15 (m, 4H); 4.15-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 6.90 (d, 1H); 7.10 (s, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 10.65 (s, 1H) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-Methyl-1H-indole hemifumarate, 1k, mp 204-7 ℃.
1H NMR (DMSO-d
6): 2.35 (s, 3H); 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.15 (m, 4H); 4.10-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 6.80 (d, 1H); 7.05 (s, 1H); 7.10 (s, 1H); 7.40 (d, 1H); 10.60 (s, 1H) .6-chloro-3-[2-[4-(7-chloro-1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 1l, mp 237-38 ℃.
1H NMR (DMSO-d
6); 3.00-3.15 (m, 2H); 3.15-3.40 (m, 10H); 4.20 (s, 4H); 6.50 (d, 1H); 6.65 (d, 1H); 7.00 (dd, 1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.60 (d, 1H); 10.95 (s, 1H) .MS m/z (%): 432 (MH+, 3%), 267 (42%), 252 (12%), 224 (10%), 178 (27%), 70 (100%) .6-chloro-3-[2-[4-(6-chloro-1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 1m, mp 216-17 ℃.
1H NMR (DMSO-d
6): 2.60 (t,? H); 2.85 (t, 2H); 3.10 (b, 4H); 3.30 (s, 4H); 4.15-4.30 (m, 4H); 6.15 (d, 1H); 6.35 (d, 1H); 7.00 (dd, 1H); 7.20 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 1 0.95 (s, 1H) .MS m/z (%): 432 (MH+, 2%), 267 (47%), 252 (16%), 224 (16%), 178 (30%), 70 (100%) .5-chloro-3-[2-[4-(2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 1n, mp 134-38 ℃.
1H NMR (DMSO-d
6): 2.65-2.80 (m, 6H); 2.90 (t, 2H); 3.00-3.25 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.05 (d, 1H); 7.25 (s, 1H); 7.35 (d, 1H); 7.60 (s, 1H); 11.05 (s, 1H) .MS m/z (%): 382 (MH+), 217 (39%), 205 (17%), 178 (38%), 143 (11%), 70 (100%) .6-chloro-3-[2-[4-(2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 1o, mp 205-7 ℃.
1H NMR (DMSO-d
6); 2.60-2.75 (m, 6H); 2.90 (t, 2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.80 (d, 1H); 6.95 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H) .MS m/z (%): 382 (MH+), 217 (33%), 202 (18%) 70 (100%) .3-[2-[4-(2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles oxalate, 1p, mp 145-49 ℃.
1H NMR (DMSO-d
6): 2.65-2.85 (m, 6H); 2.90 (t, 2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 6.90 (t, 1H); 7.25 (s, 1H); 7.25-7.35 (m, 2H); 10.95 (s, 1H) .MS m/z (%): 366 (MH+, 4%), 217 (31%), 205 (18%), 174 (16%), 162 (81%) 70 (100%) .3-[2-[4-(thionaphthene-7-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles oxalate, 1q, m.p.175.2-176.6 ℃.
1H NMR (DMSO-d
6): 3.10 (m, 2H), 3.26 (m, 2H), 3.38-3.36 (m, 6H), 7.05 (d, 1H), 7.09 (d, 1H), 7.33 (s, 1H), 7.40-7.37 (m, 3H), 7.47 (d, 1H), 7.62 (d, 1H), 7.69 (s, 1H), 7.76 (d, 1H) .MS m/z 398.1 (MH+, 1.1% (
37Cl)), 396.1 (MH+, 2.8% (
35Cl)), 230.9 (1005), 177.8 (58%), 69.8 (50.8%) .3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 1r, m.p.152-153 ℃,
1H NMR (CDCl
3): 2.08 (m, 2H), 2.75 (m, 6H), 2.83 (m, 2H), 2.98 (m, 4H), 3.05 (m, 2H), 6.80 (d, 1H), 6.99-6.94 (m, 2H), 7.08 (s, 1H), 7.14 (d, 2H), 7.26 (d, 1H), 7.59 (s, 1H), 8.00 (s, 1H) .MS m/z 412.3 (MH+, 100% (
35Cl)), 414.5 (MH+, 63.% (
37Cl)), 247.1 (23.7%) .3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-5-bromo-1H-indoles, 1s, m.p.166-167 ℃,
1H NMR (CDCl
3): 2.04 (m, 2H), 2.75 (m, 6H), 2.82 (m, 2H), 2.98 (m, 4H), 3.05 (m, 4H), 6.81 (d, 1H), 6.98-6.93 (m, 2H), 7.05 (s, 1H), 7.21 (d, 1H), 7.26 (d, 1H), 7.76 (s, 1H), 8.02 (s, 1H) .MS m/z 458.4 (MH+, 21.7% (
81Br), 456.3 (MH+, 23.9% (
79Br), 232.0 (58.7%), 143.1 (100%) .3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 1t, m.p.178-179 ℃,
1H NMR (CDCl
3): 2.07 (m, 2H), 2.75 (m, 6H), 2.83 (m, 2H), 2.96 (m, 4H), 3.04 (m, 4H), 6.80 (d, 1H), 6.98-6.92 (m, 2H), 7.04 (s, 1H), 7.08 (d, 1H), 7.33 (s, 1H), 7.52 (d, 1H), 7.95 (s, 1H) .MS m/z 412.3 (MH+, 31.8% (
