CN101410396A - Chromane derivatives - Google Patents
Chromane derivatives Download PDFInfo
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- CN101410396A CN101410396A CNA2007800095512A CN200780009551A CN101410396A CN 101410396 A CN101410396 A CN 101410396A CN A2007800095512 A CNA2007800095512 A CN A2007800095512A CN 200780009551 A CN200780009551 A CN 200780009551A CN 101410396 A CN101410396 A CN 101410396A
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Abstract
This invention relates to compounds of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> A and B are each as described herein or a pharmaceutically acceptable salt, and compositions containing such compounds and the method of treatment and the use, comprising such compounds for the treatment of a condition mediated by acid pump antagonistic activity such as, but not limited to, as gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, cancer, heartburn, nausea, esophagitis, dysphagia, hypersalivation, airway disorders or asthma.
Description
Background technology
The present invention relates to relate to chroman derivatives.This compounds has selectivity acid pump and suppresses active.The invention still further relates to pharmaceutical composition, treatment and using method, described pharmaceutical composition comprises to be used for the treatment of by sour pump regulates the said derivative that active particularly sour pump suppresses the illness of active mediation.
Determined fully that proton pump inhibitor (PPI) is a prodrug, thus described prodrug experience acid catalyzed chemical rearrangement allow they by with H
+/ K
+The covalent attachment of the cysteine residues of-ATP enzyme suppresses this enzyme (Sachs, people such as G., Digestive Diseases and Sciences, 1995,40,3S-23S; People such as Sachs, Annu Rev Pharmacol Toxicol, 1995,35,277-305.).Yet different with PPIs, sour pump antagonist passes through H
+/ K
+The reversible potassium competitive inhibition of-ATP enzyme suppresses the acid secretion.SCH28080 is in this type of reversible inhibitor, and has carried out broad research.The reagent of other renewals (revaprazan, soraprazan, AZD-0865 and CS-526) has entered clinical trial (Pope, the A. that confirms its effect in the people; Parsons, M., Trends in Pharmacological Sciences, 1993,14,323-5; Vakil, N., Alimentary Pharmacology andTherapeutics, 2004,19,1041-1049.).Usually, acid pump antagonist is used for the treatment of multiple disease, comprise gastrointestinal illness, gastroesophageal disorder, gastroesophageal reflux disease (GERD), the throat disease (laryngopharyngeal reflux disease) of backflowing, peptide ulceration, stomach ulcer, duodenal ulcer, the ulcer that nonsteroid anti-inflammatory drugs (NSAID) causes, gastritis, the infection of Hp (Helicobacter pylori), maldigestion, functional dyspepsia, Zollinger Ellison syndrome, the non-erosive disease (NERD) of backflowing, visceral pain, cancer, pyrosis, feel sick, esophagitis, dysphagia, sialism, airways disorders or asthma (are called " APA disease " hereinafter; Kiljander, Toni O, AmericanJournal of Medicine, 2003,115 (Suppl.3A), 65S-71S; People such as Ki-BaikHahm, J.Clin.Biochem.Nutr., 2006,38, (1), 1-8.).
WO 99/55705, WO 99/55706 and WO 04/046144 disclose and have reported the compound that can be used as sour pump antagonist.They are for having some compound of imidazo [1,2-a] pyridine structure.
Existence is to providing the needs of new sour pump antagonist, and described new sour pump antagonist is the excellent drug material standed for that is used for the treatment of disease, and solves the unsatisfied needs of PPI.Especially, preferred compound effectively the combined acid pump show for the minimum avidity of other acceptors simultaneously and show activity as sour excretory inhibitor in the stomach.They should fully be absorbed at gi tract, be metabolic stability and have favourable pharmacokinetics character.They should be avirulent.In addition, the ideal drug candidates can exist with stable, physical form nonhygroscopic and easy preparation.
Summary of the invention
In the present invention, found that a class has chroman part and imidazo [1,2-a] pyridine structure and on the 3rd, shown that by (hydroxyl or can be converted into the part of hydroxyl in vivo)-methyl substituted new compound sour pump suppresses active and as the favourable character of drug candidates, thus be used for the treatment of the illness APA disease for example that suppresses active mediation by sour pump.
The invention provides the have following formula compound of (I):
Or its pharmacy acceptable salt class, wherein:
-A-B-representative-O-CH
2-or-CH
2-O-;
R
1Representation hydroxy, or can in body, be converted into the part of hydroxyl;
R
2Represent C
1-C
6Alkyl;
R
3And R
4Represent C independently
1-C
6Alkyl or C
3-C
7Cycloalkyl, this C
1-C
6Alkyl and this C
3-C
7Cycloalkyl is not substituted, or is replaced this substituting group independently selected from halogen atoms, hydroxyl, C by 1 to 3 substituting group
1-C
6Alkoxyl group, and C
3-C
7Cycloalkyl; Or R
3With R
4With 4 to 7 yuan of heterocyclic radicals of the common formation of the nitrogen-atoms that is connected with them, it is not substituted or is selected from hydroxyl, C by 1 to 3
1-C
6Alkyl, C
1-C
6Alkoxyl group, and hydroxyl-C
1-C
6The substituting group of alkyl replaces; And
R
5, R
6, R
7With R
8Represent hydrogen atom, halogen atom or C independently
1-C
6Alkyl.
In addition, the present invention also provides compound or its pharmacy acceptable salt that comprises formula (I), and each as described in this article and the pharmaceutical composition that is used for the pharmaceutically acceptable carrier of described compound.
In addition, the present invention also provides compound or its pharmacy acceptable salt that comprises formula (I), and each is pharmaceutical composition as described in this article, and it also comprises the other drug promoting agent.
In addition, the invention provides the method that is used for the treatment of mammalian object by the active illness that mediates of sour pump inhibition, it comprises that each as described in this article to compound or its pharmacy acceptable salt of the formula (I) of the administration treatment significant quantity of this treatment of needs.
The example that is suppressed the illness of active mediation by sour pump includes but not limited to the APA disease.
In addition, the invention provides compound or its pharmacy acceptable salt of formula (I), each is used to prepare the purposes of medicine as described in this article, and described medicine is used for the treatment of the illness that is suppressed active mediation by sour pump.
In addition, the invention provides compound or its pharmacy acceptable salt of formula (I), be used for medicine.
Preferably, the present invention also provides compound or its pharmacy acceptable salt of formula (I), and each is used to prepare the purposes of medicine as described in this article, and described medicine is used for the treatment of the disease that is selected from the APA disease.
The compounds of this invention can show good sour pump suppress active, lower toxicity, good absorptivity, good distribution, good solubility, to the lower binding affinity of the protein that is different from sour pump, less drug-drug interactions and good metabolic stability.
Detailed Description Of The Invention
In compound of the present invention:
Work as R
2, R
3, R
4, R
5, R
6, R
7And R
8Be C
1-C
6During alkyl, this C
1-C
6Alkyl can be straight chain or the branched chain group with 1 to 6 carbon atom, and example includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1-ethyl propyl and hexyl.In these groups, C
1-C
2Alkyl is preferred; Methyl is preferred.
Work as R
3Or R
4Be C
3-C
7Cycloalkyl, or the representative of this group is when having the cycloalkyl of 3 to 7 carbon atoms, and example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.In these groups, C
3-C
5Cycloalkyl is preferred; Cyclopropyl is preferred.
R wherein
3And R
4Substituting group be C
1-C
6Alkoxyl group, it represents this C
1-C
6Have Sauerstoffatom to replace on the alkyl, example including, but not limited to, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy and hexyloxy.In these groups, C
1-C
4Alkoxyl group is preferred; C
1-C
2Alkoxyl group is preferred; Methoxyl group is more preferably.
Work as R
3And R
4When the nitrogen-atoms that connects with their forms 4 to 7 yuan of heterocyclic radicals, these 4 to 7 yuan of heterocyclic radical representatives have 3 to 6 saturated heterocyclyls that are selected from the annular atoms of carbon atom, nitrogen-atoms, sulphur atom and Sauerstoffatom except described nitrogen-atoms, and example includes but not limited to that azetidinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl, six hydrogen azetidinyls, six hydrogen diazetidine bases, morpholino base, thiomorpholine are for base and high morpholino base.In these groups, azetidinyl, pyrrolidyl, morpholino base and high morpholino base are preferred; The morpholino base is preferred.
When the substituting group of 4 to 7 yuan of heterocyclic radicals is hydroxyl-C
1-C
6During alkyl, it represents described C
1-C
6Alkyl is replaced by hydroxyl, and example includes but not limited to methylol, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyl-1-methylethyl, 4-hydroxyl butyl, 3-hydroxyl butyl, 2-hydroxyl butyl, 3-hydroxy-2-methyl propyl group, 3-hydroxyl-1-methyl-propyl, 5-hydroxyl amyl group and 6-hydroxyl hexyl.In these groups, hydroxyl-C
1-C
3Alkyl is preferred; Hydroxymethyl is preferred.
R wherein
5, R
6, R
7With R
8Be halogen atom, can be fluorine, chlorine, bromine or iodine atom.In these atoms, fluorine atom and chlorine atom are preferred.
Wherein " can be converted into the fragment of hydroxyl in body " and refer to a part, it can be converted into oh group in vivo by as hydrolysis and/or enzyme such as esterase.The example of this part is including, but not limited to ester class and ethers group, and it can easily be hydrolyzed in body.Such part has " forerunner's part " well known by persons skilled in the art, described in " Design of Prodrugs " by H.Bundgaard (Elsevier, 1985).The preferred part that can be converted into hydroxyl in body is, for example C
1-C
6Alkoxyl group, C
1-C
6Alkyl-carbonyl-oxygen base, and C
1-C
6Alkyl-carbonyl-oxygen base-methyl-oxygen base.
Wherein-A-B-is-O-CH
2-,-A-is corresponding to-O-, and-B-is corresponding to-CH
2-.
Wherein-A-B-is-CH
2-O-,-A-is corresponding to-CH
2-, and-B-is corresponding to-O-.
As used herein, term " treatment " and " treatment " are meant healing, alleviate and prophylactic treatment, comprise reverse, alleviate, suppress it is used obstacle or the process of illness or one or more symptom of this type of obstacle or illness of this term.
The compound of preferred kind of the present invention is compound or its pharmacy acceptable salt of formula (I), each as described in this article, wherein:
(a)-A-B-is-O-CH
2-or-CH
2-O-;
(b)-A-B-is-CH
2-O-;
(c) R
1Be hydroxyl, C
1-C
6Alkoxyl group, or C
1-C
6Alkyl-carbonyl-oxygen base;
(d) R
1Be hydroxyl;
(e) R
2Be C
1-C
6Alkyl;
(f) R
2Be C
1-C
2Alkyl;
(g) R
2Be methyl;
(h) R
3Be C
1-C
6Alkyl;
(i) R
3Be C
1-C
2Alkyl;
(j) R
3Be methyl;
(k) R
4Be C
1-C
6Alkyl is not substituted or is substituted base and replaces, and this substituting group is selected from hydroxyl and C
1-C
6Alkoxyl group;
(l) R
4Be C
1-C
2Alkyl is not substituted or is substituted base and replaces, and this substituting group is selected from hydroxyl and C
1-C
4Alkoxyl group;
(m) R
4Be C
1-C
2Alkyl is not substituted or is replaced by hydroxyl;
(n) R
4Be methyl, ethyl or 2-hydroxyethyl;
(o) R
3And R
4With form azetidinyl, pyrrolidyl, morpholino base or high morpholino base with the nitrogen-atoms that they were connected, this azetidinyl, this pyrrolidyl, this morpholino base and this high morpholino base are not substituted, or by 1 to 3 substituting group replacement, this substituting group is selected from hydroxyl, C
1-C
6Alkyl, C
1-C
6Alkoxyl group and hydroxyl-C
1-C
6Alkyl;
(p) R
3And R
4With form pyrrolidyl, morpholino base or high morpholino base with the nitrogen-atoms that they were connected, this pyrrolidyl, this morpholino base and this high morpholino base are not substituted, or are substituted base and replace, this substituting group is selected from hydroxyl, C
1-C
6Alkyl, C
1-C
6Alkoxyl group and hydroxyl-C
1-C
6Alkyl;
(q) R
5, R
6, R
7With R
8Be hydrogen atom, halogen atom or C independently
1-C
6Alkyl;
(r) R
5, R
6, R
7With R
8Be hydrogen atom, halogen atom or C independently
1-C
2Alkyl;
(s) R
5, R
6, R
7With R
8Be hydrogen atom, fluorine atom, chlorine atom or methyl independently;
(t) R
5, R
6, R
7With R
8Be hydrogen atom, fluorine atom or methyl independently;
(u) R
5Be hydrogen atom, fluorine atom or methyl;
(v) R
6Be hydrogen atom;
(w) R
7Be hydrogen atom or fluorine atom; And
(x) R
8Be hydrogen atom;
In the middle of the compound of these kinds, (a) any combination in (x) also is preferred.
Preferred compounds of the invention are compound or its pharmacy acceptable salt of formula (I), each as described in this article, wherein:
(A)-A-B-is-O-CH
2-or-CH
2-O-; R
1Be hydroxyl, C
1-C
6Alkoxyl group or C
1-C
6-carbonyl-oxygen base; R
2Be C
1-C
6Alkyl; R
3With R
4Be C independently
1-C
6Alkyl or C
3-C
7Cycloalkyl, this C
1-C
6Alkyl and this C
3-C
7Cycloalkyl is not substituted, or is replaced this substituting group independently selected from halogen atoms, hydroxyl, C by 1 to 3 substituting group
1-C
6Alkoxyl group and C
3-C
7Cycloalkyl; Or R
3With R
4With form azetidinyl, pyrrolidyl, morpholino base and high morpholino base with the nitrogen-atoms that they were connected; This azetidinyl, this pyrrolidyl, this morpholino base and this high morpholino base are not substituted, or are replaced by 1 to 3 substituting group, and this substituting group is independently selected from hydroxyl, C
1-C
6Alkyl, C
1-C
6Alkoxyl group and hydroxyl-C
1-C
6Alkyl; And R
5, R
6, R
7With R
8Be hydrogen atom, halogen atom or C independently
1-C
6Alkyl;
(B)-A-B-is-O-CH
2-or-CH
2-O-; R
1Be hydroxyl; R
2, R
3With R
4Be C independently
1-C
6Alkyl; Or R
3With R
4With form the morpholino base with the nitrogen-atoms that they were connected; R
5With R
7Be hydrogen atom, halogen atom or C independently
1-C
6Alkyl; And R
6With R
8Be hydrogen atom or halogen atom independently;
(C)-A-B-is-O-CH
2-; R
1Be hydroxyl; R
2, R
3With R
4Be C independently
1-C
6Alkyl; R
5With R
7Be hydrogen atom, halogen atom or C independently
1-C
6Alkyl; And R
6With R
8Be hydrogen atom or halogen atom independently; And
(D)-A-B-is-O-CH
2-; R
1Be hydroxyl; R
2, R
3With R
4Be methyl; R
5With R
7Be hydrogen atom, fluorine atom or methyl independently; And R
6With R
8Be hydrogen atom or fluorine atom independently.
Formula (I) compound that contains one or more unsymmetrical carbon can have two or a plurality of steric isomer.
What be included in the scope of the present invention is all steric isomers and the geometrical isomer of formula (I) compound, comprises the compound and one or more mixture thereof that show more than one isomery types.Also comprise the acid salt class, these counter ion (counterion) tool optical activity wherein, as, D-lactate or L-Methionin, or its racemoid, DL-tartrate or DL-arginine.
One embodiment of the invention provide and have been selected from following compound:
(S)-(-)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide;
(+)-8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also;
(S)-(-)-and 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also; And
(-)-8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also;
Or its pharmacy acceptable salt class.
The pharmacy acceptable salt class of formula (I) compound comprises its acid salt class (comprising two salt).
Form suitable acid salt by the acid that forms non-toxic salts.Example comprises acetate, adipate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, bisulfate/vitriol, borate, camsilate, Citrate trianion, cyclohexyl-n-sulfonate, ethanedisulphonate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate, the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salt.
About the summary of suitable salt, referring to " Handbook of Pharmaceutical Salts:Properties, Selection, the and Use " of Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).Can be by the solution of the compound of formula (I) and desirable acid or alkali (as suitable) be mixed the pharmacy acceptable salt of the compound of preparation formula (I) easily.Salt can be precipitated out from solution, maybe can reclaim by evaporating solvent by filtering to collect then.The degree of salt intermediate ionization can not change to almost having in the Ionized scope in complete ionization.
The pharmacy acceptable salt of the compound of its formula (I) comprises solvation and form solvation.Term " solvate " is used for describing herein and comprises for example alcoholic acid molecular complex of compound of the present invention and one or more pharmaceutically acceptable solvent molecules.When being water, uses by described solvent term " hydrate ".
Pharmaceutically acceptable solvate of the present invention comprises that wherein the crystalline solvent can be by the hydrate of isotopic and solvate, for example D
2O, d
6-acetone, d
6-DMSO.
Title complex for example clathrate complex, medicine-host's inclusion complex (drug-hostinclusion complexes) comprises within the scope of the present invention, in described inclusion complex, opposite with the aforementioned solvents thing, medicine and host exist with stoichiometry or non-stoichiometric amount.The mixture that also comprises the medicine that comprises 2 or more a plurality of organic and/or inorganic components that can exist with stoichiometry or non-stoichiometric amount.The mixture of gained can also be Ionized, partial ionization or non-centrifugal sonization.About the summary of this type of mixture, referring to
J Pharm Sci, 64 (8), 1269-1288, Haleblian work (August 1975).
The compound of formula (I) can exist with one or more crystallized forms.This type of polymorphic form comprises its mixture, is also included within the scope of the present invention.
The compound that comprises the formula (I) of one or more unsymmetrical carbon can exist with the form of 2 or more a plurality of steric isomers.
All steric isomers of the compound of formula (I) comprise that one or more mixture of the compound of the isomerism of showing a plurality of types and its comprises within the scope of the invention.
The present invention includes the compound of all pharmaceutically acceptable isotope-labeled formulas (I), one of them or more a plurality of atom are had the same atoms ordinal number but atomic mass or total mass number and nucleidic mass or the different atomic substitutions of total mass number found at occurring in nature usually.
