CN1086819A - Novel compounds having 5-hydroxytryptamine receptor antagonistic activity - Google Patents

Novel compounds having 5-hydroxytryptamine receptor antagonistic activity Download PDF

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CN1086819A
CN1086819A CN93116553A CN93116553A CN1086819A CN 1086819 A CN1086819 A CN 1086819A CN 93116553 A CN93116553 A CN 93116553A CN 93116553 A CN93116553 A CN 93116553A CN 1086819 A CN1086819 A CN 1086819A
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indoles
methyl
pyrrolin
formyl radical
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I·T·福比斯
R·T·马丁
P·汉姆
T·P·布拉克本恩
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SmithKline Beecham Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The present invention discloses compounds of formula and processes for their preparation and their use as pharmaceuticals.
P, R therein1、R2、R3、R4、R5、R7、R10、R11、R13、R14And n is as defined in the specification.

Description

The new compound that the 5-hydroxytryptamine receptor antagonistic activity is arranged
The present invention relates to the compound that a class has pharmacological activity, their preparation method contains their composition and their application in the Mammals treatment.
P.Fludzinski etc. are at J.Med.Chem.1986,29, have described N-(1 among the 2415-2418,2-dimethyl-3-ethyl-1H-indoles-5-yl)-N '-(3-trifluoromethyl) urea, this urea to the stomach of mouse at the bottom of 5-hydroxytryptamine receptor demonstrate selectivity.
Disclose on the WO92/05170 and had 5HT 1CSome carbamide derivatives of receptor antagonist activity, this 5HT 1CAcceptor has been drawn recently again makes 5HT 2CAcceptor [P.Hartig etc., Trends in Pharmacological Sciences (TIPS) 1993].
Have now found that the compound of a class formation uniqueness, this compounds is found has 5HT 2CReceptor antagonist activity.Compounds more of the present invention also demonstrate 5HT 28Receptor antagonist activity, this 5HT 28Acceptor was considered to substrate acceptor [P.Hartig etc., Trends in Pharmacological Sciences(TIPS) 1993] in the past.It is believed that 5HT 2C/ 5HT 28Receptor antagonist can be used for treating following central nervous system (CNS) disease: as anxiety disorder, dysthymia disorders, anancastic obstacle, migraine, apositia, Alzheimer's disease, dyssomnias, exessive appetite, panic attack, withdrawal Drug abuse (as Cocaine, ethanol, Nicotine and benzodiazepine Class), schizophrenia and other and spinal cord injury and/or head damage (as hydrocephalus) relevant illness.
Therefore,, the invention provides formula I compound or its salt in first aspect,
Figure 931165539_IMG7
Wherein:
P represents quinoline or isoquinoline 99.9 residue, or contains the most nearly 3 five or hexa-atomic aromatic heterocycles that are selected from nitrogen, oxygen or sulfur heteroatom;
R 1Be hydrogen or C 1-6Alkyl;
R 2, R 3, R 10And R 11Be hydrogen or C independently 1-6Alkyl, or R 10And R 11Form a key together, or R 2And R 10Or R 3And R 11Form a C together 2-6Alkylidene chain;
R 4Be hydrogen, C 1-6Alkyl, halogen, NR 8R 9Or OR 12, R wherein 8, R 9And R 12Be hydrogen or C independently 1-6Alkyl;
R 5Be hydrogen or C 1-6Alkyl;
R 7Be hydrogen, C 1-6Alkyl, OR 12Or halogen, wherein R 12Be hydrogen or C 1-6Alkyl; And
N is 2 or 3; And
Radicals R 13And R 14Be hydrogen or C independently 1-6Alkyl.
C 1-6Alkyl can be straight or branched, preferred C 1-3Alkyl is as methyl, ethyl, just or sec.-propyl.
Suitable R 4And R 7Halogen comprises chlorine and bromine.
Suitable R 1Be hydrogen or C 1-6Alkyl is as methyl, ethyl or propyl group.Preferred R 1Be methyl or ethyl.
Suitable R 2, R 3, R 10And R 11Be hydrogen or C independently 1-6Alkyl, or R 10And R 11Form a key together, or R 2And R 10Or R 3And R 11Form a C together 2-6Alkylidene chain.Preferred R 2Be hydrogen or methyl.Preferred R 3Be hydrogen.
In the indoline structure, R 10And R 11For hydrogen better.R preferably 10And R 11Forming one is good for so that obtain an indole structure.
Suitable R 4Be hydrogen, C 1-6Alkyl, halogen, NR 8R 9Or OR 12, R wherein 8, R 9And R 12Be hydrogen or C independently 1-6Alkyl.Preferred R 4Be hydrogen or methyl.
Suitable R 5Be hydrogen or C 1-6Alkyl.Preferred R 5Be hydrogen.
Suitable R 7Be hydrogen, C 1-6Alkyl, OR 12Or halogen, wherein R 12Be hydrogen or C 1-6Alkyl.Radicals R 7Can be connected on any empty position of phenyl moiety of indoles or indoline ring, promptly on 4-, the 6-or 7-position of indoles or indoline ring.Preferred R 7Be hydrogen.
Suitable P represents quinoline or isoquinoline 99.9 residue, or contains five or the hexa-atomic aromatic heterocycle that mostly is 3 heteroatomss (being selected from nitrogen, oxygen or sulphur) most.When ring P was 5-membered aromatic heterocycle, what this part was suitable had, for example, and isothiazolyl, isoxazolyl, thiadiazolyl group and triazolyl.When ring P was hexa-atomic aromatic heterocycle, what this part was suitable had, for example, and pyridyl, pyrimidyl or pyrazinyl.When P was quinoline or isoquinoline 99.9 residue, the urea part can link to each other preferably 4 with any position of its ring.
Preferred P is 4-quinolyl or 3-pyridyl.
The urea part can be connected on the carbon or any available nitrogen-atoms of ring P, preferably links to each other with carbon atom.
Suitable group-(CR 13R 14) n-can form ethylidene or propylidene, they separately can be by C 1-6Alkyl replaces.Group-(CR 13R 14) n-can be connected on indoles or indoline ring 4 or 6, preferably be connected 6.Preferred group-(CR 13R 14) n-be ethylidene.
Particularly preferred formula I compound comprises the salt that following compound or its pharmaceutically are suitable for:
5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
6-methyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
5,7-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
6-methyl-3-(4-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(2-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
5-methyl isophthalic acid-(2-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5-methyl isophthalic acid-(4-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5-methyl isophthalic acid-(3-pyridinylamino formyl radical) 2,3,6, the 7-Pyrrolidine is [2,3-f] indoles also,
5-ethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5-n-propyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5,6-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
6,7-dimethyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
1-methyl-N-(3-pyridyl)-5,6,7, the 8-tetrahydro-1 H-pyrrolo is [2,3-g] quinoline-5-methane amide also,
3-methyl-N-(3-pyridyl)-6,7,8, the 9-tetrahydro-1 H-pyrrolo is [3,2-f] quinoline-6-methane amide also,
6-methyl-3-(2-methyl-4-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(5-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(3-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles also,
5-methyl isophthalic acid-(2-methyl-4-quinolyl formamyl)-2, the 3-pyrrolin is [2,3-f] indoles also,
6,8-dimethyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(3-pyridinylamino formyl radical)-2,3,7, the 8-Pyrrolidine is [3,2-e] indoles also,
5-methyl isophthalic acid-(2-pyrazinyl formamyl)-2, the 3-pyrrolin is [2,3-f] indoles also,
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isothiazolyl formamyl)-1H-pyrrolo-[3,2-e] indoles,
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isothiazolyl formamyl)-1H-pyrrolo-[2,3-f] indoles,
2,3-dihydro-5-methyl isophthalic acid-(5-quinolyl formamyl)-1H-pyrrolo-[2,3-f] indoles,
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isoxazolyl formamyl)-1H-pyrrolo-[2,3-f] indoles,
The N-(5-isoquinolyl)-and 5-methyl-2, the 3-pyrrolin is [2,3-f] indoles-1-methane amide also,
The N-(6-quinolyl)-and 5-methyl-2, the 3-pyrrolin is [2,3-f] indoles-1-methane amide also,
The formula I compound can form acid salt with acid (for example common acid that pharmaceutically is suitable for), and these acid for example have, toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, citric acid, lactic acid, amygdalic acid, tartrate and methylsulfonic acid.
The formula I compound also can form N-oxide compound or solvate (containing thing as water), and therefore, the present invention also provides the compound of these forms.When mentioning term ' formula I compound ', be to be understood that also to comprise these forms.
Work as R 1(in indoles) and/or R 5Be hydrogen, or work as R 4Be hydrogen or R 4Be NR 8R 9And R 8And R 9In have one at least when the hydrogen, the formula I compound can more than one tautomeric forms exist.The invention provides these forms and any other tautomeric form and their mixture.
Some compounds of formula I can exist by stereoisomer form (comprising enantiomorph), therefore, the invention provides each described stereoisomer form and their mixture (comprising racemoid).Different stereoisomer forms can separate a kind of and another kind with ordinary method, or available solid method single-minded or asymmetric synthesis obtains arbitrary known isomers.
The present invention also provides the method for preparation formula I compound or their salt that pharmaceutically is suitable for, and this method comprises
(a) make formula II compound and the coupling of formula III compound;
Figure 931165539_IMG8
Wherein, A and R 6Be formation-NR when containing coupling 5 'The necessary suitable functional groups of CO part, wherein R 5 'Be the defined R of formula I 5Or can be to the group of its transformation, n is with the definition in the formula I, and variable R 1 ', R 2 ', R 3 ', R 10 ', R 11 ', R 13 ', R 14 ', R 4 ', R 5 'And R 7 'Respectively with defined R in the formula I 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, or can be to the group of its transformation, in view of the above, as arbitrary R 1 ', R 2 ', R 3 ', R 10 ', R 11 ', R 13 ', R 14 ', R 4 ', R 5 'And R 7 'Be different from R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5, and R 7The time, when can randomly it being transformed into R respectively in case of necessity by any suitable order 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, change R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, and the salt that pharmaceutically is suitable for that forms them;
Or (b) cyclization formula IV compound;
Figure 931165539_IMG9
Wherein, R 4 ', R 5 ', R 7 ', R 13 'And R 14 'With definition in formula II and (III), define in n such as the formula I, C and D contain promising formation by R 1 ', R 2 ', R 3 ', R 10 ', and R 11 'Indoles or the necessary suitable functional groups of indoline ring that (with defining in the formula III) replaces, in view of the above, as arbitrary R 1 ', R 2 ', R 3 ', R 10 ', R 11 ', R 13 ', R 14 ', R 4 ', R 5 'And R 7 'Be different from R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7The time, when can randomly being converted into R in case of necessity by any suitable order 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, change R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, and form the salt that pharmaceutically is suitable for.
Group A and R 6Suitable example comprises:
(ⅰ) A is-N=C=O and R 6For-H,
(ⅱ) A is-NR 5 'COL and R 6For-H,
(ⅲ) A is-NHR 5 'And R 6Be COL, or
(ⅳ) A is halogen and R 6For-CONHR 5 ',
R wherein 5 'Define the samely, and L is a leavings group.The example of suitable leavings group comprises imidazoles, halogen, and as chlorine or bromine, or by any phenoxy group or the thiophenyl that replaces of for example halogen.
When A is-N=C=O and R 6During for H, reaction is fit to carry out in inert solvent such as methylene dichloride or toluene at ambient temperature.
When A is-NR 5 'COL and R 6During for H, or as A be-NHR 5 'And R 6During for COL, reaction is adapted in the inert solvent (as methylene dichloride), and in carrying out in the presence of alkali (as triethylamine) selectively under the envrionment temperature, perhaps reaction is adapted at carrying out under the temperature of envrionment temperature or rising in the dimethyl formamide.
When A is halogen and R 6Be CONHR 5 'The time, reaction is adapted at carrying out in the presence of alkali selectively under the temperature that raises in the inert solvent (as toluene).
Be preparation indoles (R 10And R 11Be a key) and the ring-closure reaction of the formula IV compound that carries out can be realized by the described general method of following document, Comprehensive Heterocychc Chemistry 1984 for example, 4,313 and following or J.Het.Chem, 1988,251 pages and below.
The example of more important synthetic route comprises the Leimgruber synthesis method, Fischer synthesis method, Japp-Klingemann alternative method, Madelung synthesis method and Nordlander synthesis method.
The example of group C and D comprises in the indoles preparation:
(V) C is NO 2With D be CH=CH-NZ 2, each Z is respectively C herein 1-6Alkyl or represent C together 2-7Alkylidene group;
(ⅵ) C is NR 1 '-N=C(R 2 ')-CH 2R 3 'With D be H;
(ⅶ) C is NH-N=C(CO 2X)-CH 2R 3 'With D be H, X is C herein 1-6Alkyl;
(ⅷ) C is NR 1 'COR 2 'With D be CH 2R 3 ';
(ⅸ) C is NHCH 2CR 3 '(OR) 2With D be H, R is C herein 1-6Alkyl.
Indoline also can be by reduction (as using NaCNBH 3) prepare by the indoles of (ⅵ)～(ⅸ) generation of deriving from above.
At reaction growth (V)) the Leimgruber synthesis method) in, the formula IV compound can be pressed the method preparation: with 2-methyl nitrophenyl urea is raw material, uses dialkylformamide OHCNZ 2The dialkyl group carbonyl heat treated that contracts make, and the formula IV product can be by appropriate catalyst such as palladium and charcoal, selectively under certain pressure through the hydrogenation cyclization, produce the formula I compound, wherein R 1=R 2=R 3=H.
In reaction growth (ⅵ) (Fischer synthesis method), the formula IV compound can be pressed the method preparation: with the diazanyl phenylurea is raw material, with suitable ketone R 2 'COCH 2R 3 'Preferably make, and the formula IV product carries out cyclization with acid catalyst (example hydrochloric acid or sulfuric acid) by heating through the heating dehydrogenation.
In reaction growth (ⅶ) (Japp-Klingemann synthesis method), the formula IV compound can prepare as follows; With the aminophenyl urea is raw material, by diazotization, then under alkaline condition, makes for example CH of solvent with rare alcohol 3COCH(CO 2X)-CH 2R 3 '(wherein X is C 1-6Alkyl) processing makes.
The formula IV product can carry out cyclization by top Fischer synthesis method then.
In (Madelung) synthesis method of reaction growth (ⅷ)) in, make the formula IV compound in inert solvent with alkali selectively through the heating cyclization.
In reaction growth (ⅸ) (Nordlander synthesis method), make the formula IV compound in the mixture of trifluoroacetic anhydride/acid, pass through the heating cyclization.
Should be known in when D is hydrogen, can in the cyclization process, form any one or two indoles isomer.
Can be transformed into R respectively 2, R 3, R 4And R 7The radicals R of alkyl 2 ', R 3 ', R 4 'And R 7 'Suitable example, comprise the acyl group of common employing, this acyl group can be transformed into corresponding alkyl with general reduction method, for example uses sodium borohydride reduction in inert solvent, carries out hydrogenolysis again in inert solvent.The hydrogen substituting group can be obtained by alkoxy carbonyl, this alkoxy carbonyl can be transformed into hydrogen by hydrolysis and decarboxylation.Work as R 4During for hydroxyl, it preferably protects with for example benzyl (can slough by hydrogenation) in the formula II compound.