35Cl)), 247.3 (81.8%), 232.0 (63.9%), 178.1 (63.6%), 143.1 (100%) .3-[2-[4-(cumarone-7-yl) piperazines-1-yl] ethyl]-6-chloro-1H-indoles, 1u, m.p.202-4 ℃,
1HNMR (DMSO-d
6): 2.65-2.85 (m, 6H); 2.90 (t, 2H); 3.20-3.40 (m, 4H); 6.60 (s, 1H); 6.80 (d, 1H); 6.90 (d, 1H); 7.00 (d, 1H); 7.05-7.30 (m, 3H); 7.40 (d, 1H); 7.55 (d, 1H); 7.95 (d, 1H); 11.00 (s, 1H) .MS m/z (%): 380 (MH+, 4%), 215 (100%), 200 (12%), 178 (36%), 172 (20%) .3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine-1-yl] ethyl]-6-chloro-1H-indoles oxalate, 1v, m.p.240-47 ℃
1H NMR (DMSO-d
6): 2.70 (s, 2H); 3.10 (t, 2H); 3.20-3.70 (m, 4H); 3.80 (s, 2H); 4.25 (s, 4H); 5.85 (s, 1H); 6.75 (t, 1H); 6.80 (d, 2H); 7.05 (d, 1H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.10 (s, 1H) .MS m/z (%): 395 (MH+, 1%), 178 (100%) .6-chloro-3-[2-[4-(2,3-Dihydrobenzofuranes-7-yl)-1,2,3,6-tetrahydropyridine-1-yl] ethyl]-1H-indoles oxalate, 1x, m.p.211-14 ℃,
1H NMR (DMSO-d
6): 2.75 (s, 2H); 3.05-3.15 (m, 2H); 3.20 (t, 2H), 3.25-3.50 (m, 4H); 3.85 (s, 2H); 4.55 (t, 2H); 6.30 (s, 1H); 6.85 (t, 1H); 7.00 (d, 1H); 7.10 (d, 1H); 7.15 (d, 1H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.10 (s, 1H) .MS m/z (%): 379 (MH+, 3%), 178 (100%) .3-[2-[4-(cumarone-7-yl)-1,2,3,6-tetrahydropyridine-1-yl] ethyl]-6-chloro-1H-indoles hemifumarate, 1y, m.p.214-20 ℃,
1H NMR (DMSO-d
6): 2.65 (s, 2H); 2.75-2.85 (m, 4H); 2.90-3.00 (m, 2H); 3.10-3.50 (m, 3H); 6.55 (s, 2H); 6.90-7.00 (m, 2H); 7.15-7.30 (m, 3H); 7.35 (s, 1H); 7.50-7.60 (m, 2H); 8.00 (s, 1H); 10.90 (s, 1H), MS m/z (%): 377 (MH+, 25%), 178 (73%), 143 (22%) .3-[2-[4-(cumarone-7-yl)-1,2,3,6-tetrahydropyridine-1-yl] ethyl]-5-bromo-1H-indoles oxalate, 1z, mp 185-94 ℃.
1H NMR (DMSO-d
6): 2.90 (s, 2H); 3.10-3.20 (m, 2H); 3.25-3.55 (m, 4H); 3.95 (s, 2H); 6.60 (s, 1H); 7.00 (s, 1H); 7.20 (d, 1H); 7.20-7.45 (m, 4H); 7.60 (d, 1H); 7.80 (s, 1H); 8.05 (s, 1H); 11.20 (s, 1H) .MS m/z (%): 423 (MH+ (
81Br), 22%), 421 (MH+ (
79Br), 20%), 224 (70%), 222 (72%), 143 (33%) .3-[2-[4-(cumarone-7-yl)-1,2,3,6-tetrahydropyridine-1-yl] ethyl]-5-fluoro-1H-indoles half oxalate, 1aa, m.p.176-79 ℃,
1H NMR (DMSO-d
6): 2.75 (s, 2H); 2.90-3.25 (m, 6H); 3.65 (s, 2H); 6.60 (s, 1H); 6.85-6.95 (m, 1H); 7.00 (s, 1H); 7.20-7.40 (m, 5H); 7.60 (d, 1H); 8.00 (s, 1H); 11.00 (s, 1H) .MS m/z (%): 361 (MH+, 12%), 162 (100%), 115 (13%) .3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-6-chloro-1H-indoles hemifumarate, 1bb, m.p.245-50 ℃.
1H NMR (DMSO-d
6): 1.85-2.00 (m, 4H); 2.75 (t, 2H); 2.90 (t, 2H); 3.05 (tt, 1H); 3.25 (d, 2H); 6.55 (s, 2H); 6.95 (s, 1H); 7.00 (d, 1H); 7.15-7.25 (m, 3H); 7.40 (s, 1H); 7.50 (d, 1H); 7.55 (d, 1H); 8.00 (s, 1H); 10.95 (s, 1H) .MS m/z (%): 379 (MH+, 5%), 214 (10%), 178 (20%), 143 (100%) .3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-5-fluoro-1H-indoles oxalate, 1cc, m.p.191-94 ℃.
1H NMR (DMSO-d
6): 2.05-2.25 (m, 4H); 3.05-3.20 (m, 4H); 3.20-4.40 (m, 3H); 3.60-3.70 (m, 2H); 6.90-7.00 (m, 2H); 7.15-7.25 (m, 2H); 7.35-7.45 (m, 3H); 7.55 (d, 1H); 8.00 (s, 1H); 11.05 (s, 1H) .MS m/z (%): 363 (MH+, 5%), 214 (9%), 161 (10%), 143 (24%) .3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-5-bromo-1H-Yin draws the diindyl oxalate, 1dd, m.p.153-57 ℃.
1H NMR (DMSO-d
6): 2.05-2.20 (m, 4H); 3.05-3.20 (m, 4H); 3.20-3.40 (m, 3H); 3.70 (d, 2H); 6.95 (s, 1H); 7.15-7.25 (m, 3H); 7.30-7.40 (m, 2H); 7.55 (d, 1H); 7.80 (s, 1H); 8.00 (s, 1H); 11.20 (s, 1H) MS m/z (%): 423 (MH+, 36%), 224 (27%), 202 (45%), 143 (27%), 117 (18%). embodiment 23-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1H-indoles hemifumarate, 2a.