Be fit to be included in the isotropic substance that isotopic example in the compound of the present invention comprises hydrogen, for example
2H and
3The isotropic substance of H, carbon, for example
11C,
13C and
14The isotropic substance of C, chlorine, for example
36The isotropic substance of Cl, fluorine, for example
18The isotropic substance of F, iodine, for example
123I and
125The isotropic substance of I, nitrogen, for example
13N and
15The isotropic substance of N, oxygen, for example
15O,
17O and
18The isotropic substance of O, phosphorus, for example
32The isotropic substance of P and sulphur, for example
35S.
Some compound isotopically labelled of formula (I) for example, comprises the tissue distribution research that radioisotopic this compounds is used for medicine and/or substrate.Because its easiness of mixing and ready-made available detection method, radio isotope tritium are promptly
3H and carbon-14 are promptly
14C is particularly suitable for this purpose.
Use heavy isotope for example deuterium is
2The displacement of H can provide some that produce owing to bigger metabolic stability to treat favourable aspect, and for example the dosage of the increase of transformation period or minimizing needs in the body, thereby can be preferred in some cases.
The isotropic substance of use positron radiation for example
11C,
18F,
15O and
13The displacement of N can be used for checking that the substrate acceptor occupies position emissron tomography art (PET) research of situation.
Usually can pass through routine techniques well known by persons skilled in the art, or by being similar to the similar method of the scheme of describing among the appended embodiment, and, prepare the compound of isotope-labeled formula (I) by using suitable isotope-labeled reagent to replace the unmarked reagent that uses before.
Can be by the step described in the general method that provides below or by the ad hoc approach described in embodiment part and the preparation part or all compounds by its conventional modification preparation formula (I).The present invention also comprises any one or a plurality of method that is used for preparing these methods of comprising herein formula (I) compound outside any new intermediate that uses.
General synthetic
The method that for example following method A of method of preparation that can be by many compounds of knowing that are used for the type shows prepares compound of the present invention.
Except as otherwise noted, the R in the following method
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, A and B such as above-mentioned definition.All starting raw materials in following general synthesizing are commercial buying, maybe can be by for example WO 99/55706 and WO02/20523 acquisition of ordinary method well known by persons skilled in the art, and the disclosure of described application is incorporated herein by reference.
Method A
The preparation of present method formula (Ia) compound, wherein R
1Be OH.
Reaction scheme A
In reaction scheme A, R
aBe carboxyl-protecting group; Lv is a leavings group; Hereinafter also so use.
As using herein, " leavings group " expression can be by the nucleophilic group group that replaces of hydroxyl or amine or carboanion for example, and the example of this type of leavings group comprises halogen atom, alkyl sulphonyl and benzenesulfonyl oxygen base.In the middle of these groups, bromine atoms, chlorine atom, iodine atom, methyl sulphonyl, trifluoromethyl sulfonyl and 4-Methyl benzenesulfonyl base are preferred.
Steps A 1
In this step, nucleophilic substitution preparation formula (IV) compound of through type (II) compound, formula (II) compound is commercial buying, maybe can use formula (III) compound with the method for WO02/020523 by being described in WO 99/55706, the latter maybe can be by being described in the method preparation of WO 2000/07851 for commercial buying.
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The example of suitable solvent comprises: ethers such as tetrahydrofuran (THF) (THF), glycol dimethyl ether are Yu diox; Amides, as N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA), and N-N-methyl-2-2-pyrrolidone N-(NMP); Nitrile is as acetonitrile; Ketone is as acetone; Alcohols is as 2-methyl-2-propyl alcohol, 1-butanols, 1-propyl alcohol, 2-propyl alcohol, ethanol and methyl alcohol; And sulfoxide, as dimethyl sulfoxide (DMSO) (DMSO).Preferred in these solvents, acid amides, ketone and alcohols.More preferably acetone.
Can under the situation that alkali exists, carry out this reaction.Character to employed alkali does not have specific restriction similarly, can similarly use any alkali of the reaction that is used for the type herein.The example of this type of alkali comprises: alkali metal alkoxide, as sodium methylate, sodium ethylate and potassium tert.-butoxide; Alkaline carbonate is as Quilonum Retard, yellow soda ash (Na
2CO
3), cesium carbonate and salt of wormwood (K
2CO
3); Alkali metal hydrocarbonate is as sodium bicarbonate (NaHCO
3) and saleratus; And organic amine, as triethylamine, tripropylamine, tributylamine, dicyclohexylamine, N, N-diisopropylethylamine, N-methyl piperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU), and 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN).In these reagent, preferred salt of wormwood.
This reaction can use or not use iodine to carry out.The example of this eka iodine comprises: sodium iodide, potassiumiodide and cesium iodide.Wherein, preferred sodium iodide and potassiumiodide.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 250 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 5 minutes normally enough to about 72 hours time.
Steps A 2
In this step, after formula (IV) compound (A2a1) hydrolysis, carry out (A2a2) condensation with the formula V compound, or formula (IV) compound is carried out (A2b) substitution reaction preparation formula (VI) compound with the formula V compound steps A 1 preparation.
(A2a1) hydrolysis reaction
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: ethers such as tetrahydrofuran (THF) are Yu diox; Amides, as N, dinethylformamide; Alcohols is as ethanol and methyl alcohol; And water; Or its mixed solvent.In these solvents, particular methanol, tetrahydrofuran (THF) and water.
Can under the situation that alkali exists, carry out this reaction.Character to employed alkali does not have specific restriction similarly, can similarly use any alkali of the reaction that is used for the type herein.The example of this type of alkali comprises: alkali metal hydroxide, and as lithium hydroxide (LiOH), sodium hydroxide (NaOH) and potassium hydroxide (KOH).In these reagent, preferred sodium hydroxide.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 100 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 5 minutes normally enough to about 12 hours time.
(A2a2) condensation reaction
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: halogenated hydrocarbons, as methylene dichloride, chloroform and 1,2-ethylene dichloride; Ethers, as tetrahydrofuran (THF) Yu diox; Amides, as N, dinethylformamide and N,N-dimethylacetamide; And nitrile such as acetonitrile.In these solvents, preferred halogenated hydrocarbons and amides.More preferably methylene dichloride and N, dinethylformamide.
This is reflected under the condensation reagent existence and carries out.Similarly, there is no particular restriction for the characteristic of employed condensation reagent, and any condensation reagent that generally is used for this type reaction all can be used in this.The example of condensation reagent comprises: azo-2-carboxylic acid's two-lower alkyl esters-triphenylphosphine, as azoethane dicarboxylic acid-triphenylphosphine; 2-halogen-1-low alkyl group pyridinium halide is as 2-chloro-1-picoline iodide and 2-bromo-1-ethylpyridine a tetrafluoro borate (BEP); Diaryl phosphoryl trinitride is as diphenyl phosphoryl azide (DPPA); The carbonochloridic acid ester is as chloro ethyl formate and carbonochloridic acid isobutyl ester; Idol phosphorus cyanate (phosphorocyanidates) is as diethyl idol phosphorus cyanate (DEPC); Imdazole derivatives, as N, N '-carbonyl dimidazoles (CDI); The carbodiimide derivative, as N, N '-dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI); Imines positively charged ion salt is as 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (HBTU) and tetramethyl-fluorine methane amide hexafluorophosphate (TFFH); And microcosmic salt, as benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), and bromo-three-pyrrolidyl-phosphorus hexafluorophosphate (PyBrop).In these reagent, preferred EDCI and HBTU.
Reagent, as 4-(N, N-dimethylamino) pyridine (DMAP), and N-hydroxybenzotriazole (HOBt) can be used in this step.In these reagent, preferred HOBt.
Can under alkali existence or non-existent situation, carry out this reaction.Character to employed alkali does not have specific restriction similarly, can similarly use any alkali of the reaction that is used for the type herein.The example of this type of alkali comprises: amine, and as N-methylmorpholine, triethylamine, diisopropyl ethyl amine, N-methyl piperidine and pyridine.In these reagent, preferred triethylamine and N-methylmorpholine.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 80 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 5 minutes normally enough to about 24 hours time.
(A2b) substitution reaction
This reaction can be undertaken by reacting by heating thing in pure aminocompound or inert solvent under standard conditions.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: ethers, as glycol dimethyl ether, tetrahydrofuran (THF) Yu diox; Amides, as N, dinethylformamide and N,N-dimethylacetamide; Nitrile is as acetonitrile; And alcohols, as 2-methyl-2-propyl alcohol, 1-butanols, 1-propyl alcohol, 2-propyl alcohol, ethanol and methyl alcohol.In these solvents, preferred ethers and alcohols.More preferably tetrahydrofuran (THF).
This reaction can use or not use catalyzer to carry out.Similarly, there is no particular restriction for the characteristic of employed catalyzer, and any this type catalyst for reaction that generally is used for all can be used in this.The example of this type of catalyzer comprises: sodium cyanide or potassium cyanide.In these reagent, preferred sodium cyanide.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 200 ℃ temperature at about 40 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 30 minutes normally enough to about 24 hours time.
Steps A 3
In this step, desirable formula (Ia) compound carries out HM by steps A 2 prepared formulas (VI) and prepares, and uses formaldehyde, Paraformaldehyde 96 or 1,3, the 5-trioxane.
This reaction can be carried out under solvent exists or do not exist.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: fat hydrocarbon, as hexane, heptane and sherwood oil; Halogenated hydrocarbons is as methylene dichloride, chloroform and 1,2-ethylene dichloride; Ethers, as Anaesthetie Ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Yu diox; Arene is as benzene, toluene and oil of mirbane; Amides, as methane amide, N, dinethylformamide, N,N-dimethylacetamide and hexamethyl phosphoric triamide; Amine is as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropyl ethyl amine, dicyclohexylamine, N-methyl piperidine, pyridine, 4-pyrrolidyl pyridine, N, accelerine and N, N-Diethyl Aniline; Alcohols is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and 1-butanols; Nitrile is as acetonitrile and benzonitrile; Sulfoxide is as dimethyl sulfoxide (DMSO) and tetramethylene sulfone; And water.In these solvents, preferred acetonitrile and water.
This reacts under the reagent existence and carries out, as acid or alkali.Similarly, there is no particular restriction for the characteristic of employed acid or alkali, and any acid or alkali that generally is used for this type reaction all can be used in this.
This type of sour example comprises: carboxylic acid, as acetate and propionic acid; Mineral acid is as spirit of salt and sulfuric acid; Organic acid is as p-toluenesulphonic acids and trifluoroacetic acid; And lewis acid, as BF
3, AlCl
3, FeCl
3, AgCl, ZnI
2, Fe (NO
3)
3, CF
3SO
3Si (CH
3)
3, Yb (CF
3SO
3)
3And SnCl
4In these reagent, preferred acetate.
The example of this type of alkali comprises: alkali metal acetate, as lithium acetate, sodium acetate, potassium hydroxide and cesium acetate; Alkali metal hydroxide is as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal alkoxide is as sodium methylate, sodium ethylate and potassium tert.-butoxide; Alkaline carbonate is as Quilonum Retard, yellow soda ash and salt of wormwood; Alkali metal hydrocarbonate is as lithium bicarbonate, sodium bicarbonate and saleratus; And amine, as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropyl ethyl amine, dicyclohexylamine, N-methyl piperidine, pyridine, 4-pyrrolidyl pyridine, picoline, 4-(N, the N-dimethylamino) pyridine, 2,6-two (tertiary butyl)-4-picoline, quinoline, N, accelerine, N, N-Diethyl Aniline, DBN, 1,4-diazabicyclo [2.2.2] octane (DABCO), imidazoles and DBU.In these reagent, preferred sodium acetate.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 250 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 5 minutes normally enough to about 72 hours time.
Steps A 2 can be exchanged with the order of steps A 3.For example, the compound that position 3 is replaced by hydroxymethyl in formula (IV) compound (wherein this compound called after compound (IVa)) can use formaldehyde, Paraformaldehyde 96 or 1,3 by with formula (IV) compound, the 5-trioxane carries out methylolation and prepares, as described in steps A 3; Afterwards, as described in steps A 2, by compound (IVa) and formula V compound prepared in reaction formula (I) compound.
Method B
The preparation of present method formula (Ia) compound.
Reaction scheme B
In reaction scheme B, Hal is a halogen atom; Hereinafter also so use.
Step B1
In this step, formula (VIII) compound is by the halogenation preparation of formula (VII) compound, and the latter is commercial getting, or the available method preparation that is described in US2199839.
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: halogenated hydrocarbons, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ethers, as Anaesthetie Ether, Di Iso Propyl Ether, tetrahydrofuran (THF), cyclopentyl methyl ether Yu diox; Arene is as benzene, toluene and nitrotoluene; Amides, as N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide; Nitrile is as acetonitrile and cyanobenzene; And carboxylic acid, as acetate; Or its mixed solvent.In these solvents, preferred cyclopentyl methyl ether.
This reacts under the halide reagent existence and carries out.Similarly, there is no particular restriction for the characteristic of employed halide reagent, and any halide reagent that generally is used for this type reaction all can be used in this.The example of halide reagent comprises: chlorine, bromine, N-chlorination succinimide, N-bromination succinimide (NBS), four-n-butyl tribromide ammonium and 1,3-two bromo-5,5-dimethyl beta-lactam.In these reagent, preferred N-bromination succinimide.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 80 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 10 minutes normally enough to about 8 hours time.
Step B2
In this step, by with formula (VIII) compound and formula (IX) compound (it gets for commercial) cyclisation preparation formula (X) compound.
Usually and preferably under solvent existence or non-existent situation, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: halogenated hydrocarbons, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ethers, as Anaesthetie Ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Yu diox; Arene is as benzene, toluene and nitrotoluene; Amides, as N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide; Ketone is as acetone and 2-butanone; Alcohols is as methyl alcohol and ethanol; Carboxylic acid is as acetate; And nitrile, as acetonitrile and propionitrile; Or its mixed solvent.In these reagent, preferred propionitrile.
This reacts on reagent, carries out as acid or alkali existence or under not existing.Similarly, there is no particular restriction for the characteristic of employed acid or alkali, and any acid or alkali that generally is used for this type reaction all can be used in this.This type of sour example comprises: carboxylic acid, as acetate and propionic acid; Mineral acid, example hydrochloric acid, sulfuric acid, Hydrogen bromide and p-toluenesulphonic acids.In these reagent, preferred p-toluenesulphonic acids or anacidity exist.The example of this type of alkali comprises: alkali metal hydrocarbonate, as sodium bicarbonate and saleratus; Alkaline carbonate is as yellow soda ash and salt of wormwood; Amine is as triethylamine and diisopropyl ethyl amine.In these reagent, preferred diisopropyl ethyl amine or alkali-free exist.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 150 ℃ temperature at about 20 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 3 minutes normally enough to about 120 hours time.
Step B3
In this step, through type (X) compound and formula (XI) compound (it is commercial getting) crosslinked coupling preparation formula (IV) compound, or can be by the described method preparation of following method C.This reaction is as J.Am.Chem.Soc., carries out under 1996,118,7215 described the same terms.
This reaction generally can be finished in the solvent existence or not.Typical solvent is an aromatic hydrocarbon, as benzene and toluene.
This is reflected under the alkali existence and carries out.Typical case's alkali is sodium tert-butoxide, described in the above-mentioned document of quoting.
This is reflected under the catalyzer existence and carries out.This catalyzer is made up of the palladium source, as three (two benzal methylacetones), two palladium (Pd
2(dba)
3), and part, as three (o-tolyl) phosphine, 1,1 '-two naphthalenes-2,2 '-two bases two (diphenylphosphines) (BINAP), and 1,1 '-two (diphenylphosphino) ferrocene (DPPF).In these reagent, preferred Pd
2(dba)
3With the combination of BINAP, according to the above-mentioned document of quoting.
This reaction is carried out in 80 ℃ to 100 ℃ scopes usually.But the required time range wide region of this reaction changes, and depends on employed temperature of reaction, and the characteristic of employed parent material and catalyzer.Yet if react under above-mentioned optimum condition, about 1 hour normally enough to about 22 hours time.
Step B4
In this step, by with formula (IV) compound hydrolysis, carry out condensation reaction with the formula V compound afterwards, or formula (IV) compound is carried out substitution reaction and preparation formula (VI) compound with the formula V compound.Reaction can be carried out under steps A 2 described the same terms of method A.
Step B5
In this step, formula (VI) compound by step B2 preparation carries out HM and prepares desirable formula (Ia) compound, uses formaldehyde, Paraformaldehyde 96 or 1,3, the 5-trioxane.Reaction can be carried out under as method A steps A 3 described the same terms.
The order of step B4 and step B5 can be exchanged.For example, the compound that position 3 is replaced by methylol in formula (IV) compound (wherein this series of compounds called after compound (IVa)) but the methylolation of through type (IV) compound and preparing, use formaldehyde, Paraformaldehyde 96 or 1,3, the 5-trioxane is as described in method A steps A 3, afterwards, prepared in reaction formula (Ia) compound of reaction through type (IVa) and formula V compound is as described in method A steps A 2.
Formula (Ib) compound, wherein R
1Not OH, can be by ordinary method preparation well known by persons skilled in the art, it is described in " Design of Prodrugs " by H.Bundgaard (Elsevier, 1985).
Method C
The preparation of present method formula (XIa) compound, wherein A is CH
2
Reaction scheme C
In reaction scheme C, R
5a, R
6aWith R
7aBe hydrogen atom, C
1-C
3Alkyl or fluorine atom; R
8aBe hydrogen atom or fluorine atom.
Step C1
In this step, through type (XII) compound (it is commercial getting) carries out addition reaction preparation formula (XIV) compound with formula (XIII) compound (it is commercial getting).
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: halogenated hydrocarbons, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ethers, as Anaesthetie Ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Yu diox; Arene is as benzene, toluene and nitrotoluene; Amides, as N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide; Amine is as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropyl ethyl amine, N-methyl piperidine, pyridine, 4-pyrrolidyl pyridine, N, accelerine, and N, N-Diethyl Aniline; Alcohols is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols; Nitrile is as acetonitrile and cyanobenzene; The sulfoxide class is as dimethyl sulfoxide (DMSO) and tetramethylene sulfone; And ketone, as acetone and diethyl ketone.In these solvents, preferred acetonitrile and tetrahydrofuran (THF).