Can change R into 1R 1 'The suitable example of group comprises typical N-protected group, and for example alkoxy carbonyl (particularly tert-butoxycarbonyl), ethanoyl, trifluoroacetyl group, benzyl and to methoxy-benzyl can be transformed into R with these groups with normal condition 1Hydrogen.
Can be transformed into R 5R 5 'The suitable example of group comprises alkoxy carbonyl and benzyl or to methoxy-benzyl, these groups can be transformed into R with normal condition 5
The method of available routine is implemented R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7The phase co-conversion.
For example, as R wherein 1, R 2And R 3Be C 1-6Alkyl and R 5During for hydrogen, in inert solvent with the C of 1 mole of a great deal of 1-6Alkyl halide and 1 mole of suitable alkali of a great deal of carry out conventional alkylating, at R 5Introduce C on the position 1-6Alkyl is possible.By conventional alkylating, for example use C 1-6Alkyl halide and alkali is sodium hydride for example, perhaps by reduction C 1-6Acyl group also can be introduced R 1C 1-6Alkyl.
Use normal condition, encircle the selectivity halo of P or indoles/indoline ring respectively, can introduce R 4Halogen and R 7Halogen.
Should be known in any R of protection 1To R 12Hydrogen growth (and not requiring mutual transformation) all may be necessary.
In above-mentioned linked reaction (a) and annulation (b), protection (R particularly 1 'Hydrogen) also may be necessary.
Suitable protecting group and connection and the method for sloughing protecting group are conventional in organic chemistry filed, for example visible Greene T.W ' Protective groups in organic Synthesis'New York, Wiley(1981).
Yet, before coupling formula II and formula III compound or cyclization formula IV compound, preferably introduce and phase co-conversion R 1To R 12Group.
By the method for routine, for example use NaCNBH 3In acetate, reduce and use MnO 2In inert solvent, carry out oxidation, formula I compound (indoles of replacement and their suitable derivatives) can be transformed into corresponding indoline, and conversely also like this.
Wherein A is NHR 5 'The formula II compound be known compound, maybe can prepare similarly, for example referring to WO92/05170 by known compound.
Wherein A can be that the formula II compound of following groups prepares by handling A wherein for the formula II compound of-N=C=O:
ⅰ) A is amino, with phosgene or phosgene coordinator, in inert solvent in the presence of excess base Processing of Preparation.
ⅱ) A is that acid azide (is CON 3), with ordinary method (referring to L.S.Trifonov etc., Helv.Chim.Acta 1987,70,262) by thermal rearrangement through the nitrence Processing of Preparation.
ⅲ) A is CONH 2, with normal condition process nitrence intermediate Processing of Preparation.
Wherein A is-NR 5 'The formula II compound of COL can by in inert solvent under low temperature, if desired, in the presence of 1 equivalent free alkali (for example triethylamine), general wherein A be-NHR 5 'Formula II compound and phosgene or phosgene coordinator prepared in reaction.
The formula III compound can be pressed the method preparation:
(a) cyclization formula (V) compound restores into amine if desired,
Figure 931165539_IMG10
Wherein Q is CR 13R 14L, CR 13O or CO 2R, L is a leavings group here, R 13And R 14With the definition in the formula I, m is 1 or 2, R 1 ', R 2 ', R 3 ', R 7 ', R 10 ', R 11 ', R 13 'And R 14 'With the definition in the above-mentioned formula III, R 6 'Be the defined R of formula III 6Group, R are aryl or C 1-6Alkyl, perhaps
(b) cyclization formula VI compound,
Figure 931165539_IMG11
R wherein 6 ', R 7 ', R 13 ', R 14 'With the definition in the n cotype (V), C and D are with the definition in the above-mentioned formula IV.
The cyclization effect of formula (V) compound is adapted in the inert solvent under envrionment temperature or the elevated temperature, at random carry out in the presence of free alkali.The reduction technique of available routine carries out reductive action.The method that the cyclization of formula IV compound was summarized above the cyclization effect of formula VI compound was fit to use is carried out.
Wherein A is halogen and R 4 'For the formula II compound of hydrogen can have been bought.
Formula III and (IV) new intermediate also constitute a part of the present invention.
Salt by pharmaceutically being suitable for suitable acid or sour derivatives reaction preparation routinely.
Routinely by forming the N-oxide compound with hydrogen peroxide or percarboxylic acids reaction.
Formula I compound and the salt that pharmaceutically is suitable for thereof have 5HT 20Receptor antagonist activity, and some compound exhibits goes out 5HT 28Antagonistic activity.Therefore, it is believed that the formula I compound can be applicable to treatment or prevention of anxiety disease, dysthymia disorders, migraine, apositia, anancastic obstacle, early senile dementia, somnopathy, exessive appetite, panic attack, withdrawal Drug abuse, schizophrenia, and with spinal cord injury and/or the relevant illness of brain injury (for example hydrocephalus).
Therefore, the salt that the present invention also provides formula I compound or its pharmaceutically to be suitable for is used as therapeutant, especially for treating or prevent above-mentioned illness.
The present invention further provides treatment or prevented the method for above-mentioned illness, this method comprises and gives formula I compound or its salt that pharmaceutically is suitable for that the patient takes effective dose.
On the other hand, the invention provides salt that formula I compound or its pharmaceutically be suitable in the preparation treatment or prevent application in the medicine of above-mentioned illness.
The present invention also provides a kind of medicinal compositions, and said composition comprises salt that formula I compound or its pharmaceutically are suitable for and the carrier that pharmaceutically is suitable for.
Medicinal compositions of the present invention, can under envrionment temperature and barometric point, make suitably by mixed, the present composition is applicable to oral administration, parenteral administration or rectal administration usually, therefore, can be following formulation: but the solution of tablet, capsule, oral liquid, pulvis, granula, lozenge, recoverable pulvis, injectable or infusion or suspension liquor perhaps are suppository.Usually preferentially select liquid preparations for oral administration for use.
The tablet and the capsule that are used for oral administration can be unit dosage forms, and can contain conventional excipients, for example tackiness agent, filler, tablet lubricants, disintegrating agent and suitable wetting agent.The method of knowing in can learning according to General Medicine is with tablet coating.
Oral liquid can be a following dosage forms, for example water or oil suspension agent, solution, emulsion, syrup or elixir, or the exsiccant product form that water or other suitable carriers are prepared again before usefulness.These liquid preparations can contain typical additives for example suspension agent, emulsifying agent, nonaqueous carrier (can comprise edible oil), sanitas, if desired, also can use seasonings commonly used or pigment.
For parenteral administration, salt and sterile carrier that available The compounds of this invention or its pharmaceutically are suitable for prepare the liquid unit doses form.According to the concentration of carrier and use, with compound or suspension or be dissolved in this carrier.When the obtain solution agent, compound dissolution is as injection and first filtration sterilization before pack into suitable vial or ampoule and air-tight bottle.Additive for example local anesthetic, sanitas and buffer reagent to be dissolved in the carrier be useful.In order to increase stability, composition freezing and vacuum after the vial of packing into can be removed moisture content.With the suspension liquor of same in fact method preparation parenteral administration, only compound is to be suspended in the carrier rather than dissolving, and sterilization can not be finished with filtration.Before in being suspended in sterile carrier with the compound ethylene oxide sterilizing.Comprise tensio-active agent or wetting agent in the composition, help making the easy uniform distribution of compound.
According to medication, composition can contain 0.1% to 99%(weight percent), best 10% to 60%(weight percent) active substance.
The dosage that is used for the treatment of the compound of above-mentioned illness changes with severity of disease, patient's body weight and other similar factor usually.Yet as general guide, suitable unitary dose can be 0.05 to 1000mg, and more suitable is 0.05 to 20.0mg, and for example 0.2 to 5mg; And this unitary dose can be administered once above every day, for example administration two in a day or three times, so every day total dosage in about 0.1 to 100mg scope; And this treatment can continue several weeks or several months.
During according to administration of the present invention, unacceptable toxic side effect does not appear in The compounds of this invention.
The following examples have been set forth the preparation method with The compounds of this invention that pharmacologically active is arranged.Following illustrative examples has been set forth the intermediates preparation of The compounds of this invention.
Illustrative examples 1
The amino indoline (D1) of 1-ethanoyl-5-
Under nitrogen atmosphere, with 1-ethanoyl-5-nitro indoline (12.77g, 62mmol), hexanaphthene (62ml, 610mmol) and 5% palladium charcoal (2.34g) stirring and refluxing 18 hours.Add other a catalyzer (0.5g) and continue and refluxed 3 hours.Cooling mixture by diatomite filtration and evaporation, obtains title compound (9.33g, 85%), is the orange solid.
NMR（D 6-DMSO）δ：2.05（3H，s），3.0（2H，t，J8），3.97（2H，t，J8），4.97（2H，bs），6.33（1H，dd，J7，1），6.46（1H，d，J1），7.72（1H，d，J7）.
Illustrative examples 2
N-(1-ethanoyl-5-indolinyl)-2,2-diethoxy ethamine (D2)
Under nitrogen atmosphere with the amino indoline (D1) of 1-ethanoyl-5-(9.33g, 53mmol), bromacetal (6.0ml, 40mmol) and sodium bicarbonate (4.58g, 54mmol) stirring and refluxing is 64 hours.(2.0ml 13mmol), and continues to reflux 24 hours again to add more acetal then.Cooling mixture filters and is evaporated to dried.Through silica gel column chromatography, with ethyl acetate/petroleum ether (b.p.60-80 ℃) (50-100% ethyl acetate) wash-out, obtain title compound (6.59g), be the yellowish brown solid, obtain the raw material amine (3.09g) that reclaims in addition.The productive rate of product is that 63%(is that benchmark calculates with the raw material that expends).
NMR（CDCl 3）δ：1.25（6H，t，J7），2.2（3H，s），3.13（2H，t，J8），3.22（2H，d，J5），3.5-3.65（2H，m），3.65-3.8（2H，m），4.01（2H，t，J8），4.68（1H，t，J5），6.5（2H，m），8.03（1H，d，J7）.
Alternative method
Under 45 ℃ of hydrogen pressure conditions, the amino indoline of 1-ethanoyl-5-(D1) is carried out reductive alkylation with the oxalic dialdehyde monomethyl carbonyl that contracts with 10% palladium charcoal and 50 pounds/square inch.Remove by filter catalyzer, then evaporating solvent obtains the corresponding dimethyl carbonyl that contracts, and its alternative diethyl carbonyl that contracts directly applies in the illustrative examples 3.
Illustrative examples 3
1-ethanoyl-5-trifluoroacetyl group-2,3-dihydroxy pyrrolo-[2,3-f] indoles (D3)
Under agitation in the mixed solution of ice-cold trifluoroacetic acid (25ml) and trifluoroacetic anhydride (25ml), add N-(1-ethanoyl-5-indolinyl)-2,2-diethoxy ethamine (D2) (6.51g, 22mmol).Mixture was stirred 0.5 hour under nitrogen atmosphere in 0 ℃, and then add trifluoroacetic acid (40ml).Mixture heating up was refluxed 64 hours, cool off and be evaporated to dried.Through silica gel column chromatography, with ethyl acetate/chloroform (0-60% ethyl acetate) wash-out, obtain title compound (6.28g, 89%), be faint yellow solid, rotation then deepens a little.
NMR（CDCl 3）δ：2.33（3H，s），3.37（2H，t，J8），4.17（2H，t，J7），6.76（1H，d，J3），7.45（1H，m），8.27（1H，s），8.44（1H，s）.
Illustrative examples 4
1-ethanoyl-2,3-pyrrolin be [2,3-f] indoles (D4) also
Under agitation with 1-ethanoyl-5-trifluoroacetyl group-2, the 3-pyrrolin also [2,3-f] indoles (D3) (2.80g 9.4mmol) is suspended in the methyl alcohol (100ml), add Anhydrous potassium carbonate (1.96g, 14.2mmol).Mixture stirred 0.5 hour, was evaporated to driedly, and distributed between ethyl acetate and water.After the separation, water section merges organic layer, drying (Na with 5% methyl alcohol/chloroform extraction 2SO 4), filter and evaporation, obtain title compound (1.53g, 80%), be beige solid.
NMR（D 6-DMSO）δ：2.15（3H，s），3.18（2H，t，J8），4.08（2H，t，J8），6.33（1H，bs），7.2（2H，m），8.22（1H，s），10.9（1H，bs）.
Illustrative examples 5
1-ethanoyl-5-methyl-2,3-pyrrolin be [2,3-f] indoles (D5) also
Under nitrogen atmosphere; with sodium hydride (80%; 0.25g; 8.3mmol) place anhydrous (N; dinethylformamide (DMF) stirs in (5ml), when adding 1-ethanoyl-2, and 3-pyrrolin also [2; 3-f] effervescence arranged during indoles (D4) (1.52g, DMF(20ml 7.6mmol)) solution.Mixture stirred 0.5 hour, added methyl iodide (0.52ml, DMF(5ml 8.3mmol)) solution then.Further stir after 1 hour, superfluous sodium hydride is stopped reaction by adding entry (1ml), mixture is distributed between ethyl acetate and water and separates.Organic moiety water and salt water washing, drying (Na 2SO 4) and evaporation.Through silica gel column chromatography, with ethyl acetate/chloroform (0-50% ethyl acetate) wash-out, obtain title compound (0.80g, 49%), be faint yellow solid.
NMR(CDCl 3) about 5: 1 rotational isomer miscellany δ:
2.26(main, 3H, s), 2.51(is accessory, 3H, s), 3.16(is accessory, 2H, and t, J8), 3.3(main, 2H, t, J8), 3.74(is main, 3H, s), 3.77(is accessory, 3H, s), 4.1(main, 2H, t, J8), 4.19(is accessory, 2H, t, J8), 6.44(both, 1H, d, J2), 6.98(is main, 1H, d, J2), 7.0(is accessory, and m), 7.09(is main, 1H, s), 7.18(is accessory, 1H, and s), 7.31(is accessory, 1H, s), 8.48(is main, 1H, s).
Illustrative examples 6
5-methyl-2,3-pyrrolin be [2,3-f] indoles (D6) also
Under nitrogen atmosphere with 1-ethanoyl-5-methyl-2, the 3-pyrrolin also [2,3-f] indoles (D5) (0.70g 3.3mmol) placed 10% sodium hydroxide solution (50ml) stirring and refluxing 4 hours.With the mixture cooling, water (200ml) dilution, and use ethyl acetate extraction.Extraction liquid drying (Na 2SO 4) and evaporation obtain title compound (0.58g), be the light brown colloid, still contain 20% the raw material acid amides (NMR) of having an appointment.The not purified next step that is used for of this material.
NMR（CDCl 3）δ：3.12（2H，t，J9），3.33（1H，bs），3.56（2H，t，J9），3.7（3H，s），6.27（1H，d，J3），6.85（1H，s），6.9（1H，d，J3），7.08（1H，s）.