With 3-(2-bromotrifluoromethane)-1H-indoles (1.5g), 1-(1,4-benzodioxan-5-yl) mixture of piperazine (1.2g), salt of wormwood (1.9g) and potassiumiodide (0.1g) places methyl iso-butyl ketone (MIBK) (100mL), refluxed 16 hours, carry out general isolation of purified with ethyl acetate, obtain oily matter, this oily matter carries out purifying (eluent: heptane/ethanol/ethyl acetate/triethylamine 15: 2: 2: 1) by flash chromatography, fumarate adds fumaric acid by ethanolic soln and makes, recrystallization in ethanol obtains hemifumarate 2a (0.9g).M.p.204-7 ℃,
1HNMR (DMSO-d
6): 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.10 (m, 4H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.60 (s, 1H); 6.75 (t, 1H); 7.00 (t, 1H); 7.10 (t, 1H); 7.20 (s, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.75 (s; 1H) .MS m/z (%): 364 (MH+, 5%), 233 (57%); 218 (21%); 190 (19%), 144 (54%), 70 (100%) .1-ethanoyl-3-[2-[4-(1; 4-benzodioxan-4-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles, 2b, m.p.119-20 ℃.
1H NMR (DMSO-d
6) 1.90 (d, 1H); 2.20 (s, 4H); 2.95-3.30 (m, 11H); 3.40-3.50 (m, 1H); 3.75-3.85 (m, 1H); 4.20-4.30 (m, 4H); (6.45 dd, 1 H); 6.55 (dd, 1H); 6.75 (t, 1H); 7.00 (t, 1H); 7.20 (t, 1H); 7.30 (d, 1H); 8.05 (d, 1H) .MS m/z (%): 408 (MH+, 54%), 233 (17%), 178 (100%), 119 (20%). embodiment 33-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles hemifumarate, 3a.
With 2-(6-chloro-1H-indol-3-yl) acetate (2.0g), 1-(1,4-benzodioxan-5-yl) piperazine (3.6g), N, the mixture of N-dicyclohexylcarbodiimide (2.4g) and 4-dimethylaminopyridine (0.2g) places dry tetrahydrofuran (100mL), under room temperature and nitrogen atmosphere, stir 16h, filter and carry out general isolation of purified with methylene dichloride, obtain oily matter, this oily matter carries out purifying (eluent: ethyl acetate/heptane/methyl alcohol 16: 3: 1) by flash chromatography, obtain buttery 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl]-the 2-oxoethyl]-6-chloro-1H-indoles (2.0g).
This oil is dissolved in tetrahydrofuran (THF) (25mL), and at room temperature be added drop-wise in dry tetrahydrofuran (50mL) suspension of lithium aluminum hydride (0.9g), reflux then behind the 3h, with 2M aqueous sodium hydroxide solution termination reaction, and carry out general isolation of purified, obtain the free alkali form (1.9g) of buttery 3a, add the hemifumarate (1.0g) that fumaric acid makes 3a by ethanolic soln.m.p.215-16℃，
1H?NMR(DMSO-d
6)：2.60-2.85(m，6H)；2.85-2.95(m，2H)；2.95-3.10(m，4H)；4.10-4.30(m，4H)；6.45(d，1H)；6.50(d，1H)；6.60(s，1H)；6.70(t，1H)；7.0(dd，1H)；7.25(d，1H)；7.40(d，1H)；7.55(d，1H)；10.95(s，1H).MS?m/z(％)：398(MH+，10％)，234(13％)，233(100％)，178(12％).
Be prepared like the following compounds: 3-[2-[4-(5-chloro-2,2-dimethyl-2,3-cumarone-7-yl) piperazine-1-yl] ethyl]-1H-indoles hemifumarate, 3b, m.p.210-12 ℃,
1H NMR (DMSO-d
6): 1.40 (s, 6H); 2.55-2.75 (m, 6H); 2.80-3.00 (m, 4H); 3.05-3.20 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.80 (d, 1H); 6.95 (t, 1H); 7.05 (t, 1H); 7.15 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.70 (s, 1H) .MS m/z (%): 410 (MH+, 18%), 281 (32%), 279 (100%), 144 (39%) .6-chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-cumarone-7-yl) piperazine-1-yl] ethyl]-1H-indoles hemifumarate, 3c, m.p.130-32 ℃
1H NMR (DMSO-d
6): 1.25 (s, 6H); 2.55-2.70 (m, 6H); 2.85 (t, 2H); 3.00-3.20 (m, 4H); 4.25 (s, 2H); 6.60 (s, 1H); 6.65 (s, 1H); 6.85 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.90 (s, 1H) .MS m/z (%): 446 (8%), 444 (MH+, 11%), 281 (34%), 280 (16%), 279 (100%), 178 (15%) .6-chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-chromene-8-yl) piperazine-1-yl] ethyl]-1H-indoles fumarate, 3d, m.p.224-25 ℃
1H NMR (DMSO-d
6): 1.30 (s, 6H); 1.70 (t, 2H); 2.60-2.75 (m, 8H); 2.90 (t, 2H); 2.95-3.10 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.70 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H) .MS m/z (%): 458 (MH+, 11%), 295 (32%), 293 (100%), 259 (11%), 178 (14%) .6-chloro-3-[2-[4-(2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-1H-indoles fumarate, 3e, m.p.167-65 ℃
1H NMR (DMSO-d
6): 1.40 (s, 6H); 2.65-2.80 (m, 6H); 2.90 (t, 2H); 2.95 (s, 2H); 3.00-3.20 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.70 (t, 1H); 6.75 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H) .MS m/z (%): 410 (MH+, 6%), 245 (67%), 209 (39%), 178 (8%), 127 (51%), 45 (100%) .1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles oxalate, 3f, m.p.234-35 ℃.
