CN101304990A - Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof - Google Patents

Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof Download PDF

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CN101304990A
CN101304990A CNA200680042163XA CN200680042163A CN101304990A CN 101304990 A CN101304990 A CN 101304990A CN A200680042163X A CNA200680042163X A CN A200680042163XA CN 200680042163 A CN200680042163 A CN 200680042163A CN 101304990 A CN101304990 A CN 101304990A
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base
hexamethylene
amino
methyl
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弗兰克·希梅尔斯巴克
马科·桑塔戈斯蒂诺
伯吉特·琼
雷纳·索伊卡
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Boehringer Ingelheim International GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to bicyclic heterocycles of general formula (I), the tautomers thereof, the mixtures and salts thereof, especially the physiologically acceptable salts thereof comprising inorganic or organic acids, which have valuable pharmaceutical properties, particularly an inhibitive effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, especially tumor diseases and benign prostatic hyperplasia (BPH), lung diseases, and respiratory tract diseases, and the production thereof.

Description

Bicyclic heterocycles, the medicine that comprises this compound, its purposes and preparation method thereof
The present invention relates to the bicyclic heterocycles of general formula (I):
Figure A20068004216300061
Its tautomer, its steric isomer, its mixture and salt thereof, especially the physiologically acceptable salt that forms of itself and mineral acid or organic acid, it has the valuable pharmacological characteristic, especially inhibited to tyrosine kinase mediated signal transduction, it is used for the treatment of the disease especially purposes and the preparation thereof of tumor disease and benign prostatic hyperplasia (BPH), lung and airway disorders.
In above-mentioned general formula (I),
R aRepresent hydrogen atom,
R bExpression 3-chloro-4-fluorophenyl or 3-ethynyl phenyl,
R cExpression is selected from the group in following: 1-methoxycarbonyl-piperidin-4-yl; 1-ethoxy carbonyl-piperidin-4-yl; 1-trifluoroacetyl group-piperidin-4-yl; suitable-4-(methoxycarbonyl amino)-hexamethylene-1-base; instead-4-(methoxycarbonyl amino)-hexamethylene-1-base; suitable-4-(ethoxy carbonyl amino)-hexamethylene-1-base; instead-4-(ethoxy carbonyl amino)-hexamethylene-1-base; suitable-4-(trifluoroacetyl group amino)-hexamethylene-1-base; instead-4-(trifluoroacetyl group amino)-hexamethylene-1-base; suitable-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base; suitable-4-phthalimide-based-hexamethylene-1-base and anti--4-phthalimide-based-hexamethylene-1-base
Preferably be selected from the group in following: 1-methoxycarbonyl-piperidin-4-yl, 1-ethoxy carbonyl-piperidin-4-yl, suitable-4-(methoxycarbonyl amino)-hexamethylene-1-base, instead-4-(methoxycarbonyl amino)-hexamethylene-1-base, suitable-4-(ethoxy carbonyl amino)-hexamethylene-1-base, instead-4-(ethoxy carbonyl amino)-hexamethylene-1-base, suitable-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base, instead-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base, suitable-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base, instead-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base, suitable-4-phthalimide-based-hexamethylene-1-base and anti--4-phthalimide-based-hexamethylene-1-base
R dExpression hydrogen atom or methoxyl group, oxyethyl group or 2-methoxy ethoxy are preferably methoxy or ethoxy,
Choose wantonly and be following form: its tautomer, racemic modification, enantiomer, diastereomer and composition thereof, and optional its pharmaceutically acceptable acid additive salt, solvate and hydrate, be preferably tautomer, racemic modification, enantiomer, diastereomer and composition thereof, and optional its pharmaceutically acceptable acid additive salt.
The compound of general formula (I) can (for example) prepare by the following method:
A) make the compound of general formula (II)
Figure A20068004216300071
Wherein
R a, R bAnd R dAll as hereinbefore defined, the compound with general formula (III) reacts
Z 1-R c (III)，
Wherein
R cAs hereinbefore defined and Z 1Expression leavings group, for example halogen atom (for example chlorine atom or bromine atoms), sulfonyloxy (for example methanesulfonyloxy group or right-tosyloxy) or hydroxyl.
This reaction is optional can preferably carried out in solvent (for example ethanol, Virahol, acetonitrile, toluene, tetrahydrofuran (THF), dioxane, dimethyl formamide, methyl-sulphoxide or N-Methyl pyrrolidone) under the temperature between 80 ℃ to 140 ℃ in the presence of alkali (for example salt of wormwood or N-ethyl-Diisopropylamine) under the temperature between 20 ℃ to 160 ℃ easily.
Use wherein Z 1The compound of the general formula (III) of expression hydroxyl, this reaction can be in the presence of dewatering agent, preferably (for example at phosphine and azoformic acid derivative, triphenylphosphine/diethyl azodiformate for example) exists down easily in solvent (for example methylene dichloride, acetonitrile, tetrahydrofuran (THF), dioxane, toluene or ethylene glycol diethyl ether) under the temperature between-50 to 150 ℃, preferably under the temperature between-20 to 80 ℃, carry out.
B) make the compound of general formula (IV)
Figure A20068004216300081
R wherein cAnd R dAs hereinbefore defined, react the midbody compound that leads to formula V to form with halogenating agent (for example carboxylic acid halides, for example thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphoryl chloride),
R wherein cAnd R dAs hereinbefore defined and Z 2The expression halogen atom, for example chlorine atom or bromine atoms,
And the compound with general formula (VI) reacts subsequently
R a-NH-R b (VI)，
R wherein aAnd R bAs hereinbefore defined.
