CN1022755C - Process for preparation of N-imidazolyl-and N-imidazolyl methyl-derivatives of substituted bicyclic compounds - Google Patents

Abstract

The present invention relates to new N-imidazolyl and N-imidazolylmethyl derivatives of bicyclic compounds and salts theirof having the general formula (I), which are useful in the treatment of diseases related to an enhancement of TxA2 synthesis.

Description

Process for preparation of N-imidazolyl-and N-imidazolyl methyl-derivatives of substituted bicyclic compounds

The present invention relates to the preparation method of the TMSIM N imidazole base and the TMSIM N imidazole ylmethyl derivative of novel bicyclic compounds, particularly relate to 3,4-dihydro-2H-1-chromene, 2H-1-chromene, 3,4-dihydro-2H-1-benzo thiapyran, 2H-1-benzo thiapyran, 1,2,3,4-tetraline and 1, the preparation method of the TMSIM N imidazole base of 2-dialin and TMSIM N imidazole ylmethyl derivative and relate to the preparation method of the medicinal compositions that contains these compounds.

The invention provides novel cpd and pharmaceutical salts thereof with logical formula I

In the formula

A is group 〉=CR ₃Or＞CHR ₃, R ₃Be hydrogen or C _1-6Alkyl or group＞C=CR ₄R ₅, R wherein ₄And R ₅Be respectively hydrogen or C separately _1-5Alkyl;

Z is-CH ₂-,-O-or-S-;

N is 0 or 1;

R and R ₁Be respectively hydrogen or C separately _1-6Alkyl;

R ₂For-COCH ₂OH ,-CH ₂OR ' ,-COOR ' ,-CONR ' R " or-CH=CH-COOR ', wherein R ' and R " are respectively hydrogen or C separately _1-6Alkyl; And wherein:

A) when n is 0, then Z is-CH ₂-or-O-; When n was 1, then Z was-CH ₂-,-O-or-S-;

B) be R wherein as A ₃For hydrogen 〉=CR ₃Or＞CHR ₃The time, then n is 1; And

C) meanwhile, be R wherein as A ₃For hydrogen＞CHR ₃, Z is-CH ₂-, n is 1 and R ₂For R ' wherein as defined above-COOR ' time, then R and R at least ₁The two one of be not hydrogen.

Above-mentioned collateral condition a) has got rid of from the formula I wherein that n is 0, and Z is-compound of S-, this compound can not obtain according to methods described herein.Collateral condition (b) has been got rid of United States Patent (USP) 4510149 and 4602022 described compounds; Collateral condition c) then got rid of the described compound of E.P.-A-135177.

The present invention also comprises whole possible isomer, steric isomer and their mixture and metabolite and the metabolic precursor thereof or the bioprecursor of formula I compound.

C _1-6Alkyl or C _1-5Alkyl is with C _1-4Alkyl is good, is good with methyl, ethyl, propyl group and sec.-propyl especially, with methyl and ethyl for better.Substituent R ₂Can be connected with any carbon atom of phenyl.

The pharmaceutical salts of The compounds of this invention comprise with such as nitric acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, perchloric acid and phosphoric acid mineral acid or such as acetate, propionic acid, glycolic acid, lactic acid, oxalic acid, propanedioic acid, oxysuccinic acid, toxilic acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid and Whitfield's ointment the formed acid addition salt of organic acid and with such as the alkali gold

Belong to, especially sodium or potassium or alkaline-earth metal, especially calcium or magnesium and so on mineral alkali or with such as alkylamine, with triethylamine be good the formed salt of organic bases.

As mentioned above, the present invention also comprises the medicinal organism precursor (can also be called prodrug) of formula I compound, and promptly but its molecular formula is different from above-mentioned formula I just can be converted into the formula I compound in vivo directly or indirectly in case be applied to human body.Preferred The compounds of this invention is formula I compound and the pharmaceutical salts thereof that meets above-mentioned supplementary condition, in the formula

A is R wherein ₃Be C _1-4Alkyl 〉=CR ₃Or＞CHR ₃Group, or R wherein ₄Be hydrogen or C _1-4Group＞the C=CHR of alkyl ₄;

Z is-CH ₂-,-O-or-S-;

N is 0 or 1;

R and R ₁Be hydrogen;

R ₂For-COCH ₂OH ,-CH ₂OR ' ,-COOR ' ,-CONR ' R " or-CH=CH-COOR ', wherein R ' and R " are respectively hydrogen or C separately _1-4Alkyl.

More preferred The compounds of this invention is for meeting above-mentioned formula I compound provisory and pharmaceutical salts thereof, in the formula

A is R wherein ₃Be C _1-4Group 〉=the CR of alkyl ₃Or＞C=CH ₂;

Z is-CH ₂-;

N is 0 or 1;

R and R ₁Be hydrogen;

R ₂For R ' wherein is hydrogen or C _1-4Alkyl-COOR ' or-CONH ₂

The preferred embodiment of formula I compound is as described below:

5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene-carboxylic acid;

5,6-dihydro-8-ethyl-7-(1H-imidazoles-1-yl)-2-naphthalene-carboxylic acid;

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid;

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid;

5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid ethyl ester;

5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene-Carboxylamide;

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid ethyl ester;

5,6-dihydro-8-ethyl-7-(1H-imidazoles-1-ylmethyl)-the 2-naphthalene monocarboxylic acid; And 7,8-dihydro-6-(1H-imidazoles-1-ylmethyl)-5-methyl-2-naphthalene monocarboxylic acid; And pharmaceutical salts.

Compound of the present invention and its esters can prepare by following method, comprising:

Thereby A is 〉=C-R a) to make formula II compound generation β-elimination reaction obtain wherein ₃Group, R ₃Formula I compound as defined above

R, R in the formula ₁, R ₂, R ₃, n and Z as above limits and M represents hydrogen or acyl group; Or

B) thus the formula III compound is carried out the alkylidene group processing obtains wherein that A is group＞C=CR ₄R ₅, R ₄And R ₅Equal formula I compounds as defined above

R, R in the formula ₁, R ₂, Z and n all as above limit; Or

C) thus reduction formula IV compound obtains wherein A is＞CHR ₃Group, R ₃Formula I compound as defined above

R, R in the formula ₁, R ₂, R ₃, n and Z all as above limit; Or

D) make formula (V) thus compound isomerizate obtains wherein that A is group 〉=CR ₃, R ₃Be C _1-6The formula I compound of alkyl

R, R in the formula ₁, R ₂, n and Z as above limit R ₄And R ₅The two one of be hydrogen or C _1-5Alkyl, another then is a hydrogen; Wherein when n was 0, Z was-CH ₂-or-O-, and when n was 1, Z was-CH ₂-,-O-or-S-; Necessary words, the formula I compound is converted into another formula I compound, and/or, necessary, the formula I compound is converted into its pharmaceutical salts, and/or, necessary, salt is converted into free cpds, and/or, necessary, the isomer mixture of formula I compound is separated into individual isomer.