Illustrative examples 7
(1-methyl-5-nitro-4-indyl) acetonitrile (D7)
(0.77g, 4.4mmol) (0.88g 5.2mmol) places dry DMF (10ml) to stir, and adds potassium tert.-butoxide (1.47g, dry DMF 13.1mmol) (10ml) solution with (4-chlorophenoxy) acetonitrile with 1-methyl-5-nitro indoles at 0 ℃.Mixture stirred 15 minutes at 0 ℃, pours into again in the 1M hydrochloric acid (200ml), and till being stirred to precipitation and condensing.Leach solid and dry then.Through silica gel column chromatography, use the chloroform wash-out, obtain title compound (0.48g, 51%), be yellow solid.
NMR（CDCl 3）δ：3.9（3H，s），4.37（2H，s），6.78（1H，d，J3），7.31（1H，d，J3），7.38（1H，d，J8），8.12（1H，d，J8）.
Illustrative examples 8
2-(1-methyl-5-nitro-4-indyl) ethanol
Under nitrogen atmosphere, (3.36g 15.6mmol) places anhydrous tetrahydro furan (THF) (100ml) to stir, and adds diisobutyl aluminium hydride (1.5M toluene solution simultaneously with (1-methyl-5-nitro-4-indyl) acetonitrile (D7), 21ml, 31.5mmol).Mixture stirred 6 hours, added methyl alcohol (25ml).After other 5 minutes, water (500ml) dilution is used the 5M hcl acidifying, and is used chloroform extraction.Extraction liquid drying (Na 2SO 4), flash to the dusky colloid, be resuspended in the ethanol (100ml).(0.88g 23.1mmol), and with mixture stirring 0.5 hour, adds second part of same sodium borohydride to add sodium borohydride.After the restir 0.5 hour, mixture water (500ml) dilution.Use the 5M hcl acidifying, and use chloroform extraction.Extraction liquid salt water washing, dry (Na 2SO 4) and evaporate brown colloid.Through silica gel column chromatography, with ethyl acetate/petroleum ether (b.p.60-80 ℃) (20-60% ethyl acetate) wash-out, obtain title compound (0.50g, 15%), be brown oil.
NMR（CDCl 3）δ：3.47（2H，t，J7），3.78（3H，s），4.02（2H，t，J7），6.73（1H，d，J3），7.2（2H，m），7.89（1H，d，J8）.
Illustrative examples 9
Methylsulfonic acid 2-(1-methyl-5-nitro-4-indyl) ethyl ester (D9)
With 2-(1-methyl-5-nitro-4-indyl) ethanol (D8) (0.50g, 2.3mmol) and triethylamine (0.38ml 2.7mmol) stirs in methylene dichloride (10ml), and add methylsulfonyl chloride (0.21ml, 2.7mmol).Mixture stirred 10 minutes, added entry (10ml) simultaneously, and vigorous stirring is 10 minutes again.With layering behind the 5M hcl acidifying, organic moiety drying (Na 2SO 4) and evaporation obtain the dark oil thing.Through silica gel column chromatography, use the methylene dichloride wash-out then with chloroform earlier, obtain title compound (0.54g, 79%), be the orange solid.
NMR（CDCl 3）δ：2.44（3H，s），3.68（2H，t，J7），3.85（3H，s），4.63（2H，t，J7），6.81（1H，d，J3），7.25（1H，d，J3），7.3（1H，d，J8），8.0（1H，d，J8）.
Illustrative examples 10
6-methyl-2,3-pyrrolin be [3,2-e] indoles (D10) also
In dry DMF (20ml) with 5% palladium charcoal (0.23g) with 80 pounds of/square inch H 2Pressure is with methylsulfonic acid 2-(1-methyl-5-nitro-4-indyl) ethyl ester (D9) hydrogenation 2 hours, with ethanol (80ml) dilution, by diatomite filtration, and evaporate brown colloid.With the title compound purifying, obtain 6-methyl-2 by preparation HCl salt, the 3-pyrrolin is [3,2-e] indole hydrochloride also.
Illustrative examples 11
N-(1-ethanoyl-5-indolinyl)-2-chlorallyl amine (D11)
With the amino indoline (D1) of 1-ethanoyl-5-(4.36g, 24.8mmol), (5.1g, 37mmol) and 2, (4.5ml 48.9mmol) stirred 16 hours in 70 ℃ in dry DMF (50ml) 3-two chloro-1-propylene Anhydrous potassium carbonate.Water (500ml) diluted mixture thing then, and stirred 10 minutes.Filter and, obtain title compound (5.71g, 92%), be the dark olive solid at air drying.
NMR（CDCl 3）δ：2.19（3H，s），3.13（2H，t，J8），3.9-4.2（5H，m），5.32（1H，m），5.41（1H，m），6.4-6.6（2H，m），8.05（1H，d，J9）
Illustrative examples 12
N-(1-ethanoyl-5-indolinyl)-2-chloro-N-TFA base allyl amine (D12)
With N-(1-ethanoyl-5-indolinyl)-2-chlorallyl amine (D11) (5.71g; 24.8mmol) and triethylamine (3.8ml; 27.3mmol) in chloroform (100ml), stir, and with 1 fen clock time dropping trifluoroacetic anhydride (3.8ml, 27.3mmol).Mixture stirred 1 hour, added entry (100ml) simultaneously.Mixture vigorous stirring 20 minutes is with 5M hcl acidifying and separation.Organic moiety drying (Na 2SO 4) and evaporation, obtain title compound (7.49g, 95%), for the dark oil thing, solidify in the placement.
NMR（CDCl 3）δ：2.25（3H，s），3.24（2H，t，J8），4.16（2H，t，J8），4.52（2H，s），5.23（1H，s），5.36（1H，s），7.1（2H，m），8.23（1H，d，J8）
Illustrative examples 13
1-ethanoyl-7-methyl-5-trifluoroacetyl group-2, the 3-pyrrolin is [2,3-f] indoles (D13) also
With N-(1-ethanoyl-5-indolinyl)-(7.63g 22mmol) stirred 1.5 hours at 140 ℃ in Tripyrophosphoric acid (38g) 2-chloro-N-TFA base allyl amine (D12).Cooling mixture is dispersed in the water (200ml) and uses ethyl acetate extraction.Extraction liquid is through diatomite filtration, dry (Na 2SO 4) and evaporation obtain black colloid (about 3g).Through silica gel column chromatography, with 0-20% ethyl acetate/chloroform wash-out, obtain title compound (0.49g, 7%), be light yellow solid.
NMR（CDCl 3）δ：2.28（3H，s），2.33（3H，s），3.36（2H，t，J8），4.18（2H，t，J8），7.19（1H，s），8.24（1H，s），8.36（1H，s）.
Illustrative examples 14
1-ethanoyl-7-methyl-2,3-pyrrolin be [2,3-f] indoles (D14) also
According to the method for illustrative examples 4, but the dilute with water processing, by 1-ethanoyl-7-methyl-5-trifluoroacetyl group-2, the 3-pyrrolin is [2,3-f] indoles (D13) (0.49g, 1.58mmol) preparation title compound also.Obtain title compound (0.31g, 91%) by filtering separation and drying, be yellow solid.
NMR（D 6-DMSO）δ：2.15（3H，s），2.18（3H，s），3.17（2H，t，J8），4.09（2H，t，J8），7.00（1H，s），7.14（1H，s），8.16（1H，s），10.55（1H，bs）
Illustrative examples 15
1-ethanoyl-5,7-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D15) also
According to the method for illustrative examples 5, but the dilute with water processing, by 1-ethanoyl-7-methyl-2, the 3-pyrrolin is [2,3-f] indoles (D14) (0.31g, 1.46mmol) preparation title compound also.Obtain title compound (0.26g, 79%) by filtering separation and drying, be the orange solid.
NMR(CDCl 3) about 5: 1 rotational isomer mixture, δ:
2.27 ﹠amp; 2.30(main, 3H, s+ both, 3H, s), 2.53(accessory, 3H, s), 3.15(is accessory, 2H, t, J8), 3.30(is main, 2H, t, J8), 3.68(is main, 3H, and s), 3.70(is accessory, 3H, s), 4.10(is main, 2H, t, J8), 4.20(is accessory, 2H, and t, J8), 6.76(main, 1H, s), 6.80(is accessory, 1H, s), 7.05(is main, 1H, and s), 7.13(is accessory, 1H, s), 7.19(is accessory, 1H, s), 8.42(is main, 1H, s).
Illustrative examples 16
5,7-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D16) also
According to the method for illustrative examples 6, make solvent with 5:1 10% sodium hydroxide solution/ethanol, by 1-ethanoyl-5,7-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D15) (0.44g, 1.93mmol) preparation title compound also.React after 7 hours NMR and show that 60% reaction is arranged approximately, but this product (0.30g) is used for next step and need isolate starting raw material.
Illustrative examples 17
1-ethanoyl-5-ethyl-2,3-pyrrolin be [2,3-f] indoles (D17) also
By preparation D5 similar methods, by 1-ethanoyl-2,3-pyrrolin also [2,3-f] indoles (D4), sodium hydride and iodic ether prepares title compound, productive rate 90%.
NMR(CDCl 3) the main signal of (rotational isomer miscellany) δ
1.44（3H，t，J8），2.23（3H，s），3.29（2H，t，J10），4.0-4.25（4H，m），6.43（1H，d，J3），7.03（1H，d，J3），7.10（1H，s），8.48（1H，s）
Illustrative examples 18
5-ethyl-2,3-pyrrolin be [2,3-f] indoles (D18) also
By the similar method of preparation D6, by 1-ethanoyl-5-ethyl-2, the 3-pyrrolin is [2,3-f] indoles (D17) preparation title compound also, productive rate 100%.
NMR（CDCl 3）δ：1.41（3H，t，J8），3.12（2H，t，J10），3.58（2H，t，J10），4.08（2H，q，J8），6.26（1H，d，J3），6.84（1H，s），6.97（1H，d，J3），7.12（1H，s）
Illustrative examples 19
1-ethanoyl-5-n-propyl-2,3-pyrrolin be [2,3-f] indoles (D19) also
By the method for illustrative examples 5, with sodium hydride (80%, 0.08g, 2.8mmol), 1-ethanoyl-2, the 3-pyrrolin also [2,3-f] indoles (D4) (0.4g, 2mmol) and 1-iodo propane (0.27ml, 2.8mmol) preparation.Mixture distributes between ether/water.Organic moiety is through separating, and dry and evaporation obtains title compound (0.48g, 99%), is yellow solid.
NMR(CDCl 3) about 4: 1 rotational isomer mixture, δ:
0.92(t, 3H, J=8.4Hz), 1.84(m, 2H, J=8.4Hz), 2.25(is main, s, 3H), 2.50(is accessory, s, 3H), 3.14(is accessory, t, 2H, J=8.4Hz), 3.29(is main, t, 2H, J=8.4Hz), 4.02(t, 2H, J=8.4Hz), 4.09(is main, t, 2H, J=8.4Hz), 4.19(is accessory, t, 2H, J=8.4Hz), and 6.44(d, 1H, J=5Hz), 7.02(d, 1H, J=5Hz), 7.10(s, 1H), 8.46(s, 1H).
Illustrative examples 20
5-n-propyl-2,3-pyrrolin be [2,3-f] indoles (D20) also
By the method for illustrative examples 6, with 1-ethanoyl-5-propyl group-2, also [2,3-f] indoles (D19) (0.48g, (30ml) solution of ethanol 1.9mmol) and 10%NaOH solution (5ml) preparation of 3-pyrrolin.Through silica gel column chromatography, use 3%MeOH/CH 2Cl 2Wash-out obtains title compound (0.23g, 60%).
NMR（CDCl 3）δ：0.93（t，3H，J＝8.4Hz），1.86（m，2H，J＝8.4Hz），3.12（t，2H，J＝8.4Hz），3.56（t，2H，J＝8.4Hz），4.01（t，2H，J＝8.4Hz），6.27（d，1H，J＝5Hz），6.87（s，1H），6.97（d，1H，J＝5Hz），7.02（s，1H）.
Illustrative examples 21
N-(1-ethanoyl-5-indolinyl)-2-chloro-N-methacrylic amine (D21)
(36mmol) (5ml, 15mmol) Yu Bingzhong stirs with 3M sulfuric acid for 40% aqueous solution, 2.8ml with formaldehyde.In this mixture, add sodium borohydride (1.66g in batches; 44mmol) with N-(1-ethanoyl-5-indolinyl)-2-chlorallyl amine (D11) (3.08g; 12.2mmol) suspension in tetrahydrofuran (THF) (60ml), and holding temperature is lower than 20 ℃.At ambient temperature mixture was stirred 0.25 hour then, and alkalize with excessive solid sodium hydroxide.Supernatant decanted liquid is with in the solid residue water-soluble (150ml) and use ethyl acetate extraction.Organic phase drying (the Na that merges 2SO 4) and evaporate brown tarry materials, it is dissolved in the chloroform dry again (Na 2SO 4), filtration and evaporation obtain title compound (3.80g,＞100%), are brown solid.Use this compound to need not purifying.
NMR（CDCl 3）δ：2.20（3H，s），3.00（3H，s），3.16（2H，t，J7），3.95-4.20（4H，m），5.22（1H，m），5.30（1H，m），6.56（2H，m），8.08（1H，d，J8）
Illustrative examples 22
1-ethanoyl-5,6-dimethyl-2,3-pyrrolin be [2,3-f] indoles and 1-ethanoyl-6 also, and 7-dimethyl-2,3-pyrrolin be [3,2-e] indoles (D22) also
With N-(1-ethanoyl-5-indolinyl)-2-chloro-N-methacrylic amine (D21) (2.1g 7.9mmol) stirred 24 hours in 140 ℃ in Tripyrophosphoric acid (44g), cooling, and dispersion in water (200ml), and use ethyl acetate extraction.Extraction liquid salt water washing, dry (Na 2SO 4) and evaporation obtain pink solid.Through silica gel column chromatography, the dichloromethane solution wash-out with the 0-20% ethyl acetate obtains:
1) product of very fast wash-out, [2,3-f] indoles (0.21g, 11.6%) of straight chain is white solid.NMR is shown as the mixture of rotational isomer, and ratio is about 5: 1.
NMR(CDCl 3) δ: 2.25(3H, main, s), 2.39(3H, main, s), 2.41(3H, accessory, s), 2.50(3H, accessory, s), 3.15(2H, accessory, t, J7), 3.29(2H, main, t, J7), 3.62(3H, main, s), 3.64(3H, accessory, s), 4.10(2H, main, t, J7), 4.19(2H, accessory, t, J7), 6.22(1H, both, s), 7.03(1H, main, s), 7.11(1H, accessory, s), 7.21(1H, accessory, s), 8.38(1H, main, s).
2) product of slow wash-out, [3,2-e] indoles (0.10g, 5.5%) is white solid on the angle.NMR is shown as the mixture of rotational isomer, and ratio is about 8: 1.
NMR(CDCl 3) δ: 2.25(3H, main, s), 2.4-2.5(3H, accessory ,+3H, both: m), 3.18(2H, accessory, t, J8), and 3.33(2H, main, t, J8), 3.56(3H, both, s), 4.15(2H, main, t, J8), 4.26(2H, accessory, t, J8), 6.1(1H, both, m), 7.0-7.15(1H, both, + 1H, accessory: m), 8.20(1H, main, d, J8).
Illustrative examples 23
5,6-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D23) also
According to the method for preparing D6, by 1-ethanoyl-5,6-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D22) (0.42g, 1.84mmol) preparation title compound also.The title compound that obtains (0.30g) is brown colloid.NMR shows that about 60% is transformed into desirable product.Use this product to need not purifying.
