CN102584741A - Amides compound, method for preparing same, composition and application thereof - Google Patents
Amides compound, method for preparing same, composition and application thereof Download PDFInfo
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- CN102584741A CN102584741A CN2011100020938A CN201110002093A CN102584741A CN 102584741 A CN102584741 A CN 102584741A CN 2011100020938 A CN2011100020938 A CN 2011100020938A CN 201110002093 A CN201110002093 A CN 201110002093A CN 102584741 A CN102584741 A CN 102584741A
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- methyl
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- unsubstituted
- acceptable salt
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- GYPOLRIBHDXZAV-UHFFFAOYSA-N CN(CC1)CCN1C1CCCCC1 Chemical compound CN(CC1)CCN1C1CCCCC1 GYPOLRIBHDXZAV-UHFFFAOYSA-N 0.000 description 1
- MLONSFFEFZADMY-UHFFFAOYSA-N CN(CC1)CCN1N1CCCCC1 Chemical compound CN(CC1)CCN1N1CCCCC1 MLONSFFEFZADMY-UHFFFAOYSA-N 0.000 description 1
- RXYPXQSKLGGKOL-UHFFFAOYSA-N CN1CCN(C)CC1 Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 1
- CDAZBSOQXDITMZ-UHFFFAOYSA-N O=C(C1(CC1)c1ccc(CN(C(Nc(c2c3)ccc3Cl)=O)S2(=O)=O)cc1)NC1CCCCC1 Chemical compound O=C(C1(CC1)c1ccc(CN(C(Nc(c2c3)ccc3Cl)=O)S2(=O)=O)cc1)NC1CCCCC1 CDAZBSOQXDITMZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, in particular to a novel amides compound as shown in the following formula (1) and a method for preparing the same, and also relates to an application of the compound in preparing medicines which prevent or cure diabetes mellitus, obesity and metabolic syndrome diseases, as well as a medicinal composition which contains the compound.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field; More specifically; The present invention relates to one type of new amides and preparation method thereof; The invention still further relates to the purposes of said compound in the medicine of preparation prevention or treatment mellitus and metabolism syndrome disease, and the pharmaceutical composition that contains said compound.
Background technology
Mellitus are metabolic diseases of a kind of multi-pathogenesis, and characteristics are chronic hyperglycemias, follow because of insulin secretion and/or effect the defective sugar, fat and the protein metabolism disorder that cause.Mellitus have two types on 1 type and 2 types, and wherein the patient of diabetes B accounts for more than 90% of total number of persons.China's onset diabetes rate rises rapidly in recent years, serious threat people's health.
11beta-Hydroxysteroid dehydrogenase (11 β-hydroxysteroid dehydrogenase; 11 β-HSD) are the important metabolic enzymes of glucocorticosteroid, and its function is the mutual conversion of catalytic activity glucocorticosteroid (like hydrocortisone and Kendall compound) and inertia form (like KE and 11-dehydrocorticosterone) thereof.11 β-HSD has two kinds of isozymes i.e. 11 β-HSD1 and 11 β-HSD2, and its structure all belongs to short-chain dehydrogenase/reductase enzyme protein superfamily.The main high expression level of 11 β-HSD1 is in liver and fatty tissue, and it mainly plays the reductase enzyme effect in vivo, and the catalysis glucocorticosteroid is regulated glucocorticosteroid and arrived the amount of its acceptor and the concentration in the circulation to the conversion of activity form.And 11 β-HSD2 is a desaturase that activity is very strong, plays and 11 β-HSD1 opposite effect, can make the rapid inactivation of glucocorticosteroid.
Glucocorticosteroid and insulin resistant are closely related, and glucocorticosteroid continues too high insulin resistant, central obesity, abnormalities of sugar/lipid metabolism and the hypertension etc. of causing of level for a long time in the blood circulation.Yet; The glucocorticosteroid level is normal basically in mellitus and the circulation of metabolism syndrome blood samples of patients; And the especially high expression level or the active rising that can cause local organization endocellular sugar corticoid level unusually of 11beta-Hydroxysteroid dehydrogenase 1 in liver and the fat in its local organization; Thereby induce glycogen output to increase thus, periphery fat and muscle tissue insulin resistant.
Therefore, 11 beta-HSD 1 inhibitors of administering therapeutic significant quantity can reduce the concentration of hydrocortisone in liver or the fat, and then increase the susceptibility of Regular Insulin, thereby suppress the generation and the development of mellitus or metabolism syndrome.Present 11 β-HSD1 selective depressant has become the new focus of external mellitus original new drug research.
Summary of the invention
One object of the present invention is to provide the amides shown in one type of following general formula (1) or its pharmacy acceptable salt.
Another object of the present invention is to provide the preparation method of the amides shown in the general formula (1).
Another object of the present invention is to provide the purposes of the amides shown in the general formula (1) in the medicine of the selective depressant of preparation 11beta-Hydroxysteroid dehydrogenase I type enzyme; Thereby be used for preventing or treat application in preparation, said disease such as diabetes B, obesity, metabolism syndrome and by the other diseases of excessive glucocorticosteroid effect mediation by the medicine of the disease of 11beta-Hydroxysteroid dehydrogenase I type enzyme mediation.
An also purpose of the present invention is to provide a kind of pharmaceutical composition, and it comprises amides or its pharmacy acceptable salt shown in general formulas (1) of one or more treatment significant quantities, and acceptable auxiliary material pharmaceutically.
According to the present invention, amides or its pharmacy acceptable salt shown in one type of following general formula (1) is provided:
Wherein,
A is saturated or unsaturated 0-3 O or the heteroatomic ring of N of containing of 3-8 unit.Preferably, A is phenyl ring, pyridine ring or piperidine ring.
B does not exist or is O, S or N.Preferably, B does not exist or is oxygen.
C does not exist or is-C (R
7R
8)-.R wherein
7And R
8Be the C1-C6 alkyl identical or differently, or R
7And R
8Form the C3-C8 naphthenic base with the carbon atom that they connected.Preferably, R
7And R
8All be methyl, or R
7And R
8The carbon atom that is connected with them forms cyclopropyl.
Y is CH
2, CO, CS, SO or SO
2Preferably, Y is SO
2
X is S or O.Preferably, X is O.
R
1Representative-NR
9R
10Or be selected from following group:
R wherein
9Cyclic hydrocarbon radical for alkyl or the C3-C6 of hydrogen, replacement or unsubstituted C1-C6.
R
10Alkyl for C1-C6; The naphthenic base of replacement or unsubstituted C3-C10; The cycloalkenyl group of C3-C10; Replace or unsubstituted C6-C10 aryl (be preferably and replace or unsubstituted phenyl), replace or unsubstituted C6-C10 aryl C1-C6 alkyl (be preferably and replace or unsubstituted benzyl), perhaps replacement or the unsubstituted 1-3 of containing heteroatomic 5-7 membered aromatic heterocycle base (be preferably and replace or the unsubstituted pyridine base) that is selected from oxygen, sulphur and the nitrogen.
Said substituted substituted radical all can be selected from halogen, cyanic acid, and nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, the alkyl of C1-C6, sulfydryl, the C6-C10 aryl contains 1-3 and is selected from the heteroatomic 5-7 membered aromatic heterocycle base in sulphur, oxygen and the nitrogen ,-COOR
11,-NR
11R
12,-OR
11,-COR
11,-CONR
11R
12,-SR
11,-SO
3R
11,-SO
2NR
11R
12,-SOR
11Or-SO
2R
11In.
