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HK1125368B - Chromane substituted benzimidazoles and their use as acid pump inhibitors - Google Patents

Chromane substituted benzimidazoles and their use as acid pump inhibitors Download PDF

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Publication number
HK1125368B
HK1125368B HK09103724.8A HK09103724A HK1125368B HK 1125368 B HK1125368 B HK 1125368B HK 09103724 A HK09103724 A HK 09103724A HK 1125368 B HK1125368 B HK 1125368B
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Hong Kong
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reaction
group
compound
alkyl
benzimidazole
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HK09103724.8A
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HK1125368A1 (en
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花泽毅
小池广记
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拉夸里亚创药株式会社
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Priority claimed from PCT/IB2006/003605 external-priority patent/WO2007072146A1/en
Publication of HK1125368A1 publication Critical patent/HK1125368A1/en
Publication of HK1125368B publication Critical patent/HK1125368B/en

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Description

Chromane-substituted benzimidazoles and their use as acid pump inhibitors
Background
The present invention relates to chromane substituted benzimidazole derivatives. Such compounds have selective acid pump inhibitory activity. The invention also relates to pharmaceutical compositions, treatments and methods of use comprising the above derivatives for the treatment of conditions mediated by acid pump modulating activity, particularly acid pump inhibiting activity.
It is well established that Proton Pump Inhibitors (PPIs) are prodrugs that undergo acid-catalyzed chemical rearrangement allowing them to pass through with H+/K+The covalent binding of the cysteine residues of the ATPase to inhibit the enzyme (Sachs, G. et al, diagnostic Diseases and Sciences, 1995, 40, 3S-23S; Sachs et al, Annu Rev Pharmacol Toxicol, 1995, 35, 277-305.). However, unlike PPIs, acid pump antagonists pass through H+/K+Reversible potassium competitive inhibition of ATPase to inhibit acid secretion. SCH28080 is one of such reversible inhibitors and has been studied extensively. Other newer agents (revaprazan, soraprazan, AZD-0865, and CS-526) have been entered into clinical trials to confirm their efficacy in humans (Pope, A.; Parsons, M., Trends in pharmaceutical Sciences, 1993, 14, 323-5; Vakil, N., Alimentary pharmacy and Pharmacological Sciences, 2004, 19, 1041-1049.). In general, acid pump antagonists are useful in the treatment of a variety of diseases, including gastrointestinal disease, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease (laryngolyngial reflux disease), peptic ulcer, gastric ulcer, duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID) induced ulcer, gastritis, infection by Helicobacter pylori (Helicobacter pylori), dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, cancer, heartburn, nausea, esophagitis, dysphagia, hypersalivation, airway disorders (airwaydisorder) or asthma (hereinafter, "APA disease"; Kiljander, Toni O, America Journal of Nutritiine, 2003, 115(suppl.3A), 65S-71S; Ki-BaJ. Hashen et al., Biochem. 1, 38., 1.8).
WO04/054984 relates to compounds, such as indan-1-yloxybenzimidazole derivatives, as acid pump antagonists.
There is a need to provide new acid pump antagonists that are good drug candidates for treating diseases and address the unmet need for PPIs. In particular, preferred compounds should bind efficiently to acid pumps while showing minimal affinity for other receptors and showing activity as inhibitors of acid secretion in the stomach. They should be well absorbed in the gastrointestinal tract, be metabolically stable and have favourable pharmacokinetic properties. They should be non-toxic. In addition, the ideal drug candidate may exist in a physical form that is stable, non-hygroscopic, and easily formulated.
Summary of The Invention
In the present invention, it has now been found that a novel class of compounds having a benzimidazole structure substituted with a chromane group exhibits acid pump inhibitory activity and exhibits advantageous properties as drug candidates, thereby being useful for treating disorders mediated by acid pump inhibitory activity such as APA diseases.
The present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof:
wherein;
-A-B-represents-O-CH2-、-S-CH2-、-CH2-O-or-CH2-S-；
X represents an oxygen atom or NH;
R1represents unsubstituted or independently selected from hydroxy and C through 1 to 21-C6C substituted by substituents of alkoxy1-C6An alkyl group;
R2and R3Independently represents a hydrogen atom, C1-C6Alkyl radical, C3-C7Cycloalkyl or heteroaryl, said C1-C6Alkyl radical, said C3-C7Cycloalkyl and said heteroaryl being unsubstituted or independently selected from halogen, hydroxy, C1-C6Alkoxy radical, C3-C7Cycloalkyl, amino, C1-C6Alkylamino and di (C)1-C6Alkyl) amino substituted; or R2And R3Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclic group which is unsubstituted or selected from hydroxy, C1-C6Alkyl radical, C1-C6Acyl and hydroxy-C1-C6A heterocyclic group substituted with a substituent of an alkyl group;
R4、R5、R6and R7Independently represent a hydrogen atom, a halogen atom, a hydroxyl group, C1-C6Alkyl or C1-C6An alkoxy group; and
R8represents a hydrogen atom, a hydroxyl group or C1-C6An alkoxy group.
In addition, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein and a pharmaceutically acceptable carrier for said compound.
Furthermore, the present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, which further comprises an additional pharmaceutically active agent.
Furthermore, the present invention provides a method for treating a condition mediated by acid pump inhibitory activity in a mammalian subject comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein.
Examples of conditions mediated by acid pump inhibitory activity include, but are not limited to, APA disease.
Further, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of a condition mediated by acid pump inhibitory activity.
Preferably, the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of a disease selected from an APA disease.
The compounds of the invention may exhibit good bioavailability, lower toxicity, good absorption, good distribution, good half-life, good solubility, lower binding affinity to proteins other than the acid pump, less drug-drug interactions and good metabolic stability.
Detailed Description
In the compounds of the invention:
when R is1、R2、R3、R4、R5、R6、R7Or R8Is C1-C6The substituent of the alkyl group, or the 4-to 6-membered heterocyclic group being C1-C6When alkyl, the C1-C6The alkyl group may be a straight or branched chain group having 1 to 6 carbon atoms, and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, and hexyl. In these groups, C1-C3Alkyl groups are preferred; methyl for R1、R4 R5、R6、R7And R8Is more preferred, C1-C3Alkyl for R2Is preferred; methyl and ethyl for R2Is more preferred.
When R is2Or R3Is C3-C7Cycloalkyl, or R2Or R3The substituent is C3-C7When the cycloalkyl group, the group represents a cycloalkyl group having 3 to 7 carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In these groups, C3-C5Cycloalkyl groups are preferred; cyclopropyl is more preferred.
When R is2Or R3When heteroaryl, this group represents a5 to 6 membered ring containing at least one heteroatom selected from N, O and S, examples include, but are not limited to, 2-thienyl, 2-thiazolyl, 4-thiazolyl, 2-furyl, 2-oxazolyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl. Among these groups, a heteroaryl group containing at least one nitrogen atom is preferred; 1-pyrazolyl and 2-pyridyl are more preferred.
When R is2And R3When a 4-to 6-membered heterocyclic group is formed together with the nitrogen atom to which they are attached, the 4-to 6-membered heterocyclic group represents a saturated heterocyclic group having 3 to 5 ring atoms selected from a carbon atom, a nitrogen atom, a sulfur atom and an oxygen atom in addition to the nitrogen atom, and examples include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino. Among these groups, azetidinyl, pyrrolidinyl, morpholino, and piperazinyl are preferred; pyrrolidinyl is more preferred.
When the substituent of the 4-to 6-membered heterocyclic group is hydroxy-C1-C6When alkyl, it represents said C1-C6Alkyl is substituted with hydroxy, examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-1-methylpropyl, 5-hydroxypentyl and 6-hydroxyhexyl. Of these radicals, hydroxy-C1-C3Alkyl groups are preferred; hydroxymethyl is more preferred.
When the substituent for the 4-to 6-membered heterocyclic group is C1-C6When acyl, the radical represents said group C1-C6Examples of alkyl-substituted carbonyl groups include, but are not limited to, formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl. Among these groups, acetyl is preferable.
When R is4、R5、R6、R7、R8Or R1、R2And R3The substituent is C1-C6When alkoxy, the radical represents said group C1-C6Examples of alkyl-substituted oxygen atoms include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, pentyloxy and hexyloxy. In these groups, C1-C3Alkoxy groups are preferred; methoxy is more preferred.
When R is2Or R3The substituent is C1-C6When there is an alkylamino group, the C1-C6Alkylamino represents said radical C1-C6Alkyl-substituted amino groups. Examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino. In these groups, C1-C3Alkylamino is preferred; methylamino groups are more preferred.
When R is2Or R3The substituent of (A) is di (C)1-C6Alkyl) amino, the di (C)1-C6Alkyl) amino represents 2 of said C1-C6Alkyl-substituted amino groups. Examples include, but are not limited to, dimethylamino, N-methyl-N-ethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamino, and N, N-bis (1-methylpropyl) amino. Among these groups, di (C)1-C3) Alkylamino is preferred; dimethylamino and diethylamino groups are more preferable.
When R is4、R5、R6Or R7Or R is2Or R3When the substituent(s) is a halogen atom, the atom is a fluorine, chlorine, bromine or iodine atom. Among these atoms, fluorine is preferable.
when-A-B-is-O-CH2-or-S-CH2when-A-corresponds to-O-or-S-, -B-corresponds to-CH2-。
when-A-B-is-CH2-O-or-CH2-S-is, -A-corresponds to-CH2-, -B-corresponds to-O-or-S-.
As used herein, the terms "treat," "treating," and "treatment" refer to curative, palliative, and prophylactic therapies, including reversing, alleviating, inhibiting the progression of, or preventing the disease or condition for which the term is used or one or more symptoms of such disease or condition.
A preferred class of compounds of the invention are compounds of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, wherein:
(a) -A-B-is-O-CH2-、-S-CH2-、-CH2-O-or-CH2-S-；
(b) -A-B-is-O-CH2-or-CH2-O-；
(c) -A-B-is-CH2-O-；
(d) X is oxygen atom or NH;
(e) x is an oxygen atom;
(f)R1is unsubstituted or independently selected from hydroxy and C through 1 to 21-C6C substituted by substituents of alkoxy1-C6An alkyl group;
(g)R1is C1-C6An alkyl group;
(h)R1is methyl;
(i)R2is a hydrogen atom, C1-C6Alkyl radical, C3-C7Cycloalkyl or heteroaryl, said C1-C6Alkyl radical, said C3-C7Cycloalkyl and said heteroaryl being unsubstituted or independently selected from halogen, hydroxy, C1-C6Alkoxy radical, C3-C7Cycloalkyl, amino, C1-C6Alkylamino and di (C)1-C6Alkyl) amino substituted;
(j)R2is a hydrogen atom, or is unsubstituted or is independently selected from hydroxy, C, via 1 to 31-C6Alkoxy and di (C)1-C6Alkyl) amino-substituted C1-C6An alkyl group;
(k)R2is unsubstituted or independently selected from hydroxy and C through 1 to 31-C3C substituted by substituents of alkoxy1-C3An alkyl group;
(l)R2is methyl or ethyl, said methyl and said ethyl being unsubstituted or substituted with a substituent selected from the group consisting of hydroxy and methoxy;
(m)R3is a hydrogen atom, C1-C6Alkyl radical, C3-C7Cycloalkyl or heteroaryl, said C1-C6Alkyl radical, said C3-C7Cycloalkyl and said heteroaryl being unsubstituted or independently selected from halogen, hydroxy, C1-C6Alkoxy radical, C3-C7Cycloalkyl, amino, C1-C6Alkylamino and di (C)1-C6Alkyl) amino substituted;
(n)R3is a hydrogen atom or C1-C6An alkyl group;
(o)R3is a hydrogen atom or a methyl group;
(p)R2and R3Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclic group which is unsubstituted or substituted with 1 to 2 substituents selected from hydroxy, C1-C6Alkyl radical, C1-C6Acyl and hydroxy-C1-C6An alkyl group;
(q)R2and R3Together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperazinyl, or morpholino group, said azetidinyl, pyrrolidinyl, piperazinyl, and morpholino group being unsubstituted or selected from hydroxy, C1-C6Alkyl radical, C1-C6Acyl and hydroxy-C1-C6Alkyl substituted with a substituent; (ii) a
(r)R2And R3Together with the nitrogen atom to which they are attached form an unsubstituted or substituted radical selected from hydroxy and hydroxy-C1-C3Pyrrolidinyl substituted with a substituent for alkyl;
(s)R4is a hydrogen atom, a halogen atom, a hydroxyl group, C1-C6Alkyl or C1-C6An alkoxy group;
(t)R4is a hydrogen atom, a halogen atom or C1-C6An alkyl group;
(u)R4is a hydrogen atom, a halogen atom or C1-C3An alkyl group;
(v)R4is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group;
(w)R5is a hydrogen atom, a halogen atom, a hydroxyl group, C1-C6Alkyl or C1-C6An alkoxy group;
(x)R5is a hydrogen atom;
(y)R6is a hydrogen atom, a halogen atom, a hydroxyl group, C1-C6Alkyl or C1-C6An alkoxy group;
(z)R6is a hydrogen atom or a halogen atom;
(aa)R6is a hydrogen atom or a fluorine atom or a chlorine atom;
(bb)R7is a hydrogen atom, a halogen atom, a hydroxyl group, C1-C6Alkyl or C1-C6An alkoxy group;
(cc)R7is a hydrogen atom or a halogen atom;
(dd)R7is a hydrogen atom or a fluorine atom or a chlorine atom;
(ee)R8is a hydrogen atom, a hydroxyl group or C1-C6An alkoxy group;
(ff)R8is a hydrogen atom or a hydroxyl group; and
(gg)R8is a hydrogen atom.