With the reaction of halogenating agent optional can and choose wantonly in solvent (for example methylene dichloride, chloroform, acetonitrile or toluene) alkali (for example N, N-Diethyl Aniline or N-ethyl-Diisopropylamine) exist down 20 ℃ to 160 ℃, preferably under the temperature between 40 ℃ to 120 ℃, carry out.Yet, preferably, under the reaction mixture boiling temperature, carry out this reaction with the dimethyl formamide of thionyl chloride and catalytic amount.Also preferred and phosphoryl chloride triethylamine and as solvent with acetonitrile in the presence of carry out this reaction under the boiling temperature at reaction mixture.
The compound of logical formula V and the reaction of the compound of general formula (VI) are chosen wantonly in the presence of alkali (for example salt of wormwood or N-ethyl-Diisopropylamine) at 20 ℃ to 160 ℃, enforcement in solvent (for example ethanol, Virahol, acetonitrile, dioxane or dimethyl formamide) under the temperature between preferred 60 ℃ to 120 ℃.
Yet, preferably under the reaction mixture boiling temperature, in Virahol, implement this reaction.
Another preferred version in the presence of triethylamine and acetonitrile, preferably make as solvent and the solution of the logical formula V of phosphoryl chloride reaction back gained under the temperature between 20 to 80 ℃ with the compound solution reaction of general formula (VI).
C) for preparing wherein R cThe compound of the general formula (I) of expression following groups: 1-methoxycarbonyl-piperidin-4-yl; 1-ethoxy carbonyl-piperidin-4-yl; 1-trifluoroacetyl group-piperidin-4-yl; suitable-4-(methoxycarbonyl amino)-hexamethylene-1-base; instead-4-(methoxycarbonyl amino)-hexamethylene-1-base; suitable-4-(ethoxy carbonyl amino)-hexamethylene-1-base; instead-4-(ethoxy carbonyl amino)-hexamethylene-1-base; suitable-4-(trifluoroacetyl group amino)-hexamethylene-1-base; instead-4-(trifluoroacetyl group amino)-hexamethylene-1-base; suitable-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base
Make the compound of general formula (VII)
Figure A20068004216300091
R wherein a, R bAnd R dAs hereinbefore defined, and R c' expression piperidin-4-yl, suitable-4-amino-hexamethylene-the 1-base, anti--4-amino-hexamethylene-1-base, suitable-4-(methylamino)-hexamethylene-1-base or anti--4-(methylamino)-hexamethylene-1-base,
React with corresponding acylating agent (for example methyl-chloroformate, Vinyl chloroformate, coke dimethyl phthalate, diethylpyrocarbonate, trifluoroacetic anhydride or trifluoro-acetate).
This reaction is optional can be at-20 ℃ to 80 ℃ in the presence of alkali (for example salt of wormwood, sodium hydroxide solution or N-ethyl-Diisopropylamine), easily in solvent (for example methylene dichloride, acetonitrile, toluene, tetrahydrofuran (THF), dioxane, dimethyl formamide, methyl-sulphoxide or N-Methyl pyrrolidone), preferably in tetrahydrofuran (THF) or dioxane, implement under the temperature between preferred 0 ℃ to 40 ℃.When using trifluoro-acetate, this reaction also can be implemented in methyl alcohol.
D) for preparing wherein R cThe compound of representing the general formula (I) of suitable-4-phthalimide-based-hexamethylene-1-base or anti--4-phthalimide-based-hexamethylene-1-base makes the compound of general formula (VIII)
Figure A20068004216300101
R wherein a, R bAnd R dAs hereinbefore defined, and R c" suitable-4-amino-hexamethylene of expression-1-base or anti--4-amino-hexamethylene-1-base,
Reactive derivatives reaction with Tetra hydro Phthalic anhydride or another kind of phthalic acid.
This reaction is optional can implemented in solvent (for example acetate, acetonitrile, toluene, tetrahydrofuran (THF), dioxane, dimethyl formamide, methyl-sulphoxide or N-Methyl pyrrolidone) under the temperature between 60 ℃ to 160 ℃, preferred 80 ℃ to 120 ℃ in the presence of alkali (for example salt of wormwood or N-ethyl-Diisopropylamine) easily.
Yet this reaction is preferably implemented in acetate under the temperature between 80 ℃ to 120 ℃.
R wherein a, R b, R cAnd R dThe compound of general formula all as hereinbefore defined (I) also is suitable as initial compounds to prepare the quinazoline derivant of corresponding general formula (VII)
Figure A20068004216300102
R wherein a, R b, R c' and R dAll as hereinbefore defined.This compound is set forth among the WO 03/082290.Radicals R cMiddle dissociating of acyl group is to implement under acidity or alkaline condition, under the situation of phthalimide-based, preferably implements with hydrazine, methylamine or thanomin.
The compound of the general formula of gained (I) may be split into its diastereomer.Thereby for example, suitable/back mixing compound can (for example) split into it along reaching trans-isomer(ide) by chromatography.
In addition, the compound of gained formula (I) can be converted into its salt, especially can utilize mineral acid or organic acid to make it be converted into its physiologically acceptable salt to be used for medicinal use.The acid that can be used for this purpose comprises (for example) spirit of salt, Hydrogen bromide, sulfuric acid, methanesulfonic, phosphoric acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.
Some learns maybe and can obtain by the method for learning from document (referring to example I to X), the optional blocking group of introducing in addition by document as the compound of the general formula (II) to (VIII) of initial substance.
The compound and the physiologically acceptable salt thereof of general formula of the present invention (I) have the valuable pharmacological characteristic, especially to inhibited by EGF-R ELISA (EGF-R) Mediated Signal Transduction, wherein this effect can (for example) realize by suppressing part combination, receptor dimerizationization or Tyrosylprotein kinase itself.Also might conduct to the composition that is positioned at again the downstream by disabling signal.
