CN87104166A - Antihypertensive medicine - Google Patents

Abstract

The invention relates to fused tricyclic lactam derivatives, intermediates and processes for their preparation, to their pharmacological effects in the inhibition of angiotensin converting enzyme and to their final use in the treatment of hypertension.

Description

Antihypertensive agent

The present invention relates to fused tricyclic amide derivatives, its intermediate and preparation method, and its pharmacotoxicological effect and its final application in Hypertension in ACE is suppressed.In particular it relates to the fused tricyclic lactams of following formula

And its officinal salt, R therein and R¹Respectively

(a) hydrogen；

(b)C₁-C₆Alkyl；

The C of (c) substitution₁-C₆Alkyl, substitution base therein is hydroxyl, C₁-C₄Alkoxy and two-C₁-C₄Alkylamino；

(d)C₆-C₁₂Aryl；

The C of (e) substitution₆-C₁₂Aryl, substitution base therein is C₁-C₆Alkyl, fontanel element (F, Cl, Br, I), and C₁-C₄Alkoxy；

(f) miscellaneous (C₄-C₉) aryl, hetero atom therein can be O, N or S,

Miscellaneous (the C of (g) substitution₄-C₉) aryl or (C₄-C₉) heteroaryloxy, hetero atom therein can be O, N or S, and substitution base is C₁-C₆Alkyl, fontanel element (F, Br, Cl, I) and C₁-C₄Alkoxy；

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

R²For

(a) hydrogen；

(b)C₁-C₈Straight or branched alkyl；

(c)C₂-C₈Straight or branched alkylene；

(d)C₂-C₈Straight or branched alkynyl；

(e)C₃-C₁₀Cycloalkyl；

(f)C₆Or C₁₀Aryl,

The C of (g) substitution_1-8Alkyl, can optionally contain O, S, S=O, O=S=O, C=O, a CONR₂, NRCOOR or-NR₂Group, wherein R are defined as above and may have 1-3 to be selected from fontanel element (F, Br, Cl, I), Carboxylamide, C₁-C₄The substitution base wherein R's of alkoxy carbonyl group, sulfydryl, amino and R is as defined above.

R³It is hydrogen, C_1-12Alkyl, phenyl or benzyl；

R⁴It is hydrogen, C_1-12Alkyl, phenyl, benzyl or native amino acid residues, and

R³And R⁴6 to 8 Yuans fused moieties are combined together to form with carbon atom, can there is a sulphur or oxygen atom on the ring；

R⁵And R⁶Respectively

(a) hydrogen, hydroxyl；

(b) fontanel element (F, B r, Cl, I)；

(c)C₁-C₆Alkyl；

(d)C₁-C₆Alkoxy.

Alkyl refers to such some groups, such as methyl, ethyl, vinyl, propargyl, cyclobutenyl, isobutyl group etc..Cycloalkyl is including cyclobutyl, cyclopenta, cyclohexyl etc..C₆-C₁₂Aryl includes phenyl, naphthyl, indenyl, diphenyl and benzo cycloalkyl, such as indenyl and 1,2,3,4-tetrahydro-naphthalene base.C_4-C₉Heteroaryl group includes such some compounds, such as pyridine radicals, thienyl, furyl, imidazole radicals and thiazolyl and any bicyclic radicals, it is any of above heterocycle and another aromatic heterocyclic group such as indyl, quinolyl, isoquinolyl, benzimidazolyl during these are bicyclic, 1,5- naphthyridines base and quinoline

Quinoline base is condensed.

Preferred compound is：R therein is hydrogen, R¹It is hydrogen or preferably alkyl such as ethyl；R²It is C₆Aryl-C₁-C₄Alkyl, preferably phenethyl；R⁵And R⁶It is hydrogen, C_1-6Alkoxy or the monohydroxy or dihydroxy that represent on benzenoid form part replace base, and R³And R⁴The atom connected together with them forms -6-, 7- or 8 Yuan ring, for example, R X-6 person's rings are formed, with reference to R³And R⁴Be CH₂-CH₂-CH₂-、-CH₂-S-CH₂- or-CH₂-O-C H₂-；- 7 Yuans rings are formed, with reference to R³And R⁴Be-CH₂(CH₂)₂CH₂- R X-8 person's rings are formed, with reference to R³And R⁴Be-CH₂(CH₂)₂CH₂-。

Although wherein including all of enantiomter and diastereoisomer and its mixture, most preferably still those have the compound of the representative diastereomer configuration of following formula：

The separation of these isomers can be completed by the routine techniques in this technique.(certainly, R¹、R²、R³、R⁴、R⁵And R⁶Substitution base is defined in I formulas).

Compound of the invention can be prepared by known series reaction step in this technique; it is, in general, that when its hydrochloride is changed into, the aryl alanine of a most handy appropriate N-protected starts the reaction sequence; according to the principle that Schotl-Baumann reacts, with-appropriate (R³And/or R4 substitutions) amine combination.According to required final product whether containing the additional fused rings with benzo-aza cycloheptatriene -2- ketone part, i.e., whether R³And R⁴And a such as pyridine benzo and azepine cycloheptatriene -2- ketone part are combined to form together with the atom being connected with them, and use different intermediate and its course of reaction.But in each case, before the nitrogen-atoms being incorporated on 3 of benzo-aza cycloheptatriene -2- ketone part enters coupling step, with appropriate R³Intermediate with R first carries out Friedel-Kraft cyclizations.After cyclisation, N-protected group (such as phthalimido part) is removed, nitrogen-atoms is then by conventional coupling reaction with the R with expection required for producing¹, R²I formula compounds.

In R³And R⁴The acyl chloride derivative (III) of the L- aryl alanines of N-protected is then according to Schotl-Baumann reactions and an appropriate R in the case of the fused rings that substitution base is not added with benzo-aza ring triolefin -2- ketone part formation one⁴Substituted amino acid (IV) is combined, and now reactant is in the presence of sodium carbonate/acetone and water, preferably to be combined under room temperature condition.Preferred N blocking groups are phthalimidos.Final reaction product (V) carries out acidification.(such as benzene, toluene, chloroform etc.) is combined with R by back flow reaction thing and in azeotropic solvent in the presence of p-methyl benzenesulfonic acid to make products therefrom (V)³Aldehyde reaction, to produce intermediate

Piperazine ketone (VI), when with a lewis acid (such as polyphosphoric acid, CF₃ SO₃H or thirdly silyl ester (TMSOTF) process when can make its carbonyl protonate and is formationed-imide ionic intermediate, the intermediate so in the original location experience Friedil-Kraft react.Imide ionic intermediate is cyclized through Friedel-Kraft, produces compound VII, the compound to be converted to appropriate hydrocarbyl carbonate VIII, and described reaction is carried out according to known routine techniques.

Reacting flow chart A

Wherein Dg is-N-protected base (preferably phthalimido), and T SOH are p-methyl benzenesulfonic acid, and Ph H are phenyl hydride, R³, R⁴, R⁵And R⁶Definition is identical with I formulas, and R ' is R than hydrogen.In order to obtain the suitable final product of I formulas, normal previously prepared wherein R bases are selected from the ester of (h) group.

In certain situations it is desirable to prepare wherein R³And R⁴With the compound of azepine cycloheptatriene -2- ketone ring formation-additional fused rings, make vinyl amino acid (IXb) coupling generation intermediate (respectively Xa and Xb) of the chloride derivative (III) of the aryl alanine of N-protected according to above-mentioned Schott-Baumann reactions through being protected with an amido vinyl chloride (IXa) or-OH.In processing these intermediates with ozone at -78 DEG C in the dichloromethane containing alcohol, the product isolated is processed at a reflux temperature with dimethyl sulphide and pyridine chilling and with trifluoroacetic acid/dichloromethane to produce acyl enamine (XIa and XIb), then according to Friedel-Kraft cyclisation programs CF₃SO₃H treatment produces compounds X IIa and XIIb.Carrying out when Friedel-Kraft is cyclized preferably with lewis acid, be especially selected from perfluoro alkyl sulfonic acid, such as trifluoromethane sulfonic acid, pentafluoroethyl group sulfonic acid and heptafluoropropyl sulfonic acid.These reactions are shown in reacting flow chart B.