Among these kinds of compounds, any combination of (a) to (gg) is also preferable.
Preferred compounds of the invention are compounds of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, wherein:
(A) -A-B-is-O-CH2-、-S-CH2-、-CH2-O-or-CH2-S-; x is an oxygen atom; r1Is unsubstituted or selected from hydroxy and C via 1 to 21-C6C substituted by substituents of alkoxy1-C6An alkyl group; r2And R3Independently is C1-C6Alkyl or C3-C7Cycloalkyl radical, said C1-C6Alkyl and said C3-C7Cycloalkyl being unsubstituted or independently selected from halogen, hydroxy, C, via 1 to 31-C6Alkoxy radical, C3-C7Cycloalkyl and di (C)1-C6Alkyl) amino substituted; or R2And R3Together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidineA piperazinyl or morpholino group, said azetidinyl, said pyrrolidinyl, said piperazinyl and said morpholino group being unsubstituted or selected from hydroxy, C1-C6Alkyl radical, C1-C6Acyl and hydroxy-C1-C6Alkyl substituted with a substituent; r4、R5、R6And R7Are independently of each other a hydrogen atom, a halogen atom or C1-C6An alkyl group; r8Is a hydrogen atom;
(B) -A-B-is-O-CH2-or-CH2-O-; x is an oxygen atom; r1Is C1-C6An alkyl group; r2And R3Independently unsubstituted or independently selected from hydroxy and C through 1 to 31-C6C substituted by substituents of alkoxy1-C6Alkyl and; or R2And R3Together with the nitrogen atom to which they are attached form an unsubstituted or substituted radical selected from hydroxy, C1-C6Alkyl and hydroxy-C1-C6Pyrrolidinyl substituted with a substituent for alkyl; r4、R5、R6And R7Independently a hydrogen atom, a halogen atom or C1-C6An alkyl group; r8Is a hydrogen atom;
(C) -A-B-is-CH2-O-; x is an oxygen atom; r1Is C1-C6An alkyl group; r2And R3Independently is C1-C6An alkyl group; or R2And R3Together with the nitrogen atom to which they are attached form a pyrrolidinyl group; r4、R5、R6And R7Independently a hydrogen atom, a halogen atom or C1-C6An alkyl group; r8Is a hydrogen atom;
(D) -A-B-is-CH2-O-; x is an oxygen atom; r1Is C1-C6An alkyl group; r2And R3Independently is C1-C6An alkyl group; or R2And R3Together with the nitrogen atom to which they are attached form a pyrrolidinyl group; r4、R6And R7Independently a hydrogen atom, a halogen atom or C1-C6 alkyl; r5And R8Is a hydrogen atom;
(E) -A-B-is-CH2-O-; x is an oxygen atom; r1Is C1-C6An alkyl group; r2And R3Independently is C1-C6An alkyl group; r4、R6And R7Independently a hydrogen atom, a halogen atom or C1-C6An alkyl group; r5And R8Is a hydrogen atom.
One embodiment of the present invention provides a compound selected from the group consisting of:
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide.
Another embodiment of the present invention provides a compound selected from the group consisting of:
(-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
(-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
(-) -4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition and base salts (including the double salt (disalt)) thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate (camsylate), citrate, cyclohexylsulfamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate (naphylate), 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Pyroglutamate, sucrose salts, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
Base addition salts include alkali metal salts such as lithium, sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; an ammonium salt; organic base salts such as triethylamine salt, diisopropylamine salt, cyclohexylamine salt and the like. Preferably the salt is an alkali metal salt and more preferably the salt is a sodium salt.
For a review of suitable Salts, see Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) "Handbook of Pharmaceutical Salts: properties, Selection, and Use ". Pharmaceutically acceptable salts of compounds of formula (I) can be readily prepared by mixing together a solution of a compound of formula (I) with the desired acid or base, as appropriate. The salt may precipitate out of solution and then be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may range from completely ionized to almost no ionization.
Pharmaceutically acceptable salts of the compounds of formula (I) thereof include unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.
Pharmaceutically acceptable solvates of the invention include hydrates and solvates in which the solvent of the crystallization may be replaced by an isotope, e.g. D2O、d6-acetone, d6-DMSO。
Complexes such as clathrate complexes, drug-host complexes (drug-host complexes) in which the drug and host are present in stoichiometric or non-stoichiometric amounts as opposed to the aforementioned solvates are included within the scope of the present invention. Also included are complexes of drugs comprising 2 or more organic and/or inorganic components that may be present in stoichiometric or non-stoichiometric amounts. The resulting complex may also be ionized, partially ionized, or non-ionized. For a review of such complexes, seeJ Pharm Sci64 (8), 1269-1288, available from Haleblian (August 1975).
The compounds of formula (I) may exist in one or more crystalline forms. Such polymorphs, including mixtures thereof, are also included within the scope of the present invention.
The compounds of formula (I) containing one or more asymmetric carbon atoms may exist in the form of 2 or more stereoisomers.
All stereoisomers of the compounds of formula (I), including compounds exhibiting multiple types of isomerism and mixtures of one or more thereof, are included within the scope of the present invention.
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, for example2H and3H. the same as carbonSteric elements, e.g.11C、13C and14C. isotopes of chlorine, e.g.36Isotopes of Cl or fluorine, e.g.18F. Isotopes of iodine, e.g.123I and125I. isotopes of nitrogen, e.g.13N and15isotopes of N, oxygen, e.g.15O、17O and18isotopes of O, phosphorus, e.g.32Isotopes of P and sulfur, e.g.35S。
Certain isotopically-labeled compounds of formula (I), for example, those comprising a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotope tritium is known for its ease of integration and ready availability of detection methods3H and carbon-14 i.e14C is particularly suitable for this purpose.
Using heavy isotopes such as deuterium2Replacement of H may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances.
Using positron-emitting isotopes, e.g.11C、18F、15O and13the substitution of N can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy.
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying examples, by using a suitable isotopically-labelled reagent in place of the unlabelled reagent previously used.
So-called "prodrugs" of the compounds of formula (I) are also within the scope of the present invention. Thus, certain derivatives of the compounds of formula (I) which may themselves have little or no pharmacological activity when administered or administered to the body may be converted to compounds of formula (I) having the desired activity, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol.14, ACSSymposium Series (T Higuchi and W Stella) and BioversibleCarriers in Drug Design, Pergamon Press, 1987(ed.E B Roche, American Pharmaceutical Association).
Prodrugs of the invention may be produced, for example, by replacing suitable functional groups present in the compounds of formula (I) with certain groups known to those skilled in the art, such as the ' pro-groups ' (pro-moieties) ' described in Design of produgs, e.g., HBundgaard (Elsevier, 1985). Some examples of prodrugs of the invention include:
(i) when the compound of formula (I) contains an alcohol functional group (-OH), a compound in which a hydroxyl group is substituted with a group that can be converted into a hydroxyl group in vivo. By a group that is convertible in vivo to a hydroxyl group is meant a group that is convertible in vivo to a hydroxyl group, for example by hydrolysis and/or by an enzyme such as an esterase. Examples of such groups include, but are not limited to, ester and ether groups that are readily hydrolyzable in vivo. Groups in which the hydrogen of the hydroxyl group is replaced with an acyloxyalkyl group, a 1- (alkoxycarbonyloxy) alkyl group, a phthalidyl group and an acyloxyalkoxycarbonyl group such as pivaloyl hydroxymethoxycarbonyl group are preferred.
(ii) When the compounds of formula (I) contain an amino group, amide derivatives prepared by reaction with a suitable acid halide or a suitable acid anhydride are exemplary prodrugs. A particularly preferred amide derivative as a prodrug is-NHCO (CH)2)2OCH3、-NHCOCH(NH2)CH3And the like.
Other examples of substituent groups (replacement groups) for the above examples and examples of other prodrug types can be found in the foregoing references.
All compounds of formula (I) can be prepared by the procedures described in the general methods provided below or by the specific methods described in the examples section and the preparations section or by routine modifications thereof. The present invention also includes any one or more of these methods for preparing compounds of formula (I) other than including any novel intermediates used herein.
General Synthesis
The compounds of the invention may be prepared by a number of well known methods for the preparation of compounds of this type, for example the methods shown in methods a to B below.
All starting materials in the following general syntheses are commercially available or obtained by the following methods C to D or conventional methods known to the person skilled in the art, for example the methods described in WO 2000078751 and WO2004054984, the disclosures of which are incorporated herein by reference.
Method A
The process illustrates the preparation of compounds of formula (I).
Reaction scheme A
In reaction scheme A, R1、R2、R3、R4、R5、R6、R7、R8A and B are as defined above; hal is a halogen atom, preferably a bromine atom; prot1Is a hydroxyl protecting group or an amino protecting group; prot2Is a nitrogen-protecting group; lv is a leaving group; r1aIs R as defined above1Or R wherein the hydroxyl group is protected with a hydroxyl protecting group1；R2aIs R as defined above2R wherein the hydroxyl group is protected by a hydroxyl protecting group2Or wherein amino or C1-C6R with alkylamino protected by amino protecting group2；R3aIs R as defined above3R wherein the hydroxyl group is protected by a hydroxyl protecting group3Or wherein amino or C1-C6Alkylamino is R protected by an amino protecting group3；R4aIs R as defined above4Or R wherein the hydroxyl group is protected with a hydroxyl protecting group4；R5aIs R as defined above5Or R wherein the hydroxyl group is protected with a hydroxyl protecting group5；R6aIs R as defined above6Or R wherein the hydroxyl group is protected with a hydroxyl protecting group6；R7aIs R as defined above7Or R wherein the hydroxyl group is protected with a hydroxyl protecting group7；R8aIs R as defined above8Or R wherein the hydroxyl group is protected with a hydroxyl protecting group8(ii) a The same definitions will be used hereinafter.
As used herein, "leaving group" means a group capable of being substituted by a nucleophilic group such as hydroxyl or amine, and examples of such leaving group include a halogen atom, alkylsulfonyloxy, haloalkylsulfonyloxy and phenylsulfonyloxy. Among these groups, a bromine atom, a chlorine atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group and a 4-methylphenylsulfonyloxy group are preferable.
As used herein, the term "hydroxy protecting group" means a protecting group capable of being cleaved by various methods (e.g., hydrogenolysis, hydrolysis, electrolysis or photolysis) to produce a hydroxy group, such hydroxy protecting groups being described by t.w. greene et al (John Wiley)&Sons, 1999) Protective Groups in Organic Synthesis. E.g. C1-C4Alkoxycarbonyl group, C1-C4Alkylcarbonyl, tri-C1-C4Alkylsilyl or tri-C1-C4Alkylaryl silyl and C1-C4alkoxy-C1-C4An alkyl group. Suitable hydroxyl protecting groups include acetyl and tert-butyldimethylsilyl.
As used herein, the term "amino or nitrogen protecting group" means a protecting group capable of being cleaved by various methods (e.g., hydrogenolysis, hydrolysis, electrolysis or photolysis) to yield an amino group, such amino or nitrogen protecting groupGroups are described by t.w.greene et al (John Wiley)&Sons, 1999) Protective Groups in Organic Synthesis. E.g. C1-C4Alkoxycarbonyl group, C1-C4Alkylcarbonyl, tri-C1-C4Methylsilyl, phenylsulfonyloxy or aralkyl. Suitable amino or nitrogen protecting groups include benzyl, t-butyloxycarbonyl, and tosyl.