NMR（CDCl 3）δ：2.36（3H，s），3.12（2H，t，J7），3.56（2H，t，J7），3.58（3H，s），6.06（1H，s），6.78（1H，s），7.03（1H，s）.
Illustrative examples 24
6,7-dimethyl-2,3-pyrrolin be [3,2-e] indoles (D24) also
According to the method for preparing D6, by 1-ethanoyl-6,7-dimethyl-2,3-pyrrolin be [3,2-e] indoles (D22) (0.156g, 0.68mmol) preparation title compound also.The title compound that obtains (0.124g, 97%) is dark oily matter.
NMR（CDCl 3）δ：2.38（3H，s），3.16（2H，t，J7），3.6（5H，m），6.04（1H，s），6.63（1H，d，J8），6.95（1H，d，J8）
Illustrative examples 25
The N-(6-quinolyl) trifluoroacetamide (D25)
With the 6-quinolylamine (5.75g, 40mmol) and triethylamine (6.7ml 48mmol) stirs in chloroform (100ml), and in 2 minutes, add trifluoroacetic anhydride (6.7ml, 48mmol).Mixture stirred 1 hour, added entry (100ml) simultaneously.Stir after 5 minutes, leach the colloidal precipitation, with chloroform and water washing, and 50 ℃ of vacuum-dryings.The title compound that obtains (7.68g, 80%) is the bale of straw semisolid, includes remaining triethylamine (NMR).
NMR（CDCl 3）δ：7.57（1H，dd，J9，4），7.97（1H，dd，J9，2），8.08（1H，d，J9），8.4（2H，m），8.90（1H，dd，J5，2），11.63（1H，s）.
Illustrative examples 26
N-(1,2,3,4-tetrahydrochysene-6-quinolyl) trifluoroacetamide (D26)
With the N-(6-quinolyl) (6.84g, 28.5mmol) (1.36g 5.71mmol) stirs in methyl alcohol (100ml) trifluoroacetamide (D25) with six water nickelous chlorides.In 0.5 hour, add in batches sodium borohydride (4.3g, 113mmol).Behind the restir 0.5 hour, add other a sodium borohydride (1.0g, 26mmol).After 0.5 hour, mixture is evaporated to dried, between 5M hydrochloric acid (25ml) and ethyl acetate (100ml), distribute, and stir until limpid.Mixture neutralizes with excessive sodium bicarbonate, and separates.Water section is used ethyl acetate extraction again, the salt water washing of the organic phase of merging, dry (Na 2SO 4) and evaporation.Through silica gel column chromatography, with 0-30% ethyl acetate/chloroformic solution wash-out, obtain title compound (5.07g, 73%), be the light green solid.
NMR（CDCl 3）δ：1.44（2H，m），2.75（2H，t，J6），3.31（2H，t，J6），3.92（1H，bs），6.45（1H，d，J9），7.09（1H，dd，J9，2），7.16（1H，d，J2），7.65（1H，bs）.
Illustrative examples 27
N-(1-ethanoyl-1,2,3,4-tetrahydrochysene-6-quinolyl) trifluoroacetamide (D27)
With N-(1,2,3,4-tetrahydrochysene-6-quinolyl) trifluoroacetamide (D26) (5.64g, 23.1mmol) and Acetyl Chloride 98Min. (2.0ml 28mmol) stirs in methylene dichloride (100ml), add simultaneously pyridine (2.25ml, 28mmol).Mixture stirred 0.5 hour, added entry (100ml) simultaneously.Vigorous stirring is 0.25 hour again, uses the 5M hcl acidifying, and separates.With salt water washing organic moiety, dry (Na 2SO 4), and evaporation, obtain title compound (5.24g, 79%), be beige solid.
NMR（CDCl 3）δ：1.99（2H，m），2.25（3H，s），2.57（2H，t，J6），3.78（2H，t，J6），7.3（b），7.52（1H，bs），8.08（1H，bs）.
Illustrative examples 28
1-ethanoyl-6-amino-1,2,3,4-tetrahydroquinoline (D28)
With N-ethanoyl-1,2,3,4-tetrahydrochysene-6-quinolyl) (1.85g 6.5mmol) stirs in ethanol (15ml) trifluoroacetamide (D27), and adds sodium hydroxide (0.52g, 13.0mmol) solution in water (3ml).At ambient temperature mixture was stirred 0.5 hour, reflux is 0.25 hour then.Reflux after 0.5 hour, cooling mixture is used the 5M hcl acidifying, with solid sodium carbonate alkalization, water (100ml) dilution, and uses chloroform extraction.Extraction liquid drying (Na 2SO 4) and evaporation, obtain title compound (1.38g,＞100%), be brown oil, include remaining chloroform (NMR).
NMR（CDCl 3）δ：1.92（2H，m），2.27（3H，s），2.60（2H，m），3.67（2H，bs），3.79（2H，bm），6.5（2H，m），6.87（1H，bd，J6）.
Illustrative examples 29
1-ethanoyl-6-(2,2-diethoxy ethyl) amino-1,2,3,4-tetrahydroquinoline (D29)
Under argon atmospher, with 1-ethanoyl-6-amino-1,2,3, (2.35g, 12.4mmol) and N, (2.7ml 15.5mmol) 1, stirs in the 2-ethylene dichloride (50ml) the N-diisopropyl ethyl amine 4-tetrahydroquinoline (D28).Dripped trifluoromethanesulfonic acid 2 in 5 minutes, 2-diethoxy ethyl ester (3.78g, about 90% purity, about 13mmol) is 1, the solution in the 2-ethylene dichloride (10ml).Then mixture is refluxed and stirred 0.5 hour, cooling washes with water, dry (Na 2SO 4) and evaporation obtain the dark oil thing.This product and the product merging that obtains by same method with 1.40g quinolylamine reagent, through silica gel column chromatography, and with 0-100% ethyl acetate/chloroform wash-out.The title compound that obtains (3.72g, 61%) is amber oily thing, includes the material (NMR) of some dialkyl groupization.
NMR（CDCl 3）δ：1.25（6H，t，J7），1.92（2H，m），2.20（3H，s），2.63（2H，bm），3.25（2H，t，J5），3.5-3.9（7H，m），4.69（1H，t，J6），6.45（2H，m），6.89（1H，bd，J6）
Illustrative examples 30
5-ethanoyl-1-trifluoroacetyl group-5,6,7,8-tetrahydro-1 H-pyrrolo be [2,3-g] quinoline (D30) also
Under 0 ℃ and argon atmospher, with 1-ethanoyl-6-(2,2-diethoxy ethyl) amino-1,2,3, (3.72g 12.2mmol) places the mixed solution stirring 0.5 hour of trifluoroacetic acid (20ml) and trifluoroacetic anhydride (20ml) to 4-tetrahydroquinoline (D29).Add trifluoroacetic acid (30ml) again, solution is refluxed stirred 90 hours then, cooling and evaporation obtain the black jelly.Through silica gel column chromatography, with 0-60% ethyl acetate/chloroform wash-out, obtain title compound (2.77g, 73%), be amber oily thing.
NMR（CDCl 3/D 6-DMSO）δ：2.03（2H，m），2.25（3H，s），2.87（2H，t，J6），3.80（2H，t，J7），6.83（1H，d，J4），7.51（2H，m），8.25（1H，s）
Illustrative examples 31
5-ethanoyl-5,6,7,8-tetrahydro-1 H-pyrrolo be [2,3-g] quinoline (D31) also
With 5-ethanoyl-1-trifluoroacetyl group-5,6,7, the 8-tetrahydro-1 H-pyrrolo also [2,3-g] quinoline (D30) (2.76g, 8.9mmol) and Anhydrous potassium carbonate (3.7g 27mmol) stirred in methyl alcohol (50ml) 1 hour.With the mixture vacuum concentration, chloroform extraction is used in water (100ml) dilution then.Extraction liquid drying (Na 2SO 4) and evaporation, obtain title compound (1.40g, 73%), be the tangerine brown solid.NMR is shown as the rotational isomer mixture of about 9: 1 ratios.
NMR(CDCl 3) δ: 1.97(2H, main, m), 2.07(2H, accessory, m), 2.22(3H, both, s), 2.73(2H, main, t, J6), 3.01(2H, accessory, t, J6), 3.86(2H, both, t, J7), 6.52(1H, both, m), 7.20(2H, both, m), 7.34(1H, main, s), 8.33(1H, both, b).
Illustrative examples 32
5-ethanoyl-1-methyl-5,6,7,8-tetrahydro-1 H-pyrrolo be [2,3-g] quinoline (D32) also
In argon atmospher with under stirring; to sodium hydride (80% mineral oil solution; 0.25g; 8.3mmol) at DMF(5ml) and suspension in add 5-ethanoyl-5; 6,7,8-tetrahydro-1 H-pyrrolo also [2; 3-g] (1.39g is 6.5mmol) at the solution of anhydrous dimethyl formamide (DMF) in (20ml) for quinoline (D31).Stir after 20 minutes, and the adding methyl iodide (0.61ml, 9.8mmol).Gained suspension was stirred 1 hour, water (100ml) dilution, and use ethyl acetate extraction.Extraction liquid water and salt water washing, dry (Na 2SO 4) and evaporation obtain jelly.Through silica gel column chromatography, with 0-100% ethyl acetate/chloroform wash-out, obtain title compound (0.97g, 65%), be light bale of straw oily thing, place after fixing.NMR is shown as the rotational isomer mixture of about 6: 1 ratios.
NMR(CDCl 3) δ: 1.97(2H, both, m), 2.20(3H, both, s), 2.75(2H, main, t, J6), and 2.98(2H, accessory, t, J6), 3.78(3H, both, s), 3.84(2H, both, t, J7), 6.45(1H, both, d, J3), 7.04(1H, both, d, J3), 7.12(1H, both, s), 7.31(1H, both, s).
Illustrative examples 33
1-methyl-5,6,7,8-tetrahydro-1 H-pyrrolo be [2,3-g] quinoline (D33) also
With 5-ethanoyl-1-methyl-5,6,7, the 8-tetrahydro-1 H-pyrrolo also [2,3-g] quinoline (D32) (0.96g 4.2mmol) is dissolved in the ethanol (10ml), and adds 2.5M sodium hydroxide (90ml).Mixture refluxed under argon atmospher stirred 23 hours, cooling, water (200ml) dilution, and use ethyl acetate extraction.Extraction liquid drying (Na 2SO 4) and evaporation, obtain title compound (0.64g, 81%), be the light brown jelly.
NMR（CDCl 3）δ：2.00（2H，m），2.95（2H，t，J6），3.0（1H，b），3.30（2H，t，J5.5），3.68（3H，s），6.20（1H，d，J3），6.72（1H，s），6.87（1H，d，J3），6.92（1H，s）.
Illustrative examples 34
3-(1-methyl-5-nitro-4-indyl) propionitrile (D34)
Under 100 ℃ and argon atmospher, with methylsulfonic acid 2-(1-methyl-5-nitro-4-indyl) and ethyl ester (D9) (1.60g, 5.4mmol) and sodium cyanide (0.53g, 10.8mmol) stirring 5 hours in anhydrous dimethyl sulfoxide (15ml).After the cooling,, wash dry (Na with water with ethyl acetate (150ml) diluted mixture thing 2SO 4) and evaporation, obtain title compound (1.16g, 94%), be brown solid.
NMR（CDCl 3）δ：2.93（2H，t，J7），3.60（2H，t，J7），3.87（3H，s），6.80（1H，d，J3），7.3（2H，m），8.05（1H，d，J8）.
Illustrative examples 35
3-(1-methyl-5-nitro-4-indyl) propionic acid (D35)
With 3-(1-methyl-5-nitro-4-indyl) (1.16g 5.1mmol) refluxes in concentrated hydrochloric acid (150ml) and stirred 7.5 hours propionitrile (D34), after the cooling, uses the ethyl acetate extraction dark mixture; Extraction liquid drying (Na 2SO 4) and evaporation, obtain title compound (0.74g, 59%), be brown solid.
NMR（CDCl 3）δ：2.88（2H，t，J7），3.55（2H，t，J7），3.84（3H，s），6.76（1H，d，J3），7.21（1H，d，J3），7.25（1H，d，J8），7.98（1H，d，J8）.
Illustrative examples 36
3-(1-methyl-5-nitro-4-indyl) methyl propionate (D36)
With 3-(1-methyl-5-nitro-4-indyl) (0.94g 3.8mmol) stirs in methyl alcohol (10ml) propionic acid (D35), simultaneously thionyl chloride (1ml).Then mixture is refluxed and stirred 2 hours, and be evaporated to dark oily matter.Through silica gel column chromatography, use the methylene dichloride wash-out, obtain title compound (0.58g, 58%), be faint yellow solid.
NMR（CDCl 3）δ：2.81（2H，t，J7），3.55（2H，t，J7），3.70（3H，s），3.84（3H，s），6.73（1H，d，J3），7.20（1H，d，J3），7.24（1H，d，J8），7.97（1H，d，J8）.
Illustrative examples 37
3-(1-methyl-5-nitro-4-indyl)-1-propyl alcohol (D37)
Under argon atmospher, with 3-(1-methyl-5-nitro-4-indyl) methyl propionate (D36) (0.46g 1.8mmol) stirs in tetrahydrofuran (THF) (25ml), add simultaneously in batches lithium aluminium hydride (0.10g, 2.6mmol).After 3 hours, add entry (0.5ml), 2.5M sodium hydroxide solution (0.75ml) and water (1.5ml) continuously.Then with mixture drying (Na 2SO 4) and evaporation, obtain brown oil.Through silica gel column chromatography, with the eluant solution of 0-20% ethyl acetate in methylene dichloride, obtain title compound (0.39g, 95%), be the orange solid.
NMR（CDCl 3）δ：2.05（2H，m），3.34（2H，t，J7），3.78（2H，q，J6），3.85（4H，m），6.77（1H，d，J3），7.18（1H，d，J3），7.22（1H，d，J8），7.96（1H，d，J8）
Illustrative examples 38
Methylsulfonic acid 3-(1-methyl-5-nitro-4-indyl)-1-propyl ester (D38)
According to the method for illustrative examples 8, by 3-(1-methyl-5-nitro-4-indyl)-1-propyl alcohol (D37) (0.39g, 1.7mmol) preparation title compound.The title compound that obtains (0.54g,＞100%) is a brown oil, uses this material to need not purifying.
NMR（CDCl 3）δ：2.25（2H，m），3.05（3H，s），3.36（2H，t，J7），3.84（3H，s），4.37（2H，t，J7），6.73（1H，d，J3），7.21（1H，d，J3），7.25（1H，d，J8），7.98（1H，d，J8）.
Illustrative examples 39
3-methyl-6,7,8,9-tetrahydrochysene-3H-pyrrolo-[3,2-f] quinoline (D39)
According to the method for illustrative examples 10, by methylsulfonic acid 3-(1-methyl-5-nitro-4-indyl)-1-propyl ester (D38) (0.54g, 1.7mmol) preparation title compound.With the sodium hydrogen carbonate solution neutralization, obtain title compound (0.21g, 65%), be brown oil.