R
2Be the alkyl of hydrogen or C1-C6, preferably, R
2Be hydrogen.
R
3, R
4, R
5And R
6Be hydrogen independently, halogen, cyanic acid, nitro; Hydroxyl, methylol, trifluoromethyl, trifluoromethoxy; The alkyl of C1-C6, sulfydryl, C6-C10 aryl; Contain 1-3 and be selected from the heteroatomic 5-7 membered aromatic heterocycle base in sulphur, oxygen and the nitrogen, the substituted 1-3 of containing of the alkyl of C1-C4 5-7 unit heterocyclic radical that is selected from nitrogen-atoms ,-COOR
11,-NR
11R
12,-OR
11,-COR
11,-CONR
11R
12,-SR
11,-SO
3R
11,-SO
2NR
11R
12,-SOR
11Or-SO
2R
11Preferably, R
3, R
4, R
5And R
6Be hydrogen, halogen, cyanic acid, hydroxyl, methyl, methylol, amino methyl, trifluoromethoxy independently, to fluorophenyl, to cyano-phenyl, phenyl, pyridyl, 1; 2,4-triazol radical, imidazolyl, pyrazolyl, carboxyl, carbamyl, piperidyl, piperazinyl or 4-N-METHYL PIPERAZINE base.
Wherein, R
11And R
12Be H independently, phenyl, pyridyl, benzyl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl group; Perhaps, radicals R
11And R
12Be joined together to form 4-7 unit ring.
Most preferably, the amides shown in the general formula (1) or its pharmacy acceptable salt are specially following compound:
" pharmacy acceptable salt " described in this specification sheets is concrete enumerates the salt that organic acids such as compound provided by the present invention and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, Hydrocerol A form; Or form salt with mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, Hydrogen bromide; Or the salt that forms with organic bases, like methylamine salt, ethylamine salt etc.
According to the present invention, the amides shown in the following general formula (1) or the preparation method of its pharmacy acceptable salt are provided.Be a preparing method's of the present invention embodiment preferred below:
1) A is phenyl ring or pyridine ring, and Y is SO
2, X is O, R
2Be H, B, C, R
1, R
3, R
4, R
5And R
6When same as described above:
Compound 1a and corresponding bromide 1b are dissolved among the DMF, and reaction obtains compound 1c in the presence of mineral alkali; 1c makes compound 1d through hydrolysis in alcohol/aqueous solution; 1d makes compound 1 with corresponding organic amine in the presence of condensing agent; Perhaps 1d and excessive chloride substitute reaction makes compound 1 with corresponding organic amine reaction after making acyl chlorides again.Described mineral alkali is salt of wormwood, yellow soda ash, sodium hydride; Described condensing agent is 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDCI)/1-hydroxy benzo triazole (HOBt); Used chloride substitute comprises thionyl chloride, phosphorus trichloride, POCl3, oxalyl chloride etc.R wherein
3, R
4, R
5And R
6Substituted compound 1a is through buying or (for example using method preparation as known in the art; Referring to document Journal of the Chemical Society; Perkin Transactions 1:Organic and Bio-Organic Chemistry (1972-1999), (4), 1043-7; 1979.Its disclosed full content is incorporated among the application by reference).
Perhaps,
2) A is a piperidine ring, and B, C do not exist, and Y is SO
2, X is O, R
2Be H, R
1, R
3, R
4, R
5And R
6When same as described above:
Hydroxymethyl piperidine 1e (available from reagent company) and tert-Butyl dicarbonate (Boc
2O) reaction generates 1f; Compound 1f makes 1g in triphenyl phosphorus, N-bromo-succinimide system; 1g and compound 1a generate 1h under the effect of highly basic sodium hydride then; The protection base that 1h takes off in trifluoroacetic acid on the nitrogen obtains compound 1i; 1i makes compound 1 with the TRIPHOSGENE 99.5 reaction with corresponding organic amine in the presence of alkali;
Perhaps, corresponding organic amine and N, N '-carbonyl dimidazoles reacting generating compound 1j, 1j and iodomethane reaction make compound 1k then; 1i and 1k make compound 1 under the effect of triethylamine.
Not necessarily, carry out functional group's conversion through the reaction of for example linked reaction, with compound 1 defined a kind of residue R
3, R
4, R
5And/or R
6Change into another kind of residue R
3, R
4, R
5And/or R
6
Not necessarily, compound 1 usefulness acid or alkali separate and/or handle, to obtain its salt.
According to the present invention, a kind of pharmaceutical composition is provided, it comprises amides or its pharmacy acceptable salt shown in general formulas (1) of one or more treatment significant quantities, and acceptable auxiliary material pharmaceutically.
Compound provided by the present invention and pharmaceutical composition can be various ways, like tablet, capsule, powder, syrup, solution, suspensoid and aerosol etc., and may reside in suitable solid or liquid vehicle or the diluent.Pharmaceutical composition of the present invention also can be stored in the disinfector of suitable injection or instillation.Also can comprise odorant agent, flavouring agent etc. in this pharmaceutical composition.
In the present invention, described pharmaceutical composition contains compound or its pharmacy acceptable salt shown in the formula (1) of safe and effective amount (like the 0.1-99.9 weight part, preferred 1-90 weight part); And the pharmaceutically acceptable carrier or the vehicle of its surplus, wherein the gross weight of compsn is 100 weight parts.Perhaps, pharmaceutical composition of the present invention contains and accounts for gross weight 0.1-99.9 weight %, preferably accounts for compound or its pharmacy acceptable salt shown in the formula (1) of gross weight 1-90 weight %; And the pharmaceutically acceptable carrier or the vehicle of its surplus, wherein the gross weight of compsn is 100 weight %.
In another preference; The preferred proportion of formula (1) compound and pharmaceutically acceptable carrier, vehicle or sustained release dosage is, formula (1) accounts for gross weight more than 60% as activeconstituents, and rest part accounts for gross weight 0-40%; The amount of rest part is preferably 1-20%, most preferably is 1-10%.
In addition, in described pharmaceutical composition, also can contain the medicine of other one or more treatments or prevent diabetes: N1,N1-Dimethylbiguanide, TZD class antidiabetic drug etc.When containing the active constituents of medicine of extra treatment or prevent diabetes in the described pharmaceutical composition, this absorption of active ingredient can be conventional amount used of the prior art or lower usually.
Compounds shown in the formula provided by the invention (1) or the pharmaceutical composition that comprises formula (1) compound can comprise humans and animals to the clinical use of Mammals, and that route of administration can comprise is oral, nasal cavity suction, Transdermal absorption, pulmonary administration or gi tract etc.Preferred route of administration is oral.Be preferably unit dosage, and every dose comprise effective constituent 0.01mg-200mg, preferred 0.5mg-100mg, once or part vic.Which kind of instructions of taking that don't work, individual's optimal dose should be decided according to concrete treatment.Generally be to begin, increase dosage gradually until find only dosage from low dose.
But pharmaceutical composition administered through oral of the present invention and intravenously, intramuscular or administration such as subcutaneous.See that from the position that is easy to prepare preferred pharmaceutical composition is a solid-state composition, especially the capsule of filling of tablet and solid or liquid filling with administration.The oral administration of pharmaceutical composition is preferred.