(step A1)
In this step, compound (IV) is prepared by amide formation of the amino group of the compound of formula (II) using an acid anhydride (III), which is commercially available or can be prepared according to the method described in WO 2004054984.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reagents involved in the reaction or participation and it can dissolve the reactants at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylethylamide and hexamethylphosphoric triamide; carboxylic acids, such as acetic acid, formic acid, propionic acid; among these solvents, acetic acid is preferable, or the reaction in the absence of a solvent is preferable.
The reaction can be carried out in the presence or absence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used for this type of reaction may equally be used herein. Examples of such bases include: amines, for example N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, 1, 5-diazabicyclo [4.3.0] -non-5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DABCO) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). Among these bases, the reaction in the absence of a base is preferable.
The reaction may be carried out in the presence of an acid. Similarly there is no particular limitation on the nature of the acid used, and any acid used in this type of reaction may equally be used herein. Examples of such acids include: acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid; sulfonic acids, for example methanesulfonic acid or toluenesulfonic acid. Among these acids, sulfuric acid is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 24 hours is generally sufficient.
(step A2)
In this step, the compound of formula (V) is prepared by substituting the halogen atom of the compound of formula (IV) with a metal cyanide.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reagents involved in the reaction or participation and it can dissolve the reagents to at least some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide, 1-methylpyrrolidin-2-one, and hexamethylphosphoric triamide; among these solvents, N-dimethylformamide is preferable.
The reaction is carried out in the presence of a metal cyanide reagent, the nature of the metal cyanide reagent used being not particularly limited, and any metal cyanide reagent used for this type of reaction may likewise be used herein. Examples of such metal cyanide reagents include: zinc (II) cyanide, copper (I) cyanide, potassium cyanide, and sodium cyanide; among these metal cyanides, zinc (II) cyanide is preferred.
The reaction is carried out in the presence or absence of a palladium catalyst. There is no particular limitation on the nature of the palladium catalyst used, and any palladium catalyst used in this type of reaction may be equally employed herein. Examples of such palladium catalysts include: palladium metal, palladium chloride (palladiumchloride), palladium (II) acetate, tris (dibenzylideneacetone) dipalladium chloroform, allylpalladium chloride, [1, 2-bis (diphenylphosphino) ethane ] palladium dichloride, bis (tri-o-benzylphosphine) palladium dichloride, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, dichloro [1, 1' -bis (diphenylphosphino) ferrocene ] palladium or catalysts produced in solution by adding ligands to the reaction solution of these palladium catalysts. The ligand added to the reaction solution may be a phosphorus ligand such as triphenylphosphine, 1 '-bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphinophenyl) ether, 2' -bis (diphenylphosphino) -1, 1 '-dinaphthol, 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, tri-o-tolylphosphine, 2-diphenylphosphino-2' -methoxy-1, 1 '-dinaphthyl or 2, 2-bis (diphenylphosphino) -1, 1' -dinaphthyl. Of these ligands, tetrakis (triphenylphosphine) palladium is preferred.
The reaction can take place over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 50 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
In this reaction, the reaction can be accelerated using microwaves. In the case of using microwaves in a sealed tube, the reaction temperature may be about 50 ℃ to about 180 ℃, and a reaction time of about 5 minutes to about 12 hours is generally sufficient.
(step A3)
In this step, the compound of formula (VI) is prepared by reduction and cyclization of the compound of formula (V).
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reagents involved in the reaction or participation and it can dissolve the reagents to at least some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles such as acetonitrile and benzonitrile; among these solvents, the reaction in the absence of a solvent or ethanol is preferable.
The reaction is carried out in the presence of a reducing agent. Similarly, there is no particular limitation on the nature of the reducing agent used, and any reducing agent used in this type of reaction may be equally employed herein. Examples of such reducing agents include: mixtures of metals, such as zinc or iron, and acids, such as hydrochloric acid, acetic acid, and acetic acid-ammonium chloride complex. Among these reducing agents, a mixture of iron and acetic acid is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
(step A4)
In this step, compound (VII) is prepared by hydrolyzing the cyanide group of the compound of formula (VI) with a base or an acid.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reagents involved in the reaction or which can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; water; or a mixed solvent thereof. Of these solvents, ethylene glycol is preferred.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used in this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Among these bases, potassium hydroxide is preferred.
The reaction may be carried out in the presence of an acid. Similarly there is no particular limitation on the nature of the acid used, and any acid used in this type of reaction may equally be used herein. Examples of such acids include: carboxylic acids, such as acetic acid or propionic acid; acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid. Among these acids, hydrochloric acid is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 24 hours is generally sufficient.
In this reaction, the reaction can be accelerated using microwaves. In the case of using microwaves in a sealed tube, the reaction temperature may be about 50 ℃ to about 180 ℃, and a reaction time of about 5 minutes to about 12 hours is generally sufficient.
(step A5)
In this step, the compound of formula (VII) is amidated with a compound of formula (VIII), followed by introduction of the protecting group 2 (Prot)2) And p-protecting group 1 (Prot)1) And deprotected to produce compound (IX), said compound of formula (VIII) being commercially available or described in j.org.chem., 5935(1990) and Canadian Journal of Chemistry, 2028 (1993). Alternatively, compounds of formula (IX) may be prepared by method E described below.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reagents involved in the reaction or which can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; or a mixed solvent thereof. Among these solvents, N-dimethylformamide is preferable.
The reaction can be carried out in the presence of a base. Similarly there is no particular requirement on the nature of the base used, and any base used for this type of reaction may equally be used herein. Examples of such bases include: amines, for example N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, DBN, DABCO and DBU. Among these bases, triethylamine or diisopropylethylamine is preferable.
The reaction may be carried out in the presence of a condensing agent. Similarly there is no particular requirement on the nature of the condensing agent used, and any condensing agent used for this type of reaction may equally be used here. Examples of such condensing agents include: 2-halo-1-lower alkylpyridine halides, such as 2-chloro-1-methylpyridinium iodide and 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP); diarylphosphoryl azides, such as diphenylphosphoryl azide (DPPA); chloroformates such as ethyl chloroformate and isobutyl chloroformate; phosphorocyanate (phosphocyanidate), such as diethyl phosphorocyanate (DEPC); imidazole derivatives, such as N, N' -Carbonyldiimidazole (CDI); carbodiimide derivatives such as N, N' -Dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI); iminium salts, such as 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HBTU) and tetramethylfluoroformamidium hexafluorophosphate (TFFH); and phosphonium salts, such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and bromo-tris-pyrrolidinyl-phosphonium hexafluorophosphate (PyBrop). Among these condensing agents, EDCI or HBTU are preferable.
Reagents such as 4- (N, N-dimethylamino) pyridine (DMAP) and 1-hydroxybenzotriazole (HOBt) may be used for this step. Among these agents, HOBt is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 80 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 48 hours is generally sufficient.
(Nitrogen protecting group Prot)2Introduction of (2)
Greene et al, Protective Groups in Organic Synthesis, 369-. The following illustrates a typical reaction involving a protecting group for an alkoxycarbonyl or arylsulfonyl group.
Examples of nitrogen protecting group halides or anhydrides that can be used in the above reaction include 4-methylbenzenesulfonyl chloride, benzenesulfonyl chloride or di-tert-butyl-bicarbonate; among them, 4-methylbenzenesulfonyl chloride or di-tert-butyl-bicarbonate is preferable.
Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; or alcohols such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; or a mixed solvent thereof. Among these solvents, N-dimethylformamide is preferable.
Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, DBN, DABCO and DBU; alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide; or a mixed base thereof. Among these bases, sodium hydride or triethylamine is preferable.
(Prot1Deprotection of (2)
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; carboxylic acids, such as acetic acid or formic acid; among these solvents, acetic acid or tetrahydrofuran is preferable.
The reaction is carried out under hydrogen in the presence of a palladium catalyst. There is no particular limitation on the nature of the palladium catalyst used, and any palladium catalyst commonly used in reactions of this type may likewise be used herein. Examples of such palladium catalysts include: palladium metal, palladium carbon, palladium hydroxide, among which palladium carbon or palladium hydroxide is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 24 hours is generally sufficient.
(step A6)
In this step, compound (I) is prepared by a coupling reaction (A6-a) of a compound of formula (IX) and a compound of formula (Xa) or a substitution reaction (A6-b) using the same starting materials and a compound of formula (Xb), and only method A6-b is feasible if X is NH. The compounds of formula (Xa) and (Xb) are commercially available or can be prepared by the methods described in method C, D or Synthesis 595(1983) below.
(A6-a) coupling reaction
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile and benzonitrile; or a mixed solvent thereof. Among these solvents, tetrahydrofuran or toluene is preferable.
The reaction may be carried out in the presence of a condensing agent. Similarly there is no particular requirement on the nature of the condensing agent used, and any condensing agent used for this type of reaction may equally be used here. Examples of such condensing agents include: di-lower alkyl azodicarboxylate esters such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and di-tert-butyl azodicarboxylate (DTAD); azodicarbonamides, such as N, N ' -tetraisopropyl azodicarbonamide (TIPA), 1 ' - (azodicarbonyl) dipiperidine (ADDP), and N, N ' -tetramethyl azodicarbonamide (TMAD); phosphoranes such as (cyanomethylene) tributylphosphorane (CMBP) and (cyanomethylene) trimethylphosphine (CMMP). Of these condensing agents, DIAD or ADDP are preferred.
Phosphine reagents such as triphenylphosphine, trimethylphosphine and tributylphosphine may be used for this step. Among them, triphenylphosphine or tributylphosphine is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 48 hours is generally sufficient.
(A6-b) substitution reaction
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; ketones such as acetone and diethyl ketone; or a mixed solvent thereof. Among these solvents, N-dimethylacetamide or acetone is preferable.
The reaction can be carried out in the presence or absence of a base. Similarly there is no particular requirement on the nature of the base used, and any base used for this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, DBN, DABCO and DBU; alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide; among these bases, sodium hydride or potassium carbonate is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
(Prot2Deprotection of (2)
The deprotection reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; water; or a mixed solvent thereof. Among these solvents, methanol, tetrahydrofuran, water, or a mixed solvent thereof is preferable.
The reaction can be carried out in the presence of a base. Similarly there is no particular requirement on the nature of the base used, and any base commonly used in this type of reaction may be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; among these bases, lithium hydroxide or sodium hydroxide is preferable.
The deprotection reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the present invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 24 hours is generally sufficient.
(deprotection of hydroxy protecting group)
In which R is1a、R2a、R3a、R4a、R5a、R6a、R7a、R8aIn the case of a protected hydroxyl group, the deprotection reaction will result in a hydroxyl group. Greene et al, protective groups in Organic Synthesis, 369-. The following illustrates a typical reaction involving a protecting group, tert-butyldimethylsilyl.
Deprotection of the hydroxyl groups is carried out using an acid such as acetic acid, hydrofluoric acid, hydrogenated fluoropyridine complex (hydrogen fluoride-pyridine complex) or a fluoride ion such as tetrabutylammonium fluoride (TBAF).
The deprotection reaction is usually and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include, but are not limited to, alcohols, such as methanol, ethanol, or mixed solvents thereof.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 24 hours is generally sufficient.
Method B
The process illustrates the preparation of compounds of formula (I).
Reaction scheme B
In reaction scheme B, Alk is C1-C6Alkyl, preferably methyl and the same definitions will be used hereinafter.
(step B1)
In this step, the esterification of the compound of the formula (VII) with the corresponding alcohol is carried out, followed by introduction of Prot2And pair Prot1Deprotection to produce a compound of formula (XI), which can be produced by step a4 of method a. The introduction and deprotection of the protecting group can be performed under the same conditions as described in step a5 of method a.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; ketones such as acetone and diethyl ketone; among these solvents, the reaction in the absence of a solvent is preferable.
The reaction may be carried out in the presence of an acid. Similarly, there is no particular limitation on the nature of the acid used, and any acid used in this type of reaction may be used as such herein. Examples of such acids include: acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid; sulfonic acids, such as methanesulfonic acid or toluenesulfonic acid; acid chlorides, such as oxalyl chloride or thionyl chloride. Among these acids, hydrochloric acid or thionyl chloride is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 120 ℃. The time required for the reaction can also vary widely, depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from 5 minutes to about 24 hours is generally sufficient.
(step B2)
In this step, compound (XII) is prepared by reacting a compound of formula (XI) with a compound of formula (Xa) or (Xb) which is commercially available or can be prepared according to the method described in the following method C, D or Synthesis 595 (1983). The reaction may be carried out under the same conditions as described in step a6 of method a.
(step B3)
In this step, compound (XIII) is prepared by hydrolysis of the compound of formula (XII).
The reaction may be carried out under the same conditions as described in step a4 of method a.
(step B4)
In this step, compound (I) is prepared by amidating the compound of formula (XIII) with the compound of formula (VIII). The reaction may be carried out under the same conditions as described in step a5 of method a.
