CN1083064A

CN1083064A - Indolizino [1, the 2-b] quinolinones that replaces

Info

Publication number: CN1083064A
Application number: CN93105930A
Authority: CN
Inventors: D·A·堡吉斯; R·P·赫茨堡; R·K·约翰逊; W·D·金斯伯里
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1992-04-17
Filing date: 1993-04-17
Publication date: 1994-03-02
Also published as: CA2118324A1; AU4288893A; JPH07506099A; EP0637960A1; ZA932721B; TW264471B; EP0637960A4; KR950701219A

Abstract

The invention provides the method for indolizino [1,2-b] quinolinone compounds treatment virus infection, the indolizino of antiviral replacement [1,2-b] quinolinone compounds and pharmaceutical composition thereof with antiviral replacement.

Description

Indolizino [1, the 2-b] quinolinones that replaces

The application is an Application No. 07/870,649, the continuation of the part of application on April 17th, 1992, Application No. 07/783,063, the part of application on October 25th, 1991 continues, Application No. 07/606,216, the part of application on October 31 nineteen ninety continues.

The present invention relates to treat the method for virus infection, antiviral compound and pharmaceutical composition thereof.More specifically, the present invention relates to treat the method for virus infection, have some indolizino [1,2-b] the quinolyl derivative and the pharmaceutical composition thereof of antiviral activity.

Known some 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinolinone has cytotoxin and antiviral activity.Camptothecine is an example of these compounds.It is a kind of water-insoluble cytotoxin alkaloid, is produced by camplotheca acuminata that grows in China and the foetid nothapodytes herb that grows in India.Known camptothecine and similar congener thereof can suppress eucaryon isomerase I.In fact, the cytotoxin of camptothecine and similar congener thereof and anti-tumor activity are owing to suppress (Cancer Res.1988,48,1722 that eucaryon isomerase I is produced; Molec.Pharmacol.1988,34,755).Structurally similar but compound that can not suppress eucaryon isomerase I does not have the cytotoxin effect to mammalian cell to camptothecine, there are not anti-tumor activity (J.Med.Chem.1988,32,715 yet; Cancer Res.1989,49,1465; Cancer Res.1989,49,4358).

Many camptothecine that studies show that have antiviral activity.Yet, although camptothecine shows antiviral activity in the vitro tissue culture system, but have the camptothecine of hydroxy-lactone part and similar analogue thereof and can not be used as the interior resisting virus agent, this is because they do not suppress Mammals isomerase I and host cell DNA with meeting the requirements duplicates, and mammalian cell is had the cytotoxin effect.In addition, because camptothecine has the toxicity of unacceptable dose limitation, the toxicity that can not expect and bad water-soluble and/or unacceptable storage period stability, therefore for the drug development as antiviral agent, camptothecine is not a kind of attractive drug candidate.

Therefore, need new antiviral agent.Indolizino [1, the 2-b] quinolinones of replacement that does not contain the Alpha-hydroxy lactone part of camptothecine shows the acellular detoxifying function of mammalian cell and lacks anti-tumor activity (Ann.Rev.Pharmcol.Toxicol.1977,17,117; J.Med.Chem.1989.32,715).This is not suppress the necessary constitutional features of eucaryon isomerase I because these compounds do not contain.Yet indolizino [1, the 2-b] quinolinones that our discovery does not recently contain some replacement of Alpha-hydroxy lactone part has antiviral activity, but the camptothecine cytotoxicity that does not meet the requirements.Therefore, the indolizino of these replacements [1,2-b] quinolinones can be used for treating virus infection.

One aspect of the present invention provides the method for treatment virus infection, comprise to the infection host of needs use separately and or with formula I compound or its pharmaceutically acceptable salt of carrier blended significant quantity.

Wherein:

R ⁷Be-H ,-CN; Low alkyl group or-(CH ₂) nCH ₂V is n=0-3 wherein;

R ⁹Be-H ,-OR ,-NRR ¹,-CN ,-(CH ₂) nCH ₂V is n=0-3 wherein;

R ¹⁰Be-H ,-OR ,-NRR ¹,-CN ,-COR ¹²The R of ,-CH(OH) ¹²,-O-(CH ₂) _1-5CH ₂NRR ¹The NRR of ,-OC(O) ¹, 1,4 '-Lian piperidines-1 '-carboxyl ,-(CH ₂) nCH ₂V is n=0-3 wherein;

V is-OH-OCOR ¹⁴, OP(O) (OH) R ¹⁵Or NRR ¹;

R ¹¹Be-H or-OR;

R ¹²Be-H or low alkyl group;

R ¹³It is low alkyl group;

R and R ¹Be selected from respectively-H ,-C _1-6Alkyl is as R and R ¹When on nitrogen, replacing, R and R ¹Can form the saturated nitrogen heterocyclic ring of 5-7 joint together;

R ¹⁴Be-CR ¹²R ¹⁶R ¹⁷;

-(CH ₂) nCH ₂R ¹⁷(wherein n=1-3);

(n=0 or 1 wherein, CH ₂R ¹⁷Can go up 2,3 or 4 of phenyl and replace);

-O(CH ₂) nCH ₂R ¹⁷(wherein n=1-3);

-NRR ¹;

-NH(CH ₂) nCH ₂R ¹⁷(wherein n=1-3);

R ¹⁵Be OH, OR ¹⁸Or CH ₂NH ₂;

R ¹⁶Be H or any naturally occurring amino acid side chain;

R ¹⁷Be NRR ¹,

Wherein X is any pharmaceutically acceptable negatively charged ion;

R ¹⁸It is low alkyl group;

X is-CH(OH) CH(OH) and CH ₃,-CHR ³R ⁴Or

Y is-CH ₃Or-CH ₂OR ²;

R ²Be-H-C(O) H ,-COR ¹⁴Or-P(O) (OH) R ¹⁵;

R ³Be-OH-OCOR ¹⁴Or-OP(O) (OH) R ¹⁵;

R ⁴Be-H, low alkyl group or-OR;

R ⁶Be-H or low alkyl group.

Its condition is:

If a). R ⁷, R ⁹, R ¹⁰Or R ¹¹One of be not-H that then remaining only has one can not to be-H;

B) .R ⁷, R ⁹, R ¹⁰Or R ¹¹In only have one can be-NRR ¹;

C). when X is-CHR ³R ⁴And R ⁴Be-during OR, R ³Be-OH;

D). when Y is-CH ₂OR ²The time, X is

The present invention also provides has formula I compound as defined above, just:

A). work as R ⁷, R ⁹, R ¹⁰And R ¹¹All be-H that Y is-CH ₃The time, X is not-C(O) H, and-CH ₂OH ,-C(O) CH ₂CH ₃Or-CH(OH) CH ₂CH ₃; And

B). work as R ⁷, R ⁹, R ¹⁰And R ¹¹All be-H, Y is

-CH ₂OC(O) during H, X is not-C(O) CH ₂CH ₃

Another aspect of the present invention relates to pharmaceutical composition, comprise formula I compound and with pharmaceutically acceptable carrier of its blended or vehicle.

On the other hand, the present invention relates to the method for preparation.

Following definition is used for whole present patent application.

" aliphatic series " is meant and comprises saturated and undersaturated group.It comprises straight chain and side chain, saturated single or many unsaturated chain, and wherein two keys and triple bond can exist in any combination.Term " low alkyl group " and " C _1-6Alkyl " be meant the alkyl of 1 to 6 carbon atom, it is with any isomeric form, but particularly the straight or branched form exists." lower alkoxy " is meant low alkyl group-O-group." halogen " is meant fluorine, chlorine, bromine or iodine." acyl group " is meant the group with terminal carbonyl.

Term " 5-7 saves saturated nitrogen heterocyclic ring " is meant and comprises saturated rings, for example piperidines, tetramethyleneimine, morpholine, piperazine and N-alkylpiperazine.

Term " 1,4 '-Lian piperidines-1 '-carboxyl " be used to represent following group:

Can make various salt by these compounds, its condition is to have acidic-group or enough alkaline nitrogen in compound.Particularly preferably be the pharmaceutically acceptable salt of The compounds of this invention.It is acceptable that these salt are defined in when they are used as drug use, is meant that these salt will keep the biological activity of parent compound, and these salt do not have unsuitable or deleterious effects in its application with when being used for the treatment of disease.

Pharmaceutically acceptable salt can prepare with ordinary method.In suitable solvent, parent compound and excessive organic or inorganic acid-respons when forming the acid salt of basic moiety, when parent contains acidic-group, parent compound and excessive organic or inorganic alkali reaction.Representational acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, toxilic acid, succsinic acid and methylsulfonic acid.Cationic salts is easily prepared by basic metal such as sodium, potassium, calcium, magnesium, zinc, copper etc. and ammonia.Organic bases comprises list or bis substituted amine, quadrol, piperazine, amino acid, caffeine etc.

In whole present patent application, being used to name the chemical nomenclature of The compounds of this invention is according to the general structure by the representative of formula II.

Because substituent some combination can produce the form at chiral centre or other isomer centers in The compounds of this invention, so all these isomeric forms are believed to comprise among the present invention.When The compounds of this invention contains chiral centre, the present invention includes racemic mixture, the mixture of pure enantiomorph and any enantiomorph enrichment thereof.

The invention provides the method for treatment virus infection, comprise to the infection host of needs use independent or with aforesaid formula I compound or its pharmaceutically acceptable salt of the significant quantity of carrier or mixed with excipients.

Method of the present invention is used for the treatment of animal, Mammals particularly, and people's virus infection more especially, this virus infection is caused by various dna replication dna animal viruss.When the host who infects is a Mammals, particularly the host when infection is a man-hour, method of the present invention is used in particular for treatment by herpes simplex virus, particularly herpes simplex virus 1 type (HSV1) and herpes simplex virus 2 types (HSV2), varicella zoster virus (VZV) or the caused virus infection of cytomegalovirus (CMV).

The preferred method for the treatment of virus infection according to the present invention uses formula I M1 compound:

X is-CH(OH) CH(OH) and CH ₃,-CHR ³R ⁴Or

Y is-CH ₃Or-CH ₂OR ², formula I M1 is corresponding to R wherein ⁷, R ⁹, R ¹⁰And R ¹¹Be respectively-H, X and Y be formula 1 thus defined.Preferred method is used formula I M1 compound, and wherein working as X is CHR ³R ⁴, R ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵The time, Y is-CH ₃, when X is

R wherein ⁶Be-when H or low alkyl group, Y is-CH ₃Or-CH ₂OR ², or as X be-CH(OH) CH(OH) CH ₃The time, Y is-CH ₃

Another preferred method for the treatment of virus infection according to the present invention uses formula I M2 compound:

Formula I M2 is corresponding to R wherein ⁷, R ⁹And R ¹¹Be H, R ¹⁰Remove be not-define the formula I that defines in X and Y such as the top formula I in H such as the top formula I.Preferred method is to use formula I M2 compound, wherein R ¹⁰Be-OR-CN, COR ¹²Or-(CH ₂) nCH ₂V; Or X is-CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, Y is-CH ₃, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another preferred using method is to use formula I M3 compound according to the present invention:

Formula I M3 is corresponding to R wherein ⁷And R ¹¹Be respectively-H R ⁹And R ¹⁰Except that be not respectively-H as top formula I in define the formula I that defines in X and Y such as the top formula I.Preferred method is to use formula I M3 compound, wherein R ⁹Be-(CH ₂) nCH ₂VR ²⁰Be-OR that X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another preferred using method is to use formula I M4 compound according to the present invention:

Formula I M4 is corresponding to R wherein ⁹, R ¹⁰And R ¹¹Be respectively-H R ⁷Except that be not-H as above the definition, the formula I that defines in X and Y such as the top formula I.Preferred method is to use formula I M4 compound, wherein R ⁷Be low alkyl group ,-CN or-(CH ₂) nCH ₂V; X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another preferred using method is to use formula I M5 compound according to the present invention:

Formula I M5 is corresponding to R wherein ⁷, R ¹⁰And R ¹¹Be respectively-H R ⁹Except that be not-H as top formula I in define the formula I that defines in X and Y such as the top formula I.Preferred method is to use formula I M5 compound, wherein R ⁹Be-OR that X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another preferred using method is to use the compound that formula I M6 represents according to the present invention:

Formula I M6 is corresponding to R wherein ⁷, R ⁹And R ¹⁰Be respectively H, R ¹¹Be-OR the formula I that defines in X and Y such as the top formula I.Preferred method is to use formula I M6 compound, wherein R ¹¹Be OR, X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

The present invention also provides compound and the pharmaceutically acceptable salt thereof with antiviral activity, and described compound has the structure of being represented by top formula I, just:

A). work as R ⁷, R ⁹, R ¹⁰And R ¹¹Be-H, Y is-CH ₃The time, X is not-C(O) H, and-CH ₂OH ,-CH(OH) CH(OH) CH ₃-C(O) CH ₂CH ₃Or-CH(OH) CH ₂CH ₃;

B). work as R ⁷, R ⁹, R ¹⁰And R ¹¹Be-H, Y is-CH ₂OC(O) during H, X is not-C(O) CH ₂CH ₃

Preferred The compounds of this invention comprises formula I N1 compound:

Formula I N1 is corresponding to the formula I, R in the formula I ⁷, R ⁹, R ¹⁰And R ¹¹Be respectively-H, X is

R wherein ⁶Be-H or low alkyl group, Y is CH ₃Or CH ₂OR ²(its condition is to be-CH as Y ₃The time, R ⁶Not-CH ₂CH ₃) or X be CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-(its condition is to work as R for H or low alkyl group ³When being OH, R ⁴Be not-CH ₂CH ₃), Y is-CH ₃

According to the present invention, go back preferred formula I N2 compound:

Formula I N2 is corresponding to formula I, wherein R ⁷, R ⁹And R ¹¹Be respectively H, R ¹⁰As defining in the top formula I, be R ¹⁰Be not-H, X and Y in the top formula I definition.Preferred formula I N2 compound comprises wherein R of these compounds ¹⁰Be-OR-CN ,-COR ¹²Or-(CH ₂) nCH ₂V; X is-CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another kind of preferred The compounds of this invention is represented by formula I N3:

Formula I N3 is corresponding to formula I, wherein R ⁷And R ¹¹Be respectively-H R ⁹And R ¹⁰As defining in the top formula I, be R ⁹And R ¹⁰All be not-H, X and Y in the top formula I definition.Preferred formula I N3 compound comprises wherein R of these compounds ⁹Be-(CH ₂) nCH ₂V, R ¹⁰Be-OR that X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another kind of preferred The compounds of this invention is represented by formula I N4:

Formula I N4 is corresponding to formula I, wherein R ⁹, R ¹⁰And R ¹¹Be respectively-H R ⁷As defining in the top formula I, be R ⁷Not-H to define in X and Y such as the top formula I.Preferred formula I N4 compound comprises wherein R of these compounds ⁷Be low alkyl group ,-CN or-(CH ₂) nCH ₂V; X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is R wherein ⁶Be-H or low alkyl group, Y is-CH ₃

Another kind of preferred The compounds of this invention is represented by formula I N5:

Formula I N5 is to reply formula I, wherein R ⁷, R ¹⁰And R ¹¹Be respectively-H R ⁹As defining in the top formula I, be R ⁹Not-H to define in X and Y such as the top formula I.Preferred formula I N5 compound comprises wherein R of these compounds ⁹Be-OR that X is-CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Another kind of preferred compound is represented by formula I N6:

N6 is corresponding to R for the formula I ⁷, R ⁹And R ¹⁰Be respectively-H R ¹¹Be-OR the formula I that defines in X and Y such as the top formula I.Preferred formula I N6 compound is wherein R of these compounds ¹¹Be OR, X is CHR ³R ⁴R wherein ³Be-OH OCOR ¹⁴Or OP(O) (OH) R ¹⁵And R ⁴Be-H or low alkyl group, or X is

R wherein ⁶Be-H or low alkyl group, Y is-CH ₃Or CH ₂OR ²

Preferred especially following compounds:

The 7-[1-[(glycyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

7-[1-[(3-amino-1-oxopropyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[(2-pyrrolidyl carbonyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11)-ketone;

7-[1-[[2-amino-3-(1H-imidazol-4 yl)-and the 1-oxopropyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

7-[1-[(2-amino-3-methyl isophthalic acid-oxo butyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

7-[1-[(2-amino-2-methyl-1-oxopropyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

The 7-[1-[(glycyl) oxygen] propyl group]-2-cyano group-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[[2-pyrrolidyl carbonyl) glycyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[[(dimethylamino) ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone;

7-[1-[[(1,4 '-Lian piperidines-1 '-yl) ethanoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[(4-morpholinyl ethanoyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[[(4-methylpiperazine-1-yl) ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone;

The 7-[1-[[(1-imidazolyl) ethanoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[(pyridyl ethanoyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone iodide;

The 7-[1-[[4-[(dimethylamino) methyl] benzoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[[4-(pyridylmethyl) benzoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate;

8-[[(4-morpholino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone;

The 7-[1-[[(amino methyl) phosphonoso] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone;

The 12-[[(glycyl) oxygen] methyl]-8-methyl-7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl isophthalic acid 2-[[(4-morpholino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone;

8-methyl-7-[1-[(phosphono) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone; And

8-[[(dimethylamino ethanoyl) oxygen] propyl group]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone.

Some compound that is used for the treatment of among the present invention in the method for virus infection is known.Listed public publication is incorporated herein by reference the document The compounds of this invention in this article and can be prepared by several method by known starting raw material in these compounds of preparation are discussed, or by being prepared on the starting raw material that suitable substituents is added to the disclosed synthetic method that is used for preparing camptothecine.The preferred synthetic method of preparation The compounds of this invention is summarized in the following reacting flow chart.

Usually, the preparation of The compounds of this invention can maybe can have required R by opening camptothecine ⁷-R ¹¹The lactonic ring of substituent camptothecin derivative makes 8-methyl-7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone carries out.In addition, also can open lactonic ring, introduce R then ⁷-R ¹¹Substituting group.Other method is to change existing R ⁷-R ¹¹Group makes required compound.In case open lactonic ring, thereby the X of gained and Y group can transform on demand further and make the purpose compound.

Starting raw material can have been bought or prepare with disclosed method from the market.Camptothecine, 10-hydroxycamptothecine and 9-hydroxycamptothecine are natural products, camptothecine and 10-hydroxycamptothecine derive from the People's Republic of China (PRC).The 9-hydroxy-camptothecin alkali cpd that can be used as starting raw material in preparation in some The compounds of this invention has been described in disclosed Japanese patent application No. 59-51, in 289.Wall etc. (J.Med.Chem.1986,29,2358) have described the synthetic of 9-and 12 nitrocamptothecins.Wall etc., J.Med.Chem.1980,23,554 have described the complete synthesis of camptothecine.Synthetic methods such as 1980 Wall can be used as one or more R ⁷-R ¹¹Method in the substituting group drawing-in system I compound.The appropriate steps that it is included in this method changes the Wall synthetic method, inserts required substituting group, continues required synthesizing then.

With flow process 1 ring-opening reaction is described, for simplicity, all reaction process shown in this article are all at R ⁷-R ¹¹The place illustrates with-H alternate compound.Yet these methods also can be applicable to have R as defined above ⁷-R ¹¹In the The compounds of this invention of substituent any other combination, be included in the chemical reaction that one or more substituting groups need protection and the compound of deprotection afterwards, this is that those of ordinary skills are known.

Flow process 1

By at high boiling point, preferred nonreactive solvent such as N, heating compound in dinethylformamide or the triglyme makes formula 1 compound be converted into formula 2 compounds.

Shown in flow process 2, the ketone group of formula 2 compounds is reduced and obtains corresponding oxy-compound 3, and being derived by compound 3 obtains halogenated compound 4.Ketone group also can be converted into oxime (compound 5), and then reduction obtains primary amino compound 6.Ketone group also can be converted into ketal group as 1,3-dioxolane (compound 7, it is to be used for the further useful as intermediates of conversion).The hydroxyl of compound 3 also can be made ester, carbonic ether and carbamate (8) or be made phosphoric acid ester and phosphonic acid ester (9), wherein R by phosphorylation by acidylate ²⁰And R ²¹Thereby available known method deprotection or further handle and be separately converted to R ¹⁴And R ¹⁵Group.

Flow process 2

Shown in flow process 3, alcohol 3 dehydrations obtain alkene 10, and its hydroxylation is obtained glycol 11.The glycol oxidation cracking generates aldehyde 12, can be used for water or alcoholic solvent then and makes formula 13 compounds with covalent linkage ground solvation.Formula 12 and the reduction of 13 hydrogenation of compounds ground obtain primary alconol 14.

Flow process 3

Can also can generate by camptothecine deutero-alpha hydroxy acid 15 by the hydrogenolysis cracking of the lactonic ring shown in flow process 4.

Flow process 4

Used condition is unsettled in the preferred method of the preparation compound 2 that some ring substituents is given for flow process 1.In order to make unstable compounds under these conditions, step shown in the flow process 5 provides the method that obtains some such compound or the intermediate of other compounds of preparation is provided.

Flow process 5

More specifically, the at first protected one-tenth ketal of the carbonyl of compound 16 (17).For example in acid solvent such as acetate, the pyridine ring reduction is obtained compound 18 then with sodium cyanoborohydride.At last, for example obtain 2-hydroxyl ketal 19 with phenyl-iodide diacetin oxygenated compound 18, obtain keto compounds 20 by the acidic hydrolysis ketal, compound 19 and compound 20 all are used for preparation and have other substituent compounds, shown in flow process 6.

Flow process 6

Flow process 6(is continuous)

Flow process 6(is continuous)

Compound in the flow process 6 can be by 2-hydroxyketone 20 alkylation (compound 21) or acylations (compound 22,23 and 24) or prepare by the 2-hydroxyl in the ketal (19) of triflate (25).According to Kosugi, M waits Chem.Lett.1981, and 69 method makes the triflate cyaniding obtain compound 26, and hydrolysis obtains compound 27 then.Make the cyano group catalytic hydrogenation of compound 26 obtain amino methyl ketal 28, being hydrolyzed then obtains ketone 29.

In addition, for example use Cacchi, S waits Tetrahedron Lett.1986, and 27,3931 method uses triflate (25) as raw material, and carbonyl is incorporated on the ring.If use amine or alcohol, then obtain corresponding amide (30) or ester (32), hydrolysis obtains ketone compound 31 and 33 respectively then.Obtain primary alconol 34 with muriate ester reduction 32, being hydrolyzed then makes keto-alcohol 35, with the method that is similar to by compound 3 its derivatives of preparation, carries out acylations and obtains carboxylicesters, and carbonic ether and carbamate or phosphorylation obtain phosphoric acid ester or phosphonic acid ester.With accessing aldehyde but have precedence over the mild oxidation agent (MnO for example of acid ₂) oxidation alcohol 34 can make aldehyde (compound 36).Deprotection obtains keto-aldehyde 37.

Equally, according to Cabri, W. waits the method for (J.Org.Chem.1990,55,3654), makes triflate be converted into vinyl ether 38, and compound 38 hydrolysis obtain diketone 39 then.The enol ether functional group of selective hydrolysis compound 38 makes the 2-keto compounds, then it is reduced to secondary alcohol, removes ketal group, by the described method that is used for compound 3, alcohol functional group is carried out acylations or phosphorylation.

Introduce aminoly by ester hydrolysis 32 at 2, the acid of gained is converted into acyl halide (chloride of acid), handle acyl halide and heat product with sodiumazide, then use water treatment, generation amine (40) is separated to close and is obtained compound 41.Use known method, these amine are carried out alkylation (42) respectively, sulfonylation (44) or acylations (46), deprotection obtains compound 43,45 and 47 then.

Can not can prepare with the activation of the 2-hydroxyl of compound 19 with the substituent compound that has on 1 of the method for flow process 1 preparation, hydroxyl can be retained in the product or remove.These preparations are illustrated with flow process 7.

Flow process 7

Make 1-halo ketal 48 with ordinary method halogenated compound 19, be cracked into corresponding ketone 49 then.With the used method of synthetic compound 26, make iodide (48) carry out cyanogenation and make cyano group ketal 50.Cracking compound 50 obtains compound 51.Or, use Cacchi then in addition by compound 50 being converted into corresponding triflate 52, S, etc., Tetrahedron Lett.1986,27,5541 method, compound 52 is reduced to compound 53, thereby removes the hydroxy functional group of compound 50, hydrolysis ketal 53 obtains ketone 54.