The biological characteristic research of these new compounds is as follows:
The inhibition of human EGF receptor kinase is to measure by cytoplasmic tyrosine kinase territory (methionine(Met) 664 is to L-Ala 1186, according to Nature 309 (1984), 418 sequences of announcing).For implementing this mensuration, use baculovirus expression system in the Sf9 insect cell, protein expression to be gst fusion protein.
Measure enzymic activity in the test compounds existence or not with serial dilution.Polymkeric substance pEY (4: 1) by the SIGMA preparation is used as substrate.Add biotinylated pEY (bio-pEY) as the spike substrate.Per 100 microlitre reaction solns comprise 10 microlitres and are dissolved in inhibitor, 20 microlitre substrate solutions (2.5 mg/ml are gathered (EY), 5 mcg/ml bio-pEY for 200mM HEPES pH7.4,50mM magnesium acetate) and 20 microlitre zymins among the 50%DMSO.This enzyme reaction begins by the 100 μ M ATP solution that add 50 microlitres and be dissolved in the 10mM magnesium chloride.Regulate the extent of dilution of this zymin so that the phosphoric acid that is incorporated among the bio-pEY is being linear aspect time and the enzyme amount.Dilute this zymin with 20mM HEPES pH 7.4,1mMEDTA, 130mM salt, 0.05%Triton X-100,1mM DTT and 10% glycerine.
Carry out the enzyme analysis through 30 minutes time at ambient temperature, and finish by adding 50 microlitre stop baths (being dissolved in the 250mM EDTA among the 20mM HEPES pH 7.4).100 microlitres are placed on the microtiter plate that scribbles streptavidin and cultivated at ambient temperature 60 minutes.Use 200 microlitre washing solns (50mM Tris, 0.05%Tween 20) to wash this plate then.After adding the anti-PY antibody (by the PY20H anti-PTyr:HRP of Transduction Laboratories preparation, 250 nanograms/milliliter) of 100 microlitres, it was cultivated 60 minutes through the HRPO-mark.Wash this microtiter plate 3 times with each 200 microlitre washing lotions then.These samples and 100 microlitre TMB-peroxidase solution (A: B=1: 1, Kirkegaard Perry Laboratories) are mixed.After 10 minutes, stop this reaction.At OD 450 nanometersThe place measures extinction value with the ELISA reader.All data points are measured three times.
Use mates these data and variable Hill slope at the routine analyzer (Graph Pad Prism, 3.0 editions) of sigmoid curve by iterative computation.All iterative datas that solve all show relation conefficient greater than 0.9 and the higher limit and the lower value of these curves show that dispersion coefficient is at least 5.From the be inhibited active material concentration (IC of 50%EGF-kinase activation of these curves 50).The compounds of this invention has the IC less than 100nM 50Value.
Therefore, the compound of general formula I of the present invention suppresses tyrosine kinase mediated signal transduction, is confirmed as the example by human EGF acceptor, and therefore is used for the treatment of because of the caused pathophysiological process of the superfunction of Tyrosylprotein kinase.This is (for example) optimum or malignant tumour, especially comes from the transfer and the paraplasm (neovascularity generation) of epithelium and neurepithelial tumour, vascular endothelial cell.
The compounds of this invention also is used to prevent and treats with the increase that stimulates the mucus generation that causes because of Tyrosylprotein kinase or the air flue and the lung disease of change, for example in the air flue inflammatory diseases, for example chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, supersensitivity or non-allergic rhinitis or sinusitis paranasal sinusitis, cystic fibrosis, α1-Kang Yidanbaimeiquefazheng or cough, pulmonary emphysema, pulmonary fibrosis and hyperergy air flue.
These compounds also are applicable to that treatment destroys the relevant gi tract and the inflammatory diseases of bile duct and gall-bladder with tyrosine kinase activity, for example be found in (for example) acute or chronic inflammatory variation, for example cholecystitis, Crohn disease, ulcerative colitis and gastrointestinal ulceration or polyp, or for example can occur in the gastrointestinal tract disease relevant for example sick, secretion adenoma of Erichsen (M é n é trier ' s) and potein deficiency syndrome in the George Mehnert with secretion increasing.
And these compounds also are applicable to the inflammatory diseases (for example rheumatoid arthritis) in treatment joint, the inflammatory diseases of skin, eyes, inflammatory pseudopolyp, colitis cystica profunda or pneumatosis cystoides intestinalis (pneumatosis cystoids intestinales).These compounds also can be used for treating CNS and bone marrow injury.
The preferred application area that can mention is the inflammatory diseases of respiratory organs or enteron aisle, for example chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn disease, ulcerative colitis or polyposis intestinalis disease.
Especially Application Areas is the inflammatory diseases of respiratory tract or lung, for example chronic bronchitis (COPD) or asthma.
In addition, the compound of general formula (I) and physiologically acceptable salt thereof can be used for treating the other diseases that causes because of the Tyrosylprotein kinase dysfunction, for example (for example) epidermis hyperplasia (psoriasis), benign prostatic hyperplasia (BPH), inflammatory process, disease of immune system, hematopoietic cell hyperplasia, nasal polyp treatment etc.
