CN1020612C - Method for preparing antihypertensive tricyclic lactam derivs. - Google Patents

Abstract

This invention relates to derivatives of fused tricyclic lactams, to the intermediates and processes useful for their preparation and to their pharmacological effect in inhibiting the angiotensin converting enzyme and to their end-use application in the treatment of hypertension.

Description

Method for preparing antihypertensive tricyclic lactam derivs.

The present invention relates to the fused tricyclic amide derivatives, its intermediate and preparation method, and the pharmacotoxicological effect in suppressing angiotensin-converting enzyme and its final application in the treatment essential hypertension.Specifically, the present invention relates to the fused tricyclic lactan of following formula

Ⅰ

And pharmacologically acceptable salt, R wherein and R ¹Be respectively

(a) hydrogen

(b) C ₁-C ₆Alkyl;

(c) C of Qu Daiing ₁-C ₆Alkyl, substituting group wherein are hydroxyl, C ₁-C ₄Alkoxyl group and two-C ₁-C ₄Alkylamino:

(d) C ₆-C ₁₂Aryl;

(e) C of Qu Daiing ₆-C ₁₂Aryl, substituting group wherein are C ₁-C ₆Alkyl, halogen (F, Cl, Br, I), and C ₁-C ₄Alkoxyl group;

(f) assorted (C ₄-C ₉) aryl, heteroatoms wherein can be O, N or S,

The compounds of this invention can be with various inorganic and organic bronsted lowry acids and bases bronsted lowry salifies, and these salt also comprise within the scope of the present invention.These salt comprise ammonium salt, alkaline earth salt such as calcium and magnesium salts, organic alkali salt, dicyclohexyl amine salt for example, N-methyl D-glycosamine, amino acid salts such as arginine, the salt of Methionin etc.Also comprise the organic and inorganic acid salt that can prepare.Hydrochloric acid for example, Hydrogen bromide, carbonic acid, phosphoric acid, methylsulfonic acid, toluenesulphonic acids, maleic acid, fumaric acid, salt such as camphorsulfonic acid.Preferentially select acceptable salt on the nontoxic physiology for use, but the assorted (C that also can use other (g) to replace ₄-C ₉) aryl or (C ₄-C ₉) heteroaryloxy, heteroatoms wherein can be O, N or S, and substituting group is C ₁-C ₆Alkyl, and the fontanel element (F, Br, Cl, I) and C ₁-C ₄Alkoxyl group;

(h) diphenyl methyl, trityl group, or benzyl;

R ²For

(a) hydrogen;

(b) C ₁-C ₈The straight or branched alkyl;

(c) C ₂-C ₈The straight or branched alkylene;

(d) C ₂-C ₈The straight or branched alkynyl;

(e) C ₃-C ₁₀Cycloalkyl;

(f) C ₆Or C ₁₀Aryl,

(g) C of Qu Daiing _1-8Alkyl can selectively contain O, a S, S=O, O=S=O, C=O, CONR arbitrarily ₂, NRCOOR or-NR ₂Group, wherein the definition of R the same and have 1-3 be selected from the fontanel element (F, Br, Cl, I), Carboxylamide, C ₁-C ₄The substituting group of carbalkoxy, sulfydryl, amino and R wherein the definition of R with above-mentioned.

R ³Be hydrogen, C _1-12Alkyl, phenyl or benzyl;

R ⁴Be hydrogen, C _1-12Alkyl, phenyl, benzyl or natural amino acid residue, and

R ³And R ⁴Be combined together to form 6 to 8 Yuans condensed ring parts with carbon atom, on this ring sulphur or Sauerstoffatom can be arranged;

R ⁵And R ⁶Be respectively

(a) hydrogen, hydroxyl;

(b) the fontanel element (F, Br, Cl, I);

(c) C ₁-C ₆Alkyl;

(d) C ₁-C ₆Alkoxyl group.

Alkyl refers to some such groups, for example methyl, ethyl, vinyl, propargyl, butenyl, isobutyl-or the like.Cycloalkyl comprises such as cyclobutyl, cyclopentyl, cyclohexyl etc.C ₆-C ₁₂Aryl comprises phenyl, naphthyl, indenyl, phenylbenzene and benzo cycloalkyl, for example indenyl and 1,2,3,4-tetralin base.C ₄-C ₉Heteroaryl group comprises some compounds like this, for example pyridyl, thienyl, furyl, imidazolyl and thiazolyl and any bicyclic radicals, in these dicyclos any above-mentioned heterocycle and another aromatic heterocyclic group for example indyl, quinolyl, isoquinolyl, benzimidazolyl-, 1, the 5-naphthyridinyl is with the quinoxalinyl condensed.

Preferred compound is: R wherein is a hydrogen, R ¹For hydrogen or be preferably for example ethyl of alkyl; R ²Be C ₆Aryl-C ₁-C ₄Alkyl, preferably styroyl; R ⁵And R ⁶Be hydrogen, C _1-6Alkoxyl group or represent monohydroxy or dihydroxyl substituting group on the benzenoid form part, and R ³And R ⁴Form-6-together with the atom that they connected, 7-or 8 Yuans rings for example, form RX-6 person's ring, in conjunction with R ³And R ⁴Be CH ₂-CH ₂-CH ₂-,-CH ₂-S-CH ₂-or-CH ₂-O-CH ₂-; Form-7 Yuans rings, in conjunction with R ³And R ⁴Be-CH ₂(CH ₂) ₂CH ₂-form RX-8 person's ring, in conjunction with R ³And R ⁴Be-CH ₂(CH ₂) ₂CH ₂-.

Though wherein comprise all enantiomers and diastereomer and composition thereof, most preferred still those have the compound of the diastereomer configuration of following formula representative:

Ⅱ

The separation of these isomer can be finished by the routine techniques in this technology.(R certainly, ¹, R ², R ³, R ⁴, R ⁵And R ⁶Substituting group is defined in the I formula).

Compound of the present invention can prepare by known series reaction step in this technology.In general, when changing into its hydrochloride, the aryl alanine of the most handy one suitable N-protected starts this reaction sequence, according to the principle of Schotl-Baumann reaction, with-suitable (R ³And/or R ⁴Replace) the amine combination.Whether contain the additional fused rings of a band benzo-aza cycloheptatriene-2-ketone part according to needed final product, i.e. R whether ³And R ⁴With with atom that they were connected in conjunction with forming such as a pyridine benzo and nitrogen heterocyclic heptantriene-2-ketone part, and adopt different intermediates and reaction process thereof.But in each case,, have suitable R being incorporated into before nitrogen-atoms on 3 of benzo-aza cycloheptatriene-2-ketone part enters coupling step ³Carry out the Friedel-Kraft cyclization earlier with the intermediate of R.After the cyclisation, remove N-protected group (for example phthalimido part), nitrogen-atoms then passes through conventional linked reaction to produce the needed R that has expection ¹, R ²I formula compound.

At R ³And R ⁴Substituting group does not partly form the acyl chloride derivative (III) of the L-aryl alanine of N-protected under the situation of an additional fused rings then according to a Schotl-Baumann reaction and a suitable R with benzo-aza ring triolefin-2-ketone ⁴Amino acid (IV) combination that replaces, this moment, reactant was to have in the presence of yellow soda ash/acetone and the water, preferably bonded under the room temperature condition.Preferred N blocking group is a phthalimido.Final reaction product (V) carries out acidification.Make products therefrom (V) in the presence of tosic acid in azeotropic solvent (for example benzene, toluene, chloroform etc.) be combined with R by back flow reaction thing and ³Aldehyde reaction, producing Zhong Jian Ti oxazinone (VI), when with a lewis acid (Tripyrophosphoric acid for example, CF ₃SO ₃H or its three silyls ester (TMSOTF) can make its carbonyl protonated and form-imide ion intermediate when handling, this intermediate and then experience the Friedil-Kraft reaction in situ.Imide ion intermediate produces the compound VII through the Friedel-Kraft cyclisation, and this compound is converted to suitable hydrocarbyl carbonate VIII, and said reaction is carried out according to known routine techniques.