NMR（CDCl 3）δ：2.05（2H，m），2.95（2H，t，J6），3.32（2H，t，J6），3.63（1H，b），3.73（3H，s），6.70（1H，d，J3），6.86（1H，d，J8），6.96（1H，d，J3），7.00（1H，d，J8）
Illustrative examples 40
6-methyl-8-(N, the N-dimethylamino methyl)-3-(3-pyridyl-formamyl)-2, the 3-pyrrolin is [3,2-e] indoles (D40) also
5 ℃ and stir under; to the ethanolic soln (0.46ml) of 37% formalin (0.2ml) and 33% dimethylamine 1; add 6-methyl-3-(3-pyridinylamino formyl radical in the mixture of 4-diox (3.5ml) and glacial acetic acid (3.5ml) mixed solvent)-2; 3-pyrrolin also [3; 2-e] indoles (E2) (0.65g; 2.2mmol) 1,4-diox (10ml) suspension.Mixture was stirred 20 hours at ambient temperature, and water (80ml) dilutes and alkalizes with 10% aqueous sodium hydroxide solution then.Filter, obtain title compound (D40) (0.66g, 85%), be pale solid.
NMR（D 6-DMSO）δ：2.17（6H，s），3.41（2H，s），3.50（2H，t，J＝8Hz），3.71（3H，s），4.19（2H，t，J＝8Hz）.7.11-7.17（1H，m），7.26-7.34（1H，m），7.88（1H，d，J＝8Hz），7.95-8.01（1H，m），8.16-8.22（1H，m），8.58（1H，s），8.74（1H，d，J＝4Hz）
Illustrative examples 41
2,3-dihydro-1-(1-imidazolyl carbonyl)-5-methyl isophthalic acid H-pyrrolo-[2,3-f] indoles (D41)
In carbonyl dimidazoles (0.71g, DMF(25ml 4.4mmol)) solution, add pyrrolin diindyl (D6) (0.69g, DMF(5ml 4mmol)) solution.Mixture was stirred 1 hour cooling and impouring water at 110 ℃-140 ℃.After precipitation forms, filter solid phase prod, wash with water and drying.Crude product is recrystallization in methylene dichloride/gasoline, obtains title compound (0.45g, 42%), m.p.178-180 ℃.
NMR(D 6-DMSO) δ: 3.22(2H, t, J=8), 3.77(3H, s), and 4.24(3H, t, J=8), 6.40(1H, d, J=4), 7.08(1H, s), 7.28(1H, d, J=4), 7.38(1H, s), 7.69(1H, s), and 7.83(1H, broad peak s), 8.24(1H, s).
Illustrative examples 42
1-ethanoyl-2-methyl indoline (D42)
Under argon atmospher with 2-methyl indoline (5.0g, 0.037mol) reflux 4 hours in diacetyl oxide (40ml) and pyridine (2ml).Cooling mixture is poured in the water (100ml), places 30 minutes, and (EtOAC 2 * 250ml), and the organic solution of merging is through washing (K in extraction 2CO 3Solution, dry (Na 2SO 4).Solution is filtered, and reduction vaporization is to doing, by post layer post (SiO 2, Et 2O) purifying obtains yellow oily product (6.57g, 96%), places post crystallization.
NMR（CDCl 3）δ：1.30（3H，d），2.30（3H，s），2.68（1H，d），3.41（1H，dd），4.49（1H，m），7.04（1H，t），7.24（2H，m），8.18（1H，d）.
Illustrative examples 43
1-ethanoyl-2-methyl-5-nitro indoline (D43)
In 1-ethanoyl-2-methyl indoline (D42) (6.57g 37.5mmol) is dissolved in AcOH(56ml), and add dense HNO 3(16ml) and AcOH(8ml) mixed solution.Under argon atmospher, this blue solution is heated to 50 ℃, then that solution becomes is red/brown and begin to send brown fume., after 2 hours solution is poured in the water (500ml) 50 ℃ of stirrings, is used EtOAc(300ml) extraction, through K 2CO 3Saturated aqueous solution (200ml) washing, dry (Na 2SO 4), reduction vaporization obtains orange.This oily matter is by column chromatography (SiO 2) purifying, obtain orange oily matter (7.82g, 95%), place after fixing.
NMR（CDCl 3）δ：
1.3（3H，d），2.30（3H，s），2.72（1H，d），3.41（1H，dd），4.58（1H，m），8.10（3H，m）.
Illustrative examples 44
1-ethanoyl-5-amino-2-methyl indoline (D44)
With 1-ethanoyl-2-methyl-5-nitro indoline (D43) (16g; 0.073mol) be dissolved in EtoH(180ml) in; add 10%Pd-C(0.3g), this suspension is hydrogenation 6 hours in Pa Er rocking bar hydrogenator (Parr rocker hydrogenator) under 50 ℃ and 50 pounds of/square inch pressure.Mixture is by diatomite filtration and be evaporated to driedly, obtains product (D44) (14.0g, 100%), is red oil.
NMR（CDCl 3）δ：1.30（3H，d），2.24（3H，s），2.58（1H，d），3.38（1H，dd），4.41（1H，m），6.58（2H，m），7.98（1H，d）.
Illustrative examples 45
1-ethanoyl-5-[(2, the 2-dimethoxy-ethyl)-amino]-2-methyl indoline (D45)
In 1-ethanoyl-5-amino-2-methyl indoline (D44) (5.0g 0.027mol) is dissolved in EtOH(100ml), add 10%Pd-C(0.5g), then add hydroxy-acetaldehyde dimethyl acetal (60% aqueous solution 5.53g, 1.2 equivalents).Mixture hydrogenation under rtp is also stirred and is spent the night, and by diatomite filtration, is evaporated near doing, and is dissolved in EtOAc(200ml) in, washing (H 2O, salt solution), dry (Na 2SO 4), reduction vaporization obtains product (D45) to doing then, is brown oil (7.69g, 95%).
NMR（CDCl 3）δ：1.30（3H，d），2.24（3H，s），2.58（1H，d），3.23（2H，d），3.33（1H，dd），3.41（6H，s），4.41（1H，m），4.58（1H，t），6.51（2H，m），7.98（1H，d）.
Illustrative examples 46
1-ethanoyl-2-methyl-2,3-pyrrolin be [2,3-f] indoles (D46) also
Under argon atmospher with 1-ethanoyl-5-[(2, the 2-dimethoxy-ethyl) amino]-2-methyl indoline (D45) (7.5g 0.027mol) is dissolved in TFA(32ml) in and be cooled to 0 ℃.Add TFAA(30ml), this brown solution stirred 30 minutes at 0 ℃.Add TFA(50ml), again this mixture heating up was refluxed 6 days, be evaporated to dried.With column chromatography (SiO 2, CH 2Cl 2/ MeOH0.5-0.75%) purifying obtains product, is pale pink solid (4.84g, 58%).With 2.84g(9.2mmol) be dissolved in MeOH(70ml) in, add anhydrous K 2CO 3(1.90g, 1.5 equivalents).With this mixture vigorous stirring 1 hour, be heated to 40 ℃ momently, cooling, be evaporated to dried, then at water and CHCl 3Between distribute.Organic layer drying (Na 2SO 4) and reduction vaporization to doing, obtain product (D46) (1.89g, 96%), be the light brown solid.
NMR（CDCl 3）δ：0.72（3H，d），2.17（1H，d），2.52（3H，s），2.91（1H，m），3.98（1H，m），5.80（1H，s），6.58（1H，s），6.68（1H，s），7.70（1H，s），9.95（1H，s，N-H）
Illustrative examples 47
2-methyl-2,3-pyrrolin be [2,3-f] indoles (D47) also
Under argon atmospher with 1-ethanoyl-2-methyl-2, the 3-pyrrolin also [2,3-f] indoles (D46) (2.55g 0.0119mol) places EtOH(30ml) and 10%NaOH(120ml) reflux spend the night.Mixture EtOAc(2 * 200ml) extraction, organic solution drying (Na 2SO 4), be evaporated to driedly, use column chromatography (SiO again 2, Et 2O/MeOH 1%) purifying, obtain product (D47) (1.4g, 68%).
NMR（CDCl 3）δ：1.32（3H，d），2.71（1H，dd），3.19（1H，dd），3.98（1H，m），6.38（1H，s），6.83（1H，s），7.07（1H，s），7.12（1H，s），7.92（1H，bs，NH）
Illustrative examples 48
1-ethanoyl-2,5-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D48) also
According to the method for illustrative examples 5, with 1-ethanoyl-2-methyl-2,3-pyrrolin also [2; 3-f] indoles (D46) (1.35g; 6.3mmol) dry DMF (10ml) solution, NaH(265mg, 80% oil suspension) DMF(10ml) solution and MeI(0.55ml, 1.4 equivalents).The reaction finish after, mixture is evaporated to dried, at saturated K 2CO 3The aqueous solution (100ml) and CH 2Cl 2(distribute between 3 * 100ml), the organic solution drying merges, and revaporization is used column chromatography (SiO subsequently to doing 2, Et 2O/MeOH 2-20%) purifying obtains product (D48), is faint yellow solid (1.16g, 81%).
NMR（CDCl 3）δ：1.30（3H，d），2.32（3H，s），2.40（1H，d），2.75（1H，dd），3.76（3H，s，NMe），4.50（1H，m），6.47（1H，s），7.00（1H，s），7.12（1H，s），8.41（1H，s）.
Illustrative examples 49
2,5-dimethyl-2,3-pyrrolin be [2,3-f] indoles (D49) also
Under argon atmospher (refractory pebbles valve) with 1-ethanoyl-2; 5-dimethyl-2; 3-pyrrolin also [2; 3-f] indoles (D48) (1.1g; 4.82mmol) at EtOH(40ml) and 10%NaOH(3.45ml; 1.8 equivalent) with solid NaOH(1.93g, 10 equivalents) reflux 6 hours together, at H 2O and CH 2Cl 2Between distribute, with organic solution drying (Na 2SO 4), be evaporated to driedly, use column chromatography (SiO then 2, CHCl 3/ MeOH 10%) purifying, obtain product, be oily matter (370mg, 37%).
NMR（CDCl 3）δ：1.30（3H，d），2.72（1H，dd），3.22（1H，dd），3.78（3H，s，NMe），4.00（1H，m），6.28（1H，d），6.89（1H，d），6.80（1H，s），7.08（1H，s）.
Embodiment 1
5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E1) also
Under ammonia atmosphere, (0.56g, 3.8mmol) stirring and refluxing 0.75 hour in dry toluene (20ml) is cooled to envrionment temperature then with nicotinoyl trinitride (Nicotinoyl azide).Under agitation add 5-methyl-2, the 3-pyrrolin is methylene fluoride (20ml) solution of [2,3-f] indoles (D6) (0.59g is nominally be 3.4mmol) also, forms precipitation immediately.This suspension stirred 2.5 hours, then solid was leached, with 1: 1 methylene dichloride/toluene wash, thorough drying again.Obtain title compound (0.60g, 60%), be light grey powder.
NMR（D 6-DMSO）δ：3.28（2H，t，J8），3.73（3H，s），4.17（2H，t，J8），
6.81（1H，d，J3），7.1-7.35（3H，m），8.0（1H，m），8.03（1H，s），8.21（1H，m），8.63（1H，s），8.76（1H，d，J2）.
Measured value: C, 70.1; H, 5.6; N, 18.8%
C 17H 16N 4O theoretical value C, 69.8; H, 5.5; N, 19.2%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 2
6-methyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles (E2) also
With methylsulfonic acid 2-(1-methyl-5-nitro-4-indyl) (0.38g is 1.3mmol) in dry DMF (20ml), with 5% palladium charcoal (0.23g), with 80 pounds/square inch H for ethyl ester (D9) 2Hydrogenation 2 hours with ethanol (80ml) dilution, by diatomite filtration, is evaporated to brown jelly then.It is dissolved in the methylene dichloride (10ml); with (the 0.20g of nicotinoyl trinitride described in the embodiment 1; 2.35mmol) pyrolysis and the reaction of the isocyanic acid 3-pyridine ester that forms; but adding before the above-mentioned jelly crude product mesylate (mesylate salt); to in isocyanic ester, add triethylamine (0.18g, 1.3mmol).React after 16 hours, filter, washing, and, obtain title compound (0.16g, 44%) as preceding method drying, be shallow green powder.
NMR（D 6-DMSO）δ：3.33（2H，t，J8），3.77（3H，s），4.22（2H，t，J8），6.28（1H，d，J3），7.23（1H，d，J8），7.3（2H，m），7.89（1H，d，J8），8.0（1H，d，J8），8.2（1H，d，J5），8.61（1H，s），8.75（1H，d，J2）.
Measured value: C, 66.1; H, 5.4; N, 17.8%
C 17H 16N 4O.H 2O theoretical value C, 65.8; H, 5.8; N, 18.0%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 3
5,7-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E3) also
This compound is by 5, also [2,3-f] indoles (D16) (0.30g is nominally be 1.6mmol) the method preparation of pressing embodiment 1 of 7-dimethyl-2,3-pyrrolin.Obtain title compound (0.19g is 42% by D15 meter productive rate), be white solid, still contain trace toluene (NMR).
NMR（D 6-DMSO）δ：2.19（3H，s），3.27（2H，t，J8），3.67（3H，s），4.18（2H，t，J8），6.96（1H，s），7.21（1H，s），7.32（1H，dd，J7，4），8.00（1H，s），8.02（1H，dd，J7，2），8.22（1H，dd，J4，2），8.62（1H，s），8.77（1H，s）.
Measured value: C, 70.6; H, 6.0%; C 18H 18N 4O theoretical value C, 70.6; H, 5.9%
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 4
1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E4) also
The product that reaction is obtained is through silica gel column chromatography, and with the chloroformic solution wash-out of 0-5% methyl alcohol, at 5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is the impure product in [2,3-f] indoles (E1) sample also.Recrystallization in ethanol/sherwood oil (b.p.60-80 ℃) obtains thin grey needle crystal, and m.p.207-8 ℃ (decomposition) still contains ethanol in the crystallization.Also can make with the coupling of 3-pyridyl isocyanic ester then by hydrolysis D4.
NMR(D 6-DMSO) δ: 1.15(t, J7; EtOH), 3.34(2H, t, J8), 3.55(quintet, J7; EtOH), 4.26(2H, t, J8), 4.48(t, J6; EtOH), 6.42(1H, s), 7.31(2H, s), and 7.42(1H, dd, J7,4), 8.05-8.2(2H, m), and 8.31(1H, d, J4), 8.72(1H, s), 8.86(1H, s), 10.95(1H, s)
Measured value: C, 67.2; H, 6.1; N, 17.6%
C 16H 14N 4O.0.75(C 2H 6O) theoretical value C, 67.2; H, 6.0; N, 17.9%
Measured value: M +278, C 16H 14N 4O theoretical value 278
Embodiment 5
6-methyl-3-(4-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles (E5) also
Title compound by 4-aminopyridine, 1,1 '-carbonyl dimidazoles, 6-methyl-(2, the 3-pyrrolin is [3,2-e] indoles also) hydrochloride (D10) and triethylamine prepare in methylene dichloride/dimethyl formamide.Reaction mixture is poured in the water, obtained title compound, productive rate is 98%, m.p.＞230 ℃.