Method C
This method illustrates the preparation of compounds of formula (Xa-1) and (Xb-1) wherein A is CH2。
Reaction scheme C
In reaction scheme C, Hal is a halogen atom, Ra1kIs a hydrogen atom or C1-C6Alkyl, the same definition will be used hereinafter.
(step C1)
In this step, the compound of formula (XVII) is prepared by Michael reaction (Michael reaction) of the compound of formula (XIV) with the compound of formula (XV) (C1-a), by alkylation reaction (C1-b) of the compound of formula (XIV) with the compound of formula (XVI), or by coupling reaction (C1-C) of the compound of formula (XIV) with the compound of formula (XXIX), followed by hydrogenation reaction (C1-d). The compounds of formulae (XIV), (XV), (XVI) and (XXIX) are commercially available.
(C1-a) Michael reaction
The deprotection reaction is usually and preferably carried out in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; or a mixed solvent thereof. Among these solvents, the reaction in the absence of a solvent is preferable.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used for this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, DBN, DABCO and DBU, and benzyltrimethylammonium hydroxide; alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide; or a mixed base thereof. Among these bases, benzyltrimethylammonium hydroxide or sodium methoxide is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 20 ℃ to about 120 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 48 hours is generally sufficient.
After the above process, hydrolysis is carried out by adding an acid to a solvent to give a compound of formula (XIV), and hydrolysis may be carried out under conventional hydrolysis conditions. The acid may include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid. It is preferably hydrochloric acid. The solvent may include, for example, water; alcohols such as methanol, ethanol, propanol and tert-butanol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diethoxymethane and dioxane; or a mixed solvent thereof. Water is preferred. The reaction temperature varies depending on the starting compounds, reagents and solvents, however, it is usually 20 ℃ to reflux temperature. The reaction time varies depending on the starting compound, the reagent, the solvent and the reaction temperature, however, it is usually 60 minutes to 24 hours.
(C1-b) alkylation
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; ketones such as acetone and diethyl ketone; water; or a mixed solvent thereof. Among these solvents, water is preferred.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used for this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Among these bases, sodium hydroxide is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 20 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 24 hours is generally sufficient.
(C1-C) coupling reaction
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinylopyridine, N-dimethylaniline and N, N-diethylaniline; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; and ketones such as acetone and diethyl ketone. Of these solvents, acetonitrile and tetrahydrofuran are preferred.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used for this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4- (N, N-dimethylamino) pyridine and DBU; and tetraalkylammonium fluorides, such as tetra-n-butylammonium fluoride (TBAF). Among these bases, TBAF is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 5 minutes to about 72 hours is generally sufficient.
(C1-d) hydrogenation
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons such as toluene; alcohols such as methanol, ethanol; and carboxylic acids such as acetic acid. Among these solvents, alcohols and carboxylic acids are preferable.
The reaction is carried out under hydrogen and in the presence of a catalyst. There is no particular specific limitation on the nature of the catalyst employed, and any catalyst used for this type of reaction may be equally employed herein. Examples of such catalysts include: palladium on carbon, palladium hydroxide, platinum and Raney nickel. Of these catalysts, palladium on carbon is preferred.
In the case where hydrodehalogenation (of substituent "Hal" in reaction scheme C) is a serious problem, the reaction can be carried out in the presence of additives which reduce the activity of the catalyst used. The additive is selected from substances known to exhibit toxic effects on the catalyst to some extent. Examples of such additives include: halide ion sources such as t-n-butylammonium bromide and sodium bromide; and sulfones, such as dimethyl sulfoxide. Of these additives, sodium bromide is preferred.
The reaction can be carried out over a wide range of pressures, the precise pressure not being critical to the invention. The preferred pressure depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a pressure of from 1atm to about 10 atm. The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 50 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 12 hours is generally sufficient.
Introduction of hydroxy protecting groups
In the case of the compound of the formula (Xa-1) or (Xb-1) having a hydroxyl group, the reaction can be carried out by protecting the hydroxyl group, if necessary.
The hydroxyl protecting group may be introduced in a suitable step prior to the reaction effected by the hydroxyl group.
Greene et al, Protective Groups in Organic Synthesis, 369-. The following illustrates a typical reaction involving a protecting group, tert-butyldimethylsilyl.
For example, when the hydroxy protecting group is "t-butyldimethylsilyl", this step is carried out by reacting with the desired hydroxy protecting group halide in an inert solvent in the presence of a base.
Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof. Among these solvents, tetrahydrofuran or N, N-dimethylformamide is preferable.
Examples of hydroxyl protecting groups which may be used in the above reaction include trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane, t-butyldimethylbromosilane (tert-butyldimethylbromosilane), acetyl chloride being preferred.
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate and organic amines such as triethylamine, tributylamine, N-methylmorpholine, pyridine, imidazole, 4-dimethylaminopyridine, picoline, lutidine, collidine, DBN and DBU. Among these bases, triethylamine, imidazole or pyridine is preferable. When the organic amine is used in liquid form, it also acts as a solvent when used in large excess.
Although the reaction temperature varies depending on the nature of the starting compound, the halide and the solvent, it generally varies within the range of 0 ℃ to 80 ℃ (preferably 0 to 30 ℃). Although the reaction time varies depending on the reaction temperature and the like, it varies in the range of 10 minutes to 2 days (preferably 30 minutes to 1 day).
(step C2)
In this step, by performing a Friedel-crafts reaction (C2-a) after the halogenation reaction (C2-b), or when R isa1kBy cyclization of a compound of formula (XVII) when it is a hydrogen atom (C2-C), or when R isa1kIs C1-C6When the alkyl group is substituted, the compound of formula (XVIIIa) is produced by acid cyclization reaction (C2-d) of the compound of formula (XVII).
(C2-a) Friedel-crafts reaction
The reaction is generally and preferably carried out in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 1, 2, 2-tetrachloroethane and 1, 2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; carbon disulfide; or a mixed solvent thereof. Among these solvents, dichloromethane or carbon disulfide is preferable.
The reaction is carried out in the presence of an acid. Similarly, there is no particular limitation on the nature of the acid used, and any acid used in this type of reaction may be used as such herein. Examples of such acids include: lewis acids, e.g. BF3、AlCl3、AlBr3、FeCl3、AgCl、ZnI2、ZnCl2、Fe(NO3)3、CF3SO3Si(CH3)3、Yb(CF3SO3)3And SnCl4. Among these agents, AlCl3Is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
(C2-b) halogenation
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; amines, such as nitriles, e.g., acetonitrile and benzonitrile; or a mixed solvent thereof. Among these solvents, 1, 2-dichloroethane or dichloromethane is preferable.
The reaction is carried out in the presence of a halogenating agent. Similarly, there is no particular limitation on the nature of the halogenating agent used, and any halogenating agent commonly used in this type of reaction may be used herein. Examples of such halogenating agents include: thionyl chloride, oxalyl chloride and phosphorus oxychloride. Among these halogenating agents, thionyl chloride is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 80 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 8 hours is generally sufficient.
(C2-C) cyclization reaction
The reaction is generally and preferably carried out in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof. Among these solvents, dichloromethane or the absence of a solvent is preferred.
The reaction is carried out in the presence of an acid. Similarly, there is no particular limitation on the nature of the acid used, and any acid commonly used in this type of reaction may be used herein. Examples of such acids include: acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid; acids, such as trifluoroacetic acid or polyphosphoric acid. Among these acid reagents, polyphosphoric acid is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 20 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
(C2-d) acid cyclization reaction
The reaction is generally and preferably carried out in the presence of an acid, which serves as both a solvent and a reactant. There is no particular limitation on the nature of the acid employed, as long as it does not adversely affect the reaction and it can dissolve the substrate at least to some extent. Examples of suitable acids include: sulfuric acid or trifluoromethanesulfonic acid. Of these acid reagents, trifluoromethanesulfonic acid is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 5 hours is generally sufficient.
(step C3)
In this step, compound (Xa-1) is prepared by reducing the carbonyl group of the compound of formula (XVIIIa). In the case of using a photoactive reducing agent, the resulting compound of formula (XVIIIa) can be obtained as a photoactive compound.
The reaction is generally and preferably carried out in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; sulfones such as dimethyl sulfoxide and dioxythiophenane; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; or a mixed solvent thereof. Among these solvents, methanol or tetrahydrofuran is preferable.
The reaction is carried out in the presence of a reducing agent. Similarly, there is no particular limitation on the nature of the reducing agent used, and any reducing agent commonly used for this type of reaction may be used herein. Examples of such reducing agents include: metal borohydrides such as sodium borohydride, lithium borohydride and sodium cyanoborohydride; hydride compounds such as lithium aluminum hydride and diisobutylaluminum hydride; and borane reagents such as borane-tetrahydrofuran complex, borane-dimethyl sulfide complex (BMS), and 9-borabicyclo- [3, 3, 1] nonane (9-BBN). Among them, sodium borohydride is preferable.
With respect to the photoactive reducing agent, there is similarly no particular limitation on the nature of the reducing agent used, and any reducing agent used for this type of reaction may be equally used herein. Examples of such reducing agents include: (S) or (R) -tetrahydro-1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo [1, 2-c ] [1, 3, 2] oxazaborolidine and BMS; a combination of a photoactive ruthenium catalyst and hydrogen gas. Examples of photoactive ruthenium catalysts include: dichloro [ (S) -2, 2 '-bis (diphenylphosphino) -1, 1' -dinaphthyl ] [ (S) -1, 1 '-bis (p-methoxyphenyl) -2-isopropyl-1, 2-ethylenediamine ] ruthenium (II), dichloro [ (R) -2, 2' -bis (diphenylphosphino) -1, 1 '-dinaphthyl ] [ (R) -1, 1' -bis (p-methoxyphenyl) -2-isopropyl-1, 2-ethylenediamine ] ruthenium (II). The ruthenium catalyst was used in the presence of a catalytic amount of potassium tert-butoxide. Among them, a combination of (S) or (R) -tetrahydro-1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo [1, 2-c ] [1, 3, 2] oxazaborolidine and BMS is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 80 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 8 hours is generally sufficient.
(step C4)
In this step, the compound of formula (Xb-1) is prepared by halogenating the hydroxyl group of the compound of formula (Xa-1).
The reaction is generally and preferably carried out in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N-dimethylaniline, N-diethylaniline; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; or a mixed solvent thereof. Among these solvents, diethyl ether and tetrahydrofuran are preferable.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used in this type of reaction may equally be used herein. Examples of such bases include: amines, for example N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, 6-di (tert-butyl) -4-methylpyridine, quinoline, N-dimethylaniline, N-diethylaniline, DBN, DABCO and DBU. Among these bases, pyridine is preferable.
The reaction is carried out in the presence of a halogenating agent. Similarly, there is no particular limitation on the nature of the halogenating agent used, and any halogenating agent used in this type of reaction can likewise be used herein. Examples of such halogenating agents include: thionyl chloride, oxalyl chloride, phosphorus pentachloride and phosphorus oxychloride. Among these halogenating agents, thionyl chloride is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 10 minutes to about 8 hours is generally sufficient.
Method D
The method is as followsExamples illustrate the preparation of compounds of formula (Xa-2) and (Xb-2), wherein B is CH2。
Reaction scheme D
In reaction scheme D, RcAnd RdIndependently represent C1-C6An alkyl group.
(step D1)
In this step, the compound of formula (XX) is prepared by halogenating the methyl group of the compound of formula (XIX).
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; or a mixed solvent thereof. Among these solvents, carbon tetrachloride or1, 2-dichloroethane is preferable.
The reaction is carried out in the presence of a halogenating agent. Similarly, there is no particular limitation on the nature of the halogenating agent used, and any halogenating agent used in this type of reaction can likewise be used herein. Examples of such halogenating agents include: succinimides such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS); bromine. Among these halogenating agents, NBS is preferred.
Reagents such as benzoyl peroxide and 2, 2' -azobis (isobutyronitrile) (AIBN) may be used in this step. Among them, a peroxybenzoyl group is preferable.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 100 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
(step D2)
In this step, the compound of formula (XXII) is prepared by an ether forming reaction of a compound of formula (XX) with a compound of formula (XXI), which is commercially available.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; or a mixed solvent thereof. Among these solvents, N-dimethylformamide or tetrahydrofuran is preferable.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used in this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Among these bases, sodium hydride is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 20 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 48 hours is generally sufficient.
(step D3)
In this step, a compound of formula (XXIII) is prepared by cyclizing (Dieckmann condensation) a compound of formula (XXII).