Reacting flow chart B

Wherein R, R⁵, R⁶, with Formulas I together, Pg is N-protected group (being preferably formed as a phthalimido) to Pg, and n is 3,4 or 5.In these cases, wherein expectation obtains wherein R3 and R³The compound of the fused rings with a sulphur or oxygen on its ring can be produced, then these compounds is prepared further in accordance with reaction process C.

Reacting flow chart C

Wherein Pg is N-protected base, preferably phthalimido, R, R⁵、R⁶Definition and I formulas it is same, and X is sulphur or oxygen.

In previous reaction flow chart C, the protected phenylalanyl serine esters (XIII) of N- change into its methylsulfonyl ester in the original location, are then being dissolved in triethylamine of the atent solvent for example in dichloromethane.Middle mesyl chloride processes removing, obtains dehydroalanine.HXCH₂CH(OET)₂(XV) Michael addition compound products (XVI) are obtained with the conjugate addition of dehydroalanine intermediate (XIV), the product is cyclized into acyl enamine (sub- acid amides) through the trifluoroacetic acid effect in dichloromethane.Reacted by above-mentioned Friedel-Kraft and obtain final cyclisation product (XVIII).

In addition, in a special case, wherein R³And R⁴Condensed ring structure in X when being sulphur, then intermediate X V Ia may be by DMF (dimethylformamide), it is obtained in being alkylated, Cys ethyl ester (XIX) bromoacetaldehyde diethyl acetal and sodium iodide under the suitable base catalysis of such as triethylamine or the class of sodium hydride one.The free amino (XX) for so producing passes through N- ethoxycarbonyl -2- ethyoxyls -1; the effect of the conventional coupling agents of the class of 2- EEDQs (EEDQ) is combined with (preferably phthalyl) L-phenylalanine (XXI) of N-protected to produce intermediate (XVIa), and the intermediate is to be cyclized according to the Friedel-Kraft of conventional lewis acid one cyclisation program.

Reacting flow chart D

R therein, R⁵, R ⁶It is defined as described above with Pg.

In reaction process A, the reaction of B, C and D, fusion lactams is prepared by Friedel-Kraft cyclization processes, and the reaction is preferably to use perfluoro alkyl sulfonic acid certainly.

Once fusion lactams (such as VIII, XIIa, XIIb, and XVIII) is prepared out, i.e., N-protected group should be removed, to allow that suitable side chain is coupled on unhindered amina.The effect of this deprotection can be reached by known conventional method.In this case, wherein protection group is phthalyl, by known technology in this technique, phthalimido part can be easily removed through with hydration hydrazine reaction.It is non-enantiomeric form while it is desirable to described fusion lactams, but preferred deprotection fused lactams are with following structure person

R ' therein defines same R, and H is not included simply.

Although any of conventional coupling method is available, for this kind of coupling, it is preferred to use the method shown in following reacting flow chart E.

Reacting flow chart E

R ' therein and R '₁It is defined as described above, but they can not be H, R², R³, R⁴And R⁵And R⁶As hereinbefore.It should also be noted that although the diastereomer form of best fused lactams is XXII, XXVI and XXVII formula one depicted is answered and bright loud and clear all other diastereomer is still obtained by similar technique.

The method A of flow chart E needs-elimination reaction that participates in of (R) trifluoto ester (XIII), wherein fused lactams are in the presence of alkali such as triethylamine, but preferably at one " proton sponge " (" proton sponge "), i.e. 1, contacted with trifluoto ester in the presence of 8- pairs-(lignocaine)-naphthalene, produce compounds X XVI.

Method B needs to use the keto esters and molecular sieve one western Fu Shi alkali (Schiffsbase) of formation for being dissolved in ethanol (or other alcohols solvents), the alkali to be reduced into compound 26, it is best to use cyano group cyanogen boronation sodium.

Method C needs to carry out Isosorbide-5-Nitrae-Michael addition reactions with the aryl butenoate of ethyl -4- oxos one (such as XXV).The ketone group oxygen of intermediate X XVII (Y is oxygen) is preferably reduced generation XXVI using palladium catalyst by catalytic hydrogenation reaction in the presence of a small amount of sulfuric acid.

Because the embodiment of preferred compounds of the invention is related to those R to be hydrogen, R¹It is not the I formula compounds of hydrogen (preferably ethyl), it is noted that to the coupling method for being related to foregoing reacting flow chart E, particularly when they are related to the selective hydrolysis of R ester groups.For example, generally, selective hydrolysis for compounds X XVI are preferably to prepare group (the i.e. benzhydryl that wherein R is (h) group, trityl or benzyl) ester, because these groups can use gentle acid optionally to hydrolyze, can for example be reacted by with salt acetoacetic ester or trifluoroacetic acid, or they also can be by catalyst hydrogenolysis.Equally, because the R group hydrolysis of the reduction of ketone group second (Y is oxygen in Formula X XVII) also ester moiety in future is fallen and turns into its corresponding acid, it is therefore preferred that it is the ester group that group is organized selected from (h) that compounds X XVII has wherein R.In addition, especially for wherein R³And R⁴

6 Yuans any compounds for ring are formed together with the atom coupled with them, any R group (in addition to hydrogen) can use perfluoro alkyl sulfonic acid treatment and selective hydrolysis turn into its corresponding acid.Applicable perfluoroalkyl sulfonic acid is trifluoromethane sulfonic acid, pentafluoroethyl group sulfonic acid and heptafluoropropyl sulfonic acid.

Following embodiments further elucidate the method and condition that can prepare the compounds of this invention.The preferred diastereomer of these embodiments can be separated by conventional method.

Embodiment 1

[2 (S)] N- (the chloro- 2- cyclohexene -1- bases of 2-) -1,3- dihydro -1,3- dioxos -2H- iso-indoles -2- (S)-(benzyl -2- buserelins) (Xa)

Step A.2- (the chloro- 2- cyclohexene -1- bases of the chloro- 2- of 2-) -1H- iso-indoles -1,3 (2H)-diketone

The 11.0g (72.8mmol) 1 in 50ml anhydrous dimethyl formamides (DMF) will be dissolved in, the solution of 6- dichloro cyclohexene, 20.0g (108mmol) potassium phthalimides and 1.0g (6.0mmol) KI is stirred 24 hours under a nitrogen environment in 110 DEG C.Poured into 30ml ether after reactant mixture cooling.Dark mixture is leached, ether and dimethylformamide is removed under vacuo afterwards.Chromatographed on 500g silica gel after dark color crystallization residue is dissolved in into ethyl acetate, with the ethyl acetate-hexane elution of 10%-20%.Appropriate part is concentrated after being recrystallized from ethylacetate-hexane, that is, the phthalimide required for obtaining 14.0g (73.5%), fusing point is 99-103 DEG C.