Biological characteristics according to The compounds of this invention, it can use separately or unite use with other pharmaceutically active compounds, for example when oncotherapy, it can be treated separately or unite use with other antineoplaston medicaments, for example, its can with following medication combined use: topoisomerase enzyme inhibitor is (for example, Etoposide), mitotic inhibitor (for example, vinealeucoblastine(VLB)), with the compound of nucleic acid interaction (for example, cis-platinum, endoxan, Dx), hormone antagonist (for example, tamoxifen), metabolic process inhibitor (for example, 5-FU etc.), cytokine (for example, Interferon, rabbit) and antibody etc.For the treatment respiratory tract disease; these compounds can use separately or unite use with other air flue healing potions; for example; can unite use with following substances: expectorant (for example; Transbroncho, N-acetylcysteine), anti-asthmatic (for example; tiotropium or Rinovagos or Partusisten, Salmeterol, salbutamol) and/or anti-inflammation drugs (for example, theophylline or glucocorticosteroid).For the disease of treatment gastrointestinal region, these compounds also can be used separately, or can with to motility or to secrete influential material co-administered.These combinations can be used or use successively simultaneously.
These compounds can use separately or with other active compound combined using, its can be in intravenously, subcutaneous, intramuscular, intraperitoneal or nose etc. approach use, by through sucking or through skin or oral administration, wherein aerosol preparations is particularly suited for sucking.
With regard to pharmaceutical way, The compounds of this invention is generally used for warm-blooded vertebrate, and especially human, dosage is 0.001-100 milligram/kg body weight, preferred 0.1-15 milligram/kilogram.For throw with for, for example use W-Gum, lactose, glucose, Microcrystalline Cellulose, Magnesium Stearate, Polyvinylpyrolidone (PVP), citric acid, tartrate, water, water/ethanol, water/glycerine, water/Sorbitol Powder, water/polyoxyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substance (for example stearic fat) or its suitable mixture to be processed into conventional lid Lun Shi preparation, for example tablet or coated tablet, capsule, pulvis, suspension, solution, spray or suppository with one or more conventional inert supports and/or thinner.
The compound of general formula of the present invention (I) also is applicable to the derivative described in preparation as (for example) WO 03/082290.For example, the compound of embodiment 1 can react to form 4-[(3-chloro-4-fluoro-phenyl with sodium hydroxide solution or potassium hydroxide solution) amino]-6-(piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline (referring to the method embodiment A).
Following examples are intended to more elaborate the present invention but not limit it:
The preparation of initial compounds:
Example I
Figure A20068004216300141
3-benzyl-3,4-dihydro-4-oxo-6-acetoxyl group-7-methoxyl group-quinazoline
Make 169 grams 3,4-dihydro-4-oxo-6-acetoxyl group-7-methoxyl group-quinazoline, 118.8 milliliters of bromotoluenes and 138.2 gram salt of wormwood are heated to 35 to 40 ℃ and kept 8 hours in 1600 milliliters of acetone.Stirred this mixture at ambient temperature 15 hours and mix with 2000 ml waters then.Make this suspension be cooled to 0 ℃, the suction filtration precipitation is with 400 ml waters and 400 milliliters of t-butyl methyl ether washings and dry down at 50 ℃.This solid is dissolved in 4000 milliliters of methylene dichloride, filters and evaporation concentration.This resistates is suspended in the t-butyl methyl ether, and suction filtration also carries out drying at 50 ℃.
Productive rate: 203 grams (theoretical value 86%)
R fValue: 0.80 (silica gel, methylene dichloride/ethanol=9: 1)
Mass spectrum (ESI +): m/z=325[M+H] +
The mode that can be similar to example I obtains following compound:
(1) 3-benzyl-3,4-dihydro-4-oxo-6-acetoxyl group-7-oxyethyl group-quinazoline
(2) 3-benzyl-3,4-dihydro-4-oxo-6-acetoxyl group-quinazoline
Figure A20068004216300143
(3) 3-benzyl-3,4-dihydro-4-oxo-6-acetoxyl group-7-(2-methoxyl group-oxyethyl group)-quinazoline
Figure A20068004216300151
Example II
Figure A20068004216300152
3-benzyl-3,4-dihydro-4-oxo-6-hydroxyl-7-methoxyl group-quinazoline
Method A:
Hydroxyl-[1,3] oxazine-4-ketone is dissolved in 1200 milliliters of toluene and adds 74.7 milliliters of benzylamines 7-methoxyl group-benzo [d] to make 168.5 gram 6-.Make this mixture heating up backflow 15 hours and be cooled to envrionment temperature then.Filtering-depositing also washs with t-butyl methyl ether.
Productive rate 124 gram (theoretical value 72%)
Method B:
Make 200 gram 3-benzyls-3,4-dihydro-4-oxo-6-acetoxyl group-7-methoxyl group-quinazoline is suspended in 200 ml waters and the 1000 milliliters of ethanol.Add 300 milliliters of 10N sodium hydroxide solutions at ambient temperature and with this mixture heating up to 30 ℃ and kept 1 hour.After adding 172 milliliters of acetate and 2000 ml waters, stirred this mixture at ambient temperature 20 hours.The suction filtration precipitation, water and washing with acetone also carry out drying under 60 ℃.
Productive rate: 172.2 grams (theoretical value 98%)
R fValue: 0.25 (silica gel, methylene dichloride/ethanol=19: 1)
Mass spectrum (ESI +): m/z=283[M+H] +
The mode that can be similar to example II obtains following compound:
(1) 3-benzyl-3,4-dihydro-4-oxo-6-hydroxyl-7-oxyethyl group-quinazoline
Figure A20068004216300161
(2) 3-benzyl-3,4-dihydro-4-oxo-6-hydroxyl-quinazoline
Figure A20068004216300162
(3) 3-benzyl-3,4-dihydro-4-oxo-6-hydroxyl-7-(2-methoxyl group-oxyethyl group)-quinazoline
Figure A20068004216300163
EXAMPLE III
Figure A20068004216300164
6-hydroxyl-7-methoxyl group-benzo [d] [1,3] oxazine-4-ketone
With 1 gram 2-amino-5-hydroxyl-4-methoxyl group-phenylformic acid (by making 2-nitro-4,5-dimethoxy-methyl benzoate and potassium hydroxide solution react with obtain 2-nitro-5-hydroxyl-4-methoxyl group-phenylformic acid sylvite and subsequently in the presence of palladium-activated carbon catalytic hydrogenation and prepare) and 20 milliliters of triethyl orthoformates be heated to 100 ℃ and kept 2.5 hours.After being cooled to envrionment temperature, suction filtration precipitates and washs with ether.