1H NMR (DMSO-d
6): 2.85 (s, 4H); 2.95-3.15 (m, 6H); 4.15-4.30 (m, 4H); 4.40 (t, 2H); 6.45-6.55 (m, 3H); 6.70 (t, 1H); 7.05 (d, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.70 (s, 1H) .MS m/z (%): 398 (MH+, 45%), 218 (100%), 178 (50%) .1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles oxalate, 3g, m.p.234-35 ℃.
1H NMR (DMSO-d
6): 2.85 (s, 4H); 2.95-3.15 (m, 6H); 4.15-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.70 (t, 1H); 7.15 (d, 1H); 7.50 (s, 1H); 7.55-7.65 (m, 2H) .MS m/z (%): 398 (MH+; 44%), 218 (100%), 178 (62%) .1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles oxalate, 3h, m.p.230-31 ℃.
1H NMR (DMSO-d
6): 2.90 (s, 4H); 2.95-3.20 (m, 6H); 4.15-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.75 (t, 1H); 7.00 (t, 2H); 7.30 (d, 1H); 7.50 (s, 1H); 7.50-7.55 (m, 1H) .MS m/z (%): 382 (MH+,?), 218 (63%), 162 (100%) .1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 3i, m.p.225-29,
1HNMR (DMSO-d
6): 2.95 (s, 4H); 3.05-3.20 (m, 6H); 4.10-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.40 (s, 1H); 7.55 (t, 2H) .MS m/z (%): 364 (MH+, 100%), 218 (85%), 146 (80%) .1-[2-[4-(2,3-cumarone-7-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 3j, m.p.223-26 ℃.
1H NMR (DMSO-d
6): 2.85 (s, 4H); 3.00 (t, 2H); 3.05-3.20 (m, 6H); 4.40 (t, 2H); 4.50 (t, 2H); 6.45 (d, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.00 (t, 1H); 7.15 (t, 1H); 7.40 (d, 1H); 7.55 (dd, 2H) .MS m/z (%): 348 (MH+, 38%), 231 (50%), 201 (100%), 174 (25%), 162 (41%), 146 (98%). embodiment 43-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-1H-indoles sesquialter oxalate, 4a.
At room temperature, in batches with sodium borohydride (2 * 2.9g, interval 1.5h) with 2a (16g) trifluoroacetic acid (200mL) solution effects, at room temperature stir 2.5h then, reaction mixture is watered in the ice, alkalize with aqueous sodium hydroxide solution, carry out general isolation of purified again, the oily matter that obtains is by flash chromatography purifying (eluent: heptane/ethyl acetate/ethanol/triethylamine 15: 2: 2: 1), obtain the title compound alkali of yellow oily, the title compound oxalate adds oxalic acid by free alkali (1.4g) and obtains its crystallisate (0.9g), m.p.145-50 ℃ in ethanol.
1H NMR (DMSO-d
6): 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.95-3.30 (m, 12H); 3.60 (t, 1H); 4.20 (d, 4H); 6.50 (d, 2H); 6.60 (d, 2H); 6.75 (t, 1H); 6.95 (t, 1H); 7.10 (d, 1H) .MSm/z (%): 366 (MH+, 10%), 221 (10%), 178 (14%), 150 (20%), 118 (100%).
Be prepared like the following compounds: 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-5-fluoro-1H-indoles half oxalate, 4b, m.p.201-5 ℃
1H NMR (DMSO-d
6): 1.60-1.80 (m, 1H); 1.95-2.10 (m, 1H); 2.60-3.30 (m, 12H); 3.35 (t, 1H); 4.20 (d, 4H); 6.35-6.55 (m, 3H); 6.15-6.25 (m, 2H); 6.90 (d, 1H) .MS m/z (%): 384 (MH+, 32%), 178 (28%), 150 (12%), 136 (100%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-2,3-dihydro-1H-indoles oxalate, 4c, mp 153-57 ℃.
1H NMR (DMSO-d
6): 1.70-1.85 (m, 1H); 2.05-2.20 (m, 1H); 2.85-3.05 (m, 2H); 3.05-3.35 (m, 10H); 3.60 (t, 2H); 4.15-4.30 (m, 4H); 6.45-6.60 (m, 3H); 6.75 (t, 1H); 6.95 (dd, 1H); 7.10 (d, 1H) .MS m/z (%): 400 (MH+, 39%), 178 (39%), 152 (100%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-2,3-dihydro-1H-indoles oxalate, 4d, mp 185-88 ℃.
1H NMR (DMSO-d
6): 1.75-1.85 (m, 1H); 2.00-2.10 (m, 1H); 2.90-3.30 (m, 12H); 3.60 (t, 1H); 4.15-4.30 (m, 4H); 6.45 (s, 1H); 6.50 (d, 1H); 6.55 (t, 2H); 6.75 (t, 1H); 7.05 (d, 1H) .MS m/z (%): 400 (MH+, 14%), 221 (52%), 180 (22%), 152 (100%). embodiment 53-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-butyl-1H-indoles oxalate, 5a.
At room temperature, with 2a, dry tetrahydrofuran (1.0g), (50mL) drips of solution is added to sodium hydride, (60% in mineral oil, 0.14g) tetrahydrofuran (THF), (25mL) in the solution, after stirring 30min, drip the 1-n-butyl bromide, dry tetrahydrofuran (0.85g), (10mL) solution, carry out general isolation of purified with ethyl acetate after stirring 1h, the oily matter that obtains is by the flash chromatography purifying, (eluent: heptane/ethyl acetate/triethylamine 15: 3: 2), the oily matter that obtains adds oxalic acid in acetone, be converted into the title oxalate, (0.7g), m.p.168-74 ℃
1H NMR (DMSO-d
6): 0.90 (t, 3H); 1.25 (qv, 2H); 1.70 (qv, 2H); 3.05 (t, 2H); 3.15-3.40 (m, 8H); 4.10 (t, 2H); 4.15-4.30 (m, 4H); 6.55 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.45 (d, 1H); 7.60 (d, 1H) .MS m/z (%): 420 (MH+, 33%), 233 (39%), 200 (100%), 158 (36%).