Reacting flow chart A

Wherein Dg is-N-protected base (preferably phthalimido), and TSOH is a tosic acid, and PhH is a phenyl hydride, R ³, R ⁴, R ⁵And R ⁶Define identically with the I formula, R ' is the R except hydrogen.In order to obtain the suitable final product of I formula, often preparing wherein in advance, the R base is selected from the ester that (h) organizes.

In some cases, need prepare wherein R ³And R ⁴Form with nitrogen heterocyclic heptantriene-2-ketone ring-compound of additional fused rings, the chloride derivative (III) that makes the aryl alanine of N-protected according to above-mentioned Schott-Baumann reaction through with an amido vinyl muriate (IX a) or-vinyl amino acid (IX b) coupling of OH protection generates intermediate (being respectively X a and X b).In the methylene dichloride that contains alcohol, use these intermediates of ozonize down in-78 ℃, also under reflux temperature, handle separated products to produce acyl enamine (XI a and XI b), then according to Friedel-Kraft cyclisation program CF with dimethyl sulphide and pyridine chilling with trifluoroacetic acid/dichloromethane ₃SO ₃H handles and promptly produces compound XII a and XII b.When carrying out the Friedel-Kraft cyclisation, preferably utilize lewis acid, particularly be selected from perfluoro alkyl sulfonic acid, for example trifluoromethane sulfonic acid, pentafluoroethyl group sulfonic acid and seven fluoropropyl sulfonic acid.These reactions are shown among the reacting flow chart B.

Reacting flow chart B

Wherein R, R ⁵, R ⁶, Pg and formula I are same, and Pg is N-protected group (being preferably formed as a phthalimido), and n is 3,4 or 5.In these cases, wherein expectation obtains wherein R ³And R ³Can produce a compound that on its ring, has the fused rings of sulphur or oxygen, and then prepare these compounds according to reaction process C.

Reacting flow chart C

Wherein Pg is the N-protected base, phthalimido preferably, R, R ⁵, R ⁶Definition and the I formula with, and X is sulphur or oxygen.

In previous reaction schema C, the protected phenylalanyl serine ester of N-(X III) changes into its methylsulfonyl ester in situ, is being dissolved in for example triethylamine in methylene dichloride of an inert solvent then.In handle with methylsulfonyl chloride and to remove it, obtain dehydroalanine.HXCH ₂CH(OET) ₂(X V) obtains Michael adduct (X VI) with the conjugate addition of dehydroalanine intermediate (X IV), and the trifluoroacetic acid effect of this product in methylene dichloride is cyclized into acyl enamine (inferior acid amides).Obtain final cyclisation product (X VIII) by above-mentioned Friedel-Kraft reaction.

In addition, under special situation, R wherein ³And R ⁴The fused rings structure in X when being sulphur, then intermediate X VI a may pass through at the DMF(dimethyl formamide) in, under suitable base catalysis, L-ethycysteine (X IX) is made with bromoacetaldehyde diethyl acetal and sodium iodide alkylation such as triethylamine or sodium hydride one class.The free amino of Chan Shenging (XX) is by N-ethoxycarbonyl-2-oxyethyl group-1 like this; the effect of the conventional coupling agent of 2-dihydroquinoline (EEDQ) class combine with (preferably phthalyl) L-phenylalanine (X XI) of N-protected with produce intermediate (the X VI a), this intermediate be according to conventional lewis acid-Friedel-Kraft cyclisation program cyclisation.

Reacting flow chart D

R wherein, R ⁵, R ⁶Described as defined above with Pg.

At reaction process A, B in the reaction of C and D, merges lactan by the preparation of Friedel-Kraft cyclization process, and perfluoro alkyl sulfonic acid is preferably used in this reaction certainly.

Be produced out in case merge lactan (for example VIII, XII a, XII b and X VIII), promptly should remove the N-protected group, so that suitable side chain can be coupled on the unhindered amina.This goes provide protection to reach by known ordinary method.In this case, wherein protecting group is a phthalyl, by known technology in this technology, through removing the phthalimido part at an easy rate with the hydrazine hydrate reaction.Though expecting described fusion lactan is non-enantiomeric form, preferably go to protect fused lactams for having following structure person

ⅩⅫ

R ' wherein defines same R, does not just comprise H.

Though any known coupling method commonly used all can utilize,, preferably use the method shown in the following reacting flow chart E for this class coupling.

Reacting flow chart E

R ' wherein and R ^' ₁Described as defined above, but they can not be H, R ², R ³, R ⁴And R ⁵And R ⁶As hereinbefore.Though it should also be noted that the diastereomer form of best fused lactams is the X XII, XX VI and XX VII formula description person should be bright loud and clearly still can make all other diastereomer by similar technique.

The method A of schema E needs-(R) the elimination reaction of trifluoto ester (X III) participation, wherein fused lactams alkali for example triethylamine in the presence of, but be preferably in one " proton sponge " (" proton sponge "), promptly 1, the existence of 8-pair-(diethylin)-naphthalene contacts with trifluoto ester down, produces compound XX VI.

Method B need use the keto esters and the molecular sieve that are dissolved in ethanol (or other alcoholic solvent) to form a western Fu Shi alkali (Schiffs base), and this alkali is reduced into compound 26, preferably uses cyano group cyanogen boronation sodium.

Method C need carry out 1, the 4-Michael addition reaction with ethyl-4-oxo one aryl crotonate (for example XX V).The ketone group oxygen of intermediate XX VII (Y is an oxygen) is by catalytic hydrogenation reaction, preferably utilizes palladium catalyst to be reduced generation XX VI in the presence of a small amount of sulfuric acid having.

Because it is hydrogen that the embodiment of preferred compound of the present invention relates to those R, R ¹Not the I formula compound of hydrogen (preferably ethyl), thus it should be noted that the coupling method that relates to aforesaid reacting flow chart E, particularly when they relate to the selective hydrolysis of R ester group.For example, in general, preferably preparing R wherein for the selective hydrolysis of compound XX VI is that the group of (h) group (is a diphenyl-methyl, trityl or benzyl) ester, because these groups can be used gentle optionally hydrolysis of acid, for example can be by reacting with salt acetoacetic ester or trifluoroacetic acid, perhaps they also can be by the catalyzer hydrogenolysis.Equally because the reductive action of ketone group second (Y is an oxygen in formula XX VII) also the R group hydrolysis of ester moiety in the future fall and become its acid accordingly, so preferably compound XX VII have one wherein R for being selected from the ester group of (h) group group.In addition, particularly for R wherein ³And R ⁴Form any compound of 6 Yuans rings with the atom that they connected, all available perfluoro alkyl sulfonic acid of R group (beyond the dehydrogenation) is handled and selective hydrolysis becomes its acid accordingly arbitrarily.The perfluoroalkyl sulfonic acid that is suitable for is trifluoromethane sulfonic acid, pentafluoroethyl group sulfonic acid and seven fluoropropyl sulfonic acid.

Following embodiment further illustrates the method and the condition that can prepare The compounds of this invention.The preferred diastereomer of these embodiment can separate by ordinary method.

Embodiment 1

[2(S)] N-(2-chloro-2-tetrahydrobenzene-1-yl)-1,3-dihydro-1,3-dioxo-2H-isoindole-2-(S)-(phenmethyl-2-buserelin) (X is a)

Steps A .2-(2-chloro-2-chloro-2-tetrahydrobenzene-1-yl)-1H-isoindole-1,3(2H)-diketone

To be dissolved in the 11.0g(72.8mmol in the 50ml anhydrous dimethyl formamide (DMF)) 1,6-dichloro tetrahydrobenzene, 20.0g(108mmol) potassium phthalimide and 1.0g(6.0mmol) solution of potassiumiodide stirred 24 hours in 110 ℃ under a nitrogen environment.Pour in the 30ml ether after the reaction mixture cooling.Leach dark mixture, under vacuum, remove ether and dimethyl formamide afterwards.Dark crystallization residue is dissolved in after the ethyl acetate chromatography on 500g silica gel, with ethyl acetate-hexane wash-out of 10%-20%.From ethyl acetate-hexane, concentrate suitable part behind the recrystallization, promptly obtain 14.0g(73.5%) needed phthalic imidine, fusing point is 99-103 ℃.

