CN1516698A

CN1516698A - Arylindenopyridines with PDE inhibiting activity

Info

Publication number: CN1516698A
Application number: CNA028119746A
Authority: CN
Inventors: G・R・海恩策尔曼; G·R·海恩策尔曼; 阿维里尔; K·M·阿维里尔; 多德; J·H·多德
Original assignee: Ortho McNeil Pharmaceutical Inc
Current assignee: Janssen Pharmaceuticals Inc
Priority date: 2001-04-18
Filing date: 2002-04-16
Publication date: 2004-07-28
Anticipated expiration: 2022-04-16
Also published as: CN1293074C; WO2002085894A1; JP2004532228A; CA2445188A1; EP1385843A1

Abstract

This invention provides novel arylindenopyridines of the formula (I), and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

Description

Have PDE and suppress active aryl indenopyridine

The cross reference of related application

According to 35 U.S.C. § 119 (e) clauses, the application requires the rights and interests of the U.S. Provisional Application sequence number (SN) 60/284,465 of submission on April 18 calendar year 2001, and this provisional application is attached to herein by reference.

Field of the present invention

The present invention relates to new aryl indenopyridine and treatment and preventive use.Use the disease of these compounds for treating and/or prevention to comprise that inflammation and AIDS are diseases related.

Background of invention

Phosphodiesterase (PDE) family is known 11, extensively is distributed in many cell types and the tissue.According to its nomenclature mo, numeral family, capitalization is thereafter represented different genes.The PDE inhibitor increases the cAMP concentration in the histocyte, and therefore effective by the various diseases that the reduction of cAMP level causes to prevention or treatment, the cAMP level reduces is induced by the cAMP abnormal metabolism.These diseases comprise for example anaphylaxis, transformation reactions, sacroiliitis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhoea, esohagismus, glaucoma, premature labor, urethral disease, inflammatory bowel, apoplexy, erective dysfunction, HIV/AIDS, cardiovascular disorder, digestive tract power disease and psoriasis.

In present known phosphodiesterase, PDE1 family is activated by calcium-calmodulin, and its member comprises the PDE1A of selective hydrolysis cGMP and PDE1B and the PDE1C that cAMP and cGMP is shown high-affinity.PDE2 family is characterized as the differential stimulus by cGMP.Red-9-(2-hydroxyl-3-nonyl) VITAMIN B4 (EHNA) specificity suppresses PDE2A.The enzyme of PDE3 family (for example PDE3A, PDE3B) is suppressed by the cGMP specificity.PDE4 (for example PDE4A, PDE4B, PDE4C, PDE4D) is the cAMP specific PDE that is present in the T cell, participates in inflammatory reaction.PDE3 and/or PDE4 inhibitor are estimated effective to following disease: autoimmune disease (for example sacroiliitis), inflammatory bowel, bronchopathy (for example asthma), HIV/AIDS and psoriasis.It is effective that PDE5 (for example PDE5A) inhibitor is tackled following treatment of diseases: cardiovascular disorder and erective dysfunction.Photoreceptors PDE6 (for example PDE6A, PDE6B, PDE6C) enzyme spcificity hydrolysis cGMP.PDE8 family all has high-affinity to the hydrolysis of cAMP and cGMP, but sensitivity is lower than other PDE family specificity enzyme inhibitors relatively.

Phosphodiesterase 7 (PDE7A, PDE7B) is the specific cyclic nucleotide phosphodiesterase of a kind of 3'5'-AMP (cAMP).PDE7 is converted into adenylic acid (AMP) by 3 of hydrolysis cAMP '-phosphodiester bond catalysis cAMP.By regulating this conversion, PDE7 can make the interior skewness one of the born of the same parents of cAMP, controls the activation of different signal transduction of kinases approach thus.PDE7A mainly expresses in the T cell, shown PDE7A to induce for the T cell activation be necessary (Li, L.; Yee, C.; Beavo, J.A.Science 1999,283, and 848).Because the PDE7A activation is necessary to the T cell activation, so small molecules PDE7 inhibitor should be effective as immunosuppressor.Estimate that the PDE7A inhibitor should have the immunosuppression effect in the treatment field such as organ transplantation, autoimmune disease (for example sacroiliitis), HIV/AIDS, inflammatory bowel, asthma, transformation reactions and psoriasis etc.

Almost do not report effectively PDE7 inhibitor.The inhibitor of other phosphodiesterase of great majority is to the IC of PDE7 ₅₀In 100 μ M scopes.Recently, Martinez etc. (J.Med.Chem.2000,43,683) have reported a series of PDE7 inhibitor, wherein the PDE7 IC of two kinds of optimizing compounds ₅₀Be 8 and 13 μ M.Yet these compounds only are that optionally 2-3 is doubly to PDE4 and PDE3 to the selectivity of PDE7.

At last, following compound is disclosed, the some of them compound goes out antimicrobial acivity (Gorlitzer, K. to the strains expressed of plasmodium falciparum (Plasmodium falciparum), Candida albicans (Canduda albicans) and streptococcus aureus (Staphylococcus aureus) and so on according to reports; Herbig, S.; Walter, R.D.Pharmazie 1997,504):

Summary of the invention

The invention provides a kind of compound or its pharmacy acceptable salt with formula I structure:

Formula I

Wherein

(a) R ₁Be selected from:

(i)-COR ₅, R wherein ₅Be selected from H, the optional C that replaces _1-8The straight or branched alkyl,

Optional aryl that replaces and the optional aralkyl that replaces;

Substituting group on wherein said alkyl, aryl and the aralkyl is selected from C _1-8Alkoxyl group,

Phenylacetyl oxygen base, hydroxyl, halogen, tolysulfonyl oxygen base, mesyloxy,

Amino, cyano group, carbalkoxy or NR ₂₀R ₂₁(R wherein ₂₀And R ₂₁Independent choosing

From H, C _1-8Straight or branched alkyl, C _3-7Cycloalkyl, benzyl, aryl or assorted

Aryl) or NR ₂₀R ₂₁Constitute heterocyclic radical or heteroaryl together;

(ii)-COOR ₆, R wherein ₆Be selected from H, the optional C that replaces _1-8Straight or branched alkane

Base, the optional aryl that replaces and the optional aralkyl that replaces;

(iii) cyano group;

(iv) with R ₄Form lactone or lactan;

(v)-CONR ₇R ₈, R wherein ₇And R ₈Independently be selected from H, C _1-8Straight or branched alkane

Base, C _3-7Cycloalkyl, trifluoromethyl, hydroxyl, alkoxyl group, acyl group, alkane carbonyl

Base, carboxyl, aralkyl, aryl, heteroaryl and heterocyclic radical;

Wherein said alkyl, cycloalkyl, alkoxyl group, acyl group, alkyl carbonyl, carboxyl,

Aralkyl, aryl, heteroaryl and heterocyclic radical can by carboxyl, alkyl, aryl,

Substituted aryl, heterocyclic radical, substituted heterocyclic radical, heteroaryl, substituted heteroaryl,

Hydroxamic acid, sulfamyl, alkylsulfonyl, hydroxyl, thiol, alkoxyl group or

Aralkyl replaces,

Perhaps R ₇And R ₈Form heterocyclic radical or heteroaryl together with connected nitrogen;

(b) R ₂Be selected from the optional alkyl that replaces, the optional aryl that replaces, optional replace assorted

Aryl, the optional heterocyclic radical that replaces and the optional C that replaces _3-7Cycloalkyl;

(c) R ₃Independently be selected from following group for 1-4:

(i) H, halo, C _1-8Straight or branched alkyl, aralkyl, C _3-7Cycloalkyl, C _1-8

Alkoxyl group, cyano group, C _1-4Carbalkoxy, trifluoromethyl, C _1-8Alkyl sulfonyl

Base, halogen, nitro, hydroxyl, trifluoromethoxy, C _1-8Carboxylic acid group, aryl,

Heteroaryl and heterocyclic radical;

(ii)-NR ₁₀R ₁₁, R wherein ₁₀And R ₁₁Independently be selected from H, C _1-8Straight or branched alkane

Base, aralkyl, C _3-7Cycloalkyl, carboxyalkyl, aryl, heteroaryl and assorted

Cyclic group, perhaps R ₁₀And R ₁₁Form heteroaryl or heterocyclic radical with nitrogen;