Be prepared like the following compounds: 1-allyl group-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 5b, m.p.187-90 ℃
1H NMR (DMSO-d
6): 3.05 (t, 2H); 3.10-3.40 (m, 10H); 4.20 (d, 4H); 4.75 (d, 2H); 5.05 (d, 1H); 5.15 (d, 1H); 5.90-6.05 (m, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.40 (d, 1H); 7.60 (d, 1H) .MS m/z (%): 404 (MH+, 38%), 233 (38%), 184 (43%), 120 (29%) .3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-propargyl-1H-indoles oxalate, 5c, m.p.168-72 ℃.
1H NMR (DMSO-d
6): 3.00-3.30 (m, 12H); 3.40 (t, 1H); 4.25 (d, 4H); 5.05 (d, 2H); 6.50 (d, 2H); 6.55 (d, 1H); 7.10 (t, 1H); 7.20 (t, 1H); 7.30 (s, 1H); 7.50 (d, 1H); 7.65 (d, 1H) .MS m/z (%): 402 (MH+, 52%), 233 (50%), 182 (57%), 167 (100%).Embodiment 63-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-1-Methyl-1H-indole oxalate, 6a.
At room temperature, with 4a, dry tetrahydrofuran (1.5g), (50mL) drips of solution is added to sodium hydride, (60% in mineral oil, 0.21g) tetrahydrofuran (THF), (25mL) in the solution, after stirring 30min, drip methyl iodide, dry tetrahydrofuran (0.75g), (25mL) solution, carry out general isolation of purified with ethyl acetate after stirring 1h, the oily matter that obtains is by the flash chromatography purifying, (eluent: heptane/ethyl acetate/triethylamine 15: 3: 2), the oily matter that obtains adds oxalic acid in acetone, be converted into the title oxalate, (0.3g), m.p.155-65 ℃
1H NMR (DMSO-d
6) 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.70 (s, 3H); 2.90-3.25 (m, 12H); 3.40 (t, 1H); 4.15-4.30 (m, 4H); 6.45-6.55 (m, 3H); 6.65 (t, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H) .MS m/z (%): 380 (MH+, 4%), 178 (4%), 132 (53%).
Be prepared like the following compounds: 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-benzyl-2,3-dihydro-1H-indoles oxalate, 6b, m.p.158-65 ℃
1H NMR (DMSO-d
6): 1.75-1.85 (m, 1H); 2.10-2.20 (m, 1H); 2.90-3.30 (m, 12H); 3.45 (t, 1H); 4.15-4.25 (m, 5H); 4.35 (d, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.65-6.70 (m, 2H); 6.75 (t, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.30 (t, 1H); 7.35 (s, 4H) .MS m/z (%): 456 (MH+, 19%), 236 (25%), 178 (100%), 130 (11%) .1-allyl group-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-1H-indoles oxalate, 6c, mp 133-36 ℃.
1H NMR (DMSO-d
6): 1.75-1.85 (m, 1H); 2.10-2.20 (m, 1H); 2.95-3.35 (m, 12H); 3.50 (t, 1H); 3.65 (dd, 1H); 3.75 (dd, 1H); 4.25 (d, 4H); 5.15 (d, 1H); 5.30 (d, 1H); 5.85-5.95 (m, 1H); 6.50 (d, 1H); 6.55 (d, 2H); 6.65 (t, 1H); 6.75 (t, 1H); 7.00 (t, 1H); 7.10 (d, 1H) .MS m/z (%): 406 (MH+, 15%); 178 (178%), 158 (24%), 130 (31%); 117 (20%). embodiment 71-ethanoyl-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1H-indoles oxalate, 7a.
With 2a (2.0g), hydrogen sulfate tetrabutylammonium (0.21g), the mixture of sodium hydroxide (1.0g) and methylene dichloride (40mL) stirs 10min, the dichloromethane solution of dripping acetyl chloride (0.97g) at room temperature subsequently, add entry after stirring 1h, and carry out general isolation of purified, the oily matter that obtains is by flash chromatography purifying (eluent: heptane/ethyl acetate/ethanol/triethylamine 17: 1: 1), the yellow oil that obtains adds oxalic acid in acetone, be converted into title oxalate (0.75g), m.p.199-202 ℃
1H NMR (DMSO-d
6): 2.65 (s, 3H); 3.05 (t, 2H); 3.15 (s, 10H); 4.20 (d, 2H); 4.25 (d, 2H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.30-7.40 (m, 2H); 7.70 (d, 1H); 7.80 (s, 1H); 8.35 (d, 1H) .MS m/z (%): 406 (MH+, 28%), 233 (44%), 218 (39%), 144 (100%). pharmacology test
The compounds of this invention is to 5-HT
1AThe avidity of acceptor is by measuring radioligand in conjunction with 5-HT
1AThe restraining effect of acceptor and measuring is as described in following test: right
3H-5-CT is in conjunction with people 5-HT
1AThe restraining effect of acceptor
According to this method, at the external test medicine to 5-HT
1AAgonist
3H-5-formamido group tryptamines (
3H-5-CT) with human cloning 5-HT with Hela cell (HA7) stably express of transfection
1AThe restraining effect of receptors bind (Fargin, people such as A., J.Biol.Chem., 1989,264,14848).According to Harrington, people such as M.A., J.Pharmacol.Exp.Ther., the remodeling of 1994,268,1089 described methods is measured.