Step B

To be dissolved in the 6.0g(120mmol of 150ml MeOH) hydrazine hydrate and 26.1g(100mmol) solution of N phthalimido-6-amino-1-chlorine tetrahydrobenzene refluxed 3 hours under nitrogen environment, was cooled to 25 ℃ and stirred 3 hours.Filtering mixt, concentrate, in the impouring 300mmll N hydrochloric acid and use the 200ml washed with dichloromethane.The alkalization water layer is also with three parts of 500ml dichloromethane extractions.With dried over mgso organic phase, filtration and the concentrated 9.25g(70mmol that obtains) thick amine.Concentrate neutral extract and obtain the untreated initial phthalic imidine of 6.0g.In under 25 ℃ of nitrogen environments to the 21g(71mmol that is dissolved in 200mlCHCl) benzene imide base-L-phenylalanine and 18.5g(75mmol) in 30 minutes, add in the solution of stirring of EEDQ and be dissolved in 20ml CH ₂Cl ₂9.25g(70mmol) 6-amino-1-chlorine tetrahydrobenzene.Stir after 18 hours, reaction mixture is with two parts of 200ml 10% hydrochloric acid solns, 200ml saturated sodium bicarbonate solution and salt water washings.Organic phase is with dried over mgso, filtration and concentrate and obtain solids.Recrystallization goes out the needed 2-(s of 26.1g from dichloromethane/hexane) (X mixture a), this product fail to separate (overall yield 64%) to the diastereomer acid amides in this step.

IR（KBr）3400，1775，1715，1650，1530，1380，cm ^-1;NMRδ1.60（m，2H），1.82（m，2H），2.05（m，2H），3.49（s，1H），3.59（s，1H），4.60（m，1H），5.05（dd，1/2H，J _a＝10Hz，J _b＝2Hz），5.17（dd，1/2H，J _a＝10Hz，J _b＝2Hz），5.95（t，1H，J＝7Hz），6.45（m，1H），7.10（s，5H），7.70（m，4H）.

Anal.Calcd.for C ₂₃H ₂₁ClN ₂O ₃：C，67.56;H，5.18;N，6.85.Found：C，67.40;H，5.30;N，6.80.

Embodiment 2

[S(R*, R*)]-1-[2-(1,3-dihydro-1,3-dioxo-2H isoindole-2-yl)-1-oxo-3-hydrocinnamyl]-1,2,3,4-tetrahydrochysene-2-pyridine-3-carboxylic acid, (XI a) will be dissolved in the 300ml CH that contains the 20ml anhydrous methanol to methyl esters ₂Cl ₂In the 12.2g(30mmol that obtains by embodiment 1) (X solution a) is cooled to-70 ℃ and stir to vinylchlorid, feeds in solution by the frit pipe simultaneously and is contained in (the air-flow of usefulness-Welsbach ozonizer generation of bromine oxygen in the oxygen.When solution becomes is blue, in solution, feed exsiccant nitrogen to remove excessive ozone, reaction mixture 20mlMe ₂Heat to 25 ℃ gradually after S and 4ml pyridine are handled and stirred 20 hours.Pour the 200ml10% hydrochloric acid soln into and isolate organic phase in solution, the water thorough washing is through dried over mgso and the concentrated amber oily thing of 13.0g that obtains.Be dissolved in thick ozone degradation production in the 200ml methylene dichloride that contains 0.5ml trifluoroacetic acid (TFA) and under nitrogen environment, refluxed 3 hours.Wash through refrigerative solution with saturated sodium bicarbonate solution, with dried over mgso and the concentrated amber oily thing of 12.2g that obtains.Use 50%Et OAc/ hexane to be prepared high pressure liquid chromatography (HPLC) (HPLC) separation (recirculation of Waters Prep-500) and obtain 4.3g(10.1mmol separately) diastereomer acyl enamine XI a and XI b(n=2), (overall yield 68%).Recrystallization XI a isomer obtains white crystals shape fine powder from dichloromethane/hexane:

146-147℃;[α] ^Amb _D＝-320.1°（c＝1.1，CHCl ₃）;IR（KBr）1770，1740，1720，1670，1650，1390，1220，722cm ^-1;NMR δ1.85（m，2H），2.30（m，2H），3.50（d，2H，J＝7Hz），3.72（s，3H），4.71（m，1H），5.20（m，1H），5.27（t，1H，J＝7Hz），6.45（d，1H，J＝9Hz），7.12（s，5H），7.71（m，4H）.

Anal.Calcd.for C ₂₃C ₂₂N ₂O ₅：C，68.89;H，5.30;N，6.69.Found：C，68.61;H，5.26;N，6.56.

Embodiment 3

[4S-(4 α, 7 α, 12b β)]-7-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1,2,, 3,4. ,-6,7,8,12b-octahydro-6-oxy picolinate is [2,1-a] [2] benzo-aza cycloheptatriene-4-carboxylic acid also, and (XII is a) for benzhydryl ester *

To being dissolved in 20ml CH under the nitrogen environment ₂Cl ₂In by embodiment 2 resulting 4.20g(10.0mmol) acyl enamine XI a in the solution of stirring, add 6ml CF ₃SO ₃The H(trifluoromethane sulfonic acid).20 ℃ were stirred down after 18 hours, solution were inclined on ice and with 200mlEtOAe extract.Organic phase water thorough washing is with dried over mgso and concentrated.Nubbin is dissolved in the methylene dichloride and handles and place 12 hours concentrated this solution with 2.2g diazonium ditane, resistates is carried out flash chromatography with the 33%EtOAe/ hexane obtain 4.5g(7.7mmol, 77% yield on 400ml silica gel) spumescence benzhydryl ester XII (R=CHPh ₂).Slowly recrystallization comes out from dichloromethane/hexane, thereby obtains 4.3 gram (75% yield) pure transparent sheet-like things:

mp.156-157℃;[α] ^Amb _D＝-87.6℃（c＝0.6，CHCl ₃）;IR1780，1717，1643，1450，1379cm ^-1;NMRδ1.8-2.1（m，4H），2.38（m，2H）;3.23（dd，1H，J _a＝18Hz，J _b＝16Hz），4.38（dd，1H，J _a＝19Hz，J _b＝12Hz），5.30（dd，1H，J _a＝6Hz，J _b＝2Hz），5.42（dd，1H，J _a＝6Hz，J _b＝4Hz，6.05（dd，1H，J _a＝12Hz，J _b＝6Hz），6.30（s，1H），6.61（d，1H，J＝7Hz），6.9-7.4（m，13H），7.75（m，2H），7.92（m，2H）.

Anal.Calcd.for C ₃₆H ₃₀N ₂O ₅：C，75.77;H，5.30;N，4.91.Found：C，75.79;H，5.46;N，4.77.

* (R in the XII formula compound is a diphenyl-methyl, R ⁵, R ⁶Be hydrogen, n is 3.）

Embodiment 4

[4S-(4 α, 7 α, 12b β)]-7-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1,2,, 3,4,6,7,8 ,-12b-octahydro-6-oxy picolinate is [1-a] [2] nitrogen heterocyclic heptantriene-4-carboxylic acid also, methyl esters

Available in addition diazomethane is handled cyclisation product, obtains the methyl esters XII (R=CH among the embodiment 3 ₃):

mp 138-149℃[α] ^Amb _D＝-122.4°（c＝0.97，EtOH）;IR1778，1720，1655，1620，1375cm ^-1，NMRδ1.7-2.2（m，4H），2.43（m，2H），3.10（s，3H），3.44（dd，1H，J _a＝17Hz，J _b＝6Hz），4.42（dd，1H，J _a＝17Hz，J _b＝12Hz），5.23（dd，1H，J _a＝6Hz，J _b＝2Hz），5.47（dd，1H，J _a＝6Hz，J _b＝4Hz），6.08（dd，1H，J _a＝12Hz，J _b＝6Hz），7.23（m，4H），7.77（m，2H），7.89（m，2H）.