(iii)-NR ₁₂COR ₁₃, R wherein ₁₂Be selected from H or alkyl, and R ₁₃Be selected from H, alkane

Base, substituted alkyl, C _1-3Alkoxyl group, carboxyalkyl, R ₃₀R ₃₁N (CH ₂) _P-,

R ₃₀R ₃₁NCO (CH ₂) _P-, aryl, aralkyl, heteroaryl and heterocyclic radical, or

Person R ₁₂And R ₁₃Form the heterocyclic radical that contains carbonyl, wherein R with carbonyl ₃₀With

R ₃₁Independently be selected from H, OH, alkyl and alkoxyl group, and p is the integer of 1-6,

Wherein said alkyl can be by carboxyl, alkyl, aryl, substituted aryl, heterocycle

Base, substituted heterocyclic radical, heteroaryl, substituted heteroaryl, hydroxamic acid, ammonia sulphur

Acyl group, alkylsulfonyl, hydroxyl, thiol, alkoxyl group or aralkyl replace;

(c) R ₄Be selected from following group: (i) hydrogen, (ii) C _1-3Straight or branched alkyl, (iii) benzyl

The base and (iv)-NR ₁₃R ₁₄, R wherein ₁₃And R ₁₄Independently be selected from H and C _1-6Alkyl;

Wherein said C _1-3Alkyl and benzyl are optional to be selected from following base by one or more

Group replaces: C _3-7Cycloalkyl, C _1-8Alkoxyl group, cyano group, C _1-4Carbalkoxy,

Trifluoromethyl, C _1-8Alkyl sulphonyl, halogen, nitro, hydroxyl, fluoroform

Oxygen base, C _1-8Carboxylic acid group, amino, NR ₁₃R ₁₄, aryl and heteroaryl; And

(e) X is selected from S and O;

Prerequisite is to work as R ₄During for sec.-propyl, R then ₃It or not halogen.

In a selectivity embodiment, the present invention relates to the compound of formula I, wherein R ₁, R ₃And R ₄As mentioned above, and R ₂Be-NR ₁₅R ₁₆, R wherein ₁₅And R ₁₆Independently be selected from hydrogen, the optional C that replaces _1-8Straight or branched alkyl, aralkyl, C _3-7Cycloalkyl, aryl, heteroaryl and heterocyclic radical, perhaps R ₁₅And R ₁₆Form heteroaryl or heterocyclic radical with nitrogen; Prerequisite is to work as R ₂Be NHR ₁₆The time, R then ₁Be not-COOR ₆, R wherein ₆Be ethyl.

The present invention also provides a kind of medicinal compositions that contains described compound and a kind of pharmaceutically acceptable carrier.

The present invention further provides a kind of method for the treatment of ill curee, wherein said disease can improve by the PDE activity that reduces suitable cell, and this method comprises and gives the described medicinal compositions that described curee treats significant quantity.

At last, the invention provides a kind of in the curee prophylactic method, described disease can improve by the PDE activity that reduces suitable cell, this method is included in expection and causes before or after the pathogenic process of disease (can improve by the PDE activity that reduces the suitable cell of curee), gives the compound that described curee prevents the claim 1 of significant quantity.

Detailed Description Of The Invention

The compound of formula I is effective small molecules phosphodiesterase inhibitor, and verified its has restraint to PDE7, PDE5 and PDE4.Some compound of the present invention is effective small molecules PDE7 inhibitor, confirms that also it has good selectivity to PDE5 and PDE4.

R ₁Preferred embodiment be COOR ₆, R wherein ₆Be selected from H, the optional C that replaces _1-8Straight or branched alkyl, the optional aryl that replaces and the optional aralkyl that replaces.R ₆Be preferably the C that H maybe can choose the substituting group replacement that is selected from CN and hydroxyl wantonly _1-8The straight or branched alkyl.

R ₂Preferred embodiment be optional aryl that replaces and the optional heteroaryl that replaces.Preferred substituted is 1-3 and is selected from following group: halogen, alkyl, alkoxyl group, alkoxyl phenyl, halo, trifluoromethyl, trifluoromethoxy or difluoro-methoxy, amino, alkylamino, hydroxyl, cyano group and nitro.R ₂Be preferably the optional phenyl or naphthyl that replaces, perhaps R ₂Be selected from by 1-3 for optional that following group replaces

Halogen, alkyl, hydroxyl, cyano group and nitro.In another embodiment of described compound, R ₂For-NR ₁₅R ₁₆

Preferred R ₃Substituting group comprises:

(i) H, halo, C _1-8Straight or branched alkyl, C _1-8Alkoxyl group, cyano group, C _1-4

Carbalkoxy, trifluoromethyl, C _1-8Alkyl sulphonyl, halogen, nitro and hydroxyl

Base;

Base, aryl C _1-8Alkyl, C _3-7Cycloalkyl, carboxyl C _1-8Alkyl, aryl,

Heteroaryl and heterocyclic radical, perhaps R ₁₀And R ₁₁With nitrogen form heteroaryl or

Heterocyclic radical;

(iii)-NR ₁₂COR ₁₃, R wherein ₁₂Be selected from hydrogen or alkyl, and R ₁₃Be selected from hydrogen, alkane

Base, substituted alkyl, C _1-3Alkoxyl group, carboxyl C _1-8Alkyl, aryl, aralkyl

Base, R ₃₀R ₃₁N (CH ₂) _P-, R ₃₀R ₃₁NCO (CH ₂) _P-, heteroaryl and heterocyclic radical,

Perhaps R ₁₂And R ₁₃Form the heterocyclic radical that contains carbonyl, wherein R with carbonyl ₃₀

And R ₃₁Independently be selected from H, OH, alkyl and alkoxyl group, and p is the whole of 1-6

Number.

R ₃Be selected from following group especially:

Alkyl (CO) NH-, NH ₂And NO ₂

R ₄Preferred embodiment comprise hydrogen, C _1-3Straight or branched alkyl, particularly methyl and amino.

In another embodiment of described compound, R ₁Be COOR ₆, and R ₂Be selected from substituted-phenyl and substituted naphthyl, perhaps R ₂Be NR ₁₅R ₁₆

More particularly, R ₁Be COOR ₆, R wherein ₆Be alkyl, R ₂Be the phenyl or naphthyl that replaces, perhaps R ₂Be NR ₁₅R ₁₆, and R ₃Be selected from H, nitro, amino, NHAc, halo, hydroxyl, alkoxyl group or following formula group:

Alkyl (CO) NH-, and R ₄Be selected from H, C _1-3Straight or branched alkyl, particularly methyl and amino.

Described in a preferred embodiment compound is selected from the hereinafter compound shown in the table 1.

Described compound more preferably is selected from following compound:

Compound 22

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzo dioxane penta-5-yl)-5-oxo, ethyl ester

Compound 24

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, ethyl ester

Compound 40

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, ethyl ester

Compound 49

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, methyl esters

Compound 51

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters

Compound 56

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8-(kharophen)-4-(1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, ethyl ester

Compound 67

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 2-methyl-4-(3-aminomethyl phenyl)-5-oxo, methyl esters

Compound 82

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-amino-4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters

Compound 90

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl isophthalic acid-naphthyl)-5-oxo, methyl esters

Compound 169

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo, methyl esters

Compound 170

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7,8-two chloro-4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-5-oxo, methyl esters

Compound 192

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-bromo-4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-5-oxo, methyl esters

Compound 193

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8-bromo-4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-5-oxo, methyl esters

Compound 241

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8-[(3-carboxyl-1-oxopropyl) amino]-4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters

Compound 242

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8-[(3-carboxyl-1-oxopropyl) amino]-2-methyl-4-(4-methyl isophthalic acid-naphthyl)-5-oxo, methyl esters

Compound 245

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-8-[[4-(hydroxylamino)-1,4-dioxo butyl] amino]-2-methyl-5-oxo, methyl esters

Compound 250

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl) amino] ethanoyl] amino]-2-methyl-5-oxo, methyl esters

Compound 251

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8-[(4-carboxyl-1-oxo butyl) amino]-4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters

Compound 254

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl) methylamino] ethanoyl] amino]-2-methyl-5-oxo, methyl esters

Compound 261

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinyl ethanoyl) amino]-the 5-oxo, methyl esters

Compound 262

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinyl ethanoyl) amino]-, methyl esters

Separable described compound and with it as free alkali.Can also separate they and with it as pharmacy acceptable salt.The example of these salt comprises: hydrobromate, hydriodate, hydrochloride, perchlorate, vitriol, maleate, fumarate, malate, tartrate, Citrate trianion, benzoate, mandelate, mesylate, isethionate, benzene sulfonate, oxalate, palmitate (palmoic), 2-naphthalenesulfonate, tosilate, hexanaphthene aminosulfonyl salt and saccharic acid salt.