Solid-state carrier comprises: starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose and white bole etc.; And liquid carrier comprises: sterilized water, polyoxyethylene glycol, non-ionics and edible oil (like Semen Maydis oil, peanut oil and til) etc., as long as be fit to the characteristic of activeconstituents and required specific administration mode.Normally used adjuvant also can advantageously be comprised in pharmaceutical compositions, for example seasonings, pigment, sanitas and inhibitor such as vitamin E, vitamins C, BHT and BHA.
Injectable preparation includes, but are not limited to, aseptic, injectable, aqueous, butyraceous solution, suspension liquid, emulsion etc.These preparations can also be configured parenteral suitable diluent, dispersion agent, wetting agent, suspension agent etc.Injectable like this preparation can be through filtration sterilization in holding back the strainer of bacterium.These preparations can also dispose with sterilant, described sterilant dissolving or be dispersed in the injectable medium or use additive method known in the art.
Compound shown in the formula (1) or its pharmacy acceptable salt and compsn thereof also can with the activeconstituents or the medication combined administration of other treatment or prevent diabetes.When two or more medication combined administration, generally have and be superior to the individually dosed respectively effects of two kinds of medicines.
In addition, the present invention also provides the method for a kind of prevention or treatment diabetes B, it is characterized in that, needs the object of prevention or treatment diabetes B to treat amides or its pharmacy acceptable salt shown in the general formula (1) of significant quantity.
Embodiment
Below will further specify the present invention with embodiment.These embodiment only are used to illustrate the present invention, but do not limit the present invention in any way.All parameters among the embodiment and all the other explanations except that explaining in addition, all are foundation with the quality.The experimental technique of unreceipted actual conditions among the embodiment, usually according to normal condition, or the condition of advising according to manufacturer.
Only if definition separately, the same meaning that employed all specialties and scientific words and those skilled in the art are familiar with in the literary composition.In addition, any with the institute similar content of putting down in writing or the equalization method and material all can be applicable in the inventive method.
Embodiment 1 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-phenylcyclohexane methane amide
7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1,1-dioxide
(10g drips p-Chlorobenzoic acid amide (7.7g, Nitromethane 99Min. 60mmol) (50mL) solution in Nitromethane 99Min. 74mmol) (90mL) solution to chlorosulfonic acid isocyanate in the time of 0 ℃.After 15 minutes, add Aluminum chloride anhydrous (10g), reflux 30 minutes, cooling, reaction solution is poured in the frozen water, filters, and filter cake use water washing, must product after the drying, not purifiedly directly carry out next step reaction.
4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] oil of Niobe
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1, (460mg 1.98mmol) is dissolved in DMF (15mL) to the 1-dioxide, adds K
2CO
3(150mg).(230mg, 1mmol), room temperature reaction spends the night to add the 4-bromomethyl-benzoic acid methyl ester after 30 minutes.Filter, filtrating concentrates the back column chromatography and gets white solid product (110mg), yield 28.7%.
1HNMR (400MHz, DMSO-d
6): δ 3.81 (s, 3H), 5.03 (s, 2H), 7.29 (d, J=8.4Hz 1H), 7.44 (d, J=8.8Hz2H), 7.74 (dd, J=2.4 and 8.8Hz 1H), 7.90 (m, 2H), 7.98 (d, J=2.4Hz 1H), 11.66 (s, 1H).
4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenylformic acid
With 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] (200mg 0.53mmol) joins in methanol (1: the 1) mixing solutions (15mL) oil of Niobe; Add NaOH (63mg), room temperature reaction spends the night.Remove methyl alcohol under reduced pressure, (3 * 5mL) wash water, and the aqueous solution is transferred pH=2 with 1mol/L HCl, separates out white solid, and filtration drying gets product (140mg), yield 73% with ETHYLE ACETATE.
1H NMR (300MHz, DMSO-d
6): δ 5.05 (s, 2H), 7.31 (d, J=8.7Hz 1H), 7.43 (d, J=8.4Hz 2H), 7.78 (dd, J=2.4 and 8.7Hz 1H), 7.89 (d, J=8.4Hz2H), 8.00 (d, J=2.1Hz 1H), 11.68 (s, 1H), 12.91 (s, 1H).
4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-phenylcyclohexane methane amide
With 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] phenylformic acid (100mg, 0.27mmol); 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) (79mg, 0.41mmol) (60mg 0.41mmol) joins in the dry methylene chloride (10mL) with 1-hydroxy benzo triazole (HOBt); (41mg, 0.41mmol) room temperature reaction spent the night stirring at room to add hexahydroaniline then to clarification in 45 minutes.The reaction solution water (3 * 10mL) washings, organic phase is used anhydrous sodium sulfate drying, filters, and removes solvent under reduced pressure, and the residue column chromatography gets the 90mg white solid.Yield 60.0%.
1H?NMR(300MHz，DMSO-d
6)：δ1.24-1.79(m，10H)，3.72(m，1H)，5.02(s，2H)，7.30(d，J＝8.7Hz?1H)，7.38(d，J＝8.1Hz?2H)，7.75-7.82(m，3H)，8.00(d，J＝2.1Hz?1H)，8.14(d，J＝8.4Hz?1H)，11.66(s，1H)。MS(ESI)：m/z?448(M+H)
+446(M-H)
-。
Embodiment 2 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-phenylcyclohexane methane amide
With 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenylformic acid (200mg, 0.55mmol) and sulfur oxychloride (0.2mL) add in the dry methylene chloride (15mL) reflux 2 hours.Remove solvent and unnecessary sulfur oxychloride under reduced pressure, add dry methylene chloride (15mL), triethylamine (0.14mL) again, N-methylcyclohexylamine (120mg); TLC detects, reaction accomplish afterreaction liquid successively water (10mL) (2 * 10mL) wash, and organic phase is used anhydrous sodium sulfate drying with Hydrogen chloride; Filter, remove solvent under reduced pressure, the residue column chromatography gets 130mg 4-[(7-chloro-1; 1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2; 4-benzothiadiazine-2-yl) methyl]-N-methyl-N-phenylcyclohexane methane amide, yield 52%.
1H NMR (400MHz, DMSO-d
6): δ 0.81-1.82 (m, 10H), 2.75,2.80 (2 * m, 3H), 325 (m, 1H), 5.01 (s, 2H), 7.30 (m, 3H), 7.37 (d, J=8.4Hz, 2H), 7.78 (dd, J=2.0 and 8.8Hz, 1H), 7.99 (d, J=2.4Hz, 1H), 10.04 (s, 1H).MS(ESI)：m/z?462(M+H)
+。
Embodiment 3 3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-phenylcyclohexane methane amide
3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] oil of Niobe
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1, (920mg 3.96mmol) is dissolved in DMF (40mL) to the 1-dioxide, adds K
2CO
3(300mg).(460mg, 2mmol), room temperature reaction spends the night to add the 3-bromomethyl-benzoic acid methyl ester after 30 minutes.Filter, filtrating concentrates the back column chromatography and gets white solid product (270mg), yield 35%.
3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenylformic acid
With 3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] (300mg 0.79mmol) joins in methanol (1: the 1) mixing solutions (30mL) oil of Niobe; Add NaOH (80mg), room temperature reaction spends the night.Remove methyl alcohol under reduced pressure, (3 * 10mL) wash water, and the aqueous solution is transferred pH=2 with 1mol/LHCl, separates out white solid, and filtration drying gets product (210mg), yield 75% with ETHYLE ACETATE.