Productive rate: 0.97 gram (theoretical value 93%)
R fValue: 0.86 (silica gel, methylene chloride/acetate=90: 10: 1)
Mass spectrum (ESI +): m/z=194[M+H] +
The mode that can be similar to EXAMPLE III obtains following compound:
(1) 6-hydroxyl-7-oxyethyl group-benzo [d] [1,3] oxazine-4-ketone
Figure A20068004216300171
(2) 6-hydroxyl-benzo [d] [1,3] oxazine-4-ketone
Figure A20068004216300172
(3) 6-hydroxyl-7-(2-methoxyl group-oxyethyl group)-benzo [d] [1,3] oxazine-4-ketone
Figure A20068004216300173
EXAMPLE IV
Suitable-1-(methanesulfonyloxy group)-4-(N-methane sulfonyl-N-methyl-amino)-hexanaphthene
By being reacted in tetrahydrofuran (THF), suitable-1-hydroxy-4-methyl amino-hexanaphthene and methane sulfonyl chloride prepare.
Mass spectrum (ESI +): m/z=286[M+H] +
The mode that can be similar to EXAMPLE IV obtains following compound:
Figure A20068004216300181
Figure A20068004216300191
EXAMPLE V
Figure A20068004216300201
3-benzyl-3,4-dihydro-4-oxo-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline
By make 56.46 gram 3-benzyls-3 under 100 ℃ to 120 ℃ in the presence of 41.46 gram salt of wormwood in being dissolved in 500 milliliters of N-methyl-pyrrolidone, 4-dihydro-4-oxo-6-hydroxyl-7-methoxyl group-quinazoline and 62.82 gram 1-ethoxy carbonyl-4-methanesulfonyloxy group-piperidines react and prepare.
Mass spectrum (ESI +): m/z=438[M+H] +
The mode that can be similar to EXAMPLE V obtains following compound:
Figure A20068004216300211
Figure A20068004216300221
Figure A20068004216300231
Example VI
Figure A20068004216300241
3,4-dihydro-4-oxo-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline
In the presence of 6 gram activated carbon-palladiums (10%Pd), make 58.5 gram 3-benzyls-3, the mixture hydrogenation of 4-dihydro-4-oxo-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline and 600 milliliters of glacial acetic acids 3 hours in 80 ℃ of hydrogen pressures at 50psi.The suction filtration catalyzer is concentrated into 100 milliliters and mix with 600 milliliters of t-butyl methyl ether by evaporated filtrate.The suction filtration precipitation is also dry.
Productive rate: 46 grams (theoretical value 99%)
R fValue: 0.26 (silica gel, methylene dichloride/ethanol=19: 1)
Mass spectrum (ESI +): m/z=348[M+H] +
The mode that can be similar to example VI obtains following compound:
Figure A20068004216300242
Figure A20068004216300251
Figure A20068004216300261
Figure A20068004216300271
Figure A20068004216300281
Example VII A
Figure A20068004216300282
4-chloro-6-(1-trifluoroacetyl group-piperidin-4-yl oxygen base)-quinazoline hydrochloride
Make to be stored in the gram of 5.3 in 25 milliliters of acetonitriles 3,4-dihydro-4-oxo-6-(1-trifluoroacetyl group-piperidin-4-yl oxygen base)-quinazoline mixes with 25 milliliters of thionyl chloride and several dimethyl formamides.This mixture was refluxed 2 hours, and vacuum-evaporation concentrates, and mixes also evaporation concentration once more with toluene.Also can obtain free alkali by alkaline purification.
R fValue: 0.92 (silica gel, ethyl acetate)
The mode that can be similar to example VII A obtains following compound:
Figure A20068004216300291
Figure A20068004216300301
Figure A20068004216300311
Figure A20068004216300321
Also can obtain the free alkali of above-claimed cpd by alkaline purification.
Example VII A I
Figure A20068004216300322
Suitable-1-hydroxyl-4-(N-tert-butoxycarbonyl-N-methyl-amino)-hexanaphthene
By the reaction of suitable-1-hydroxy-4-methyl amino-hexanaphthene and coke acid di-t-butyl ester is prepared.
Mass spectrum (ESI +): m/z=230[M+H] +
The mode that can be similar to example VII A I obtains following compound:
Figure A20068004216300323
Figure A20068004216300331
Example I X
Figure A20068004216300332
3-benzyl-3,4-dihydro-4-oxo-6-(suitable-4-methylamino-hexanaphthene-1-base oxygen base)-7-methoxyl group-quinazoline
Can be by handling 3-benzyl-3 with spirit of salt or trifluoroacetic acid at ambient temperature, 4-dihydro-4-oxo-6-{ is suitable-4-[N-(tert-butoxycarbonyl)-N-methyl-amino]-hexanaphthene-1-base oxygen base }-7-methoxyl group-quinazoline and obtaining.After using the ethanol or aqueous isopropanol cracking tert-butoxycarbonyl of spirit of salt, the separated salt hydrochlorate.