When the M in the formula II compound was acyl group, for instance, it can be C _2-4Carboxylic acyl radical, especially ethanoyl, or methylsulfonyl or tosyl group.β-the elimination reaction of the formula II compound that aforesaid method is mentioned in a) can about 50 ℃ to the scope of reflux temperature, in the presence of organic solvent suitable such as Glacial acetic acid, acetic anhydride-pyridine mixtures, dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) (DMSO) or benzene, at suitable consumption or even catalytic amount strong acid such as dense H ₂SO ₄, HCl or tosic acid carry out under existing.By concentrated acid for example in hydrochloric acid, trifluoroacetic acid or the Hydrogen bromide backflow formula II compound can finish this conversion process equally.When the M in the formula II compound be acyl group, especially during ethanoyl, can also be by in about 200～300 ℃ of these preferred range, finishing this reaction through pyrolysis.

The alkylene glycosylation reaction of formula III compound is that olefination can be finished by currently known methods such as Witting reaction or Horner-Emmons reaction.For instance, the formula III compound can react with formula VI De phosphonium salt

R in the formula ₄And R ₅As above limit; Q is aryl, especially phenyl; Hal is a halogen, is good with iodine or bromine.

The reaction of formula III compound and formula VI compound can be such as C _1-6Lithium alkylide, being good with butyllithium, phenyl lithium, sodium alkoxide or potassium alcoholate, is good with potassium tert.-butoxide, and sodium amide or sodium hydride and so on strong basicity reagent carries out under existing.This reaction can be in about-60～90 ℃ this preferred range such as tetrahydrofuran (THF), diox, dimethyl sulfoxide (DMSO), N, carry out in the suitable organic solvent of dinethylformamide, benzene or low-level chain triacontanol and so on.

In addition, the formula III compound can also react with the phosphoric acid ester of formula (VII)

R wherein ₂And R ₃As above limit; R ₅, for instance, be C _1-6Alkyl, be good with methyl or ethyl, or phenyl.

The reaction of formula II compound and formula (VII) compound can be according to carrying out with the reactions steps of formula II compound and formula VI compound.For instance, by such as palladium, platinum, PtO ₂, the suitable catalyzer of ruthenium or Raney nickel and so on exists down among suitable organic solvent, be good to be selected from low-level chain triacontanol, for example methyl alcohol or ethanol, hydrochloric acid, acetate, hexanaphthene, normal hexane, ethyl acetate, benzene, toluene or their mixture, normal atmosphere to about 30 atmospheric pressure ranges and room temperature just can be to about 100 ℃ temperature range according to method c through shortening) thereby reduction formula IV compound obtains the formula I compound.Adopt currently known methods, for example by among strong organic acid such as trifluoroacetic acid or tosic acid or at mineral acid such as sulfuric acid or such as AlCl ₃And so on heating just can be according to method d among the Lewis acid) make formula (V) thus compound isomerizate obtains the formula I compound.Can in about 60～120 ℃ of these preferred range, carry out this reaction as solvent or among being selected from the organic solvent of for example benzene, toluene or acetate by using identical acid.

Necessary, the formula I compound can be converted into another formula I compound.

Can finish these by currently known methods and look particular case and the conversion process of carrying out.

By to about 100 ℃ temperature range, the formula I compound that contains esterifying carboxyl group being converted into the formula I compound that contains free carboxy through acidolysis or alkaline hydrolysis in room temperature.

By esterification, for example by corresponding carboxylic acid halides (for example chlorine), subsequently with excessive suitable C _1-6Alkyl alcohol reacts or passes through by an acidic catalyst promptly at dry HCl or SOCl ₂Or BF ₃Carry out direct esterification under-etherate exists and the formula I compound that contains free carboxy can be converted into the formula I compound that contains esterifying carboxyl group.In The suitable solvent such as water by hydrolysis, be good or with acidolysis by using NaNO ₂With strong inorganic acid be H ₂SO ₄The aqueous solution is handled and the formula I compound that contains formamyl can be converted into the formula I compound that contains free carboxy, and its operating temperature range is room temperature～100 ℃.

The formula I compound that contains free or esterifying carboxyl group can be converted into and contain group

, R ' and R " formula I compound as defined above.

Therefore, esterifying carboxyl group is converted into the process of corresponding amide can be by directly reacting with ammonia or suitable amine in the aprotonic solvent such as ether or benzene or by adopting excessive amine to finish as solvent, its operating temperature range is that room temperature is to reflux temperature suitable.

Free carboxy is converted into the process of corresponding amide can be by carrying out by intermediate reaction derivative separated or can not be separated.

The intermediate reaction derivative can be such as NO ₂-phenylester or N-hydroxy-succinamide ester and so on active ester, carboxylic acid halides (is good with chlorine), mixed anhydride such as ethoxycarbonyl or tertiary butyl carbonyl acid anhydrides, or by the sour reaction intermediate that obtains on the spot with dicyclohexyl carbodiimide or carbonyl dimidazoles reaction.As the compound that is generally used for synthetic peptide, the reaction intermediate that obtains according to traditional method is reacting in The suitable solvent or with excessive amine itself with ammonia or suitable amine approximately-10～50 ℃ down.

By traditional method of reducing, to adopt Li Al H ₄In The suitable solvent is good wherein R among ether or the tetrahydrofuran (THF) for example ₂For the formula I compound of free or esterifying carboxyl group, especially rudimentary alcoxyl carboxyl is converted into wherein R ₂For-CH ₂The formula I compound of OH group.

Not only the looking particular case of formula I compound and the salification process of carrying out but also also have by salt and be converted into free cpds and the process that isomer mixture is separated into individual isomer can be undertaken by traditional method.

For instance, geometrical isomer, for example the sepn process of the mixture of cis and trans-isomer(ide) can be by carrying out by fractional crystallization in the suitable solvent or by column chromatography or high pressure lipuid chromatography (HPLC).

By reduce wherein Z, R, R according to known method ₁, R ₂With n formula III compound as defined above, for example, by using such as NaBH ₄And so on alkali metal borohydride in such as methyl alcohol or ethanol or water/alcohol mixture, handling in the suitable solvent, perhaps by with Li Al H ₄In anhydrous solvent such as ether or tetrahydrofuran (THF), handle and prepare wherein M and R ₃Be the formula II compound of hydrogen, in these two kinds of processing modes, the temperature range value is good with 0 ℃～reflux temperature, and the reaction times is about 1～6 hour

By making formula III compound and wherein R as defined above ₃Be C _1-6Alkyl, X are the formula R of halogen atom, especially chlorine or bromine ₃The reaction of-Mg-X compound can obtain wherein, and M is hydrogen, R ₃Be C _1-6The formula II compound of alkyl.This reaction can be carried out according to known green reaction step, for example approximately-78 ℃ to the scope of reflux temperature, ℃ to be good approximately-10～30, operation is about 1～6 hour in anhydrous solvent suitable such as ether or tetrahydrofuran (THF).

Can adopt currently known methods; for example by to make M wherein be formula II compound and the suitable acyl group of hydrogen or alkylsulfonyl halogen (is good with chlorine) (for example Acetyl Chloride 98Min. or toluene sulfonyl chloride or methylsulfonyl chloride) at anhydrous pyridine or such as dry-out benzene among the inert solvent, necessary words are at the temperature range internal reaction of equimolar amount such as triethylamine in the presence of the alkali, in about room temperature to 60 ℃, can preparing wherein, M is the above-mentioned formula II compound of acyl group.In addition, by making wherein R, R ₁, R ₂, R ₃With Z as defined above formula (VIII) compound and imidazoles or its salt (is good with an alkali metal salt or silver salt such as sodium or potassium) reaction can to obtain wherein M be that hydrogen, n are 0 and R, R ₁, R ₂, R ₃With Z formula II compound as defined above.