Step B

The solution of 6.0g (120mmol) hydrazine hydrates and 26.1g (100mmol) N phthalimido -6- amino -1- chlorine cyclohexene that will be dissolved in 150ml Me OH flows back 3 hours in a nitrogen environment, is cooled to 25 DEG C and stirs 3 hours.Mixture is filtered, concentrated, be poured into 300mml 1N hydrochloric acid and washed with 200ml dichloromethane.Alkalization water layer is simultaneously extracted with three parts of 500ml dichloromethane.Organic phase is dried with magnesium sulfate, is filtered and be concentrated to give the thick amine of 9.25g (70mmol).The neutral extract of concentration obtains the untreated initial phthalimides of 6.0g.In under 25 DEG C of nitrogen environments to the solution of the stirring for being dissolved in the 21g of 2000mlCHCl (71mmol) benzene imidodicarbonic diamide base-L-phenylalanine and 18.5g (7mmol) EEDQ 20ml CH are dissolved in addition in 30 minutes₂ Cl₂9.25g (70mmol) 6- amino -1- chlorine cyclohexene.After stirring 18 hours, reactant mixture two parts of 200ml10% hydrochloric acid solutions, 200ml saturated sodium bicarbonate solutions and salt water washing.Organic phase magnesium sulfate dries, filters and be concentrated to give solids.The mixture of 2- (s) diastereomers acid amides (Xa) required for 26.1g is recrystallized from dichloromethane/hexane, the product fails to separate (gross production rate 64%) in this step.

IR (KBr) 3400,1775,1715,1650,1530,1380, cm^-1；NMR δ 1.60 (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 C₂₃H₂₁ClN₂O₃：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 iso-indoles -2 - yl) -1- oxo -3- phenylpropyls] -1,2,3,4- tetrahydrochysene -2- pyridine-3-carboxylic acids, methyl esters (X Ia)

The 300ml CH containing 20ml absolute methanols will be dissolved in₂Cl₂In obtained by embodiment 1

The solution of 12.2g (30mmol) vinyl chloride (Xa) is cooled to -70C and stirs, while being contained in the (air-flow that use-Welsbach ozonizers are produced of bromine oxygen in oxygen to being passed through in solution by glass expects pipe.When solution becomes orchid, dry nitrogen is passed through toward solution to remove excessive ozone.Reactant mixture 20ml Me₂25 DEG C are gradually heated up to after the treatment of S and 4ml pyridines and are stirred 20 hours.To pouring into the hydrochloric acid solutions of 200ml 10% in solution and isolating organic phase, fully washed with water, through magnesium sulfate in dry and be concentrated to give the amber grease of 13.0g.Thick ozonolysis product is dissolved in and contains 0.5ml

In the 200ml dichloromethane of fluoroacetic acid (T FA) and flow back 3 hours in a nitrogen environment, the solution through cooling down is washed with saturated sodium bicarbonate solution, be dried and concentrated with magnesium sulfate and obtain the amber grease of 12.2g.High pressure liquid chromatography (HPLC) (HP is prepared using 50%Et OAc/ hexanes) separate (Waters Prep-500 are once recycled) and each obtain that 4.3g (10.1mmol) is relative to reflect body fat acyl enamine X Ia and X Ib (n=2), (gross production rate 68%) recrystallizes X Ia isomers from dichloromethane/hexane and obtains white crystalline fine powder：

146-147℃；

(c=1.1, CHCl₃)；IR (KB r) 1770,1740,1720,1670,1650,1390,1220,722cm^-1；NMR δ 1.85 (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 C₂₃C ₂₂N₂O₅：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)] (1,3- dihydro -1, -2H- is different for 3- dioxos for -7- Indoles -2- bases) -1,2,3,4., -6,7,8,12b- octahydro -6- oxy picolinates simultaneously [2,1-a] [2 Benzo-aza cycloheptatriene -4- carboxylic acids, benzhydryl ester * (X IIa)

To the molten C of 20ml in a nitrogen environment H₂C l₂In the agitated solution by 4.20g (10.0mmo l) acyl enamine X I a obtained by embodiment 2 in add 6ml CF₃S O₃H (trifluoromethane sulfonic acid).At 20 DEG C stir 18 hours after, by solution incline on ice and with 200m lEt OAe extraction.Organic phase water is fully washed, and is dried and concentrated with magnesium sulfate.Nubbin is dissolved in dichloromethane and is processed with 2.2g diazonium diphenyl-methanes and placed 12 hours and concentrates the solution, residue is carried out into flash chromatography with 33%Et O Ae/ hexanes on 400ml silica gel and obtains 4.5g (7.7mmo l, 77% yield) foam-like benzhydryl ester X I I (R=C H Ph₂).Slowly it is recrystallized from dichloromethane/hexane, so as to obtain 4.3 grams of (75% yield) pure transparent sheet-like things：

mp.156-157℃；

(c=0.6, CHCl₃)；IR1780,1717,1643,1450,1379cm^-1；NMR δ 1.8-2.1 (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 C₃₆H₃0N₂O₅：C, 75.77；H, 5.30；N, 4.91.Found：C, 75.79；H, 5.46；N, 4.77.

* (R in X II formula compounds is benzhydryl, R⁵, R⁶It is hydrogen, n is 3.)

Embodiment 4

[4S- (4 α, 7 α, 12b β)] (1,3- dihydro -1, -2H- is different for 3- dioxos for -7- Indoles -2- bases) -1,2,3,4,6,7,8, -12b- octahydro -6- oxy picolinates simultaneously [1-a] [2] Azepine cycloheptatriene -4- carboxylic acids, methyl esters

Available diazomethane treatment cyclisation product, obtains the methyl esters X II (R=CH in embodiment 3 in addition₃)：

mp 138-149℃

(c=0.97, EtOH)；IR1778,1720,1655,1620,1375cm^-1, NMR δ 1.7-2.2 (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, JX=6Hz), 7.23 (m, 4H), 7.77 (m, 2H), 7.89 (m, 2H)

Anal.Cacd.for  C₂₄H₂₂N 2O5：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) -3- phenylpropyls] amino] -1,2,3, 4,6,7,8,12b- octahydro -6- oxy picolinates simultaneously [2,1-a] [2] benzo-aza cycloheptatriene -4- Carboxylic acid, diphenyl methyl esters (IIa)

To containing the 2.3ml 1N hydrazine hydrate solutions that are added in 1.17g (2.0mmol) phthalimide X II solution for being obtained in the embodiment 3 of 15ml Me OH and be dissolved in methyl alcohol are dissolved in, stirred 3 days in 25 DEG C.Solvent is removed under vacuo, residue is dissolved in chloroform, filter and be concentrated to give the thick amine of pale yellowish oil.By the thick amine (about 2.0mmol) 25 DEG C in be dissolved under nitrogen environment 6ml dichloromethane and with 545mg (2.5mmol) 1,8- it is double-(dimethylamino) naphthalene and 850mg (2.5mmol) (R)-ethyl -4- phenyl -2- fluoroforms

Epoxide butyl ester (XXIII) treatment.Solution forms precipitation mixture for 18 hours and is placed directly within 100m l silica gel in 25 DEG C of stirrings, the pure oily S that flash chromatography obtains 1.11g (1.76mmo l) (yield 88%) is carried out with 25%Et OAc/ hexanes, S, S, R diester (IIa) (R³, R⁴=-C H₂CH₂CH₂-, R=C HPh₂)：

IR (KBr) 1734,1657,1495,1452,1185,1155cm^-1；NMR δ 1.28 (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) -3- phenylpropyls] ammonia Base] -1,2,3,4,6,7,12b- octahydro -6- oxy picolinates simultaneously [2,1-a] [2] benzo-azaCycloheptatriene -4- carboxylic acids

To 900mg (1.42mmol) (S, S, S, the R) benzhydryl ester II (R obtained in the stirred embodiment 5 under 25 DEG C of nitrogen environments³、R⁴=-CH₂CH₂CH₂-, R=CHPh₂) return addition 7ml trifluoroacetic acids in the solution of fragrant ether with 2.5ml.Stirring removes volatile materials and obtains oily residue after 2 hours in high vacuum, then is dissolved in 4ml absolute ethers, and strong stirring is simultaneously diluted with hexane.Supernatant is poured out from colloidal solid, jelly is ground with hexane and is vacuum dried, obtain 750mg (1.3mmol) (S, S, S, R) II (R³, R⁴=CH₂CH₂CH₂-, R=H) brown color solid-state tfa salt (yield 91%)：

Amb=25.5 DEG C of [α] (c=0.57, CH3OH)；IR (KBr) 2300-3400,1735,1660,1195,1140cm^-1；NMR δ (CD3CN, 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)

.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=2Hz) 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 C₂₉H₃₃F₃N₂OX：C, 60.20；H, 5.75；N, 4.84.Found：C,

.12；H, 5.72；N, 4.45.