Anal.Cacd.for C ₂₄H ₂₂N ₂O ₅：C，68.89;H，5.30;N，6.69.Found：C，68.98;H，5.83;N，6.63.

Embodiment 5

[4 α, 7 α, 12b β]-7-[[-(ethoxycarbonyl)-and the 3-hydrocinnamyl] amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxy picolinate is [2,1-a] [2] benzo-aza cycloheptatriene-4-carboxylic acid also, and (II is a) for the phenylbenzene methyl esters

The 1.17g(2.0mmol that in containing the embodiment 3 that is dissolved in 15mlMe OH, obtains) adds the 2.3ml1N hydrazine hydrate solution that is dissolved in methyl alcohol in the phthalic imidine XII solution, stirred 3 days in 25 ℃.Under vacuum, remove and desolvate, resistates is dissolved in chloroform, filter and the concentrated thick amine of light yellow oily that obtains.Should thick amine (approximately 2.0mmol) under nitrogen environment, be dissolved in the 6ml methylene dichloride and use 545mg(2.5mmol at 25 ℃) 1,8-is two-(dimethylamino) naphthalene and 850mg(2.5mmol) (R)-ethyl-4-phenyl-2-trifluoro-methanesulfonyl oxy butyl ester (XX III) processing.Solution stirs at 25 ℃ and formed precipitation in 18 hours.Reaction mixture is directly placed 100ml silica gel, carries out flash chromatography, obtain 1.11g(1.76mmol with 25%Et OAc/ hexane) the pure oily S of (productive rate 88%), S, S, (II is (R a) for the R diester ³, R ⁴=-CH ₂CH ₂CH ₂-, R=CHPh ₂):

IR（KBr）1734，1657，1495，1452，1185，1155 cm ^-1;NMRδ1.28（t，2H，J＝7Hz），1.7-2.2（m，6H），2.43（m，2H），2.68（dd，1H，J _a＝17Hz，J _b＝13Hz），2.80（m，2H），3.25（dd，1H，J _a＝17Hz，J _b＝6Hz），3.46（t，1H，J＝7Hz），4.17（q，1H，J＝7Hz），4.38（dd，1H，J _a＝13Hz，J _b＝6Hz），5.35（dd，1H，J _a＝6Hz，J＝4Hz），5.40（dd，1H，J _a＝6Hz，J _b＝2Hz），6.25（s，1H）.

Embodiment 6

[4 α, 7 α (R*)] 12b β-7-[I1-(-ethoxycarbonyl)-and the 3-hydrocinnamyl] amino]-1,2,3,4,6,7,12b-octahydro-6-oxy picolinate 900mg(1.42mmol that also [2,1-a] [2] benzo-aza cycloheptatriene-4-carboxylic acid (II) obtains in the embodiment 5 of the stirring under 25 ℃ of nitrogen environments) (S, S, S, R) benzhydryl ester II (R ³, R ⁴=-CH ₂CH ₂CH ₂-, R=CHPh ₂) return with 2.5ml and to add the 7ml trifluoroacetic acid in the solution of fragrant ether.Stir and in high vacuum, remove volatile matter after 2 hours and obtain the oily residue, again it is dissolved in the 4ml anhydrous diethyl ether, powerfully stir and dilute with hexane.Inclining from colloidal solid supernatant liquor, grinds jelly and vacuum-drying with hexane, obtains 750mg(1.3mmol) (S, S, S, R) II (R ³, R ⁴=CH ₂CH ₂CH ₂-, pale brown look solid-state tfa salt (productive rate 91%) R=H):

[α] ^Amb＝25.5℃（c＝0.57，CH ₃OH）;IR（KBr）2300-3400，1735，1660，1195，1140cm ^-1;NMRδ（CD ₃CN，TFA）1.31（t，3H，J＝7Hz），1.78（m，2H），2.3-2.5（m，4H），2.84（m，2H），3.26（dd，1H，J _a＝17Hz，J _b＝13Hz），3.68（dd，1H，J _a＝17Hz，J _b＝6Hz），4.07（t，1H，J＝6Hz），4.29（m，2H），5.10（dd，1H，J _a＝6Hz），J _b＝2（Hz）5.20（dd，1H，J _a＝13Hz，J _b＝6Hz），5.35（dd，1H，J _a＝5Hz，J _b＝1Hz），7.1-7.4（m，9H）.

Anal.Calcd.for C ₂₉H ₃₃F ₃N ₂O ₇：C，60.20;H，5.75;N，4.84.Found：C，60.12;H，5.72;N，4.45.

Embodiment 7

[4 α, 7 α (R*)] 12b β-7-[[1-carboxyl-3-hydrocinnamyl] amino]-1,2,, 3,4,6,7,12b-octahydro-6-oxy picolinate also [2,1-a] [2] benzo-aza cycloheptatriene-4-carboxylic acid (II) under 25 ℃ of nitrogen environments to the 116mg(0.20mmol that is dissolved in 5ml95% ethanol) ester group (the II R=H that embodiment 6 obtains, R ³, R ⁴=-CH ₂-CH ₂-CH ₂-) add 0.5ml1N lithium hydroxide stock solution in the solution.Stir after 18 hours, under brute force stirs, dropwise add 0.5ml1N hydrochloric acid.Filtering separation zwitter-ion and vacuum-drying obtain 80mg(0.17mmol) white solid (productive rate 85%), make it homogeneous phaseization (Whatman Pprtisil 10ODS-3 post, the 0.1M ammonium formiate damping fluid in 50% methanol) with analytical high pressure liquid chromatography (HPLC) method.Continuous replicate analysis one duplicate samples obtains the colourless meticulous crystallization of 8mg from the elution damping fluid:

mp259-260℃（dec.）;[α] ^Amb _D＝+24°（c＝0.05，MeOH）;IR（KBr）1745，1653，1630，1495，1420，1305，1220，752，695cm ^-1;NMR（CD ₃CN，TFA）δ1.80（m，4H），2.3-2.4（m，2H），2.9（m，2H），3.29（dd，1H，J _a＝17Hz，J _b＝13Hz），3.70（dd，1H，J _a＝17Hz，J _b＝6Hz），4.13（dd，1H，J _a＝10Hz，J _b＝5Hz），5.13（dd，1H，J _a＝6Hz，J _b＝2Hz），5.24（dd，1H，J _a＝13Hz），J _b＝6Hz），5.36（dd，1H，J _a＝6Hz，J _b＝1Hz），7.2-7.4（m，9H）.

Anal.Calcd.for C ₂₅H ₂8N ₂O ₅：C，68.79;H，6.46;N，6.42.Found：C，68.49;H，6.53;N，6.50.

Embodiment 8

Second-amino-5-heptenoic acid, methyl esters

In under-78 ℃ to the 15.4ml(110mmol that is dissolved in the anhydrous THF of 250ml) add the 39ml(105mmol that is dissolved in hexane in the solution of diisopropylamine) the 2.7M n-butyllithium solution.Stir after 30 minutes, add the 20ml hexamethyl phosphoric triamide and be dissolved in the 17.7g(100mmol that contains of 25mlTHF)] phenyl aldehyde is 30 minutes with the solution joining day of the western Fu Shi alkali of glycine methyl ester.After 15 minutes, add 13.5g(100mmol) 5-bromo-1-amylene and solution slowly is warming up to 25 ℃.After 3 hours, place water to extract reaction mixture with ether.Extract salt solution repetitive scrubbing with dried over mgso and concentrated, obtains the amber oily thing of 25g then.Oily matter is dissolved in the 400ml ether and stirred 2 hours with 300ml0.5N hydrochloric acid.Separate water layer and PH is transferred to 9 with 1N sodium hydroxide.Use chloroform extraction, through dried over mgso and the concentrated liquid required compound of 4.5 grams that obtains.

Replace 5-bromo-1-amylene and make the methyl esters of 2-amino-6-octylenic acid and second-amino-7-nonenoic acid according to the method for present embodiment respectively with the 6-bromo-1-hexene of equivalent or 7-bromo-1-heptene.(these three kinds of compounds correspond respectively to the compound that n wherein is 3,4 or 5 IX b formula).