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; or a mixed solvent thereof. Among these solvents, toluene is preferable.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used in this type of reaction may equally be used herein. Examples of such bases include: alkali metals such as lithium and sodium; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Among these bases, sodium is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 0 ℃ to about 150 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 30 minutes to about 24 hours is generally sufficient.
(step D4)
In this step, a compound of formula (XVIIb) is prepared by decarboxylation of a compound of formula (XXIII).
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; nitriles such as acetonitrile and benzonitrile; sulfones such as dimethyl sulfoxide and dioxythiophenane; water; or a mixed solvent thereof. Among these solvents, ethanol is preferred.
The reaction can be carried out in the presence of a base. Similarly there is no particular limitation on the nature of the base used, and any base used in this type of reaction may equally be used herein. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Among these bases, sodium hydride is preferred.
The reaction may be carried out in the presence of an acid. Similarly, there is no particular limitation on the nature of the acid used, and any acid used in this type of reaction may be used as such herein. Examples of such acids include: carboxylic acids, such as acetic acid or propionic acid; acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid. Among these acid reagents, hydrochloric acid is preferred.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 20 ℃ to about 120 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 48 hours is generally sufficient.
(step D5)
In this step, the compound of formula (Xa-2) is prepared by reducing the compound of formula (XVIIb). The reaction may be carried out under the same conditions as described in step C3 of method C.
(step D6)
In this step, the compound of formula (Xb-2) is prepared by halogenating the compound of formula (Xa-2). The reaction may be carried out under the same conditions as described in step C4 of method C. If the compound of formula (Xb-2) has a hydroxyl group, the reaction for introducing a hydroxyl-protecting group described in method D can be used in an appropriate step.
(step D7)
In this step, the compound of formula (XXVI) is prepared by an ether forming reaction of a compound of formula (XXIV) with a compound of formula (XXV), which is commercially available. The reaction may be carried out under the same conditions as described in step D2 of method D.
(step D8)
In this step, a compound of formula (XXVII) is prepared by hydrolysis of a compound of formula (XXIV). The reaction may be carried out under the same conditions as described in step a4 of method a.
(step D9)
In this step, a compound of formula (XVIIb) is prepared by cyclization of a compound of formula (XXVII) (D9-a) or by formation of an acid halide (D9-b), followed by Friedel-crafts reaction of a compound of formula (XXVII) (D9-c). The reaction may be carried out under the same conditions as described in step C2 of method C.
Method E
This method illustrates the preparation of a compound of formula (IX).
Reaction scheme E
(step E1)
In this step, the compound of formula (XXVIII), which can be prepared by step a1 of method a, is prepared by reduction and cyclization (E1-a) of the compound of formula (IV), followed by protection of the nitrogen atom (E1-b). The reduction reaction and cyclization reaction (E1-a) may be performed under the same conditions as described in step A3 of method a, and protection of the nitrogen atom may be performed under the same conditions as described in step a5 of method a.
(step E2)
Under this procedure, the compound of formula (XXVIII) is amidated with a compound of formula (VIIII) under a carbon monoxide atmosphere, followed by the protection of the group 1 (Prot)1) Deprotection to produce a compound of formula (IX). May be described in step A5 of method AProtecting group (Prot) was performed under the same conditions as described above1) And (4) deprotection.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it does not adversely affect the reagents involved in the reaction or that it can dissolve the reagents at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; amides such as formamide, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile and benzonitrile; and ketones such as acetone and diethyl ketone. Among these solvents, tetrahydrofuran is preferred.
The reaction is carried out in the presence of a palladium catalyst. There is no particular limitation on the nature of the palladium catalyst used, and any palladium catalyst used in this type of reaction may be equally employed herein. Examples of such palladium catalysts include: palladium metal, palladium carbon, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium chloroform, [1, 2-bis (diphenylphosphino) ethane ] palladium dichloride, bis (tri-o-tolylphosphine) palladium dichloride, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, dichloro [1, 1' -bis (diphenylphosphino) ferrocene ] palladium or catalysts produced in solution by adding ligands to the reaction solution of these palladium catalysts. The ligand added to the reaction solution may be a phosphorus ligand such as 1, 1 '-bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphinophenyl) ether, 2' -bis (diphenylphosphino) -1, 1 '-dinaphthol, 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, tri-o-tolylphosphine, triphenylphosphine, 2-diphenylphosphino-2' -methoxy-1, 1 '-dinaphthyl or 2, 2-bis (diphenylphosphino) -1, 1' -dinaphthyl. The palladium catalyst is preferably tetrakis (triphenylphosphine) palladium.
The reaction can be carried out over a wide temperature range, the precise reaction temperature not being critical to the invention. The preferred reaction temperature depends on such factors as the nature of the solvent and the starting materials. In general, however, it is convenient to carry out the reaction at a temperature of from about 20 ℃ to about 120 ℃. The time required for the reaction may also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the starting materials and solvents employed. However, if the reaction is carried out under the preferred conditions described above, a time period of from about 60 minutes to about 72 hours is generally sufficient.
The compounds of formula (I) and intermediates in the above preparation processes can be isolated and purified by conventional methods such as distillation, recrystallization or chromatographic purification.
The compounds of the invention, which are intended for pharmaceutical use, may be administered in the form of crystalline or amorphous products. They may be obtained by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying, in the form of, for example, solid plugs (solid plugs), powders or films. For this purpose, microwave drying or high-frequency drying (radio frequency drying) may be used.
Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral High Pressure Liquid Chromatography (HPLC).
Alternatively, the method of optical resolution (optical resolution) of the racemic compound (or racemic precursor) may suitably be selected from conventional methods, e.g. preferably crystallization or resolution of a diastereomeric salt between the base moiety of the compound of formula (I) and a suitable optically active acid, e.g. tartaric acid.
They may be administered alone or together with one or more other compounds of the invention or together with one or more other drugs (or in any combination thereof). Generally, they are administered in the form of a pharmaceutical composition or formulation in combination with one or more pharmaceutically acceptable carriers or excipients. The term "carrier" or "excipient" is used herein to describe any component other than a compound of the invention. The choice of carrier and excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for preparing them will be apparent to those skilled in the art. Such compositions and methods for preparing them can be found, for example, in ' Remington's Pharmaceutical Sciences ', 19 th edition (Mack Publishing Company, 1995).
Oral administration
The compounds of the present invention may be administered orally. Oral administration may include swallowing, to allow the compound to enter the gastrointestinal tract, or buccal or sublingual administration may be used, by which route the compound may pass directly from the mouth into the bloodstream.
Formulations for oral administration include solid formulations such as tablets, capsules containing microparticles, liquids or powders, lozenges (including liquid-filled), chewables, multiparticulates and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesives), ovules, sprays and liquid formulations.
Liquid preparations include, for example, suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers for soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example from a sachet.
The compounds of the invention are also useful in fast dissolving, fast disintegrating dosage forms such asExpertOpinion in Therapeutic Patents，11(6) 981-.
For tablet dosage forms, depending on the dose, the drug may constitute from about 1% to about 80% by weight of the dosage form, more typically from about 5% to about 60% by weight of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant comprises from about 1% to about 25%, preferably from about 5% to about 20% by weight of the dosage form.
Binders are commonly used to impart cohesive properties to the tablet dosage form. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, pregelatinized cellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.
The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. When present, the surfactant may be included in about 0.2% to about 5% by weight of the tablet and the glidant may be included in about 0.2% to about 1% by weight of the tablet.
Tablets may also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant is typically included in the tablet in an amount of about 0.25% to about 10% by weight, preferably about 0.5% to about 3% by weight.
Other possible ingredients include antioxidants, colorants, flavorants, preservatives, and taste-masking agents.
Exemplary tablets comprise up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% lubricant, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant.
The tablets may be formed by direct compression or by roller compression of the tablet mixture. The tablet mixture or portion of the mixture may optionally be wet granulated, dry granulated or melt granulated, melt congealed (melt congealed) or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
In "Pharmaceutical Dosage Forms" in H.Lieberman and L.Lachman, Marcel Dekker, N.Y., N.Y., 1980(ISBN 0-8247-6918-X): tablet formulation is described in Tablets, volume 1 ".
Solid formulations for oral administration may be formulated as immediate release and/or modified release (modifiedrelease). Modified release formulations include sustained release, pulsed release, controlled release, targeted release and programmed release formulations.
Suitable sustained release formulations for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Other suitable delivery techniques such as high energy dispersion and penetration and coated particles are described in detail in Verma et al,PharmaceuticalTechnology On-line,25(2),1-14(2001). The use of chewing gum for obtaining controlled release is described in WO 00/35298.
Parenteral administration
The compounds of the invention may also be administered directly into the bloodstream, into muscles or into internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.
Parenteral formulations are typically aqueous solutions containing excipients such as salts, sugars and buffers (preferably having a pH of from about 3 to about 9), but for some applications they may more suitably be formulated as sterile nonaqueous solutions or in dry form for use with a suitable vehicle such as sterile, pyrogen-free water.
Preparation of parenteral formulations can be readily accomplished under sterile conditions, e.g., by freeze-drying, using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of the compound of formula (I) for the preparation of parenteral solutions is increased by using suitable formulation techniques, such as the incorporation of a solubilizer.
Formulations for parenteral administration may be formulated for immediate release and/or variable release. Modified release formulations include sustained release, pulsed release, controlled release, targeted release and programmed release formulations. The compounds of the present invention may therefore be formulated as a solid, semi-solid or thixotropic liquid (thixotropic liquid) for administration in an implantable depot for providing a modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
Topical administration of drugs
The compounds of the present invention may also be administered topically to the skin or mucosa, i.e., through the skin or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Common carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated-see, for example, J Pharm Sci,88(10) 955 Across 958, Finnin and Morgan (October 1999).
Other methods of topical administration include by electroporation, iontophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject)TM、BiojectTMEtc.) for injection.
Formulations for topical administration may be formulated for immediate release and/or variable release. Modified release formulations include sustained release, pulsed release, controlled release, targeted release and programmed release formulations.
Inhalation/intranasal administration
The compounds of the invention may also be administered intranasally or by inhalation, typically from a dry powder inhaler in the form of a dry powder (alone, as a mixture with lactose, e.g., in a dry blend, or as a mixed component particle, e.g., mixed with a phospholipid, e.g., phosphatidylcholine), or as a spray, from a pressurized container, pump, nebulizer, atomizer (preferably one that uses electrohydrodynamic fine mist generation), or misting device, with or without the use of a suitable propellant, e.g., 1, 1, 1, 2-tetrafluoroethane or1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.
A pressure vessel (pressurized container), pump, sprayer, atomizer or mister contains a solution or suspension of a compound of the invention containing, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, dissolving or slowly releasing the active agent, a propellant as a solvent and any surfactant such as sorbitan trioleate, oleic acid or oligomeric lactic acid.
Prior to use in dry powder or suspension formulations, the drug is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). The micronization may be carried out by any suitable comminuting method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.
Capsules (made, for example, from gelatin or HPMC), blisters and cartridges (cartridges) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier 1-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or present as a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
Suitable solution formulations for use in nebulizers that generate fine mist using electrohydrodynamics may comprise from 1 μ g to about 20mg of a compound of the invention per actuation (actuation), and the actuation volume may be in the range of from about 1 μ l to about 100 μ l. Common formulations may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.
Suitable flavouring agents, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to such formulations of the invention intended for inhalation/intranasal administration. Formulations for inhalation/intranasal administration may be formulated as immediate release and/or modified release using, for example, poly (DL-lactic-co-glycolic acid) (PGLA). Variable release formulations include sustained release, pulsed release, controlled release, targeted release and programmed release.
In the case of dry powder inhalation devices and aerosols, the dosage units are determined by a valve delivering a measured amount. According to the present invention, the unit in which the measured dose or "puff" is typically set for the administrator contains from about 1 to about 100 μ g of the compound of formula (I). The total daily dose, which is usually from about 50 μ g to about 20mg, may be administered in a single dose or, more commonly, in divided doses throughout the day.
Rectal/intravaginal administration
The compounds of the invention may be administered rectally or vaginally in the form of suppositories, pessaries or enemas. Cocoa butter is a conventional suppository base, but different options may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated for immediate and/or modified release. Modified release formulations include sustained release, pulsed release, controlled release, targeted release and programmed release formulations.
Other techniques
The compounds of the invention may be mixed with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polymers comprising polyethylene glycol to enhance their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the above modes of administration.
For example, drug-cyclodextrin complexes are commonly found in most dosage forms and routes of administration. Inclusion bodies and non-inclusion bodies may be used. As an alternative to direct complexation with drugs (complexation), cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in WO91/11172, WO 94/02518 and WO 98/55148.