This reaction is to carry out to good under one of following two kinds situation:

A) solvent-free existence, temperature range with room temperature to about 180 ℃ be good, the reaction times is several minutes extremely about 20 hours, in case of necessity, uses excessive imidazoles or its salt, perhaps

B) in the presence of The suitable solvent such as dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphine triamide, toluene, benzene, ethyl acetate, ethanol, diox or acetone, temperature range is good with about 0 ℃ to reflux temperature, and the reaction times is that several minutes was to about 12 hours.

Wherein n be 0 formula III compound be known compound or can be according to such as J.Het.Chem.(1984), 21; 311; J.Het.Chem.(1985) 22,441 and J.Med.Chem.(1986), 26,404 described and so on currently known methods preparations.

Wherein n be 1 formula III compound can be according to currently known methods, for example make wherein R, R by comprising ₁, R ₂The method preparation of formula IX mannich base that as above limit with Z, X is chlorine or bromine and imidazoles reaction.

This reaction can be at water or water one alcohol mixture, with water-ethanol or water one carbinol mixture in for good, carry out to reflux temperature in room temperature.Formula (IX) mannich base can be according to such as " synthetic learn " (1984), currently known methods preparation described in 604 and so on.

The formula IV compound is group 〉=CR for A wherein ₃Formula I compound of the present invention and can a) prepare by aforesaid method.

Formula (V) compound for A wherein is＞C=CR ₄R ₅The formula I compound of the present invention of group and can preparing by aforesaid method (b).

Therefore, according to method c) reduction formula IV compound with according to method d) formula (V) compound is carried out isomerization handle all can be considered and look particular case the formula I compound is converted into another kind of formula I examples for compounds.Formula (VIII) compound can be known compound or can obtain by well-known method such as epoxidation formula (X) compound

R, R in the formula ₁, R ₂, R ₃As above limit with Z.

This reaction is finished to good to take one of following dual mode:

A) adopt superoxide suitable such as hydrogen peroxide or such as peracetic acid or metachloroperbenzoic acid suitable peracid in The suitable solvent such as water or acetate at 0 ℃ of processing formula (X) compound to the temperature range of room temperature, the reaction times is several minutes to 20 hour; Or

B) adopt halogen, with bromine be good or N-halo succinimide, with N-bromosuccinimide be good at catalytic amount such as potassium hydroxide in the presence of alkali or all example hydrochloric acids and so on acid, in The suitable solvent such as water or tetrahydrofuran (THF) or water one tetrahydrofuran compound in 0 ℃ of processing formula (X) compound to the scope of reflux temperature, last 1～20 hour, and use alkali suitable such as sodium methylate in to reflow temperature range, handling resulting halohydrin crude product in room temperature among The suitable solvent such as the methyl alcohol, last 1～12 hour.

Formula VI, (VII) and (X) are known compound and can prepare by well-known method in the organic chemistry.When in The compounds of this invention and intermediate product thereof, being present in the group that needs protection between the above-mentioned reaction period, can before taking place, reaction protect these groups with ordinary method, remove protection according to known method after question response is finished subsequently.

Pharmacology

We find that formula I compound and pharmaceutical salts thereof are thromboxan A ₂(TxA ₂) the synthetic selective depressant, thereby be applicable to that treatment especially with in the mammalian body that comprises the mankind promotes TxA ₂Synthetic diseases associated.

For instance, in glass test tube, measure the formula I compound and suppress TxA in the mouse body ₂The activity of synthase is (by the TxB that produces in whole blood at duration of coagulation ₂Reflect).

Method

The representational compound of the present invention is to TxB ₂The synthetic effect that is produced can by with the whole blood of common Sprague Dawley mouse (Charles River, Italy) in known products relatively recently assess.Extract blood in the aorta abdominalis by animal under slight etherization condition.Immediately blood is divided into the mass part that is respectively 0.5ml and they are allocated in the glass test tube that contains finite concentration test compound or control compounds separately.

Make sample in 37 ℃ of following grumeleuses 1 hour then, with 3000 rev/mins by centrifugation 10 minutes, collect serum and it be stored under-20 ℃ till measuring.(Thromb.Res.17,3/4,317,1980) adopt hypersensitivity antibody to measure TxB by RIA according to the method described above ₂Level.

Under tabulate and 1 show that The compounds of this invention can suppress TxA significantly in whole blood ₂Synthetic.

The table I

In glass test tube to the intravital TxB of normal mice ₂The synthetic effect that is produced.Data IC ₅₀(M) represent and be limited to p=0.95

Compound I C(M) limit

FCE25672 2.9×10M （1.2-5.4×10）

FCE26333 4.3×10M （1.2-10×10）

FCE26252 7.4 * 10M (not calculating)

FCE22178 1.0×10M （0.56-1.6×10）

ASA 3.1×10M （2.6-3.8×10）

FCE25672 represents 5 in the table, 6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid;

FCE26333 represents 5 in the table, 6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid;

FCE26252 represents 5,6,7 in the table, 8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-8-methylene radical-2-naphthalene monocarboxylic acid;

FCE22178 represents 5 in the table, 6-dihydro-7-(1H-imidazoles-1-yl)-the 2-naphthalene monocarboxylic acid, it is disclosed in United States Patent (USP) 4510149 and is the thromboxan synthetic inhibitor;

Acetylsalicylic acid (ASA) is the cyclooxigenase inhibitor.

Can suppress TxA selectively ₂The The compounds of this invention that forms for instance, at all thrombosis, on every side under the situation of vasculopaties and coronary artery disease, all can be used as vasodilator and antithrombotics.In fact, to TxA ₂Formation and vasoconstrictive possibility that the restraining effect that generates can reduce thrombus are attended by local asphyxia simultaneously, cause PGI ₂Growing amount constant (or increase), so just improved vasorelaxation, tissue blood supply and protected blood vessel wall.

Another purposes of The compounds of this invention is the treatment migraine.For instance, just as is known, under migrainous situation, show by platelet T xA ₂The superfluous diffustivity vasoconstriction that is caused of generation [J.Clin.Pathol.(1971), 24,250; J.Headache(1977) 17,101].Confirmed TxA in the diabetes already ₂With the MDA(mda) thrombocyte generate superfluous relevant with ill microcirculation defective [Metabolism(1979) 28,394; Eu.J.Chin.Inuest.(1979) 9,223; Thrombosis Haemost.(1979), 42,983; J.Lab.Clin.Med.(1981) 97,87].Therefore, for instance, compound of the present invention can be used for treating diabetes, especially diabetic subject's microangiopathy.

In addition, The compounds of this invention can also be to be used as antiphlogistic.For instance, just as known, eicosatetraenoic acid can be converted into TxA in glass test tube by the fluid that granuloma produced that causes because of carrageenin ₂, TxA ₂The liquid of quantity inflammation in the mouse body that the neutralization of the synovia of patient with rheumatoid arthritis is caused by carrageenin in increase to some extent [Prostaglandis(1977), 13,17; Scand.J.Rheum.