Embodiment 9

2-[[2-(1,3-dihydro-1,3-dioxo-2H-one isoindole-2-yl)-1-oxo-3-hydrocinnamyl] amino]-the 6-heptenoic acid, methyl esters

To being dissolved in 30mlCH ₂Cl ₂6.0g(20mmol) phthalimido-L-hydrocinnamyl propylhomoserin and 6.0g(24mmol) add in the solution of EEDQ and be dissolved in 10mlCH ₂Cl ₂The product of it (21mmol) embodiment 8.Observed that gas is emitted and continuously stirring 18 hours.Solution is diluted with methylene dichloride, with the washing of 10% hydrochloric acid soln, saturated sodium bicarbonate solution and through dried over mgso.Concentrate and to obtain the 8.3g yellow oil, with 25%Et OAe/ hexane flash chromatography it, obtain 6.0g spumescence diastereomer acid amides X b(n=3).

Equally, replace 2-amino-5-heptenoic acid methyl esters and can make the respective compound that n wherein is 4 or 5 X b formula respectively with equivalent 2-amino-6-octylenic acid methyl esters or 2-amino-7-nonenoic acid methyl esters according to the method for present embodiment.

Embodiment 10

1,2,3,4-tetrahydrochysene-1-[2-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1-oxo-3-hydrocinnamyl]-pyridine-2-carboxylic acids, methyl esters

The alkene (10mmol) that embodiment 9 is obtained is dissolved in the methylene dichloride that 100ml contains the 10ml anhydrous methanol and is cooled to-78 ℃.It is colour-stable up to orchid to feed the oxygen flow that contains ozone in the solution that stirs.With after the nitrogen degassing, add 10ml dimethyl sulfide and 0.5ml pyridine, solution slowly is warming up to 25 ℃ and stirred 18 hours.With three part of 10% this solution of salt acid elution, through dried over mgso and the concentrated oily matter that obtains.This crude product is dissolved in the 150ml trichloroethane and with 0.5ml trifluoroacetic acid reflow treatment 18 hours.Concentrate also flash chromatography, but obtain the diastereomer acyl alkenyl amine XI a and the XI b(n=3 of chromatographic separation).

Embodiment 11

7-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1,2,3,4,6,7,8,12b-octahydro-6-oxy picolinate is [2,1-a] benzo-aza suberene-4-carboxylic acid also, benzhydryl ester

(XI a) is dissolved in 5ml methylene dichloride and handled 18 hours with the 2.0ml trifluoromethanesulfonic acid in 25 ℃ to the acyl enamine (1.6mmol) that embodiment 10 is obtained under nitrogen environment.Reaction mixture is distributed between water and ethyl acetate.Water thorough washing organic extract, concentrate and with excessive diazonium ditane solution-treated it.

Obtain spumescence cyclisation ester XII a(n=3, R=CHPh through flash chromatography ₂).

When using 6-bromo-1-hexene and 7-bromo-1-heptene, can make three similar ring intermediate XII a(n=4 respectively according to the method that is similar to embodiment 8 to 11) and XII a(n=5).

As described in embodiment 5, available hydrazine makes these three ring intermediate XII (n=4,5) go to protect and be coupled on the R-trifluoto ester of XX III, to obtain diester II (R respectively ³, R ⁴=-CH ₂-(CH ₂) ₂-CH ₂-, R=CHPh ₂) and II (R ³, R ⁴=-CH ₂-(CH ₂) ₃-CH ₂-, R=CH Ph ₂).These diester can obtain corresponding prodrug ester acid (II) (R=H) according to embodiment 6 described method selective hydrolysis.

Embodiment 12

[4R-[4 α, 7 α (S), 12b β]]-7-[(1-carboxyl-3-hydrocinnamyl] amino]-3,4,6,7,8,12b-six hydrogen-6-oxo-1H-[1,4] thiazine [3,4-a] [2]-benzo-aza cycloheptatriene-4-carboxylic acid also

Steps A .(R*, R*)-(-)-4-[2-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1-oxo-3-hydrocinnamyl]-3,4-dihydro-2H-1,4-thiazine-3-carboxylic acid, ethyl ester X VII

Under stream of nitrogen gas, use the 10ml anhydrous hexane with 7.75g(191mmol) dispersive 59% sodium hydride/paraffin washed twice.In the sodium hydride of purifying, add the 90ml dry DMF.In nitrogen, add 17.9g(96.7mmol carefully with 20 fens clock times when cooling off to this mixture with ice/methanol bath) hydrochloride of serine ethyl ester.The mixture stirring was added 5.2g(32mmol after 5 minutes) potassiumiodide.In this mixture, splash into 14.5ml(96.7mmol with 5 fens clock times) the bromoacetaldehyde diethyl acetal.Made the reaction mixing temperature rise to 30 ℃ again through 10 minutes after removing cryostat.At room temperature mixture was stirred after 8 hours and be divided into two equal portions, a 40ml that adds contains 14.2g(48mmol) phthalimide phenylalanine and 11.9g(48mmol) anhydrous THF solution of EEDQ.In the nitrogen environment mixture was stirred 18 hours under the room temperature.Mixture is allocated in 200ml water and the 200ml ether.Separate two-phase, add 200ml ether once more in aqueous phase and extract it.Combined ether solution is continuously with (a) 2 * 200ml1N hydrochloric acid, (b) 2 * 200ml saturated sodium bicarbonate and (c) 50ml brine treatment.With the yellow ethereal solution dried over mgso that extracts like this, filter, vacuum concentration obtains the required orange oily acetal X VI a(R=CH of 27.2g ₂CH ₃, X=S).Contain 16.1g(30.3mmol to 500ml) add the 4.5ml trifluoroacetic acid in the chloroformic solution of acetal.Gained solution was refluxed 4 hours under nitrogen environment, and cooling with the extraction of 300ml saturated sodium bicarbonate once, is filtered by anhydrous magnesium sulfate.The gained solution for vacuum concentration is become dark spumescence, and on 500ml silica gel chromatography, successively use 1500ml35%Et OAc-hexane and 55%Et OAc-hexane wash-out.Merge to concentrate after the required component and obtain 4.0g(29%) white foam shape acyl enamine X VII (R=-CH ₂CH ₃, X=S), this product crystallized out from methyl alcohol promptly obtains white needles analytical pure product.

Mp193℃，[α] ^Amb _D＝-375.5°（c＝0.8，CHCl ₃），IR（KBr）3400，1770，1740，1720，1680，1620，1380，1180，770，690cm ^-1， ¹H NMR δ（300MHz）;1.28（t，3H，J＝7.2Hz）;3.01（dd，1H，J _a＝13.2Hz，J _b＝3.1Hz）;3.36（ddd，1H，J _a＝13.3Hz，J _b＝3.1Hz，J _c＝2.4Hz）;3.48（d，1H，J＝2.6Hz）;3.50（S，1H）;4.23（q，2H，J＝7.3Hz）;5.19（dd，1H，J _a＝8.6Hz，J _b＝2.1Hz）;5.33（dd，1H，J _a＝8.9Hz，J _b＝6.8Hz）;5.74（t，1H，J＝3.1Hz）;5.57（d，1H，J＝8.6Hz）;7.15（s，5H）;7.71（m，2H）;7.76（m，2H）. ¹³C NMRδ（75.4MHz）：14.1，26.9，35.0，51.0，53.3，61.9，101.9，119.3，123.4，126.7，128.3，129.0，130.9，134.1，136.3，166.3，166.8，167.2.

Anal.Calcd.for C ₂₄H ₂₂N ₂O ₅S：C，63.99%;H，4.92%;N，6.22%.Found：C，64.07%;H，4.97%;N，6.20%.