NMR（D 6-DMSO）δ：3.30（2H，t，J7），3.75（3H，s），4.25（2H，t，J7），6.30（1H，d，J4）;7.21（1H，d，J10），7.30（1H，d，J4），7.58（1H，s），7.62（1H，s），7.90（1H，d，J10），8.31（1H，s），8.36（1H，s），8.75（1H，s）.
Measured value: C, 69.5; H, 5.6; N, 19.1%, C 17H 16N 4O theoretical value C, 69.8; H, 5.5; 19.1%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 6
6-methyl-3-(2-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles (E6) also
With embodiment 5 similar methods, by 2-aminopyridine, 1,1 '-carbonyl dimidazoles, 6-methyl-(2, the 3-pyrrolin is [3,2-e] indoles also) hydrochloride (D10) and triethylamine prepare title compound, productive rate 39%, m.p.143-4 ℃.
NMR（D 6-DMSO）δ：3.35（2H，t，J7），3.85（3H，s），4.38（2H，t，J7），6.40（1H，d，J4），7.08-7.15（1H，m），7.33（1H，d，J7），7.41（1H，d，J4），7.79-7.89（1H，m），7.95-8.05（2H，m），8.39（1H，d，J4），9.00（1H，s）.
Measured value: C, 69.6; H, 5.6; N, 19.1%, C 17H 16N 4O theoretical value C, 69.8; H, 5.5; 19.2%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 7
5-methyl isophthalic acid-(2-pyridine formamyl)-2, the 3-pyrrolin is [2,3-f] indoles (E7) also
With embodiment 5 similar methods, by 2-aminopyridine, 1,1 '-carbonyl dimidazoles and 5-methyl-(2, the 3-pyrrolin is [2,3-f] indoles also) (D7) prepare title compound, productive rate 75%, m.p.137-8 ℃.
NMR（D 6-DMSO）δ：3.25（2H，t，J7），3.75（3H，s），4.21（2H，t，J7），6.31（1H，d，J4），7.03（1H，t，J4），7.20（1H，s），7.30（1H，s），7.75（1H，t，J7），7.95（1H，d，J7），8.04（1H，s），8.30（1H，d，J4），8.95（1H，s）.
Measured value: C, 66.0; H, 5.6; N, 18.0%, C 17H 16N 4O.H 2O theoretical value C, 65.8; H, 5.8; 18.0%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 8
5-methyl isophthalic acid-(4-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E8) also
With embodiment 5 similar methods, by 4-aminopyridine, 1,1 '-carbonyl dimidazoles and 5-methyl-(2, the 3-pyrrolin is [2,3-f] indoles also) (D7) prepare title compound, productive rate 84%, m.p.251-3 ℃.
NMR（D 6-DMSO）δ：3.25（2H，t，J7），3.72（3H，s），4.18（2H，t，J7），6.32（1H，d，J4），7.18（1H，d，J4），7.27（1H，s），7.62（2H，d，J7），8.05（1H，s），8.35（2H，d，J7），8.85（1H，s）.
Measured value: C, 69.2; H, 5.7; N, 19.0%, C 17H 16N 4O theoretical value C, 69.8; H, 5.5; 19.2%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 9
5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2,3,6, the 7-Pyrrolidine is [2,3-f] indoles (E9) also
At room temperature with 5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin also [2,3-f] indoles (E1) (0.8g, 2.7mmol) (0.86g, Glacial acetic acid 13.7mmol) (20ml) solution was handled 4 hours together with sodium cyanoborohydride.Add entry (100ml), mixture alkalizes with 10% aqueous sodium hydroxide solution.Use dichloromethane extraction, then dry (Na 2SO 4) and be evaporated to driedly, obtain solid.Recrystallization in methyl alcohol/60-80 gasoline obtains title compound (E9) (0.43g, 53%), is white crystalline solid, m.p.153-155 ℃.
NMR（D 6-DMSO）δ：2.62（3H，s），2.80（2H，t，J8），3.05（2H，t，J8），3.17（2H，t，J8），4.10（2H，t，J8），6.40（1H，s），7.30（1H，q，J4），7.65（1H，s），7.91-7.98（1H，m），8.19（1H，d，J4），8.55（1H，s），8.72（1H，d，J4）
Measured value: C, 68.7; H, 6.2; N, 18.9%, C 17H 18N 4O theoretical value C, 69.4; H, 6.2; 19.0%
Measured value: M +294, C 17H 18N 4O theoretical value 294
Embodiment 10
5-ethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E10) also
With being similar to the method for preparing E1, by 5-ethyl-2, the 3-pyrrolin is [2,3-f] indoles (D18) and isocyanic acid 3-pyridine ester (being made in the original place by the nicotinoyl trinitride) preparation title compound also, productive rate 58%, m.p.202-203 ℃.
NMR（D 6DMSO）δ：1.33（3H，t，J8），3.28（2H，t，J10），4.16（4H，m），6.31（1H，d，J3），7.24（1H，d，J3），7.30（1H，s），7.32（1H，m），8.00（1H，m），8.03（1H，s），8.22（1H，m），8.65（1H，s），8.77（1H，s）.
Measured value: C, 70.70; H, 6.01; N, 18.46%, C 18H 18N 4O theoretical value C, 70.57; H, 5.92; 18.29%
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 11
5-n-propyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E11) also
Press the method for embodiment 1, and usefulness nicotinoyl trinitride (0.19g, 1.4mmol) with 5-propyl group-2, also [2,3-f] indoles (0.23g, 1.2mmol) preparation of 3-pyrrolin.Through silica gel column chromatography, use 5%MeOH/CH 2Cl 2Wash-out obtains title compound (0.27g, 70%), is shallow green powder.
NMR（CDCl 3）δ：0.93（t，3H，J＝8.4Hz），1.87（m，2H，J＝8.4Hz），3.31（t，2H，J＝8.4Hz），4.05（t，2H，J＝8.4Hz），4.28（t，2H，J＝8.4Hz），6.45（d，1H，J＝2.8Hz），6.77（brs，1H），7.06（d，1H，J＝2.8Hz），7.18（s，1H），7.29（m，1H），7.92（s，1H），7.85（m，1H），8.30（dd，1H，J＝2.8Hz），8.51（s，1H）
Measured value: C, 70.54; H, 6.34; N, 17.39%
C 19H 20N 4O1/6H 2O theoretical value C, 70.58; H, 6.39; 17.33%
Measured value: M +=320, C 19H 20N 4O theoretical value 320
Embodiment 12
5,6-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E12) also
According to the method for embodiment 1, by 5, also [2,3-f] indoles (D23) (0.30g is nominally the be 1.61mmol) preparation of 6-dimethyl-2,3-pyrrolin.Obtain title compound (0.219g counts 39% by D22), be cream-coloured powder, contain remaining CH 2Cl 2(NMR), and in about 225 ℃ of decomposition.
NMR（D 6-DMSO）δ：2.36（3H，s），3.26（2H，t，J8），3.60（3H，s），4.17（2H，t，J8），6.11（1H，s），7.21（1H，s），7.32（1H，dd，J7，4），7.93（1H，s），8.00（1H，d，J7），8.21（1H，d，J4），8.63（1H，s），8.75（1H，d，J2）.
Measured value: C, 69.2; H, 5.9; N, 17.6%
C 18H 18N 4O(0.08CH 2Cl 2) theoretical value C, 69.3; H, 5.8; 17.9%
Measured value: M +=306, C 18H 18N 4O theoretical value 306
Embodiment 13
6,7-dimethyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles (E13) also
According to the method for embodiment 1, by 6, also [3,2-e] indoles (D24) (0.124g, 0.67mmol) preparation of 7-dimethyl-2,3-pyrrolin.Obtain title compound (0.128g, 62%), be light brown powder, contain remaining CH 2Cl 2(NMR), m.p.216-8 ℃ (decomposition).
NMR（D 6-DMSO）δ：2.45（3H，s），3.33（2H，t，J8），3.70（3H，s），4.28（2H，t，J8），6.15（1H，s），7.21（1H，d，J9），7.37（1H，dd，J8，5），7.86（1H，d，J9），8.06（1H，dm，J9），8.26（1H，d，J5），8.67（1H，s），8.81（1H，d，J2）.
Measured value: C, 69.4; H, 5.9; N, 17.7%
C 18H 18N 4O(0.08CH 2Cl 2) theoretical value C, 69.3; H, 5.8; 17.9%
Measured value: M +=306, C 18H 18N 4O theoretical value 306
Embodiment 14
1-methyl-N-(3-pyridyl)-5,6,7, the 8-tetrahydro-1 H-pyrrolo is [2,3-g] quinoline-5-methane amide (E14) also
According to the method for embodiment 1, by 1-methyl-5,6,7, the 8-tetrahydro-1 H-pyrrolo also [2,3-g] quinoline (D33) (0.64g 3.4mmol) prepares this material.Obtain light orange look solid, 0.64g(60%).Recrystallization in ethanol/sherwood oil (b.p.60-80 ℃) gets glossiness light orange look flap (0.56g), m.p.154.5-155.5 ℃.
NMR（D 6-DMSO）δ：1.93（2H，m），2.80（2H，t，J7），3.72（2H，t，J7），3.77（3H，s），6.34（1H，d，J3），7.25（3H，m），7.49（1H，s），7.89（1H，dt，J8，2），8.15（1H，dd，J4，2），8.65（2H，m）.
Measured value: C, 70.2; H, 5.4; N, 18.0%, C 18H 18N 4O theoretical value C, 70.6; H, 5.9; 18.3%
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 15
3-methyl-N-(3-pyridyl)-6,7,8,9-tetrahydrochysene-3H-pyrrolo-[3,2-f] quinoline-6-methane amide (E15)
According to the method for embodiment 1, by 3-methyl-6,7,8,9-tetrahydrochysene-3H-pyrrolo-[3,2-f] quinoline (D39) (0.21g, 1.1mmol) preparation.This reaction gets brown oil by evaporation process, through silica gel column chromatography, with 0-10% ethanol/methylene wash-out.Recrystallization in ethanol/sherwood oil (b.p.60-80 ℃) gets title compound (0.26g, 75%) at last, is beige solid, m.p.174-5 ℃, contains residual ethanol (NMR).
NMR（D 6-DMSO）δ：1.98（2H，m），2.94（2H，t，J7），3.75（5H，m），6.41（1H，d，J3），7.13（1H，d，J8），7.23（1H，d，J8），7.25-7.30（2H，m），7.89（1H，m），8.15（1H，d，J3），8.64（1H，m），8.77（1H，s）
Measured value: C, 70.2; H, 6.1; N, 17.8%, C 18H 18N 4O(0.14C 2H 6O) theoretical value C, 70.2; H, 6.1; N, 17.9%
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 16
6-methyl-3-(2-methyl-4-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles (E16) also
By 2-methyl-4-quinolylamine, 1,1 '-carbonyl dimidazoles, 6-methyl-(2, the 3-pyrrolin is [3,2-e] indoles also) hydrochloride (D10) and triethylamine prepare title compound, productive rate 76%, m.p.＞230 ℃.
NMR（D 6-DMSO）δ：2.60（3H，s），3.34（2H，t，J7），3.75（3H，s），4.42（2H，t，J7），6.31（1H，d，J3），7.25（1H，d，J8），7.35（1H，d，J3），7.52（1H，t，J7），7.70（1H，t，J7），7.80（1H，s），7.88（1H，s），7.92（1H，s），8.17（1H，d，J7），8.70（1H，s）
Measured value: C, 73.3; H, 5.8; N, 15.5%
C 22H 20N 40.1/4H 2O theoretical value C, 73.3; H, 5.7; 15.5%
Measured value: M +356, C 22H 20N 4O theoretical value 356
Embodiment 17
6-methyl-3-(5-quinolyl formamyl)-2,3-dihydro-pyrrolo-[3,2-e] indoles (E17)
By 5-quinolylamine, 1,1 '-carbonyl dimidazoles, 6-methyl-(2, the 3-pyrrolin is [3,2-e] indoles also) hydrochloride (D10) and triethylamine prepare title compound, productive rate 42%, m.p.＞240 ℃.
NMR（D 6-DMSO）δ：3.35（2H，t，J7），3.75（3H，s），4.38（2H，t，J7），6.30（1H，d，J4），7.19（1H，d，J8），7.30（1H，d，J4），7.50-7.58（1H，m），7.62（1H，d，J7），7.75（1H，t，J7），7.83-7.93（2H，m），8.45（1H，d，J7），8.70（1H，s），8.92（1H，d，J4）.
Measured value: C, 73.6; H, 5.50; N, 16.3%
C 21H 18N 4O theoretical value C, 73.7; H, 5.3; 16.4%
Measured value: M +342, C 21H 18N 4O theoretical value 342
Embodiment 18
6-methyl-3-(3-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles (E18) also
By 3-quinolylamine, 1,1 '-carbonyl dimidazoles, 6-methyl-(2, the 3-pyrrolin is [3,2-e] indoles also) hydrochloride (D10) and triethylamine prepare title compound, productive rate 53%, m.p.222-4 ℃
NMR（D 6-DMSO）δ：3.35（2H，d，J7），3.78（3H，s），4.32（2H，d，J7），6.30（1H，d，J4），7.25（1H，d，J8），7.32（1H，d，J4），7.50-7.68（2H，m），7.83-8.00（3H，m），8.54（1H，d，J4），8.82（1H，s），9.05（1H，s）
Measured value: C, 72.9; H, 5.5; N, 16.2%
C 21H 18N 40.1/4H 2O theoretical value C, 72.7; H, 5.3; N, 16.2%
Measured value: M +342, C 21H 18N 4O theoretical value 342
Embodiment 19
5-methyl isophthalic acid-(2-methyl-4-quinolyl formamyl)-2, the 3-pyrrolin is [2,3-f] indoles (E19) also
By 2-methyl-4-quinolylamine, 1,1 '-carbonyl dimidazoles and 5-methyl-(2, the 3-pyrrolin is [2,3-f] indoles also) (D6) prepare title compound, productive rate 57%, m.p.＞240 ℃.
NMR（D 6-DMSO）δ：2.64（3H，s），3.30（2H，t，J7），3.72（3H，s），4.38（2H，t，J7），6.3（1H，d，J4），7.20（1H，d，J4），7.30（1H，s），7.53（1H，t，J7），7.70（1H，t，J7），7.78（1H，s），7.90（1H，d，J7），8.08（1H，s），8.15（1H，d，J7），8.73（1H，s）
Embodiment 20
6,8-dimethyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles (E20) also
Under standard temperature and pressure (STP); with 6-methyl-8-(N; the N-dimethylamino methyl)-and 3-(3-pyridinylamino formyl radical)-2; 3-pyrrolin also [3; 2-e] indoles (D40) (0.5g; 1.4mmol) in ethanol (50ml), with 10% palladium-Pd/carbon catalyst (0.5g) hydrogenation 24 hours, hydrogenation 4 hours under 50 pounds/square inch again.By diatomite filtration, be evaporated to driedly then, obtain crude product.Through flash chromatography on silica gel, with 0-5% ethanol/methylene wash-out, use the ethyl acetate/methanol recrystallization then, obtain title compound (E20) (0.174g, 40%), be white crystal.m.p.228-230℃。
NMR（D 6-DMSO）δ：2.32（3H，s），3.55（2H，t，J＝8Hz），3.65（3H，s），4.21（2H，t，J＝8Hz），7.00（1H，s），7.10（1H，d，J＝8Hz），7.24-7.33（1H，m），7.83（1H，d，J＝8Hz），7.94-8.03（1H，m），8.19（1H，d，J＝4Hz），8.57（1H，s），8.73（1H，d，J＝3Hz）.