The present invention also provides a kind of medicinal compositions that comprises described compound and a kind of pharmaceutically acceptable carrier.

Pharmaceutically acceptable carrier is well known to those skilled in the art, includes but not limited to the salt solution of about phosphoric acid buffer of 0.01 to about 0.1M (preferred 0.05M) or 0.8%.Described pharmaceutically acceptable carrier can be water-based or non-aqueous solution, suspension and emulsion.The example of non-aqueous solvent is propylene glycol, polyoxyethylene glycol, vegetables oil (as sweet oil) and injectable organic ester (as ethyl oleate).Aqueous vehicles comprises water, ethanol, alcohol/aqueous solution, glycerine, emulsion or suspension, comprises salt solution and buffering medium.Oral carrier can be elixir, syrup, capsule, tablet etc.The typical solid carrier is an inert substance, as lactose, starch, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, N.F,USP MANNITOL etc.The parenteral carrier comprises sodium chloride solution, RingerShi glucose, glucose and sodium-chlor, lactic acid RingerShi and non-volatile oils.Intravenous vehicles comprises liquid and nutritious fill-in, electrolyte supplements (as those materials based on RingerShi glucose) etc.Can also there be sanitas and other additive, for example biocide, antioxidant, sequestrant, rare gas element etc.All carriers can use mixing such as routine techniques known in the art and disintegrating agent, thinner, granulating agent, lubricant, tackiness agent as required.

The present invention also provides a kind of method for the treatment of ill curee, and described disease can improve by the PDE activity that reduces suitable cell, and this method comprises and gives the described medicinal compositions that described curee treats significant quantity.

Described in one embodiment disease is an inflammatory diseases.Described in another embodiment disease is that AIDS is diseases related.The disease example of available described medicinal compositions treatment includes but not limited to organ transplantation, autoimmune disease (for example sacroiliitis), immune attack (as bee sting), inflammatory bowel, bronchopathy (for example asthma), HIV/AIDS, cardiovascular diseases, erective dysfunction, transformation reactions and psoriasis.Described in preferred embodiments disease is a rheumatoid arthritis.

Term used herein " curee " includes but not limited to that any animal or human's wage reform very makes it suffer from the animal of the active amendatory disease of PDE of passing through the suitable cell of reduction.Described in a preferred embodiment curee behaves.Behave curee described in the preferred embodiment.

As an example, " suitably cell " used herein comprise and show the active cell of PDE.Suitably the specific examples of cell includes but not limited to T-lymphocyte, muscle cell, neurocyte, fat tissue cell, monocyte, scavenger cell, inoblast.

Can use in the whole bag of tricks well known by persons skilled in the art any, implement or carry out giving of described medicinal compositions.But described compound is intravenously, intramuscular, oral and subcutaneous administration for example.Described in preferred embodiments medicinal compositions orally give.In addition, administration can be included in and give the curee multiple dosage in the suitable time period.Such dosage regimen can be determined according to ordinary method.

" the treatment significant quantity " of medicinal compositions used herein is meant the amount that is enough to stop, reverse or slow down disease process." the prevention significant quantity " of medicinal compositions is meant the amount that is enough to preventing disease (promptly eliminate, improve and/or postpone disease and take place).Measuring the treatment of described medicinal compositions and the method for prevention significant quantity is known in this area.For example, can determine the significant quantity of the described medicinal compositions of administration of human according to the result of zooscopy with mathematical method.

The described in one embodiment significant quantity that treats and/or prevents is to be enough to transmit the amount of about 0.001mg/kg body weight to the described medicinal compositions of about 200mg/kg body weight.The described in another embodiment significant quantity that treats and/or prevents is to be enough to transmit the amount of about 0.05mg/kg body weight to the described medicinal compositions of about 50mg/kg body weight.More particularly, in one embodiment, oral dosage every day about 0.05mg/kg to the scope of about 100 mg/kg.In another embodiment, oral dosage every day about 0.05mg/kg to the scope of about 50mg/kg, and in a further embodiment, oral dosage is at the every day of about 0.05mg/kg extremely in the scope of about 20mg/kg.In another embodiment again, the infusion dosage range be at about several minutes to several days approximately periodic regime, give and pharmaceutical carrier blended, about 1.0 μ g/kg/ about 10mg/kg/ minute inhibitor minute extremely.In a further embodiment, for topical administration, described compound can with pharmaceutical carrier with the combination of about 0.001 to about 0.1 drug/vehicle ratio.

The present invention also further provides the method for a kind of curee's of prevention inflammatory reaction, is included in to estimate to cause before or after described curee's the inflammatory reaction, gives the described medicinal compositions that described curee prevents significant quantity.Described in preferred embodiments incident is insect sting or animal bite.

Definition and nomenclature mo

Except as otherwise noted, employed standardized denomination in the whole specification sheets, at first the distal portion of side chain is specified in narration, narrates the adjacent functional group of tie point then.

The employed following technical term of chemistry of this paper should have the implication that following paragraph is set forth: " independence " should represent that then described substituting group can be identical or different if there is more than 1 substituting group when the chemical substituting group of association.

" alkyl " will represent straight chain, ring-type and branched-chain alkyl.Except as otherwise noted, described alkyl will comprise 1-20 carbon atom.Except as otherwise noted, described alkyl will be chosen wantonly by following one or more groups and replace: for example halogen, OH, CN, sulfydryl, nitro, amino, C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkylthio, C ₁-C ₈-alkyl-amino, two (C ₁-C ₈-alkyl) amino, (one, two, three and four-) halo-alkyl, formyl radical, carboxyl, alkoxy carbonyl, C ₁-C ₈-alkyl-CO-O-, C ₁-C ₈-alkyl-CO-NH-, formamido-, hydroxamic acid, sulfoamido, alkylsulfonyl, thiol, aryl, aryl (C ₁-C ₈) alkyl, heterocyclic radical and heteroaryl.

" alkoxyl group " will be represented-the O-alkyl, and except as otherwise noted, alkoxyl group will have 1-8 carbon atom.

" halogen " will represent fluorine, chlorine, bromine or iodine; " PH " or " Ph " represents phenyl; " Ac " represents acyl group, and " Bn " represents benzyl.

No matter term used herein " acyl group " uses is separately still used as a substituent part, all represents to derive from the organic radical that organic acid has 2-6 carbon atom (side chain or straight chain) by removing hydroxyl.No matter term as used herein " Ac " is used is separately still used as a substituent part, all represents ethanoyl.

No matter " aryl " or " Ar " uses is separately still used as a substituent part, all is isocyclic aryl, and it includes but not limited to phenyl, 1-or 2-naphthyl etc.Isocyclic aryl can replace by 1-5 the hydrogen atom that following group independently replaces on it: halogen, OH, CN, sulfydryl, nitro, amino, C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkylthio, C ₁-C ₈-alkyl-amino, two (C ₁-C ₈-alkyl) amino, (one, two, three and complete-) halo-alkyl, formyl radical, carboxyl, alkoxy carbonyl, C ₁-C ₈-alkyl-CO-O-, C ₁-C ₈-alkyl-CO-NH-or formamido-.The illustrative aryl comprises for example phenyl, naphthyl, xenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxy phenyl, carbethoxy phenyl, acetylphenyl, ethoxyl phenenyl, Phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethyl, methoxy ethyl phenyl, acetylamino phenyl, tolyl, xylyl, dimethylamino formyl radical phenyl etc." Ph " or " PH " represents phenyl.