Step B.[4S-(4 α, 7 α, 12b β)]-7-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-3,4,6,7,8,12b-six hydrogen-6-oxo-1H-[1,4] thiazine [3,4-a] [2]-benzo-aza cycloheptatriene-4-carboxylic acid also, methyl esters X VIII

With 0.5g(1.1mmol) solution that is dissolved among the 5ml methylene dichloride of the acyl enamine of steps A adds 1.5mlCF under nitrogen environment ₃SO ₃In the H.With mixture in stirring at room 18 hours, then in the suspension liquid that the excessive NaHCO that stirred of impouring is become in 10ml methyl alcohol carefully.The gained mixture is concentrated in a vacuum, and it is middle also with another part dichloromethane extraction water to make it to be allocated in methylene dichloride and water.Merge organic phase, use anhydrous magnesium sulfate drying, vacuum concentration obtains yellow foam.Foam is dissolved in methyl alcohol, spends the night in 0 ℃ of placement.Collect the gained crystallization,, obtain 0.35g(72% in 60 ℃ of following dryings of about 0.5mmHg then with the cold methanol washing) required colourless needle-like triclazate X VIII (R=CH ₃, X=S),

mp130-134℃，[α] ^Amb _D＝-71.5°（c＝0.4，CHCl ₃）.IR（KBr）：3450，1780，1730，1670，1650，1380，1300，770，720cm ^-1. ¹H NMRδ（300MHz）：2.93（dd，1H，J _a＝13.6Hz，J _b＝3.7Hz）;3.03（dd，1H，J _a＝14.2Hz，J _b＝4.0Hz）;3.26（dd，1H，J _a＝16.4Hz，J _b＝5.5Hz）;3.30（s，3H）;3.38（ddd，1H，J _a＝13.8Hz，J _b＝5.8Hz，J _c＝1.1Hz）;3.50（dd，1H，J _a＝14.0Hz，J _b＝6.7Hz）;4.40（dd，1H，J _a＝16.5Hz，J _b＝12.3Hz）;5.06（t，1H，J＝4.3Hz）;5.39（dd，1H，J _a＝6.0Hz，J _b＝4.3Hz）;5.39（dd，1H，J _a＝12.4Hz）;7.20-7.45（aromatic，4H）;7.75（m，2H）;7.88（m，2H）. ¹³C NMRδ（75.4MHz，proton decoupled）：27.3，29.8，33.9，351.7，57.0（broad），59.0（broad），123.4，126.6，127.1，128.3，130.2，133.9，135.9，136.0，167.8，168.8，169.2.

Anal.Calcd.for C ₂₃H ₂₀N ₂O ₅S.H ₂O：C，60.78%;H，4.88%;N，6.16%;S，7.05%，Found：C，61.12%;H，4.71%;N，6.10%;S，7.07%.

Step C.[4R-(4 α, 7 α, 12b β)]-7-amino-3,4,6,7,8,12b-six hydrogen-6-oxo-1H-[1,4] thiazine [3,4-a] [2]-benzo-aza cycloheptatriene-4-carboxylic acid also, methyl esters

To 0.67g(1.5mmol) triclazate that obtains of step B adds 3mlg(3.0mmol in institute's pulp solution in 5ml methyl alcohol) 1N hydrazine hydrate methanol solution.Mixture was stirred 60 hours under the room temperature nitrogen environment.Pass through CH thereupon ₂Cl ₂Thoroughly the diatomaceous earth filter of washing filters vacuum concentrated filtrate, is dissolved in methylene dichloride again and washes once organic phase solution with water back slowly filtering by sal epsom.The filtrate vacuum concentration is obtained the required yellow crystal shape solid amine of 419mg.To obtain purified fusing point be 143 ℃ transparent needle-like analytic sample to recrystallization from acetate-hexane.

IR（KBr）3420，2900，1730，1715，1660，1430，1370，1320，1300，1270，890，760cm ^-1.NMRδ（300MHz，CDCl ₃）δ1.82（s，2H），2.93（dd，1H，J _a＝13.6Hz，J _b＝4.8Hz），2.97（dd，1H，J _a＝16.2Hz），J _b＝13.2Hz），3.07（s，3H），3.19（dd，1H，J _a＝14.5Hz，J _b＝5.0Hz），3.31（ddd，1H，J _a＝14.5Hz，J _b＝3.8Hz，J _c＝2.1Hz），3.43（dd，1H，J _a＝14.5Hz，J _b＝3.4Hz），3.44（dd，1H，J _a＝17.4Hz，J _b＝6.2Hz），6.50（dd，1H，J _a＝12.8Hz，J _b＝6.0Hz），5.56（t，1H，J＝4.4Hz），5.62（dd，1H，J _a＝4.6Hz，J _b＝2.9Hz），7.10-7.25（complex，3H），7.37（m，1H）.

Anal.Calcd.for C ₁₅H ₁₈N ₂O ₃S：C，58.80;H，5.92;N，9.14.Found：C，58.70;H，5.97;N，9.00.

Step D.[4R-(4 α, 7 α (S*), 12b β)]-the 7-1-(ethyl ester)-3-benzo base amino-3,4,6,7,8,12b-six hydrogen-6-oxo-1H-[1,4] thiazine [3,4-a] [2]-benzo-aza cycloheptatriene-4-carboxylic acid also, methyl esters

With 374mg(1.22mmol) amine and the 282mg(1.34mmol of step C gained) 1,8-is two-the dimethylamino naphthalene is dissolved in the 9ml methylene dichloride, adds 457mg(1.34mmol in this solution) the used trifluoto ester of embodiment 5.Mixture was stirred 24 hours under the room temperature nitrogen environment, filter afterwards.Filtrate is refiltered after with the dilution of 10ml50% ethyl acetate-hexane.Gained filtrate vacuum concentration is become the deep green glassy mass.With glassy mass chromatography on 150ml silica gel, with 800ml37% ethyl acetate-hexane wash-out.Vacuum concentration and drying obtain 514mg(84.8%) required white foam shape diester.

IR（KBr）：3300，2950，2920，1730，1650，1490，1430，1320，1180，910，730，690cm ^-1. ¹H NMRδ（300MHz）：1.22（t，3H，J＝7.0Hz）;2.02（m，2H）;2.96（s，3H）;3.18-3.47（complex，5H）;4.12（m，2H）;4.41（dd，1H，J _a＝13.0Hz，J _b＝6.0Hz）;5.46（t，1H，J＝3.8Hz）;5.52（t，1H，J＝3.2Hz）;7.04-7.30（aromatic，9H.） ¹³C NMRδ（75.4MHz，proton decoupled）：14.4，28.2，28.4，32.2，35.0，39.0，50.0，51.0，51.9，55.3，60.3，60.9，125.3，125.4，125.9，127.5，128.3，130.3，134.9，137.1，141.1，169.4，174.1，174.9.MS（chemical ionization，methane）：MH ⁺＝497.3.

Step e .[4R-[4 α, 7 α (S*), 12b β]]-the 7-[[1-(ethoxycarbonyl)-the 3-hydrocinnamyl] amino]-3,4,5,7,8,12b-six hydrogen-6-oxo-1H-[1,4 thiazines are [3,4-a] [2]-benzo-aza cycloheptatriene-4-carboxylic acid also

Under 15 ℃ to 766mg(1.54mmol) add 2.7ml(31mmol in the diester that obtains of step D) trifluoromethanesulfonic acid diester dissolving when being chilled to 0 ℃.With gained dark solution careful 4.03g(46mmol that is dissolved in 60ml water that adds after stirring 24 hours under the 0-5 ℃ of argon gas body environment) sodium carbonate solution.With two parts of 30ml ethyl acetate extraction gained mixtures.Discard organic phase.With remainder water solution with hcl acidifying to PH5.With turbid mixture with three parts of 60ml ethyl acetate extractions.Merge after the organic phase with the water washing of two portions of 30ml salt.Organic phase solution concentrates by the anhydrous magnesium sulfate drying final vacuum, obtains 288mg(38%) fusing point is 138 ℃ of yellow glass shape things.Analytical data shows that this material contains the 80% required acid esters II (R that has an appointment ³, R ⁴=-CH ₂SCH ₂-, R=H), major impurity is the sodium salt of trifluoromethanesulfonic acid.