Measured value: C, 69.77; H, 6.00; N, 18.08%
C 18H 18N 40.1/5H 2O theoretical value C, 69.77; H, 5.94; N, 18.09%
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 21
6-methyl-3-(3-pyridinylamino formyl radical)-2,3,7, the 8-Pyrrolidine is [3,2-e] indoles (E21) also
At ambient temperature, with 6-methyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin also [3,2-e] indoles (E2) (1.0g 3.4mmol) is dissolved in the Glacial acetic acid (25ml), and (1.0g 0.016mol) handles with sodium cyanoborohydride.Mixture was stirred 4 hours water (100ml) dilution then.Mixture alkalizes with 10% aqueous sodium hydroxide solution, uses the dichloromethane extraction product again, uses dried over sodium sulfate.With solvent evaporation,,, obtain the white solid resistates with 0-5% ethanol/methylene wash-out then through flash chromatography on silica gel.With ethyl acetate/60-80 gasoline recrystallization, obtain title compound (E21), be m.p.201-203 ℃ of white crystal (0.68g, 67%).
NMR（D 6-DMSO）δ：2.75（3H，s），2.89（2H，t，J＝8Hz），3.15（2H，t，J＝8Hz），3.31（2H，t，J＝8Hz），4.22（2H，t，J＝8Hz），6.40（1H，d，J＝7Hz），7.33-7.45（1H，m），7.70（1H，d，J＝7Hz），8.03-812（1H，m），8.30（1H，d，J＝4Hz），8.65（1H，s），8.85（1H，d，J＝4Hz）.
Measured value: C, 69.07; H, 6.29; N, 18.90%, C 17H 18N 4O theoretical value C, 69.37; H, 6.16; N, 19.03%
Measured value: M +294, C 17H 18N 4O theoretical value 294
Embodiment 22
5-methyl isophthalic acid-(2-pyrazinyl formamyl)-2, the 3-pyrrolin is [2,3-f] indoles (E22) also
With embodiment 5 similar methods, by the amino pyrazine negatively charged ion (preparing) of 2-with sodium hydride, 1,1 '-carbonyl dimidazoles and 5-methyl-2,3-pyrrolin also [2,3-f] indoles prepares title compound, productive rate 75%, m.p.196-198 ℃ in dimethyl formamide.
NMR（D 6DMSO）δ：3.26（2H，t，J＝10），3.76（3H，s），4.25（2H，t，J＝10），6.33（1H，d，J＝3），7.20（1H，d，J＝3），7.28（1H，s），8.07（1H，s），8.28（1H，d，J＝2），8.37（1H，d，J＝2），9.19（1H，m），9.38（1H，s）.
Measured value: C, 65.55; H, 5.36; N, 23.54%, C 16H 15N 5O theoretical value C, 65.52; H, 5.15; N, 23.88%
Measured value: M +293, C 16H 15N 5O theoretical value 293
Embodiment 23
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isothiazolyl formamyl)-1H-pyrrolo-[3,2-e] indoles (E23)
To ice-cooled carbonyl dimidazoles (CDI) (0.445g, 2.75mmol) methylene dichloride (15ml) solution in add 5-amino-3-methyl isoniazthiolane hydrochlorate (0.38g, 2.5mmol) and triethylamine (0.35ml, methylene dichloride 2.5mmol) (15ml) solution.Mixture stirred 1 hour at 0 ℃, was evaporated to dried then.Resistates be dissolved in dimethyl formamide (DMF) (15ml) in, add pyrrolin diindyl hydrochloride (D10) (0.52g, 2.5mmol) and the DMF(2.5ml of triethylamine (0.35ml)) solution to this solution.This mixture heats and stirred 1 hour at about 130 ℃, then in cooling and the impouring water.Solid product is leached, wash with water and drying, grind with methylene chloride then.Milling liquid adds gasoline simultaneously through concentrating, and obtains precipitation, filters and merges with the resistates of development.Obtain title compound (0.42g, 54%) through vacuum-drying, m.p.＞250 ℃.
NMR（D 6-DMSO）δ：2.29（3H，s），3.33（2H，t，J＝7），3.75（3H，s），4.20（2H，t，J＝7），6.29（1H，d，J＝4），6.74（1H，s），7.25（1H，d，J＝9），7.32（1H，d，J＝4），7.90（1H，d，J＝9），10.41（1H，s）.
Measured value: C, 61.13; H, 5.16; N, 17.84%, C 16H 16N 4OS theoretical value C, 61.52; H, 5.16; N, 17.93%
Embodiment 24
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isothiazolyl formamyl)-1H-pyrrolo-[2,3-f] indoles (E24)
Method according to embodiment 23, with 5-amino-3-methyl isoniazthiolane hydrochlorate (0.60g, 4mmol), CDI(0.71g, 4.4mmol), triethylamine (0.56ml, 4mmol) with pyrrolin diindyl (D6) (0.69g, 4mmol) preparation title compound.Triethylamine only adds with the isoniazthiolane hydrochlorate.
With in the last mixture impouring water and after leaching product, crude product obtains title compound (0.76g, 61%), m.p.254-255 ℃ with methylene chloride/gasoline recrystallization.
NMR（D 6-DMSO）δ：2.30（3H，s），3.30（2H，t，J＝7），3.74（3H，s），4.14（2H，t，J＝7），6.35（1H，d，J＝4），6.76（1H，s），7.20（1H，d，J＝4），7.29（1H，s），8.08（1H，s），10.48（1H，s）.
Measured value: C, 61.31; H, 5.24; N, 17.74%, C 16H 16N 4OS theoretical value C, 61.52; H, 5.15; N, 17.93%
Embodiment 25
2,3-dihydro-5-methyl isophthalic acid-(5-quinolyl formamyl)-1H-pyrrolo-[2,3-f] indoles (E25)
According to the method for embodiment 23, with the 5-quinolylamine (0.58g, 4mmol), CDI(0.71g, 4.4mmol) and pyrrolin diindyl (D6) (0.69g, 4mmol) preparation title compound.Without triethylamine, and initial reaction mixture stirred 1 hour at 0 ℃, again stirring at room 0.5 hour.
With in the final mixture impouring water and after filtering out product, crude product is with methylene chloride/gasoline recrystallization, title compound (0.48g, 35%), m.p.240-243 ℃.
NMR（D 6-DMSO）δ：3.43（2H，t，J＝8），3.84（3H，s），4.42（2H，t，J＝8），6.37（1H，d，J＝4），7.27（1H，d，J＝4），7.38（1H，s），7.63（1H，dd，J＝8.5），7.72（1H，d，J＝8），7.87（1H，t，J＝8），7.99（1H，d，J＝8），8.08（1H，s），8.55（1H，d，J＝8），8.84（1H，s），9.00（1H，d，J＝5）.
Measured value: C, 72.85; H, 5.45; N, 16.36%, C 21H 18N 4O theoretical value C, 73.67; H, 5.30; N, 16.36%
Embodiment 26
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isoxazolyl formamyl)-1H-pyrrolo-[2,3-f] indoles (E26)
((0.12g 1.24mmol), stirs mixture 20 minutes at 0 ℃ to add 5-amino-3-methyl-isoxazole in dry DMF 1.33mmol) (10ml) suspension for 80% oil solution, 40mg to sodium hydride.(0.32g, 1.20mmol), mixture stirred 1.5 hours at 100-130 ℃, then in cooling and the impouring water to add imidazolyl formamyl pyrrolo-indole (D41) then.Sedimentation and filtration is come out, wash with water and drying, obtain title compound (0.17g, 48%), m.p.212-215 ℃.
NMR（D 6-DMSO）δ：2.19（3H，s），3.24（2H，t，J＝7），3.73（3H，s），4.14（2H，t，J＝7），6.07（1H，s），6.33（1H，d，J＝4），7.20（1H，d，J＝4），7.28（1H，s），8.05（1H，s），10.20（1H，s）.
Measured value: C, 64.83; H, 5.51; N, 18.83%, C 16H 16N 4O 2Theoretical value C, 64.85; H, 5.44; N, 18.91%
Embodiment 27
The N-(5-isoquinolyl)-and 5-methyl-2, the 3-pyrrolin is [2,3-f] indoles-1-methane amide (E27) also
With embodiment 25 similar methods, by 5-aminoisoquinoline, carbonyl dimidazoles and 1-amino-5-methyl-2,3-pyrrolin also [2,3-f] indoles prepares title compound, productive rate 15%, m.p.245-250 ℃.
NMR（D 6DMSO）δ：3.48（2H，t，J＝6），3.86（3H，s），4.42（2H，t，J＝6），6.38（1H，d，J＝2），7.28（1H，d，J＝2），7.40（1H，s），7.80，（1H，t，d＝6），7.91（1H，d，J＝6），7.99（1H，d，J＝6），8.08（2H，d，J＝6），8.60（1H，d，J＝6），8.79（1H，s），9.42（1H，s）.
Measured value: M +342.40, C 21H 18N 4O theoretical value 342.40
Embodiment 28
The N-(6-quinolyl)-and 5-methyl-2, the 3-pyrrolin is [2,3-f] indoles-1-methane amide (E28) also
With embodiment 25 similar methods, by 6-quinolylamine, carbonyl dimidazoles and 1-amino-5-methyl-2,3-pyrrolin also [2,3-f] indoles prepares title compound, productive rate 12%, m.p.217-220 ℃.
NMR（D 6DMSO）δ：3.30（2H，t，J＝6），3.74（3H，s），4.23（2H，t，J＝6），6.32（1H，d，J＝2），7.20（1H，d，J＝2），7.29（1H，s），7.42-7.49（1H，m），7.94（2H，s），8.09（1H，s），8.27（2H，m），8.74-8.79（2H，m）.
Measured value: M +342.40, C 21H 18N 4O theoretical value 342.40
Embodiment 29
2-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles (E29) also
Under argon atmospher, (0.142g is 0.96mmol) in dry toluene (40ml) with the nicotinoyl trinitride; stirring and refluxing 1 hour makes its cooling, adds 2-methyl-2 again; the 3-pyrrolin is [2,3-f] indoles (D47) (0.15g, dry toluene 0.87mmol) (10ml) solution also.With this solution stirring 1 hour, leach the precipitation that obtains, with a small amount of ether (Et 2O) washing, thorough drying obtains title compound (E29) (70mg, 28%) then.
NMR（D 6-DMSO）δ：1.25（3H，d），2.75（1H，d），3.46（1H，dd），4.82（1H，m），6.32（1H，s），7.20（1H，s），7.33（1H，dd），8.01（1H，m），8.01（1H，s），8.21（1H，d），8.68（1H，s）8.78（1H，d），10.83（1H，bs，NH）.
Measured value: C, 69.69; H, 5.71; N, 19.16%
C 17H 16N 4O theoretical value C, 69.85; H, 5.52; N, 19.16%
Measured value: M +292, C 17H 16N 4O theoretical value 292
Embodiment 30
2,5-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f]-indoles (E30) also
Under argon atmospher; with nicotinoyl trinitride (28.7mg; 1.1 equivalent) in dry toluene (40ml); stirring and refluxing 1 hour makes its cooling, adds 2 again; 5-dimethyl-2; the 3-pyrrolin is [2,3-f] indoles (D49) (0.37g, dry toluene 1.76mmol) (10ml) solution also.With this solution stirring 1 hour and be evaporated to dried, with column chromatography (SiO 2, CHCl 3/ MeOH9: 1) purifying, obtain product, be light yellow oil, with itself and Et 2O grinds together, obtains light yellow solid (170mg).
NMR（CDCl 3）δ：1.33（3H，d），2.89（1H，d），3.62（1H，dd），3.84（3H，s，NMe），4.96（1H，m），6.42（1H，d），7.30（1H，d），7.39（1H，s），7.42（1H，dd），8.08（1H，s），8.13（1H，s），8.32（1H，d），8.80（1H，s），8.85（1H，s，NH）.
Measured value: C, 69.98; H, 6.11; N, 17.72%
C 18H 18N 4O1/6H 2O theoretical value C, 69.90; H, 6.04; N, 18.10%
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 31
5-ethyl-1-(3-pyridinylamino formyl radical)-2,3,6, the 7-tetrahydropyridine is [2,3-f] indoles (E31) also
With 5-ethyl-1-(3-pyridinylamino formyl radical)-2; 3-pyrrolin also [2; 3-f] (0.7g 2.3mmol) is dissolved in the Glacial acetic acid (15ml) indoles (E10) and (0.72g 11.4mmol) handles with sodium cyanoborohydride in envrionment temperature with under stirring.This mixture stirred 1 hour, and water (100ml) dilution then with the alkalization of 10% aqueous sodium hydroxide solution, is used methylene dichloride (2 * 100ml) extractions again.With organic solution drying (Na 2SO 4), filter and be evaporated to dried.Through flash chromatography on silica gel, with 2-5% ethanol/methylene wash-out, then, obtain title compound (E31) with the solid ethyl acetate/40-60 gasoline recrystallization that obtains, be white crystalline solid (0.45g, 64%), m.p.151-153 ℃.
NMR（D 6-DMSO）δ：1.10（3H，t，J7），2.81（2H，t，J7），2.98-3.11（4H，m），3.21（2H，t，J7），4.07（2H，t，J7），6.41（1H，s），7.29（1H，q，J5），7.62（1H，s），7.93-7.96（1H，m），8.19（1H，d，J2），8.51（1H，s），8.70（1H，s）.
Measured value: C, 69.56; H, 6.50; N, 18.04%
C 18H 20N 4O1/8H 2O theoretical value C, 69.58; H, 6.57; N, 18.03%
Measured value: M +308, C 18H 20N 4O theoretical value 308
Embodiment 32
5-methyl isophthalic acid-(2-methyl-4-quinolyl formamyl)-2,3,6, the 7-Pyrrolidine is [2,3-f] indoles (E32) also
Method according to embodiment 9; with 5-methyl isophthalic acid-(2-methyl-4-quinolyl formamyl)-2; 3-pyrrolin also [2; 3-f] and indoles (E19) (0.7g, (0.58g 9.0mmol) handles glacial acetic acid solution 2.0mmol) (15ml) with sodium cyanoborohydride; obtain title compound (E32); be light yellow crystallization (0.44g, 63%), m.p.242-244 ℃.
NMR（D 6-DMSO）δ：2.61（3H，s），2.69（3H，s），2.80（2H，t，J7），3.10-3.22（4H，m），4.29（2H，t，J7），6.45（1H，s），7.45-7.53（1H，m），7.64-7.77（3H，m），7.88（1H，d，J8），8.12（1H，d，J8），8.54（1H，s）
Measured value: C, 72.69; H, 6.37; N, 15.36%
C 22H 22N 4O1/4H 2O theoretical value C, 72.83; H, 6.21; N, 15.45%
Measured value: M +358, C 22H 22N 4O theoretical value 358
Embodiment 33
5-methyl isophthalic acid-(2-methyl-4-pyridyl carbamyl)-2, the 3-pyrrolin is [2,3-f] indoles (E33) also
According to embodiment 5 similar methods, by 2-methyl-4-aminopyridine negatively charged ion (preparing), 1,1 with sodium hydride '-carbonyl dimidazoles and 5-methyl-2, the 3-pyrrolin also dimethyl formamide solution of [2,3-f] indoles prepares title compound, productive rate 45%.