No matter term used herein " heteroaryl " uses is separately still used as a substituent part, all is meant the full unsaturated group of the ring-type with 5-10 annular atoms, and one of them annular atoms is selected from S, O and N; 0-2 annular atoms is the other heteroatoms that independently is selected from S, O and N; And remaining annular atoms is a carbon.Described group can be connected to remaining molecule by any annular atoms.Representational heteroaryl for example comprises: pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl oxazolyl isoxazolyl, thiadiazolyl group, triazolyl, triazinyl oxadiazole base, thienyl, furyl, quinolyl, isoquinolyl, indyl, isothiazolyl, 2-Evil azepine _ base, azepine _ base, N-oxo-pyridyl, 1-dioxo thienyl, benzothiazolyl benzoxazolyl, benzothienyl, quinolyl-N-oxide compound, benzimidazolyl-, benzopyranyl, the benzisothiazole base, the benzoisoxazole base, the benzodiazine base, benzo furazan base, benzimidazole thiophanate is for pyranyl, indazolyl, the indolizine base, benzofuryl, the chromone base, the tonka bean camphor base, the cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, (for example furan [2 for the furan pyridyl, 3-c] pyridyl, furan [3,2-b] pyridyl or furan [2,3-b] pyridyl), (for example imidazo [4 for imidazopyridyl, 5-b] pyridyl or imidazo [4,5-c] pyridyl), 1, the 5-phthalazinyl, the 2 base, purine radicals, the pyridopyridine base, quinazolyl, the thienofuran base, the thienopyridine base, thienothiophene base and furyl.Heteroaryl can be replaced by 1-5 the hydrogen atom that following group independently replaces on it: halogen, OH, CN, sulfydryl, nitro, amino, C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkylthio, C ₁-C ₈-alkyl-amino, two (C ₁-C ₈-alkyl) amino, (one, two, three and complete-) halo-alkyl, formyl radical, carboxyl, carbalkoxy, C ₁-C ₈-alkyl-CO-O-, C ₁-C ₈-alkyl-CO-NH-or formamido-.Heteroaryl can replace with an oxo, produces for example 4-oxo-1H-quinoline.

Term " heterocyclic radical " is meant the optional saturated wholly or in part cyclic group that replaces, and for example it is monocycle system of 4-7 unit, 7-11 unit's bicyclic ring system or 10-15 unit three ring systems, and it has at least one heteroatoms in comprising the ring of at least one carbon atom.Each ring that contains heteroatomic heterocyclic radical can have 1,2 or 3 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and wherein N and S heteroatoms can also be randomly oxidized.The N atom can be randomly by quaternized.Described heterocyclic radical can be connected on any heteroatoms or the carbon atom.

Representational monocyclic heterocycles base comprises: pyrrolidyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidyl oxazolyl oxazolidinyl isoxazoline-3-yl, thiazolidyl, the isothiazole alkyl, tetrahydrofuran base, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, the 4-piperidone base, THP trtrahydropyranyl, tetrahydro thiapyran base, the tetrahydro thiapyran base sulfone, morpholinyl, thio-morpholinyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, 1,3-dioxolane alkyl dioxin, the Thietane base, thiiranes group etc.Representative bicyclic heterocyclic radical comprises quinuclidinyl, tetrahydro isoquinolyl, dihydro-iso indolyl, dihydroquinazoline base (for example 3,4-dihydro-4-oxo-quinazolyl), dihydro benzo furyl, dihydrobenzo thienyl, thiochroman base, thiochroman base sulfone, dihydrobenzopyrans base, indolinyl, isochroman base, iso-dihydro-indole-group, piperonyl, tetrahydric quinoline group etc.

Substituted aryl, substituted heteroaryl and substituted heterocyclic radical can also be replaced by second substituted aryl, second substituted heteroaryl or second substituted heterocyclic radical, produce for example 4-pyrazol-1-yl-phenyl or 4-pyridine-2-base-phenyl.

Specified carbonatoms (C for example _1-8) represent the carbon atom number in the alkyl or cycloalkyl part independently, perhaps represent the carbon atom number in the moieties (wherein alkyl occurs as the prefix root than large-substituent) than large-substituent independently.

Except as otherwise noted, any substituting group otherwise in molecule on particular location or the definition of variable are all irrelevant in definition of other any position of that molecule with its.Be appreciated that those of ordinary skill in the art just can be chosen in substituting group and the replacement form on the The compounds of this invention, to provide chemically stable and can be by technology known in the art and those methods as herein described synthetic compound easily.

When compound according to the present invention had at least one solid (stereogenic) center, they can correspondingly exist as enantiomorph.When described compound had two or more three-dimensional centers, they can exist as diastereomer in addition.In addition, the crystalline form of some described compounds can be used as polymorph and exists, and also it is included in the scope of the present invention.In addition, some described compounds can form solvate with water (being hydrate) or ordinary organic solvents, also these solvates are included in the scope of the present invention.

Some compound of the present invention can have trans and cis-isomeride.In addition, when the method that is used to prepare The compounds of this invention produces the mixture of steric isomer, can be by routine techniques such as preparative chromatography with these isomer separation.Described compound can be prepared into the racemic form mixture of single steric isomer or some possibility steric isomer.Can obtain non-racemic form by synthetic or fractionation.Can with described compound for example by standard technique (as by form the salt formation diastereo-isomerism to) split into the enantiomer of its composition.Also can form chiral auxiliary(reagent) by covalent bonding, with after chromatographic separation and/or Crystallization Separation and remove chiral auxiliary(reagent) described compound is split.Perhaps, described compound can use the chirality chromatography to split.

Can understand the present invention better with reference to following experiment detailed description, but those skilled in the art should be easily understood that: these experiments are described in detail and only are used to set forth the present invention, and claims have hereinafter more fully been described the present invention.In addition, various public publications have been quoted in this application.The disclosure of these public publications is attached among the application by reference, so that more fully set forth the state in the affiliated field of the present invention.

Experiment is described in detail

I. General synthesis flow

Can synthesize representative compounds of the present invention according to universal synthesis method described below, and illustrate with following generalized flow chart.The product of some flow process can be used as intermediate and produces more than a kind of described compound.The intermediate that selection is used to produce follow-up The compounds of this invention is a decision problem, belongs to fully within those skilled in the art's the limit of power.

Flow process 1

The step that flow process 1 is described can be used for preparing compound of the present invention, and wherein X is O, the R in the flow process 1 _3a, R _3b, R _3cAnd R _3dIndependent is any R ₃Group, and R ₁, R ₂, R ₃, and R ₄As mentioned above.

Benzylidene 2 can be obtained (Bullington, J.L. by currently known methods; Cameron, J.C.; Davis, J.E.; Dodd, J.H.; Harris, C.A.; Henry, J.R.; Pellegrino-Gensey, J.L.; Rupert, K.C.; Siekierka, J.J.Bioorg.Med.Chem.Lett.1998,8,2489; Petrow, V.; Saper, J.; Sturgeon, B.J.Chem.Soc.1949,2134).The Hantzsch reaction of benzal compound and enamine 3 can be carried out (Petrow etc., the same) in backflow acetate.In the time that needed enamine can't be obtained, can use the substituting Hantzsch condition that ammonium acetate is added reaction that comprises.The dihydropyridine 4 chromium trioxide oxidation that obtains is to obtain required pyridine 1 (Petrow etc., the same).At fused aromatic rings (R ₃) on the replacement form produce under the situation of regional isomer (regioisomers) mixture, can pass through the column chromatography for separation product.

In some cases, particularly at R ₂Under the situation for alkyl, can use another modified version Hantzsch reaction (Bocker, the R.H. of three kinds of components; Buengerich, P.J.Med.Chem.1986,29,1596).Work as R ₂Also must be with DDQ or MnO during for alkyl ₂Replace chromic oxide (VI) to carry out oxidation (Vanden Eynde, J.J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y.Tetrahedron 1995,51, and 6511).

Flow process 2

In order to obtain corresponding carboxylic acid and acid amides, as above prepare cyanogen ethyl ester 5.By acetone and the aqueous solution processing ester is converted into carboxylic acid (Ogawa, T. with NaOH; Matsumoto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K.J.Chem.Soc., Perkin Trans.11993,525).Can use standard method to obtain corresponding acid amides then by acid.

Flow process 3

Can revise a little and prepare wherein R ₄Be NH ₂The method of compound.Shown in flow process 4, by benzylidene 2 and acid amidine and these compounds of acetic ester one step preparation (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K.; Kimura, T.Chem.Pharm.Bull.1995,43,788), the R in the flow process 4 is aforesaid R ₅Or R ₆

Flow process 4

Shown in flow process 5, by benzylidene 8 (Zimmer, H.; Hillstrom, W.W.; Schmidt, J.C.; Seemuth, P.D.; Vogeli, R.J.Org.Chem.1978,43,1541) and 2,3-dihydro-1, but 3-indenes diketone synthesizing dihydro pyridine lactone 9 are then by using MnO ₂Oxidation obtains corresponding pyridine.