IR（KBr）：3420，1730，1650，1500，1430，1250，1160，1030，750，690，630cm ^-1. ¹H NMRδ（300MHz，CD ₃CN）：1.23（t，3H，J＝7.1Hz）;2.0（m，2H，from CDCl ₃）;2.70（t，2H，J＝7.9Hz）;2.86（dd，1H，J _a＝17.5Hz，J _b＝12.2Hz）;2.95（dd，1H，J _a＝13.7Hz，J _b＝4.7Hz）;3.17（dd，1H，J _a＝14.7Hz，J _b＝4.9Hz）;3.22-3.43（complex，4H）;4.12（q，2H，J＝7.1Hz）;4.54（dd，1H，J _a＝12.9Hz，J _b＝5.7Hz）;5.45（dd，1H，J _a＝4.6Hz，J _b-2.8Hz）;5.60（t，1H，J＝4.0Hz）;7.01-7.36（aromatic，9H.）

Step F .[4R-[4 α, 7 α (S*), 12b β]]-7-[[1-(carboxyl-3-hydrocinnamyl] amino]-3,4,6,7,8,12b-six hydrogen-6-oxo-1H-[1,4]-piperazine [3,4-a] [2]-benzo-aza cycloheptatriene-4-carboxylic acid also

With 100mg(0.2mmol) step D gained diester is dissolved in the 2.27ml methyl alcohol, adds 0.5ml(0.5mmol in this solution) the 1N lithium hydroxide.Solution is muddy in short-term, but under agitation very fast clarification.Solution was stirred 60 hours under the room temperature nitrogen environment.Vacuum concentration obtains white residue.With resistates half-25cm * enterprising horizontal high voltage liquid chromatography (LC) of 22mm ID Partisil 10-ODS3 post with purifying it, moving phase is for being dissolved in 40% methyl alcohol, one water 0.1MpH=6.2 ammonium formate solution.Collect first elution peak.Merging suitably, composition part final vacuum concentrates.Under 90 ℃ of 1mmHg, remove remaining ammonium formiate and obtain 13mg(26% with the Kugelrohr distillation method) required diacid.

Mp232-235 ℃ of (dec.) IR(KBr): 3420, broad 3100-2200,1720,1650,1630,1490,1400,1200,750,690cm ^-1. ¹H NMR δ (300MHz, D ₂O-TFA): 2.35(m, 2H); 2.89(td, 2H, J _a=10.3Hz, J _b=6.7Hz); 3.01(dd, 1H, J _a=14.0Hz, J _b=4.7Hz); 3.23(dd, 1H, J _a=15.0Hz, J _b=4.8Hz); 3.33(d, 1H, J=2.6Hz); 3.39(d, 1H, J=2.6Hz); 3.42(dd, 1H, J _a=15.0Hz, J _b=5.8Hz); 3.71(dd, 1H, J _a=16.1Hz, J _b=6.3Hz); 4.10(broad s, 1H); 5.31(broad, 1H); 5.48(d, 1H, J=4.2Hz); 5.52(d, 1H, J=4.2Hz); 7.16-7.38(aromatic, 8H); 7.49(d, 1H, J=8.3Hz); 7.88(broad d, 2H, J=27.0Hz). salt is as in separating or the product in the purifying.

The formation of salt can make as free acid that makes product or alkali or sour the reaction in solvent that can not dissolve this salt or medium or in the water kind solvent that free alkali forms and monovalent is suitable by ordinary method, can or another positively charged ion of cationic exchange of existing salt be obtained by vacuum or freeze-drying subsequently.

Compound of the present invention suppresses Zinc metallopeptidase Zace1 and therefore blocks the decapeptide angiotensin to be converted into angiotensin.Angiotensin is a powerful supercharging material.Therefore can reach hypotensive purpose by suppressing its biosynthesizing.Especially for those hypertension animal and human relevant with angiotensin.And then the conversion enzyme also can bring high blood pressure down by the booster action of bradykinin.The proof though relative importance this and other possibility mechanism awaits, but angiotensin converting enzyme inhibitor is strictly effective antihypertensive drug for various animal models, and many human patientses had clinical effectiveness, for example to kidney vascular, pernicious and primary hypertension patient.(as seeing D.W.Cushman, et al., Biochemistry16,5484(1977).

The evaluation of converting enzyme inhibitor is undertaken by vitro enzyme inhibition method of inspection.For example, one of a kind of useful method is Y.Diguilloud, A.Reinharz and M.Rorh(Biochem.Biophys, Aeta, 206 N36(1970)) propose wherein measured the leucic hydrolytic action of carbobenzoxy phenylalanyl histidyl-.Evaluation can be according to J.R.Weeks and J.A.Jones(Droc.Soc.Exp.Biol.Med.104 in the body, 646(1960) the technology of Jie Shaoing, attacking with angiotensin has normotensive rat or according to people's such as S.Koletsky method, (Proc.Soc.Exp.Biol.Med.125,96(1967).Getting the renin rat model at height carries out on one's body.

Therefore, compound of the present invention can be used as the hypertension Mammals that the medicinal treatment of hypertension comprises the people, and can by they are mixed with have be beneficial to the suitable component of taking preparation to reach hypotensive purpose.The dosage range of taking The compounds of this invention for the patient who needs this treatment is each patient 0.5-100mg, and take for several times general every day, and the total dose of every day is 0.5-400mg like this.This dosage will be according to the severity of disease, patient's body weight and technician know can other factors and different.

So, the hypertensive pharmaceutical composition of treatment that can provide a kind of I formula compound that is used to suppress carrier Zinc metallopeptidase Zace1 or that pharmacology can be accepted and pharmacology effective dose to form according to the present invention.

For ease of taking, component of the present invention also can contain other conventional pharmaceutically acceptable component under the situation of needs.These components generally are to be used as carrier or thinner.The method of available routine prepares this component with suitable dosage form.Dosage form whatsoever all must contain the present invention's of effective dose compound.

This composition can be according to oral or non-oral (for example, promptly be blown into outside enteron aisle, part, rectum etc.) mode administration.Use appropriate formulations form such as tablet, capsule, suspension, solution etc. are used for oral; Suspension emulsions etc. are that non-enteron aisle uses; Solution is used for intravenous injection; Ointment, plaster etc. are used for topical.Can produce according to any known medicament method of manufacturing technology and prepare for oral preparation, said preparation can contain one to multiple kind of sweeting agent, and staining agent and sanitas are so that preparation is attractive in appearance and good to eat.Also available currently known methods is manufactured on the tablet that contains activeconstituents on the mixture with nontoxic, pharmaceutically acceptable vehicle.Usual excipients can be (1) inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium; (2) granule and agent of disintegration body such as W-Gum, or Lalgine; (3) caking agent such as starch, gelatin or Sudan Gum-arabic, and (4) lubricant such as Magnesium Stearate, stearic acid or talcum.Tablet can be not dressing or by the currently known methods dressing postponing disintegration and the absorption in gi tract, and therefore produce a long continuous action.For example, can use a kind of time-delay material such as glyceroyl monostearate or glyceroyl SUNSOFT Q-182S.They also can be according to US Patent No 4,256,108; 4,160,452 and 4,265, the method dressing described in 874 is convenient to the sustained release osmotic therapeutic tablets to make.

In some cases, oral preparations can be form of hard gelatin capsules, active ingredient wherein and an inert solid diluent such as lime carbonate, and calcium phosphate or kaolin mix.They also can be soft cohesion form, active ingredient wherein and water or oil medium such as peanut oil, whiteruss or mixed with olive oil.

Water suspending agent generally is to contain active substance with the vehicle institute resulting mixture that is suitable for making water suspending agent.Such vehicle can be:

(1) suspension agent such as Xylo-Mucine, methylcellulose gum, hydroxyl third methylcellulose gum, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and Sudan Gum-arabic;

(2) dispersion agent or wetting agent can be

(a) natural phosphatide such as ovum phosphoric acid fat,

(b) condensation product of alkylene oxide and lipid acid such as polyoxyethylene stearic acid ester,

(c) condensation product of oxyethane and long chain aliphatic alcohol is as 17 carbon vinyloxy grouies alcohol ceryl alcohol,

(d) product of oxyethane and lipid acid and the condensation of hexitol deutero-partial ester is as the polyoxyethylene sorbitol monoleate, perhaps

(e) product of oxyethane and lipid acid and the condensation of hexitan deutero-partial ester is as polyoxy ethene sorbitan monooleate.