With tetramethyl-diamino methane and acid compound 19 is converted into compound 55.Hydrolysis dioxolane protecting group obtains ketone compound 56 then.

Preparation has the method for the compound of different substituents to illustrate with flow process 8 on 7.

Flow process 8

Flow process 8(is continuous)

As Sugasawa, T. etc., Chem.Pharm.Bull.1974,22, the 771 described oxy-compound 57 that prepare.Can prepare triflate (58) with ordinary method.The identical method that utilization is used for compound 52 is carried out the reductive action of compound 59.Utilize preparation compound 26 method therefors to make the triflate cyaniding get compound 60, the alkoxyl group vinylation of carrying out triflate as preparation compound 38 gets compound 61; The ketone 62 that the vinyl ether acid hydrolysis obtains, according to Kametani, T, the method that waits (Heterocycles, 1975,3,167) gets methyl-derivatives 63 with diazomethane reaction, and it gets pure 64 by hydride reduction.According to Echavarren, A, M, and Stille, J, the method for K. (J.Am.Chem.Soc.1988,110,1557) triflate and the coupling of 3-dialkylamino propine get compound 65, and it gets compound 66 through catalytic hydrogenation.According to Chen, Q-Y, and Yang, the method for Z-Y. (Tetrahedron Lett.1986,27,1171) makes triflate carry out vinylation and obtains compound 67, and it gets ethyl compound 68 through catalytic hydrogenation.In the presence of amine or alcohol, utilize the method for preparing compound 30 and 32 to make triflate carry out carbonylation and can make acid amides 69 and ester 70 respectively, as described in compound 62, with diazomethane compound 70 being methylated obtains derivative 71, with hydride it is reduced into alcohol 72 then.Triflate functional group with mercaptan displacement compound 58 gets sulfide 73, and it can be oxidized to sulfoxide 74.

Having substituent compound on 12 prepares shown in flow process 9.

Flow process 9(is continuous)

Flow process 9(is continuous)

Utilize Miyaska, the method for T etc. (Heterocycles, 1981,16,1713) is used ferrous sulfate, hydrogen peroxide and contain vitriolic methyl alcohol and prepare 12-methylol compound 76.As described in compound 3, these pure acidylates or phosphorylation are made carboxylicesters, carbonic ether and carbamate, or phosphoric acid ester and phosphonic acid ester.Similarly, utilize Miyasaka, the method for T. etc. (U.S. Patent number 4,399,282) can prepare 12-alkylate 77.For example, with the hydrogen peroxide oxidation compound in the acetate 78 N-oxide compound 79, it is at N, in the dinethylformamide with Benzoyl chloride heat 12-chlorinated compound 80, it can be transformed into many other compounds.Chlorinated compound and fragrant and mellow, as phenol heat 12-aryloxy compound 81, its deprotection gets ketone 82; If but comprise aminomethyl aromatic hydrocarbons in the reaction, then product is a compound 83, it gets ketone compound 84 through hydrolysis.By with the acetate that contains some diacetyl oxides in potassiumiodide heating, the chlorine substituent of compound 80 can be replaced by iodine group (85).Iodo derivative can easily be used for the similar various coupled reaction of carrying out to triflate 25 and 58.The compound 86 that cyanogenation obtains, separate close ketone 87 or be reduced into aminomethylation compound 88, it gets ketone 89 through hydrolysis.Similarly, can make proyl amine 90 and deprotection get 91 or catalytic hydrogenation get compound 92 and 94, it is hydrolyzed into ketone compound 93 and 95 respectively.With compound 85 and sodium acetate in acetate heat 12-oxy-compound 96, its available bases and haloalkane or the alkylation of diazonium alkane get 12-alkoxy compound 97, its deprotection gets ketone 98.12-methylol compound 76 can be protected and be activated as methanesulfonates and be used for substitution reaction by being transformed into sulphonate (99).The prussiate of compound 99 replace ketal 100, its hydrolyzable becomes 12-cyanogen methyl ketone 101.The cyano group ketal also can be reduced into aminoethyl compound 102, gets ketone 103 after its hydrolysis.Handle sulphonate 99 with alcohol and get ether 104 in the presence of alkali, it can be transformed into ether ketone 105.

The reaction that is used for 12-methylol compound 76 shown in the flow process 9 can be used for the derivative of methylol compound 34 preparations corresponding to compound 99-105 equally.

Shown in Figure 10 as flow process, with the open loop form of the compound 107(compound 106 described in the common unsettled Application No. 07/839,823).As acidylate as described in the compound 3 or phosphorylation respectively compound 108 and 109.

Flow process 10

The animal virus that The compounds of this invention has antiviral activity and is generally used for treating dna replication dna infects, the particularly infection that causes of bleb coe virus.More specifically, these compounds can be used for treating the infection that following people's pathogenic agent causes:

Herpes simplex virus types 1 and 2;

Cytomegalovirus

Varicella zoster virus;

Epstein-Barr virus; With

Papilloma virus (compound).

The compounds of this invention also can be treated the infection that following animal pathogen causes:

The simplexvirus of horse;

The simplexvirus of pig;

Marek's disease virus;

Feline rhinotracheitis virus; With

The simplexvirus of ox.

Test

The detection method that is used for the test of The compounds of this invention antiviral activity can adopt the method for document and the improved known method in order to be suitable for the conventional technology of using.What this detection method was total is described below.

Test method

The well type culture dish that will have suitable well number is with every well 1 * 10 ⁵The cell concn inoculation, cell suspension contains in the Earle minimal essential medium (EMEM) of 10% N of tire serum (FBS) and antibiotic and antimycotic solution in 0.5ml.After cell 80-90% merges (24 hours), remove old substratum and use Hank buffered saline solution (HBSS) washing.Made cell infection 1 hour in 37 ℃ of hsvs that are suspended among the 250ml HBSS with every well 100-200 PFUC.After the absorption, add following ingredients:

A) contain the 250ml/ well 2 * EMEM of human IgG

(about 0.1mg/ml; Sigma No.G-6763);

B) contain the 250ml/ well EMEM of 10%FBS and antibiotic/antimycotic solution;

C) contain the 250ml/ well HBSS of suitable diluted compounds.

After 24-48 hour (microscopically is by observing the determined Cui time of patch), the old substratum of sucking-off.(0.5% in MeOH: H with selectively staining solution for every well ₂O7: the Viola crystallina rowland in 3) dyeing, light Xian of water and dry air are counted patch number then.According to untreated infection to the percentage that reduces of the patch effectiveness of assessing compound recently relatively in the same old way.

Itself and test virus are matched and according to top described method, present method can be used for the usefulness of the anti-many viruses except that hsv of test compounds by revising the cell type be used for the first step simply.Other cell type that can be used in this test method comprises mouse breast tumor cell, human lung fibroblast, sheep chorion plexus (Chorioplexus) cell and green monkey kidney cell.

Other test method that can be used for measuring the The compounds of this invention antiviral activity comprises following type: cell counting, clone produces (Clonogenic), cytopathy effect, culture dish-bacterium colony forms, micro-titration-growth-inhibiting, the thymidine combination also produces reductive action, and each in these known test methods all is recorded in the document and method selected is commercial attainable.

Pharmaceutical composition and methods of treatment

The invention provides various compositions by the The compounds of this invention preparation.These compositions have the purposes to people and animal doctor's antivirus action, and are used for the treatment of plant, the virus infection of for example agricultural or ornamental seed or plant.These compositions comprise that the ultimate purpose for expection is acceptable carrier and at least a The compounds of this invention.For example, in the animal doctor used, carrier can be liquid or sprays, or was mixed with solid, is suitable for inserting the non-degraded or the degraded form of cud.For the application on the agricultural, compound can or kill insect etc. and mix with chemical fertilizer, other mycocide, and The compounds of this invention also can be mixed with and be suitable for pulvis or the sprays that plant surface uses.

Pharmaceutical composition of the present invention comprises that one or more The compounds of this invention reach and the pharmaceutically acceptable carrier or the thinner of its blended inert.Composition can contain the The compounds of this invention of significant quantity in a unit, for example in the syringe that a particle, capsule or the intravenous dosages of measuring in advance or injection are substituted the bad for the good in advance, or come to this usually, composition can be formulated into single dosage form, one of them unit (for example particle) contains secondary dose,optimum, need use two or more unitary doses and the user is proposed each treatment.When composition existed with cream forms, it can contain the medicine of dispersion amount and emulsifiable paste that the user can use significant quantity one or many alleviates or cures effectively until the state of an illness.The latter's enriched material also can be mixed with thinner by the end user, for example intravenous injection and multiple dosage injection.

Normally the medicament field is known for carrier that uses in these compositions or thinner.Spendable this class material can be with reference to known editor such as Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18042, USA.

Certainly, the kind of composition and pharmaceutically acceptable carrier or thinner depends on route of administration, for example intravenously and intramuscularly, and administered parenterally, topical, oral or by the inhalation administration.

The pharmaceutical composition of administered parenterally can be liquid form such as ampoule or water-based or the non-aqueous liquid suspension agent that aseptic injectable is used.

The pharmaceutical composition of topical can be to be suitable for ointment, ointment, the liniment that skin, eye, ear, nose or sexual organ are used, lotion, paste, sprays or drops form.

Oral pharmaceutical composition can be tablet, capsule, pulvis, granula, atroche, lozenge, syrup, liquid or emulsion.

Employed medicine is that acceptable carrier can be solid or liquid.The example of solid carrier is lactose, kaolin, carclazyte, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, N.F,USP MANNITOL, stearic acid etc.

The suitable pharmaceutically acceptable liquid vehicle or the example of thinner comprise: Aquo System, water; Non-aqueous system, ethanol, glycerine, propylene glycol, oil of maize, oleum gossypii seminis, peanut oil, sesame oil, whiteruss and with the mixture of water.For the aerosol system, pharmaceutically acceptable carrier comprises Refrigerant 12, chloro-trifluoro-ethane and compression arbon dioxide.The carrier or thinner on medicine, the present composition also comprises other composition such as stablizer, antioxidant, sanitas, lubricant, suspension agent, viscosity modifier etc., and to be other composition have no adverse effect to the therapeutic action of the present composition condition.Equally, carrier or thinner can contain time-delay material well known in the art, as independent or with wax blended glycerol monostearate or glycerol disterate, ethyl cellulose, HPMC, methyl methacrylate etc.

In order to obtain stable aqueous solution formulation, the pharmaceutically acceptable salt of The compounds of this invention can be dissolved in the aqueous solution of organic or inorganic acid or alkali.If can not get soluble salt, The compounds of this invention can be dissolved in cosolvent or its mixture.The example of the cosolvent that this class is suitable includes but are not limited to alcohol, propylene glycol, Liquid Macrogol, tween 80, glycerine etc., and its concentration range is the 0-60% of cumulative volume.

Be understandable that, be used for medicine of the present invention or other composition in the actual preferred dose of The compounds of this invention along with used concrete mixture, the concrete composition of being prepared, administering mode and concrete position, host who is treated and disease and change.These compounds are at two kinds of antiviral drug Cytovene(ganciclovir that bought on can market) and concentration range Zovirax(acyclovir) in effectively, for example, the latter is made the capsule of 200mg, take 1 capsules by per 4 hours, treat hsv but must not surpass 5 capsules every day.

In the following example, temperature be centigradetemperature (℃).Except as otherwise noted, all starting raw materials have all been bought from the market.Need not further elaboration, believe that those skilled in the art can farthest use the present invention with preceding method.These embodiment that provide are for the present invention is described, rather than limit its scope.Claims that the content that the contriver kept can vide infra.

Embodiment 1

(±)-1-methoxyl group-7-(hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9-(11H)-ketone

With 1-methoxyl group-8-methyl-7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone (5.0mg, 15 μ mol) is in MeOH(0.2ml), CH ₂Cl ₂(0.6ml) and THF(0.2ml) solution in the mixture handles with a sodium borohydride (4.0mg, 110 μ mol).In stirring at room after 1.5 hours, with the reaction mixture concentrating under reduced pressure.Resistates 10%NH ₄The Cl aqueous solution (350 μ l) handle and with it in 4 ℃ of standing over night.The solid by filtration that generates is collected, and uses H ₂The careful washing of O is also dry, gets title compound.