Mass spectrum (ESI +): m/z=394[M+H] +
The mode that can be similar to example I X obtains following compound:
Figure A20068004216300341
Embodiment X
Figure A20068004216300342
3-benzyl-3,4-dihydro-4-oxo-6-(suitable-4-{N-[(morpholine-4-yl) carbonyl]-the N-methylamino }-hexanaphthene-1-base oxygen base)-7-methoxyl group-quinazoline
By make 3-benzyl-3 in the presence of N-ethyl-Diisopropylamine in acetonitrile, 4-dihydro-4-oxo-6-(suitable-4-methylamino-hexanaphthene-1-base oxygen base)-7-methoxyl group-quinazoline obtains with the reaction of (morpholine-4-yl)-carbonyl chloride.
Mass spectrum (ESI +): m/z=507[M+H] +
The mode that can be similar to embodiment X obtains following compound:
Figure A20068004216300351
The preparation of final compound
Embodiment 1
Figure A20068004216300352
4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline
Make 24 grams 3,4-dihydro-4-oxo-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline, 75 milliliters of thionyl chloride and 0.1 milliliter of dimethyl formamide reflux 2 hours.Utilize rotatory evaporator to remove the volatility part of this reaction mixture and make this resistates and 350 milliliters of Virahols and 23.29 restrain 3-chloro-4-fluoro-aniline and mix.This mixture was refluxed 2.5 hours.Add 350 ml waters then and cool off this mixture.Suction filtration solid and water and Virahol wash.Make this solid suspension in 400 ml methanol, be adjusted to alkalescence with strong aqua.This mixture is mixed and this solid of suction filtration and under 70 ℃, carry out drying with frozen water.
Productive rate: 29 grams (theoretical value 88%)
R fValue: 0.36 (silica gel, methylene dichloride/ethanol=19: 1)
Mass spectrum (ESI +): m/z=475,477[M+H] +
The mode that can be similar to embodiment 1 obtains following compound:
(1) amino 4-[(3-ethynyl-phenyl)]-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline hydrochloride
Mass spectrum (ESI +): m/z=447[M+H] +
The also available method that is similar to the foregoing description of following compound reaches the additive method of learning from document and prepares:
Figure A20068004216300362
Figure A20068004216300371
Figure A20068004216300381
Figure A20068004216300391
Figure A20068004216300401
Figure A20068004216300411
Figure A20068004216300421
Figure A20068004216300441
Embodiment 2
The coated tablet that contains 75 milligrams of active substances
1 label comprises:
75.0 milligrams of active substances
93.0 milligrams in calcium phosphate
35.5 milligrams of W-Gums
10.0 milligrams of Polyvinylpyrolidone (PVP)s
15.0 milligrams of HPMC
Magnesium Stearate 1.5 milligram
230.0 milligram
Preparation:
The Magnesium Stearate of active substance with calcium phosphate, W-Gum, Polyvinylpyrolidone (PVP), HPMC and half specified amount mixed.Making diameter in pelleter is about 13 millimeters blank and at suitable machine these blanks is rubbed then and be 1.5 millimeters sieve and mix with all the other Magnesium Stearates by width of mesh.Compressed granulate is to form desired shaped tablets in pelleter.
Core is heavy: 230 milligrams
Mould: 9 millimeters, convex
Make the label of manufacturing like this apply the film of forming by HPMC basically.With the final film-coated tablets of beeswax polishing.
The weight of film-coated tablets: 245 milligrams.
Embodiment 3
The tablet that contains 100 milligrams of active substances
Form:
1 tablet of tablet comprises:
100.0 milligrams of active substances
80.0 milligrams of lactose
34.0 milligrams of W-Gums
4.0 milligrams of Polyvinylpyrolidone (PVP)s
Magnesium Stearate 2.0 milligram
220.0 milligram
The preparation method:
Active substance, lactose and starch are mixed and evenly moistening with the Polyvinylpyrolidone (PVP) aqueous solution.Make this moisturizing compositions sieve (width of mesh is 2.0 millimeters) and under 50 ℃ behind stent-type moisture eliminator inner drying, it sieved (width of mesh is 1.5 millimeters) once more and add lubricant.Suppress this mixture to form tablet.
Tablet weight: 220 milligrams
Diameter: 10 millimeters, biplane, the two sides is all facet and one side cutting.
Embodiment 4
The tablet that contains 150 milligrams of active substances
Form:
1 tablet of tablet comprises:
150.0 milligrams of active substances
89.0 milligrams of powdery lactose
40.0 milligrams of W-Gums
10.0 milligrams of colloid silicas
10.0 milligrams of Polyvinylpyrolidone (PVP)s
Magnesium Stearate 1.0 milligram
300.0 milligram
Preparation:
Wetting with lactose, W-Gum and silicon-dioxide blended active substance and to make it be 1.5 millimeters sieve by width of mesh with the 20% Polyvinylpyrolidone (PVP) aqueous solution.Make 45 ℃ of following dry granules and mix by identical sieve and with the Magnesium Stearate of specified amount once more.From this mixture compressed tablets.
Tablet weight: 300 milligrams
Mould: 10 millimeters, flat
Embodiment 5
The hard gelatin capsule that contains 150 milligrams of active substances
Form:
1 capsule comprises:
50.0 milligrams of active substances
About 80.0 milligrams of W-Gum (drying)
About 87.0 milligrams of lactose (powdery)
Magnesium Stearate 3.0 milligram
About 420.0 milligrams
Preparation:
Make active substance and mixed with excipients, make it to be 0.75 millimeter sieve and to make its uniform mixing at suitable device by width of mesh.Final mixture is packed in No. 1 hard gelatin capsule.
Capsule is filled: about 320 milligrams
Capsule shell: No. 1 hard gelatin capsule.