（1977），6，151]。Confirmed TxA recently already ₂Excessive generation relevant with hypertensive pathogenesis, therefore, specific TxA ₂Formation inhibitor can be used to treat hypertension [Eu.J.Pharmacol.(1981), 70,247].

In fact, compound of the present invention can be used as depressor.

For instance, it is reported, in the vascular hypertension that pregnancy causes, TxA ₂Synthetic increasing to some extent and prostacyclin is synthetic descends to some extent [Am.J.Obstet:Gynecol.(1987), 157,325, hypertension (1988), 11,550].Therefore, adopt this class disease of thromboxane synthetase inhibitor appropriate therapeutic.

In addition, shown already because TxA ₂In the pathogeny of stomach ulcer, play a part to make the stomach blood vessel to shrink forcefully, therefore, also can use TxA in the field ₂Inhibitor.[Nature（1981），202，472]。In fact, The compounds of this invention can be used to treat stomach ulcer.

The compounds of this invention also can be used as antitumour drug.For instance, as known content, suppress TxA selectively ₂Synthesize and confirmed to reduce the number of pulmonary metastases and the growth of tumor speed that slows down [nature (1982), 295,188] already.

Consider TxA ₂Dependency between synthetic and calcium shifts, some author points out TxA specific such as The compounds of this invention recently ₂Synthetase inhibitors also can be used to treatment osteoporosis [prostaglandin(PG) (1981), 21,401] such as postclimacteric osteoporosis.

In addition, The compounds of this invention can be used to the in heart failure and heart hinge pain of treatment.

In this respect, for instance, as known content, in patient [prostaglandin(PG) and the medical science (1979) of suffering from Prinzmetal heart hinge pain disease, 2,243] show effect in patient's body with recurrent heart hinge pain [in October, 1980, AbsN ° 140 for the 6th thrombus international conference, Monte carlo] can find high-load TxB ₂

Can according to Born and Silver improve one's methods in body and glass test tube in assess the thrombocyte anti-freezing of The compounds of this invention poly-active [Born.G.V.R., nature 194,927(1962)] and [Silver M.J., science 183,1085(1974)].

Have found that, compound of the present invention in glass test tube to by collagen protein or ADP(adenosine-5 in the thrombocyte enrichment blood plasma of cavy '-bisphosphate) platelet aggregation that causes possesses and suppresses active [Dunkin Hantley Iva:PDH(SPF) Ivanouas Gm BH, Germany].

Therefore, during The compounds of this invention can be used to prevent or reduces extracorporeal circulation, for example carry out thrombocyte loss during operation of coronary bypass-forming operation and graft or the kidney dialysis.

In addition, also find, such as endotoxin shock with go out that the circulation shock is attended by TxA the sanguinin shock ₂Synthetic increases, thereby makes The compounds of this invention be applicable to these diseases of treatment.In addition, The compounds of this invention is applicable to that also the segmental bronchus of treatment asthma reacted strong disease.

Can be according to the active deduction of its bronchoconstriction in experimental animal model TxA ₂Role in asthma [Br.J.Pharmacol.(1984), 82(3) 565].Inhibition activity for the bronchospasm that is caused by thrombocyte activation factor (PAF) in the mouse body reports equally to some extent, for example the described TxA of English Patent No.2205494 ₂Synthetase inhibitors.

Compound of the present invention can also be used for the treatment of such as the ephrosis of glomerulonephritis, diabetic nephropathy or systemic lupus erythematosus (SLE) secondary ephrosis and can be used for preventing and treating the ephrosis that Cyclosporin A causes.Therefore, The compounds of this invention can also be used to prevent and treat gestation time toxicaemia, typically be preeclampsia, eclampsia and preeclampsia (puerperal eclampsia, cause convulsions) toxicaemia.

Recently, TxA in the confirmation kidney in immunity and the different animals model of non-immunity injury of the kidney and human body ₂Synthetic improves with the chronic glomerulus disease definite dependency [J.Clin.Invest.(1985) 75,94, J.Clin.Invest.(1985), 76,1011].

Therefore, for instance, TxA has been described recently in English Patent No.2205240 ₂Synthetase inhibitors, it possesses the activity that reduces proteinuria and creatinine serum amount in the nephrosis that mouse body internal cause doxorubicin causes and reduces in the normotensive race of Milan (MNS) the mouse body albuminuretic activity in the spontaneous focus glomerulosclerosis and improve in the case glomerular filtration speed.

Compound of the present invention also can be used to suppress the transplant rejection of kidney and heart.In fact, after transplanting, to TxB in people and the mouse urine ₂Movement or whole blood TxA ₂The synthetic increase all to some extent the report [Lancet(1981), ii, 431; Transplantation (1987) 43,346].

Another purposes of The compounds of this invention is the treatment hyperlipidemia, i.e. hypercholesterolemia and be secondary to the hypertriglyceridemia disease of nephrotic syndrome.

Hyperlipidemia is the general feature [New England's medical science impurity (1983) 312(24) 1544] of human body nephrotic syndrome, in addition, in the animal model such as suffering from the nephrotic syndrome that doxorubuin causes, can be observed triglyceride and cholesteric concentration increase to some extent [Expt.Mol.Pathology(1983), 39,282]; The increase of albumin excretion makes the people associate pathogenesis [Kidney International(1987), 32,813] in the urine.Recently, in English Patent No.2205240, also disclosed Tx A synthetase inhibitors, for example, it is proved and is possessing activity aspect the intravital triglyceride of mouse that reduces aged Milan blood pressure intravital cholesterol of normal ethnic mouse and three acid glycerols and reduction process doxorubicin processing.

Showed equally already that in through the cholesteric rabbit body of throwing something and feeding, as cause atherosclerotic animal model by diet, eicosatetraenoic acid metabolism was an important factor in the lesion development in early days.Especially in metabolic processes, take place by TxA ₂To PGE ₂Transfer the time, can be in the hypercholesterolemia disease suppress the development (being atheromatous plaque) of infringement.

So the present invention can be used to these pathology.

Compound of the present invention can also follow thrombolytic agent (for example tPA, streptokinase, uPA) to be used jointly so that reduce the latter required dosage and reduction generation recurrent locking disease and hemorrhage possibility in the thrombolytic treatment process.

The toxicity of The compounds of this invention can be ignored, thereby can be used for the treatment of process safely.With The compounds of this invention with escalated dose oral administration applied once in mouse that stopped eating 9 hours and rat, put back to subsequently in the cage and to recover normal feeding.Assessed in the 7th day after treatment and locate acute toxicity (LD ₅₀), for instance, in the compound that the form with FCE26572 is added into, be higher than 800mg/kg.

In view of their high therapeutic index, The compounds of this invention can be used for medicine safely.

The treatment system that is applicable to different clinical syndromes must be considered pathological type, generally also will consider route of administration, administration form and curee's age, body weight and symptom.In general, oral administration route is applicable to the symptom that all need this compounds.It is good treating acute disease in the mode of selecting intravenous injection for use or inculcate.

For keeping treatment plan, to select for use oral or parenterai administration, for example intramuscular injection is for good.