¹H-NMR（CDCl ₃/MeOH-d ₄）d8.77（s，1H），7.69（m，2H），7.59（s，1H），6.92（dd，J＝6.8，1.7Hz，1H），5.23（br s，2H），4.89（m，1H），4.05（s，3H），2.24（s，3H），1.79（m，2H），1.03（t，J＝7.4Hz，3H）.

Embodiment 2

(±)-2-cyano group-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9-(11H)-ketone

Except using 2-cyano group-8-methyl-7-(1-oxopropyl) ketone of indolizino [1,2-b] quinoline-9(11H), prepare title compound according to the method for embodiment 1.

¹H-NMR（CDCl ₃/MeOH-d ₄）d8.29（s，1H），8.32（d，J＝1.7Hz，1H），8.20（d，J＝8.9Hz，1H），7.92（dd，J＝8.8，1.8Hz，1H），7.67（s，1H），5.30（br s，2H），4.91（m，1H），2.26（s，3H），1.79（m，2H），1.03（t，J＝7.4Hz，3H）.

Ultimate analysis C ₂₀H ₁₇N ₃O ₂H ₂O:

Calculated value: C, 68.75; H, 5.48; N, 12.03;

Measured value: C, 68.97; H, 5.26; N, 11.72.

Embodiment 3

(±)-7-[1-[(glycyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

3A.(±)-8-methyl-7-[1-[[[[(1,1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Under the argon atmospher to N-[(1,1-dimethyl oxyethyl group) carbonyl] glycine (1.15g, CH 6.6mmol) ₂Cl ₂Add 1 in the suspension (50ml), and the 3-dicyclohexylcarbodiimide (1.35g, 6.5mmol).After 0.5 hour, add (±)-7-(1-hydroxypropyl in stirring at room)-8-methyl indolizino [1,2-b] quinoline-9(11H)-(1.0g 3.3mmol), adds several milligrams of 4-Dimethylamino pyridines to ketone immediately.The gained mixture in stirred overnight at room temperature, is filtered then, and filtrate is used 2.5%NaHCO successively ₃The aqueous solution (100ml), 0.1N HCl(100ml) and H ₂O(100ml) washing is with dried over sodium sulfate and vacuum concentration.Solid residue by the column chromatography purifying, is used 0.2%MeOH/CH on silica gel ₂Cl ₂Solvent gradient liquid wash-out gets title compound.

¹H-NMR（CDCl ₃）d8.34（s，1H），8.21（d，J＝8.8Hz，1H），7.91，

(d, J=8.3Hz, 1H), 7.81(m, 1H), 7.63, (m, 1H), 7.32(s, 1H), 5.96(tangible br t, J=7.0Hz, 1H), 5.25(s, 2H), 5.03(br s, 1H), 4.15-3.94(m, 2H), 2.36(s, 3H), 2.04-1.84(m, 2H), 1.44(s, 9H), 0.99(t, J=7.4Hz, 3H).

Ultimate analysis C ₂₆H ₂₉N ₃O ₅1/8H ₂O

Calculated value: C, 67.04; H, 6.33; N, 9.02.

Measured value: C, 66.95; H, 6.54; N, 8.83.

3B.(±)-the 7-[1-[(glycyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

(±)-8-methyl-7-[1-[[[[(1 under the argon atmospher under stirring; 1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1; 2-b] quinoline-9(11H)-ketone (1.15g; 2.5mmol) 1, add trifluoroacetic acid (13ml) in the suspension of 3-dimethoxy benzene (12ml).In stirring at room after 1.5 hours, with the mixture concentrating under reduced pressure.Resistates is dissolved in H ₂O uses Et ₂The O extraction is filtered and lyophilize gets light yellow solid shape title compound.

¹H NMR(DMSO-d ₆) d.8.68(s, 1H), 8.24(m, 1H), 8.13(m, 1H), the tangible br t of 7.86(, 1H), the tangible br t of 7.70(, 1H), 7.19(s, 1H), the tangible br t of 5.91(, 1H), 5.26(s, 2H), 4.02(br s, 2H), 2.25(s, 3H), 2.06-1.81(m, 2H), 0.96(t, J=7.2Hz, 3H).

Ultimate analysis C ₂₁H ₂₁N ₃O ₃CF ₃CO ₂H9/4H ₂O:

Calculated value: C, 53.33; H, 5.16; N, 8.11.

Measured value: C, 53.09; H, 4.91; N, 7.74.

Embodiment 4

(±)-7-[1-[(3-amino-1-oxopropyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone acetate

4A.(±)-8-methyl-7-[1-[[3-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-1-oxygen propyl group] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

To contain (±)-7-(1-hydroxypropyl under the argon atmospher)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (61.2mg, 0.20mmol), 4-Dimethylamino pyridine (7.4mg, 0.06mmol), 3-[[(1,1-dimethyl oxyethyl group) carbonyl] amino] propionic acid 4-nitro phenyl ester (248mg, 0.80mmol) and anhydrous ethylamine (222ml, 1.60mmol) in 1, mixture heating up in the 2-ethylene dichloride (5ml) refluxed 5 days, this moment, thin-layer chromatographic analysis showed that reaction is incomplete, mixture is transferred in the pressure bottle and in 90-95 ℃ heated 1 day.After, add 3-[[(1 again, 1-dimethyl oxyethyl group) carbonyl] amino] propionic acid 4-nitro phenyl ester (and 248mg, 0.80mmol) and anhydrous triethylamine (222ml 1.60mmol), and continues heating 13 days.Mixture is used 0-3%MeOH/CH by the flash chromatography purifying then ₂Cl ₂Solvent gradient liquid wash-out, isolated material is in Et ₂Title compound is carried in O recrystallization and vacuum-drying, mp155-8 ℃. ¹H NMR

（CDCl ₃）d8.35（s，1H），8.22（d，J＝8.6Hz，1H），7.91（d，J＝7.2Hz，1H），7.81（m，1H），7.63（m，1H），7.32（s，1H），5.90（dd，J＝7.7，6.1Hz，1H），5.26（s，2H），5.02（br s，1H），3.44（m，2H），2.66（q，J＝5.8Hz，2H），2.02-1.80（m，2H），1.38（s，9H），0.98（t，J＝7.4Hz，3H）.

Ultimate analysis C ₂₇H ₃₁N ₃O ₅1/5H ₂O:

Calculated value: C, 67.40; H, 6.58; N, 8.73.

Measured value: C, 67.78; H, 6.48; N, 8.35.

4B.(±)-7-[1-[(3-amino-1-oxopropyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone acetate

Method according to embodiment 3B, only be to use (±)-8-methyl-7-[1-[[3-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-the 1-oxopropyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone, product is gone up by the reverse-phase chromatography purifying in Partisil 40 ODS-3, with 0-100% in the H that contains 1% acetate ₂MeOH gradient liquid wash-out among the O, the preparation title compound. ¹H NMR

(CDCl ₃/ MeOH-d ₄) d8.42(s, 1H), 8.20(d, J=8.4Hz, 1H), 7.96(d, J=8.3Hz, 1H), 7.84(m, 1H), 7.67(m, 1H), 7.43(s, 1H), 5.92(dd, J=7.7,6.0Hz, 1H), 5.28(s, 2H), 3.02(br s, 2H), the tangible br t of 2.69(, J=5.9Hz, 2H), 2.36(s, 3H), 2.02(s, 3H), 2.02-1.82(m, 2H), 1.01(t, J=7.4Hz, 3H) .CIMS(NH ₃, m/e, rel.int.) 378(100) and [(M+H) ⁺].

Ultimate analysis C ₂₂H ₂₃N ₃O ₃C ₂H ₄O ₂13/4H ₂O:

Calculated value: C, 58.11; H, 6.81; N, 8.47.

Measured value: C, 58.22; H, 6.13; N, 8.10.

Embodiment 5

8-methyl-7-[1-[(2-pyrrolidyl carbonyl) oxygen] propyl group] the separating of indolizino [1,2-b] quinoline-9(11H)-ketone trifluoroacetate and isomer

5A.(R, S)-the 8-methyl-7-[1-[[(S) 1-[(1,1-dimethyl oxyethyl group) and carbonyl]-2-pyrrolidyl carbonyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Except using N-[(1,1-dimethyl oxyethyl group) carbonyl]-L-proline(Pro), N, N '-DIC and (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3A.

5B.(R, S)-the 8-methyl-7-[1-[[(S)-2-pyrrolidyl carbonyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

To containing (R, S)-the 8-methyl-7-[1-[[(S) 1-[(1,1-dimethyl oxyethyl group) carbonyl]-2-pyrrolidyl carbonyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone (1.66g, CH 3.3mmol) ₂Cl ₂Add trifluoroacetic acid (10ml) in the mixture (50ml).With the gained mixture in stirring at room 1.5 hours, concentrating under reduced pressure then.Resistates is dissolved in H ₂O(150ml) and lyophilize get title compound, be non-enantiomer mixture. ¹H NMR(D ₂O) d7.68 and 7.64(2s, 1H), 7.45 and two d of 7.36(, 1H), 7.33-6.95(m, 3H), 6.94 and two s of 6.91(, 1H), 5.93(m, 1H), the m that the 4.9-4.6(HOD peak is fuzzy), 4.2-3.9(m, 2H), 3.523.43(eclipsed m and t, 2H), 2.73-2.55(m, 1H), 2.45-1.95(m, 5H), 2.12 and two s of 2.06(, 3H), 1.08(m, 3H).

Ultimate analysis C ₂₄H ₂₅N ₃O ₃11/4CF ₃CO ₂H:

Calculated value: C, 49.41; H, 3.90; N, 5.86.

Measured value: C, 49.84; H, 4.16; N, 6.00.

5C.(S)-8-methyl-7-[1-[[(S)-2-pyrrolidyl carbonyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Will (R, S)-the 8-methyl-7-[1-[[(S)-2-pyrrolidyl carbonyl] oxygen] propyl group] non-enantiomer mixture of indolizino [1,2-b] quinoline-9(11H)-ketone (loaded 2Kg 15-20mm Vydac C by preparative chromatography ₁₈The JY post of RP silica gel) purifying is used 0.1/25/75TFA/CH ₃CN/H ₂The O wash-out.Title compound at first obtains by wash-out and after removal of solvent under reduced pressure and lyophilize.

¹H NMR(D ₂O) d7.99(s, 1H), 7.75(d, J=8.5Hz, 1H), 7.57(m, 1H), 7.51(d, J=8.2Hz, 1H), 7.33(m, 1H), 7.20(s, 1H), 6.09(dd, J=7.9,5.6Hz, 1H), the m that the 4.9-4.7(HOD peak is fuzzy), 4.52(d, J=18.9Hz, 1H), 4.40(d, J=18.8Hz, 1H), 3.53(t, J=7.3Hz, 2H), 2.75(m, 1H), 2.45-2.08(m, 5H), 2.30(s, 3H), and 1.19(t, J=7.4Hz, 3H).

Ultimate analysis C ₂₄H ₂₅N ₃O ₃2CF ₃CO ₂H1/4H ₂O:

Calculated value: C, 52.88; H, 4.36; N, 6.61.

Measured value: C, 52.76; H, 4.50; N, 6.64.

5D.(R)-8-methyl-7-[1-[(S)-3-pyrrolidyl carbonyl) oxygen] propyl group indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

The remaining ingredient that obtains in the embodiment 5C sepn process is merged concentrating under reduced pressure.Utilize the condition of embodiment 5C after other preparative chromatography is separated, to obtain title compound.

¹H NMR(D ₂O) d8.00(s, 1H), 7.68(d, J=8.5Hz, 1H), 7.56-7.49(m, 2H), 7.32(m, 1H), 7.19(s, 1H), 6.09(dd, J=8.0,5.2Hz, 1H), and the m 4.49(d that 4.93-4.679 HOD peak is fuzzy, J=18.9Hz, 1H), 4.40(d, J=19.0Hz, 1H), 3.66-3.57(m, 2H), 2.78(m, 1H), 2.47(m, 1H), 2.29(m, 2H), 2.24(s, 3H), 2.15(m, 2H), 1.17(t, 3H).