Can under the situation that alkali exists, carry out this reaction.Character to employed alkali does not have specific restriction similarly, can similarly use any alkali of the reaction that is used for the type herein.The example of this type of alkali comprises: alkali metal hydroxide, as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkalimetal hydride is as lithium hydride, sodium hydride and potassium hydride KH; Alkali metal alkoxide is as sodium methylate, sodium ethylate and potassium tert.-butoxide; Alkaline carbonate is as Quilonum Retard, yellow soda ash and salt of wormwood; Alkali metal hydrocarbonate is as lithium bicarbonate, sodium bicarbonate and saleratus; Amine, as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropyl ethyl amine, N-methyl piperidine, pyridine, 4-(N, N-dimethylamino) pyridine, and DBU; And tetralkyl ammonium fluorides, as four-n-butyl Neutral ammonium fluoride (TBAF).In these reagent, preferred TBAF.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 100 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 5 minutes normally enough to about 72 hours time.
Step C2
In this step, hydrogenation of formula (XIV) compound formula (XV) compound.
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: arene, as toluene; Alcohols is as methyl alcohol and ethanol; And carboxylic acid, as acetate.In these solvents, preferred alcohols and carboxylic acid.
This reaction can and be carried out in the presence of catalyzer under hydrogen environment.Similarly, there is no particular restriction for employed specificity of catalyst, and any this type catalyst for reaction that generally is used for all can be used in this.The example of this type of catalyzer comprises: palladium on carbon, platinum and Raney's nickel.In these catalyzer, preferred palladium on carbon.
If (in reaction scheme C substituting group for " Hal ") hydrogen dehalogenateization (hydrodehalogenation) is serious problems, this reaction can be carried out under additive exists, and it can reduce employed catalyst activity.This additive is selected from the known material that can produce some murder by poisoning degree to catalyzer.This class example additives comprises: the halide-ions source, as four-n-butyl brometo de amonio and Sodium Bromide; And the sulfoxide class, as dimethyl sulfoxide (DMSO).In these reagent, preferred Sodium Bromide.
This reaction can be carried out under wide region pressure, and definite reaction pressure is not a key of the present invention.Preferred reaction pressure depends on multiple factor, as starting raw material and solvent properties.Yet, generally speaking, more conveniently react to about 10atm in the about 1atm of pressure.Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 50 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 30 minutes normally enough to about 12 hours time.
Step C3
In this step, cyclisation formula (XV) compound formula (XVI) compound.
Usually and preferably under the situation that acid exists, carry out this reaction, as solvent and reagent.Character to employed acid does not have specific restriction, as long as it does not have disadvantageous effect and its dissolving substrate on certain degree at least to reaction.This type of sour example comprises: sulfuric acid and trifluoromethane sulfonic acid.In these reagent, preferred trifluoromethane sulfonic acid.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 150 ℃ temperature at about 0 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 30 minutes normally enough to about 5 hours time.
Step C4
In this step, use formula (XVII) compound (it is commercial getting), reductive amination process preparation formula (XVIII) compound of through type (XVI) compound.If the optically active compound of use formula (XVII) can the optically active compound mode obtain gained formula (XVIII) compound.
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it does not have disadvantageous effect and its solubilizing reaction thing on certain degree at least to reaction or reagent of participating in.The appropriate solvent example comprises: halogenated hydrocarbons, and as methylene dichloride and 1, the 2-ethylene dichloride; Ethers, as Anaesthetie Ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Yu diox; Arene is as benzene and toluene; Amides, as methane amide, N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide; Amine is as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropyl ethyl amine, dicyclohexylamine, N-methyl piperidine, pyridine, 4-pyrrolidyl pyridine, N, accelerine, and N, N-Diethyl Aniline; And alcohols, as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.In these solvents, preferred tetrahydrofuran (THF).
This is reflected at dewatering agent and carries out under existing or not existing.Similarly, there is no particular restriction for employed dewatering agent characteristic, and any dewatering agent that generally is used for this type reaction all can be used in this.The example of this type of dewatering agent comprises: different third titanium oxide (IV), sal epsom and molecular sieve.In these reagent, preferred different third titanium oxide (IV).
This is reflected under the reductive agent existence and carries out.Similarly, there is no particular restriction for employed reductive agent characteristic, and any reductive agent that generally is used for this type reaction all can be used in this.The example of this type of reductive agent comprises: metal borohydride, as sodium borohydride and sodium cyanoborohydride; Hydrogen supply agent combination is as hydrogen and ammonium formiate; Catalyzer is as palladium on carbon, platinum and Raney's nickel; Metallic combination is as zinc and iron; Acid, example hydrochloric acid, acetate and acetate ammonium chloride complex compound; Hydride is as lithium aluminum hydride, sodium borohydride and diisobutyl aluminium hydride; And borane reagent, as borine-tetrahydrofuran complex, borine-dimethyl sulphide complex compound (BMS), and 9-boron dicyclo [3,3,1] nonane (9-BBN).In these reagent, preferred sodium borohydride.
Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, approximately-40 ℃ to about 20 ℃ temperature, reacting easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 30 minutes normally enough to about 24 hours time.
Step C5
In this step, hydrogenolysis preparation formula (XIa) compound of through type (XVIII) compound.
Usually and preferably under the situation that solvent exists, carry out this reaction.Character to the solvent that adopted does not have specific restriction, as long as it is to reaction or participate in catalyzer and do not have disadvantageous effect and its solubilising reagent on certain degree at least.The appropriate solvent example comprises: ethers, as Anaesthetie Ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Yu diox; Arene is as benzene and toluene; Alcohols is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols; And carboxylic acid, as acetate; Or the mixture of above-mentioned solvent.In these solvents, particular methanol.
This reaction can be supplied under agent and the catalyzer existence in hydrogen and be carried out.Similarly, there is no particular restriction with specificity of catalyst for employed hydrogen supply agent, and any hydrogen that generally is used for this type reaction supplies agent and catalyzer all can be used in this.The example of this hydrogen-like supply agent comprises hydrogen and ammonium formiate.In these reagent, preferred hydrogen.This type of catalyzer example comprises: palladium on carbon, palladium hydroxide and Palladous chloride.In these reagent, preferred palladium on carbon.
This reaction can be carried out under wide region pressure, and definite reaction pressure is not a key of the present invention.Preferred reaction pressure depends on multiple factor, as starting raw material and solvent properties.Yet, generally speaking, more conveniently react to about 10atm in the about 1atm of pressure.Can carry out this reaction in wide temperature range, accurate temperature of reaction is not vital for the present invention.Preferable reaction temperature depends on the character of such factor such as solvent and starting raw material.Yet, usually, react to about 100 ℃ temperature at about 20 ℃ easily.React the required time, depend on many factors particularly temperature of reaction and the starting raw material that is adopted and the character of solvent, also wide variation can take place.Yet if react under above-mentioned optimum condition, about 30 minutes normally enough to about 12 hours time.
Preparation/the separation of single enantiomer can be carried out according to usual manner, as carrying out asymmetric synthesis, or use and carry out the fractionation (or racemic modification of salt or derivative) of racemic modification as chirality high pressure liquid chromatography (HPLC) method (HPLC) from suitable optical purity precursor (its according to method C preparation).
Selectively, the method of the optical resolution (opticalresolution) of racemic compound (or racemize precursor) can suitably be selected from ordinary method, for example, the alkali part and the suitable for example fractionation of the non-corresponding body salt between the tartrate of photolytic activity acid of the compound of preferred crystallization process or formula (I).
Can by for example distillation of ordinary method, recrystallize or chromatography purification separates and the above-mentioned preparation method of purifying in the compound and the intermediate product of formula (I).
Can use the compound of the present invention of wishing to be used for pharmaceutical use with the form of crystal or amorphous products.Can for example precipitation, crystallization, lyophilize, spraying drying or evaporation drying obtain them with the form of for example solid embolism (solid plug), pulvis or film by method.For this purpose, can use microwave drying or radio-frequency seasoning (radio frequency drying).
Can use them individually or with one or more other compounds of the present invention or with one or more other drugs (or with its any combination).Usually, use them with pharmaceutical composition or with the form of one or more pharmaceutically acceptable carriers or vehicle bonded preparation.Term " carrier " or " vehicle " are used to describe any component except compound of the present invention herein.Following factor is depended in the selection of carrier and vehicle to a great extent, and for example specific mode of administration, vehicle are to solubility and the influence of stability and the character of formulation.
The method that the pharmaceutical composition of sending and being used to that is suitable for compound of the present invention prepares them is obvious to those skilled in the art.The method that this based composition and being used to prepares them for example is found in ' Remington ' s Pharmaceutical Sciences ', the 19th edition (Mack Publishing Company, 1995).
Oral administration
Compound of the present invention can carry out oral administration.Oral administration can comprise to be swallowed, so that compound enters gi tract, maybe can use oral cavity or sublingual administration, can directly enter blood flow from mouth by this approach compound.
The preparation that is used for oral administration for example comprises solid preparation, tablet, the capsule that comprises particulate, liquid or pulvis, lozenge (comprising liquid-filled), masticatory, many granules and nano particle, gel, sosoloid, liposome, film (comprising mucoadhesive), pearl agent (ovules), sprays and liquid preparation.
Liquid preparation comprises, for example, and suspensoid, solution, syrup and elixir.This type of preparation can be used as the filling agent of soft or hard capsule, and comprises carrier usually, for example water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil, one or more emulsifying agents and/or suspension agent.Also can for example prepare liquid preparation by the solid reprovision from cachet.
Compound of the present invention for example also can be used for quick dissolving, rapidly disintegrating dosage form
Expert Opinion in Therapeutic Patents,
11(6), 981-986, the formulation of describing in Liang and the Chen work (2001).
For Tabules, depend on dosage, medicine can be formed about 1 weight % of formulation to about 80 weight %, and more commonly about 5 weight % of formulation are to about 60 weight %.Except medicine, tablet also comprises disintegrating agent usually.The example of disintegrating agent comprises hydroxypropylcellulose, starch, pregelatinized starch and the sodium alginate that sodium starch glycolate, Xylo-Mucine, calcium carboxymethylcellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, low alkyl group replace.Usually, disintegrating agent comprises about 1 weight % of formulation to about 25 weight %, and preferably approximately 5 weight % are to about 20 weight %.
Usually use tackiness agent to give adhesive property to Tabules.Suitable binder comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetic is gummy, polyvinylpyrrolidone, pregelatinized starch, pregelatinized Mierocrystalline cellulose and Vltra tears.Tablet also can comprise thinner, for example lactose (monohydrate, spray-dired monohydrate, anhydrous etc.), N.F,USP MANNITOL, Xylitol, glucose, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and dicalcium phosphate dihydrate (dibasic calcium phosphate dihydrate).
Tablet also can at random comprise tensio-active agent, for example for example silicon-dioxide and talcum powder of Sodium Lauryl Sulphate BP/USP and polysorbate80 and glidant.When existing, tensio-active agent can comprise about 0.2 weight % of accounting for described tablet to about 5 weight %, glidant can comprise account for described tablet about 0.2 weight % to about 1 weight %.
Tablet also can comprise lubricant for example Magnesium Stearate, calcium stearate, Zinic stearas, sodium stearyl fumarate usually, and the mixture of Magnesium Stearate and Sodium Lauryl Sulphate BP/USP.Lubricant comprises about 0.25 weight % of accounting for tablet usually to about 10 weight %, and preferably approximately 0.5 weight % is to about 3 weight %.
Other possible components comprise antioxidant, tinting material, flavouring agent, sanitas and mask agent.
Exemplary tablet comprises the medicine until about 80%, about 10 weight % are to the tackiness agent of about 90 weight %, about 0 weight % is to the lubricant of about 85 weight %, the lubricant of about 2 weight % to the disintegrating agent of about 10 weight % and about 0.25 weight % to about 10 weight %.
Can directly suppress or form tablet by roller compressed tablets mixture.Selectively can be before compressing tablet to the part of tablet mixture or mixture carry out wet granulation, non-slurry pelletizing or melt pelletization, fusion is condensed (melt congeale) or extrude.Whole preparation can comprise one or more layers and can be the bag quilt or do not wrap quilt; Even it can be enclosed capsule.
At H.Lieberman and L.Lachman, Marcel Dekker, N.Y., N.Y. has described the preparation of tablet in 1980 (ISBN 0-8247-6918-X) " Pharmaceutical Dosage Forms:Tablets, the 1st volume ".
The solid preparation that is used for oral administration can be mixed with instant release type and/or type (modifiedrelease) released in accent.Transfer release formulation to comprise that slowly-releasing, lasting release, pulse release, sustained release, target discharge and the sequencing delivery formulations.
At United States Patent (USP) 6,106, the suitable accent release formulation that is used for purpose of the present invention has been described in 864.Other suitable release techs for example high energy disperse (high energy dispersion) and the particulate detailed content of perviousness and bag quilt to see people such as Verma,
Pharmaceutical Technology On-line, 25 (2), 1-14 (2001).The purposes that chewing gum is used to obtain sustained release has been described in WO 00/35298.
Parenteral admin
Also compound of the present invention directly can be applied blood flow, apply muscle or apply internal organs.The suitable method that is used for parenteral admin comprises in intravenously, intra-arterial, intraperitoneal, the sheath, in the ventricle, in the urethra, in the breastbone, encephalic, intramuscular and subcutaneous administration.Be used for the suitable device that parenteral uses and comprise pin type (comprising micro-needle) syringe, needleless injector and and infusion techniques.
Parenteral formulation is the aqueous solution normally, this aqueous solution comprises vehicle for example salt, carbohydrate and buffer reagent (preferred pH is about 3 to about 9), but use for some, more suitably they can be formulated as aseptic non-aqueous solution or be formulated as dried forms to use with for example aseptic, the pyrogen-free water of suitable vehicle.
Can use standard pharmaceutical technology well known to those skilled in the art easily under aseptic condition, for example to finish the preparation of parenteral formulation by lyophilize.
By using suitable compounding process, for example the integration of solubilizing agent increases the solubleness of compound of the formula (I) of the preparation that is used for parenteral solution.
The preparation that is used for parenteral admin can be formulated as instant release type and/or type released in accent.Transfer release formulation to comprise that slowly-releasing, lasting release, pulse release, sustained release, target discharge and the sequencing delivery formulations.Therefore compound of the present invention can be mixed with solid, semisolid or the thixotropic fluid (thixotropic liquid) of transferring implanted storage storehouse (implanted depot) form administration of releasing release of active compounds to be used to provide.This type of examples of formulations comprises the support and the PGLA microballoon of pharmaceutical pack quilt.
Topical
Also can be with compound of the present invention to skin or mucous membrane topical, that is, and by skin or transdermal administration.Be used for this purpose exemplary formulations and comprise gelifying agent, hydrogel, lotion, solution, emulsifiable paste, ointment, face powder, dressing, foaming agent, film, skin patch, wafer, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Common vector comprises alcohol, water, mineral oil, Liquid Paraffin, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.Penetration enhancers can be integrated into-referring to, for example, J Pharm Sci,
88(10), 955-958, Finnin and Morgan work (October 1999).
The additive method of topical comprises by electroporation, iontophoresis, phonophoresis, phonophoresis and micro-needle or needleless (Powderject for example
TM, Bioject
TMDeng) injection.
The preparation that is used for topical can prepare instant release type and/or type released in accent.Transfer release formulation to comprise that slowly-releasing, lasting release, pulse release, sustained release, target discharge and the sequencing delivery formulations.
Suction/intranasal administration
Also can be by using compound of the present invention in the nose or by suction, usually with dry powder (individually from Diskus, as in the dry blending thing for example with the mixture of lactose, or as for example with phosphatide phosphatidylcholine blended blending ingredients particulate for example) form, or using or do not using suitable propellant for example 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3, under the situation of 3-heptafluoro-propane with the form of sprays from pressurized vessel, pump, atomizer, spraying gun (preferably using electrofiuid mechanics to produce the spraying gun of mist), or Atomizer is used described compound.For using in the nose, pulvis can comprise bioadhesive agents, for example, and chitosan or cyclodextrin.
Pressurizing vessel, pump, atomizer, spraying gun or Atomizer comprise the solution or the suspension of compound of the present invention, described solution or suspension comprise for example ethanol, aqueous ethanolic solution or be used to disperse, the suitable selectable reagent of dissolving or slowly-releasing promoting agent, as the propellant of solvent and for example three oleic acid sorbitanics, oleic acid or lactic acid oligomer of tensio-active agent arbitrarily.
Before being used for dry powder or suspension formulation, make the medicine micronize to the size (usually less than 5 microns) that is fit to send by suction.Can carry out this micronize by any suitable for example spiral air flow pulverizing of means of comminution, supercutical fluid processing, high pressure homogenize or the spraying drying that nanoparticle was pulverized, formed to fluidized bed airflow.
Capsule (being made by for example gelatin or HPMC), bubble-cap and the cartridge case that is used for sucker or insufflator can be made and comprise The compounds of this invention, suitable pulvis matrix for example lactose or starch and performance improver (performance modifier), as the powder mixture of 1-leucine, N.F,USP MANNITOL or Magnesium Stearate.Lactose can be anhydrous or with monohydrate, the preferred latter's form exists.Other suitable vehicle comprise dextran, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.
The suitable each driving of solution preparaton that is used for using electrohydrodynamics to produce the spraying gun of mist can comprise the of the present invention compound of 1 μ g to about 20mg, and driving volume can be at about 1 μ l to the scope of about 100 μ l.Common preparation can comprise compound, propylene glycol, sterilized water, ethanol and the sodium-chlor of formula (I).The alternative solvent that can be used for alternative propylene glycol comprises glycerine and polyoxyethylene glycol.
Can be used for to hope sucking/this type of preparation of the present invention of intranasal administration adds suitable seasonings, for example mentha camphor and l-Menthol, or sweetener, for example asccharin or soluble saccharin.For example can use poly-(DL-lactic acid-copolymerization oxyacetic acid) (PGLA) will be used to suck/preparation of intranasal administration is formulated as instant release type and/or type is released in change.Become delivery formulations and comprise that slowly-releasing, lasting release, pulse release, sustained release, target release and sequencing discharge.