Flow process 5

Below list the substituent representative flow process on the improvement fused aromatic rings.Obtain amine 11 (flow process 6) by the nitro-compound 10 of going back the reason correspondence with tin chloride (II).Amine and excess acetyl chloride produce acid amides 12.

Flow process 6

According to flow process 7, the alkyl chain that also end can be had carboxylic acid joins amine 11, and Y is O in flow process 7, and n is the integer of 1-3.For example, with succinyl oxide (Omuaru, V.O.T.; Indian J.Chem.Sect B.1998,37,814) or β-Bing Chunsuanneizhi (Bradley, G.; Clark, J.; Kernick, W.J.Chem.Soc., Perkin Trans.1 1972,2019) reaction can produce corresponding carboxylic acid 13.By handling these carboxylic acids are converted into hydroxamic acid 14 (Reddy, A.S. then with Vinyl chloroformate and azanol; Kumar, M.S.; Reddy, G.R.Tetrahedron Lett.2000,41,6285).

Flow process 7

Shown in flow process 8, also available oxyacetic acid is handled amine 11 and is produced alcohol 15 (Jursic, B.S.; Zdravkovski, Z.Synthetic Comm.1993,23,2761).

Flow process 8

Shown in flow process 9, can also successively produce more complicated amine 16 (Weissman, S.A. with handling amino indenopyridine 11 with amine behind the chloroacetyl chloride; Lewis, S.; Askin., D.; Volante, R.P.; Reider, P.J.Tetrahedron Lett.1998,39,7459).At R ₆During for hydroxyethyl, described compound can further change piperazine ketone 17 into.

Flow process 9

Can use known method (Gorlitzer, K.; Herbig, S.; Walter, R.D.Pharmazie 1997,504) or by palladium catalysis coupling, by the amino indenopyridine 18 (flow process 10) of 4-chlorine indenopyridine 19 synthetic 4-.

Flow process 10

II. Synthesizing of specific compound

Can prepare the representational specific compound of the present invention according to following examples.The output that does not also have to attempt obtaining in these reactions is optimized.But according to following content, how those skilled in the art increases output by reaction times, temperature, solvent and/or reagent being carried out the routine change if should knowing.

Some synthetic product can be used as intermediate and produces more than a kind of described compound.In the case, the intermediate of selecting to be used to produce The compounds of this invention is a decision problem, belongs to fully within those skilled in the art's the limit of power.

Embodiment 1

The Hantzsch condensation forms dihydropyridine 4

(R ₁=COOMe; R ₂=3, the 5-3,5-dimethylphenyl; R _{3b, c}=Cl; R _{3a, b}=H; R ₄=Me)

To benzylidene 2 (0.500g, add in the reflux solution of acetate 1.5mmol) (10ml) solution methyl-3-amino-butenate (0.695g, 6.0mmol).Reactant is heated to backflow reaches 20 minutes, add entry then, until beginning to form precipitation.Reactant is cooled to room temperature.Filtering mixt washes with water, obtains the red solid of 0.354g (55%).MSm/z?450(M ⁺+23)，428(M ⁺+1)。

Embodiment 2

Substituting Hantzsch condition forms dihydropyridine 4

(R ₁=CO ₂Me; R ₂=2, the 4-3,5-dimethylphenyl; R ₃=H; R ₄=Et)

To benzylidene 2 (1.00g, add in the reflux solution of acetate 3.82mmol) (12ml) solution the propionyl methyl acetate (1.98g, 15.2mmol) and ammonium acetate (1.17g, 15.2mmol).With reactant heating 20 minutes, be cooled to room temperature then.Solution does not have the product precipitation, so reactant is heated to backflow, adds entry then, begins precipitation until solid.Mixture is cooled to the room temperature after-filtration, washes red solid with water, obtain 1.29g (90%) product.MSm/z?396(M ⁺+23)，374(M ⁺+1)。

Embodiment 3

Dihydropyridine 4 is oxidized to pyridine 1

(R ₁=COOMe; R ₂=3, the 5-3,5-dimethylphenyl; R _{3b, c}=Cl; R _{3a, d}=H; R ₄=Me)

(0.250g adds chromic oxide (VI) (0.584g, 1mL aqueous solution 0.58mmol) in the reflux solution of acetate 0.58mmol) (10ml) solution to dihydropyridine 4.Reflux after 30 minutes, the dilute with water reactant is until beginning to form precipitation.Mixture is cooled to room temperature, allows its standing over night.Filtering mixt washes with water, produces 0.199g (81%) yellow solid.MS?m/z?448(M ⁺+23)，426(M ⁺+1)。

Embodiment 4

Dihydropyridine 4 is oxidized to pyridine 1

(R ₁=COOMe; R ₂=(4-methyl)-1-naphthyl; R _{3b, c}=H, NO ₂/ NO ₂, H; R=Me)

(3.59g adds chromic oxide (VI) (0.816g, 3ml aqueous solution 8.16mmol) in the backflow suspension of acetate 8.16mmol) (40ml) solution to regional isomer dihydropyridine 4.Reflux after 20 minutes, the dilute with water reactant is until beginning to form precipitation.Mixture is cooled to room temperature, allows its standing over night.Filtering mixt washes with water, is produced as the regional isomer intermixture of yellow solid.By the column chromatography purification product, use hexane: eluent ethyl acetate produces the pyridine 1 (R of 1.303g (37%) _3b=NO ₂R _3c=H) and its regional isomer (R of 0.765g (21%) _3b=H; R _3c=NO ₂).MS?m/z?461(M ⁺+23)，439(M ⁺+1)。

Embodiment 5

Substituting three component Hantzsch reaction forms dihydropyridine 4

(R ₁=CO ₂Me; R ₂=cyclohexyl; R ₃=H; R ₄=Me)

Make hexanaphthene formaldehyde (2.0g, 17.8mmol), 2,3-dihydro-1,3-indenes diketone (2.6g, 17.8mmol), methyl acetoacetate (2.0g, 17.8mmol) and ammonium hydroxide (1ml) in 8ml methyl alcohol, refluxed 1.5 hours.Temperature is reduced to about 50 ℃, and reactant stirs and spends the night.Reactant is cooled to room temperature, filters, and wash solid with water.Dissolve resistates with hot ethanol then, filtered while hot.Filtrate is concentrated, produce 4.1g (68%) product, this product just can use without purifying.MS?m/z?336(M ^--1)。

Embodiment 6

DDQ oxidation dihydropyridine 4

(R ₁=CO ₂Me; R ₂=cyclohexyl; R ₃=H; R ₄=Me)

To dihydropyridine 4 (2.50g adds 2 in 15ml dichloromethane solution 7.40mmol), 3-two chloro-3,6-dicyano-1, the 4-benzoquinones (1.70g, 7.40mmol).In stirring at room reactant 4 hours.Filtering mixt is used the washed with dichloromethane resistates.Behind the concentrated filtrate, by the column chromatography purification resistates, use ethyl acetate: the hexane wash-out produces the yellow solid of 0.565g (23%).MS?m/z?358(M ⁺+23)，336(M ⁺+1)。

Embodiment 7

MnO ₂Oxidation dihydropyridine 4

(R ₁=CO ₂Me; R ₂=4-(dimethylamino) phenyl; R ₃=H; R ₄=Me)

(0.50g adds MnO in 10ml dichloromethane solution 1.3mmol) to dihydropyridine 4 ₂(2.5g, 28.7mmol).Spend the night in the stirring at room reactant, filter then, and use washed with dichloromethane.Concentrated filtrate, the orange solids 1 of generation 0.43g (88%).MS?m/z?395(M ⁺+23)，373(M ⁺+1)。

Embodiment 8

The cracking of carboxylicesters 5

(R ₂=2, the 4-3,5-dimethylphenyl; R ₃=H; R ₄=Me)

(2.75g adds the 1M NaOH aqueous solution (100ml) in acetone 6.94mmol) (50ml) suspension to ester 5.After 24 hours, use 100ml water diluted reaction mixture in stirring at room, and (2 * 100ml) wash with methylene dichloride.Water layer is cooled to 0 ℃, uses the concentrated hydrochloric acid acidifying.Filtering mixt washes with water, produces the yellow solid 6 of 1.84g (77%).MS?m/z366(M ⁺+23)，343(M ⁺+1)。