3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-phenylcyclohexane methane amide
With 3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] phenylformic acid (100mg, 0.27mmol); EDCI (79mg, 0.41mmol) and HOBt (60mg 0.41mmol) joins in the dry methylene chloride (10mL); (41mg, 0.41mmol) room temperature reaction spent the night stirring at room to add hexahydroaniline then to clarification in 45 minutes.The reaction solution water (3 * 10mL) washings, organic phase is used anhydrous sodium sulfate drying, filters, and removes solvent under reduced pressure, and the residue column chromatography gets product.Yield 67.4%.
1H?NMR(300MHz，DMSO-d
6)：δ1.23-1.78(m，10H)，3.75(m，1H)，5.02(s，2H)，7.32-7.46(m，3H)，7.72-7.81(m，3H)，7.98(d，J＝2.4Hz?1H)，8.17(d，J＝8.1Hz?1H)，11.65(s，1H)。MS(ESI)：m/z?448(M+H)
+；446(M-H)
-。
Embodiment 4 3-[(7-bromo-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-(2-adamantyl) BM
Replace 3-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenylformic acid with 3-[(7-bromo-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenylformic acid; N-methyl-N-2-amantadine replaces hexahydroaniline, and all the other desired raw materials, reagent and preparation method make target compound with embodiment 3.(ESI)：m/z?558(M+H)
+；556(M-H)
-。
Embodiment 5 1-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-N-cyclohexyl ring propyl formamide
1-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl } the cyclopropyl carboxylic acid methyl esters
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1, (1.4g 6mmol) is dissolved in DMF (40mL) to the 1-dioxide, adds K
2CO
3(0.41g).(0.81mg, 3mmol), room temperature reaction spends the night the methyl cyclopropanecarboxylate to add 1-[4-(brooethyl) phenyl] after 15 minutes.Filter, filtrating concentrates the back column chromatography and gets white solid (0.57g), yield 45.3%.
1H NMR (300MHz, CDCl
3): δ 1.12 (m, 2H), 1.58 (m, 2H), 3.58 (s, 3H), 5.04 (s; 2H), 6.97 (d, J=8.4Hz 1H), 7.27 (d, J=8.4Hz 2H), 7.37 (d, J=8.4Hz 2H); (7.50 dd, J=2.1 and 9.0Hz 1H), 7.83 (d, J=2.4Hz 1H), 9.42 (s, 1H).
1-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl } cyclopropyl carboxylic acid
With 1-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] phenyl } (556mg 1.32mmol) joins in methanol (1: the 1) mixing solutions (50mL) the cyclopropyl carboxylic acid methyl esters; Add NaOH (159mg), room temperature reaction spends the night.Remove methyl alcohol under reduced pressure, (3 * 6mL) wash water, and the aqueous solution is transferred pH=2 with 1mol/L HCl, separates out white solid, and filtration drying gets product (430mg), yield 80.7% with ETHYLE ACETATE.
1-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-N-cyclohexyl ring propyl formamide
With 1-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl } cyclopropanecarboxylic acid (100mg, 0.25mmol), EDCI (95mg, 0.50mmol) and HOBt (67mg 0.50mmol) joins dry CH
2Cl
2(15mL), stirring at room added hexahydroaniline (49mg, 0.50mmol) stirred overnight at room temperature to clarification in 45 minutes then.The reaction solution water (3 * 15mL) washings, organic phase is used anhydrous sodium sulfate drying, filters, and removes solvent under reduced pressure, and the residue column chromatography gets the 77mg white solid.Yield 63.9%.
1H NMR (300MHz, DMSO-d
6): δ 0.94-1.68 (m, 14H), 3.64 (m, 1H), 5.02 (s, 2H), 7.24-7.33 (m, 5H), 7.76 (dd, J=2.1 and 8.4Hz 1H), 7.95 (d, J=2.1Hz 1H), 11.61 (s, 1H).MS(ESI)：m/z?488(M+H)
+；486(M-H)
-。
Embodiment 6 2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-N-cyclohexyl-2-methyl propanamide synthetic
2-[4-(methyl) phenyl]-2 Methylpropionic acid methyl esters
(1.6g 0.01mol) is dissolved among the DMF (50mL), and 0 ℃ adds sodium hydride (1.6g), and methyl iodide (2.5mL) rises to the room temperature afterreaction gradually and spends the night with 4-methylphenyl acetic acid methyl esters.Do not generate ethyl acetate extraction, saturated common salt water washing ethyl acetate layer to wherein slowly adding frozen water to there being gas in the time of 0 ℃.Column chromatography gets 1.4g oily matter behind the anhydrous magnesium sulfate drying, yield 72%.
1H?NMR(300MHz，CDCl
3)：δ1.56(s，6H)，2.32(s，3H)，3.64(s，3H)，7.12(m，4H)。
2-[4-(brooethyl) phenyl]-2 Methylpropionic acid methyl esters
With 2-[4-(methyl) phenyl]-2 Methylpropionic acid methyl esters (1.92g 0.01mol) is dissolved in the tetracol phenixin (50mL), adds azo-bis-isobutyl cyanide (AIBN) successively (0.1g), the N-bromo-succinimide (3.6g, 0.02mol).The reaction solution reflux after 24 hours directly the evaporating column chromatography obtain product, yield 80%.
1H?NMR(300MHz，CDCl
3)：δ1.57(s，6H)，3.65(s，3H)，4.48(s，2H)，7.34(m，4H)。
2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-the 2 Methylpropionic acid methyl esters
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1, (1.4g 6mmol) is dissolved in DMF (40mL) to the 1-dioxide, adds K
2CO
3(0.41g).[4-(brooethyl) phenyl]-(0.81mg, 3mmol), room temperature reaction spends the night the 2 Methylpropionic acid methyl esters to add 2-after 15 minutes.Filter, filtrating concentrates the back column chromatography and gets white solid, yield 30%.MS(ESI)：m/z?445(M+Na)
+；421(M-H)
-。
2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-2 Methylpropionic acid
With 2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] phenyl }-(822mg 2mmol) joins in methanol (1: the 1) mixing solutions (50mL) the 2 Methylpropionic acid methyl esters; Add NaOH (240mg), room temperature reaction spends the night.Remove methyl alcohol under reduced pressure, (3 * 10mL) wash water, and the aqueous solution is transferred pH=2 with 1mol/L HCl, separates out white solid, and filtration drying gets product (470mg), yield 58% with ETHYLE ACETATE.
2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-N-cyclohexyl-2-methyl propanamide
With 2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenyl }-2 Methylpropionic acid (100mg, 0.25mmol), EDCI (95mg, 0.50mmol) and HOBt (67mg 0.50mmol) joins dry CH
2Cl
2(15mL), stirring at room added hexahydroaniline (49mg, 0.50mmol) stirred overnight at room temperature to clarification in 45 minutes then.The reaction solution water (3 * 15mL) washings, organic phase is used anhydrous sodium sulfate drying, filters, and removes solvent under reduced pressure, and the residue column chromatography gets product, yield 24.3%.