Under powder inhaler and aerocolloidal situation, the valve of the amount by sending measurement is determined dose unit.According to the present invention, for user typically the unit of the dosage of setting measurement or " puff " comprise the compound of about 1 formula (I) to about 100 μ g.Total per daily dose is typically about 50 μ g to about 20mg, can be with single agent or more commonly used this per daily dose with fractionated dose in one day.
Rectum/intravaginal administration
Compound of the present invention can be carried out rectum or vagina administration with the form of suppository, vaginal suppository or enema.Theobroma oil is a conventional suppository bases, but suitably can use different selections.
The preparation that is used for rectum/vagina administration can be mixed with instant release type and/or type released in accent.Transfer release formulation to comprise that slowly-releasing, lasting release, pulse release, sustained release, target discharge and the sequencing delivery formulations.
Other technologies
Compound of the present invention can with soluble large molecule entity for example cyclodextrin and its suitable derivative or comprise the mixed with polymers of polyoxyethylene glycol, with improve its solvability, dissolution rate (dissolution rate), hide flavor, bioavailability and/or stability to be to be used for arbitrary pattern of above-mentioned mode of administration.
For example find that the drug-cyclodextrin mixture is generally used for most of formulations and route of administration.Can use inclusion body and non-inclusion body.As to the other selection of directly compound (complexation) of medicine, cyclodextrin can be used as supplementary additive, promptly as carrier, thinner or solubilizing agent.What be most commonly used to these purposes is α, β and γ cyclodextrin, and the example is found in WO91/11172, WO 94/02518 and WO 98/55148.
The test kit of assembly (KIT-OF-PARTS)
Because may want to use the combination of active compound, for example, treating specific disease or illness, therefore within the scope of the invention can be easily unite two or more pharmaceutical compositions (wherein at least a comprise compound of the present invention) with the form of the test kit of using altogether that is suitable for composition.
Test kit of the present invention comprises 2 or more a plurality of separated drug composition (wherein at least one comprises the compound of formula of the present invention (I)) and is used for separately keeping the instrument of described composition, for example container, the bottle that separates or the paper tinsel box that separates.The example of such test kit is the common Blister Package that is used for package troche, capsule etc.
Test kit of the present invention is particularly suitable for using different dosage form, for example is used for using with different dosing intervals the oral and parenteral admin of composition separately, or is applicable to the composition that titration is separated from each other.In order to help compliance, test kit comprises usually to be used guidance and so-called memory aid can be provided.
Dosage
About the administration to people patient, total per daily dose of compound of the present invention in the scope of the extremely about 500mg of about 0.05mg, depends on mode of administration usually certainly, preferably in the scope of about 0.1mg to 400mg and the extremely about 300mg of more preferably about 0.5mg.For example, oral administration can need the total per daily dose of about 1mg to about 300mg, and intravenous administration can only need extremely approximately 100mg of about 0.5mg.Can use total per daily dose with single agent or fractionated dose.
These dosage are based on having the average man study subject of about 65kg to about 70kg weight.The doctor can easily can be identified for weight and drop on the study subject dosage of baby and old study subject for example outside this scope.
Combination
As discussed above, compounds show acid pump of the present invention suppresses active.Sour pump antagonist of the present invention can with another kind of pharmaceutical active compounds, or be used from, especially for the treatment of gastroesophageal reflux disease with two or more other drug active substances one.For example, can be with the compound of sour pump antagonist, particularly formula (I), or its pharmacy acceptable salt and one or more are selected from following medicine simultaneously, use in succession or dividually as defined above:
(i) histamine H
2Receptor antagonist, for example, Ranitidine HCL, lafutidine, nizatidine, Cimitidine Type A/AB, famotidine and roxatidine;
(ii) proton pump inhibitor, for example omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, lY 81149 (ilaprazole) and lansoprazole;
(iii) oral antiacid mixture, for example
With
(iv) mucosa protective agent, for example zinc L-carnosine, Ecabet Sodium, rebamipide, teprenone, cetraxate, sucralfate, CHLOROPHYLLINE-copper and plaunotol;
(v) anti-stomach (anti-gastric) medicine, for example anti-gastrin vaccine (Anti-gastrinvaccine), itriglumide (itriglumide) and Z-360;
(vi) 5-HT
3Antagonist, for example Tegaserod, dolasetron, Palonosetron, Lotronex, azasetron, ranimustine, mirtazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron;
(vii) 5-HT
4Agonist, for example, mosapride, cinitapride and oxtriptane;
(viii) caccagogue, for example
With
(ix) GABA
BAgonist, for example baclofen and AZD-3355;
(x) GABA
BAntagonist, for example GAS-360 and SGS-742;
(xi) calcium channel blocker, for example Aranidipine, Lacidipine (62, falodipine, Azelnidipine, clinidipine, lomerizine, diltiazem, Procorum, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, Isrodipine, benidipine, verapamil, nitrendipine, barnidipine, Propafenone, Manidipine, Bepridil, nifedipine, nilvadipine, nimodipine and fasudil;
(xii) dopamine antagonist, for example metoclopramide, domperidone and levosulpiride;
(xiii) tachykinin (NK) antagonist, NK-3 particularly, NK-2 and NK-1, nepadutant for example, Saredutant, Talnetant, (α R, 9R)-7-[3, two (trifluoromethyl) phenyl of 5-]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] diazocine [2,1-g] [1,7] naphthridine-6-13-diketone (TAK-637) also, 5-[[(2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone (MK-869), lanepitant, Dapitant and 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl] methylamino-]-2-phenyl-piperidines (2S, 3S);
(xiv) Hp (Helicobacter pylori) infectious agent, for example clarithromycin (clarithromicyn), Roxithromycin, rokitamycin, Flurithromycin, Ketek, amoxycilline Trihydrate bp, Ampicillin Trihydrate, temocillin, bacampicillin, aspoxicillin, sultamicillin, piperacillin, lenampicillin, tsiklomitsin, metronidazole, bismuth citrate and bismuth subsalicylate;
(xv) nitric oxide synthase inhibitors, for example GW-274150, tilarginine, P54, GE disulphide and nitroflurbiprofen;
(xvi) class vanilla acceptor 1 (vanilloid receptor 1) antagonist, for example AMG-517 and GW-705498;
(xvii) muscarinic receptor antagonist, for example Trospium cation (trospium), solifenacin, tolterodine, tiotropium (tiotropium), west holder ammonium (cimetropium), oxygen holder ammonium (oxitropium), Rinovagos, tiquinamide (tiquizium), dalifenacin and imidafenacin;
(xviii) calmodulin antagonist, for example squalamine (squalamine) and DY-9760;
(xix) potassium channel activator, for example Pinacidil, tilisolol, Nicoril, NS-8 and retigabine;
(xx) β-1 agonist, for example dobutamine, denopamine, xamoterol, denopamine, Docarpamine and xamoterol;
(xxi) β-2 agonist, for example salbutamol; Terbutaline, arformoterol, meluadrine (meluadrine), Mabuterol, ritodrine, Partusisten, clenbuterol, formoterol, procaterol, tulobuterol, pirbuterol, bambuterol, tulobuterol, dopexamine and levosalbutamol;
(xxii) beta-agonists, for example Racemic isoproterenol and terbutaline;
(xxiii) α 2 agonists, clonidine for example, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine;
(xxiv) endothelin A antagonist, bonsetan for example, atrasentan, ambrisentan, clazosentan, sitaxsentan, fandosentan and darusentan;
(xxv) opioid MU agonist, for example morphine, fentanyl and Loperamide;
(xxvi) opioid μ antagonist, for example naloxone, buprenorphine and Aiweimopan (alvimopan);
(xxvii) motilin agonist, for example erythromycin, Mi Tanxinuo (mitemcinal), SLV-305 and atilmotin;
(xxviii) Ge Ruilin agonist, for example capromorelin and TZP-101;
(xxix) AchE release of irritants, for example Z-338 and KW-5092;
(xxx) CCK-B antagonist, for example itriglumide, YF-476 and S-0509;
(xxxi) glucagon antagonists, for example NN-2501 and A-770077;
(xxxii) piperacillin, lenampicillin, tsiklomitsin, metronidazole, bismuth citrate and bismuth subsalicylate;
(xxxiii) glucagon-like peptide-1 (GLP-1) antagonist, for example PNU-126814;
(xxxiv) small-conductance calcium-activated potassium channel 3 (SK-3) antagonist, for example apamin, quinoline ammonium, atracurium, pancuronium (pancuronium) and tubocurarine chloride
(xxxv) mGluR5 antagonist, for example ADX-10059 and AFQ-056;
(xxxvi) 5-HT3 agonist, for example pumosetrag (DDP733);
(xxxvii) mGluR8 agonist, (S)-3 for example, 4-DCPG and mGluR8-A.
Be used to estimate the method for biologic activity:
Determine that by following method the sour pump of The compounds of this invention suppresses active and other biological is learned active.Symbol has its common meaning: mL (milliliter), μ L (microlitre), Kg (kilogram), g (gram), mg (milligram), μ g (microgram), pmol (picomole), mmol (mmole), M (molar mass (m
3/ mol)), mM (mmole quality), μ M (micromole's quality), quant. (quantitatively), nm (nanometer), min (minute), Cat# (accession number), mV (millivolt), ms (millisecond), i.p (intraperitoneal).
Preparation from the stomach vesicles (gastric vesicle) of live hog stomach
By tetrafluoroethylene with driving fit (tight-fitted)
Homogenizer homogenate mucous membrane preparation from the live hog stomach in 4 ℃ of following 0.25M sucrose is used for the pig stomach vesicles of pig stomach H+/K+-ATP EIA.By 20, removed in centrifugal 30 minutes under the 000g and slightly put forward precipitation.Then with 100,000g centrifugal 30 minutes to supernatant liquor.With the precipitation resuspending of gained in 0.25M sucrose, then with it 132,000g is experience density gradient centrifugation down, carried out 90 minutes.The stomach vesicles is collected at interface from the 0.25M sucrose layer that comprises 7%FicollTM PM400 (Amersham Biosciences).This step is carried out in the cold house.
The inhibition of ion seepage (Ion-leaky) pig stomach H+/K+-ATP enzyme
According to Biochemical Pharmacology, 1988,
37, the modification method of describing among the 2231-2236 is measured ion seepage pig stomach H
+/ K
+The inhibition of-ATP enzyme.
The isolating vesicles of lyophilize is kept in the cryogenic refrigerator it until use then.For the mensuration of enzyme, with comprising 3mM MgSO
440mM Bis-tris (pH 6.4, under 37 ℃) the freeze dried vesicles of reconstruct.
Then test-compound exist or non-existent situation under, under 37 ℃ in the reaction mixture (40mM Bis-tris, pH 6.4) of 60 μ l final volume incubation 5mM KCl, 3mMNa
2ATP, 3mM MgSO
4Carried out enzyme reaction in 30 minutes with the vesicles of the reconstruct of 1.0 μ g.Stop enzyme reaction by adding 10% sodium lauryl sulphate (SDS).By detecting the inorganic phosphate that discharges from ATP with the ammonium molybdate tetrahydrate of in 15mM zinc acetate hydrate, preparing of 1 part of 35mM and the mixture incubation (this incubation causes having at the 750nm place phosphomolybdate of optical density(OD)) of 4 part of 10% xitix (pH 5.0).All embodiment compound exhibits go out strong inhibition activity.
The inhibition of the pig stomach H+/K+-ATP enzyme of non-leakage ion (Ion-tight porcine)
According to Biochemical Pharmacology, 1988,
37, the method for the improvement of describing among the 2231-2236 is measured Ion-tight pig stomach H
+/ K
+The inhibition of-ATP enzyme.
Isolating vesicles is kept in the cryogenic refrigerator until use.For the mensuration of enzyme, with comprising 3mM MgSO
45mM Tris (pH 7.4, under 37 ℃) dilution vesicles.
Then test-compound exist or non-existent situation under, under 37 ℃ in the reaction mixture (5mM Tris, pH 7.4) of 60 μ l final volume incubation 150mM KCl, 3mM Na
2ATP, 3mM MgSO
4, 15 μ M Aminomycins and 3.0 μ g vesicles carried out enzyme reaction in 30 minutes.Stop enzyme reaction by adding 10% sodium lauryl sulphate (SDS).Detect the inorganic phosphate that discharges from ATP by mixture incubation (this incubation is created in the phosphomolybdate that the 750nm place has optical density(OD)) with the xitix (pH 5.0) of the ammonium molybdate tetrahydrate of in 15mM zinc acetate hydrate, preparing of 1 part of 35mM and 4 part 10%.
The active IC of the inhibition of the compound of the following example
50The results are shown in the table 1 of value.
Table 1.
| The embodiment numbering | IC 50(μM) |
| 1-1 | |
| 1-2 | 0.084 |
| 1-3 | 0.089 |
| 2-1 | 0.075 |
| 2-2 | 0.061 |
| 2-3 | 0.067 |
| 3-1 | |
| 3-2 | 0.037 |
| 3-3 | 0.041 |
| 4-2 | 0.029 |
| 4-3 | 0.030 |
| 6-2 | 0.043 |
| 6-3 | 0.061 |
| 7-1 | 0.140 |
| 7-2 | 0.096 |
| 7-3 | 0.110 |
| 8-1 | 0.055 |
| 8-2 | 0.040 |
| 8-3 | 0.052 |
| 9-1 | 0.047 |
| 9-2 | 0.072 |
| 9-3 | 0.061 |
All test compounds all show sour pump antagonistic activity.
Dog kidney Na
+
/ K
+
The inhibition of-ATP enzyme
With comprising 3mM MgSO
440mM Tris (pH 7.4, under 37 ℃) reconstruct through the dog kidney Na of powdered
+/ K
+-ATP enzyme (Sigma).Then test-compound exist or non-existent situation under, under 37 ℃ in the reaction mixture (40mM Tris, pH 7.4) of 60 μ l final volume incubation 100mM NaCl, 2mM KCl, 3mM Na
2ATP, 3mM MgSO
4Carried out enzyme reaction in 30 minutes with the enzyme of 12 μ g.Stop enzyme reaction by adding 10%SDS.By detecting the inorganic phosphate that discharges from ATP with the ammonium molybdate tetrahydrate of in 15mM zinc acetate hydrate, preparing of 1 part of 35mM and the mixture incubation (this incubation is created in the phosphomolybdate that the 750nm place has optical density(OD)) of 4 part of 10% xitix (pH 5.0).
Sour excretory in the rat that the stomach inner chamber is poured suppresses
According to people such as Watanabe [people such as Watanabe K, J.Physiol. (Paris) 2000;
94: 111-116] measure the acid secretion in the rat that the stomach inner chamber is poured.
With 8 ages in week of urethane (1.4g/kg, intraperitoneal) anesthesia, fasting 18 hours but arbitrarily contact the male Sprague-Dawley rat of water before experiment, tracheostomize then.Behind middle abdominal incision, insert orifice of the stomach hole (forestomach) with geminative polyethylene trustship, pour into stomach with 1ml/ minute speed with salt solution (37 ℃, pH 5.0) then.Every 5 minutes, by determining acid output in the perfusion liquid to pH5.0 with 0.02M NaOH titration.After the acid basis excretory is determined to carry out 30 minutes, come the stimulating acid secretion by continuous intravenous infusion pentagastrin (16 μ g/kg/ hours).After reaching plateau, use test-compound by single intravenous push or intraduodenal administration in the acid secretion that stimulates.Monitoring acid secretion after administration.
By suppressing to estimate active in 0 hour to 1.5 or 3.5 hours total acid excretory inhibition or the maximum after the administration after the administration.
The compound of embodiment 1-9 all shows to have good inhibition activity.
Operating weight 7 to 15kg, have male beagle [the HeidenhainR:Arch Ges Physiol.1879 of Heiden because of microgastria;
19: 148-167].Allow animal before experiment at least 3 weeks of postoperative recovery.Animal is remained under the rhythm and pace of moving things of 12 hours illumination-dark, bar up separately.They the morning every day 11:00 accept standard food 1 time, random drinking public water supply, overnight fasting before experiment arbitrarily contacts water then.In whole experiment, collect the gastric juice sample by per 15 minutes gravity drainages.Measure acidity in the gastric juice by titration to the terminal point of pH 7.0.Continuous intravenous infusion stimulating acid secretion by histamine (80 μ g/kg/ hours).Back 90 minutes of histamine perfusion beginning, carry out the single intravenous injection of test-compound.Monitoring acid secretion after administration.Suppress to estimate active by maximum with respect to corresponding control value.
The inhibition of the gastric acid secretion in the Heidenhain's pouch dog (Heidenhain pouch dog)
Operating weight 7 to 15kg, have male beagle [the HeidenhainR:Arch Ges Physiol.1879 of Heiden because of microgastria;
19: 148-167].Allow animal before experiment at least 3 weeks of postoperative recovery.Animal is remained under the rhythm and pace of moving things of 12 hours illumination-dark, bar up separately.They the morning every day 11:00 accept standard food 1 time, random drinking public water supply, overnight fasting before experiment arbitrarily contacts water then.In whole experiment, collect the gastric juice sample by per 15 minutes gravity drainages.Measure acidity in the gastric juice by titration to the terminal point of pH 7.0.Continuous intravenous infusion stimulating acid secretion by histamine (80 μ g/kg/ hours).Back 90 minutes of histamine perfusion beginning, carry out the single intravenous injection of test-compound.Monitoring acid secretion after administration.Suppress to estimate active by maximum with respect to corresponding control value.