Ultimate analysis C ₂₄H ₂₅N ₃O ₃7CF ₃CO ₂H4H ₂O:

Calculated value: C, 35.83; H, 3.17; N, 3.30.

Measured value: C, 35.86; H, 3.24; N, 3.64.

5E.(R, S)-the 8-methyl-7-[1-[[(R)-1-[(1,1-dimethyl oxyethyl group) carbonyl]-2-pyrrolidyl carbonyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Under the argon atmospher, to N-[(1,1-dimethyl oxyethyl group) carbonyl]-D-proline(Pro) (6.74g, CH 31.3mmol) ₂Cl ₂(47ml) add in the mixture dicyclohexylcarbodiimide (3.22g, 15.6mmol).After 2 hours, filtering mixture also, concentrating under reduced pressure gets N-[(dimethyl oxyethyl group in stirring at room) carbonyl]-the D-proline anhydride.It is joined (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (1.5g, 4.9mmol) and 4-dimethylaminopyridine (609mg, CH 5.0mmol) ₂Cl ₂(450ml) in the suspension, under the argon atmospher with mixture in stirred overnight at room temperature.Reaction mixture H ₂O(2 *) washing, the dry and concentrating under reduced pressure of salt of wormwood.Resistates is used 0-2%MeOH/CHCl by the flash chromatography purifying ₃Solvent gradient liquid wash-out gets title compound.

5F. (R, S)-the 8-methyl-7-[1-[((R)-2-pyrrolidyl carbonyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Except using (R, S)-the 8-methyl-7-[1-[[(R)-1-[(1,1-dimethyl oxyethyl group) carbonyl]-2-pyrrolidyl carbonyl] oxygen] propyl group indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 5B. ¹The H NMR compound with embodiment 5B basically is identical.

Ultimate analysis C ₂₄H ₂₅N ₃O ₃2CF ₂CO ₂H:

Calculated value: C, 53.25; H, 4.31; N, 6.65;

Measured value: C, 53.07; H, 4.68; N, 7.02.

5G. (R)-the 8-methyl-7-[1-[((R)-2-pyrrolidyl carbonyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

According to the method for embodiment 5C, through (R, S)-the 8-methyl-7-[1-[((R)-2-pyrrolidyl carbonyl) oxygen] propyl group] separation of diastereomer of indolizino [1,2-b] quinoline-9(11H)-ketone obtains title compound,

Ultimate analysis C ₂₄H ₂₅N ₃O ₃3CF ₃CO ₂HH ₂O:

Calculated value: C, 47.19; H, 3.96; N, 5.50;

Measured value: C, 47.24; H, 4.30; N, 5.83.

5H. (S)-the 8-methyl-7-[1-[((R)-2-pyrrolidyl carbonyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

According to the method for embodiment 5C, through (R, S)-the 8-methyl-7-[1-[((R)-2-pyrrolidyl carbonyl) oxygen] propyl group] separation of diastereomer of indolizino [1,2-b] quinoline-9(11H)-ketone obtains title compound.

Ultimate analysis C ₂₄H ₂₅N ₃O ₃8/3CF ₃CO ₂HH ₂O:

Calculated value: C, 48.56; H, 4.12; N, 5.79;

Measured value: C, 48.61; H, 4.53; N, 6.10.

Embodiment 6

(R, S)-7-[1-[[(S)-2-amino-3-(1H-imidazol-4 yl)-the 1-oxopropyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

6A.(R, S)-the 8-methyl-7-[1-[[(S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-the 3-(1H-imidazol-4 yl)-the 1-oxopropyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Except using N, two [(1,1-dimethyl oxyethyl group) the carbonyl]-L-Histidines of 1-, N, N '-DIC and (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3A.

6B. (R, S)-7-[1-[[(S)-2-amino-3-(1H-imidazol-4 yl)-the 1-oxopropyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Method according to embodiment 5B, only be to use (R, S)-the 8-methyl-7-[1-[[(S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-the 3-(1H-imidazol-4 yl)-the 1-oxopropyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone and by preparation MPLC purifying, at first use 0.1%TFA/H ₂O contains the H of 0.1%TFA immediately with 20-50% ₂MeOH wash-out among the O, the preparation title compound. ¹H NMR(D ₂O) two s of d8.64 and 8.35(, 1H), 8.22(d, 1H), 7.90(d, 1H), 7.70(m, 2H), 7.45(m, 2H), 7.20(s, 1H), 6.04(m, 1H), the m that the 4.9-4.6(HOD peak is fuzzy), 3.68-3.47(m, 2H), 2.23 and two s of 2.19(, 3H), 2.15-1.96(m, 2H), 1.04 and two t of 0.96(, 3H).

Ultimate analysis C ₂₅H ₂₅N ₅O ₃2.8CF ₃CO ₂H:

Calculated value: C, 48.18; H, 3.67; N, 9.18.

Measured value: C, 48.29; H, 3.93; N, 9.15.

Embodiment 7

(±)-7-[1-[(2-amino-3-methyl isophthalic acid-oxo butyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

(7A. ±)-8-methyl-7-[1-[[2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-3-methyl isophthalic acid-oxo butyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Except using N-[(1,1-dimethyl oxyethyl group) carbonyl]-L-Xie Ansuan and (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3A.

¹H NMR(CDCl ₃) d8.34(s, 1H), 8.22(m, 1H), 7.91(d, J=8.2Hz, 1H), 7.80(m, 1H), 7.62(m, 1H), two s of 7.34(, 1H), 5.94(m, 1H), 5.26(s, 2H), two br d of 5.04(, J=9.3Hz, 1H), two d of 4.36(, J=4.5Hz, 1H), 2.36(s, 3H), 2.4-2.2(m, 1H), 2.1-1.8(m, 2H), 1.44 and two s of 1.38(, 9H), t and d that 1.00(covers, 9H).

Oxygen (7B. ±)-7-[1-[(2-amino-3-methyl isophthalic acid-oxo butyl)] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Except using (±)-8-methyl-7-[1-[[2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-3-methyl isophthalic acid-oxo butyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3B. ¹H-NMR

(CDCl ₃, MeOH-d ₄) d8.39 and two s of 8.35(, 1H), 8.20-8.13(m, 1H), 7.94-7.81(m, 2H), the tangible br t of 7.66(, 1H), two s of 7.41(, 1H), 6.05(m, 1H), 5.25(s, 2H), two d of 3.98(, J=4.4Hz, 1H), 2.55-2.36(m, 1H), 2.33(s, 3H), 2.14-1.90(m, 2H), 1.15-1.01(m, 9H).

Ultimate analysis C ₂₄H ₂₇N ₃O ₃CF ₃CO ₂H7/4H ₂O:

Calculated value: C, 56.67; H, 5.76; N, 7.63.

Measured value: C, 56.65; H, 5.62; N, 7.29.

Embodiment 8

(±)-7-[1-[(2-amino-2-methyl-1-oxopropyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoro-acetate

(8A. ±)-8-methyl-7-[1-[[2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-methyl isophthalic acid-oxopropyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Under the argon atmospher to containing 2-methyl-2-[N-[(1,1-dimethyl oxyethyl group) carbonyl] amino] propionic acid (and 406mg, 2.0mmol) and dicyclohexylcarbodiimide (432mg, CH 2.0mmol) ₂Cl ₂Add (±)-7-(1-hydroxypropyl in the mixture (3ml))-8-methyl indolizino [1,2-b] quinoline-9(11H)-(153ml is 0.5mmol) with 4-Dimethylamino pyridine (25mg) for ketone.Under the room temperature gained mixture was stirred 4 days, then impouring CH ₂Cl ₂In, use 5%NaHCO successively ₃The aqueous solution, 0.5NHCl and H ₂Dried over sodium sulfate is used in the O washing.Solvent removed in vacuo by column chromatography (silica gel) purifying resistates, is used 1.5-5%MeOH/CH ₂Cl ₂Solvent gradient liquid wash-out get pale solid shape title compound.

¹H NMR（CDCl ₃）d8.33（s，1H），8.20（d，J＝8.9Hz，1H），7.90（d，J＝8.3Hz，1H），7.80（m，1H），7.62（m，1H），7.33（s，1H），5.92（dd，J＝7.5，6.3Hz，1H），5.25（s，2H），5.10（br s，1H），2.38（s，3H），2.08-1.82（m，2H），1.56（s，3H），1.55（s，3H），1.41（s，9H），0.99（t，J＝7.4Hz，3H）.

Oxygen (8B. ±)-7-[1-[(2-amino-2-methyl-1-oxopropyl)] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Except using (±)-8-methyl-7-[1-[[2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-methyl isophthalic acid-oxopropyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3B. ¹H NMR

（DMSO-d ₆）d8.67（s，1H），8.11（m，2H），7.84（m，1H），7.70（m，1H），7.21（s，1H），5.85（dd，J＝7.9，5.8Hz，1H），5.25（s，2H），2.24（s，3H），2.1-1.83（m，2H），1.52（s，3H），1.49（s，3H），0.97（t，J＝7.3Hz，3H）.

Ultimate analysis C ₂₃H ₂₅N ₃O ₃CF ₃CO ₂H2H ₂O:

Calculated value: C, 55.45; H, 5.58; N, 7.76.

Measured value: C, 55.85; H, 5.19; N, 7.83.

Embodiment 9

(±)-7-[1-[(glycyl) oxygen] propyl group]-2-cyano group-8-methyl indolizino [1; 2-b] quinoline-9(11H)-ketone trifluoroacetate 9A. (±)-2-cyano group-8-methyl-7-[1-[[[[(1; 1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Except using (±)-2-cyano group-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3A.

Oxygen (9B. ±)-7-[1-[(glycyl)] propyl group]-2-cyano group-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

Except using (±)-2-cyano group-8-methyl-7-[1-[[[[(1,1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3B.

¹H NMR(DMSO-d ₆) d8.81(d, J=1.5Hz, 1H), 8.77(s, 1H), 8.27(d, J=8.9Hz, 1H), 8.13(dd, J=8.9,1.8Hz, 1H), 7.24(s, 1H), the tangible br t of 5.91(, J=6.7Hz, 1H), 5.29(s, 2H), 3.98(br s, 2H), 2.26(s, 3H), 2.05-1.81(m, 2H), 0.96(t, J=7.4Hz, 3H).

Ultimate analysis C ₂₂H ₂₀N ₄O ₃3/2CF ₃CO ₂HH ₂O:

Calculated value: C, 52.00; H, 4.10; N, 9.70.

Measured value: C, 52.04; H, 4.32; N, 9.73.

Embodiment 10

(±)-7-[1-[(glycyl) oxygen] propyl group]-12-cyano group-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

(10A. ±)-12-cyano group-8-methyl-7-[1-[[[[(1,1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Except using (±)-12-cyano group-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3A.

¹H NMR(CDCl ₃) d8.31(dJ=8.5Hz, 1H), 8.27(d, J=8.3Hz, 1H), 7.95(m, 1H), 7.84(m, 1H), 7.32(s, 1H), the tangible br t of 5.95(, J=7.0Hz, 1H), 5.43(s, 2H), 5.0(br s, 1H), 4.03(m, 2H), 2.38(s, 3H), 0.99(t, J=7.4Hz, 3H).

Oxygen (10B. ±)-7-[1-[(glycyl)] propyl group]-12-cyano group-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Except using (±)-12-cyano group-8-methyl-7-[1-[[[[(1,1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 3B.

¹H NMR(CDCl ₃/ MeOH-d ₄) d8.28(d, J=8.5Hz, 1H), 8.22(d, J=8.4Hz, 1H), 7.95(m, 1H), 7.82(m, 1H), 7.36(s, 1H), the tangible t of 6.00(, J=6.6Hz, 1H), 5.41(s, 2H), 3.92(br s, 2H), 2.33(s, 3H), 2.08-1.82(m, 2H), 1.00(t, J=7.2Hz, 3H).

Ultimate analysis C ₂₂H ₂₀N ₄O ₃3/2CF ₃CO ₂H5/2H ₂O:

Calculated value: C, 49.67; H, 4.42; N, 9.27.

Measured value: C, 49.41; H, 4.23; N, 9.29.