Embodiment 7

[4 α, 7 α (R*)] 12b β -7- [[1- carboxyl -3- phenylpropyls] amino] - 1,2,3,4,6,7,12b- octahydro -6- oxy picolinates simultaneously [2,1-a] [2] benzo-aza cycloheptyl Triolefin -4- carboxylic acids (II)

In under 25 DEG C of nitrogen environments to 116mg (0.20mmol) ester group (the II R=H, R that embodiment 6 is obtained for being dissolved in the ethanol of 5ml 95%³, R⁴=-CH₂-CH₂-CH₂-) 0.5ml 1N lithium hydroxide stock solutions are added in solution.After stirring 18 hours, 0.5ml 1N hydrochloric acid is added dropwise under strong stirring.It is separated by filtration amphion and vacuum drying obtains 80mg (0.17mmol) white solid (yield 85%), homogeneousization (Whatman Pprtisil 10O DS-3 posts, the 0.1M Ammonium formate buffers in 50% methanol/water) is allowed to analytical HPLC.A sample of analysis is continuously repeated, the colourless fine crystals of 8mg are obtained from elution buffer：

mp259-260℃(dec.)；

(c=0.05, MeoH)；IR (KBr) 1745,1653,1630,1495,1420,1305,1220,752,695cm^-1；NMR (CD3CN, TFA) δ 1.80 (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  C₂₅H₂₈N₂O₅：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 acids, methyl esters

In 9ml (105mmol) the 2.7M n-butyllithium solutions for being dissolved in hexane at -78 DEG C to addition in being dissolved in the solution of 15.4ml (110mmol) diisopropylamine of the anhydrous T H F of 250ml.After stirring 30 minutes, adding 20ml HPTs and be dissolved in (100mmol) containing 17.7g of 25ml T H F] benzaldehyde and the solution addition time of the western Fu Shi alkali of glycine methyl ester is 30 minutes.After after 15 minutes, solution is simultaneously to slowly warm up to 25 DEG C by the addition bromo- 1- amylenes of 13.5g (100mmol) 5-.After 3 hours, reactant mixture is placed in water and is extracted with ether.Extract salt solution cyclic washing, is then dried and concentrated with magnesium sulfate, obtains the amber grease of 25g.Grease is dissolved in 400ml ethers and is stirred 2 hours with 300ml0.5N hydrochloric acid.PH is simultaneously transferred to 9 and is extracted with chloroform by separate aqueous layer with 1N NaOH, dried over magnesium sulfate and be concentrated to give compound needed for 4.5 grams of liquid.

Replace the bromo- 1- amylenes of 5- with the bromo- 1- hexenes of the 6- of equivalent or the bromo- 1- heptene of 7- and the cresols (these three compounds correspond respectively to the compound of the IXb formulas that wherein n is 3,4 or 5) of 2- amino -6- octenoic acids and second-amino -7- nonenoic acids is obtained respectively according to the method for applying example

Embodiment 9

2- [[2- (1,3- dihydro -1, the iso-indoles -2- bases of 3 dioxo -2H- one) -1- oxos -3- Phenylpropyl] amino] -6- heptenoic acids, methyl esters

To being dissolved in 30ml CH₂、Cl₂6.0g (20mmol) phthalimido-L- phenylpropyls propylhomoserin and 6.0g (24mmo l) EEDQ solution in add be dissolved in 10mlCH₂Cl₂The product of its (21mmol) embodiment 8.It was observed that there is gas to release and continuously stir 18 hours.Will be molten

Dchloromethane, is washed and dried over magnesium sulfate with 10% hydrochloric acid solution, saturated sodium bicarbonate solution.Be concentrated to give 8.3g yellow oils, with 25%Et OAe/ hexanes flash chromatography it, obtain 6.0g foam-likes diastereomer acid amides Xb (n=3).

Equally, 2- amino -5- heptenoic acids methyl esters is replaced with equivalent 2- amino -6- octenoic acids methyl esters or 2- amino -7- nonenoic acid methyl esters and the method according to the present embodiment can be respectively obtained the respective compound of the Xb formulas that wherein n is 4 or 5.

Embodiment 10

1,2,3,4- tetrahydrochysene -1- [2- (1,3- dihydro -1,3- dioxo -2H- iso-indoles -2- bases) 1- oxo -3- phenylpropyls]-pyridine-2-carboxylic acids, methyl esters

The alkene (10mmol) that embodiment 9 is obtained is dissolved in the dichloromethane that 100ml contains 10ml absolute methanols and is cooled to -78 DEG C.The oxygen flow containing ozone is passed through toward the solution of stirring until blue stabilization.After being deaerated with nitrogen, 10ml methyl sulfides and 0.5ml pyridines are added, solution is to slowly warm up to 25 DEG C and is stirred 18 hours.With three part of 10% salt acid elution solution, through magnesium sulfate in dry and be concentrated to give grease.This crude product is dissolved in 150ml trichloroethanes and with 0.5ml trifluoroacetic acids reflow treatment 18 hours.Concentrate and flash chromatography, obtain can chromatography diastereomer acyl alkenyl amine XIa and XIb (n=3).

Embodiment 11

7- (1,3- dihydro -1,3- dioxo -2H- iso-indoles -2- bases) -1,2,3,4,6,7,8,12 B- octahydro -6- oxy picolinates simultaneously [2,1-a] benzazepine -4- carboxylic acids, benzhydryl ester

The acyl enamine (1.6mmol) (XIa) that embodiment 10 is obtained is dissolved in 5ml dichloromethane simultaneously

25 DEG C are processed 18 hours with 2.0ml TFMSs in a nitrogen environment.Reactant mixture is set to be distributed between water and ethyl acetate.Organic extract is fully washed with water, is concentrated and is processed it with excessive diazonium diphenyl-methane solution.

Foam-like cyclisation ester XIIa (n=3, R=CHPh are obtained through flash chromatography₂)。

When using the bromo- 1- hexenes of 6- and 7- bromo- 1- heptene, arrived according to similar to embodiment 8

Method can respectively be obtained similar three ring intermediate Xs IIa (n=4) and XIIa (n=5

As described in Example 5, can deprotect these three rings intermediate Xs II (n=4,5) with hydrazine to be coupled on the R- trifluoto esters of XXIII, to respectively obtain diester II (R³, R

-CH₂-(CH₂)₂-CH₂-, R=CHPh₂) and II (R³, R⁴=-CH₂CH₂)₃-CH₂-, R-CHPh₂).These diester can obtain corresponding prodrug ester acid (II) (R=H) according to the methods described selective hydrolysis of embodiment 6.