Be applicable to the oral The compounds of this invention of grownup for example 5,6-dihydro-7-(1H-imidazoles-1-yl)-dosage of 8-methyl-2-naphthalene monocarboxylic acid is about 50～500mg by taking 1～3 every dose of every day.

Certainly, can regulate these dosage so that optimum therapeuticing effect is provided.

Certainly, the characteristic that contains the medicinal compositions of The compounds of this invention and pharmaceutical carrier or thinner will depend on required route of administration.Said composition can be prepared with general component in a conventional manner.For instance, The compounds of this invention can water or the form of oil solution, suspension, tablet, pill, capsule, syrup, drops or suppository be applied.

Therefore, for oral administration, the medicinal compositions that contains The compounds of this invention is with tablet, pill or capsule are good, wherein contain active substance with such as lactose, glucose, sucrose, mannitol, Sorbitol Powder, the thinner of Mierocrystalline cellulose and so on, such as silicon-dioxide, talcum, stearic acid, the lubricant of Magnesium Stearate or calcium and/or polyoxyethylene glycol and so on, they can also contain tackiness agent such as starch, gelatin, methylcellulose gum, carboxymethyl cellulose, Sudan Gum-arabic, tragacanth gum, Polyvinylpyrolidone (PVP), depolymerizing agent such as starch, alginic acid, alginate, sodium starch glycollate, effervescent mixture, dyestuff, sweetener, wetting agent such as Yelkin TTS, polyethoxy ether ether lauryl sulfate ester, and the common non-toxicity and the pharmacology inactive substance that are used for medicinal compositions.Described pharmaceutical preparation can be according to currently known methods, for example by mixing, and method manufacturings such as granulation, compressing tablet, parcel sugar-coat or coating rete.For instance, the liquid oral dispersion agent can be syrup, emulsion and suspension.

Syrup can contain carrier such as sucrose or sucrose and glycerine and/or mannitol and/or Sorbitol Powder.Suspension and emulsion can contain carrier such as natural gum, agar, sodiun alginate, pectin, methylcellulose gum, carboxymethyl cellulose or polyvinyl alcohol.

The suspension or the solution that are used for intramuscularly can contain active compound and pharmaceutical carrier such as sterilized water, sweet oil, ethyl oleate, glycol such as propylene glycol, and is necessary, can also contain an amount of lidocaine.The solution that is used for intravenous injection or inculcates can contain the carrier such as sterilized water, and it is good oozing sterile saline solution with grade.

Suppository can contain active compound and pharmaceutical carrier such as theobroma oil, polyoxyethylene glycol, polyoxyethylene sorbitan fatty acid esters tensio-active agent or Yelkin TTS.

The following example still is not construed as limiting it for the usefulness of describing the present invention.

Embodiment 1

With 5,6,7,8-tetrahydrochysene-8-hydroxyl-8-methyl-7-(1H-imidazoles-1-yl)-solution that 2-naphthalene monocarboxylic acid (4g) forms in the Glacial acetic acid (50ml) and the vitriol oil (12ml) was heated to 80 ℃ through 4 hours.

After the cooling, reaction mixture is inclined to the 100ml frozen water, with ammonium hydroxide neutralization and use ethyl acetate extraction.With the dried over sodium sulfate organic layer and be evaporated to drying.Resulting crude product is placed in silica gel (eluant CHCl ₃: CH ₃OH=90: 10) enterprising circumstances in which people get things ready for a trip spectrum is separated, and obtains 3.7g 5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid, m.p.241～243 ℃ (decomposition).

C ₁₅H ₁₄N ₂O ₂Ultimate analysis

Measured value C 70.52; H 5.65; N 10.84

Theoretical value C 70.85; H 5.54; N 11.01

N.M.R.（DMSO-d ₆）ppm

1.97（3H，t，CH ₃）2.50～3.21（4H，m，CH ₂-CH ₂）

7.00～8.00(6H, m, phenyl and imidazoles)

Similarly, can prepare following compounds:

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-and 8-methyl-2-naphthalene monocarboxylic acid, m.p.278～280 ℃.

C ₁₆H ₁₆N ₂O ₂Ultimate analysis

Measured value C 70.05; H 5.98; N 10.39

Theoretical value C 71.62; H 6.01; N 10.44;

5,6-dihydro-8-ethyl-7-(1H-imidazoles-1-yl)-the 2-naphthalene monocarboxylic acid;

3-(1H-imidazoles-1-ylmethyl)-4-methyl-2H-1-benzo thiapyran-6-carboxylic acid;

3-(1H-imidazoles-1-ylmethyl)-4-ethyl-2H-1-chromene-6-carboxylic acid.

Embodiment 2

With 1.9g 5,6-dihydro-7,8-epoxy group(ing)-8-methyl-2-naphthalene monocarboxylic acid is (by epoxidation 5,6-dihydro-8-methyl-2-naphthalene monocarboxylic acid preparation, m.p.150～153 ℃) solution in dry DMF adds to by in the formulated imidazoles potassium salt soln of 3.16g imidazoles and 1.81g potassium and dry DMF (100ml) and in 130 ℃ of following vigorous stirring limits heating, lasts 6 hours.Solvent evaporated under reduced pressure and with resistates in the water-soluble and ethyl acetate.Separate water layer and it is acidified to PH=5 with acetate.Remove water under reduced pressure, (eluant CHCl on silica gel ₃: CH ₃OH=70: 30) the chromatographic separation resistates obtains 1.6g 5,6,7,8-tetrahydrochysene-8-hydroxyl-8-methyl-7-(1H-imidazoles-1-yl)-the 2-naphthalene monocarboxylic acid.

Embodiment 3

Original pressure be in the Parr-Burgess low-voltage device of 50psi under room temperature to by 5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid (1.5g), 10% palladium/gac (0.65g), alcohol 95 %(100%), the mixture formed of Glacial acetic acid (30ml) and concentrated hydrochloric acid (10ml) carried out hydrotreatment 8 hours.

When to be finished, absorbed hydrogen amount reaches theoretical value.

Filtration catalizer is used 95% washing with alcohol, reduction vaporization solution.Solid residue crystallization in 95% alcohol-ether mixture produces 1.4g 5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid hydrochloride.

Similarly, can make following compounds:

5,6,7,8-tetrahydrochysene-8-ethyl-7-(1H-imidazoles-1-yl)-2-naphthalene monocarboxylic acid hydrochloride;

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid hydrochloride; With

3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-4-methyl-2H-1-benzo thiapyran-6-carboxylic acid hydrochloride.

Treat after the over-stoichiometric sodium bicarbonate is handled, can make following compounds:

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid m.p.283～285 ℃

T.L.C. eluant CHCl ₃: CH ₃OH: CH ₃COOH=85: 15: 0.5

Rf＝0.36

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid m.p.259～261 ℃.

Embodiment 4

Will be by 3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-solution that 4-hydroxyl-2H-1-chromene-6-carboxylic acid (3.0g) forms in the Glacial acetic acid (60ml) and the vitriol oil (30ml) is 80 ℃ of heating 3 hours down.After the cooling, reaction mixture is inclined to trash ice, with ammonium hydroxide neutralization and use dichloromethane extraction.Be evaporated to drying with the dried over sodium sulfate organic layer and with it.Handle resulting resistates with ether, obtain 1.5g 3-(1H-imidazoles-1-ylmethyl)-2H-1-chromene-6-carboxylic acid m.p.258～259 ℃.