Embodiment 6
The suppository that contains 150 milligrams of active substances
Form:
1 suppository comprises:
150.0 milligrams of active substances
550.0 milligrams of polyethylene glycol 1500s
460.0 milligrams of polyethylene glycol 6000s
The polyoxy thiazolinyl sorbitol monostearate that anhydrates 840.0 milligram
2,000.0 milligrams
Preparation:
After making the fusing of suppository group, active substance is dispersed in wherein and this melt is poured in the refrigerative mould.
Embodiment 7
The suspension that contains 50 milligrams of active substances
Form:
Comprise in 100 milliliters of suspension:
Active substance 1.00 grams
Sodium carboxymethyl-cellulose 0.10 gram
Methyl p-hydroxybenzoate 0.05 gram
Propylparaben 0.01 gram
Glucose 10.00 grams
Glycerine 5.00 grams
70% sorbitol solution, 20.00 grams
Correctives 0.30 gram
Distilled water to 100 milliliter
Preparation:
Distilled water is heated to 70 ℃.Methyl p-hydroxybenzoate and propylparaben under agitation are dissolved in wherein with glycerine and sodium carboxymethyl-cellulose.Make this solution be cooled to envrionment temperature and stir the following active substance that adds and make its homodisperse.After adding sugar, sorbitol solution and correctives and dissolving, under agitation this suspension is vacuumized to remove air.
5 milliliters of suspension comprise 50 milligrams of active substances.
Embodiment 8
The ampoule that contains 10 milligrams of active substances
Form:
10.0 milligrams of active substances
0.01N hydrochloric acid is an amount of
Bi-distilled water to 2.0 milliliter
Preparation:
Active substance is dissolved among the 0.01N HCl of necessary amounts, makes it have isotonicity with salt, sterile filtration also is transferred to them in 2 milliliters of ampoules.
Embodiment 9
The ampoule that contains 50 milligrams of active substances
Form:
50.0 milligrams of active substances
0.01N hydrochloric acid is an amount of
Bi-distilled water to 10.0 milliliter
Preparation:
Active substance is dissolved among the 0.01N HCl of necessary amounts, makes its isotonicity with salt, sterile filtration also is transferred to them in 10 milliliters of ampoules.
Embodiment 10
The powder inhalation capsules that contains 5 milligrams of active substances
1 capsule comprises:
5.0 milligrams of active substances
The suction lactose 15.0 milligram
20.0 milligram
Preparation:
Active substance is mixed with lactose with suction.In in the capsule rigging equipment, mixture being incapsulated (heavily about 50 milligrams of capsulae vacuus).
Capsule is heavy: 70.0 milligrams
Capsule size: No. 3
Embodiment 11
Contain the suction solution that the manual sprayer of 2.5 milligrams of active substances is used
Once spraying comprises:
2.500 milligrams of active substances
0.001 milligram of benzalkonium chloride
1N hydrochloric acid is an amount of
Ethanol/water (50/50) is to 15.000 milligrams
Preparation:
Active substance and benzalkonium chloride are dissolved in the ethanol/water (50/50).Regulate the pH value of this solution with 1N hydrochloric acid.Filter this gained solution and it is transferred to the appropriate vessel that is used for hand-held atomizer.
The content of this container: 4.5 grams
The method embodiment A
Figure A20068004216300491
4-[(3-chloro-4-fluoro-phenyl) amino]-6-(piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline
Make 14.3 gram 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-ethoxy carbonyl-piperidin-4-yl oxygen base)-7-methoxyl group-quinazoline and 15 gram potassium hydroxide reflux 48 hours in 250 milliliters of Virahols.This reaction mixture vacuum-evaporation is concentrated into about 50 milliliters and it is mixed with frozen water.The suction filtration solid also makes its recrystallize in ethyl acetate and t-butyl methyl ether.
Productive rate: 9.6 grams (theoretical value 79%)
Mass spectrum (ESI +): m/z=403,405[M+H] +
The mode that can be similar to the method embodiment A obtains following compound:
Figure A20068004216300501
Figure A20068004216300511
Figure A20068004216300521
The method Embodiment B
4-[(3-chloro-4-fluoro-phenyl) amino]-6-(1-methane sulfonyl-piperidin-4-yl oxygen base)-7-oxyethyl group-quinazoline
This title compound can react under reflux temperature in Virahol by 4-chloro-6-(1-methyl sulphonyl-piperidin-4-yl oxygen base)-7-oxyethyl group-quinazoline hydrochloride (example VII A (25)) and 3-chloro-4-fluoro-aniline and obtain.Implement aftertreatment in the mode described in the embodiment 1.
The mode that can be similar to the method Embodiment B obtains following compound:
Figure A20068004216300523
Figure A20068004216300531
Figure A20068004216300541
Figure A20068004216300551
The method Embodiment C
Figure A20068004216300562
4-[(3-chloro-4-fluoro-phenyl) amino]-6-(suitable-4-amino-hexanaphthene-1-base oxygen base)-7-methoxyl group-quinazoline
This title compound can be by with methylamine or ethanolamine treatment 4-[(3-chloro-4-fluoro-phenyl) amino]-6-(suitable-4-phthalimide-based-hexanaphthene-1-base oxygen base)-7-methoxyl group-quinazoline (embodiment 1 (17)) obtains.