Embodiment 12

[4R- [4 α, 7 α (S), 12b β]] -7- [(1- carboxyl -3- phenylpropyls] ammonia Base] -3,4,6,7,8,12b- hexahydro -6- oxos -1H- [Isosorbide-5-Nitrae] thiazines simultaneously [3,4-a] [ 2]-benzo-aza cycloheptatriene -4- carboxylic acids

Step A. (R*, R*)-(-) -4- [2- (1,3- dihydro -1, the different Yin of 3- dioxos -2H- Diindyl -2- bases) -1- oxo -3- phenylpropyls] -3,4- dihydros -2H-1,4- thiazine -3- carboxylic acids, second Ester XVII

7.75g (191mmol) scattered 59% sodium hydride/paraffin is washed twice with 10ml anhydrous hexanes under stream of nitrogen gas.90ml dry DMFs are added toward the sodium hydride of purifying.It is carefully added into the hydrochloride of 17.9g (96.7mmol) serine ethyl ester when being cooled down with ice/methanol bath to the mixture in nitrogen with 20 minutes.5.2g (32mmol) KI is added after stirring the mixture for 5 minutes.With 5 minutes to instillation 14.5ml. (96.7mmol) bromoacetaldehyde diethyl acetal in the mixture.Reaction temperature was set to rise to 30 DEG C through 10 minutes again after removing cryostat.It is divided into two equal portions after stirring the mixture at room temperature 8 hours, portion adds the anhydrous THF solution that 40ml contains 14.2g (48mmol) phthalimide phenylalanines and 11.9g (48mmol) EEDQ.Stirred the mixture in nitrogen environment at room temperature 18 hours.Mixture is set to be allocated in 200ml water and 200ml ether.Two-phase is separated, adds 200ml ethers to extract it in Yu Shuixiang again.Merge ethereal solution, it is continuous to use (a) 2 × 200ml 1N hydrochloric acid, (b) 2 × 200ml saturated sodium bicarbonates, and (c) 50ml saline treatments.The yellow ethereal solution of such extraction is dried with magnesium sulfate, filtering, vacuum concentration, the orange oily acetal XVIa (R=CH needed for obtaining 27.2g₂CH₃, X=S).Contain addition 4.5ml trifluoroacetic acids in the chloroformic solution of 16.1g (30.3mmol) acetal to 500ml.Resulting solution is flowed back in a nitrogen environment 4 hours, cooled down, extracted once with 300ml saturated sodium bicarbonates, filtered by anhydrous magnesium sulfate.Resulting solution is concentrated in vacuo into dark colored foam shape, and is chromatographed on 500ml silica gel, successively with 1500ml35%Et OAc- hexanes and 55%Et OAc- Hex.4.0g (29%) white foam acyl enamine XVII (R=-CH are concentrated to give after component needed for merging₂CH₃, X=S), the product is crystallized out from methyl alcohol and obtains white needles analysis pure products.

193 DEG C of Mp,

(c=0.8, CHCl₃), 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 NMR δ (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 C₂₄H₂₂N₂O₅S：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- dioxies Generation -2H- iso-indoles -2- bases) -3,4,6,7,8,12b- hexahydros -6- oxos -1H- [Isosorbide-5-Nitrae] And [3,4-a] [2]-benzo-aza cycloheptatriene -4- carboxylic acids, methyl esters XVIII

The acyl enamine of 0.5g (1.1mmo l) step A is dissolved in the solution among 5ml dichloromethane and adds 1.5ml CF in a nitrogen environment₃ SO₃In H.Mixture is stirred at room temperature 18 hours, then be carefully poured into the excessive NaHCO that has stirred in the 10ml methyl alcohol institute into suspension liquid in, gained mixture is concentrated in a vacuum, is allowed to be allocated in the middle of dichloromethane and water and with another point of dichloromethane aqueous phase extracted.Merge organic phase, dried with anhydrous magnesium sulfate, vacuum concentration obtains yellow foam.Foam is dissolved in methyl alcohol, is stood overnight in 0 DEG C.Gained crystallization is collected, is usedMethyl alcohol is washed, then the colourless needles triclazate XVIII (R=CH needed for 0.35g (72%) is dried to obtain at 60 DEG C of about 0.5mm Hg₃, X=S),

Mp 130-134 DEG C,

(c=0.4, CHCl₃).IR(KBr)：3450,1780,1730,1670,1650,1380,1300,770,720cm^-1.1H NMR δ(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)；5.69 (dd, 1H, J_a=12.4Hz)；7.20-7.45 (aromatic, 4H)；7.75 (m, 2H)；7.88 (m, 2H) .13C NMR δ (75.4MHz, proton decoupled)：27,29.8,33.9,351.7,57.0 (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 C₂₃H₂0N₂O₅S.H₂O：C, 60.78%；H, 4.88%；N, 6.16%；S, 7.05%.Found：C, 61.12%；H, 4.71%；N, 6.10%；S, 7

7%.

Step C.

- hexahydro -6- oxos -1H-

4] thiazine simultaneously [3,4-a

2]-benzo-aza cycloheptyl Triolefin -4- carboxylic acids, methyl esters

The triclazate obtained to 0.67g (1.5mmol) steps B adds 3ml (3.0mmol) 1N hydrazine hydrate methanol solutions in institute's pulp solution in 5ml methyl alcohol.Mixture is stirred 60 hours under room temperature under nitrogen environment.Therewith by CH₂Cl₂The diatom main filter filtering vacuum for thoroughly washing

Filtrate, again molten dry methane dioxide and by organic phase solution with water Xian once afterwards pass through magnesium sulfate

Consider.Yellow crystals solid amine needed for filter vacuum to be concentrated to give 4.19mg.From acetic acid-

Punching is recrystallized to give the transparent needle-like analysis sample that pure fusing point is 143 DEG C,

IR (KBr) 3420,2900,1.730,1715,1660r, 1430,1370,1320,1300,1270,890,760cm^-1.NMR δ (300MHz, CDCl3) δ 1.82 (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_c=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 C15

2O3S：C, 53.80；H, 5.92；N, 9.14.Found：Cr58.70；H, 5.97；N, 3.00.

Step D. [4R-4 α .7 α (S*) 12b β)] -7-1- (ethyl ester) -3-

Base amino -3,4,6,7,8.12b- hexahydro -6- oxos -1H- [Isosorbide-5-Nitrae] thiazines simultaneously [3,4-a] [2]-benzo-aza cycloheptatriene -4- carboxylic acids, methyl esters

Amine obtained by 374mg (1.22mmol) steps C and 282mg (1.34mmol) 1,8- pairs-diformazan cyano group naphthalene are dissolved in 9ml dichloromethane, to the trifluoto ester that the gained of 457mg (1.34mmol) embodiment 5 is added in the solution.Mixture is stirred 24 hours under room temperature under nitrogen environment, is filtered afterwards.Refiltered after filtrate is diluted with the ethylacetate-hexanes of 10ml 50%.Gained filter vacuum is condensed into dark-green glass shape thing.Glassy mass is chromatographed on 150ml silica gel, with the ethyl acetate of 800ml 37%-

Alkane is eluted.White foam diester needed for being concentrated in vacuo and being dried to obtain 514mg (84.8%).

IR (KBr), 3300,2950,2920,1730,1650,1490,1430,1320,1180,910,130,690cm^-1.1HNMR δ(300MHz)：1.22 (t, 3H, J=7.0Hz)；2.02 (m, 2H)；2.96 (s, 3H)；3.18-3.47(

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 (a romatic, 9H.) 13C NMR δ (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*), [2b, β]] -7- [[1- (ethyl esters Base) -3- phenylpropyls] amino] -3,4,5,7,8,12b- six oxygen -6- oxos -1H- [1.4] Thiazine simultaneously [3,4-a] [2]-benzo-aza cycloheptatriene -4- carboxylic acids

The diester dissolving when being cooled to 0 DEG C of 2.7ml (31mmol) TFMSs is added in the diester obtained to 766mg (1.54mmol) steps D at l5 DEG C.4.03g (46mmol) the sodium carbonate liquors mixtures obtained by two parts of 30ml ethyl acetate extractions for being dissolved in 60ml water are carefully added into after gained dark solution is stirred 24 hours under 0-5 DEG C of argon gas environment.Discard organic phase.Will be remaining water-soluble

Hydrochloric acid is acidified to PH5.Turbid mixture is extracted with three parts of 60ml ethyl acetate.It is associated with

Afterwards with two parts of 30ml salt water washings；Organic phase solution vacuum after anhydrous magnesium sulfate is dried is dense

It is that 138 DEG C of yellow glassy mass analyze datas show that the material contains to 288mg (37%) fusing point

Acid esters needed for 80%

CH₂ SCH₂-, R-H) it is main miscellaneous

The sodium salt of fluorine methanesulfonic acid.