NMR（D 6-DMSO）δ：2.40（3H，s），3.27（2H，t，J7），3.72（3H，s），4.18（2H，t，J7），6.32（1H，d，J3），7.19（1H，d，J3），7.26（1H，s），7.43（1H，d，J8），7.50（1H，s），8.05（1H，s），8.22（1H，d，J8），8.74（1H，s）.
Measured value: M +306, C 18H 18N 4O theoretical value 306
Embodiment 34
Being used for oral medicinal compositions can make by making up following material:
1) solid preparation prescription
%W/W
Formula I compound 10%
Magnesium Stearate 0.5%
Starch 2.0%
Vltra tears (HPM Cellulose) 1.0%
Microcrystalline Cellulose 86.5%
This mixture can be pressed into tablet, or insert in the hard gelatine capsule.
Tablet can be applied to the suspension dressing of film (as Vltra tears), pigment (as titanium dioxide) and softening agent (as diethyl phthalate)), and the evaporation by solvent and with the film drying.Film coating can account for 2.0%～6.0% of tablet weight, and preferably about 3.0%.
2) capsule
%W/W
Formula I compound 20%
Polyoxyethylene glycol 80%
Medicinal compound is dispersed or dissolved in the liquid vehicle, if necessary, can adds thickening material simultaneously.By suitable technology, the material of this prescription is enclosed in the soft gelatin capsule then.
Embodiment 35
The medicinal compositions that is used for parenteral administration can make by making up following material:
Preferred content
Formula 1 compound 1.0%
Salt solution 99.0%
With this solution sterilization and be sealed in the sterile chamber.
Pharmacology data
External [ 3H]-big white mouse or the people 5-HT that express in mesulergine and 293 cells 2CClone's combination.
The evidence of document is thought 5-HT 2CAntagonist can have a lot of treatment indications, comprises treatment anxiety disorder, migraine, dysthymia disorders, eating disorder and anancastic obstacle (Curzon and Kennett, 1990; Fozard and Gray, 1989), and presenile dementia (Lawlor, 1989, J.Arch, Gen, 542 pages of Psychiat.Vol.46).
Be subjected to reagent thing and 5-HT 2CThe avidity of binding site can be by assessing the 5-HT that they are expressed from 293 groups of born of the same parents 2CDisplace among the clone [ 3H]-ability of mesulergine measures (Julius etc., 1988).The method that is adopted is similar to the method for (1984) such as Pazos.
With cell suspending liquid (400ml) with [ 3H]-mesulergine(0.5nM) place Tutofusin tris (Tris) HCl damping fluid (PH7.4) to hatch 30 minutes together at 37 ℃.At the toluene pyrrole
Figure 931165539_IMG12
(10 -6M) non-specific binding is measured in existence down.10 kinds of concentration are subjected to reagent thing (3 * 10 -9～10 -4The M ultimate density) adds with the volume of 50ml respectively.Total mensuration volume is 500ml.Stop to hatch by using the Brandel cell harvestor to filter fast, and measure radioactivity with scintillation counting technique.Measure half-inhibition concentration (IC with four parameter table of logarithms (DeLean 1978) 50), and suppress the negative logarithm of constant with following Cheng Prusoff Equation for Calculating pki():
Figure 931165539_IMG13
Ki=suppresses constant
C=[ 3H]-concentration of mesulergine
Kd=mesulergine is to 5-HT 2CThe avidity of binding site
Curzon, G.A. and Kennett, G.A.(1990) .TIPS, Vol.11,181-182.
Fozard, J.R. and Gray, J.A.(1989) .TIPS, Vol.10,307-309.
Pazos, A. etc. (1984) .Eur.J.Pharmacol., 106,531-538.
Julius etc. (1988) Science 241,558-564
DeLean A，Munson P.J.，Rodbaud D（1978）Am.J.Physiol 235，E97-E102.
The pki value of result: embodiment 1～11 compound is 6.04～9.29.
The reverse of MCPP-inductive hypomotility disease (hypolocomotion).
Between taking to big white mouse-(chloro-phenyl-) piperazine (mCPP), the not enough disease (Kennett and Curzon 1988, Luckie etc. 1989) of inducedmotion, this with give related drugs 1-(m-trifluoromethyl phenyl) piperazine (TFMPP) situation about being seen is the same.(Lucki and Frazer1982, Kennett and Curzon1988), this effect can be by nonspecific 5-HT 20/ 5-HT 2AReceptor antagonist toluene pyrrole
Figure 931165539_IMG14
, the match
Figure 931165539_IMG15
Pyridine and liserdol may also have mesulergine to block.This effect is not by the 5-HT of corresponding dosage 2AReceptor antagonist ketanserin and ritanserin blocking-up (Kennett and Curzon 1991) be not also by 5-HT 1A, 5-HT 18, 5-HT 3, α 2Adrenoceptor or dopamine D 2Receptor antagonist is blocked.Therefore, the effect of mCPP is considered to by 5-HT 20Receptor-mediated (Kennett and Curzon 1988), this is confirmed (Lucki etc., 1989) by afterwards institute.Because when mCPP is injected the ventricles of the brain, cause hypomotility disease, so think that this effect may be (Kennett and the Curzon 1988) of maincenter mediation.
Size be 56cm length * 161/2cm wide * measure mCPP-inductive hypomotility in the high cage made from the black synthetic glass that can move automatically of 25cm.The side of two-beam at the bottom of the cage shone along cage cross direction level.Close moving of light beam measurement cage then.
Is one group of raising with male Spragne Dawley big white mouse (200-250g) (Charles River) with 6.Gave the rat oral pharmaceutical in preceding 1 hour in test, give the mCPP(7mg/kg abdominal injection after 40 minutes again).After 20 minutes,, under red light, they are placed on respectively in the cage that moves automatically with 4 one group in adjacent room.Finish test after 10 minutes.The reverse of mCPP inductive hypomotility disease is considered to maincenter 5-HT in the body 20The evidence of receptor antagonist effect.
Kennett，G.A.，Curzon，G.，（1991）.Brit.J.Pharmacol.103，2016-2020.
Lucki, I., Frazer, A., (1982) .Am.Soc.Neurosci.8(summary), 101.
Lucki，I.，Ward，H.R.，Frazer，A.，（1989）.J.Pharmacol.Exp.Therap.249，155-164.
The ID of result: embodiment 1,2 and 4 compounds 5Be 5.5～22.3mg/kg, oral.
The social interaction test
Use is according to File(1980 J.Neurosci.Meth., 2,219) described social interaction test, estimated the possible angst resistance effect of test-compound.Usually can measure the social interaction of active between the male white rat by the number of times of counting communication behavior (for example follow, feed, smell news, climb up and climb down, bait, climb and ride, beat up).When big white mouse met in environment novelty or that illumination is bright each other, this communication behavior was suppressed.In this case, anxiolytic medicament will improve the level of social interaction.
Big white mouse was raised 8 days in adjoining the receptacle of experimental box with 8 one group.Then, the experiment before with them same indoor individually the raising 3 days.On test same day,, gave before test 1 hour big white mouse per os perfusion carrier or medicine in couples every 15 minutes since at 10 in the morning.They are mixed into to the partner (meeting for the first time) by body weight after 60 minutes, be placed in the social interaction test box of chummery not.This box is made by the white pmma of 54 * 37 * 26cm, does not have lid.The box base plate is divided into 24 equal portions squares, and cage is shone brightly.By the active social interaction in after the RTV remote television monitoring 15 minutes, and carry out objective counting, thereby obtain overall social interaction counting.The number that every big white mouse is crossed square also is counted and adds up.After each off-test box is carefully cleaned with wet cloth.Different with anxiolytic medicament, increase the processing of social interaction by hormesis, also will increase and move.Can reduce mobile with the tranquilizer processing.
With the dosage of 10mg/kg, embodiment 2 compound exhibits go out the effect of tangible increase social interaction.
The Geller-Seifter method
With Geller and Seifter, (1960) at Psychopharmacologia, and 1, the first Geller-Seifter experimental sequence of describing is estimated possible angst resistance effect in the 482-492 page or leaf.Shown that this method is to the medicine with angst resistance effect selective (Cook and Sepinwall, (1975) " Mechanism of Action of Benzodiazepines " ed.Costa, E. and Greengard, P., Raven Press, New, York, pp.1-28).
By 30 seconds scheme (VI30) training big white mouse of variable interval, depression bar is to obtain the food award.5 minutes VI 30 schemes and 2-5 minute FR5 scheme hocket, and in the FR5 scheme, every the 5th depression bar is promptly given a secondary eclipse piece, simultaneously with 0.5 second slight foot's electric shock.Total research continues about 30 minutes.Typical results is, big white mouse has the reaction of two-forty depression bar under VI 30 experimental programs, and in the FR5 scheme in the conflict phase, then big white mouse shows as low depression bar speed of reaction.Anxiolytic medicament can increase big white mouse pent-up depression bar speed of reaction in the conflict phase.
Big white mouse is pressed an only component group of 3-8, in test preceding 30 minutes, to big white mouse with abdominal injection or oral administration.Test-results is to conflict at FR5 ' ' percentage ratio of the square root increase of depression bar sum in the phase represents.Subduplicate conversion is necessary for the data with parameter method do standardization.
Embodiment 2 compounds go out tangible increase in ' conflict ' depression bar reaction and display in the phase under the dosage level of oral 5mg/kg.

Claims (10)

1, formula I compound or its salt
Figure 931165539_IMG2
Wherein:
P represents quinoline or isoquinoline 99.9 residue, or contains the most nearly 3 five or hexa-atomic aromatic heterocycles that are selected from nitrogen, oxygen or sulfur heteroatom;
R 1Be hydrogen or C 1-6Alkyl;
R 2, R 3, R 10And R 11Be hydrogen or C independently 1-6Alkyl, or R 10And R 11Form a key together, or R 2And R 10Or R 3And R 11Form a C together 2-6Alkylidene chain;
R 4Be hydrogen, C 1-6Alkyl, halogen, NR 8R 9Or OR 12, R wherein 8, R 9And R 12Be hydrogen or C independently 1-6Alkyl;
R 5Be hydrogen or C 1-6Alkyl;
R 7Be hydrogen C 1-6Alkyl, OR 12Or halogen, wherein
R 12Be hydrogen or C 1-6Alkyl; And n is 2 or 3; And
Radicals R 13And R 14Be hydrogen or C independently 1-6Alkyl.
2, compound according to claim 1, wherein R 1Be methyl or ethyl.
3, compound according to claim 2, wherein R 2And R 3Be hydrogen, R 10And R 11Form a key together.
4, compound according to claim 3, wherein R 4Be hydrogen or methyl.
5, compound according to claim 4.R wherein 5And R 7Be hydrogen.
6, compound according to claim 5.(CHR wherein 13) nBe ethylidene.
7, compound according to claim 1, they are to be selected from following compound or its salt that pharmaceutically is suitable for:
5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
6-methyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
5,7-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
6-methyl-3-(4-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(2-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
5-methyl isophthalic acid-(2-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5-methyl isophthalic acid-(4-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5-methyl isophthalic acid-(3-pyridinylamino formyl radical)-2,3,6, the 7-Pyrrolidine is [2,3-f] indoles also,
5-ethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5-n-propyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
5,6-dimethyl-1-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [2,3-f] indoles also,
6,7-dimethyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
1-methyl-N-(3-pyridyl)-5,6,7, the 8-tetrahydro-1 H-pyrrolo is [2,3-g] quinoline-5-methane amide also,
3-methyl-N-(3-pyridyl)-6,7,8,9-tetrahydrochysene-3H-pyrrolo-[3,2-f] quinoline-6-methane amide,
6-methyl-3-(2-methyl-4-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(5-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(3-quinolyl formamyl)-2, the 3-pyrrolin is [3,2-e] indoles also,
5-methyl isophthalic acid-(2-methyl-4-quinolyl formamyl)-2, the 3-pyrrolin is [2,3-f] indoles also,
6,8-dimethyl-3-(3-pyridinylamino formyl radical)-2, the 3-pyrrolin is [3,2-e] indoles also,
6-methyl-3-(3-pyridinylamino formyl radical)-2,3,7, the 8-Pyrrolidine is [3,2-e] indoles also,
5-methyl isophthalic acid-(2-pyrazinyl formamyl)-2, the 3-pyrrolin is [2,3-f] indoles also,
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isothiazolyl formamyl)-1H-pyrrolo-[3,2-e] indoles,
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isothiazolyl formamyl)-1H-pyrrolo-[2,3-f] indoles,
2,3-dihydro-5-methyl isophthalic acid-(5-quinolyl formamyl)-1H-pyrrolo-[2,3-f] indoles,
2,3-dihydro-5-methyl isophthalic acid-(3-methyl-5-isoxazolyl formamyl)-1H-pyrrolo-[2,3-f] indoles,
The N-(5-isoquinolyl)-and 5-methyl-2, the 3-pyrrolin is [2,3-f] indoles-1-methane amide also,
The N-(6-quinolyl)-and 5-methyl-2, the 3-pyrrolin is [2,3-f] indoles-1-methane amide also.
8, according to any one described compound that is used for the treatment of of claim 1-7.
9, carrier or vehicle that medicinal compositions, said composition contain any one described compound of with good grounds claim 1-7 and pharmaceutically be suitable for.
10, the method for preparing the formula I compound or its salt, this method comprises:
(a) make formula II compound and the coupling of formula III compound;
Wherein, A and R 6Be formation-NR when containing coupling 5 'The necessary suitable functional groups of CO part, wherein R 5 'Be the defined R of formula I 5Or can be to the group of its transformation, n is with the definition in the formula I, and variable R 1 ', R 2 ', R 3 ', R 10 ', R 11 ', R 13 ', R 14 ', R 4 ', R 5 'And R 7 'Respectively with defined R in the formula I 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5, and R 7, or can be to the group of its transformation, in view of the above, as arbitrary R 1 ', R 2 ', R 3 ', R 10 ', R 11 ', R 13 ', R 14 ', R 4 ', R 5 'And R 7 'Be different from R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7The time, when can randomly it being transformed into R respectively in case of necessity by any suitable order 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, change R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, and the salt that pharmaceutically is suitable for that forms them;
Or (b) cyclization formula IV compound;
Figure 931165539_IMG5
Wherein, R 4 ', R 5 ', R 7 ', R 13 'And R 14 'With definition in formula II and (III), define in n such as the formula I, C and D contain promising formation by R 1 ', R 2 ', R 3 ', R 10 'And R 11 'Indoles or the necessary suitable functional groups of indoline ring that (with defining in the formula III) replaces, in view of the above, as arbitrary R 1 ', R 2 ', R 3 ', R 10 ', R 11 ', R 13 ', R 14 ', R 4 ', R 5 'And R 7 'Be different from R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7The time, when can randomly being converted into R in case of necessity by any suitable order 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, change R 1, R 2, R 3, R 10, R 11, R 13, R 14, R 4, R 5And R 7, and form the salt that pharmaceutically is suitable for.
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