Embodiment 9

The preparation of acid amides 7

(R ₂=2, the 4-3,5-dimethylphenyl; R ₃=H; R ₄=Me; R ₅=H; R ₆=Me)

With carboxylic acid 6 (0.337g, thionyl chloride 0.98mmol) (10ml) solution reflux 1 hour.Cooling solution, vacuum concentration.Use CCl ₄The dilution resistates concentrates and removes remaining thionyl chloride.Use THF (3.5ml) dissolving resistates then, (the THF solution of the 2.0M of 1.47ml is in 6.5ml THF solution 2.94mmol) with its methylamine that joins 0 ℃.To room temperature, stirring is spent the night with the reactant temperature.Mixture is inclined to water, filter, wash with water, drying obtains 0.263g (75%) brown solid.MS?m/z?357(M ⁺+1)。

Embodiment 10

The preparation of pyridine 1

(R ₁=CO ₂Et; R ₂=4-nitrophenyl; R ₃=H; R ₄=NH ₂)

To benzylidene 2 (1.05g, add in the reflux solution of 10ml acetic acid solution 3.76mmol) ethyl amidine and acetic ester acetate (0.720g, 3.76mmol).The solution reflux that obtains spends the night.After being cooled to room temperature, take out the precipitation that produces, wash with water by filtering.The resistates that this is impure heats in small amount of ethanol, filters then to produce 0.527g (35%) yellow solid.MS?m/z?412(M ⁺+23)，390(M ⁺1)。

Embodiment 11

The Hantzsch condensation of benzylidene 8

(R ₂=3-p-methoxy-phenyl and 2,3-dihydro-1,3-indenes diketone)

With benzylidene 8 (2.00g, 9.2mmol), 2,3-dihydro-1,3-indenes diketone (1.34g, 0.2mmol) and ammonium acetate (2.83g 36.7mmol) joins in the 30ml ethanol, and being heated to refluxes spends the night.Reaction mixture is cooled to room temperature, uses alcohol dilution.Collect yellow mercury oxide by filtering, use washing with alcohol, vacuum-drying, the dihydropyridine 9 of generation 1.98g (63%).MS?m/z346(M ⁺+1)。

Embodiment 12

Reduction preparation amine 11

(R ₁=CO ₂Me; R ₂=4-methyl naphthyl; R ₄=Me)

(0.862g adds tin chloride dihydrate (II) (1.33g, 1: 1 ethanol of 6ml 5.90mmol): concentrated hydrochloric acid solution in the backflow suspension of 35ml ethanolic soln 1.97mmol) to pyridine 10.The solution reflux that obtains is spent the night.Add entry,, reactant is cooled to room temperature until beginning to form precipitation.Filtering mixt washes with water then.After the drying, by the column chromatography purification resistates, use hexane: eluent ethyl acetate produces the orange solids of 0.551g (69%).MS?m/z?431(M ⁺+23)，409(M ⁺+1)。

Embodiment 13

The acetylize of amine 11

(R ₁=CO ₂Et; R ₂=3,4-methylenedioxyphenyl base; R ₄=Me)

To amine 11 (0.070g, add in 15ml dichloromethane solution 0.174mmol) triethylamine (0.026g, 0.261mmol) and Acetyl Chloride 98Min. (0.015g, 0.192mmol).After stirred overnight at room temperature, the dilute with water reaction mixture is used methylene dichloride (3 * 35ml) extractions then.With the organic phase of salt water washing merging, through MgSO ₄Dry and concentrated.By silica gel column chromatography purifying resistates, use hexane: eluent ethyl acetate produces the acid amides 12 of 0.054g (70%).MS?m/z467(M ⁺+23)，445(M ⁺+1)。

Embodiment 14

The preparation of carboxylic acid 13

(R ₁=CO ₂Me; R ₂=3, the 5-3,5-dimethylphenyl; R ₄=Me; Y=O; N=2)

To amine 11 (0.079g, add in 5ml benzene suspension 0.212mmol) succinyl oxide (0.021g, 0.212mmol).Behind the reflux 24 hours, filter reaction mixture, and wash with benzene.Dried residue under high vacuum is then with the ether washing, to remove excessive succinyl oxide.Produce the carboxylic acid 13 of 0.063g (63%) thus.MS?m/z?473(M ⁺+1)。

Embodiment 15

The preparation of carboxylic acid 13

(R ₁=CO ₂Me; R ₂=3, the 5-3,5-dimethylphenyl; R ₄=e; Y=H ₂N=1)

To amine 11 (0.078g, add in the reflux solution of 5ml acetonitrile solution 0.210mmol) β-Bing Chunsuanneizhi (0.015g, 0.210mmol).Reactant is heated to backflow reaches 72 hours, be cooled to room temperature then.Concentrated reaction mixture.With resistates and 10%NaOH aqueous solution, and with ether and the sequential washing of ethyl acetate.With concentrated hydrochloric acid acidifying water layer, and with methylene dichloride (2 * 25ml) extraction.The organic phase that merges is through MgSO ₄Dry, filtration and concentrated.By the column chromatography purification resistates, with dichloromethane solution wash-out generation 0.020g (21%) orange solids of 5%MeOH.MS?m/z?467(M ⁺+23)，445(M ⁺+1)。

Embodiment 16

The preparation of hydroxamic acid 14

(R ₁=CO ₂Me; R ₂=(4-methyl)-1-naphthyl; Y=O; N=2; R ₄=Me)

To carboxylic acid 13 (0.054g, add in 0 ℃ of suspension of 10ml ether 0.106mmol) triethylamine (0.014g, 0.138mmol), add then Vinyl chloroformate (0.014g, 0.127mmol).Stirred the mixture 30 minutes in 0 ℃, with its temperature to room temperature.Add the methanol solution of azanol (0.159mmol), reactant is in stirred overnight at room temperature.Filtering mixt is used the ether debris, and vacuum-drying produces 0.030g (54%) yellow solid.MS?m/z?524(M ⁺+1)。

Embodiment 17

The preparation of acid amides 15

(R ₁=CO ₂Me; R ₂=3, the 5-3,5-dimethylphenyl; R ₄=Me)

With amine 11 (0.201g, 0.54mmol) and oxyacetic acid (0.049g, mixture 0.65mmol) in 120-160 ℃ the heating 30 minutes.In heat-processed, add more ethanol acid, to guarantee to exist excess reagent.In case raw material exhausts, reactant is cooled to room temperature, dilute with methylene dichloride.The following extracting substances of mixture that obtains: 20%NaOH, then for 10%HCl, be water at last.Concentrate the organic phase that merges, grind with ether.By column chromatography purification, use ethyl acetate: the hexane wash-out produces 0.012g (5%) yellow solid.MS?m/z?453(M ⁺+23)，431(M ⁺+1)。

Embodiment 18

The preparation of acid amides 16

(R ₁=CO ₂Me; R ₂=3, the 5-3,5-dimethylphenyl; R ₄=Me; NR ₆R ₇=morpholino)

To amine 11 (0.123g, 2ml 20%NaHCO 0.331mmol) ₃Add in 0 ℃ of mixture of the aqueous solution and 3ml ethyl acetate solution chloroacetyl chloride (0.047g, 0.413mmol).The reactant temperature to room temperature, and was stirred 45 minutes.Mixture is inclined to separating funnel, remove water layer.Just can use the organic layer that contains thick chloro-acid amide without purifying.(0.086g 0.992mmol), is heated to about 65 ℃ with reactant and spends the night to add morpholine in ethyl acetate solution.The dilute with water reactant, and be cooled to room temperature.(after 3 * 25ml) extractions, the organic phase of using the salt water washing to merge is through MgSO with ethyl acetate ₄Dry and concentrated, produce 0.130g (79%) yellow solid.MS?m/z?522(M ⁺+23)，500(M ⁺+1)。

Embodiment 19

The preparation of piperazine ketone 17

(R ₁=CO ₂Me; R ₂=3, the 5-3,5-dimethylphenyl; R ₄=Me; R ₇=H)