IR(KBr)：3420,1730,1650,1500,1430,1250,1160,1030,750,690,630cm^-1.1H NMR δ (300MHz, CD3CN)：1.23 (t, 3H, J=7.1Hz)；2.0 (m, 2H, from CDCl3)；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-

(acomatic, 98.)

Step F.

Phenylpropyl] amino] -3,4,6,7,8,12b- hexahydros -6- oxos -1H- [Isosorbide-5-Nitrae]---- --- --- --- --- --- --- --- --- --- thiophenePiperazine simultaneously [3,4-a] [2]-benzo-aza cycloheptatriene -4- carboxylic acids

100mg (0.2mmol) steps D gained diester is dissolved in 2.27ml methyl alcohol, to addition 0.5ml (0.5mmol) (N lithium hydroxides in the solution.Solution is muddy in short-term, but clarifies quickly under agitation.Solution is stirred 60 hours under room temperature under nitrogen environment.Vacuum concentration obtains white residue.By the half of residue in -25cm × 22mm ID Partisil enterprising horizontal high voltage LCs of 10-OD S3 posts to purify it, mobile phase is molten to be dissolved in the water 0.1M pH=6.2 ammonium formates of 40% methyl alcohol one

, collect first eluting peak.It is concentrated in vacuo after merging appropriate composition part.The ngelrohr way of distillations remove the diacid needed for remaining ammonium formate obtains 13mg (26%) under 90 DEG C of 1mm Hg.

mp 232-235℃(dec.)TR(KB r)：3420, broad 3100-2200,1720,1650,1630,1490,1400,1200,750,690cm^-1.1H NMR δ (300MHz, D₂O-TFA)：2.35 (m, 2H)；2.89 (td, 2H, J_a=10.3Hz, J_b=6.7Hz)；3.01 (dd, 1H, J_a=1.4.0Hz, J_b=4.

Hz 

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,

5.0Hz, J_b=

.8Hz, 3.71 (dd, 1H, J_a=16.1Hz, J_b=6.3Hz)；4.10 (broad s, 1H 1.5.31 (broad, 1H)；5.48d.1H, J=4.2Hz)；5.52 (d, 1H, J=6.2Hz)；7.16-7.38(

Omatic, 8H)；7.49 (d, 2H, J=8.3Hz)；7.88 (b road d, 2H,

27.0Hz)。

The various inorganic and organic bronsted lowry acids and bases bronsted lowry used by the compounds of this invention into salt is set also to be included within the scope of the present invention.These salt include the salt of ammonium salt, alkali salt such as calcium and magnesium salts, such as organic alkali salt, dicyclohexyl amine salt, N- methyl-D-glucosamines, amino-acid salt such as arginine, lysine etc..Also the salt such as the organic and inorganic acid salt that can be prepared, such as hydrochloric acid, hydrobromic acid, carbonic acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid, camphorsulfonic acid are included.Preferentially select nontoxic physiologically acceptable salt, but it is also possible to use other salt, the product in such as separating or in purifying.

The formation of salt forms can by conventional method such as the free acid of product or free alkali react in the solvent or medium that can not dissolve the salt or in water class solvent and be obtained with the appropriate alkali of monovalent or acid, then by vacuum or can freeze or make another cation of cation exchange of existing salt on appropriate ion exchange resin and obtain.

It is Angiotensin II that compound of the invention suppresses Angiotensin-Converting and therefore blocks decapetide angiotensin I converting.Angiotensin II is a strength supercharging material.Therefore hypotensive purpose can be reached by suppressing its biosynthesis, particularly with those hypertension animal related to Angiotensin II and people.And then, converting Enzyme can also be reduced blood pressure by the booster action of bradykinin.Although this and other mechanisms relative importances need to prove, but angiotensin converting enzyme inhibitor is strictly effective antihypertensive for various animal models, and there is clinical effectiveness to many human patientses, such as to renovascular, pernicious and primary hypertension patient.(such as see D.W.Cushman, et al., Biochemistry 16,5484 (1977).

What the identification to converting enzyme inhibitor was carried out by external enzyme level method of inspection.For example, a kind of one of useful method is Y.Diguilloud, the hydrolysis for wherein measuring carbobenzoxy group phenylalanyl histidyl- leucine that A.Reinharz and M.Rorh (Biochem.Biophys.Aeta, 206 N36 (1970)) is proposed.Identification in vivo can according to J.R.Weeks and J.A.Jones (Droc.Soc.Exp.Biol.Med., 104,646 (1960) technologies introduced,

The method of Koieisky et al.

Proc.Soc.Exp.Biol.Med.125,96 (1967).Carried out with renin rat model in high obtaining.

Therefore, compound of the invention as the medicinal treatment of anti-hypertension hypertensive mammals including people, and can be configured to the preparation with the appropriate component for being beneficial to take to reach the purpose of hypotensive by by them.The dosage range that the compounds of this invention is taken to the patient of this treatment of needs is each patient 0.5-100mg, is typically taken daily for several times, and so daily accumulated dose is 0.5-400mg.The dosage by according to the order of severity of disease, the body weight of patient and technical staff know can other factorses and it is different.

So, according to the present invention can provide the I formulas compound group of a kind of carrier acceptable for suppress Angiotensin-Converting or pharmacology and pharmacological effective dose into treatment hypertension pharmaceutical composition.

For ease of taking, component of the invention can also contain acceptable component on other conventional pharmaceuticals in case of need.These components are generally used as being carrier or diluent.This component with appropriate dosage form can be prepared with conventional method.Whatsoever dosage form, must the present invention containing effective dose compound.

This composition can be administered according to oral or parenteral (for example, be parenterally blown into, part, rectum etc.) mode.Using appropriate dosage form such as tablet, capsule, suspension, solution etc. is for oral；Suspended emulsion etc. is parenteral use；Solution is used to be injected intravenously；Ointment, plaster etc. are used for local administration.Can be produced according to any of medicament method of manufacturing technology and prepare for oral preparation, said preparation can be containing one to multiple kind of sweetener, coloring agent and preservative so that preparation is attractive in appearance and good to eat.Also can be manufactured with known method with the tablet containing active component on the mixture of nontoxic, pharmaceutically acceptable excipient.Usual excipients can be (1) inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium；(2) granule and

Disintegration agent such as cornstarch, or alginic acid；(3) bonding agent such as starch, gelatin or gum arabic, with

Lubrication prescription such as magnesium stearate, stearic acid or talcum.Tablet can be

Collapse

Suction in the gastrointestinal tractTherefore

For a long time

For example, can be with

When for example sweet turbid acyl monostearate of material or glyceroyl distearate.They are also dependent on United States Patent (USP) N.4,256,108；4,160,452 and 4, the method described in 265,874 is coated, and control release osmotic therapeutic tablets are easy to be made.

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

Aqueous suspension agent is usually to be contained within active principle with the excipient institute resulting mixture for being suitable to manufacture aqueous suspension agent.Such excipient can be：

(1) suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, mosanom, polyvinylpyrrolidone, bassora gum and gum arabic；

(2) dispersant or wetting agent can be

(a) natural phosphatide such as ovum phosphate ester,

The condensation product such as Myrj 45 of (b) alkylene oxide and aliphatic acid,

The condensation product such as 17 carbon ethyleneoxy alcohol ceryl alcohols of (c) oxirane and long-chain fatty alcohol,

(d) oxirane and aliphatic acid and the product of partial ester condensation derived from hexitol, such as polyoxyethylene 80 sorbitan monooleate, or

(e) oxirane and aliphatic acid and the product of partial ester condensation derived from hexitan, such as polyoxy ethene sorbitan monooleate.

Aqueous suspension agent can also contain one or more preservatives, such as ethyl or n- propyl p-hydroxybenzoates；One or various colouring agents；One or more flavor enhancements；And one or more sweeteners such as sucrose or saccharin.