3Under the existence of H-5-CT, with people 5-HT
1AAcceptor (40 μ g cell tissue homogenate) in 37 ℃ be that 7.7 50mM Tutofusin tris (Tris) damping fluid was hatched 15 minutes at pH, 10 μ Mmetergoline are counted interior and measure non-specific binding.Filter rapidly with the Unifilter GF/B filter on the Tomtec cell harvestor (Tomtec Cell Harvester), termination reaction, filter is counted on Pakard Top counter (Pakard Top Counter), and the gained result sees table 1:
| Compound number | 3The H-5-CT bonded suppresses IC 50(nM) |
| ????1a | ????17 |
| ????1b | ????7.2 |
| ????1c | ????2.5 |
| ????1d | ????55 |
| ????1e | ????11 |
| ????1f | ????6.1 |
| ????1g | ????2.8 |
| ????1h | ????4.6 |
| ????1i | ????6.9 |
| ????1j | ????14 |
| ????1k | ????2.0 |
| ????1l | ????12 |
| ????1m | ????99 |
| ????1n | ????8.2 |
| ????2a | ????2.9 |
| ????2b | ????13 |
| ????1v | ????0.81 |
| ????3a | ????1.2 |
| ????3b | ????3.6 |
| ????3d | ????21 |
| ????4d | ????14 |
| Pindolol * | ????100 |
Table 1
*Reference compound
In following test, also measured the influence of The compounds of this invention: the mouse brain synaptosome is absorbed to serotonin reuptake transporter
3The restraining effect of H-5-HT
Adopt this method, right at the external test medicine
3H-5-HT is in the inhibition ability of whole mouse brain synaptosome accumulation.Press Hyttel, J., Psychopharmcology., 1978,60,13 described methods are measured, and the gained result sees table 2:
| Compound number | Serotonin reuptake transporter suppresses IC 50(nM) |
| ????1a | ????5.0 |
| ????1b | ????2.8 |
| ????1c | ????45 |
| ????1d | ????36 |
| ????1e | ????0.25 |
| ????1f | ????5.9 |
| ????1g | ????3.8 |
| ????1h | ????1.7 |
| ????1i | ????6.8 |
| ????1j | ????3.5 |
| ????1k | ????18 |
| ????1l | ????7.7 |
| ????1m | ????57 |
| ????1n | ????2.1 |
| ????1v | ????0.85 |
| ????2a | ????3.5 |
| ????2b | ????12 |
| ????3a | ????5.3 |
| ????3b | ????8.3 |
| ????3d | ????15 |
| ????4d | ????4.3 |
| Pindolol * | ????0.29 |
Table 2
*Reference compound
For 5-HT with the clone of HeLa cell (HA7) stably express of transfection
1AAcceptor, the 5-HT of some compounds of the present invention
1AAntagonistic activity has carried out external test, in measuring method, by measuring compound antagonism 5-HT inductive, for the inhibition that forskolin causes the ability of cyclic amp (cAMP) accumulation, determines its 5-HT
1AAntagonistic activity, according to Pauwels, people such as P.J., Biochem.Pharmacol., the remodeling of 1993,45,375 described methods is measured.The gained result sees table 3:
Table 3
*Reference compound
| Compound number | 3The H-5-CT bonded suppresses IC 50(nM) |
| ????1a | ????2900 |
| ????1b | ????5000 |
| ????1e | ????2400 |
| ????1f | ????1800 |
| ????1g | ????1800 |
| ????1h | ????280 |
| ????1i | ????620 |
| ????1j | ????980 |
| ????1k | ????580 |
| ????1n | ????1900 |
| ????1o | ????3200 |
| ????1t | ????5900 |
| ????1u | ????2000 |
| ????1v | ????3300 |
| ????1x | ????3000 |
| ????2a | ????160 |
| ????2b | ????250 |
| ????3a | ????500 |
| ????3c | ????2600 |
| ????3d | ????2300 |
| ????4d | ????890 |
| ????6a | ????100 |
| Pindolol * | ????270 |
According to Sanchez, people such as C., Eur.J.Pharmacol., 1996,315, the described measuring method of PP245 is also to the 5-HT of some compounds of the present invention
1AThe effect of acceptor has been carried out measuring in the body.In the method, by measuring to the syndromic inhibition ability of 5-MeO-DMT inductive 5-HT, the antagonistic action of confirmed test compound.
It is active and to 5-HT that The compounds of this invention has valuable serotonin reuptake inhibitor
1AThe antagonistic activity of acceptor.Therefore The compounds of this invention can be used for treatment to serotonin reuptake transporter restraining effect or 5-HT
1AThe disease of receptor antagonism sensitivity or functional disorder.Disease to serotonin reuptake transporter restraining effect sensitivity is known in the art, comprises the emotionality mental disorder, as dysthymia disorders, and psychosis, anxiety disorder comprises general anxiety disease, Phobias and mandatory symptom or the like.
As explained above, the 5-HT of The compounds of this invention
1AReceptor antagonist activity can be offset negative feedback mechanism by the serotonin reuptake transporter restraining effect, and inhibiting the repairing really of the serotonin reuptake transporter of The compounds of this invention is expected to improve thus.
Therefore, claimed compound is specially adapted to the fast-acting medicine as the treatment dysthymia disorders, and these compounds can also be used for the treatment of now using the insensitive dysthymia disorders of SSRI.Pharmaceutical preparation
Pharmaceutical preparation of the present invention can be according to the ordinary method preparation of this area, and for example the preparation of tablet can be suppressed activeconstituents and adjuvant and/or mixing diluents commonly used in flakes with mixture on general pelleter then.Adjuvant or thinner comprise W-Gum, potato starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc. for example.Be generally used for painted, seasoning, other adjuvant of purpose such as anticorrosion or additive and also can use, as long as they and activeconstituents are compatible.
The preparation of injection solution can be with regard to the additive solvent of activeconstituents and permission in a injection solvent (preferred sterilized water), and regulator solution is to needed volume, with solution disinfection and charge in the suitable ampoule or bottle.This area any suitable additives commonly used all can add.As toughener, sanitas, antioxidant etc.