1H?NMR(300MHz，DMSO-d
6)：δ0.99-1.63(m，16H)，3.53(m，1H)，4.94(s，2H)，6.92(d，1H)，7.25(m，5H)，7.77(d，2H)，7.97(s，1H)，11.58(s，1H)。MS(ESI)：m/z?489(M+H)
+；488(M-H)
-。
Embodiment 7 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-cyclohexyl piperidines-1-methane amide
4-(methylol) piperidines-1-t-butyl formate
(add triethylamine (10.8mL) among the 6g, dichloromethane solution 52mmol) (200mL), drip Boc to the 4-hydroxymethyl piperidine
2(room temperature reaction spends the night O for 12.4g, methylene dichloride 57mmol) (50mL) solution.(2 * 100mL) washings, column chromatography gets colorless oil 4-(methylol) piperidines-1-t-butyl formate 9.98g, yield 89% to reaction solution behind drying, the evaporate to dryness with Hydrogen chloride.
1H?NMR(300MHz，CDCl
3)：δ1.10(m，2H)，1.43(s，9H)，1.59-1.72(m，3H)，2.64-2.73(m，2H)，3.47(d，J＝3.0Hz?2H)，4.08(m，2H)。
4-(brooethyl) piperidines-1-t-butyl formate
To 4-(methylol) piperidines-1-t-butyl formate (2.2g, add successively in methylene dichloride 10mmol) (80mL) solution triphenyl phosphorus (5.4g, 20mmol), N-bromo-succinimide (NBS) (3.6g, 20mmol), under the room temperature reaction spend the night.Column chromatography gets oily matter 4-(brooethyl) piperidines-1-t-butyl formate 1.69g, yield 59.7% after the solvent evaporated.
1H?NMR(300MHz，CDCl
3)：δ1.14-1.23(m，2H)，1.44(s，9H)，1.77-1.84(m，3H)，2.63-2.72(m，2H)，3.27(d，J＝6.0Hz?2H)，4.10(m，2H)。
4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] piperidines-1-t-butyl formate
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1; (1.8g 7.8mmol) is dissolved among the DMF (25mL) the 1-dioxide, slowly adds sodium hydride (0.34g) in batches; (0.87g 3.1mmol), is heated to 60 ℃ of reactions and spends the night to add 4-(brooethyl) piperidines-1-t-butyl formate after 30 minutes.After being cooled to room temperature, in reaction solution, slowly add entry (50mL), ethyl acetate extraction (3 * 50mL); The combined ethyl acetate layer, with saturated nacl aqueous solution washing (3 * 60mL), drying; Column chromatography gets white solid 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1 after the solvent evaporated; 2,4-benzothiadiazine-2-yl) methyl] piperidines-1-t-butyl formate 0.29g, yield 21.5%.
1H NMR (300MHz, DMSO-d
6): δ 113-1.22 (m, 2H), 1.38 (s, 9H), 1.67-2.01 (m, 3H), 2.72 (m; 2H), 3.95 (m, 2H), 4.17 (d, J=6.3Hz 2H), 7.27 (d, J=9.0Hz 1H); (7.68 dd, J=2.4 and 8.7Hz 1H), 7.81 (d, J=2.4Hz 1H), 12.28 (s, 1H).
7-chloro-2-(piperidin-4-yl methyl)-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1,1-dioxide
With 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2; 4-benzothiadiazine-2-yl) methyl] piperidines-1-t-butyl formate (0.35g) is dissolved in the dioxane (20mL), adds trifluoroacetic acid (20mL), is heated to 60 ℃; Reaction finishes the trifluoroacetate that the back solvent evaporated gets target compound, not purifiedly directly is used for next step reaction.
3-methyl isophthalic acid-{ [methyl (cyclohexyl) amido] formyl radical }-1H-iodate imidazoles-3-
N-methylcyclohexylamine (113g), N, N '-carbonyl dimidazoles (1.92g) join in the methylene dichloride (40mL) successively, room temperature reaction 24h, and the evaporate to dryness methylene dichloride gets oily matter.Oily matter is dissolved in the acetonitrile (20mL), adds methyl iodide (3mL), room temperature reaction after 24 hours solvent evaporated make 3-methyl isophthalic acid-{ [methyl (cyclohexyl) amido] formyl radical }-1H-iodate imidazoles-3-, not purifiedly directly be used for next step reaction.
4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-cyclohexyl piperidines-1-methane amide
With 7-chloro-2-(piperidin-4-yl methyl)-2H-1; 2; 4-benzothiadiazine-3 (4H)-ketone-1, the trifluoroacetate (0.16g) of 1-dioxide (12) joins in the methylene dichloride (15mL), adds triethylamine (0.13mL) successively; 3-methyl isophthalic acid-{ [methyl (cyclohexyl) amido] formyl radical }-1H-iodate imidazoles-3-(0.3g), room temperature reaction 24 hours.The reaction solution water (2 * 5mL) washings, column chromatography gets off-white color solid 4-[(7-chloro-1,1-titanium dioxide-3-oxo-3 behind organic phase drying, the evaporate to dryness; 4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-cyclohexyl piperidines-1-methane amide 0.1g, yield 59.2%.
1H NMR (300MHz, DMSO-d
6): δ 1.10-1.80 (m, 14H), 2.56-2.60 (m, 3H), 3.06-3.13 (m, 6H), 3.40 (m, 1H), 3.66 (m, 1H), 7.28 (d, J=8.7Hz 1H), 7.77 (dd, J=2.7 and 9.0Hz 1H), 7.94 (d, J=2.4Hz 1H).
13CNMR(400MHz，DMSO-d
6)164.27，150.11，135.36，134.08，127.61，123.59，121.94，119.81，56.58，46.77，46.25，35.96，31.08，29.84，29.42，26.00，25.64，9.15。MS(ESI)：m/z?469(M+H)
+；467(M-H)
-。
Embodiment 8 6-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-suberyl nicotinic acid methane amide
6-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] nicotinic acid methyl ester
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1, (1000mg 4.4mmol) is dissolved in DMF (20mL) to the 1-dioxide, adds K
2CO
3(300mg).(500mg, 2.2mmol), room temperature reaction spends the night to add 6-brooethyl nicotinic acid methyl ester after 30 minutes.Filter, filtrating concentrates the back column chromatography and gets white solid product (580mg), yield 35%.
6-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] nicotinic acid
(380mg 1mmol) joins in methanol (1: the 1) mixing solutions (30mL), adds NaOH (80mg), and room temperature reaction spends the night with 6-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] nicotinic acid methyl ester.Remove methyl alcohol under reduced pressure, (3 * 10mL) wash water, and the aqueous solution is transferred pH=2 with 1mol/LHCl, separates out white solid, and filtration drying gets product (300mg), yield 82% with ETHYLE ACETATE.