Ultimate analysis

Measured value C 65.58; H 4.70; N 10.96

C ₁₄H ₁₂N ₂O ₃

Calculated value C 65.62; H 4.72; N 10.93.

N.M.R.（CF ₃COOD）ppm：

4.91(2H, S, CH ₂N), 5.06(2H, S, OCH ₂) 6.68(1H, wide S, H-4), 6.98～8.80(6H, m, phenyl and imidazoles).

Similarly, can prepare following compounds:

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-2-naphthalene monocarboxylic acid m.p.298～300 ℃.

Ultimate analysis

Measured value C 70.70; H 5.55; N 10.98

C ₁₅H ₁₄N ₂O ₂

Calculated value C 70.90; H 5.51; N 11.00.

TLC: eluant CHCl ₃: CH ₃OH: CH ₃COOH=100: 45: 5Rf=0.67

N.M.R.（DMSO-d）δppm：

2.27(2H, t, CH ₂CH-=CH), 2.91(2H, t, CH ₂-CH ₂C=CH) 5.07(2H, S, CH ₂N), 6.56(1H, S ,-HC=C-CH ₂CH ₂), 7.24～9.22(6H, m, phenyl and imidazoles).

3-(1H-imidazoles-1-ylmethyl)-2H-1-benzo thiapyran-6-carboxylic acid;

3-(1H-imidazoles-1-ylmethyl)-2-methyl-2H-1-benzo thiapyran-6-carboxylic acid;

Ultimate analysis

Measured value C 63.4; H 4.90; N 9.85; S 11.40

C ₁₅H ₁₄N ₂O ₂S

Calculated value C 62.92; H 4.93; N 9.78; S 11.20

TLC: eluant CH ₂Cl ₂: CH ₃OH: CH ₃COOH=80: 20: 0.5 Rf=0.45

N.M.R.（DMSO-d ₆）δppm：

1.04(d, 3H); 3.5(q, 1H); 4.87(wide S, 2H); 6.43(wide S, 1H); 6.95(dd, 1H); 7.22(dd, 1H); 7.35(dd, 1H); 7.6～7.8(m, 3H);

3-(1H-imidazoles-1-ylmethyl)-2-methyl-2H-1-chromene-6-carboxylic acid;

3-(1H-imidazoles-1-ylmethyl)-2H-1-benzo thiapyran-6-carboxylic acid, ethyl ester;

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-2-naphthalene monocarboxylic acid ethyl ester; With

3-(1H-imidazoles-1-ylmethyl)-2H-1-benzo thiapyran-6-methyl alcohol.

The front used 3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-4-hydroxyl-2H-1-chromene-6-carboxylic acid is prepared as follows:

In 10～15 ℃ with NaBH ₄(4.2g adds to 3 in batches, 4-dihydro-3-(1H-imidazoles-1-ylmethyl)-4-oxygen-2H-1-chromene-6-carboxylic acid (10g) is in the solution of methyl alcohol (500ml).After stirring 2 hours under the room temperature, water (600ml) added in this mixture and with hydrochloric acid neutralize.Use CHCl ₃Extract this solution, dry organic solvent is evaporated to drying, obtains 6.6g 3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-4-hydroxyl-2H-1-chromene-6-carboxylic acid.M.p.265 ℃ (decomposition).

Ultimate analysis

Measured value C 61.22; H 5.15; N 10.23

C ₁₄H ₁₄N ₂O ₄

Theoretical value C 61.30; H 5.14; N 10.21.

Use previously 3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-4-oxygen-2H-1-chromene-6-carboxylic acid can be by corresponding mannich base hydrochloride (27.8g) [3,4-dihydro-3-N, N-dimethylamino methyl-4-oxygen-2H-1-chromene-6-carboxylic acid hydrochloride, p.f 200 ℃ (decomposition)] and imidazoles (66.2g) in water (280ml), make.This mixture is stirred 3 hours and is evaporated to drying under room temperature.Resistates obtains 20g 3,4-dihydro-3-(1H-imidazoles-1-ylmethyl after methyl alcohol-ether is handled)-4-oxygen-2H-1-chromene-6-carboxylic acid, m.p.205 ℃ (decomposition).

Ultimate analysis

Measured value C 61.58; H 4.45; N 10.31

C ₁₄H ₁₂N ₂O ₄

Theoretical value C 61.76; H 4.44; N 10.29.

Embodiment 5

Will be by 3-(1H-imidazoles-1-ylmethyl)-2H-1-chromene-6-carboxylic acid (0.6g), 10% palladium/gac (0.3g), alcohol 95 %(50ml), to place Parr-Burgess low pressure hydrogenator be to carry out hydrogenation under 50psi and the room temperature condition 7 hours in original pressure to the mixture formed of Glacial acetic acid (25ml) and concentrated hydrochloric acid (5ml).

During end, absorbed hydrogen reaches theoretical amount.

Filtration catalizer and make solution in down evaporation of decompression.

Handle solid residue with ethanol 99% and ether, obtain 0.6g 3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-2H-1-chromene-6-carboxylic acid hydrochloride, m.p.270 ℃ (decomposition).

Ultimate analysis

Measured value C 56.96; H 5.14; N 9.52; Cl 12.02

C ₁₄H ₁₅ClN ₂O ₃

Theoretical value C 57.05; H 5.13; N 9.50; Cl 11.98.

N.M.R.（DMSO-d ₆）δppm：

2.7(3H, m, CH-CH ₂) 3.8～4.5(4H, m, OCH ₂And NCH ₂), 6.84～7.7(5H, m, benzene H and NCHCHN), 9.25(1H, wide S, NCHN).

Similarly, can make following compounds:

3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-2H-1-benzo thiapyran-6-carboxylic acid hydrochloride;

3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-2-methyl-2H-1-benzo thiapyran-6-carboxylic acid hydrochloride; With

3,4-dihydro-3-(1H-imidazoles-1-ylmethyl)-2H-1-chromene-6-carboxylic acid, ethyl ester hydrochloride.

Embodiment 6

Under room temperature and under the drying nitrogen existence, while stirring iodate Jia base San Ben Phosphonium (5.68g) is added in the mixture of being made up of potassium tert.-butoxide (1.58g) and anhydrous tetrahydro furan (60ml) in batches.Stirred this mixture 30 minutes under room temperature, portion-wise addition is by 5,6,7 subsequently, 8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-solution that 8-oxygen-2-naphthalene monocarboxylic acid ethyl ester (2.0g) and anhydrous tetrahydro furan (60ml) are formed.Stirring is after 3 hours down in 40 ℃, and filter reaction mixture also is evaporated to drying.Resistates is dissolved in methylene dichloride, washes formed solution with water and use 8% hcl as extraction agent.Merge acid water layer, with sodium bicarbonate neutralization and use dichloromethane extraction.Use the dried over sodium sulfate organic layer, obtain solid residue, adopt methylene chloride-methanol (20: 1) eluant to carry out silica gel column chromatography and purify through evaporation.