The combination of people's P162a
The HEK293S cell of preparation Human ether a-go-go genes involved (HERG) transfection, inner (in-house) cultivates then.The cell of expressing the HEK-293 cell of HERG product can be stuck with paste and to be suspended in that (this damping fluid is adjusted to pH 7.5 with 2M HCl down at 25 ℃, comprises 1mM MgCl at the 50mM of 10 times of volumes Tris damping fluid
2, 10mM KCl) in.Use Polytron homogenizer (carrying out 20 seconds) homogenate cell with peak power, then under 4 ℃ with 48, centrifugal 20 minutes of 000g.Resuspension, homogenate and centrifugation is once more in an identical manner.Discard the supernatant liquor of gained, resuspension (the 50mM Tris damping fluids of 10 times of volumes) precipitates eventually then, with peak power homogenate, carries out 20 seconds.With film homogenate five equilibrium, store until use down at-80 ℃.Use Protein Assay Rapid test kit (wako) and Spectramax plate reader (Wallac), five equilibrium is used for determining of protein concn.All operations, stock solution and device all remain on ice if having time in institute.About saturated mensuration (saturationassay), experimentize with the cumulative volume of 200 μ l.By at room temperature, incubation 36 μ l[under the situation that final concentration 10 μ M P162as (4 μ l) do not exist or exist
3H]-the film homogenate (every hole 20-30 μ g protein) of P162a and 160 μ l, carried out 60 minutes, determine saturation ratio with regard to total or non-specific binding respectively.Use the Skatron cell harvestor, filter and stop all incubations, use 50mM Tris damping fluid (pH 7.4, under 25 ℃) washing 2 times then by on PEI wetted glass fiber filter paper, carrying out fast vacuum.Use Packard LS counter, come quantitative receptors bind radioactivity by liquid scintillation counting(LSC).
About competition assay, with 4 dilution methods of semilog form (as 4-pointdilutions in semi-log format) with diluted chemical compound in 96 hole polypropylene boards.At first in DMSO, carry out all dilutions, be transferred to then and comprise 1mM MgCl
2, 10mM KCl 50mM Tris damping fluid (at 25 ℃ of following pH 7.4) in so that whole DMSO concentration becomes 1%.With compound to be dispensed in triplicate in the assay plate (4 μ l).In 6 apertures (having the P162a that identical vehicle and final concentration are 10 μ M), set up total combination and non-specific binding aperture respectively.Prepare radioligand with the 5.6x final concentration, in each aperture (36 μ l), add this solution.Start mensuration by adding YSi poly-L-Lysine SPA microballon (50 μ l, 1mg/ hole) and film (110 μ l, 20 μ g/ holes).At room temperature continued incubation 60 minutes.With plate at room temperature more other 3 hours of incubation so that the microballon sedimentation.By the quantitative receptors bind radioactive intensity of counting WallacMicroBeta plate counter.
The perviousness of Caco-2
According to Shiyin Yee, Pharmaceutical Research, 763 (1997) the middle methods of describing are measured the perviousness of Caco-2.
The Caco-2 cell is gone up cultivation 14 days at strainer upholder (filter supports) (Falcon HTS porous insertion system (multiwell insert system)).Substratum is removed from top and basolateral compartment, and damping fluid (basolateral buffer) preincubation individual layer is 0.5 hour outside the 0.3ml top damping fluid (apical buffer) of using preheating under 37 ℃ in 50 rev/mins shaking bath and 1.0ml substrate.The top damping fluid is by Hanks balanced salt solution, 25mM D-Glucose monohydrate, 20mM 2-morpholino b acid (morpholinoethanesulphonic acid) (MES) biological buffer, 1.25mMCaCl
2With 0.5mM MgCl
2(pH 6.5) are formed.Substrate outside damping fluid is by Hanks balanced salt solution, 25mM D-Glucose monohydrate, 20mM 2-[4-(2-hydroxyethyl)-1-piperazinyl] ethylsulfonic acid (HEPES) biological buffer, 1.25mM CaCl
2With 0.5mM MgCl
2(pH 7.4) are formed.When preincubation finishes, remove substratum, in the compartment of top, be added in the test-compound solution of preparing in the damping fluid (10 μ M).Inset (insert) moved to the aperture that comprises new matrix prepared outside damping fluid at the 1st hour.By the drug level in the LC/MS analysis to measure damping fluid.
The slope that accumulation according to the substrate on the receiver-side manifests (cumulative appearance) calculates flux rate (F, quality/time), calculates apparent permeability coefficient (P according to following formula
App).
P
app(cm/sec)＝(F×VD)/(SA×MD)
Wherein SA is the surface-area (0.3cm that is used to transport
2), VD is donor volume (0.3ml), MD is the total amount of the medicine on the donor side when t=0.The mean value of all data represented 2 insets.Determine the integrity of individual layer by the transportation of Lucifer Yellow.
Transformation period in people's liver microsome (HLM)-1
Under 37 ℃ on 96 deep-well plates with the 3.3mM MgCl for preparing in test-compound (1 μ M) and the 100mM potassium phosphate buffer (pH 7.4)
2With 0.78mg/mL HLM (HL101) incubation together.Reaction mixture is divided into 2 groups, non-P450 group and P450 group.Only in the reaction mixture of P450 group, add NADPH.Collect the five equilibrium of the sample of P450 group on the 0th, 10,30 and 60 minute time point, wherein the 0th minute time point represents to add the time of NADPH in the reaction mixture of P450 group.Collected the five equilibrium of the sample of non-P450 group on the time point at the-10 and 65 minutes.Five equilibrium with the acetonitrile solution extraction collection that comprises internal standard.Make sedimentary protein deposition in centrifugal (2000rpm, 15 minutes).Use the compound concentration in the LC/MS/MS systematic survey supernatant liquor.
By being mapped to the time, the natural logarithm of the peak area ratio of compound/internal standard obtains elimination half life values.The slope of the line of the match by point produces metabolic rate (k).By using following formula to be translated into elimination half life values:
The transformation period=1n 2/k
HERG patch clamp (patch clamp) test
In order to measure the potentiality that compound suppresses the hERG passage, described quick active type clone's copy Delayed Rectifier Potassium Current albumen (rapidly inactivating delayed rectifierpotassium current; IKr).
The stable HEK293 cell that shows the hERG passage is used for full cell patch clamps electric Physiological Experiment, (26.5-28.5 ℃) carries out under room temperature.In the HEK293 cell method of this passage of stable transfection be found in other places (people 1998 such as Zhou, Biophysical Journal, 74, pp230-241).The solution that uses in the experiment has following composition (mM): NaCl, 137 as the outer solution of standard cell lines; KCl, 4; CaCl
2, 1.8; MgCl
2, 1; Glucose, 10; HEPES, 10; PH 7.4 ± 0.05, adjust with NaOH/HCl; And solution in the standard cell lines of the following composition of tool (mM): KCl, 130; MgCl
2, 1; HEPES, 10; EGTA, 5; MgATP, 5; PH 7.2 ± 0.05, adjust with KOH.Design applies the scheme of voltage with activation hERG passage, and allows the measurement medicine to block this passage, and is as follows.At first, this membrane potential is increased to+30mV by keeping current potential-80mV, the time is 1s.Reduce voltage afterwards, speed is 0.5mV/ms, gets back to and keeps current potential-80mV, measures the spike of replying during polarizing and flows out electric current.This scheme repeats once (0.25Hz) per 4 seconds.After setting up during the stable reference line, in the presence of carrier (0.1%v/v DMSO), four that add testing compound subsequently in regular turn increase concentration, arrive stable state or 10 minutes (taking place earlier whichsoever) up to reaction.Terminal point in each experiment adopts 10 micromoles/many husbands of L Z-TEK as inner positive controls, and defines maximum blocking-up value.
Bioavailability in the rat
Use the Si Pula-Dao that grows up to come (family name) rat strain.Before experiment 1 to 2 day, under the situation of anesthesia, prepare all rats by right jugular cannulation.Intubate is placed on nape portion.Behind intravenously or Orally administered test-compound, extract blood sample (0.2-0.3mL) from jugular vein with the interval that reaches 24 hours.Freezing sample is until analysis.Estimate bioavailability by calculating the merchant between the plasma concentration area under a curve (AUC) behind oral administration or the intravenous administration.
Bioavailability in the dog
Use the beagle that grows up.Behind intravenously or Orally administered test-compound, extract blood sample (0.2-0.5mL) from cephalic vein with the interval that reaches 24 hours.Freezing sample is until analysis.By estimating bioavailability the merchant between the plasma concentration area under a curve (AUC) behind oral administration or the intravenous administration.
The plasma proteins combination
Use of the plasma proteins combination of the device of 96 orifice plate types by the method measurement test-compound (1 μ M) of equilibrium dialysis.With Spectra-Por
, regenerated fibre film (molecular weight cutoff value 12,000-14,000,22mm * 120mm) soaks in distilled water and spends the night, and carries out in 30% ethanol 20 minutes then, (Dulbecco ' s phosphate buffered saline(PBS) carried out 15 minutes in pH7.4) at dialysis buffer liquid at last.End user, Si Pula-Dao come the frozen plasma of (family name) rat and beagle.The assembling dialysis apparatus adds the blood plasma that 150 μ L compounds are strengthened to a side of each aperture, adds 150 μ L dialysis buffer liquid to the opposite side of each aperture.Under 37 ℃ with the 150r.p.m incubation after 4 hours, to the halving sampling of blood plasma and damping fluid.The acetonitrile that comprises internal standard compound with 300 μ L extracts compound in blood plasma and the damping fluid to analyze.Use LC/MS/MS to analyze and determine compound concentrations.
Calculate the mark (fraction) of unconjugated compound by following more formula:
Fu=1-{ ([blood plasma]
Eq-[damping fluid]
Eq)/([blood plasma]
Eq)
Wherein [blood plasma]
Eq[damping fluid]
EqIt is respectively the compound concentrations in blood plasma and the damping fluid.
Water solubility
Determine aqueous solubilities in the substratum (a)-(c) by following method:
Vibration at room temperature comprises Whatman mini-UniPrep cell above 0.5mg compound and each substratum of 0.5mL (Clifton, NJ USA) spend the night (above 8 hours).Before analysis, all samples is gone into Whatman mini-UniPrep plunger by 0.45 μ M poly(vinylidene fluoride) (PVDF) membrane filtration.Analyze filtrate by HPLC.
＜substratum〉(a) do not contain enzyme simulation gastric juice (SGN), pH 1.2: 2.0g NaCl is dissolved in 7.0mL 10M HCl and the enough water to produce 1000mL; (b) phosphate buffered saline(PBS) (PBS), pH 6.5: with 6.35g KH
2PO
4, 2.84g Na
2HPO
4Be dissolved in the enough water with 5.50g NaCl, produce 1000mL, adjust pH to 6.5; (c) the 3.94mg Taurocholic acid sodium salt (NaTC) and the 1.06mg 1-palmityl-2-oleoyl-L-GranulestinLecithin (POPC) of preparation in 1mL PBS (pH 6.5).
The hepatocellular metabolic stability of end user is estimated hepatic clearance
Under 37 ℃ at 95% air/5%CO
2Down with test-compound (1 μ M) with from people's liver cell incubation still, target cell density is 0.5 * 10
6Individual cell/ml, cumulative volume 50 μ L.On each time point, stop incubation by adding ice-cold acetonitrile (ACN).The five equilibrium of sample is mixed with 10% the ACN that comprises internal standard, analyze to carry out LC/MS/MS.After sample ultrasonic was handled 10 minutes, with 2,000rpm centrifugal 15 minutes to sample was transferred to supernatant liquor in other plates then to analyze.Use the compound concentration in the LC/MS/MS systematic survey supernatant liquor.
By being mapped to the time, the denary logarithm of the peak area ratio of compound/internal contrast obtains the disappearance rate of test-compound.The slope of the line of best fit by point produces metabolic rate (k
e).As illustrated in the formula 1, by considering liver cell weight, liver weight and body weight, this value is produced in proportion with what ml/ minute/kg represented a clearance rate value (CL
Int).Use the parallel pipe model (parallel tube model) that shows in the formula 2 from this intrinsic clearance value prediction hepatic clearance (CL
h).The clearance rate of prediction is divided by hepatic blood flow (Q
h) extraction yield (extraction ratio) (E is provided
h) (formula 3).
Formula 1:k
eX (g liver/kg body weight) * (cell number in ml incubation/incubation) * (cell/g liver)
Formula 2:CL
h=Q
h* { 1-exp (CL
Int/ Q
h)
Formula 3:E
h=CL
h/ Q
h
Wherein, " liver weight/kg body weight " is 21, and " cell/g liver " is 1.2 * 10
8, " cell number in ml incubation/incubation " is 2.0 * 10
-6, Q
hBe 20ml/ minute/kg.
If hepatic metabolism is the main path that medicine is removed, use the general exposure (AUC after formula 4 calculates oral administration so
Po).
Formula 4AUC
Po=dosage * (1-E
h)/CL
h
Embodiment
The providing of the following example only is used for further illustrating and do not wish is qualification to invention disclosed.Unless point out in addition in the following example, general experiment condition is as follows: promptly carry out all operations in room temperature or envrionment temperature in 18-25 ℃ scope; Use rotary evaporator to carry out the evaporation of solvent under the pressure that reduces, bath temperature reaches 60 ℃; Use thin-layer chromatography (TLC) monitoring reaction, the reaction times that provides only is to illustrate for example; The fusing point that provides (mp) not calibrated (polymorphism can cause different fusing points); By following technology: TLC (precoating Merck silica gel 60F
254TLC plate or precoating Merck NH
2Gel (silica gel of coating amine) F
254sThe TLC plate), at least one technology in mass spectrometry, nuclear magnetic resonance spectrum (NMR), infrared absorption spectrum (IR) or the trace analysis guarantees the structure and the purity of all separating compounds.The productive rate that provides only is to illustrate for example.Use Biotage KP-SIL (40-63 μ m), Biotage KP-NH (silica gel of coating amine) (40-75M) or Wako silica gel 300HG (40-60 μ M).Use Merck silica gel 60F
254The TLC plate of precoating (0.5 or 1.0mm thickness) is prepared type TCL.Use ZMD
TMOr ZQ
TM(Waters) and mass spectrograph obtain all qualitative datas in the low resolution mass-spectrometric data (ESI).Except as otherwise noted, the NMR data are measured with 270MHz (JEOL JNM-LA 270 spectrographs) or 300MHz (JEOLJNM-LA300 spectrograph), use deuterate chloroform (99.8%) or dimethyl sulfoxide (DMSO) (99.9%) as solvent, with respect to tetramethylsilane (TMS), it is the internal standard product, and unit is 1,000,000/(ppm); Conventional being abbreviated as of using: that s=is unimodal, d=is bimodal, m=multimodal, dd=are bimodal is bimodal, wide unimodal, the br.d=of sep=septet, br.s=is wide bimodal etc.Use Fourier transform infrared line spectrophotometer (Shimazu FTIR-8300) to measure IR spectrum.Use P-1020 numeral polariscope to measure (Japan Spectroscopic CO, Ltd.) specific rotation.Use Rigaku RINT-TTR powder X-ray-optical diffraction instrument to measure powder X-ray-optical diffraction (PXRD) pattern, it is equipped with automatic sample changement, 2theta-theta protractor, light dispersion slit, secondary monochromator and scintillometer.Be loaded into the sample for preparing on the aluminium sample container for analysis by powder.The sample speed of rotation is 60.00rpm, with 4 ° of/minute scannings, at room temperature uses the Cu-ka ray.
Embodiment 1
3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl)
Amino] imidazo [1,2-a] pyridine-6-methane amide
Step 1:4-chloro-5-methyl chroman
With thionyl chloride (81mL, 1.1mol) diethyl ether solution (370mL) add to 5-methyl chroman-4-alcohol (61g in 0 ℃, 370mmol, Tetrahedron Asym., 1997,8,3059.) and in the mixture of the diethyl ether (80mL) of pyridine (1.4mL) and chloroform (200mL) solution.Reaction mixture stirred under room temperature 13 hours.After the thing vacuum volatilization to be mixed, in the resistates impouring frozen water, and with ethyl acetate extraction (500mL * 2).The extract that merges salt water washing, dried over mgso, and vacuum concentration get title compound, are yellow oil (68g, quantitative yield).
1H NMR(CDCl
3，300MHz)δ：7.21-7.04(m，1H)，6.86-6.62(m，2H)，5.36-5.17(m，1H)，4.59-4.43(m，1H)，4.43-4.30(m，1H)，2.41(s，3H)，2.57-2.24(m，2H)ppm。
Step 2:8-amino-2-methyl imidazo [1,2-a] pyridine-6-isopropyl formate
Under room temperature, to 5,6-diamino isopropyl nicotinate (65g, and (500mL) adding bromo acetone in pimelinketone solution 333mmol) (51g, 333mmol).Reaction mixture stirred 2 hours in 95 ℃.Thing to be mixed is cooled to 0 ℃, filters the gained precipitation, and with normal hexane (500mL) and diisopropyl ether (500mL) washing.Solid is dissolved in methylene dichloride (1000mL) and the saturated sodium hydrogen carbonate solution (800mL).Isolate organic layer, dried over mgso, and vacuum concentration.By by purification by silica gel column chromatography resistates (dichloromethane/ethyl acetate=1/1 is as elutriant), get the compound of title, be brown syrup (43g, 55%).
1H NMR(CDCl
3，270MHz)δ：8.30(d，J＝1.3Hz，1H)，7.33(s，1H)，6.84(d，J＝1.3Hz，1H)，5.35-5.15(m，1H)，4.60-4.39(m，2H)，2.45(s，3H)，1.37(d，J＝6.0Hz，6H)ppm。
MS(ESI)m/z：234(M+H)
+。
Step 3:2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] miaow
Azoles is [1,2-a] pyridine-6-isopropyl formate also
Under 45 ℃, to 8-amino-2-methyl imidazo [1,2-a] pyridine-6-isopropyl formate (43g, 183mmol, step 2), sodium iodide (14g, 91mmol) with salt of wormwood (88g, in acetone 640mmol) (480mL) mixture, add 4-chloro-5-methyl chroman (50g, 274mmol, the acetone of step 1) (80mL) solution, mixture stirred 15 hours in 56 ℃.After being cooled to room temperature, mixture water (300mL) stopped reaction, and with dichloromethane extraction (500mL * 2).The extract dried over mgso that merges, and vacuum volatilization.Resistates gets title compound with normal hexane (300mL), 2-propyl alcohol/diisopropyl ether (20mL/200mL) and methyl alcohol (80mL) washing, is yellow solid (30g, 43%).