Medicinal compositions of the present invention or those can any suitable way administrations by the pharmaceutical composition of the present invention's preparation, as with tablet, capsule, powder, syrup etc. are oral, or with the solvent version injection parenteral admin.For preparing these compositions, pharmaceutical carrier, thinner, vehicle or other additive that can adopt method well known to those skilled in the art and this area to adopt usually.
To contain the unit dosage form administration of the about 0.01-1000mg of described compound amount, the whole day dosage of active compound of the present invention is generally 0.05-500mg to The compounds of this invention simply, and 0.1-50mg most preferably.
Claims (19)
1. the indoles or 2 that has formula (I), 3-indolin derivatives, its enantiomer or its mixture or their acid salt,
Wherein:
X is-O-,-S-or-CR
4R
5-; With
Y is-CR
6R
7-,-CR
6R
7-CR
8R
9-or-CR
6=CR
7-; Perhaps
X and Y form group-CR together
4=CR
5-or-CR
4=CR
5-CR
6R
7
Z is-O-or-S-;
W is N, C or CH;
A is the group that is selected from formula (II), (III) and (IV) represents
Dotted line wherein is meant an optional key; R
1, R
2, R
3, R
12, R
13, R
14, R
15, R
16And R
17Be selected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxyl group, hydroxyl, formyl radical, acyl group, amino, alkylamino, dialkyl amido, amido, alkoxycarbonyl amido, amino carbonyl amino, alkyl amino-carbonyl amino, dialkyl amino carbonyl amino, nitro and cyano group independently of one another; R
4, R
5, R
6, R
7, R
8And R
9Be selected from hydrogen and alkyl independently of one another; And R
11Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, acyl group and formyl radical.
2. according to the compound of claim 1, wherein Z is-O-.
3. according to the compound of claim 1, wherein Z is-S-.
4. according to the compound of claim 1, wherein A is formula (II) group.
5. according to the compound of claim 1, wherein A is formula (III) group.
6. according to the compound of claim 1, wherein A is formula (IV) group.
7. according to the compound of claim 2, wherein A is formula (II) group.
8. according to the compound of claim 2, wherein A is formula (III) group.
9. according to the compound of claim 2, wherein A is formula (IV) group.
10. according to the compound of claim 3, wherein A is formula (II) group.
11. according to the compound of claim 3, wherein A is formula (III) group.
12. according to the compound of claim 3, wherein A is formula (IV) group.
13. according to each compound of claim 1-12, wherein R
4, R
5, R
6, R
7, R
8And R
9Be selected from hydrogen or methyl.
14. compound according to claim 1; be 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-bromo-1H-indoles; 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 2-Methyl-1H-indole, 6-chloro-3-[2-[4-(2,2; 5-trimethylammonium-2; 3-Dihydrobenzofuranes-7-yl) piperidines-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-4-chloro-1H-indoles; 6-chloro-3-[2-[4-(2; 2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperidines-1-yl] ethyl]-the 1H-indoles, 6-chloro-3-[2-[4-(2; 2-dimethyl-2; 3-Dihydrobenzofuranes-7-yl)-1,2,3; 6-tetrahydrochysene-1-pyridyl] ethyl]-the 1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-methoxyl group-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(5-chloro-2,2-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 6-chloro-3-[2-[4-(5-chloro-3; 3-dimethyl-2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 6-chloro-3-[2-[4-(6-chloro-2; 2-dimethyl-3; 4-dihydro-2H-1-chromene-8-yl) piperazine-1-yl] ethyl]-the 1H-indoles, and 6-chloro-3-[2-[4-(2,2-dimethyl-2; 3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 5-Methyl-1H-indole, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 6-Methyl-1H-indole; 6-chloro-3-[2-[4-(6-chloro-1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 5-chloro-3-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(2,3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(thionaphthene-7-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-5-bromo-1H-indoles, 3-[2-[4-(benzo thiapyran-8-yl) piperazine-1-yl] ethyl]-6-chloro-1 H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(1; 4-benzodioxan-5-yl)-1,2,3; 6-tetrahydropyridine-1-yl] ethyl]-5-fluoro-1H-Yin draws diindyl; 3-[2-[4-(1,4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-6-chloro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-5-chloro-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperidines-1-yl] ethyl]-5-fluoro-1H-indoles, 6-chloro-3-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(cumarone-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-6-chloro-1H-Yin draws diindyl; 3-[2-[4-(cumarone-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-5-bromo-1H-indoles; 3-[2-[4-(cumarone-7-yl)-1; 2,3,6-tetrahydropyridine-1-yl] ethyl]-5-fluoro-1H-indoles; 3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-5-bromo-1H-indoles, 3-[2-[4-(cumarone-7-yl) piperidines-1-yl] ethyl]-5-fluoro-1H-indoles, 1-ethanoyl-3-[2-[4-(1; 4-benzodioxan-4-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles, 1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles; 1-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles, 1-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 1-[2-[4-(2; 3-Dihydrobenzofuranes-7-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-5-fluoro-1H-indoles; 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-5-chloro-2,3-dihydro-1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-butyl-1H-indoles; 1-allyl group-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles, 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-propargyl-1H-indoles; 3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2,3-dihydro-1-Methyl-1H-indole; 3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-1-benzyl-2,3-dihydro-1H-indoles, 1-allyl group-3-[2-[4-(1; 4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-2; 3-dihydro-1H-indoles, 1-ethanoyl-3-[2-[4-(1,4-benzodioxan-5-yl) piperazine-1-yl] ethyl]-the 1H-indoles; 3-[2-[4-(phendioxin; 4-dithiane-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(phendioxin, 4-dithiane-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(phendioxin; 4-dithiane-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, 3-[2-[4-(phendioxin-thia-4-oxa--hexanaphthene-5-yl) piperazine-1-yl] ethyl]-5-chloro-1H-indoles, 3-[2-[4-(phendioxin-thia-4-oxa--hexanaphthene-5-yl) piperazine-1-yl] ethyl]-6-chloro-1H-indoles; 3-[2-[4-(phendioxin-thia-4-oxa--hexanaphthene-5-yl) piperazine-1-yl] ethyl]-5-fluoro-1H-indoles, or their acid salt.