6-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-suberyl nicotinic acid methane amide
With 6-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] nicotinic acid (130mg, 0.35mmol), HOBt (72mg, 0.53mmol) and EDCI (102mg 0.53mmol) joins the dry CH of 10mL
2Cl
2In, stirring at room added cycloheptylamine (0.068mL) stirred overnight at room temperature to clarification in 45 minutes then.The reaction solution water (3 * 10mL) washings, organic phase is used anhydrous sodium sulfate drying, filters; Remove solvent under reduced pressure, residue silica gel column chromatography (methylene dichloride: methyl alcohol=150: 1, volume ratio) gets 64mg white solid 6-[(4-methyl-7-chloro-1; 1-dioxo-3,4-dihydro-2H-1,2; 4-benzothiadiazine-2-yl) methyl]-N-suberyl cigarette methane amide, yield 40%.MS(ESI)：m/z?463(M+H)
+461(M-H)
-。
Embodiment 9 5-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-cyclohexyl-2-pyridine carboxamide
Replace 6-brooethyl nicotinic acid methyl ester with 5-bromo methyl cycloheptapyridine-2-carboxylate methyl ester, hexahydroaniline replaces cycloheptylamine, and all the other desired raw materials, reagent and preparation method obtain target compound with embodiment 8.MS(ESI)：m/z?449(M+H)
+447(M-H)
-。
Embodiment 10 3-[(7-cyanic acid-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-(2-adamantyl) BM
In dry tube sealing, add dry DMF (5mL) successively, Virahol (0.3mL), yellow soda ash (159mg; 1.5mmol), palladium (1.4mg, 0.006mmol); 3-[(7-bromo-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-(2-adamantyl) BM (840mg, 1.5mmol).After reaction solution is heated to 140 ℃ to wherein adding yellow prussiate of potash (K
4Fe (CN)
4, 221mg, 0.6mmol).Tube sealing is sealed continued reaction 10 hours.Be cooled to room temperature, filter, column chromatography gets product 63mg behind the evaporate to dryness DMF, yield 8.3%.MS(ESI)：m/z?505(M+H)
+503(M-H)
-。
Embodiment 11 2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenoxy }-2-methyl-N-cyclopropyl-N-cyclohexyl propionic acid amide
2-methyl-2-is to the tolyloxy methyl propionate
With p-cresol (11g, 10mmol), 2-methyl-2 bromopropionic acid methyl esters (3.7g, 20mmol), (2.76g 20mmol) is added in DMF (100mL) solution salt of wormwood successively, and room temperature reaction 48 hours filters back solvent evaporated column chromatography and gets product 1.2g, yield 54%.
2-methyl-2-para-bromo toluene oxygen base methyl propionate
To 2-methyl-2-to tolyloxy methyl propionate (2.1g; Add AIBN (0.1g), N-bromo-succinimide (3.6g in tetracol phenixin 10mmol) (50mL) solution successively; 20mmol), the reaction solution reflux after 24 hours directly the evaporating column chromatography obtain product, yield 80%.
2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenoxy }-the 2 Methylpropionic acid methyl esters
With 7-chloro-2H-1,2,4-benzothiadiazine-3 (4H)-ketone-1, (2.8g 12mmol) is dissolved in DMF (50mL) to the 1-dioxide, adds K
2CO
3(0.85g).Methyl-(1.7g, 6mmol), room temperature reaction spends the night 2-para-bromo toluene oxygen base methyl propionate to add 2-after 15 minutes.Filter, filtrating concentrates the back column chromatography and gets white solid, yield 24%.
2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenoxy }-2 Methylpropionic acid
With 2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl] phenoxy }-(880mg 2mmol) joins in methanol (1: the 1) mixing solutions (50mL) the 2 Methylpropionic acid methyl esters; Add NaOH (200mg), room temperature reaction spends the night.Remove methyl alcohol under reduced pressure, (3 * 10mL) wash water, and the aqueous solution is transferred pH=2 with 1mol/L HCl, separates out white solid, and filtration drying gets product (630mg), yield 74% with ETHYLE ACETATE.MS(ESI)：423(M-H)
-。
2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenoxy }-2-methyl-N-cyclopropyl-N-cyclohexyl propionic acid amide
With 2-{4-[(7-chloro-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl] phenoxy }-2 Methylpropionic acid (110mg, 0.25mmol), EDCI (95mg, 0.50mmol) and HOBt (67mg 0.50mmol) joins dry CH
2Cl
2(15mL), stirring at room added N-cyclopropyl rings hexylamine (70mg, 0.50mmol) stirred overnight at room temperature to clarification in 45 minutes then.The reaction solution water (3 * 15mL) washings, organic phase is used anhydrous sodium sulfate drying, filters, and removes solvent under reduced pressure, and the residue column chromatography gets product, yield 28%.MS(ESI)：m/z?546(M+H)
+；544(M-H)
-。
Embodiment 12 3-[(7-carbamyl-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-(2-adamantyl) BM
With 3-[(7-cyanic acid-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-(2-adamantyl) BM (100mg, 0.18mmol), ethylidenehydroxylamine (177mg, 3mmol), InCl
3(11mg 5%mmol) joins in toluene (2mL) solution, and reflux 3 hours is filtered, and column chromatography gets product behind the solution evaporate to dryness, yield 80%.MS(ESI)：m/z?523(M+H)
+521(M-H)
-。
Embodiment 13 3-[(7-bromo-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-suberyl BM
Replace N-methyl-2-amantadine with N-methyl cycloheptylamine, all the other desired raw materials, reagent and preparation method make target compound with embodiment 4.(ESI)：m/z?520(M+H)
+；518(M-H)
-。
Embodiment 14 3-[(7-(4-N-METHYL PIPERAZINE-1-yl)-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-suberyl BM
3-[(7-bromo-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1; 2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-suberyl BM (210mg, 0.4mmol), 4-N-METHYL PIPERAZINE (48mg; 0.48mmol), 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene (BINAP) (25mg; 0.04mmol), sodium tert-butoxide (112mg, 1.12mmol), Pd
2(dba)
3(118.2mg 0.02mmol) joins in the dry toluene (5mL) successively, and nitrogen protection refluxed 3 hours; Add ETHYLE ACETATE in the cooling afterreaction liquid, filter, organic phase has the sodium bicarbonate aqueous solution washing; Anhydrous magnesium sulfate drying, column chromatography gets product 43mg behind the evaporate to dryness, yield 20%.(ESI)：m/z?540(M+H)
+；538(M-H)
-。
Embodiment 15 3-[(7-(1H-1,2,4-triazole-1-yl)-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-suberyl BM
With 3-[(7-bromo-1,1-titanium dioxide-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-2-yl) methyl]-N-methyl-N-suberyl BM (182mg, 0.35mmol), anti-form-1, the 2-cyclohexanediamine (210mg, 0.4mmol), K
3P0
4(8.5mg, 0.06mmol), 1,2, (28mg 0.6mmol) joins in the tube sealing that dioxane (3mL) is housed the 4-triazole successively, is heated to 120 ℃ and reacts to raw material and disappear the appoint to office is airtight.Cooling adds methylene dichloride in the solution, filter back evaporate to dryness column chromatography and get product (18mg), yield 10%.(ESI)：m/z?509(M+H)
+；507(M-H)
-。
Embodiment 16-94
According to the method for describing among the embodiment 1-15, such scheme or known by one of skill in the art other similar approach, use other suitable reagent, synthesize the embodiment 16-94 in table 1.