1H NMR(CDCl
3，300MHz)δ：8.26(s，1H)，7.31(s，1H)，7.12(t，J＝8.1Hz，1H)，6.85-6.68(m，3H)，5.36-5.21(m，2H)，4.78-4.67(m，1H)，4.33-4.15(m，2H)，2.39(s，3H)，2.35-2.00(m，5H)，1.40(d，J＝5.9Hz，6H)ppm。
MS(ESI)m/z：380(M+H)
+。
Step 4:2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] imidazoles
And [1,2-a] pyridine-6-formic acid
With 2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-isopropyl formate (8.6g, 23mmol, the methyl alcohol (15mL) of step 3) and 2M sodium hydroxide solution (34mL) and tetrahydrofuran (THF) (15mL) mixture stirred 0.5 hour down in 60 ℃.After being cooled to room temperature, with 2M hydrochloric acid (34mL) neutralise mixt.Filter and collect the gained throw out, and dry, get title compound, be white solid (7.5g, 98%).
1H NMR (DMSO-d
6, 270MHz) δ: 8.52 (s, 1H), 7.72 (s, 1H), 7.13 (t, J=7.9Hz, 1H), and 6.83-6.66 (m, 3H), 5.71-5.62 (m, 1H), 4.86-4.75 (m, 1H), 4.30-4.06 (m, 2H), 2.28 (s, 3H), 2.20-1.85 (m, 5H) ppm. (COOH does not observe)
MS(ESI)m/z：338(M+H)
+，336(M-H)
-。
Step 5:N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) ammonia
Base] imidazo [1,2-a] pyridine-6-methane amide
Under 0 ℃, to 2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-formic acid (7.5g, 22mmol, step 4), N-methyl methylamine hydrochloride (2.7g, 33mmol), I-hydroxybenzotriazole hydrate (HOBt) (4.1g, 27mmol) with triethylamine (9.3mL, in methylene dichloride 67mmol) (110mL) mixture, (5.1g, 27mmol), reaction mixture stirred under room temperature 1 day to add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI).In reaction mixture, add entry, and with dichloromethane extraction.With salt water washing extract, with dried over sodium sulfate, and vacuum volatilization.Remaining system gets title compound through purification by silica gel column chromatography (dichloromethane/ethyl acetate=1/2 is to 1/3, as elutriant), is white solid (8.1g, quantitative yield).
1H NMR(CDCl
3，300MHz)δ：7.63(s，1H)，7.27(s，1H)，7.12(t，J＝8.1Hz，1H)，6.75(t，J＝8.1Hz，2H)，6.26(s，1H)，5.36(d，J＝6.6Hz，1H)，4.69-4.61(m，1H)，4.31-4。17(m，2H)，3.13(s，6H)，2.38(s，3H)，2.32-2.15(m，4H)，2.12-1.95(m，1H)ppm。
MS(ESI)m/z：365(M+H)
+，363(M-H)
-。
Step 6:3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-look
Alkene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide (embodiment 1-1)
With N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide (8.1g, 22mmol, step 5), the formaldehyde 37wt% aqueous solution (18g, 222mmol), acetate (3.2mL, 56mmol) and sodium acetate (4.6g, acetonitrile 56mmol) (220mL) mixture in 80 ℃ the heating 1.3 hours.After being cooled to room temperature, add saturated sodium bicarbonate solution (200mL) to reaction mixture, and with ethyl acetate extraction (200mL * 2).With the extract of salt water washing merging, with dried over sodium sulfate, and vacuum volatilization.Resistates gets title compound through purification by silica gel column chromatography (methylene chloride=20/1 is as elutriant), is white solid (8.4g, 95%).
1H NMR(CDCl
3，300MHz)δ：7.77(s，1H)，7.12(t，J＝8.1Hz，1H)，6.75(t，J＝8.1Hz，2H)，6.35(s，1H)，5.38(d，J＝6.6Hz，1H)，4.88(s，2H)，4.72-4.62(m，1H)，4.33-4.16(m，2H)，3.13(s，6H)，2.37(s，3H)，2.31-2.14(m，4H)，2.14-1.98(m，1H)，1.88-1.78(m，1H)ppm。
MS(ESI)m/z：395(M+H)
+，393(M-H)
-。
Step 7:(S)-(-)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-two
Hydrogen-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide (fraction-1), and
(R)-(+)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-
Chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide (fraction-2)
Following by HPLC,, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl from racemize 3-(methylol)-N) amino] imidazo [1,2-a] pyridine-6-methane amide (5.9g) prepares this fraction-1 (2.46g) and-2 (2.39g).
Post:
OD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/ethanol/diethylamine (85/15/0.1)
Flow velocity: 18.9mL/ minute
(S)-(-)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-
Chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide (fraction-1) (embodiment
1-2)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 22=-5.3 ° (C=1.03, methyl alcohol)
Retention time: 8 minutes
(R)-(+)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-
Chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide (fraction-2) (embodiment
1-3)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 21=+6.0 ° (C=1.08, methyl alcohol)
Retention time: 14 minutes
Embodiment 2
8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-N, N, 2-trimethylammonium miaow
Azoles is [1,2-a] pyridine-6-methane amide also
Step 1: (3,4-dihydro-2H-chromene-4-base is amino)-glyoxal ethyline also for sec.-propyl 8-
[1,2-a] pyridine-6-manthanoate
With the described same procedure of embodiment 1 step 3, by 4-chlorobenzene and dihydropyrane (7.6g, 45mmol, Indian Journal of Chemistry, Section B, 1981,20B (12), 1063) and 8-amino-2-methyl imidazo [1,2-a] pyridine-6-isopropyl formate (7.0g, 30mmol, the step 2 of embodiment 1) preparation title compound, productive rate is 93% (10.2g, oily)
1H NMR (CDCl
3, 300MHz) δ: 8.26 (s, 1H), 7.37-7.17 (m, 3H), and 6.98-6.82 (m, 2H), 6.77 (s, 1H), and 5.47-5.38 (m, 1H), 5.35-5.21 (m, 1H), and 4.87-4.76 (m, 1H), 4.33-4.23 (m, 2H), 2.40 (s, 3H), 2.30-1.95 (m, 2H), 1.39 (d, J=5.9Hz, 6H) ppm.
MS(ESI)m/z：366(M+H)
+。
Step 2:8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-2-methyl
Imidazo [1,2-a] pyridine-6-isopropyl formate
With embodiment 1 step 6 same way as, by 8-(3,4-dihydro-2H-chromene-4-base is amino)-glyoxal ethyline also [1,2-a] pyridine-6-isopropyl formate (step 1) prepares title compound for 10.2g, 27.9mmol, and productive rate is 63% (7.0g, white solid).
1H NMR(CDCl
3，300MHz)δ：8.37(s，1H)，7.40-7.14(m，2H)，6.95-6.81(m，3H)，5.44-5.37(m，1H)，5.36-5.22(m，1H)，4.97(d，J＝5.1Hz，2H)，4.88-4.79(m，1H)，4.33-4.24(m，2H)，2.42(s，3H)，2.30-2.20(m，2H)，1.40(d，J＝6.6Hz，6H)ppm。(OH does not observe)
MS(ESI)m/z：396(M+H)
+。
Step 3:8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-2-methyl miaow
Azoles is [1,2-a] pyridine-6-formic acid also
With the same way as of example 1 step 4, by 8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-glyoxal ethyline also [1,2-a] pyridine-6-isopropyl formate (5.1g, 12.9mmol, step 2) preparation title compound, quantitative yield (4.8g, yellow solid).
1H NMR(DMSO-d
6，300MHz)δ：13.2-12.9(m，1H)，8.35(s，1H)，7.31-7.07(m，2H)，6.93-6.68(m，3H)，6.20-5.90(m，1H)，5.30-5.13(m，1H)，5.08-4.90(m，1H)，4.84-4.66(m，2H)，4.36-4.13(m，2H)，2.32(s，3H)，2.24-2.01(m，2H)ppm。
MS(ESI)m/z：354(M+H)
+，352(M-H)
-。
Step 4:8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-N, N, 2-three
Methylimidazole is [1,2-a] pyridine-6-methane amide (embodiment 2-1) also
Under 0 ℃, to the 8-(3 that stirs, 4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-glyoxal ethyline [1,2-a] pyridine-6-formic acid (760mg, step 3) and N-methyl methylamine hydrogenchloride (370mg also, 4.5mmol) and triethylamine (0.84mL, 6.0mmol) dimethyl formamide (15mL) mixture in add O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) (1.1g, 3.0mmol).Reaction mixture stirred under room temperature 3 hours.In reaction mixture, add entry, the mixture ethyl acetate extraction.With salt water washing extract, dried over sodium sulfate, and vacuum volatilization.Resistates gets title compound through purification by silica gel column chromatography (ethanol/methylene=1/20 is as elutriant), is white solid (344mg).
1H NMR(CDCl
3，300MHz)δ：7.75(s，1H)，7.34-7.16(m，2H)，6.94-6.82(m，2H)，6.30(s，1H)，5.52(d，J＝6.6Hz，1H)，4.93-4.82(m，2H)，4.81-4.72(m，1H)，4.33-4.22(m，2H)，3.10(s，6H)，2.46-2.10(m，5H)ppm。(OH does not observe)
MS(ESI)m/z：381(M+H)
+，379(M-H)
-。
Step 5:(+)-8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (fraction-1) also, and
(-)-8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-N, N, 2-front three
Base imidazo [1,2-a] pyridine-6-methane amide (fraction-2)
Following by HPLC, by racemize 8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(hydroxymethyl)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (335mg) preparation fraction-1 (132mg) and fraction-2 (130mg) also.
Separation condition
Post:
OD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/ethanol/diethylamine (85/15/0.1)
Flow velocity: 18.9mL/ minute
(+)-8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-N, N, 2-front three
Base imidazo [1,2-a] pyridine-6-methane amide (fraction-1) (embodiment 2-2)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 21=+12.3 ° (C=0.20, methyl alcohol)
Retention time: 8 minutes
(-)-8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-N, N, 2-front three
Base imidazo [1,2-a] pyridine-6-methane amide (fraction-2) (example 2-3)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 21=-10.0 ° (C=0.27, methyl alcohol)
Retention time: 13 minutes
Embodiment 3
8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also
Step 1:5,7-difluoro chroman-4-alcohol
Under 0 ℃, to 5 of stirring, 7-two chloro-2, (0.49g, 13mmol), mixture stirred under room temperature 20 hours (30mL) adding sodium borohydride in the methanol solution of 3-dihydro-4H-chromene-4-ketone (US 2005038032 for 2.0g, 11mmol).After the thing vacuum volatilization to be mixed, resistates water (20mL) is handled, and with ethyl acetate extraction (30mL * 2).The extract that merges is through salt water washing, dried over mgso, and vacuum concentration, gets title compound, is white solid (2.0g, 97%).
1H NMR(CDCl
3，270MHz)δ：6.50-6.33(m，2H)，5.07-4.95(m，1H)，4.36-4.18(m，2H)，2.16-1.94(m，2H)ppm。(OH does not observe)
Step 2:4-chloro-5,7-difluoro chroman
With the same way as of embodiment 1 step 1, by 5, (step 1) prepares title compound to 7-difluoro chroman-4-alcohol for 2.0g, 11mmol, quantitative yield (2.1g, yellow oil).
1H NMR(CDCl
3，300MHz)δ：6.56-6.30(m，2H)，5.45-5.25(m，1H)，4.62-4.33(m，2H)，2.53-2.20(m，2H)ppm。
Step 3:8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
Imidazo [1,2-a] pyridine-6-isopropyl formate
Same way as with embodiment 1 step 3, by 8-amino-2-methyl imidazo [1,2-a] pyridine-6-isopropyl formate (1.6g, 7.0mmol, embodiment 1 step 2) and 4-chloro-5,7-difluoro chroman (2.1g, 11mmol, step 2) preparation title compound, productive rate is 82% (2.8g, yellow solid).
1H NMR(CDCl
3，300MHz)δ：8.28(s，1H)，7.32(s，1H)，6.78(s，1H)，6.48-6.34(m，2H)，5.37-5.20(m，2H)，4.98-4.89(m，1H)，4.38-4.23(m，2H)，2.41(s，3H)，2.36-2.24(m，1H)，2.21-2.01(m，1H)，1.39(d，J＝6.6Hz，6H)ppm。
MS(ESI)m/z：402(M+H)
+。
Step 4:8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl miaow
Azoles is [1,2-a] pyridine-6-formic acid also
With the same way as of embodiment 1 step 4, by 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-glyoxal ethyline [1,2-a] pyridine-6-isopropyl formate (2.8g, 6.8mmol also, step 3) prepares title compound, productive rate 64% (1.5g, yellow solid).
1H NMR(DMSO-d
6，300MHz)δ：8.37(s，1H)，7.66(s，1H)，6.83-6.67(m，2H)，6.67-6.48(m，1H)，6.02(d，J＝7.3Hz，1H)，4.99-4.86(m，1H)，4.37-4.15(m，2H)，2.27(s，3H)，2.17-1.83(m，2H)ppm。(COOH does not observe).
MS(ESI)m/z：360(M+H)
+。
Step 5:8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, 2-three
Methylimidazole is [1,2-a] pyridine-6-methane amide also
With the same way as of embodiment 1 step 5, by 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-glyoxal ethyline [1,2-a] pyridine-6-formic acid (0.80g, 2.2mmol also, step 4) prepares title compound, and productive rate is 92% (0.79g, white solid).
1H NMR(CDCl
3，300MHz)δ：7.64(s，1H)，7.27(s，1H)，6.50-6.33(m，2H)，6.26(s，1H)，6.35(d，J＝5.8Hz，1H)，4.91-4.80(m，1H)，4.36-4.25(m，2H)，3.12(s，6H)，2.40(s，3H)，2.34-2.20(m，1H)，2.08-1.91(m，1H)ppm。
MS(ESI)m/z：387(M+H)
+。
Step 6:8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (embodiment 3-1) also
With the same way as of embodiment 1 step 6, by 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (0.79g, 2.0mmol also, step 5) prepares title compound, and productive rate is 94% (0.79g, white solid).
1H NMR(CDCl
3，270MHz)δ：7.76(s，1H)，6.52-6.25(m，3H)，5.40(d，J＝5.9Hz，1H)，4.97-4.76(m，3H)，4.41-4.18(m，2H)，3.12(s，6H)，2.34(s，3H)，2.32-2.12(m，2H)，2.11-1.91(m，1H)ppm。
MS(ESI)m/z：417(M+H)
+。
Step 7:(R)-(+)-and 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) ammonia
Base]-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (fraction also
-1), and
(S)-(-)-and 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (fraction-2) also
Following use HPLC, by racemize 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (0.78g) preparation fraction-1 (0.25g) and fraction-2 (0.26g) also.
Separation condition
Post:
AD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/2-propyl alcohol/diethylamine (90/10/0.1)
Flow velocity: 18.9mL/ minute
(R)-(+)-and 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (fraction-1) (embodiment also
3-2)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 24=+48.7 ° (c=1.01, methyl alcohol)
Retention time: 13 minutes
(S)-(-)-and 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl
Methyl)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (fraction-2) (embodiment also
3-3)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 24=-49.9 ° (c=1.01, methyl alcohol)
Retention time: 18 minutes
mp：186℃
PXRD pattern angle (2-Theta °): 10.6,13.0,14.4,16.7,19.7,22.6,26.5
Embodiment 4
8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(methylol)-N, N, 2-three
Methylimidazole is [1,2-a] pyridine-6-methane amide also
Step 1:5-fluorobenzene and dihydropyrane-4-alcohol
With the same way as of example 3 steps 1, by 5-fluoro-2,3-dihydro-4H-chromene-4-ketone (GB2355264) preparation title compound is dark oil thing, quantitative yield.
1H NMR(CDCl
3，300MHz)δ：7.25-7.11(m，1H)，6.75-6.60(m，2H)，5.13-5.02(m，1H)，4.40-4.18(m，2H)，2.25-1.95(m，3H)ppm。
Step 2:4-chloro-5-fluorobenzene and dihydropyrane
With the same way as of example 1 step 1, (step 1) prepares title compound for 13g, 77mmol, quantitative yield (15g, orange oily matter) by 5-fluorobenzene and dihydropyrane-4-alcohol.
1H NMR(CDCl
3，270MHz)δ：7.24-7.10(m，1H)，6.71-6.56(m，2H)，5.43-5.33(m，1H)，4.58-4.32(m，2H)，2.50-2.19(m，2H)ppm。
Step 3:
8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-glyoxal ethyline also [1,2-a]
Pyridine-6-isopropyl formate
Same way as with embodiment 1 step 3, by 4-chloro-5-fluorobenzene and dihydropyrane (14g, 77mmol, embodiment 4 steps 2) and 8-amino-2-methyl imidazo [1,2-a] pyridine-6-isopropyl formate (2.2g, 7.1mmol, embodiment 1 step 2) preparation title compound, productive rate 61% (12g, yellow solid).
1H NMR(CDCl
3，270MHz)δ：8.27(s，1H)，7.31(s，1H)，7.24-7.10(m，1H)，6.80(s，1H)，6.74-6.57(m，2H)，5.40-5.21(m，2H)，5.04-4.93(m，1H)，4.36-4.25(m，2H)，2.40(s，3H)，2.36-2.23(m，1H)，2.19-1.97(m，1H)，1.39(d，J＝5.9Hz，6H)ppm。
MS(ESI)m/z：384(M+H)
+。
Step 4:8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-glyoxal ethyline is also
[1,2-a] pyridine-6-formic acid
With the same way as of embodiment 1 step 4,, 4-dihydro-2H-chromene-4-yl) amino by 8-[(5-fluoro-3]-glyoxal ethyline also [1,2-a] (step 3) prepares title compound to pyridine-6-isopropyl formate for 11g, 28mmol, productive rate is 98% (9.5g, white solid).
1H NMR (DMSO-d
6, 300MHz) δ: 8.51 (s, 1H), 7.72 (s, 1H), 7.32-7.16 (m, 1H), 6.78-6.64 (m, 3H), 6.12 (d, J=7.3Hz, 1H), 5.06-4.94 (m, 1H), 4.35-4.15 (m, 2H), 2.29 (s, 3H), 2.16-1.93 (m, 2H) ppm (COOH does not observe).