Embodiment 11

(R, S)-the 8-methyl-7-[1-[[(S)-the pyrrolidyl carbonyl) glycyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

11A.(R, S)-the 8-methyl-7-[1-[[[[(S) 1-[(1,1-dimethyl oxyethyl group) and carbonyl]-2-pyrrolidyl carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone

Except using (±)-7-[1-[(glycyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 5E.

11B.(R, S)-the 8-methyl-7-[1-[[(S)-(2-pyrrolidyl carbonyl) glycyl] and oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Except using (R; S)-1-[(1 of 8-methyl-7-1-[[[[(S); 1-dimethyl oxyethyl group) carbonyl]-2-pyrrolidyl carbonyl] amino] ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 5B.

Ultimate analysis C ₂₆H ₂₈N ₄O ₄3/2CF ₃CO ₂HH ₂O

Calculated value: C, 53.62; H, 4.89; Nitrogen, 8.63.

Measured value: C, 53.64; H, 5.29; Nitrogen, 8.50.

Embodiment 12

(±)-8-methyl-7-[1-[[(dimethylamino) ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

12A.(±)-the 7-[1-[(chloracetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

To (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-(306mg is 1.0mmol) with the CHCl that newly steamed for ketone ₃Add in the suspension (45ml) the chloracetic acid acid anhydride (205mg, 1.2mmol), pyridine (80ml, 1.0mmol) and the 4-Dimethylamino pyridine (12.2mg, 0.1mmol).To after 20 minutes, become uniform gained mixture in stirred overnight at room temperature, the mixture concentrating under reduced pressure, and resistates is dissolved in CH ₂Cl ₂, use H successively ₂O(2 *), 0.1N NaOH and H ₂The O washing is also used dried over sodium sulfate.Solvent removed in vacuo gets title compound.

¹H NMR（CDCl ₃）d8.35（s，1H），8.24（d，1H），7.93（d，1H），7.85（m，1H），7.65（m，1H），7.33（s，1H），5.99（dd，1H），5.28（s，2H），4.19（s，2H），2.40（s，3H），2.12-1.95（m，2H），1.00（t，3H）.

Ultimate analysis C ₂₁H ₁₉ClN ₂O ₃1/2 H ₂O:

Calculated value: C, 64.37; H, 5.14; N, 7.15.

Measured value: C, 64.29; H, 4.86; N, 6.82.

(12B. ±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

To (±)-7-[1-[(chloracetyl) oxygen] propyl group]-8-methyl indolizino [1; 2-b] quinoline-9(11H)-ketone (100mg; 0.26mmol) add sodium iodide (150mg in the mixture in acetone (10ml); 1.0mmol); with the vlil that obtains 1 hour, cooling had the solid precipitation generation down.Solvent removed in vacuo, resistates is in CH ₂Cl ₂And H ₂Distribute between O.Organic extract liquid H ₂O(3 *) washing, dried over sodium sulfate and concentrating under reduced pressure get title compound.

¹H NMR（CDCl ₃）d8.35（s，1H），8.22（d，J＝8.2Hz，1H），7.92（d，J＝8.0Hz，1H），7.81（m，1H），7.66（m，1H），7.38（s，1H），5.91（dd，J＝7.9，6.0Hz，1H），5.26（two s，2H），3.84（d，J＝10.1Hz，1H），3.75（d，J＝10.1Hz，1H），2.36（s，3H），2.10-1.83（m，2H），1.03（t，J＝7.4Hz，3H）.

Ultimate analysis C ₂₁H ₁₉IN ₂O ₃1/2H ₂O:

Calculated value: C, 52.19; H, 4.17; N, 5.80.

Measured value: C, 52.16; H, 4.05; N, 5.39.

Ethanoyl (12C. ±)-8-methyl-7-[1-[[(dimethylamino)] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

The introducing of dimethylamine gas is contained (±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (50mg, anhydrous CH 0.11mmol) ₂Cl ₂In the solution (15ml).With gained solution stirring 2 hours, concentrating under reduced pressure then.Resistates is in CH ₂Cl ₂And H ₂Distribute organic layer H between O ₂O washing several is also used dried over sodium sulfate.In this solution, be blown into HCl gas, the cotton-shaped mixture that obtains was stirred 15 minutes, vacuum concentration then, resistates is dissolved in H ₂O and lyophilize get orange solids shape title compound.

¹H NMR(DMSO-d ₆) d8.68(s, 1H), the d of 8.15a and two coverings of 8.12(, 2H), 7.86(m, 1H), 7.71(m, 1H), 7.17(s, 1H), the tangible br t of 5.96(, 1H), 5.26(s, 2H), 4.41(s, 2H), 2.84(br s, 6H), 2.26(s, 3H), 2.20-1.86(m, 2H), 0.96(t, J=7.3Hz, 3H) .CIMS(NH ₃, m/e, relative intensity) and 392(100) [(M+H) ⁺].

Ultimate analysis C ₂₃H ₂₅N ₃O ₃2HCl13/8H ₂O:

Calculated value: C, 55.96; H, 6.18; N, 8.51.

Measured value: C, 56.27; H, 6.03; N, 8.04.

Embodiment 13

(±)-7-[1-[[(1,4 '-Lian piperidines-1 '-yl) ethanoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone hydriodide

To (±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (50mg, CH 0.11mmol) ₂Cl ₂Adding 4-piperidinyl piperidine in the suspension (4ml) (17.6mg, 0.11mmol).After 3.5 hours, thin-layer chromatographic analysis shows that reaction is incomplete in stirring at room.(2.7mg 0.016mmol), continues to stir 2 days to add the 4-piperidinyl piperidine again.The mixture concentrating under reduced pressure, and with resistates by the column chromatography purifying, contain the H of HOAc with 0-100% ₂The solvent gradient liquid wash-out of MeOH among the O gets title compound after the lyophilize.

¹H NMR(CDCl ₃) d8.35(s, 1H), 8.21(d, J=8.4Hz, 1H), 7.92(d, J=8.3Hz, 1H), 7.83(m, 1H), 7.63(m, 1H), 7.34(s, 1H), the tangible t of 5.94(, 1H), 5.26(s, 2H), 3.32(s, 2H), 3.00(br m, 2H), 2.37(s, 3H), 2.6-1.4(m, 13H), 0.98(t, J=7.4Hz, 3H).

Ultimate analysis C ₃₁H ₃₈N ₄O ₃1/4 HI3/8H ₂O:

Calculated value: C, 67.28; H, 7.10; N, 10.12.

Measured value: C, 67.67; H, 6.79; N, 9.69.

Embodiment 14

(±)-8-methyl-7-[1-[(4-morpholinyl ethanoyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

Except using (±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone and morpholine, prepare title compound according to the method for embodiment 13.

¹H NMR(CDCl ₃/ MeOH-d ₄) d8.51(s, 1H), 8.26(d, J=8.5Hz, 1H), 7.99(d, J=8.3Hz, 1H), 7.88(m, 1H), 7.70(m, 1H), 7.53(s, 1H), 5.98(dd, J=7.4,5.9Hz, 1H), 5.30(s, 2H), 4.29(s, 2H), 4.02(br s, 4H), the brs that 3.45(HOD peak part is fuzzy), 2.33(s, 3H), 2.10-1.87(m, 2H), 1.03(t, J=7.4Hz, 3H).

Ultimate analysis C ₂₅H ₂₇N ₃O ₄2HClH ₂O:

Calculated value: C, 57.25; H, 5.96; N, 8.01.

Measured value: C, 57.37; H, 6.28; N, 7.65.

Embodiment 15

(±)-8-methyl-7-[1-[[(4-methylpiperazine-1-yl) ethanoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

Except using (±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone and N methyl piperazine, prepare title compound according to the method for embodiment 13.

¹H NMR（DMSO-d ₆）d8.67（s，1H），8.15（m，2H），7.87（m，1H），7.72（m，1H），7.11（s，1H），5.84（m，1H），5.25（s，2H），3.5-2.6（m，13H），2.23（s，3H），2.04-1.82（m，2H），0.95（t，J＝7.5Hz，3H）.

Ultimate analysis C ₂₆H ₃₀N ₄O ₃2HCl9/2H ₂O:

Calculated value: C, 52.00; H, 6.88; N, 9.33.

Measured value: C, 52.12; H, 9.11; N, 9.30.

Embodiment 16

(±)-7-[1-[[(1-imidazolyl) ethanoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

Except using (±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone and imidazoles, prepare title compound according to the method for embodiment 13.

¹H NMR（CDCl ₃/MeOH-d ₄）d9.17（s，1H），8.60（s，1H），8.34（d，1H），8.04（d，1H），7.95（m，1H），7.75（m，1H），7.61（s，1H），7.51（br s，1H），7.41（br s，1H），5.95（m，1H），5.65（d，1H），5.42（d，1H），5.33（s，2H），2.36（s，3H），2.1-1.9（m，2H），1.07（t，3H）.

Ultimate analysis C ₂₄H ₂₂N ₄O ₃2HCl11/4H ₂O:

Calculated value: C, 53.68; H, 5.35; N, 10.43.

Measured value: C, 53.52; H, 5.58; N, 10.29.

Embodiment 17

(±)-8-methyl-7-[1-[(pyridyl ethanoyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone iodide

Except using (±)-7-[1-[(iodoacetyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone and pyridine, prepare title compound according to the method for embodiment 13.

¹H NMR（CDCl ₃/MeOH-d ₄）d9.09（d，J＝5.5Hz，2H），8.65（t，J＝7.9Hz，1H），8.51（s，1H），8.17（m，3H），7.99（d，J＝8.1Hz，1H），7.89（m，1H），7.70（m，1H），7.50（s，1H），6.05（d，J＝17.2Hz，1H），6.02（m，1H），5.87（d，J＝17.2Hz，1H），5.30（s，2H），2.31（s，3H），2.18-1.94（m，2H），1.09（t，J＝7.4Hz，3H）.

Ultimate analysis C ₂₆H ₂₄IN ₃O ₃1/4H ₂O:

Calculated value: C, 55.97; H, 4.43; N, 7.53.

Measured value: C, 55.72; H, 4.30; N, 7.26.

Embodiment 18

(±)-7-[1-[[4-[(dimethylamino) methyl] benzoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

18A.(±)-the 7-[1-[[4-(chloromethyl) benzoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

Except using (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone and 4-(chloromethyl) phenylformic acid, prepare title compound according to the method for embodiment 3A.

¹H NMR（CDCl ₃）d8.33（s，1H），8.16（m，3H），7.91（br d，J＝7.3Hz，1H），7.78（m，1H），7.61（m，1H），7.51（d，J＝8.3Hz，2H），7.40（s，1H），6.11（dd，J＝8.1，6.1Hz，1H），5.26（s，2H），4.63（s，2H），2.45（s，3H），2.21-1.93（m，2H），1.08（t，J＝7.3Hz，3H）.

Ultimate analysis C ₂₇H ₂₃CIN ₂O ₃1/2H ₂O:

Calculated value: C, 69.30; H, 5.17; N, 5.99.

Measured value: C, 69.39; H, 5.16; N, 6.02.

18B.(±)-the 7-[1-[[4-[(dimethylamino) methyl] benzoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

To contain (±)-the 7-[1-[[4-(chloromethyl) benzoyl] oxygen] propyl group]-8-methyl indolizino [1; 2-b] quinoline-9(11H)-ketone (35mg; 0.08mmol) and sodium iodide (57mg; 0.38mmol) anhydrous propanone (50mg) suspension reflux 1 hour, then with its cooling and in stirred overnight at room temperature.Bubbling is blown into diethylamine number minute in this mixture, with mixture in stirring at room 1 hour, the mixture concentrating under reduced pressure, resistates is in H ₂O and CH ₂Cl ₂Between distribute.Organic layer H ₂The O washing is also used dried over sodium sulfate.Solvent removed in vacuo, resistates is used 0-5%MeOH/CH by the column chromatography purifying ₂Cl ₂Solvent gradient liquid wash-out.Isolated material 3ml H ₂O and 0.3ml 0.1N NCl handle and lyophilize gets taupe brown solid state title compound.

¹H NMR（CDCl ₃/MeOH-d ₄）d8.44（s，1H），8.26（d，J＝8.3Hz，2H），8.17（d，J＝8.6Hz，1H），7.96（d，J＝8.4Hz，1H），7.82（m，1H），7.74（d，J＝8.4Hz，2H），7.66（m，1H），7.55（s，1H），6.14（dd，J＝7.9，5.8Hz，1H），5.28（s，2H），4.31（s，2H），2.80（s，6H），2.44（s，3H），2.20-1.95（m，2H），1.11（t，J＝7.4Hz，3H）.