Table 1
Embodiment 95 The compounds of this invention are to the active restraining effect of mouse 11 β-HSD1
Adopt molecular biology method; To be cloned into the PcDNA3-VSVtag carrier for expression of eukaryon available from mouse 11 β-HSD1 gene order of NIH Mammalian Gene Collection (NIH MGC); Transfection obtains the cell mixing clone of stable transfection in the HEK293 cell after G418 (0.75g/L) screening after restriction enzyme digestion and dna sequencing checking.The trysinization cell mixing is cloned and with unicellular inoculation 96 well culture plates, is given conditionality cell culture fluid (HEK293 cell culture supernatant) simultaneously, after 14-20 days, obtains unicellular propagation clone.Amplification back trysinization collecting cell, centrifugal after the ultrasonication (4 ℃, 1500rpm, 10min), supernatant once more ultracentrifugation (4 ℃, 100000g, 1h), phosphate buffered saline buffer (40mM Na
2HP0
4, 1mM EDTA, 5% glycerine) and mouse 11 β-HSD1 purifying enzyme that resuspended post precipitation obtains ,-80 ℃ are frozen subsequent use.
Adopting SPA (Scintillation proximity assay) is that liquid dodges near determination techniques, measures the restraining effect of compound to mouse 11 β-HSD1.The testing compound of different concns is added in 96 orifice plates, add afterwards 80 μ l the A reaction solution (1.25mM NADPH, 25nM KE [and 1,2-(n)
3H] and the HEPES damping fluid), add 37 ℃ of concussion reaction 1h after 80 μ g/ml mouse, 11 β-HSD1 purifying enzyme again.Reaction finishes every hole, back and adds 70 μ l β liquid (10mg/ml resin particle, 314 μ M glycyrrhetinic acids, 3ug/ml HYDROCORTISONE INJECTIONS antibody and confining liquid), and 15 ℃ of concussions stopped reading the CPM value after the enzyme reaction in 2 hours.Experiment is provided with enzyme control wells (containing the DMSO with the test hole same amount) and this bottom outlet (containing the DMSO with the test hole same amount, no mouse 11 β-HSD1 purifying enzyme) simultaneously.By the inhibiting rate of following formula computerized compound to mouse 11 β-HSD1, and the computerized compound suppresses the IC of mouse 11 β-HSD1
50Value.Inhibiting rate=(testing compound hole this bottom outlet of CPM-CPM)/(this bottom outlet of enzyme control wells CPM-CPM) * 100%.Record part of compounds the test result of mouse 11 β-HSD1 activity inhibition is shown the IC of The compounds of this invention
50Between 10 μ M and 1nM, wherein the test result of part of compounds is seen table 2.
Embodiment 96 The compounds of this invention are to the active restraining effect of people 11 β-HSD1
The expression of people 11 β-HSD1 and purification experiment method are with embodiment 95, and people 11 β-HSD1 gene order is available from NIHMammalian Gene Collection (NIH MGC).Compound to people 11 β-HSD1 activity inhibition testing method with embodiment 95, the used purifying enzyme 11 β-HSD1 that behaves.Record part of compounds the test result of people 11 β-HSD1 activity inhibition is shown the IC of The compounds of this invention
50Between 10 μ M and 1nM, wherein the test result of part of compounds is seen table 2.
Table 2 part of compounds is active to the inhibition of people, mouse 11 β-HSD1 enzyme
Industrial applicibility
The preparation method of amides of the present invention has advantages such as reaction conditions gentleness, operation and aftertreatment be simple.
Amides of the present invention has very high inhibition activity to people and mouse 11 β-HSD1, and therefore compound of the present invention can be used to prepare the medicine of treating and preventing to be regulated by 11 β-HSD1 disorderly associated diseases.
The aforementioned detailed explanation and the embodiment of companion only are illustrative, but not are intended to limit scope of the present invention.Under the situation that does not depart from essence of the present invention and scope thereof, can carry out all kinds of variations and modification.
Claims (10)
1. the amides shown in one type of following general formula (1) or its pharmacy acceptable salt:
Wherein,
A is saturated or unsaturated 0-3 O or the heteroatomic ring of N of containing of 3-8 unit;
B does not exist or is O, S or N;
C does not exist or C is-C (R
7R
8)-; R wherein
7And R
8Be the C1-C6 alkyl identical or differently, or R
7And R
8Form the C3-C8 naphthenic base with the carbon atom that they connected;
Y is CH
2, CO, CS, SO or SO
2
X is S or O;
R
1Representative-NR
9R
10Or be selected from following group:
R wherein
9Cyclic hydrocarbon radical for alkyl or the C3-C6 of hydrogen, replacement or unsubstituted C1-C6.
R
10Alkyl for C1-C6; The naphthenic base of replacement or unsubstituted C3-C10; The cycloalkenyl group of C3-C10; Replace or unsubstituted C6-C10 aryl, replace or unsubstituted C6-C10 aryl C1-C6 alkyl, perhaps replacement or the unsubstituted 1-3 of containing is selected from the heteroatomic 5-7 membered aromatic heterocycle base in oxygen, sulphur and the nitrogen;
Said substituted substituted radical all is selected from halogen, cyanic acid, and nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, the alkyl of C1-C6, sulfydryl, the C6-C10 aryl contains 1-3 and is selected from the heteroatomic 5-7 membered aromatic heterocycle base in sulphur, oxygen and the nitrogen ,-COOR
11,-NR
11R
12,-OR
11,-COR
11,-CONR
11R
12,-SR
11,-SO
3R
11,-SO
2NR
11R
12,-SOR
11Or-SO
2R
11In;
R
2Alkyl for hydrogen or C1-C6;
R
3, R
4, R
5And R
6Be hydrogen independently, halogen, cyanic acid, nitro; Hydroxyl, methylol, trifluoromethyl, trifluoromethoxy; The alkyl of C1-C6, sulfydryl, C6-C10 aryl; Contain 1-3 and be selected from the heteroatomic 5-7 membered aromatic heterocycle base in sulphur, oxygen and the nitrogen, the substituted 1-3 of containing of the alkyl of C1-C4 5-7 unit heterocyclic radical that is selected from nitrogen-atoms ,-COOR
11,-NR
11R
12,-OR
11,-COR
11,-CONR
11R
12,-SR
11,-SO
3R
11,-SO
2NR
11R
12,-SOR
11Or-SO
2R
11
Wherein, R
11And R
12Be H independently, phenyl, pyridyl, benzyl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl group; Perhaps, radicals R
11And R
12Be joined together to form 4-7 unit ring.
2. the amides shown in the general formula according to claim 1 (1) or its pharmacy acceptable salt, wherein, in the general formula (1):
A is phenyl ring, pyridine ring or piperidine ring;
B does not exist or is oxygen;
C does not exist or is-C (R
7R
8)-, be R wherein
7And R
8All be methyl, or R
7And R
8The carbon atom that is connected with them forms cyclopropyl;
Y is SO
2
X is O;
R
2Be hydrogen;
R
1, R
3, R
4, R
5And R
6Definition with claim 1.