To 0 ℃ acid amides, 16 (R ₆=CH ₂CH ₂OH) (0.093g, 0.20mmol), (0.055g slowly adds di-t-butyl azodicarboxylate (0.062g, 0.20ml ethyl acetate solution 0.27mmol) to tri-n-butyl phosphine in 0.35ml ethyl acetate solution 0.27mmol).Allow reactant leave standstill 15 minutes, be heated to 40 ℃ then and spend the night.Drip the acidic alcohol of 4.2M.Mixture is cooled to 0 ℃, and allows it leave standstill 2 hours.Filtering mixt, and wash with cold ethyl acetate.By using the CH of 1-5%MeOH ₂Cl ₂The column chromatography purification of solution produces 0.011g (12%) white solid.MS?m/z?478(M ⁺+23)，456(M ⁺+1)。

Embodiment 20

The preparation of the amino indenopyridine 19 of 4-

(R ₁=CO ₂Me; R ₄=Me; R ₆=Me; R ₇=phenyl)

To 4-chlorine indenopyridine 18 (0.069g, add in 10ml cellosolvo solution 0.240mmol) methylphenylamine (0.026g, 0.240mmol).With reactant reflux 96 hours.After being cooled to room temperature, concentrate described solution.By the column chromatography purification resistates, use hexane: eluent ethyl acetate produces 0.029g (34%) orange solids.MS?m/z?359(M ⁺+1)。

Embodiment 21

Prepare the amino indenopyridine 19 of 4-by palladium catalysis coupling

(R ₁=CO ₂Me; R ₄=Me; R ₆=H; R ₇=cyclopentyl)

With 4-chlorine indenopyridine 18 (0.100g, 0.347mmol), cyclopentamine (0.035g, 0.416mmol), acid chloride (II) (0.004g, 0.0017mmol), 2-(di-t-butyl phosphino-) xenyl (0.010g, 0.0035mmol) and cesium carbonate (0.124g, the mixture reflux of 10ml dioxane solution 0.382mmol) spends the night.Reactant is cooled to room temperature, dilute with water, and with ethyl acetate (3 * 35ml) extraction.With the organic phase of salt water washing merging, through Na ₂SO ₄Dry and concentrated.By the column chromatography purification resistates, use ethyl acetate: the hexane wash-out.With the oily matter of ether dissolution purifying, be cooled to 0 ℃.The diethyl ether solution that in this solution, slowly adds 1.0M HCl.Precipitation by filtering separation produces with ether washing, vacuum-drying, produces the yellow solid of 0.032g (25%).MS?m/z?359(M ⁺+23)，337(M ⁺+1)。

According to the universal synthesis method and the embodiment 1-21 of above general introduction, the compound of preparation following table 1.

Table 1

III. biological assay and activity

Based on following principle: the linear kernel thuja acid is measured phosphodiesterase activity preferentially in conjunction with the yttrium silicate pearl according to homology SPA (scintillation proximity assay) mode when having zinc sulfate.

In this was measured, described enzyme changed radiolabeled cyclic nucleotide (reaction substrate) into linear kernel thuja acid (reaction product), and the linear kernel thuja acid is captured on the pearl that contains scintillator through the ion chelating selectivity.The radio-labeling product combines with bead surface and causes energy to transfer to the pearl scintillator, but produces the signal of detection by quantitative.Unconjugated radio-labeling can't be realized closely approaching with scintillator therefore can not producing any signal.

Specifically, with the PDE damping fluid (50mM pH7.4Tris, the 8.3mM MgCl that contain 0.1% ovalbumin ₂, 1.7mM EGTA) the dilution enzyme, make final signal to noise ratio (enzyme: non-enzyme) for 5-10.With PDE (4,5,7A) damping fluid with substrate (2,8- ³H-cAMP or 8- ³H-cGMP is available from Amersham Pharmacia) be diluted to 1nCi/ μ l (or 1 μ Ci/ml).For each test hole, 48 μ l enzymes and 47 μ l substrates and 5 μ l test compounds (or DMSO) are blended in the white Packard plate, then jolting mixed, in room temperature incubation 15 minutes.The solution of zinc sulfate of the yttrium silicate SPA pearl that evenly suspends is added each hole with 50 μ l equal portions, with termination reaction and catch product.Use Topseal-S (Packard) sheet to seal described plate, made pearl free setting 15-20 minute, it is gauged to have a color quenching in use then ³Count on the Packard TopCount scintillometer of H glassprogram.Be output as with the gauged dpm of color quenching.

Dilute test compounds with 100%DMSO, make its concentration be final 20 times of measuring concentration.Independent DMSO carrier is joined in the control wells that does not suppress.Following calculating suppresses (%):

Non-specific binding (NSB)=(the CPM mean value in hole of substrate+damping fluid+DMSO)

Total binding (TB)=(mean value in hole of enzyme+substrate+DMSO)

Table 1 is listed

Use Deltagraph 4 parametric line fit procedure to calculate IC ₅₀Value.Compound shown in following table 2 has been listed is to the IC of PDE 4,5 and 7A ₅₀With inhibition % data.

Table 2

Claims

1. compound and pharmacy acceptable salt, ester and prodrug form with following structure:

Formula I

Wherein

(a) R ₁Be selected from:

Optional aryl that replaces and the optional aralkyl that replaces;

Amino, cyano group, carbalkoxy or NR ₂₀R ₂₁, R wherein ₂₀And R ₂₁Independent choosing

Aryl, perhaps NR ₂₀R ₂₁Form heterocyclic radical or heteroaryl together;

(ii) COOR ₆, R wherein ₆Be selected from H, the optional C that replaces _1-8The straight or branched alkyl,

Optional aryl that replaces and the optional aralkyl that replaces;

(iii) cyano group;

(iv) with R ₄Form lactone or lactan;

(v)-CONR ₇R ₈, R wherein ₇And R ₈Independently be selected from H, C _1-8The straight or branched alkyl,

C _3-7Cycloalkyl, trifluoromethyl, hydroxyl, alkoxyl group, acyl group, alkyl carbonyl, carboxylic

Base, aralkyl, aryl, heteroaryl and heterocyclic radical;

Hydroxamic acid, sulfamyl, alkylsulfonyl, hydroxyl, thiol, alkoxyl group or

Aralkyl replaces,

(c) R ₃Independently be selected from following group for 1-4:

(i) hydrogen, halo, C _1-8Straight or branched alkyl, aralkyl, C _3-7Cycloalkyl, C _1-8

Alkoxyl group, cyano group, C _1-4Carbalkoxy, trifluoromethyl, C _1-8Alkyl sulphonyl,

Halogen, nitro, hydroxyl, trifluoromethoxy, C _1-8Carboxylic acid group, aryl, assorted virtue

Base and heterocyclic radical;

(ii)-NR ₁₀R ₁₁, R wherein ₁₀And R ₁₁Independently be selected from H, C _1-8The straight or branched alkyl,

Aralkyl, C _3-7Cycloalkyl, carboxyalkyl, aryl, heteroaryl and heterocyclic radical,

Perhaps R ₁₀And R ₁₁Form heteroaryl or heterocyclic radical with nitrogen;

(iii)-NR ₁₂COR ₁₃, R wherein ₁₂Be selected from hydrogen or alkyl, and R ₁₃Be selected from hydrogen, alkyl,

Substituted alkyl, C _1-3Alkoxyl group, carboxyalkyl, R ₃₀R ₃₁N (CH ₂) _P-,

R ₃₀R ₃₁NCO (CH ₂) _P-, aryl, aralkyl, heteroaryl and heterocyclic radical, perhaps

R ₁₂And R ₁₃Form the heterocyclic radical that contains carbonyl, wherein R with carbonyl ₃₀And R ₃₁

Independently be selected from H, OH, alkyl and alkoxyl group, and p is the integer of 1-6;

(d) R ₄Be selected from: (i) hydrogen, (ii) C _1-3Straight or branched alkyl, (iii) benzyl and (iv)

-NR ₁₃R ₁₄, R wherein ₁₃And R ₁₄Independently be selected from H and C _1-6Alkyl;

Trifluoromethyl, C _1-8Alkyl sulphonyl, halogen, nitro, hydroxyl, trifluoro methoxy

Base, C _1-8Carboxylic acid group, amino, NR ₁₃R ₁₄, aryl and heteroaryl; And

(e) X is selected from S and O;

2. the compound of claim 1, wherein R ₁Be COOR ₆, R wherein ₆Be selected from H, the optional C that replaces _1-8Straight or branched alkyl, the optional aryl that replaces and the optional aralkyl that replaces.