Ultimate analysis C ₂₉H ₂₉N ₃O ₃3/2HCl7/2H ₂O:

Calculated value: C, 59.51; H, 6.46; N, 7.18.

Measured value: C, 59.91; H, 6.85; N, 6.85.

Embodiment 19

(±)-8-methyl-7-[1-[[4-(pyridylmethyl) benzoyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Under the argon atmospher to (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (77mg adds the 4-(chloromethyl in pyridine 0.25mmol) (8ml) suspension) phenylformic acid (250mg, 1.3mmol).With the mixture that obtains in stirring at room 2.5 days, concentrating under reduced pressure then.Resistates is in H ₂O and CH ₂Cl ₂Between distribute and separate each phase.Water is by adding 5%NaHCO ₃The aqueous solution transfers to pH7.5 and uses CH ₂Cl ₂Extraction again.With the water layer concentrating under reduced pressure, resistates is applied to RP ₁₈Post is also used H ₂The solvent gradient liquid wash-out of O-MeOH.Isolated material is again in RP ₁₈Post is to carry out chromatographic separation twice, uses 0.1%TFA/H ₂O-0.1%TFA/MeOH solution gradient liquid wash-out gets title compound after the lyophilize.

¹H NMR（CDCl ₃/MeOH-d ₄）d 9.07（d，J＝5.7Hz，2H），8.46（m，1H），8.39（s，1H），8.23（d，J＝8.2Hz，2H），8.16（d，J＝8.6Hz，1H），8.05（m，2H），7.93（d，J＝8.5Hz，1H），7.81（m，1H），7.65（m，1H），7.59（d，J＝8.2Hz，2H），7.49（s，1H），6.13（dd，J＝7.8，5.9Hz，1H），6.00（s，2H），5.27（s，2H），2.42（s，3H），2.2-2.0（m，2H），1.08（t，J＝7.4Hz，3H）.

Ultimate analysis C ₃₄H ₂₈F ₃N ₃O ₅5/2CF ₃CO ₂H5/2H ₂O:

Calculated value: C, 49.53; H, 3.78; N, 4.44.

Measured value: C, 49.53; H, 3.31; N, 4.27.

Embodiment 20

(±)-7-[1-[[(chloromethyl) hydroxyl oxygen phosphino-] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone triethylamine salt

Under the argon atmospher to (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (92mg, CH 0.3mmol) ₂Cl ₂Add Et in the suspension (5ml) ₃N(42ml, 0.3mmol), add subsequently the chloromethyl phosphine dichloride (31ml, 0.3mmol).The gained mixture in stirring at room 2.5 days, is added Et then ₃N(42ml) and MeOH(200ml) also continue to stir to spend the night.With the mixture concentrating under reduced pressure, resistates is in H ₂O and CH ₂Cl ₂Between distribute organic layer H ₂O(2 *) washing, and with the water extraction lyophilize that merges, will obtain thing and place RP ₁₈Post is used H ₂The solvent gradient liquid wash-out of O-MeOH, lyophilize gets title compound.

¹H NMR（CDCl ₃）d8.27（br s，1H），8.13（m，1H），7.9-7.5（m，4H），5.60（m，1H），5.19（br s，2H），3.49（br d，J＝10.2Hz，2H），3.05（m，～3H），2.0-1.8（m，2H），1.28（t，J＝7.3Hz，～5-6H）1.00（t，J＝7.2Hz，3H）.

Ultimate analysis C ₂₀H ₂₀ClN ₂O ₄P1/2C ₆H ₁₅N7/4H ₂O:

Calculated value: C, 55.15; H, 6.24; N, 6.99.

Measured value: C, 54.94; H, 5.81; N, 6.92.

Embodiment 21

(±)-7-[1-[(2-cyanogen oxyethyl group) oxygen hydroxyl oxygen phosphino-)] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-the ketone sodium salt

Repel under the condition of moisture will be in (±)-7-(1-hydroxypropyl in the anhydrous pyridine (4.0ml))-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (153mg, 0.50mmol), 2-cyanoethyl phosphoric acid ester is (according to Moffatt, J.G.Am.Chem.Soc.1963,85,1118 method is by 322mg, 1.0mmol barium salt deutero-) and N, (462mg is 2.24mmol) in 45 ℃ of heating 24 hours for N '-dicyclohexylcarbodiimide.In this reaction, add entry and MeOH, solvent is all stripped under vacuum, add other H with NaOAc ₂O and MeOH remove by filter insoluble solids, and solvent is stripped once more.Be applied to Partisil40 ODS-3 reversed-phase column on the aqueous solution form resistates and use 0-10%MeOH/H ₂The gradient liquid wash-out of O gets title compound.

¹H NMR（MeOH-d ₄）d8.58（s，1H），8.19（d，J＝8.1Hz，1H），8.05（dd，J＝8.1，1.0Hz，1H），7.86（m，1H），7.71（s，1H），7.68（m，1H），5.54（m，1H），5.29（s，2H），3.98（m，2H），2.65（t，J＝6.1Hz，2H），2.36（s，3H），2.07-1.88（m，2H），1.10（t，J＝7.4Hz，3H）.

Ultimate analysis C ₂₂H ₂₁N ₃NaO ₅P15/4H ₂O:

Calculated value: C, 49.96; H, 5.43; N, 7.94.

Measured value: C, 49.95; H, 5.22; N, 7.63.

Embodiment 22

(±)-8-methyl-7-[1-[(phosphono) oxygen] propyl group] methyl indolizino [1,2-b] quinoline-9(11H)-ketone front three amine salt

To in MeOH(1.0ml) in (±)-7-[1-[(2-cyano group oxyethyl group) the hydroxyl oxygen phosphino-) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone sodium salt (89.4mg, 0.19mmol) in add 1N NaOH(1.65ml), with reaction mixture stirring at room 7 hours under argon atmospher.Reaction 1N HCl(1.75ml) acidifying, stripping also is dissolved in H again ₂Among the O.Be applied to this solution on the Partisil40ODS-3 reversed-phase column and use 0-100%MeOH/H ₂The gradient liquid wash-out of O.Behind some title compounds under the sodium-salt form wash-out, other component major part under the later wash-out is a free acid form.Acidic components are dissolved in MeOH, are incorporated in (the CH among the MeOH ₃) ₃It is about 10 that N rises to pH, and stripping is removed MeOH, adds H ₂O also gets title compound with the solution lyophilize.

¹H NMR（MeOH-d ₄/D ₂O）d8.58（s，1H），8.16（d，J＝8.5Hz，1H），8.04（d，J＝8.3Hz，1H），7.85（m，1H），7.74（s，1H），7.68（m，1H），5.50（br dd，1H），5.26（s，2H），2.92（s，～6.5H），2.33（s，3H），1.95（m，2H），1.08（t，J＝7.4Hz，3H）.

Ultimate analysis C ₁₉H ₁₈N ₂O ₅P3/4C ₃H ₁₀N1/4Na9/2H ₂O:

Calculated value: C, 49.35; H, 6.72; N, 7.45.

Measured value: C, 49.41; H, 6.43; N, 7.02.

Embodiment 23

(±)-7-[1-[[(aminomethyl) hydroxyl oxygen phosphino-] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

Carbonyl (23A. ±)-7-[1-[[[[[(9-fluorenyl methoxy)] amino] methyl] the hydroxyl oxygen phosphino-] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

Except using (±)-7-(1-hydroxypropyl)-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone and [[[(9-fluorenyl methoxy) carbonyl] amino] methyl] phosphonic acids, prepare title compound according to the method for embodiment 21.

Ultimate analysis C ₃₅H ₃₂N ₃O ₆P9/8H ₂O:

Calculated value: C, 65.49; H, 5.38; N, 6.55.

Measured value: C, 65.83; H, 5.28; N, 6.14.

Hydroxyl oxygen phosphino-(23B. ±)-7-[1-[[(aminomethyl)] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone

In phial with cover with Mt ₂NH(10ml) and (±)-7-[1-[[[[[(9-fluorenyl methoxy) carbonyl] amino] methyl] the hydroxyl oxygen phosphino-] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone (328mg, 0.51mmol) mixture in stirring at room 3 hours, reaction mixture is stripped to dried, adds H ₂O.Part solution is extracted with EtOAc, and filtration and lyophilize get thickness oily matter, and it is used CH ₃CN develop golden yellow solid.Solid is dissolved in H ₂O and lyophilize get part Et ₂The title compound of NH salt form.

¹H NMR(CDCl ₃/ MeOH-d ₄) d8.49(s, 1H), 8.12(d, J=8.7Hz, 1H), 8.00(d, J=8.3Hz, 1H), 7.84(m, 1H), 7.69(eclipsed s and m, 2H), 5.59(dd, J=14.9,6.5Hz, 1H), 5.27(s, 2H), 2.98(q, J=7.2Hz ,～1.1H), 2.85(dd, J=12.7,2.6Hz, 2H), 2.31(s, 3H), 2.02-1.83(m, 2H), 1.31(t, I=7.3Hz ,～1.8H), and 1.05(t, J=7.4Hz, 3H).

Ultimate analysis C ₂₀H ₂₂N ₃O ₄P1/4C ₄H ₁₁N5H ₂O:

Calculated value: C, 49.68; H, 6.90; N, 8.97.

Measured value: C, 50.08; H, 6.49; N, 8.46.

Embodiment 24

The 12-[[(glycyl) oxygen] methyl]-8-methyl-7-(1-oxopropyl) indolizino [1; 2-b] quinoline-9(11H)-ketone trifluoroacetate 24A. 8-methyl isophthalic acid 2-[[[[[(1; the 1-dimethyl ethoxy) carbonyl] amino] ethanoyl] oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone

Except using the 12-(methylol)-8-methyl-7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone and N-[(1,1-dimethyl oxyethyl group) carbonyl] glycine, prepare title compound according to the method for embodiment 5E.

24B. the oxygen 12-[[(glycyl)] methyl]-8-methyl-7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-the ketone trifluoroacetate

Except using 8-methyl isophthalic acid 2-[[[[[(1,1-dimethyl oxyethyl group) carbonyl] amino] ethanoyl] oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone, prepare title compound according to the method for embodiment 5B. ¹H NMR（D ₂O/DSS）d7.6-7.3（m，4H），6.64（s，1H），5.58（s，2H），4.58（s，2H），4.20（s，2H），2.92（q，J＝7.2Hz，2H），1.94（s，3H），1.22（t，J＝7.2Hz，3H）.

Ultimate analysis C ₂₂H ₂₁N ₃O ₄CF ₃CO ₂HH ₂O:

Calculated value: C, 55.07; H, 4.62; N, 8.03.

Measured value: C, 55.32; H, 4.69; N, 7.98.

Embodiment 25

8-methyl isophthalic acid 2-[[(4-morpholino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

Under the room temperature argon atmospher to 12-methylol-8-methyl-7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone (523mg, anhydrous CH 1.56mmol) ₂Cl ₂Add in the suspension (58ml) anhydrous pyridine (130 μ l, 1.61mmol) and Dimethylamino pyridine (19mg, 0.16mmol).To react and stir 10 minutes, (554mg 1.57mmol) handles to use a iodo diacetyl oxide then.After 1 hour, (815 μ l 9.4mmol) handle and stir 1 hour to muddy orange solution with morpholine.Reaction mixture is removed by filter morpholine hydroiodic acid HI sodium, in 15 ℃ with the filtrate vacuum concentration, by the flash chromatography purifying, use 2%CHCl ₃In the MeOH wash-out, remove after desolvating yellow powder, it is suspended in H ₂O(10ml) also use 0.1N HCl(16ml in) handle to pH1.7.The pulpous state liquid that obtains is filtered and use MeCN, use Mt subsequently ₂The O washing gets yellow sheet title compound (mp.148-150 ℃ (decomposition)).

¹H NMR（CDCl ₃）d8.22（d，J＝8.6Hz，1H），8.11（d，J＝8.6Hz，1H），7.84（m，1H），7.70（m，1H），7.25（s，1H），5.77（s，2H），5.50（s，2H），3.73（m，4H），3.33（s，2H），2.92（q，J＝7.6Hz，2H），2.58（m，4H），2.31（s，3H），1.26（t，J＝7.6Hz，3H）.