15. a pharmaceutical composition comprises compound or its pharmaceutically-acceptable acid addition of claim 1-14 and at least a pharmaceutically acceptable carrier or thinner.
16. the compound of claim 1-14 or its pharmaceutically-acceptable acid addition are used to prepare the purposes of medicine, described medicine is suitable for treatment to serotonin reuptake transporter restraining effect or 5-HT
1AThe functional disorder of receptor antagonism sensitivity or disease.
17. according to the use of a compound of claim 16, described medicine is suitable for treating the emotionality mental disease, comprises depression, psychosis, and anxiety disorder comprises general anxiety disease, Phobias and mandatory symptom.
18. a living animal that comprises the people to serotonin reuptake transporter restraining effect or 5-HT
1AThe functional disorder of receptor antagonism sensitivity or methods for the treatment of diseases, this method comprise, the described people's of comprising living animal are imposed claim 1-14 compound or its pharmaceutically-acceptable acid addition of treatment significant quantity.
19. according to the methods of treatment of claim 18, described functional disorder or disease are the emotionality mental diseases, comprise dysthymia disorders, psychosis, and anxiety disorder comprises general anxiety disease, Phobias and mandatory symptom.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK89297 | 1997-07-25 | ||
| US60/053,713 | 1997-07-25 | ||
| DK0892/1997 | 1997-07-25 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03106002 Division CN1286833C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-indoline derivative, their preparation and application |
| CNB03106003XA Division CN1293075C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-indoline derivative, their preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1265107A true CN1265107A (en) | 2000-08-30 |
| CN1127501C CN1127501C (en) | 2003-11-12 |
Family
ID=8098721
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03106002 Expired - Fee Related CN1286833C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-indoline derivative, their preparation and application |
| CN 98807554 Expired - Fee Related CN1127501C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-dihydronindole derivatives, their prepn. and use |
| CNB03106003XA Expired - Fee Related CN1293075C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-indoline derivative, their preparation and application |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03106002 Expired - Fee Related CN1286833C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-indoline derivative, their preparation and application |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB03106003XA Expired - Fee Related CN1293075C (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-indoline derivative, their preparation and application |
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| Country | Link |
|---|---|
| CN (3) | CN1286833C (en) |
| AR (1) | AR013206A1 (en) |
| BR (1) | BR9810790A (en) |
| EA (1) | EA001890B1 (en) |
| HK (3) | HK1030220A1 (en) |
| IL (1) | IL133990A (en) |
| IS (1) | IS2024B (en) |
| NO (1) | NO318610B1 (en) |
| PL (1) | PL190924B1 (en) |
| SK (1) | SK284866B6 (en) |
| TR (1) | TR200000231T2 (en) |
| UA (1) | UA59408C2 (en) |
| ZA (1) | ZA986237B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420989A (en) * | 2012-05-15 | 2013-12-04 | 华中科技大学 | Benzodioxane derivative and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8830312D0 (en) * | 1988-12-28 | 1989-02-22 | Lundbeck & Co As H | Heterocyclic compounds |
| DE4127849A1 (en) * | 1991-08-22 | 1993-02-25 | Merck Patent Gmbh | BENZODIOXAN DERIVATIVES |
| FR2692264B1 (en) * | 1992-06-12 | 1994-08-05 | Adir | NOVEL 1,4-DISUBSTITUTED PIPERAZINES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
-
1998
- 1998-07-13 AR ARP980103400 patent/AR013206A1/en active IP Right Grant
- 1998-07-14 ZA ZA986237A patent/ZA986237B/en unknown
- 1998-07-20 PL PL338194A patent/PL190924B1/en not_active IP Right Cessation
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- 1998-07-20 CN CN 03106002 patent/CN1286833C/en not_active Expired - Fee Related
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- 2001-02-21 HK HK01101274A patent/HK1030220A1/en not_active IP Right Cessation
-
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- 2004-12-13 HK HK04109853A patent/HK1066807A1/en not_active IP Right Cessation
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103420989A (en) * | 2012-05-15 | 2013-12-04 | 华中科技大学 | Benzodioxane derivative and applications thereof |
| CN103420989B (en) * | 2012-05-15 | 2016-03-23 | 华中科技大学 | Benzodioxane derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| IS5334A (en) | 2000-01-11 |
| CN1515568A (en) | 2004-07-28 |
| AR013206A1 (en) | 2000-12-13 |
| PL338194A1 (en) | 2000-10-09 |
| PL190924B1 (en) | 2006-02-28 |
| IS2024B (en) | 2005-08-15 |
| NO318610B1 (en) | 2005-04-18 |
| ZA986237B (en) | 1999-03-31 |
| HK1066806A1 (en) | 2005-04-01 |
| CN1286833C (en) | 2006-11-29 |
| TR200000231T2 (en) | 2000-07-21 |
| IL133990A0 (en) | 2001-04-30 |
| EA200000162A1 (en) | 2000-10-30 |
| CN1515569A (en) | 2004-07-28 |
| BR9810790A (en) | 2000-07-25 |
| EA001890B1 (en) | 2001-10-22 |
| CN1127501C (en) | 2003-11-12 |
| SK284866B6 (en) | 2006-01-05 |
| HK1066807A1 (en) | 2005-04-01 |
| UA59408C2 (en) | 2003-09-15 |
| IL133990A (en) | 2003-09-17 |
| CN1293075C (en) | 2007-01-03 |
| NO20000372D0 (en) | 2000-01-25 |
| NO20000372L (en) | 2000-03-21 |
| SK952000A3 (en) | 2001-03-12 |
| HK1030220A1 (en) | 2001-04-27 |
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