3. the compound of claim 2, wherein R ₆Be selected from H, maybe can choose the C that the substituting group that is selected from CN and OH replaces wantonly _1-8The straight or branched alkyl.

4. the compound of claim 1, wherein R ₂Be selected from optional aryl that replaces and the optional heteroaryl that replaces.

5. the compound of claim 4, wherein said aryl or heteroaryl are selected from following group by 1-5 and replace: halogen, alkyl, alkoxyl group, alkoxyl phenyl, halo, trifluoromethyl, trifluoromethoxy or difluoro-methoxy, amino, alkylamino, hydroxyl, cyano group and nitro.

6. the compound of claim 4, R ₂Be the optional phenyl or naphthyl that replaces, perhaps R ₂Replace for optional Wherein said optional substituting group is 1-3 and is selected from following group: halogen, alkyl, hydroxyl, cyano group and nitro.

7. the compound of claim 1, wherein R ₃Be selected from:

Carbalkoxy, trifluoromethyl, C _1-8Alkyl sulphonyl, halogen, nitro and hydroxyl;

Aryl C _1-8Alkyl, C _3-7Cycloalkyl, carboxyl C _1-8Alkyl, aryl, heteroaryl

And heterocyclic radical, perhaps R ₁₀And R ₁₁Form heteroaryl or heterocyclic radical with nitrogen;

Substituted alkyl, C _1-3Alkoxyl group, carboxyl C _1-8Alkyl, aryl, aralkyl,

R ₃₀R ₃₁N (CH ₂) _P-, R ₃₀R ₃₀R ₃₁NCO (CH ₂) _P-, heteroaryl and heterocyclic radical, or

R ₃₁Independently be selected from H, OH, alkyl and alkoxyl group, and p is the integer of 1-6.

8. sharp 7 compound, the wherein R of requiring ₃Be selected from:

Alkyl (CO) NH-, NH ₂And NO ₂

9. the compound of claim 1, wherein R ₄Be selected from hydrogen and C _1-3The straight or branched alkyl.

10. the compound of claim 9, wherein R ₄Be selected from methyl and amino.

11. the compound of claim 1, wherein R ₁Be COOR ₆, and R ₂Be selected from substituted-phenyl and substituted naphthyl.

12. the compound of claim 1, wherein R ₁Be R wherein ₆COOR for alkyl ₆, R ₂Be the phenyl or naphthyl that replaces, and R ₃Be selected from H, nitro, amino, NHAc, halo, OH, alkoxyl group or following formula group:

Alkyl (CO) NH-, and R ₄Be selected from H, C _1-3Straight or branched alkyl and amino, X are oxygen.

13. compound and pharmacy acceptable salt, ester and prodrug form with following structure:

Formula I

Wherein

(a) R ₁Be selected from:

Optional aryl that replaces and the optional aralkyl that replaces;

(iii) cyano group;

(iv) with R ₄Form lactone or lactan;

Base, aralkyl, aryl, heteroaryl and heterocyclic radical;

Hydroxamic acid, sulfamyl, alkylsulfonyl, hydroxyl, thiol, alkoxyl group or

Aralkyl replaces,

(b) R ₂Be-NR ₁₅R ₁₆, R wherein ₁₅And R ₁₆Independently be selected from hydrogen, the optional C that replaces _1-8

Straight or branched alkyl, aralkyl, C _3-7Cycloalkyl, aryl, heteroaryl or assorted

Cyclic group, perhaps R ₁₅And R ₁₆Form heteroaryl or heterocyclic radical with nitrogen; Prerequisite

Be to work as R ₂Be NHR ₁₆The time, R then ₁Be not-COOR ₆, R wherein ₆Be ethyl;

(c) R ₃Independently be selected from following group for 1-4:

Base and heterocyclic radical;

Independently be selected from H, OH, alkyl and alkoxyl group, and p is the integer of 1-6, its

Described in alkyl can by carboxyl, alkyl, aryl, substituted aryl, heterocyclic radical,

Substituted heterocyclic radical, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfamyl,

Alkylsulfonyl, hydroxyl, thiol, alkoxyl group or aralkyl replace;

(e) X is selected from S and O.

14. the compound of claim 13, wherein R ₁Be COOR ₆, R wherein ₆Be alkyl, R ₂Be NR ₆R ₇, and R ₃Be selected from:

Alkyl (CO) NH-, NH ₂, NO ₂, halogen and hydrogen, and R ₄Be selected from H, C _1-3Straight or branched alkyl and amino, X are oxygen.

15. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters.

16. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 8-(kharophen)-4-(1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, ethyl ester.

17. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 7-amino-4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters.

18. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl isophthalic acid-naphthyl)-5-oxo, methyl esters.

19. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo, methyl esters.

20. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 7, and 8-two chloro-4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-5-oxo, methyl esters.

21. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 8-[(3-carboxyl-1-oxopropyl) amino]-4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters.

22. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 8-[(3-carboxyl-1-oxopropyl) amino]-2-methyl-4-(4-methyl isophthalic acid-naphthyl) 5-oxo, methyl esters.

23. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-8-[[4-(hydroxylamino)-1,4-dioxo butyl] amino]-2-methyl-5-oxo, methyl esters.

24. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl) amino] ethanoyl] amino]-2-methyl-5-oxo, methyl esters.

25. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 8-[(4-carboxyl-1-oxo butyl) amino]-4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo, methyl esters.

26. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl) methylamino] ethanoyl] amino]-2-methyl-5-oxo, methyl esters.

27. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinyl ethanoyl) amino]-the 5-oxo, methyl esters.

28. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(3, the 5-3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinyl ethanoyl) amino]-, methyl esters.

29. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzo dioxane penta-5-yl)-5-oxo, ethyl ester.

30. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, ethyl ester.

31. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, ethyl ester.

32. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzo dioxane penta-5-yl)-2-methyl-5-oxo, methyl esters.

33. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 2-methyl-4-(3-aminomethyl phenyl)-5-oxo, methyl esters.

34. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 7-bromo-4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-5-oxo, methyl esters.

35. the compound of claim 1, it is 5H-indeno [1, a 2-b] pyridine-3-carboxylic acid, 8-bromo-4-(3,5-two bromo-4-hydroxyphenyl)-2-methyl-5-oxo, methyl esters.

36. a medicinal compositions, it comprises the compound and the pharmaceutically acceptable carrier of claim 1.

37. a medicinal compositions, it comprises the compound and the pharmaceutically acceptable carrier of claim 13.

38. the ill curee of treatment method, wherein said disease can improve by the PDE activity that reduces suitable cell, and this method comprises and gives claim 1 that described curee treats significant quantity or 13 compound.

39. prophylactic method, wherein said disease can improve by the PDE activity that reduces the suitable cell of curee, this method is included in expection can be by before or after the active improved disease incidence of the PDE that reduces the suitable cell of curee, gives claim 1 that described curee prevents significant quantity or 13 compound.

40. comprising, the method for claim 38 or 39, this method give described curee's treatment or the claim 36 of prevention significant quantity or 37 medicinal compositions.

41. one kind is suppressed the active method of curee PDE, this method comprises makes one or more T cells contacting treat the claim 1 of significant quantities or 13 compound.

42. claim 38,39 or 41 method, wherein said disease be selected from transplant diseases related, inflammation is diseases related, AIDS is diseases related, vascular disease and erective dysfunction.

43. the method for claim 38, wherein said disease are selected from anaphylaxis, transformation reactions, sacroiliitis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhoea, esohagismus, glaucoma, premature labor, urethral disease, inflammatory bowel, apoplexy, erective dysfunction, HIV/AIDS, cardiovascular disorder, digestive tract power disease and psoriasis.

44. the method for an artificial modified animal, this method comprise the compound that gives described animal T cell claim 1 or 13.

45. the method for claim 44, wherein said animal are Mammals.

46. the method for claim 45, wherein said animal is selected from mouse, rat, rabbit and cavy.

47. the ill curee of treatment method, wherein said disease can improve by the PDE activity that reduces suitable cell, and this method comprises and gives the compound with formula I structure that described curee treats significant quantity, wherein R ₄Be C _1-8The straight or branched alkyl, and X is O.