Oleaginous suspension by the preparation of the method for the suspension effective ingredient in vegetable oil, vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or can use mineral oil such as atoleine.Oleaginous suspension can contain thickener, such as beeswax, solid paraffin or cetanol.Adding sweetener and flavor enhancement can make preparation good mouthfeel.Adding antioxidant such as ascorbic acid can treat that these compositions are obtained

Protection.

Scattered powder and particle are suitable to prepare aqueous suspension agent.With dispersant or wetting agent, the composition for suppressing is contained in a kind of suspending agent and the admixture of one or more preservatives.Applicable dispersant or wetting agent and suspending agent is above illustrated.Also other excipient those sweeteners as described above, flavor enhancement and coloring agent have been addressed.

Pharmaceutical composition of the invention can also the presence of oil-in-water emulsion form.Oil phase can be vegetable oil or atoleine or its mixture.Suitable emulsifying agent is (1) naturally-produced natural gum such as gum arabic and bassora gum, (2) naturally-produced phosphatide such as soybean lecithin, (3) aliphatic acid and ester or partial ester derived from hexitan, for example, sorbitan monooleate, (4) condensation product of above-mentioned partial ester and oxirane, such as polyoxyethylene sorbitan monooleate.Emulsion can also contain sweetener and flavor enhancement.

Syrup and ingredients can be prepared with Sweetening agents such as glycerine, propylene glycol, D-sorbite or sucrose.The formula can also contain stimulation buffer, preservative, flavor enhancement and colouring agent.

This pharmaceutical composition can be the form of aseptic injection water or oleagenous suspension.The suspension can be prepared according to the suitable dispersant of known method those described above or wetting agent and suspending agent.Aseptic injection preparation is alternatively the aseptic injectable solution or suspension being made in the acceptable diluent of nontoxic, non-bowel or solvent such as excipient, and solvent for use can be water, Ringes ' s solution and isotonic sodium chlorrde solution.In addition, aseptic, nonvolatile oil is conventionally used as solvent or suspension media.For this purpose, any gentle nonvolatile oil can be used, including the list or two glyceride for synthesizing.In addition, the aliphatic acid such as oleic acid also can be with preparing injectable formulation.

Composition of the invention can be in the form of suppository, for the rectally of medicine.Therefore these compositions can melt for liquid and in the rectum and discharge drug excipient and mix and be obtained for solid with appropriate non-stimulated, normal temperature by by medicine under rectal temperature.Such excipient includes coconut oil and polyethylene glycol.

The emulsion containing the present composition, ointment, pastel, solution or suspension etc. are can use for local application.

The effective ingredient amount of the dose pattern for producing can be merged with carrier mass, object and specific administering mode according to treatment is different.

But, it should be understood that, for any particular patients ', specific dosage level will be depending on a series of factor, and it includes the order of severity of activity, the age of patient, body weight, constitution, sex, food, administration time, instructions of taking, excretion rate, medicine composition and the special disease treated of particular compound used.

Compound of the invention also can be with other antihypertensives and/or diuretics and/or calcium channel blocker administering drug combinations.For example, the compounds of this invention can be with following compound administering drug combinations：Acetazolamide,Benzene thiazine,Bumetanide,Cloroqualone,Plug can be urinated,Clonidine,Chlorine lamb's-quarters pacifies acetate and cryptenamine tannate,Anhydron,Deserpidine,Diazoxiide,Ground that sulphur,(s)-1-[[2-(3,4- dimethoxy phenyls)-ethyl] amino] -3-] 4- (2- thienyls) -1-1H- imidazoles -2- bases] phenoxy group] -2- propyl alcohol,thacrynicacid,Flumethiazide,Furosemide,Guanethidine monosulphate,Salt solution hydralazine,Hydrochlorothiazide,Hydroflumethiazide,(1) -4- [3- [- [2- (1- hydroxy-cyclohexyls)-ethyl] -4- oxo -2- thiazolidinyls]-propyl group]-benzoic acid,The optical isomer of indacrinon and its various ratios,Merethoxylline procaine,Methyl chlorothiazide,Ethyldopa bar,Aldomet Ester Hydrochloride salt,Metolazone,Metoprolol tartrate,Minoxidil,Receive Lip river Dorr (nal dolol),Nifedipine,Pargyline hydrochloride,Pindolol,Poly- thiazine,Croak azoles piperazine,propanolol,Hydromox,Luo Mei rattans are flat using blood,Rescinnamine,Reserpine,According to his tail acid sodium,The general sodium of nitro,Spiral shell stays lactone,Ticrynafen,Timolol,Phenalgin dish pyridine,Trichloromethiazide,Arfonad,Benperidol,Ground that sulphur,Etafenone,Take using handkerchief rice,Felodipine,Flunarizine,Gallopamil,Indoles amine,Lidoflazine,Nicardipine,Nifedipine,Nimodipine,Nitrendipine,Perhexiline,Segondin,For A Pa meter,Verapamil etc.,And its mixture and merging medicament.

When being administered alone, these typical individual daily dose scopes for merging medicaments can be from 1/5th of the minimum clinical dosage recommended to maximum recommended level.

To illustrate that these merge medicament, one of antihypertensive of the present invention can be used in combination with the amount of daily 0.5-1000mg with following compounds (with pointed daily dosage scope)：The Shuan Qing chlorine Qin (10-100)；Gram urine plug (125-2000mg)；Control optical isomer ratio

rinone(25-150mg)；Ethacrynic acid (15-2000mg)；Amiloride (5-20mg)；Furan

Amino acid (5-80mg)；Propranolol (20-480mg)；Timolol (5-60mg)；With ethyldopa (65-2000mg)；And the pivaloyl 2-ethoxyethyl acetate (30-1000) of ethyldopa.In addition, during three kinds of Drug combinations, if the indacrinone (25-150) plus amiloride (5-20mg) plus converting enzyme inhibitor of the present invention of hydrochlorothiazide (10-100mg) plus amiloride (5-20mg) plus converting enzyme inhibitor (0.5-1000mg) of the present invention or control optical isomer ratio, the ware pressure to controlling hyperpietic is effective drug combination mode.These dosage ranges it is of course possible to if necessary in adjusting daily fractionated dose on basis, and as described above, dosage used is by according to the property and the order of severity of disease, the body weight of patient, specific diet and other factorses and it is different.Preferred compound pays group's group (Subgeneri cgroups)

Wherein R²It is phenethyl

Wherein R⁵It is H or hydroxyl,

Wherein R⁶It is H or hydroxyl,

Wherein R is C_1-6Alkyl,

Wherein R¹It is ethyl,

Wherein R is H,

Wherein X is CH₂, and

Wherein X is S.

Preferred aforementioned structural formula compound is that those have R specific shown in following table, R¹, R², X,R ⁵ , R ⁶ Person.