3. the amides shown in the general formula according to claim 2 (1) or its pharmacy acceptable salt, wherein, in the general formula (1):
R
1Representative-NR
9R
10Or be selected from following group:
R wherein
9Cyclic hydrocarbon radical for alkyl or the C3-C6 of hydrogen, replacement or unsubstituted C1-C6;
R
10Be the alkyl of C1-C6, the naphthenic base of replacement or unsubstituted C3-C10, the cycloalkenyl group of C3-C10 replaces or unsubstituted phenyl, replaces or unsubstituted benzyl, perhaps replaces or the unsubstituted pyridine base;
Said substituted substituted radical all is selected from halogen, cyanic acid, and nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, the alkyl of C1-C6, sulfydryl, the C6-C10 aryl contains 1-3 and is selected from the heteroatomic 5-7 membered aromatic heterocycle base in sulphur, oxygen and the nitrogen ,-COOR
11,-NR
11R
12,-OR
11,-COR
11,-CONR
11R
12,-SR
11,-SO
3R
11,-SO
2NR
11R
12,-SOR
11Or-SO
2R
11In;
R
11And R
12Be H independently, phenyl, pyridyl, benzyl, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl group; Perhaps, radicals R
11And R
12Be joined together to form 4-7 unit ring;
R
3, R
4, R
5And R
6Be hydrogen, halogen, cyanic acid, hydroxyl, methyl, methylol, amino methyl, trifluoromethoxy independently, to fluorophenyl, to cyano-phenyl, phenyl, pyridyl, 1; 2,4-triazol radical, imidazolyl, pyrazolyl, carboxyl, carbamyl, piperidyl, piperazinyl or 4-N-METHYL PIPERAZINE base.
4. the amides shown in the general formula according to claim 1 (1) or its pharmacy acceptable salt, wherein, said compound specifically is selected from the following compound:
5. the preparation method of an amides or its pharmacy acceptable salt wherein, comprises following technical scheme:
1) A is phenyl ring or pyridine ring, B, C, R
1, R
3, R
4, R
5And R
6When identical with claim 1:
Compound 1a and corresponding bromide 1b are dissolved among the DMF, and reaction obtains compound 1c in the presence of mineral alkali; 1c makes compound 1d through hydrolysis in alcohol/aqueous solution; 1d makes compound 1 with corresponding organic amine in the presence of condensing agent; Perhaps 1d and excessive chloride substitute reaction makes compound 1 with corresponding organic amine reaction after making acyl chlorides again; Described mineral alkali is selected from salt of wormwood, yellow soda ash and the sodium hydride; Described condensing agent is selected from 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDCI) and the 1-hydroxy benzo triazole (HOBt); Used chloride substitute is selected from thionyl chloride, phosphorus trichloride, POCl3 and the oxalyl chloride;
Perhaps,
2) R
1, R
3, R
4, R
5And R
6When identical with claim 1:
Hydroxymethyl piperidine 1e and tert-Butyl dicarbonate Boc
2The O reaction generates 1f; Compound 1f makes 1g in triphenyl phosphorus, N-bromo-succinimide system; 1g and compound 1a generate 1h under the effect of highly basic sodium hydride then; The protection base that 1h takes off in trifluoroacetic acid on the nitrogen obtains compound 1i; 1i makes compound 1 with the TRIPHOSGENE 99.5 reaction with corresponding organic amine in the presence of alkali;
Perhaps, corresponding organic amine and N, N '-carbonyl dimidazoles reacting generating compound 1j, 1j and iodomethane reaction make compound 1k then; 1i and 1k make compound 1 under the effect of triethylamine.
6. the amides shown in the described general formula of claim 1 (1) or its pharmacy acceptable salt purposes in the medicine of the selective depressant of preparation 11beta-Hydroxysteroid dehydrogenase I type enzyme.
7. the amides shown in the described general formula of claim 1 (1) or its pharmacy acceptable salt are used for preventing or treating the purposes of the medicine of the disease that is mediated by 11beta-Hydroxysteroid dehydrogenase I type enzyme in preparation.
8. the amides shown in the described general formula of claim 1 (1) or its pharmacy acceptable salt are used for preventing or treat the purposes of the medicine of diabetes B, obesity or metabolism syndrome in preparation.
9. pharmaceutical composition, it comprises amides or its pharmacy acceptable salt shown in described general formulas of claim 1 (1) of one or more treatment significant quantities, and acceptable auxiliary material pharmaceutically.
10. pharmaceutical composition according to claim 9 is characterized in that, said pharmaceutical composition is a unit dosage, and amides or its pharmacy acceptable salt shown in every dose of described general formula of claim 1 (1) that comprises 0.01mg-200mg.
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|---|---|---|---|
| CN2011100020938A CN102584741A (en) | 2011-01-06 | 2011-01-06 | Amides compound, method for preparing same, composition and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| Publication Number | Publication Date |
|---|---|
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Family
ID=46474068
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8933239B1 (en) | 2013-07-16 | 2015-01-13 | Dow Global Technologies Llc | Bis(aryl)acetal compounds |
| US8962779B2 (en) | 2013-07-16 | 2015-02-24 | Dow Global Technologies Llc | Method of forming polyaryl polymers |
| US9063420B2 (en) | 2013-07-16 | 2015-06-23 | Rohm And Haas Electronic Materials Llc | Photoresist composition, coated substrate, and method of forming electronic device |
| US9410016B2 (en) | 2013-07-16 | 2016-08-09 | Dow Global Technologies Llc | Aromatic polyacetals and articles comprising them |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726206A (en) * | 2002-12-20 | 2006-01-25 | 麦克公司 | Triazole derivative as 11-beta-hydroxysteroid dehydrogenase-1 inhibitor |
| CN1729158A (en) * | 2002-12-23 | 2006-02-01 | 詹森药业有限公司 | Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors |
| CN1795181A (en) * | 2003-05-29 | 2006-06-28 | 麦克公司 | Triazole derivatives as inhibitors of 11-beta hydroxysteroid dehydrogenase-1 |
| WO2006122319A2 (en) * | 2005-05-11 | 2006-11-16 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| EP1787982A2 (en) * | 2003-04-11 | 2007-05-23 | Novo Nordisk A/S | 11Beta-Hydroxysteroid dehydrogenase type 1 active compounds |
| CN101817767A (en) * | 2009-02-26 | 2010-09-01 | 中国科学院上海药物研究所 | Substituted sulphonamide compound and preparation method, medicine composition and application thereof |
-
2011
- 2011-01-06 CN CN2011100020938A patent/CN102584741A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726206A (en) * | 2002-12-20 | 2006-01-25 | 麦克公司 | Triazole derivative as 11-beta-hydroxysteroid dehydrogenase-1 inhibitor |
| CN1729158A (en) * | 2002-12-23 | 2006-02-01 | 詹森药业有限公司 | Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors |
| EP1787982A2 (en) * | 2003-04-11 | 2007-05-23 | Novo Nordisk A/S | 11Beta-Hydroxysteroid dehydrogenase type 1 active compounds |
| CN1795181A (en) * | 2003-05-29 | 2006-06-28 | 麦克公司 | Triazole derivatives as inhibitors of 11-beta hydroxysteroid dehydrogenase-1 |
| WO2006122319A2 (en) * | 2005-05-11 | 2006-11-16 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| CN101817767A (en) * | 2009-02-26 | 2010-09-01 | 中国科学院上海药物研究所 | Substituted sulphonamide compound and preparation method, medicine composition and application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8933239B1 (en) | 2013-07-16 | 2015-01-13 | Dow Global Technologies Llc | Bis(aryl)acetal compounds |
| US8962779B2 (en) | 2013-07-16 | 2015-02-24 | Dow Global Technologies Llc | Method of forming polyaryl polymers |
| US9063420B2 (en) | 2013-07-16 | 2015-06-23 | Rohm And Haas Electronic Materials Llc | Photoresist composition, coated substrate, and method of forming electronic device |
| US9410016B2 (en) | 2013-07-16 | 2016-08-09 | Dow Global Technologies Llc | Aromatic polyacetals and articles comprising them |
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