KIT OF PARTS (KIT-OF-PARTS)
Since it may be desirable to administer a combination of active compounds, for example, to treat a particular disease or condition, it may be convenient within the scope of the present invention to combine 2 or more pharmaceutical compositions (at least one of which comprises a compound of the invention) in a kit suitable for co-administration of the compositions.
The kit of the invention comprises 2 or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I) of the invention, and means for separately retaining the compositions, such as a container, a separate bottle or a separate foil box. Examples of such kits are the common blister packs, capsules, etc. used for packaging tablets.
The kits of the invention are particularly suitable for administration of different dosage forms, for example for oral and parenteral administration of separate compositions at different dosing intervals, or for titration of separate compositions. To aid compliance, kits often contain administration instructions and may provide a so-called memory aid.
Dosage form
With respect to administration to human patients, the total daily dose of the compounds of the invention will generally be in the range of from about 0.5mg to about 300mg, and will, of course, preferably be in the range of from about 1mg to 100mg and more preferably from about 1mg to about 20mg, depending on the mode of administration. For example, oral administration may require a total daily dose of about 1mg to about 20mg, while intravenous administration may require only about 0.5mg to about 10 mg. The total daily dose may be administered in a single dose or in divided doses.
These doses are based on a mean human subject having a weight of about 65kg to about 70 kg. A physician may be readily able to determine a dose for subjects whose weights fall outside of this range, such as infants and elderly subjects.
Combination of
As discussed above, the compounds of the present invention exhibit acid pump inhibitory activity. The acid pump antagonists of the invention may be used with another pharmaceutically active compound, or with 2 or more other pharmaceutically active substances, in particular for the treatment of gastroesophageal reflux disease. For example, an acid pump antagonist, in particular a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined above, may be used simultaneously, sequentially or separately with one or more drugs selected from:
(i) histamine H2Receptors such as ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine;
(ii) inhibitors such as omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;
(iii) antacid mixtures for oral administration, e.g.And
(iv) mucosa protective agents, such as polyprenyl zinc, ecabet sodium, rebamipide, teprenone, cetrimide, sucralfate, chlorophyllin-copper, and plaunotol;
(v) anti-gastric (Anti-gastrotic) agents, such as Anti-gastrin vaccine (Anti-gastrostatin), itramine (itriglumide), and Z-360;
(vi)5-HT3such as tegaserod, dolasetron, palonosetron, alosetron, azasetron, ramosetron, mirtazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron;
(vii)5-HT4for example, mosapride, cinidide and oxytriptane; (viii) laxatives, e.g.And
(ix)GABABsuch as baclofen and AZD-3355;
(x)GABABfor example GAS-360 and SGS-742;
(xi) Calcium channel blockers such as aranidipine, lacidipine, falodipine, azelnidipine, clinodipine, lomerizine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine, and fasudil;
(xii) Dopamine such as mefloxamine, domperidone and levosulpiride;
(xiii) Tachykinins (NK), in particular NK-3, NK-2 and NK-1, for example nepadutant, saredutant, talnetutant, (aR, 9R) -7- [3, 5-bis (trifluoromethyl) phenyl ] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1, 4] diazocino [2, 1-g ] [1, 7] naphthridine-6-13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), lanepitant, dapitant, and 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] methylamino ] -2-phenyl-piperidine (2S, 3S);
(xiv) Helicobacter pylori (Helicobacter pylori) infectious agents, such as clarithromycin (clarithromycin), roxithromycin, rotamycin, flurubicin, telithromycin, amoxicillin, ampicillin, temocillin, amoxicillin, aspoxicillin, sultamicin, piperacillin, lenacilin, tetracycline, metronidazole, bismuth citrate, and bismuth subsalicylate;
(xv) Nitric oxide synthase inhibitors such as GW-274150, tilargine, P54, guanidinoethyl disulfide and nitroflurbiprofen;
(xvi) Vanilloid receptor 1(vanilloid receptor1), such as AMG-517 and GW-705498;
(xvii) Muscarinic receptors such as trospium (trospium), solifenacin, tolterodine, tiotropium (tiotropium), cetrimide (cimetropium), oxitropium (oxitropium), ipratropium (ipratropium), tiquinamide (tiquizium), dalifenac in and imidafanacin;
(xviii) Calmodulin proteins, such as squalamine (squaamine) and DY-9760;
(xix) Potassium channels such as pinadil, tiliprolol, nicorandil, NS-8, and retigabine;
(xx) Beta-1, such as dobutamine, dienopamine, zamoterol, dienopamine, polycarbobamine, and zamoterol;
(xxi) Beta-2, such as salbutamol; terbutaline, arformoterol, meluadrine (meluadrine), mabuterol, ritodrine, fenoterol, clenbuterol, formoterol, procaterol, tulobuterol, pirbuterol, bambuterol, tulobuterol, dopexamine, and levosalbutamol;
(xxii) β, such as isoproterenol and terbutaline;
(xxiii) α 2, such as clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine;
(xxiv) Endothelin a such as bonesetan, atrasentan, ambrisentan, clazosentan, sitaxsentan, fandosentan and darussentan;
(xxv) Opioid μ (opioid μ), such as morphine, fentanyl, and loperamide;
(xxvi) Opioids μ, such as naloxone, buprenorphine and alvimopan (alvimopan);
(xxvii) Motilin, such as erythromycin, mitocinol (mitemcinal), SLV-305, and atilmotin;
(xxviii) ghrelin, such as capromorelin and TZP-101;
(xxix) AchE release stimulators such as Z-338 and KW-5092;
(xxx) CCK-B, such as itramine, YF-476, and S-0509;
(xxxi) Glucagon, such as NN-2501 and A-770077;
(xxxii) Piperacillin, rycillin, tetracycline, metronidazole, bismuth citrate and bismuth subsalicylate;
(xxxiii) Glucagon-like peptide-1 (GLP-1), such as PNU-126814;
(xxxiv) Small conductance calcium-activated potassium channels 3(SK-3), such as amimin (apamin), dequalinium (Dequalinium), atracurium, pancuronium (pancuronium) and tubocurarine
(xxxv) mGluR5 antagonists, such as ADX-10059 and AFQ-O56;
(xxxvi)5-HT3, such as pumosetrag (DDP 733);
(xxxvii) mGluR8, e.g. (S) -3, 4-DCPG and mGluR 8-A.
Methods for evaluating biological activity:
the acid pump inhibitory activity and other biological activities of the compounds of the present invention were determined by the following methods. The symbols have their usual meaning in the description: mL (mL), μ L (microliter), Kg (kilogram), g (gram), mg (milligram), μ g (microgram), pmo1 (picomole), mmo1 (millimole), M (molar mass (M)3,/mol)), mM (millimolar mass), μ M (micromolar mass), atm (standard atmospheric pressure), r.p.m. (revolutions per minute), quant. (quantitative), nm (nanometers), min (minutes), Cat # (accession number).
Preparation of gastric vesicles (gastic vesicles) from live pig stomach
By using a tight fit (light-fit)d) Of polytetrafluoroethylene (A), (B) and (C)) Homogenizer for homogenization of porcine stomach H from mucous membrane in live porcine stomach in 0.25M sucrose at 4 deg.C+/K+-porcine gastric vesicles for the ATPase inhibition assay. The crude precipitate was removed by centrifugation at 2O,000g for 3O minutes. The supernatant was then centrifuged at 10O,00Og for 30 min. The resulting pellet was resuspended in 0.25M sucrose and then subjected to density gradient centrifugation at 132, OO0g for 90 minutes. From a mixture containing 7% FicollTMThe gastric vesicles were collected at the interface on a 0.25M sucrose layer of PM400(Amersham Biosciences). This step is performed in a cold chamber.
Inhibition of Ion-leak (Ion-leak) porcine gastric H +/K + -ATPase
According to Biochemical Pharmacology, 1988,37measurement of ion leakage in pig stomach H by the improved method described in 2231-+/K+-inhibition of atpase.
The isolated vesicles were freeze-dried and then stored in a low temperature freezer until use. For enzyme assay, 3mM MgSO was included440mM Bis-tris (pH 6.4, at 37 ℃) to reconstitute the lyophilized vesicles.
Then 5mM KCl, 3mM Na, were incubated in a final volume of 60. mu.l reaction mixture (40mM Bis-tris, pH 6.4) at 37 ℃ in the presence or absence of the test compound2ATP、3mM MgSO4And 1.0 μ g of reconstituted vesicles for 30 minutes. The enzyme reaction was stopped by adding 10% Sodium Dodecyl Sulfate (SDS). Inorganic phosphate released from ATP is detected by incubation with a mixture of 1 part 35mM ammonium molybdate tetrahydrate formulated in 15mM zinc acetate hydrate and 4 parts 10% vitamin C (pH5.0), which incubation results in phosphomolybdate having an optical density at 750 nm.
Inhibition of Ion-leak-free (Ion-light porcine) porcine gastric H +/K + -ATPase
According to Biochemical Pharmacology, 1988,37ion-light pig stomach H measurement by the improved method described in 2231-+/K+-inhibition of atpase.
The isolated vesicles were stored in a cryorefrigerator until use. For enzyme assay, 3mM MgSO was included45mM Tris (pH7.4, at 37 ℃) diluted vesicles.
Then incubated in a final volume of 60. mu.l of reaction mixture (5mM Tris, pH7.4) at 37 ℃ with 150mM KCl, 3mM Na, in the presence or absence of the test compound2ATP、3mM MgSO415 μ M of vanmycin and 3.0 μ g of vesicles for 30 minutes. The enzyme reaction was stopped by adding 10% Sodium Dodecyl Sulfate (SDS). Inorganic phosphate released from ATP is detected by incubation with a mixture of 1 part 35mM ammonium molybdate tetrahydrate formulated in 15mM zinc acetate hydrate and 4 parts 10% vitamin C (pH5.0), which incubation yields phosphomolybdate with an optical density at 750 nm. IC for inhibitory Activity of the Compounds of the examples50The results of the values are shown in table 1.
Table 1.
Example numbering IC50(μM)
1 0.19
2 0.086
3 0.098
4 0.058
5 0.032
6 0.030
7 1.1
8 0.61
9 0.13
10 0.14
11 0.12
12 0.23
13 0.13
14 0.22
15 0.21
16 0.068
17 0.099
18 0.13
19 0.24
20 0.071
21 0.082
22 0.57
23 0.11
24 0.37
25 0.16
Canine kidney Na + /K + Inhibition of ATPase
With a medium containing 3mM MgSO440mM Tris (pH7.4, at 37 ℃) reconstituting powdered canine kidney Na+/K+ATPase (Sigma). 100mM NaCl, 2mM KCl, 3mM Na were then incubated in a final volume of 60. mu.l reaction mixture (40mM Tris, pH7.4) at 37 ℃ in the presence or absence of the test compound2ATP、3mM MgSO4And 12. mu.g of the enzyme for 30 minutes. The enzyme reaction was stopped by adding 10% SDS. Inorganic phosphate released from ATP is detected by incubation with a mixture of 1 part 35mM ammonium molybdate tetrahydrate formulated in 15mM zinc acetate hydrate and 4 parts 10% vitamin C (pH5.0), which incubation yields phosphomolybdate with an optical density at 750 nm.
Inhibition of acid secretion in rats with perfused gastric lumen
According to Watanabe et al [ Watanabe K et al, J.Physiol. (Paris) 2000;94：111-116]acid secretion was measured in rats with perfused gastric lumen.
Male sprague-dawley rats 8 weeks old, fasted for 18 hours before the experiment but exposed to water ad libitum, were anesthetized with urethane (1.4g/kg, intraperitoneally) and then the trachea was dissected. After the ventral incision, the cardiac sinus (forstomach) was inserted with a double polyethylene catheter and then the stomach was perfused with saline (37 ℃, pH5.0) at a rate of 1 ml/min. Every 5 minutes, the acid output in the perfusate was determined by titration with 0.02M NaOH to ph 5.0. After determination of the basal acid secretion was carried out for 30 minutes, the acid secretion was stimulated by continuous intravenous infusion of pentagastrin (16. mu.g/kg/hr). The test compounds were administered by a single intravenous bolus or intraduodenal administration after the stimulated acid secretion reached a plateau. Acid secretion was monitored after administration.
Activity was assessed by inhibition of total acid secretion from 0 to 1.5 or 3.5 hours post-administration or maximal inhibition post-administration.