R    R ¹        R ²        RX       R ⁵        R ⁶

H ethyl phenethyls CH ₂       H        H

H ethyl phenethyls CH ₂       OH       H

H ethyl phenethyls CH ₂       OH       OH

H ethylo benzenes

H

H ethyl phenethyl O H H

H ethyl phenethyl S OH H

Claims (23)

1. FF-6. and its officinal salt method, wherein R and R¹Respectively

   (a) hydrogen；

   (b)C₁-C₆Alkyl；

   The C of (c) substitution₁-C₆Alkyl, wherein substitution base is hydroxyl, C₁-C₄Alkoxy and two-(C₁-C₄)-alkylamino；

   (d)C₆-C₁₂Aryl；

   The C of (e) substitution₆-C₁₂Aryl, wherein substitution base is C₂-C₆Alkyl, fontanel element (F, Cl, BR, I), and C₁-C₄Alkoxy；

   (f) miscellaneous (C₄-C₉) aryl, wherein hetero atom can be O, N or S；

   Miscellaneous (the C of (g) substitution₄-C₉) aryloxy group, wherein hetero atom can be O, N or S ,-and substitution base be C₁-C₆Alkyl, fontanel element (F, Cl Br, I), and C₁-C₄Alkoxy；

   R²For

   (a) hydrogen；

   (b)C₁-C₈Straight or branched alkyl；

   (c)C₂-C₈Straight or branched alkylene；

   (d)C₂-C₈Straight or branched alkynyl；

   (e)C₃-C₁₀Cycloalkyl；

   (f)C₆Or C₁₀Aryl (C₁-C₄) alkyl；

   The C of (g) substitution₁-C₈Alkyl, can optionally contain O, S, S=O, O=S=O, C=O, a CONR₂、SO₂NR₂、NRCO、NRCONRR₂、OCONR₂, NRCOOR or-NR₂The definition of group, wherein R is same as described above, and may have 1-3 selected from fontanel element (F, Cl, Br, I), carboxy and amide groups, C₁-C₄The substitution base of oxygen carbonyl, sulfydryl, amino and R, the wherein definition of R is same as described above,

   R³It is hydrogen, C₁-C₁₂Alkyl, phenyl and benzyl；

   R⁴It is native amino acid residues, including hydrogen, C₁-C₄, alkyl, phenyl or benzyl；And

   R³And R⁴- 6 to 8 Yuans being combined together to form with the carbon atom being connected with them and condensing loop section, a sulphur or oxygen atom can be optionally contained on the ring,

   R⁵And R⁶Respectively

   (a) hydrogen, hydroxyl；

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

   (c)C₁-C₆Alkyl；

   (d)C₁-C₆Alkoxy,

   It includes making the fused lactams in following formula

   

   With following formula: compound A, B or C

   

   Coupling (wherein R ' and R₁' it is group in addition to hydrogen, Y is oxygen), above-mentioned coupling can optionally remove R ' and R₁' ester group or first,

   It is above-mentioned in the presence of a base reactant to be made to be in contact with the coupling of the compound of formula A and completed,

   It is above-mentioned in the presence of a molecular sieve to make with the coupling of formula B compounds reactant contact to form western husband (Schiff ' s) alkali and complete, and the described schiff alkali of most handy cyanoborohydride reduction,

   The above-mentioned lotus root connection with formula C compounds reduces Y after being carried out according to Isosorbide-5-Nitrae-Michael addition reactions using Catalytic Hydrogenation Techniques.

   Following formula: compound

   And its officinal salt, wherein R and R¹Respectively

   (a) hydrogen；

   (b)C₁-C₆Alkyl；

   The C-C alkyl of (c) substitution, wherein substitution base is hydroxyl, C₁-C₄Alkoxy and two-(C₁-C₄)-alkylamino；

   (d)C₆-C₁₂Aryl；

   The C of (e) substitution₆-C₁₂Aryl, wherein substitution base is C₁-C₆Alkyl, fontanel element (F, Cl, Br, I), and C₁-C₄Alkoxy；

   (f)(C₄-C₉) heteroaryl, wherein hetero atom can be oxygen, nitrogen, or sulphur；

   Miscellaneous (the C of (g) substitution₄-C₉) aryloxy group, wherein hetero atom can be oxygen, nitrogen or sulphur, and substitution base is C₁-C₄Alkyl, fontanel element (F, Cl Br, I), and C₁-C₆Alkoxy；

   R²For

   (a) hydrogen；

   (b)C₁-C₈Straight or branched alkyl；

   (c)C₂-C₈Straight or branched alkylene；

   (d)C₂-C₈Straight or branched alkynyl；

   (e)C₃-C₁₀Cycloalkyl；

   (f)C₆Or C₁₀Aryl (C₁-C₄) alkyl；

   The C of (g) substitution₁-C₈Alkyl, can optionally contain O, S, S=O, O=S=O, C=O, a CONR₂、SO₂NR₂、NRCO、NRCONR₂、OCONR₂, NRCOOR or-NR₂Group, wherein R are as defined above and can have 1-3 selected from fontanel element (F, Cl, Br, I), Carboxylamide, C₁-C₄The substitution base of alkoxy carbonyl group, sulfydryl, amino and R, wherein R's is as defined above,

   R³It is hydrogen, C₁-C₁₂Alkyl phenyl and benzyl；

   R⁴It is native amino acid residues, including hydrogen, C₁-C₁₂Alkyl, phenyl or benzyl；And

   R³And R⁴- 6 to 8 Yuans being combined together to form with carbon atom and condensing loop section, a sulphur or oxygen atom can be contained on the ring.

   R⁵And R⁶Respectively

   (a) hydrogen, hydroxyl；

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

   (c)C₁-C₆Alkyl；

   (d)C₁-C₆Alkoxy.
2. 2. the compound of claim 1, diastereomer configuration therein is as follows：

   
3. 3. compound according to claim 2, it has structural formula

   

   Wherein X is C H₂, O or S.
4. 4. compound according to claim 3, R therein⁵And R⁶It is hydrogen.
5. 5. compound according to claim 3, R therein⁵It is hydroxyl, R⁶It is hydrogen.
6. 6. compound according to claim 3, wherein R is H.
7. 7. compound according to claim 6 wherein R²It is phenethyl.
8. 8. compound according to claim 7 wherein X is CH₂
9. 9. compound according to claim 8, wherein R¹It is ethyl.
10. 10. compound according to claim 9, wherein X is S.
11. 11. compounds according to claim 9, wherein X is O.
12. 12. compounds according to claim 3, wherein R is H, R¹It is ethyl, X is C H₂, R²It is phenethyl, R⁵And R⁶It is H.
13. 13. compounds according to claim 3, wherein R is H, R¹It is ethyl, X is S, R²It is phenethyl R⁵And R⁶It is H.
14. 14. compound according to claim 3 wherein R and R¹It is H, X is CH₂, R⁵And R⁶It is H, R²It is phenethyl.
15. 15. compounds according to claim 3, wherein R and R¹It is ethyl, X is CH₂, R⁵And R⁶It is H, R²It is phenethyl.
16. 16. is according to claim 3, wherein R and R¹For H, X are S, R⁵And R⁶It is H, R²It is phenethyl.
17. 17. compounds according to claim 3, wherein R and R¹It is ethyl, X is S, R⁵And R⁶It is H, R²It is phenethyl.
18. A kind of 18. methods for preparing following formula: compound
19. 19. methods according to claim 16, produce following formula: compound

    

    It is included with the fused lactams of following formula

    

    With the reactant of a following formula

    

    Coupling, once there is above-mentioned coupling, i.e. optionally R ' is fallen in hydrolysis₁And R₁Ester functional groups, wherein R '₂It is phenethyl, X is CH₂, O or S, R⁵And R⁶Definition it is identical with described in claim 16, R '₁It is the group beyond H with R ', it is above-mentioned be with formula B compounds coupling make in the presence of a molecular sieve reactant be in contact together with formation-schiff alkali and the described schiff alkali of most handy cyanoborohydride reduction and carry out, above-mentioned and formula C compounds coupling can be according to 1,4-Michael addition reactions are carried out, and are afterwards reduced Y with Catalytic Hydrogenation Techniques.
20. The method of 20. compounds for preparing following formula

    

    , wherein Q is (H, H) or N-protected group, and as claimed in claim 17 but be not H, X is C H for the definition of R₂, S or O, the method is including making following formula: compound

    

    Friedel-Kraft cyclisation is carried out, optionally except-N-protected base of no longer holding the post, the cyclisation is completed using lewis acid.
21. 21. methods according to claim 18, wherein lewis acid are perfluoroalkyl sulfonic acid.
22. The method of 22. claims 18, wherein Q are phthalimido.
23. The method of 23. claims 20, wherein phthalimido protecting group are removed by with hydrazine reaction is hydrated.