Evaporation of eluate obtains 1.1g5 to dry, and 6,7,8-tetrachloro-7-(1H-imidazoles-1-yl)-8-methylene radical-2-naphthalene monocarboxylic acid ethyl ester.

Ultimate analysis

Measured value C 72.02; H 6.43; N 9.89

C ₁₇H ₁₈N ₂O ₂

Theoretical value C 72.32; H 6.42; N 9.92

N.M.R.（CDCl ₃）ppm：

1.41(3M, t, CH ₃), 2.2～2.5(2H, m, CH ₂-CH), 3.0(2H, m, CH ₂-phenyl), 4.40(2H, q, OCH ₂), 4.87(1H, d ,=CH), and 5.01(1H, m, CH-N), and 5.86(1H, d ,=CH), 6.95-8.36(6H, m, phenyl and imidazoles).

Similarly, can prepare following compounds:

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-8-methylene radical-2-naphthalene monocarboxylic acid tert-butyl ester;

5,6,7,8-tetrahydrochysene-8-ethylidene-7-(1H-imidazoles-1-yl)-2-naphthalene monocarboxylic acid ethyl ester;

5,6,7,8-tetrahydrochysene-8-ethylidene-7-(1H-imidazoles-1-ylmethyl)-the 2-naphthalene monocarboxylic acid tert-butyl ester and

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-ylmethyl)-8-methylene radical-2-naphthalene monocarboxylic acid tert-butyl ester.

Embodiment 7

Will be under reflux temperature, 8-tetrahydrochysene-7-(1H-imidazoles-1-yl) by 5,6,7-solution heating that 8-methylene radical-2-naphthalene monocarboxylic acid ethyl ester (0.46g), sodium hydroxide (0.8g), ethanol (40ml) and water (5ml) are formed 2 hours.Evaporate this solution, resistates is soluble in water, and solution is used dichloromethane extraction after the acetate acidifying.Use the dried over sodium sulfate organic layer, obtain 0.35g5 after the evaporation, 6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-8-methylene radical-2-naphthalene monocarboxylic acid.m.p.227～229℃。

Ultimate analysis

Measured value C 70.48; H 5.62; N 10.90

C ₁₅H ₁₄N ₂O ₂

Theoretical value C 70.85; H 5.55; N 11.01

N.M.R.（DMSO-d ₆）ppm：

2.25(2H, m, CH ₂-CH) 2.90(2H, m, CH ₂-

), 4.50(1H, d ,=CH), and 5.15(1H, dd, CHN), and 5.80(1H, d ,=CH), 6.92～8.20(6H, m, phenyl and imidazoles)

TLC: eluant CH ₂Cl ₂: CH ₃OH: CH ₃COOH=190: 20: 5Rf=0.45

Similarly, can prepare following compounds:

5,6,7,8-tetrahydrochysene-8-ethylidene-7-(1H-imidazoles-1-ylmethyl)-the 2-naphthalene monocarboxylic acid.

Ultimate analysis

Measured value C 71.96; H 6.39; N 9.88

C ₁₇H ₁₈N ₂O ₂

Theoretical value C 72.32; H 6.42; N 9.92

5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-ylmethyl)-8-methylene radical-2-naphthalene monocarboxylic acid; With

5,6,7,8-tetrahydrochysene-8-ethylidene-7-(1H-imidazoles-1-yl)-the 2-naphthalene monocarboxylic acid.

Embodiment 8

Will be by 5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-yl)-8-methylene radical-2-naphthalene monocarboxylic acid (2.1g) and the formed solution backflow of trifluoroacetic acid (100ml) 40 hours.After the cooling, remove solvent and resistates is soluble in water under reduced pressure.With rare NaOH alkalizing solution, use the acetate acidifying then.Leach precipitated solid, wash with water and drying, obtain 2.0g 5.6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid, m.p.241-243 ℃ (decomposition).

Similarly, can prepare following compounds:

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid;

5,6-dihydro-8-ethyl-7-(1H-imidazoles-1-yl)-the 2-naphthalene monocarboxylic acid.

Embodiment 9

To add to by the drips of solution that methyl iodide (1.3g) and anhydrous diethyl ether (6ml) are formed by among anhydrous magnesium (0.23g) and iodine crystal and the formed suspension of anhydrous diethyl ether (3ml).This mixture was refluxed 1 hour, subsequently it is cooled to room temperature.Will be by 5,6,7,8-tetrahydrochysene-7-(1H-imidazoles-1-ylmethyl)-8-oxygen-2-naphthalene monocarboxylic acid tert-butyl ester (1.0g) adds in this mixture with the drips of solution that anhydrous tetrahydro furan (25ml) is formed.After stirring 2 hours under the room temperature, this reaction mixture is poured in the water, with the dilute hydrochloric acid neutralization and use dichloromethane extraction.With the dried over sodium sulfate organic layer and make it be evaporated to drying.Resistates is dissolved in trifluoroacetic acid and refluxed 45 minutes.Make formed solution evaporation under the decompression, adopt methylene chloride-methanol-acetate (180: 20: 2) as eluant, by silica gel column chromatography purification resistates, obtain 0.6g 5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid m.p.278～280 ℃.

Ultimate analysis

Measured value C 71.01; H 5.99; N 10.40

C ₁₆H ₁₆N ₂O ₂

Theoretical value C 71.62; H 6.01; N 10.44

N.M.R.（DMSO-d ₆）ppm

2.05 （2H，m，CH ₂-CH ₂-C＝C）

2.20 （3H，s，CH ₃-C＝C）

2.70 （2H，m，CH ₂φ）

4.89 （2H，s，CH ₂N）

6.87～7.88(6H, m, phenyl and imidazoles)

TLC: eluant CH ₂Cl ₂: CH ₃OH: CH ₃COOH=190: 20: 5Rf=0.27

Similarly, can prepare following compounds:

5,6-dihydro-8-ethyl-7-(1H-imidazoles-1-ylmethyl)-and the 2-naphthalene monocarboxylic acid, m.p.257～260 ℃

Ultimate analysis

Measured value C 72.02; H 6.44; N 9.89

C ₁₇H ₁₈N ₂O ₂

Theoretical value C 72.32; H 6.42; N 9.92

N.M.R.（DMSO-d ₆）ppm：

1.07 （3H，t，CH ₃-CH ₂）

1.98 （2H，t，CH ₂-C＝）

2.65 （4H，m，CH ₂φ，CH ₂-CH ₃）

4.83 （2H，s，CH ₂N）

6.87～8.02(6H, m, phenyl and imidazoles)

7,8-dihydro-6-(1H-imidazoles-1-ylmethyl)-5-methyl-2-benzene carboxylic acid.

Embodiment 10

Under ice bath cooling, oxalyl chloride (0.37ml) is dropped to by dry-out benzene (25ml) and 5 6-dihydro-7-(1H-imidazoles-1-yl)-suspension that the 8-methyl-2-naphthalene monocarboxylic acid (0.5g) is formed among.

Stirred these reaction mixtures 2 hours in 8～10 ℃, make it under decompression, be evaporated to drying subsequently.Resistates is dissolved in the dry DMF (15ml).By stirring this solution and cooling formation in 5 hours gas NH in ice bath ₃Under decompression, make reaction mixture be evaporated to drying.In resistates, add 1N NaOH and use ethyl acetate extraction.