Inhibition of gastric acid secretion in Haidenhaine small stomach dogs (Heidenhain Pouch dog)
Male beagle dogs with a small stomach of hederin, weighing 7 to 15kg [ heidenhaiinr: arch Ges physiol.1879;19：148-167]. Animals were allowed to recover at least 3 weeks post surgery prior to the experiment. Animals were kept under a 12 hour light-dark rhythm and individually housed. They received standard food 1 time daily at 11:00 am, tap water ad libitum, and were fasted overnight prior to the experiment, with water ad libitum. Gastric fluid samples were collected throughout the experiment by gravity drainage every 15 minutes. The acidity in gastric fluid was measured by titration to the end point of ph 7.0. Acid secretion was stimulated by continuous intravenous infusion of histamine (80 μ g/kg/hr). A single intravenous injection of the test compound was performed 90 minutes after the start of histamine infusion. Acid secretion was monitored after administration. Activity was assessed by maximal inhibition relative to the corresponding control value.
The compound of example 2 showed good inhibitory activity.
Human dofetilide binding
Human ether a-go-go related gene (HERG) transfected HEK293S cells were prepared and then cultured internally (in-house). Cell paste of HEK-293 cells expressing HERG product can be suspended at 50m in 10-fold volumeM Tris buffer (adjusted to pH7.5 with 2M HCl at 25 ℃ C.) containing 1mM MgCl210mM KCl). The cells were homogenized using a Polytron homogenizer (20 seconds at maximum power) and then centrifuged at 48,000g for 20 minutes at 4 ℃. Resuspend, homogenize, and centrifuge once again in the same manner. The resulting supernatant was discarded and the final pellet was resuspended (10 volumes of 50mM Tris buffer) and homogenized at maximum power for 20 seconds. The membrane homogenate was aliquoted and stored at-80 ℃ until use. Aliquots were used for Protein concentration determination using the Protein Assay Rapid kit (wako) and the Spectramax plate reader (Wallac). All operations, stock solutions and devices were kept on ice at all times. For saturation assay (saturationassay), experiments were performed in a total volume of 200 μ l. By incubating 36 μ l of the [ mu ] l ] in the absence or presence of a final concentration of 10 μ M of dofetilide (4 μ l) at room temperature3H]Doffilide and 160. mu.l of membrane homogenate (20-30. mu.g protein per well) for 60 minutes, saturation was determined for total or non-specific binding, respectively. All incubations were terminated by rapid vacuum filtration on PEI soaked glass fiber filter paper using Skatron cell collectors, followed by 2 washes with 50mM Tris buffer (pH7.4 at 25 ℃). Receptor-bound radioactivity was quantified by liquid scintillation counting using a Packard LS counter.
For competition assays, compounds were diluted in 96-well polypropylene plates in a semilog format 4-point dilution (as 4-potentials in semi-log format). All dilutions were first made in DMSO and then transferred to a column containing 1mM MgCl210mM KCl in 50mM Tris buffer (pH7.4 at 25 ℃) so that the final DMSO concentration becomes 1%. Compounds were dispensed in triplicate into assay plates (4 μ Ι). Total binding and non-specific binding wells were established in 6 wells (dofetilide with the same vehicle and final concentration of 10. mu.M), respectively. Radioligand was prepared at 5.6x final concentration and the solution was added to each well (36 μ l). The assay was initiated by the addition of YSi poly-L-lysine SPA microbeads (50. mu.l, 1 mg/well) and membrane (110. mu.l, 20. mu.g/well). Incubation was continued at room temperature for 60 minutes. Incubate the plate at room temperatureThe beads were allowed to settle for an additional 3 hours. Receptor binding radioactivity was quantified by counting a wallacicrobeta plate counter.
Permeability of Caco-2
The permeability of Caco-2 was measured as described in Shiyin Yee, Pharmaceutical Research, 763 (1997).
Caco-2 cells were cultured on filter supports (Falcon HTS Multi well insert System) for 14 days. The medium was removed from the apical and basolateral compartments and the monolayers were pre-incubated with pre-warmed 0.3ml of apical buffer (apical buffer) and 1.0ml of basolateral buffer (basolateral buffer) in a 50 rpm shaking water bath at 37 ℃ for 0.5 hours. The apical buffer was composed of Hanks' balanced salt solution, 25mM D-glucose monohydrate, 20mM 2-morpholinoethanesulfonic acid (MES) biological buffer, 1.25mM CaCl2And 0.5mM MgCl2(pH 6.5). The buffer solution on the outer side of the substrate was composed of Hanks balanced salt solution, 25mM D-glucose monohydrate, 20mM 2- [4- (2-hydroxyethyl) -1-piperazinyl]Ethylsulfonic acid (HEPES) biological buffer, 1.25mM CaCl2And 0.5mM MgCl2(pH 7.4). At the end of the preincubation, the medium was removed and a test compound solution (10 μ M) in buffer was added to the top zone chamber. Insert (insert) was moved to the well containing freshly prepared buffer outside the matrix at 1 hour. The drug concentration in the buffer was measured by LC/MS analysis.
Flux rate (F, mass/time) was calculated from the slope of cumulative appearance (cumulative appearance) of the substrate on the receiver side, and apparent permeability coefficient (P) was calculated according to the following formulaapp)。
Papp(cm/sec)＝(FxVD)/(SAxMD)
Wherein SA is the surface area for transport (0.3 cm)2) VD is the donor volume (0.3ml) and MD is the total amount of drug on the donor side at t ═ 0. All data represent the mean of 2 inserts. By passingTransportation of Lucifer Yellow to determine the integrity of the monolayer.
Half-life in Human Liver Microsome (HLM) -1
Test compounds (1. mu.M) were mixed with 3.3mM MgCl prepared in 100mM potassium phosphate buffer (pH7.4) at 37 ℃ in 96-deep well plates2Incubated with 0.78mg/mL HLM (HL 101). The reaction mixture was divided into 2 groups, non-P450 group and P450 group. NADPH was added to the reaction mixtures of the P450 group only. Aliquots of the P450 group samples were collected at time points 0, 10, 30 and 60 minutes, where the 0 minute time point represents the time to add NADPH to the reaction mixtures of the P450 group. Aliquots of samples from the non-P450 group were collected at the-10 and 65 minute time points. The collected aliquots were extracted with acetonitrile solution containing internal standards. The precipitated protein was sedimented in a centrifuge (2000rpm, 15 minutes). The concentration of the compound in the supernatant was measured using an LC/MS system.
Half-life values were obtained by plotting the natural log of peak area ratio of compound/internal standard versus time. The slope of the best fit line through the points yields the metabolic rate (k). This is converted to a half-life value by using the following formula:
half-life equal to 1n2/k
Half-life in Human Liver Microsome (HLM) -2
Test compounds (1. mu.M) were mixed with 1mM MgCl prepared in 100mM potassium phosphate buffer (pH7.4) at 37 ℃ in a number of 384-well plates21mM NADP +, 5mM isocitrate, 1U/mL isocitrate dehydrogenase, and 0.8mg/mL HLM. At several time points, the plates were removed from the incubator and the reaction was stopped with 2 incubation volumes of acetonitrile. The concentration of the compound in the supernatant was measured using an LC/MS system. The intrinsic clearance value was calculated using the following formula:
wherein the slope of k-1 n (concentration) versus time (min-1)
Studies on in vitro drug-drug interactions of 5 major CYPs (fDDI)
CYP1A2The test compound (3. mu.M) was preincubated at 30 ℃ for 5 minutes with recombinant CYP1A2(Baculosome lot #21198 Invitrogen, 50pmol P450/ml) and 10. mu.M Vivid blue 1A2 probe (Invitrogen) as substrates, formulated in 100mM potassium phosphate buffer (pH 7.4). The reaction was initiated by adding a warmed solution of NADPH regenerating system A consisting of 0.50mM NADP and 10mM MgCl26.2mM DL-isocitrate and 0.5U/ml isocitrate dehydrogenase (ICD). The plates were placed in a plate reader at 30 ℃ and read-off every 1.5 minutes with 10 seconds shaking between each reading for 15 cycles. The excitation/emission wavelength was 408/465nm, respectively.
CYP2C9The test compound (3. mu.M) was preincubated with recombinant CYP2C9(Baculosome lot #20967Invitrogen, 50pmol P450/ml) and 30. mu.M MFC probe (Gentest) as substrates, formulated in 100mM potassium phosphate buffer (pH7.4), at 37 ℃ for 5 minutes. The reaction was started by adding a warm NADPH regenerating solution of system a. The plate was placed in a plate reader at 37 ℃ and read every 2.0 minutes with 10 seconds shaking between each reading for 15 cycles. The excitation/emission wavelength was 408/535 nm, respectively.
CYP2C19The test compound (3. mu.M) was preincubated with recombinant CYP2C19(Baculosome lot #20795Invitrogen, 5pmol P450/ml) and 10. mu.M Vivid blue 2C19 probe (Invitrogen) as substrates, formulated in 100mM potassium phosphate buffer (pH7.4), at 37 ℃ for 5 minutes. The reaction was initiated by adding a warm solution of NADPH regenerating system A. The plate was placed in a plate reader at 37 ℃ and read every 1.5 minutes with 10 seconds shaking between each reading for 15 cycles. The excitation/emission wavelengths were 408/465n, respectivelym。
CYP2D6Test compound (3. mu.M) was mixed with recombinant CYP2D6(Baculosome lot #21248Invitrogen, 20pmol P450/ml) and 1. mu.M 3- [2- (N, N-diethyl-N-methylammonium) ethyl ] as substrates, formulated in 100mM potassium phosphate buffer (pH7.4)]The-7-methoxy-4-methylcoumarin (AMMC) probe (Gentest) was preincubated at 37 ℃ for 5 minutes. The reaction was initiated by adding a warmed solution of NADPH regenerating system B consisting of 0.03mM NADP and 10mM MgCl26.2mM DL-isocitric acid and 0.5U/ml ICD. The plate was placed in a plate reader at 37 ℃ and read every 2.0 minutes with 10 seconds shaking between each reading for 15 cycles. The excitation/emission wavelength was 400/465nm, respectively.
CYP3A4Test compound (3. mu.M) was mixed with substrate at 100mM K+Recombinant CYP3A4(Baculosome lot #20814Invitrogen, 5pmol P450/ml) formulated in phosphate buffer (pH7.4) was preincubated with 2. mu.M Vivid Red probe (Invitrogen) for 5 min at 30 ℃. The reaction was initiated by adding a warm NADPH regenerating system a fluid. The plates were placed in a plate reader at 30 ℃ and read at minimum intervals with 10 seconds of shaking between each reading for 15 cycles. The excitation/emission wavelength was 530/595nm, respectively.
Drug-drug interactions were evaluated by the rate of metabolite formation calculated using the slope in the linear region (time versus fluorescence units) or by the percent inhibition of the test compound calculated by the following formula.
Inhibition { (v) (%)o-vi)/vo}x100, where voIs the speed of the control reaction (no test compound), viIs the reaction rate in the presence of the test compound.
I HERG Measurement of
Human ether a-go-go related gene (HERG) transfected HEK293 cells were prepared and then cultured internally (in-house). Methodologies for stable transfection of this channel in HEK cells can be found elsewhere (z. zhou et al, 1998, Biophysical journal, 74, 230-. On the day of the experiment, cells were collected from culture flasks and cultured in standard external solutions (see below for their composition) in the form of cell suspensions at 23 ℃ in room atmosphere. Cells were studied between 0.5 and 5 hours after harvest.
HERG currents were studied using standard patch clamp techniques in whole cell mode. During the experiment, cells were superfused with standard external solutions of the following composition: (mM) NaCl, 130; KCl, 4; CaCl2，2；MgCl21, 1; glucose, 10; HEPES, 5; pH7.4 adjusted with NaOH. Using a patch clamp amplifier and patch pipette (the patch pipette, when filled with the following composition (mM); KCl, 130; MgATP, 5; MgCl)21, 1; HEPES, 10; EGTA 5, pH7.2(KOH adjusted) standard external solution with a resistance of 1-3 MOhm) was recorded. Only cells with an access resistance below 10Mohm and a blocking resistance (sealResistiances) above 1GOhm received further experiments. The series resistance compensation is applied to a maximum of 80% without any leakage reduction. After obtaining the whole cell morphology (whole cell configuration) and sufficient time (> 5 minutes) for cell dialysis using pipette solution, the membrane was depolarized from a holding potential of-80 mV to +30mV for 1000ms, then ramped (rate 0.5mV msec)-1) And drops back to the holding potential. The depolarization and ramp voltage were applied to the cells continuously every 4 seconds (0.25 Hz). The amplitude of the peak current around-40 mV induced during the ramp was measured. Once a stable evoked current response to minimal changes in amplitude is obtained in the external solution, the test compound is applied to individual cells in multiple doses for 10 to 20 minutes. Cells were also exposed to high doses of dofetilide (5 μ M) (specific IKr blockers) to assess insensitive endogenous flow (endogenouscurent).