Step 5:8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, 2-trimethylammonium
Imidazo [1,2-a] pyridine-6-methane amide
With the same way as of embodiment 1 step 5,, 4-dihydro-2H-chromene-4-yl) amino by 8-[(5-fluoro-3]-glyoxal ethyline also [1,2-a] pyridine-6-formic acid (step 4) prepares title compound for 0.64g, 1.9mmol, productive rate 99% (0.67g, white solid).
1H NMR(CDCl
3，270MHz)δ：7.63(s，1H)，7.33-7.23(m，1H)，7.24-7.10(m，1H)，6.76-6.55(m，2H)，6.27(s，1H)，5.43(d，J＝5.8Hz，1H)，4.97-4.84(m，1H)，4.36-4.23(m，2H)，3.12(s，6H)，2.39(s，3H)，2.32-2.22(m，1H)，2.11-1.93(m，1H)ppm。
MS(ESI)m/z：369(M+H)
+。
Step 6:8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, 2-trimethylammonium
Imidazo [1,2-a] pyridine-6-methane amide (fraction-1) and (fraction-2)
Following use HPLC, by racemize 8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, 2-tri-methylimidazolium also [1,2-a] pyridine-6-methane amide (0.66g) prepare this fraction-1 (0.25g) and fraction-2 (0.25g).
Post:
OD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/EtOH/ diethylamine (80/20/0.1)
Flow velocity: 20mL/ minute
8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, the 2-tri-methylimidazolium is also
[1,2-a] pyridine-6-methane amide (fraction-1)
NMR: spectroscopic data is identical with racemoid
Retention time: 7 minutes
MS(ESI)m/z：369(M+H)
+
8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-N, N, the 2-tri-methylimidazolium is also
[1,2-a] pyridine-6-methane amide (fraction-2)
NMR: spectroscopic data is identical with racemoid
Retention time: 11 minutes
MS(ESI)m/z：369(M+H)
+。
Step 7:(-)-and 8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (embodiment 4-2) also
With the same way as of embodiment 1 step 6, by 8-[(5-fluoro-3,4-dihydro-2H-alkene-4-yl) amino]-N, N, the 2-tri-methylimidazolium is [1,2-a] pyridine-6-methane amide (0.13g, 0.35mmol also, the fraction of step 6-1) preparation title compound, productive rate is 93% (0.13g, white solid).
1H NMR(CDCl
3，300MHz)δ：7.78(s，1H)，7.25-7.12(m，1H)，6.73-6.55(m，2H)，6.36(s，1H)，5.42(d，J＝5.8Hz，1H)，4.97-4.82(m，3H)，4.36-4.20(m，2H)，3.13(s，6H)，2.38(s，3H)，2.32-2.20(m，1H)，2.12-1.92(m，1H)，1.80-1.65(m，1H)ppm。
MS(ESI)m/z：399(M+H)
+。
Specific rotation: [α]
D 23=-49.7 ° (c=1.01, methyl alcohol)
Step 8:(+)-and 8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(hydroxyl first
Base)-and N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide (embodiment 4-3) also
With the same way as of embodiment 1 step 6, by 8-[(5-fluoro-3,4-dihydro-2H-alkene-4-yl) amino]-N, N, the 2-tri-methylimidazolium is [1,2-a] pyridine-6-methane amide (0.13g, 0.35mmol also, the fraction of step 6-2) preparation title compound, productive rate is 94% (0.13g, white solid).
1H NMR(CDCl
3，300MHz)δ：7.78(s，1H)，7.24-7.10(m，1H)，6.73-6.56(m，2H)，6.36(s，1H)，5.42(d，J＝5.8Hz，1H)，4.97-4.83(m，3H)，4.36-4.19(m，2H)，3.13(s，6H)，2.39(s，3H)，2.34-2.21(m，1H)，2.12-1.92(m，1H)，1.69-1.53(m，1H)ppm。
MS(ESI)m/z：399(M+H)
+。
Specific rotation: [α]
D 24=+54.3 ° (c=1.01, methyl alcohol)
Embodiment 5
(S)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene
-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide
Step 1:3-(2-chloro-5-methylphenoxy) methyl acrylate
Under room temperature, (10.0g, 70.1mmol) ((1.0M is purchased solution to the THF solution of 5.95mL, acetonitrile solution 71.5mmol) (30mL) TBAF in add stirring, and 14mL 14mmol), lasts 1 hour with methyl propionate with 2-chloro-5-sylvan.After interpolation is finished, stirred lasting 1 hour.Reaction mixture dilution with toluene (50mL), and wash secondary (50mL+25mL) with water.Isolated organic layer concentrating under reduced pressure gets title compound, is brown oil (17.2g,＞99%, the genial trans-isomer(ide) mixture of 6:4, ca.10wt% toluene) that it can be used for next step and need not to be further purified.
1H NMR (CDCl
3, 300MHz) δ: 7.71 (d, J=12.5Hz, 0.4H), 7.30 (m, 1H), 6.98-6.93 (m, 2H), 6.74 (d, J=7.3Hz, 0.6H), 5.47 (d, J=12.5Hz, 0.4H), 5.20 (d, J=7.3Hz, 0.6H), 2.77 (s, 1.8H), 3.73 (s, 1.3H), (two is unimodal, 3H) ppm for 2.34-2.33.
Step 2:3-(2-chloro-5-methylphenoxy) methyl propionate
Under room temperature hydrogen (1atm) environment, ((10mg 0.097mmol) spends the night with methyl alcohol (5mL) the mixture stirring of 10% palladium on carbon (50mg) for step 1), Sodium Bromide for 1.00g, 4.41mmol with 3-(2-chloro-5-methylphenoxy) methyl acrylate.The reaction mixture warp
Pad filters, with toluene (10mL) drip washing catalyzer.Filtrate water (5mL) washing that merges, and concentrating under reduced pressure, title compound (963mg, 95%), be orange oily matter, can be used for next step and need not to be further purified.
1H NMR(CDCl
3，300MHz)δ：7.21(d，J＝8.1Hz，1H)，6.78(br.s，1H)，6.73(br.d，J＝8.8Hz，1H)，4.30(t，J＝6.6Hz，2H)，3.74(s，3H)，2.86(t，J＝6.6Hz，2H)，2.32(s，3H)ppm。
Step 3:8-chloro-5-methyl-2,3-dihydro-4H-chromene-4-ketone
Under 80 ℃, the mixture of 3-(2-chloro-5-methylphenoxy) methyl propionate (430mg, 1.88mmol, step 2) and trifluoromethayl sulfonic acid (0.86mL, 2mL/g substrate) was stirred 40 minutes.After cooling under the room temperature, the reaction mixture dilute with water, product extracts with toluene.Organic layer is used K continuously
2CO
3The aqueous solution and water washing, concentrating under reduced pressure, title compound (355mg, 96%), be the light brown solid, can be used for next step and need not to be further purified.
1H NMR(CDCl
3，300MHz)δ：7.41(d，J＝8.1Hz，1H)，6.76(d，J＝8.1Hz，1H)，4.61(t，J＝6.6Hz，2H)，2.85(t，J＝6.6Hz，2H)，2.61(s，3H)ppm。
Step 4:(4S)-8-chloro-5-methyl-N-[(1S)-the 1-phenylethyl] chroman
-4-phenylamino-4-methyl benzyl sulphonate
Under 22 ℃, to 8-chloro-5-methyl-2,3-dihydro-4H-chromene-4-ketone (1.97g, 10mmol, add in the tetrahydrofuran (THF) of step 3) (4mL) solution (S)-1-phenyl ethyl amine (1.64mL, 13mmol) and titanium isopropoxide (IV) (4.44mL, 15mmol).This yellow solution stirred 18 hours in 22 ℃.After reacting completely (with
1H-NMR confirms), mixture dilutes (20mL) with methyl alcohol, and is cooled to-30 ℃ approximately.Under nitrogen environment, last 30 minutes (internal temperature is maintained at-20 to-25 ℃), triethylene glycol dme (triglyme) solution of adding 2.0M sodium borohydride in this solution (2.5mL, 5mmol).Reaction mixture adds 10%w/v sodium citrate aqueous solution (35mL) afterwards in-20 ℃ of stirrings 30 minutes.This yellow mixture adds ethyl acetate (60mL) then in 22 ℃ of vigorous stirring 5 minutes.The gained mixture stirred separates two 15 hours in 22 ℃.Organic layer washs (20mL) with the 5%w/v sodium chloride aqueous solution, and concentrates.Crude product (69.8%, use HPLC to confirm) is dissolved in the methyl alcohol (65mL), and solution is warmed to 70 ℃ (outside temperatures).In this yellow solution, be added dropwise to the aqueous solution of 4-methyl-benzyl sulfonic acid monohydrate (2.47g, 13mmol is in 15mL water), last 10 minutes.Add extra water (45mL), mixture slowly cools to 22 ℃, and in 22 ℃ of stirrings spend the night (12 hours).After the filtration, with ethyl acetate (20mL) washing white solid, then in 50 ℃ of vacuum-dryings 2 hours, title compound (2.82g, 59%, 99.3%de), be white solid.
1H NMR(DMSO-d
6，300MHz)δ：8.98(br.s，1H)，8.71(br.s，1H)，7.65(d，J＝6.6Hz，2H)，7.49-7.46(m，5H)，7.39(d，J＝8.1Hz，1H)，7.12(d，J＝7.3Hz，2H)，6.87(d，J＝8.1Hz，1H)，4.72-4.68(m，2H)，4.42-4.32(m，2H)，2.40(s，3H)，2.29(s，3H)，2.13-2.00(m，2H)，1.69(d，J＝5.8Hz，3H)ppm。
Analysis condition (HPLC)
Post: Xterra MS C183.5 μ m (2.1mm I.D. * 150mm, Waters).
Temperature: 40 ℃
Detect: UV (230nm)
Moving phase: CH
3CN (A), 10mM CH
3COONH
4(B).Gradient table is as follows.
| Time (minute) | ％A | ％B | Flow velocity (mL/ minute) |
| 0.0 | 20 | 80 | 0.3 |
| 25.0 | 95 | 5 | 0.3 |
| 30.0 | 95 | 5 | 0.3 |
Retention time
Fraction 1:21.8 minute (undesirable diastereomer)
Fraction 2:22.6 minute (diastereomer of hope)
Step 5:(4S)-5-methyl chroman-4-amine hydrochlorate
Under 22 ℃, to (4S)-8-chloro-5-methyl-N-[(1S)-1-phenylethyl] (2.37g, 5.0mmol add 1M aqueous sodium hydroxide solution (10mL) to chroman-4-phenylamino-4-methyl benzyl sulphonate in the ethyl acetate of step 4) (19mL) suspension.This suspension was in 22 ℃ of vigorous stirring 10 minutes.Separates two.Organic layer washes (5mL) with water, and concentrates, and gets unhindered amina, is colorless oil.Unhindered amina is dissolved in the methyl alcohol (20mL), and solution exists down in 10% palladium on carbon (31mg), and (1atm) hydrogenation is 3 hours under 50 ℃ of hydrogen environments.After reaction mixture is cooled to 22 ℃, use
The pad filtering catalyst, and use methanol wash.Filtrate concentrates, title compound (1.00g, 100%, 99.4%ee), be white solid.
1H NMR(DMSO-d
6，300MHz)δ：8.52(br.s，3H)，7.17(t，J＝8.0Hz，1H)，6.79(d，J＝7.0Hz，1H)，6.70(d，J＝8.0Hz，1H)，4.55(s，1H)，4.32(d，J＝10.3Hz，2H)，2.39(s，3H)，2.30(d，J＝14.7Hz，1H)，2.05-2.20(m，1H)ppm。
Analysis condition (HPLC)
Post:
AD-H
Temperature: 40 ℃
Detecting: UV (230nm)
Moving phase: normal hexane/ethanol/diethylamine (90/10/0.1)
Flow velocity: 1.0mL/ minute
Retention time
Fraction 1:8.0 minute (R-isomer)
Fraction 2:9.6 minute (S-isomer)
Step 6:2-methyl-8-{[(4S)-5-methyl-3,4-dihydro-2H-chromene-4-yl] ammonia
Base } imidazo [1,2-a] pyridine-6-isopropyl formate
Step 6-1: sec.-propyl 6-amino-5-bromo nicotine acid esters
Under 22 ℃, (14.9g, cyclopentyl methyl ether (CPME) 82.5mmol) (150mL) in the 3-neck bottle of suspension, divide seven times and add NBS (2.93g * 7 are total up to 116mmol), 10 minutes at interval to contain 6-amino-nicotinic acid isopropyl ester at 500mL.Stir after 15 minutes, with 3% Sulfothiorine (Na
2S
2O
3) (150mL) and 5%NaHCO
3The aqueous solution (150mL) stopped reaction.In this mixture, add toluene (300mL), stirred the mixture 10 minutes.Isolated organic layer is driven (chase) solvent (90mL * 2) through concentrating under reduced pressure with the 2-propyl alcohol, and partial concentration is to 75mL.Mixture stirred under room temperature 15 hours, stirred 5 hours down in 0 ℃ then.The gained solid after filtration, and with ice-cold 2-propyl alcohol (30mL) washed twice, title compound (16.4g, 63.3mmol, 77%), be the yellowish brown solid.
1H NMR(CDCl
3，300MHz)δ：8.66(s，1H)，8.24(s，1H)，5.40(br.s，2H)，5.22(sep，J＝6.6Hz，1H)，1.35(d，J＝6.6Hz，6H)ppm。
Step 6-2:8-bromo-glyoxal ethyline is [1,2-a] pyridine-6-isopropyl formate also
With 6-amino-5-bromo isopropyl nicotinate (15.0g, 57.9mmol, step 6-1), acetone dichloride (14.0mL, 174mmol) and the mixture of propionitrile (150mL) in 100 ℃ of stirrings.Stir after 71 hours, (4.7mL 58mmol), continues to stir 24 hours down in uniform temp to add acetone dichloride.Add then another partly acetone dichloride (4.7mL, 58mmol) and propionitrile (60mL).Stir after 9 hours, reaction mixture is cooled to room temperature, uses 0.5M NaOH solution (116mL) and water (34mL) stopped reaction then.Add toluene (150mL) in this mixture, mixture stirred 15 minutes.Isolating organic layer carries out concentrating under reduced pressure, and solvent is driven (heptane: ethyl acetate=1: 1,50mL * 2) with mixed solvent.Resistates is with mixture (300mL) dilution of 1: 1 heptane and ethyl acetate, and adds silica gel (30g).Stir after 10 minutes, mixture after filtration, and with the mixture washing (150mL * 2) of 1: 1 heptane and ethyl acetate.Filtrate decompression concentrates.Drive solvent (150mL * 2) and partial concentration to about 20mL with the 2-propyl alcohol.Add heptane (70mL), mixture stirred under room temperature 1 hour, stirred 3 hours in 0 ℃ then.The gained solid after filtration, and with 19: 1 heptane and 2-propanol mixture washed twice (30mL), title compound (8.3g, 28mmol, 48%), be light milk look brown solid.
1H NMR(CDCl
3，300MHz)δ：8.78(d，J＝1.4Hz，1H)，7.96(s，1H)，7.50(s，J＝8Hz，1H)，5.28(s ep，J＝5.8Hz，1H)，2.52(s，3H)，1.39(d，J＝5.8Hz，6H)ppm。
Step 6-3:2-methyl-8-{[(4S)-5-methyl-3,4-dihydro-2H-chromene-4-yl]
Amino } imidazo [1,2-a] pyridine-6-isopropyl formate
In the two neck round-bottomed bottles (20mL) that are equipped with reflux exchanger, inject Pd
2(dba)
3(3.7mg, 0.004mmol) with BINAP (5.6mg, 0.009mmol), and with nitrogen purging.Add toluene (1mL), mixture produces uneven purple solution in 22 ℃ of stirrings 5 minutes.((85mg, 0.88mmol) and toluene (1mL), mixture was in 60 ℃ of stirrings 5 minutes for the step 5) sodium tert-butoxide for 80mg, 0.4mmol to add (4S)-5-methyl chroman-4-amine hydrochlorate.Add also [1,2-a] pyridine-6-isopropyl formate (119mg, 0.4mmol, step 6-2) and toluene (1mL) of 8-bromo-glyoxal ethyline, mixture stirred 5 hours in 80 ℃ then.Reaction mixture is cooled to 22 ℃, and with diisopropyl ether dilution (3mL).Gained suspension warp
Pad filters, and filtrate decompression concentrates.(heptane: ethyl acetate=4: 1), get title compound (118mg, 78%), it is rose pink powder to crude product through purification by silica gel column chromatography.
1H NMR(CDCl
3，300MHz)δ：8.26(s，1H)，7.32(s，1H)，7.12(t，J＝8.1Hz，1H)，6.78-6.72(m，3H)，5.32-5.24(m，2H)，4.73(br.，1H)，4.27-4.19(m，2H)，2.39(s，3H)，2.29(d，J＝15.0Hz，1H)，2.22(s，3H)，2.14-2.09(m，1H)，1.40(d，J＝5.8Hz，6H)ppm。
Step 7:2-methyl-8-{[(4S)-5-methyl-3,4-dihydro-2H-chromene-4-yl] amino }
Imidazo [1,2-a] pyridine-6-formic acid
With the same way as of embodiment 1 step 4, by 2-methyl-8-{[(4S)-5-methyl-3,4-dihydro-2H-chromene-4-yl] amino } imidazo [1,2-a] pyridine-6-isopropyl formate (step 6-3) preparation title compound.
Step 8:N, N, the 2-trimethylammonium-8-{[(4S)-and 5-methyl-3,4-dihydro-2H-chromene-4-
Base] amino } imidazo [1,2-a] pyridine-6-methane amide
With the same way as of embodiment 1 step 5, by 2-methyl-8-{[(4S)-5-methyl-3,4-dihydro-2H-chromene-4-yl] amino } pyridine-(step 7) prepares title compound to 6-formic acid to imidazo [1,2-a].