The mode that can be similar to the method Embodiment C obtains following compound:
Figure A20068004216300571

Claims (9)

1. the bicyclic heterocycles of general formula (I),
Wherein
R aThe expression hydrogen atom,
R bExpression 3-chloro-4-fluoro-phenyl or 3-ethynyl phenyl,
R cExpression is selected from the group in following: 1-methoxycarbonyl-piperidin-4-yl; 1-ethoxy carbonyl-piperidin-4-yl; 1-trifluoroacetyl group-piperidin-4-yl; suitable-4-(methoxycarbonyl amino)-hexamethylene-1-base; instead-4-(methoxycarbonyl amino)-hexamethylene-1-base; suitable-4-(ethoxy carbonyl amino)-hexamethylene-1-base; instead-4-(ethoxy carbonyl amino)-hexamethylene-1-base; suitable-4-(trifluoroacetyl group amino)-hexamethylene-1-base; instead-4-(trifluoroacetyl group amino)-hexamethylene-1-base; suitable-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base; suitable-4-phthalimide-based-hexamethylene-1-base and anti--4-phthalimide-based-hexamethylene-1-base
R dExpression hydrogen atom, methoxyl group, oxyethyl group or 2-methoxy ethoxy,
The optional form that is tautomer, racemic modification, enantiomer, diastereomer and composition thereof, and optional its pharmaceutically acceptable acid additive salt, solvate and hydrate.
2. the bicyclic heterocycles of general formula as claimed in claim 1 (I), wherein
R a, R bAnd R dCan have specified implication, and
R cExpression is selected from the group in following: 1-methoxycarbonyl-piperidin-4-yl, 1-ethoxy carbonyl-piperidin-4-yl, suitable-4-(methoxycarbonyl amino)-hexamethylene-1-base, instead-4-(methoxycarbonyl amino)-hexamethylene-1-base, suitable-4-(ethoxy carbonyl amino)-hexamethylene-1-base, instead-4-(ethoxy carbonyl amino)-hexamethylene-1-base, suitable-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base, instead-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base, suitable-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base, instead-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base, suitable-4-phthalimide-based-hexamethylene-1-base and anti--4-phthalimide-based-hexamethylene-1-base.
3. compound as claimed in claim 1 or 2 and physiologically acceptable salt inorganic or that organic acid forms.
4. pharmaceutical composition comprises at least a compound as claimed in claim 1 or 2 or physiologically acceptable salt as claimed in claim 3 and chooses any one kind of them or multiple inert support and/or thinner.
As each described compound in the claim 1 to 3 be suitable for use in the optimum or malignant tumour of treatment in preparation, be suitable for preventing and treating air flue and lung disease, be used for the treatment of the purposes in the pharmaceutical composition of disease of gi tract and bile duct and gall-bladder.
6. method for preparing the compound of general formula I as claimed in claim 1 or 2 is characterized in that:
(a) make the compound of general formula (II):
Figure A20068004216300031
Wherein
R a, R bAnd R dSuch as in claim 1 or 2 definition,
Compound reaction with general formula (III):
Z 1-R c (III)，
Wherein
R cSuch as in claim 1 or 2 definition, and
Z 1Expression leavings group or hydroxyl,
Or
(b) make the compound of general formula (IV):
Figure A20068004216300041
R wherein cAnd R dSuch as in claim 1 or 2 definition,
React the midbody compound that leads to formula V to form with halogenating agent,
Figure A20068004216300042
R wherein cAnd R dSuch as in claim 1 or 2 definition; And
Z 2The expression halogen atom,
And the compound with general formula (VI) reacts then:
R a-NH-R b (VI)，
R wherein aAnd R bSuch as in claim 1 or 2 definition.
7. a method for preparing the compound of general formula as claimed in claim 1 or 2 (I) is characterized in that
R a, R bAnd R dSuch as in claim 1 or 2 definition, and
R cExpression is selected from the group in following: 1-methoxycarbonyl-piperidin-4-yl; 1-ethoxy carbonyl-piperidin-4-yl; 1-trifluoroacetyl group-piperidin-4-yl; suitable-4-(methoxycarbonyl amino)-hexamethylene-1-base; instead-4-(methoxycarbonyl amino)-hexamethylene-1-base; suitable-4-(ethoxy carbonyl amino)-hexamethylene-1-base; instead-4-(ethoxy carbonyl amino)-hexamethylene-1-base; suitable-4-(trifluoroacetyl group amino)-hexamethylene-1-base; instead-4-(trifluoroacetyl group amino)-hexamethylene-1-base; suitable-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-methoxycarbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-ethoxy carbonyl-N-methyl-amino)-hexamethylene-1-base; suitable-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base; instead-4-(N-TFA base-N-methyl-amino)-hexamethylene-1-base
Make the compound of general formula (VII):
Figure A20068004216300051
Wherein
R a, R bAnd R dSuch as in claim 1 or 2 definition, and
R c' expression is selected from the group in following: piperidin-4-yl, suitable-4-amino-hexamethylene-the 1-base, anti--4-amino-hexamethylene-1-base, suitable-4-(methylamino)-hexamethylene-1-base or anti--4-(methylamino)-hexamethylene-1-base, with corresponding acylation reaction.
8. a method for preparing the compound of general formula as claimed in claim 1 or 2 (I) is characterized in that
R a, R bAnd R dSuch as in claim 1 or 2 definition, and
R cRepresent suitable-4-phthalimide-based-hexamethylene-1-base or anti--4-phthalimide-based-hexamethylene-1-base, and
Make the compound of general formula (VIII):
Figure A20068004216300052
Wherein
R a, R bAnd R dSuch as in claim 1 or 2 definition, and
R c" suitable-4-amino-hexamethylene of expression-1-base or anti--4-amino-hexamethylene-1-base, with the reactive derivatives reaction of Tetra hydro Phthalic anhydride or another kind of phthalic acid.
9. a method for preparing the compound of general formula as claimed in claim 7 (VII) is characterized in that making the compound reaction of general formula as claimed in claim 1 or 2 (I) to form the quinazoline derivant of general formula (VII).
CNA200680042163XA 2005-12-12 2006-11-17 Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof Pending CN101304990A (en)

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