Water suspending agent also can contain one or more sanitas, for example ethyl or n-propyl group p-hydroxybenzoate; One or multiple tinting material; One or more seasonings; And one or more sweeting agent such as sucrose or asccharin.

The oiliness suspension agent can be by being suspended with the method preparation of effective constituent, vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois, or use mineral oil such as whiteruss in vegetables oil.The oiliness suspension agent can contain thickening material, for example beeswax, solid paraffin or hexadecanol.Add sweeting agent and seasonings and can make the preparation good mouthfeel.Adding oxidation inhibitor such as xitix can make these compositions be protected.

Dispersive powder and particle are suitable for preparing water suspending agent.Have dispersion agent or wetting agent, containing the composition of inhibition in the dopant of a kind of suspension agent and one or more sanitas.Dispersion agent or wetting agent and the suspension agent that is suitable for for example understood in the front.Also by the vehicle of having addressed other such as above-mentioned those sweeting agents, seasonings and staining agent.

Pharmaceutical composition of the present invention can also the oil-in-water emulsion form exist.Oil phase can be vegetables oil or whiteruss or its mixture.Examples of suitable emulsifiers is natural gum such as the Sudan Gum-arabic and the tragacanth gum of (1) natural generation, (2) phosphatide of natural generation such as soybean lecithin, (3) lipid acid and hexitan deutero-ester or partial ester, for example, sorbitan monooleate, (4) condensation product of above-mentioned partial ester and oxyethane, for example polyoxyethylene sorbitan monooleate.Emulsion also can contain sweeting agent and seasonings.

Available sweeting agent is glycerine, propylene glycol, Sorbitol Powder or sucrose obtain syrup and ingredients for example.This prescription also can contain the stimulation buffer reagent, sanitas, seasonings and tinting material.

This pharmaceutical composition can be the form of aseptic injection water or oleagenous suspension.This suspension can be according to known method with above-mentioned those suitable dispersion agents or wetting agent and suspension agent preparation.Aseptic injection preparation also can be at nontoxic, non-enteron aisle acceptable diluent or solvent.As aseptic injectable solution or the suspension of making in the vehicle, solvent for use can be a water, Ringes ' s solution and isotonic sodium chlorrde solution.In addition, aseptic, nonvolatile oil is conventionally used as solvent or suspension medium.For this purpose, nonvolatile oil of any gentleness all can use, and comprises synthetic list or two glyceryl ester.In addition, the also available preparation injectable formulation of lipid acid such as oleic acid.

Composition of the present invention can also suppository form, be used for the rectal administration of medicine.These compositions can by with under medicine and suitable non-stimulated, the normal temperature for solid under rectal temperature for liquid and therefore can in rectum, melt and discharge drug excipient and mix and make.Such vehicle comprises Oleum Cocois and polyoxyethylene glycol.

Can be with the emulsion that contains the present composition, ointment, mashed prod, solution or suspension etc. for local application.

The effective ingredient amount of the dose pattern that can merge produce with carrier substance will be according to the object of treatment and specific administering mode and different.

Yet, should be understood that, for any particular patients ', concrete dosage level will depend on a series of factor, and it comprises that activity, patient's age, body weight, physique, sex, food, administration time, instructions of taking, excretion rate, the medicine composition of used particular compound reach the severity of the special disease for the treatment of.

Compound of the present invention also can with other antihypertensive drug and/or diuretic(s) and/or calcium channel blocker Combined Preparation.For example, The compounds of this invention can with following compound Combined Preparation: acetazolamide, the benzene thiazine, bumetanide, cloroqualone, can urinate plug, clonidine, chlorine lamb's-quarters peace acetate and Cryptenamine tannate, cyclothiazide, deserpidine, diazoxide, diltiazem, (s)-1-[[2-(3, the 4-dimethoxy phenyl)-and ethyl] amino]-3-] the 4-(2-thienyl)-1-1H-imidazoles-2-yl] phenoxy group]-the 2-propyl alcohol, thacrynic acid, flumethiazide, furosemide, Isobarin, the salt solution hydralazine, Zestoretic, Hydroflumethiazide, (+)-4-[3-[-[2-(1-hydroxy-cyclohexyl)-ethyl]-4-oxo-2-thiazolidyl]-propyl group]-phenylformic acid, the optically active isomer of indacrinon and multiple ratio thereof, merethoxylline procaine, methyl chlorothiazide, the methyldopa crust, Aldomet Ester Hydrochloride salt, metolazone, metoprolol tartrate, minoxidil, receive Lip river Dorr (naldolol), nifedipine, pargyline hydrochloride, pindolol, poly-thiazine, croak azoles piperazine, propanolol, quinethazone, the Luo Mei rattan utilizes blood, rescinnamine, serpentine, according to his tail acid sodium, the general sodium of nitro, spiral shell stays lactone, Tienilic Acid, timolol, the pyridine of phenalgin dish, trichlormethiazide, Arfonad, benperidol, diltiazem, Pagano-Cor, expense is utilized handkerchief rice, felodipine, flunamic, Gallopamil, indoles amine, lidoflazine, nicardipine, NIFEDIPINE, nimodipine, nitrendipine, perhexiline, Segontin, for A Pami, verapamil or the like, and composition thereof with merge medicament.

When individually dosed, these merge medicaments typical individual per daily dose scope can from the minimum clinical dosage recommended 1/5th to the maximum recommended level.

For illustrating that these merge medicament, can with one of antihypertensive drug of the present invention with every day 0.5-1000mg amount be used in combination with following compounds (with pointed dosage range every day): Zestoretic (10-100); Gram urine plug (125-2000mg); The indacrinone(25-150mg of control optically active isomer ratio); Ethacrynic Acid (15-2000mg); Guanamprazine (5-20mg); Furapromide acid (5-80mg); Proprasylyte (20-480mg); Timolol (5-60mg); And methyldopa (65-2000mg); And the pivalyl 2-ethoxyethyl acetate (30-1000) of methyldopa.In addition, during three kinds of medication combined uses, if Zestoretic (10-100mg) adds the indacrinone(25-150 that guanamprazine (5-20mg) adds converting enzyme inhibitor of the present invention (0.5-1000mg) or control optically active isomer ratio) add guanamprazine (5-20mg) and add converting enzyme inhibitor of the present invention, be effective drug combination mode to control hyperpietic's blood pressure.These dosage ranges are certainly adjusted the fractionated dose of every day on the unit basis, and as mentioned above, used dosage will be according to the character and the severity of disease, patient's body weight, concrete diet and other factors and different.Preferred compound is paid group group

(Subgeneric groups) is

R wherein ²Be styroyl

R wherein ⁵Be H or hydroxyl,

R wherein ⁶Be H or hydroxyl,

Wherein R is C _1-6Alkyl,

R wherein ¹Be ethyl,

Wherein R is H,

Wherein X is CH ₂, and

Wherein X is S.

Preferred aforementioned structural formula compound is that those have R specific shown in the following table, R ¹, R ², X, R ⁵, R ⁶The person.

R R ¹R ²Rx R ⁵R ⁶

H ethylbenzene ethyl CH ₂H H

H ethylbenzene ethyl CH ₂OH H

H ethylbenzene ethyl CH ₂OH OH

H ethylbenzene ethyl S H H

H ethylbenzene ethyl O H H

H ethylbenzene ethyl S OH H

Claims (1)

1, a kind of method for preparing following formula: compound and pharmaceutical salts thereof

Wherein R is hydrogen or methyl,

R ^' ₁Be hydrogen or ethyl,

R ₂Be styroyl,

R ₃And R ₄Be jointly-CH ₂CH ₂CH ₂-or-CH ₂-S-CH ₂-,

Comprising fused lactams with following formula

With following formula: compound A

Coupling, wherein R ¹Be methyl, R ^' ₁Be ethyl, alternative hydrolysis R after the above-mentioned coupling ¹And R ^' ₁One of or both, the coupling of the compound of above-mentioned and formula A can contact reactant in the presence of alkali and finish,

In case of necessity the gained compound is become pharmaceutical salts.