Use Na ₂SO ₄Dry organic phase, and filter, be evaporated to drying, use the ether dissolution resistates, obtain 5 after the filtration, 6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene Carboxylamide (0.24g) m.p.207～210 ℃.

Ultimate analysis

Measured value C 70.16; H 6.04; N 15.69

C ₁₅H ₁₅N ₃O ₄

Theoretical value C 71.12; H 5.96; N 16.58

TLC elutriant CHCl ₃: CH ₃OH(80: 20) Rf=0.53

N.M.R.（DMSO-d ₆）ppm：

1.95 （3H，t，CH ₃）

2.61 （2H，m，CH ₂-C＝）

2.98 （2H，t，CH ₂-φ）

7.03～8.01(8H, m, phenyl, imidazoles and CONH ₂)

Embodiment 11

With 5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid hydrochloride (0.5g) adds in the solution of being made up of hydrogenchloride and dehydrated alcohol (50ml).

In under 60 ℃ this reaction mixture being heated 3 hours and under decompression, making it be evaporated to drying.Use the ether dissolution resistates, obtain 5 after the filtration, 6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid carbethoxy hydrochloride (0.45g) m.p.202～203 ℃.

Ultimate analysis

Measured value C 62.89; H 6.02; N 8.45; Cl 10.73

C ₁₇H ₁₈N ₂O ₂

Theoretical value C 64.04; H 6.00; N 8.78; Cl 11.12

TLC elutriant CHCl ₃: CH ₃OH: CH ₃COOH(45: 5: 0.5) Rf=0.67

N.M.R.（DMSO-d ₆）ppm

1.32 （3H，t，COOCH ₂CH ₃）

1.98 （3H，t，CH ₃-C＝）

2.71 （2H，m，CH ₂-C＝）

3.08 （2H，t，CH ₂-φ）

4.32 （2H，q，COOCH ₂）

7.44～9.29(6H, m, phenyl and imidazoles)

Similarly, can prepare following compounds:

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid carbethoxy hydrochloride.

Through obtaining following compounds after the stoichiometric sodium bicarbonate processing

5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid ethyl ester;

5,6-dihydro-7-(1H-imidazoles-1-ylmethyl)-8-methyl-2-naphthalene monocarboxylic acid ethyl ester.

Embodiment 12

Handle by 5 6-dihydro-7-(1H-imidazoles-1-yl with 37% hydrochloric acid (0.2ml))-suspension that 8-methyl-2-naphthalene monocarboxylic acid (0.5g) and dehydrated alcohol (40ml) are formed, and add ether.

Leach precipitation and wash, obtain 0.41g 5,6-dihydro-7-(1H-imidazoles-1-yl with ether)-8-methyl-2-naphthalene monocarboxylic acid hydrochloride.

Embodiment 13

While stirring with 0.5g 5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid adds among the 39ml 0.05N NaOH, regulates the pH value of this solution till obtaining as clear as crystal solution with several 0.05N NaOH.

Make solution in the following evaporation of decompression and in 90 ℃ vacuum oven resistates, thereby obtain 5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid sodium salt.

Embodiment 14

Preparing every according to the following step heavily is 150mg and the tablet that contains the 50mg active substance:

Form (10000)

5,6-dihydro-7-(1H-imidazoles-1-yl)-8-

Methyl-2-naphthalene monocarboxylic acid 500g

Lactose 710g

W-Gum 237.5g

Talcum powder 37.5g

Magnesium Stearate 15g

Mix 5,6-dihydro-7-(1H-imidazoles-1-yl)-8-methyl-2-naphthalene monocarboxylic acid, lactose and half W-Gum; Making this mixture subsequently is the sieve of 0.5mm by perforate.W-Gum (18mg) is suspended among the warm water (180ml).Resulting mashed prod is used to make the powder granulation.Dried particles, be the sieve segmentation of 1.4mm with the eyelet size after, add remaining starch, talcum and magnesium, after carefully mixing, adopting diameter is that the puncturing machine of 8mm is processed as tablet with it.

Claims (3)

1, a kind of method for preparing the formula I compound or pharmaceutically acceptable salt thereof:

In the formula

A is group 〉=CR ₃Or＞CHR ₃, R ₃Be hydrogen or C _1-6Alkyl or group＞C=CR ₄R ₅, R wherein ₄And R ₅Be respectively hydrogen or C separately _1-5Alkyl;

Z is-CH ₂-or-O-;

N is 0 or 1;

R and R ₁Be respectively hydrogen or C separately _1-6Alkyl;

R ₂For-CH ₂OR ' ,-COOR ' or-CONR ' R ", wherein R ' and R " are respectively hydrogen or C separately _1-6Alkyl; And wherein:

B) be R wherein as A ₃For hydrogen 〉=CR ₃Or＞CHR ₃The time, then n is 1; And

C) meanwhile, be R wherein as A ₃For hydrogen＞CHR ₃, Z is-CH ₂-, n is 1 and R ₂For R ' wherein as defined above-COOR ' time, then R and R at least ₁, the two one of be not hydrogen.

Described method comprises:

Thereby A is 〉=C-R a) to make formula II compound generation β-elimination reaction obtain wherein ₃Group, R ₃Formula I compound as defined above

R, R in the formula ₁, R ₂, R ₃, n and Z as above limit, and M represents hydrogen or acyl group; Or

B) thus the formula III compound is carried out the alkylidene group processing to obtain its A is group＞C=CR ₄R ₅, R ₄And R ₅Equal formula I compounds as defined above

R, R in the formula ₁, R ₂, Z and n all as above limit; Or

C) thus reduction formula IV compound obtains wherein A is＞CHR ₃Group, R ₃Formula I compound as defined above

R, R in the formula ₁, R ₂, R ₃, n and Z all as above limit; Or

D) make formula (V) thus it is group 〉=CR that compound isomerizate obtains its A ₃-, R ₃Be C _1-6The formula I compound of alkyl

R, R in the formula ₁, R ₂, n and Z as above limit R ₄And R ₅The two one of be hydrogen or C _1-5Alkyl, another then is a hydrogen; Necessary words, the formula I compound is converted into another formula I compound, and/or, necessary, the formula I compound is converted into its pharmaceutical salts, and/or, necessary, salt is converted into free cpds, and/or, necessary, the isomer mixture of formula I compound is separated into individual isomer.

2, in accordance with the method for claim 1, wherein A is R wherein ₃Be C _1-4Group 〉=the CR of alkyl ₃Or＞CHR ₃Or R wherein ₄Be hydrogen or C _1-4Group＞the C=CHR of alkyl ₄; Z is-CH ₂-or-O-; N is zero or 1; R and R ₁Be hydrogen; R ₂For wherein R ' and R " are respectively hydrogen or C _1-4Alkyl-CH ₂OR ' ,-COOR ' or-CONR ' R ".

3, in accordance with the method for claim 1, wherein A is R wherein ₃Be C _1-4Group 〉=the CR of alkyl ₃Or＞C=CH ₂; Z is-CH ₂-; N is 0 or 1; R and R ₁Be hydrogen; R ₂For R ' wherein is hydrogen or C _1-4Alkyl-COOR ' or-CONH ₂