Step 9:3-(hydroxymethyl)-N, N, the 2-trimethylammonium-8-{[(4S)-and 5-methyl-3,4-two
Hydrogen-2H-chromene-4-yl] amino } imidazo [1,2-a] pyridine-6-methane amide
With the same way as of embodiment 1 step 6, by N, N, the 2-trimethylammonium-8-{[(4S)-and 5-methyl-3,4-dihydro-2H-chromene-4-yl] amino } pyridine-(step 8) prepares title compound to the 6-methane amide to imidazo [1,2-a].
Embodiment 6
[2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino]-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol
Step 1:2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine
Under 0 ℃, to the 2-methyl-8-[(5-methyl-3 that stirs, 4-dihydro-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-formic acid (0.60g, 1.8mmol, the step 4) of embodiment 1 and morpholine (0.31g, 3.6mmol) methylene dichloride (8.0mL) mixture in add I-hydroxybenzotriazole hydrate (HOBt) (0.36g, 2.7mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (0.51g, 2.7mmol), reaction mixture stirred under room temperature 20 hours.With saturated sodium bicarbonate stopped reaction mixture, and with dichloromethane extraction (30mL * 2).The extract salt solution washed twice that merges, dried over sodium sulfate, and vacuum-evaporation.Resistates gets title compound through purification by silica gel column chromatography (hexane/ethyl acetate=1/2 is as elutriant), is white solid (0.73g, quantitative yield).
1H NMR(CDCl
3，300MHz)δ：7.64(s，1H)，7.28(s，1H)，7.18-7.07(m，1H)，6.80-6.69(m，2H)，6.21(s，1H)，5.41(d，J＝5.8Hz，1H)，4.70-4.60(m，1H)，4.34-4.17(m，2H)，3.81-3.61(m，8H)，2.38(s，3H)，2.22(s，3H)，2.31-1.95(m，2H)ppm。
MS(ESI)m/z：407(M+H)
+。
Step 2:2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine (fraction-1 and fraction-2)
Following use HPLC prepares this fraction-1 (0.27g) and fraction-2 (0.28g) by racemize 2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine (0.72g).
Separation condition
Post:
OJ-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/ethanol/diethylamine (65/35/0.1)
Flow velocity: 20mL/ minute
2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine-4-base carbonyl)
Imidazo [1,2-a] pyridine-8-amine (fraction-1)
NMR: spectroscopic data is identical with racemoid
MS(ESI)m/z：407(M+H)
+
Retention time: 8 minutes
2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine-4-base carbonyl)
Imidazo [1,2-a] pyridine-8-amine (fraction-2)
NMR: spectroscopic data is identical with racemoid
MS(ESI)m/z：407(M+H)
+。
Retention time: 14 minutes
Step 3:(-)-[2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) ammonia
Base]-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (embodiment 6-2)
With 2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine (0.22g, 0.55mmol, the fraction of step 2-1), the aqueous solution (0.45g of 37wt% formaldehyde, 5.5mmol), acetate (0.78mL, 1.4mmol) with sodium acetate (0.11g, acetonitrile 1.4mmol) (5mL) mixture in 70 ℃ the heating 3 hours.To be cooled to room temperature, with 1M sodium hydroxide stopped reaction reaction mixture, and with ethyl acetate extraction (20mL * 2).The extract that merges salt water washing, dried over sodium sulfate, and vacuum volatilization.Resistates gets title compound through silica gel column chromatography (methylene chloride=15/1 is as elutriant) and NH gel (ethyl acetate is as elutriant) purifying, is white solid (0.18g, 76%).
1H NMR(CDCl
3，300MHz)δ：7.76(s，1H)，7.13(t，J＝8.1Hz，1H)，6.81-6.69(m，2H)，6.30(s，1H)，5.46(d，J＝6.6Hz，1H)，4.91-4.78(m，2H)，4.70-4.60(m，1H)，4.33-4.17(m，2H)，3.87-3.60(m，8H)，2.49-2.38(m，1H)，2.33(s，3H)，2.21(s，3H)，2.29-2.15(m，1H)，2.15-1.97(m，1H)ppm。
MS(ESI)m/z：437(M+H)
+。
Specific rotation: [α]
D 23=-12.0 ° (c=1.01, methyl alcohol)
Step 4:(+)-[2-methyl-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) ammonia
Base]-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (embodiment 6-3)
Same way as with embodiment 6 steps 3, by 2-methyl-N-(5-methyl-3,4-dihydro-2H-chromene-4-yl)-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine (0.23g, 0.56mmol, the fraction of step 2-2) preparation title compound, productive rate is 73% (0.18g, white solid).
1H NMR(CDCl
3，300MHz)δ：7.76(s，1H)，7.13(t，J＝8.1Hz，1H)，6.81-6.69(m，2H)，6.30(s，1H)，5.46(d，J＝6.6Hz，1H)，4.91-4.78(m，2H)，4.70-4.60(m，1H)，4.33-4.17(m，2H)，3.87-3.60(m，8H)，2.81-2.64(m，1H)，2.33(s，3H)，2.21(s，3H)，2.29-2.15(m，1H)，2.15-1.97(m，1H)ppm。
MS(ESI)m/z：437(M+H)
+。
Specific rotation: [α]
D 24=+11.8 ° (c=1.01, methyl alcohol)
Embodiment 7
[8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine-4-base carbonyl)
Imidazo [1,2-a] pyridin-3-yl] methyl alcohol
Step 1:[8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine-4-
The base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (embodiment 7-1)
Under 0 ℃, to the 8-that stirs (3,4-dihydro-2H-chromene-4-base is amino)-3-(methylol)-glyoxal ethyline [1,2-a] pyridine-6-formic acid (2.4g also, 6.9mmol, the step 3) of embodiment 2, morpholine (1.8g, 21mmol) and triethylamine (1.44mL adds O-benzotriazole-1-base-N in dimethyl formamide 10mmol) (70mL) mixture, N, N ', and N '-tetramethyl-urea hexafluorophosphate (HBTU) (3.9g, 10mmol).Reaction mixture stirred under room temperature 3 hours.In reaction mixture, add entry, use the ethyl acetate extraction mixture.Extract salt water washing, with dried over sodium sulfate, and vacuum-evaporation.With silica gel column chromatography purifying resistates (ethyl acetate/methanol=20/1 is as elutriant), get title compound, be white solid (1.6g, 53%).
1H NMR(CDCl
3，300MHz)δ：7.78(s，1H)，7.33-7.16(m，2H)，6.94-6.82(m，2H)，6.25(s，1H)，5.57-5.50(m，1H)，4.94-4.86(m，2H)，4.80-4.70(m，1H)，4.32-4.23(m，2H)，3.80-3.60(m，8H)，2.40(s，3H)，2.30-2.15(m，2H)ppm。(OH does not observe)
MS(ESI)m/z：423(M+H)
+，421(M-H)
-。
Step 2:(-)-[8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-1) and
(+)-[8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine-4-base carbonyl)
Imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-2)
Following use HPLC prepares this fraction-1 (570mg) and fraction-2 (570mg) by racemize [8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (1.4g).
Separation condition
Post:
AD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/2-propyl alcohol/diethylamine (85/15/0.1)
Flow velocity: 18.9mL/ minute
(-)-[8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine-4-base carbonyl
Base) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-1) (embodiment 7-2)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 24=-3.21 ° (C=1.00, methyl alcohol)
Retention time: 16 minutes
(+)-[8-(3,4-dihydro-2H-chromene-4-base is amino)-2-methyl-6-(morpholine-4-base carbonyl
Base) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-2) (embodiment 7-3)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 25=+4.21 ° (C=0.91, methyl alcohol)
Retention time: 19 minutes
Embodiment 8
[8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol
Step 1:N-(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl)-2-methyl-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine
With the same way as of embodiment 6 steps 1, by 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-glyoxal ethyline [1,2-a] pyridine-6-formic acid (5.00g, 13.9mmol also, the step 4) of embodiment 3 prepares title compound, and productive rate is 75% (4.49g, white solid).
1H NMR(CDCl
3，300MHz)δ：7.64(d，J＝1.3Hz，1H)，7.27(s，1H)，6.47-6.36(m，2H)，6.22(s，1H)，5.40(d，J＝6.6Hz，1H)，4.95(m，1H)，4.35-4.23(m，2H)，3.71(m，8H)，2.39(s，3H)，2.30-2.22(m，1H)，2.09-1.95(m，1H)ppm。
MS(ESI)m/z：429(M+H)
+。
Step 2:[8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (embodiment 8-1)
With the same way as of embodiment 6 steps 3, by N-(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl)-2-methyl-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridine-8-amine (4.49g, 10.5mmol, step 1) prepares title compound, and productive rate is 97% (4.68g, white solid).
1H NMR(CDCl
3，300MHz)δ：7.76(s，1H)，6.45-6.35(m，2H)，6.30(s，1H)，5.48(d，J＝6.6Hz，1H)，4.86(s，3H)，4.92-4.85(m，1H)，4.38-4.22(m，2H)，3.71(m，8H)，2.33(s，3H)，2.33(m，1H)，2.10-1.95(m，1H)ppm。
MS(ESI)m/z：459(M+H)
+。
Step 3:(+)-[8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-
Methyl-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-1) with
And (-)-[8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-2)
Following use HPLC, by racemize [8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (1.50g) prepares this fraction-1 (0.49g) and fraction-2 (0.48g).
Separation condition
Post:
AD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/ethanol/diethylamine (85/15/0.1)
Flow velocity: 18.9mL/ minute
(+)-[8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-1) (embodiment
8-2)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 23=+54.2 ° (c=1.20, methyl alcohol)
Retention time: 11 minutes
(-)-[8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-2) (embodiment
8-3)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 24=-51.2 ° (c=1.34, methyl alcohol)
Retention time: 18 minutes
Embodiment 9
[8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(morpholine-4-
The base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol
Step 1:N-(5-fluoro-3,4-dihydro-2H-chromene-4-yl)-2-methyl-6-(morpholine-4-
The base carbonyl) imidazo [1,2-a] pyridine-8-amine
With the same way as of embodiment 6 steps 1,, 4-dihydro-2H-chromene-4-yl) amino by 8-[(5-fluoro-3]-glyoxal ethyline also [1,2-a] (step 4) of embodiment 4 prepares title compound to pyridine-6-formic acid for 3.9g, 11mmol, productive rate is 96% (4.5g, light brown solid).
1H NMR(CDCl
3，300MHz)δ：7.64(s，1H)，7.35-7.10(m，2H)，6.78-6.57(m，2H)，6.29(s，1H)，5.80-5.68(m，1H)，5.00-4.85(m，1H)，4.40-4.27(m，2H)，3.88-3.61(m，8H)，2.39(s，3H)，2.33-1.84(m，2H)ppm。
MS(ESI)m/z：411(M+H)
+。
Step 2:[8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (embodiment 9-1)
With the same way as of embodiment 6 steps 3, by N-(5-fluoro-3,4-dihydro-2H-chromene-4-yl)-2-methyl-6-(morpholine-4-base carbonyl) imidazo [1,2-a] (step 1) prepares title compound to pyridine-8-amine for 4.5g, 11mmol, productive rate is 93% (4.4g, white solid).
1H NMR(CDCl
3，270MHz)δ：7.77(s，1H)，7.24-7.12(m，1H)，6.72-6.57(m，2H)，6.32(s，1H)，5.50-5.45(m，1H)，4.94-4.84(m，3H)，4.37-4.22(m，2H)，3.81-3.61(m，8H)，2.35(s，3H)，2.30-2.20(m，1H)，2.12-1.98(m，1H)ppm。(OH does not observe)
MS(ESI)m/z：441(M+H)
+。
Step 3:(+)-[8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-the 2-methyl
-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-1), and
(-)-[8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-2)
Following use HPLC is by racemize [8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(morpholine-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (1.5g) prepares this fraction-1 (0.59g) and fraction-2 (0.61g).
Separation condition
Post:
AD-H (20mm I.D. * 250mm, DAICEL)
Moving phase: normal hexane/2-propyl alcohol/diethylamine (80/20/0.1)
Flow velocity: 20mL/ minute
(+)-[8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(morpholine
-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-1) (embodiment 9-2)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 24=+51.7 ° (c=1.04, methyl alcohol)
Retention time: 7 minutes
(-)-[8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-2-methyl-6-(
Quinoline-4-base carbonyl) imidazo [1,2-a] pyridin-3-yl] methyl alcohol (fraction-2) (embodiment 9-3)
NMR: spectroscopic data is identical with racemoid
Specific rotation: [α]
D 24=-53.1 ° (c=1.04, methyl alcohol)
Retention time: 10 minutes
All publications, patent, patent application and the journal article that includes but not limited to the announcement of quoting among the application separately with it in full by with reference in being incorporated herein.
Although invention has been described in the above with reference to disclosed embodiment, those skilled in the art will readily appreciate that the particular experiment of detailed description just has in illustrating of the present invention.Be to be understood that and carry out different modifications and do not deviate from spirit of the present invention.
Claims (10)
1. the compound of formula (I):
Or its pharmacy acceptable salt class, wherein:
-A-B-representative-O-CH
2-or-CH
2-O-;
R
1Representation hydroxy, or can in body, be converted into the part of hydroxyl;
R
2Represent C
1-C
6Alkyl;
R
3And R
4Represent C independently
1-C
6Alkyl or C
3-C
7Cycloalkyl, this C
1-C
6Alkyl and this C
3-C
7Cycloalkyl is not substituted, or is replaced this substituting group independently selected from halogen atoms, hydroxyl, C by 1 to 3 substituting group
1-C
6Alkoxyl group, and C
3-C
7Cycloalkyl; Or R
3With R
4With 4 to 7 yuan of heterocyclic radicals of the common formation of the nitrogen-atoms that is connected with them, it is not substituted or is selected from hydroxyl, C by 1 to 3
1-C
6Alkyl, C
1-C
6Alkoxyl group, and hydroxyl-C
1-C
6The substituting group of alkyl replaces; And
R
5, R
6, R
7With R
8Represent hydrogen atom, halogen atom or C independently
1-C
6Alkyl.
2. the compound of claim 1 or pharmacy acceptable salt class, wherein:
R
1Be hydroxyl, C
1-C
6Alkoxyl group or C
1-C
6Alkyl-carbonyl-oxygen base; And
R
3And R
4Be C independently
1-C
6Alkyl or C
3-C
7Cycloalkyl, this C
1-C
6Alkyl and this C
3-C
7Cycloalkyl is not substituted, or is replaced this substituting group independently selected from halogen atoms, hydroxyl, C by 1 to 3 substituting group
1-C
6Alkoxyl group and C
3-C
7Cycloalkyl; Or R
3With R
4Form azetidinyl, pyrrolidyl, morpholinyl or high morpholinyl jointly with the nitrogen-atoms that is connected with them, this azetidinyl, this pyrrolidyl, this morpholinyl and this high morpholinyl are not substituted, or by 1 to 3 substituting group replacement, this substituting group is selected from hydroxyl, C
1-C
6Alkyl, C
1-C
6Alkoxyl group and hydroxyl-C
1-C
6Alkyl.
3. the compound of claim 1 or pharmacy acceptable salt class, wherein:
-A-B-is-CH
2-O-;
R
1Be hydroxyl;
R
2, R
3With R
4Be C independently
1-C
6Alkyl;
R
5And R
7Be hydrogen atom, halogen atom or C independently
1-C
6Alkyl; And
R
6And R
8Be hydrogen atom or halogen atom independently.
4. the compound of claim 1, this compound is selected from:
(5)-(-)-and 3-(methylol)-N, N, 2-trimethylammonium-8-[(5-methyl-3,4-dihydro-2H-chromene-4-yl) amino] imidazo [1,2-a] pyridine-6-methane amide;
(+)-8-(3,4-dihydro-2H-chromene-4-base is amino)-3-(hydroxymethyl)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also;
(S)-(-)-and 8-[(5,7-two fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also;
And (-)-8-[(5-fluoro-3,4-dihydro-2H-chromene-4-yl) amino]-3-(methylol)-N, N, 2-tri-methylimidazolium be [1,2-a] pyridine-6-methane amide also;
Or its pharmacy acceptable salt class.
5. pharmaceutical composition, it comprises each compound or its pharmacy acceptable salt class of claim 1-4, and pharmaceutically acceptable carrier.
6. the pharmaceutical composition of claim 5, it further comprises other pharmacologically active agent.
7. the method that is suppressed the active illness that is mediated in the treatment Mammals by sour pump, it comprises each compound or its pharmacy acceptable salt class of claim 1-4 of the Mammals treatment significant quantity that needs this treatment.
8. the method for claim 7, wherein this illness be gastrointestinal illness, stomach esophagus disease, stomach esophagus backflow disease (GERD), throat backflow ulcer, gastritis, Helicobacter pylori infection, maldigestion, functional dyspepsia, Zollinger Ellison syndrome, non-erosive that disease, peptide ulceration, stomach ulcer, duodenal ulcer, NSAID-bring out backflow disease (NERD), visceral pain, cancer, pyrosis, feel sick, esophagitis, dysphagia, sialism, respiratory tract obstruction or asthma.
9. each compound or its pharmacy acceptable salt class of claim 1-4 is used for preparing the treatment Mammals is suppressed the medicine of the active illness that is mediated by sour pump purposes.
10. the purposes of claim 9, wherein this illness be gastrointestinal illness, stomach esophagus disease, stomach esophagus backflow disease (GERD), throat backflow ulcer, gastritis, Helicobacter pylori infection, maldigestion, functional dyspepsia, Zollinger Ellison syndrome, non-erosive that disease, peptide ulceration, stomach ulcer, duodenal ulcer, NSAID-bring out backflow disease (NERD), visceral pain, cancer, pyrosis, feel sick, esophagitis, dysphagia, sialism, respiratory tract obstruction or asthma.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78366306P | 2006-03-17 | 2006-03-17 | |
| US60/783,663 | 2006-03-17 | ||
| US60/804,872 | 2006-06-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101410396A true CN101410396A (en) | 2009-04-15 |
Family
ID=40572752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800095512A Pending CN101410396A (en) | 2006-03-17 | 2007-03-06 | Chromane derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101410396A (en) |
-
2007
- 2007-03-06 CN CNA2007800095512A patent/CN101410396A/en active Pending
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Open date: 20090415 |