Ultimate analysis C ₂₆H ₂₇N ₃O ₅HCl1/2H ₂O:

Calculated value: C, 61.60; H, 5.77; N, 8.29.

Measured value: C, 61.62; H, 5.94; N, 8.25.

Embodiment 26

8-[[(dimethylamino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

26A. oxygen 8-[[(iodo ethanoyl)] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone

Under the argon atmospher to (±)-3-ethyl-1,11-dihydro-3-hydroxyl-3H, the 13H-furo [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-13-ketone (320mg, anhydrous CH 1.00mmol) ₂Cl ₂(1.10ml, 1.0M is in CH to add diisobutylaluminium hydride in the suspension (20ml) in 4 minutes ₂Cl ₂In).Add a iodo diacetyl oxide (530mg 1.50mmol), after 2 hours, adds MeOH(10ml in reaction) after 15 minutes, stir after 20 minutes solvent removed in vacuo.Resistates is dissolved in CH ₂Cl ₂And, use 0-5%MeOH/CH in the separation of the enterprising circumstances in which people get things ready for a trip spectrum of silica gel ₂Cl ₂Gradient liquid wash-out gets title compound and some unreacted raw materials.

¹H NMR（CDCl ₃）d8.42（s，1H），8.24（d，J＝8.4Hz，1H），7.96（d，J＝8.3Hz，1H），7.85（m，1H），7.69（m，1H），7.29（s，1H），5.33（s，4H），3.70（s，2H），2.99（q，J＝7.2Hz，2H），1.28（t，J＝7.2Hz，3H）.CIMS（NH ₃，m/e，rel.int.）489（100）[（M+H） ⁺].

Ultimate analysis C ₂₁H ₁₇IN ₂O ₄1/2H ₂O:

Calculated value: C, 50.72; H, 3.65; N, 5.63.

Measured value: C, 50.53; H, 3.35; N, 5.45.

26B. oxygen 8-[[(dimethylamino ethanoyl)] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

With (CH ₃) ₂NH gas (balloon) is with 8-[[(iodo ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone (48.8mg, anhydrous CH 0.098mmol) ₂Cl ₂Suspension (5ml) covers.The interior solid dissolving of several minutes also was stripped to reaction dried after 5 minutes.Resistates is dissolved in CH ₂Cl ₂, use 5%NaHCO earlier ₃Solution washing is used H again ₂The O washing, Na ₂SO ₄Dry.Solvent removed in vacuo is suspended in H with resistates ₂O(20ml) in, add 1N HCl(100 μ l) dissolve most of solid, after the filtration, title compound is carried in lyophilize. ¹H NMR

（CDCl ₃/MeOH-d ₄）d8.47（s，1H），8.23（d，J＝8.3Hz，1H），7.98（d，J＝7.5Hz，1H），7.87（m，1H），7.71（m，1H），7.44（s，1H），5.38（s，2H），5.35（s，2H），3.95（s，2H），3.05（s，6H），3.02（q，J＝7.1Hz，2H），1.27（t，J＝7.1Hz，3H）.

Ultimate analysis C ₂₃H ₂₃N ₃O ₄HCl7/4H ₂O:

Calculated value: C, 58.35; H, 5.86; N, 8.88.

Measured value: C, 58.26; H, 5.51; N, 8.68.

Embodiment 27

8-[[(4-morpholino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride

Repelling under the moisture condition 8-[[(iodo ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone (138.2mg, 0.278mmol) contain morpholine (75 μ l, anhydrous CH 0.86mmol) ₂Cl ₂Suspension (18ml) stirred 1.5 hours, added H ₂O and layering.Organic layer is used H successively ₂O, 5%NaHCO ₃The aqueous solution is used H at last ₂The O washing.Na ₂SO ₄After the drying, organic layer is stripped to dried, adds H ₂O(50ml) and 1N HCl(284 μ l) dissolve whole resistatess.Lyophilize gets title compound.

¹H NMR（CDCl ₃/MeOH-d ₄）d8.50（s，1H），8.23（d，J＝8.6Hz，1H），8.00（d，J＝8.1Hz，1H），7.88（m，1H），7.72（m，1H），7.47（s，1H），5.37（s，2H），5.35（s，2H），4.08（br s，4H），3.99（s，2H），3.50（br s，4H），3.05（s，6H），3.03（q，J＝7.1Hz，2H），1.28（t，J＝7.2Hz，3H）.

Ultimate analysis C ₂₅H ₂₅N ₃O ₅5/4HCl7/4H ₂O:

Calculated value: C, 57.24; H, 5.72; N, 8.01.

Measured value: C, 57.17; H, 5.33; N, 7.62.

Claims

1, formula I compound or its pharmaceutically acceptable salt:

Wherein:

R ⁷Be-H ,-CN; Low alkyl group or-(CH ₂) _nCH ₂V wherein

n=0-3；

R ⁹Be-H ,-OR ,-NRR ¹,-CN ,-(CH ₂) _nCH ₂V wherein

n=0-3；

R ¹⁰Be-H ,-OR ,-NRR ¹,-CN ,-COR ¹²,

-CH(OH)R ¹²、-O-(CH ₂) _1-5CH ₂NRR ¹、

-OC (O) NRR ¹, 1,4 '-Lian piperidines-1 '-carboxyl,

-(CH ₂) _nCH ₂V is n=0-3 wherein;

V is-OH-OCOR ¹⁴, (OH) R of OP (O) ¹⁵Or NRR ¹

R ¹¹Be-H or-OR;

R ¹²Be-H or low alkyl group;

R ¹⁴Be-CR ¹²R ¹⁶R ¹⁷

-(CH ₂) _nCH ₂R ¹⁷(wherein n=1-3);

(n=0 or 1 wherein, CH ₂R ¹⁷Can go up 2,3 or 4 of phenyl and replace);

-O (CH ₂) _nCH ₂R ¹⁷(wherein n=1-3);

-NRR ¹；

-NH (CH ₂) _nCH ₂R ¹⁷(wherein n=1-3);

R ¹⁵Be OH, OR ¹⁸Or CH ₂NH ₂

R ¹⁶Be H or any naturally occurring amino acid side chain;

R ¹⁷Be NRR ¹,

Wherein X is any pharmaceutically acceptable negatively charged ion;

R ¹⁸It is low alkyl group;

X is-CHR ³R ⁴Or

Y is-CH ₃Or-CH ₂OR ²

R ²Be-H-C (O) H ,-COR ¹⁴Or-(OH) R of P (O) ¹⁵

R ³Be-OH-OCOR ¹⁴Or-(OH) R of OP (O) ¹⁵

R ⁴Be-H, low alkyl group or-OR;

R ⁶Be-H or low alkyl group.

Its condition is:

B) .R ⁷, R ⁹, R ¹⁰Or R ¹¹In only have one can be-NRR ¹

C). when X is-CHR ³R ⁴And R ⁴Be-during OR, R ³Be-OH;

D). when Y is-CH ₂OR ²The time, X is

E). work as R ⁷, R ⁹, R ¹⁰And R ¹¹All be-H, Y is-CH ₃The time, X is not-C (O) H ,-CH ₂OH ,-C (O) CH ₂CH ₃Or-CH (OH) CH ₂CH ₃

F). work as R ⁷, R ⁹, R ¹⁰And R ¹¹All be-H, Y is

-CH ₂During OC (O) H, X is not-C (O) CH ₂CH ₃With

G). work as R ⁷, R ⁹, R ¹⁰And R ¹¹With Y all be-during H, X is not-CH ₂OH or-C (O) H.

2, the compound of claim 1, wherein R ⁷, R ⁹, R ¹⁰And R ¹¹Be respectively-H, X is-CHR ³R ⁴R wherein ⁴Be-H or low alkyl group; Or X is

R wherein ⁶Be-H or low alkyl group; Y is-CH ₃Or CH ₂OR ²

3, the compound of claim 2, wherein said compound are the 7-[1-[(glycyl) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

4, the compound of claim 2, wherein said compound are 7-[1-[(3-amino-1-oxopropyls) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

5, the compound of claim 2, wherein said compound are 8-methyl-7-[1-[(2-pyrrolidyl carbonyls) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone.

6, the compound of claim 2, wherein said compound are 7-[1-[(2-amino-2-methyl-1-oxopropyls) oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

7, the compound of claim 2, wherein said compound are 8-methyl-7-[1-[[(2-pyrrolidyl carbonyls) glycyl] oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone.

8, the compound of claim 2, wherein said compound are 8-methyl-7-[1-[(4-morpholinyl ethanoyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone.

9, the compound of claim 2, wherein said compound are 8-methyl-7-[1-[(pyridyl ethanoyl) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-the ketone iodide.

10, the compound of claim 2, wherein said compound are the 7-[1-[[4-[(dimethylaminos) methyl] benzoyl] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

11, the compound of claim 2, wherein said compound are 8-methyl-7-[1-[(phosphonos) oxygen] propyl group] indolizino [1,2-b] quinoline-9(11H)-ketone.

12, the compound of claim 2, wherein said compound are the 7-[1-[[(amino methyls) the hydroxyl oxygen phosphino-] oxygen] propyl group]-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

13, the compound of claim 1, wherein X is

Y is CH ₂OR ²

14, the compound of claim 13, wherein said compound are 8-[[(4-morpholino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone.

15, the compound of claim 1, wherein R ⁷Be CH ₂OR ², X is

Y is-CH ₃

16, the compound of claim 15, wherein said compound are 8-methyl isophthalic acid 2-[[(4-morpholino ethanoyl) oxygen] methyl]-the 7-(1-oxopropyl) indolizino [1,2-b] quinoline-9(11H)-the ketone hydrochloride.

17, the compound of claim 1, wherein R ⁷, R ⁹And R ¹¹For-H, its condition is R ¹⁰Be not-H.

18, the compound of claim 17, wherein R ¹⁰Be-OR-CN ,-COR ¹²Or-(CH ₂) nCH ₂V; X is-CHR ³R ⁴R wherein ⁴Be-H or low alkyl group, or X is

19, the compound of claim 18, wherein said compound are the 7-[1-[(glycyl) oxygen] propyl group]-2-cyano group-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

20, the compound of claim 18, wherein R ¹⁰Be-(CH ₂) nCH ₂V, X is

R ⁶Be CH ₂CH ₃

21, the compound of claim 1, wherein R ⁷And R ¹¹Be respectively-H; Its condition is R ⁹And R ¹⁰All be not-H.

22, the compound of claim 21, wherein R ⁹Be-(CH ₂) nCH ₂V; R ¹⁰Be-OR; X is-CHR ³R ⁴R wherein ⁴Be-H or low alkyl group, or X is Y is-CH ₃Or CH ₂OR ²

23, the compound of claim 1, wherein R ⁹, R ¹⁰And R ¹¹Be respectively-H; Its condition is R ⁷Be not-H.

24, the compound of claim 23, wherein R ⁷Be low alkyl group ,-CN or-(CH ₂) nCH ₂V; X is-CHR ³R ⁴R wherein ⁴Be-H or low alkyl group, or X is

25, the compound of claim 24, wherein said compound are the 7-[1-[(glycyl) oxygen] propyl group]-12-cyano group-8-methyl indolizino [1,2-b] quinoline-9(11H)-ketone.

26, the compound of claim 1, wherein R ⁷, R ¹⁰And R ¹¹Be respectively-H; Its condition is R ⁹Be not-H.

27, the compound of claim 26, wherein R ⁹Be-OR that X is-CHR ³R ⁴R wherein ⁴Be-H or low alkyl group.

28, the compound of claim 1, wherein R ⁷, R ⁹And R ¹⁰Be respectively-H; Its condition is R ¹¹Be not-H.

29, a kind of preparation, it comprise claim 1 compound and with its blended carrier or vehicle.

30, the preparation of claim 29, wherein carrier is pharmaceutically acceptable carrier or vehicle.

31, a kind of method for the treatment of virus infection, it comprise to the infection host of needs use independent or with compound or its pharmaceutically acceptable salt of arbitrary claim of the claim 1-28 of carrier blended significant quantity, or the preparation of claim 29 or 30.