All experiments were performed at 23+/-1 ℃. Induced membrane currents were recorded on-line on a computer, filtered at 500-1000Hz (Besse1-3dB) and sampled at 1-2 KHz. Changes in permeability and pH induced by the test compound in the external solution were examined at the highest concentration.
The arithmetic mean of these 10 peak current values was calculated under control conditions and in the presence of the drug. By using the following formula: i isN＝(IC-ID)/(IC-Idof) X 100 normalized Current value to obtain I in each experimentNIs reduced in percentage of (A), wherein ICIs the average current value under control conditions, IDIs the average current value in the presence of the test compound, IdofIs the average current value in the case of dofetilide applications. Separate experiments were performed and the mixed data from the arithmetic mean of each experiment was defined as the results of this study.
Bioavailability in rats
Adult speprala-dow rat strains were used. All rats were prepared under anesthesia by cannulation of the right jugular vein 1 to 2 days prior to the experiment. The cannula was placed externally on the back of the neck. Blood samples (0.2-0.3mL) were drawn from the jugular vein at intervals up to 24 hours after intravenous or oral administration of the test compound. The samples were frozen until analysis. Bioavailability was assessed by calculating the quotient between the area under the plasma concentration curve (AUC) after oral or intravenous administration.
Bioavailability in dogs
Adult beagle dogs were used. Blood samples (0.2-0.5mL) were drawn from the cephalic vein at intervals up to 24 hours after intravenous or oral administration of the test compounds. The samples were frozen until analysis. Bioavailability was assessed by the quotient between the area under the plasma concentration curve (AUC) after oral or intravenous administration.
Plasma protein binding
Plasma protein deposition of test compounds (1 μ M) was measured by means of equilibrium dialysis using a 96-well plate type deviceAnd (6) mixing. Will be provided withThe regenerated fiber membrane (molecular weight cut-off 12,000-14,000, 22 mm. times.120 mm) was soaked overnight in distilled water, then in 30% ethanol for 20 minutes, and finally in dialysis buffer (Dulbecco's phosphate buffered saline solution, pH7.4) for 15 minutes. Human, spera-dow rats and beagle dogs frozen plasma were used. The dialysis device was assembled and 150. mu.L of compound-enhanced plasma was added to one side of each well and 150. mu.L of dialysis buffer was added to the other side of each well. After incubation at 37 ℃ for 4 hours at 150r.p.m, aliquots of plasma and buffer were sampled. Compounds in plasma and buffer were extracted for analysis with 300 μ L acetonitrile containing internal standard compounds. The concentration of the compound was determined using LC/MS analysis.
The fraction of unbound compound (fraction) was calculated by the following formula:
fu ═ 1- { ([ plasma)]eq- [ buffer solution]eq) /([ plasma)]eq)}
Wherein [ blood plasma]eqAnd [ buffer solution]eqConcentrations of the compounds in plasma and buffer, respectively.
Water solubility
The aqueous solubility in the media (a) to (c) was determined by the following method:
whatman mini-UniPrep cells (Clifton, NJ, USA) containing more than 0.5mg of compound and 0.5mL of each medium were shaken overnight (more than 8 hours) at room temperature. All samples were filtered through a 0.45 μ M polyvinylidene fluoride (PVDF) membrane into a Whatman mini-UniPrep syringe plunger prior to analysis. The filtrate was analyzed by HPLC.
<Culture medium>(a) Enzyme-free simulated gastric fluid (SGN), ph 1.2: dissolve 2.0g NaCl in 7.0mL 10M HCl and enough water to yield 1000 mL; (b) phosphate Buffered Saline (PBS), ph 6.5: mixing 6.35g KH2PO4、2.84g Na2HPO4And 5.50g NaCl dissolved in enough water to yield 1000mL, adjusting the pH to 6.5; (c) 3.94mg sodium taurocholate (NaTC) and 1.06mg 1-palmitoyl-2-oleoyl-L-phospholecithin (POPC) in 1mL PBS (pH 6.5).
Evaluation of liver clearance Using metabolic stability of human hepatocytes
At 37 ℃ in 95% air/5% CO2Next, the test compound (1. mu.M) was incubated with human-derived hepatocytes at rest with a target cell density of 0.5X 106Individual cells/ml, total volume 50. mu.L. The incubation was stopped at each time point by the addition of ice-cold Acetonitrile (ACN). Aliquots of the samples were mixed with 10% ACN containing internal standards for LC/MS analysis. After sonicating the samples for 10 minutes, the samples were centrifuged at 2,000rpm for 15 minutes and then the supernatants were transferred to other plates for analysis. The concentration of the compound in the supernatant was measured using an LC/MS system.
The disappearance of the test compound was obtained by plotting the usual logarithm of the peak area ratio of compound/internal control against time. The slope of the optimal line through the points yields the metabolic rate (k)e). This value was scaled to yield a clearance value (CL) expressed in ml/min/kg by taking into account hepatocyte weight, liver weight and body weight as illustrated in equation 1int). Liver Clearance (CL) was predicted from this intrinsic clearance value using the parallel tube model (parallel tube model) shown in equation 2h). Predicted clearance divided by hepatic blood flow (Q)h) Provides an extraction ratio (E)h) (equation 3).
Equation 1: ke (Chinese character of 'ke')x(g liver/kg body weight) x (ml incubation/number of cells in incubation) x (cells/g liver)
Equation 2: CLh＝Qhx{1-exp(-CLint/Qh)}
Equation 3: eh＝CLh/Qh
WhereinThe "liver weight/kg body weight" was 21, and the "cells/g liver" was 1.2X 108The "number of cells in ml incubation/incubation" was 2.0X 10-6，Qh20 ml/min/kg.
Assuming liver metabolism is the major route of drug clearance, systemic exposure (AUC) following oral administration is calculated using equation 4po)。
Equation 4AUCpoDose x (1-E)h)/CLh
Methods for determining potential phototoxicity of a compound:
phototoxicity potentials were measured exactly as described in OECD Guidelines for the Testing of Chemicals 432 (2002). Chlorpromazine (CPZ) and Sodium Dodecyl Sulfate (SDS) were used as positive and negative controls, respectively.
Balb/3T3, clonal 31 cells (ATCC, CCL-163) were seeded into 96-well plates (Nunc, 167008) at a density of 1X 104 cells/well. Cells were incubated in medium-DMEM (GIBCO; cat # 11885-plus 084) under standard conditions (37 ℃, 95% air and 5% CO2 in a humid atmosphere) for 24 hours. After incubation, the medium-DMEM was discarded, the cells were carefully washed with 150. mu.l of Earle's balanced salt solution (EBSS; Sigma, Cat # E3024), and then 100. mu.l of test compound solution formulated in EBSS or solvent control (EBSS containing 1% dimethyl sulfoxide or 1% ethanol) was added. Plates were prepared in duplicate. All plates were incubated under standard conditions for 60 minutes in the dark. One of the duplicate plates was used to determine cytotoxicity (-Irr) and was kept in the dark at room temperature for 50 minutes. For determination of the phototoxicity (+ Irr), another plate was exposed to a solar simulator (UVA irradiation: 1.7mW/cm 2; SOL500, Dr. Honle UV Technology, Germany) for 50 minutes (UVA dose ═ 5 joules/cm)2). The solution was then discarded from both plates and immediately washed carefully with 150 μ l of EBSS. Cells were further incubated with 150. mu.l/well of DMED medium for 18 to 22 hours.
After incubation, the medium was discarded, the cells were carefully washed with 150(1 EBSS and then immediately incubated with 100 μ l/well of 50 μ g/ml Neutral Red (NR) (3-amino-7-dimethylamino-2-methylphenazine hydrochloride, Kanto chemical co., inc., Japan) formulated in serum-free DMEM for 3 hours under standard conditions after the neutral red had been integrated into the lysosomes, the NR-DMED medium was discarded, the cells were carefully washed with 150 μ l of EBSS, accurate 150 μ l of ethanol/acetic acid/water (50: 1: 49) was added to each well of the Plate, followed by extraction by gentle shaking at room temperature for 10 minutes, then the optical density (NR) of the NR extract was measured at 540nm using a spectrophotometer (Plate-reader, POLARstar optoma; bmbiotechnology, Germany), the software "3T 3 nrotu @ 892.o" (version 0.890,78, federal institute for Risk Association, Germany) used the OD values to calculate the Mean Photoelectric Effect (MPE) value. The results of the controls (CPZ and SDS) were used for quality assurance of the assay.
MPE values < 0.1 evaluated as "no phototoxicity"; MPE values of 0.1 and 0.15 are evaluated as "potential phototoxicity" and MPE values of 0.15 and 0.1 are evaluated as "phototoxicity".
Examples
The following examples are provided for further illustration only and are not intended to be limiting of the disclosed invention. Unless otherwise indicated in the following examples, general experimental conditions are as follows: all operations are carried out at room or ambient temperature, i.e. in the range of 18-25 ℃; evaporating the solvent using a rotary evaporator under reduced pressure with a water bath temperature of up to 60 ℃; the reaction was monitored using Thin Layer Chromatography (TLC), the reaction times provided are for illustration only; the melting point (mp) given is uncorrected (polymorphism can lead to different melting points); by the following technique: TLC (Merck precoated silica gel 60F)254TLC plate or precoated Merck NH of2Gel (amine-coated silica gel) F254sTLC plate of (c), mass spectrometry, nuclear magnetic resonance spectroscopy (NMR), infrared absorption spectroscopy (IR) or microanalysis. Provide forThe yields of (a) are for illustration only. Flash column chromatography was performed using Biotage KP-SIL (40-63 μ M), Biotage KP-NH (amine coated silica gel) (40-75 μ M), Fuji Silysia aminated gel (30-50 μ M) or Wako silica gel 300HG (40-60 μ M). The microwave reaction was carried out using a Personal Chemistry emerys Optimizer or BiotageInitiator. Merck silica gel 60F was used254Preparation of TCL (preparative TLC) was carried out on pre-coated TLC plates (thickness of 0.5 or 1.0 mm). Using ZMDTMOr ZQTM(Waters) and Mass spectrometer all mass data in Low-resolution mass spectrometry data (ESI) were obtained. Unless otherwise indicated, NMR data were determined at 270MHz (JEOL JNM-LA270 spectrometer) or 300MHz (JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8%) or dimethylsulfoxide (99.9%) as solvent, in parts per million (ppm) relative to Tetramethylsilane (TMS) as internal standard; conventional abbreviations are used: s-singlet, d-doublet, t-triplet, m-multiplet, dd-doublet (doublet of doublet), br. -broad (broad), and so on. The IR spectrum was measured using a Fourier transform infrared spectrophotometer (Fourier transform infrared spectrophotometer) (Shimazu FTIR-8300). Optical rotations were measured using JASCO DOP-370 and P-1020 digital polarimeters (Digital polarimeter) (Japan Spectroscopic CO, Ltd.).
Example 1
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N-2-trimethyl-1H-benzimidazole-6-carboxamide
Step 1: n- { 4-bromo-2-nitro-6- [ (phenylmethyl) oxy]Phenyl acetamide
Concentrated sulfuric acid (2 drops) was added to a solution of 4-bromo-2-nitro-6- [ (benzyl) oxy ] aniline (33.0g, 102mmol, WO 2004054984) and acetic anhydride (14.5mL, 153mmol) in acetic acid (90mL) at 70 ℃. The mixture was stirred at 70 ℃ for 20 minutes. After cooling to room temperature, water (800mL) was added and the precipitate formed was collected by filtration and washed with diisopropyl ether to give the title compound as a brown solid (30.9g, 83%).
1H NMR(CDCl3，270MHz)δ：7.69(d，J＝2.0Hz，1H)，7.56(br.s，1H)，7.47-7.38(m，5H)，7.34(d，J＝2.0Hz，1H)，5.14(s，2H)，2.16(s，3H)ppm。
MS(ESI)m/z：365(M+H)+。
Step 2: n- { 4-cyano-2-nitro-6- [ (phenylmethyl) oxy]Phenyl acetamide
A mixture of N- { 4-bromo-2-nitro-6- [ (benzyl) oxy ] phenyl } acetamide (6.5g, 17.8mmol, step 1), zinc cyanide (4.18g, 35.6mmol) and tetrakis (triphenylphosphine) palladium (2.06g, 1.78mmol) in N, N-dimethylformamide (100mL) was heated to 170 ℃ for 20 min in a microwave synthesizer (Biotage, Emrys Optizer). After cooling to room temperature, the suspension was filtered and washed with ethyl acetate. The organic layers were combined, washed with water, then dried over magnesium sulfate, and concentrated in vacuo. The residual solid was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3: 1) to obtain the title compound (5.5g, 99%) as a white solid.
1H NMR(CDCl3，300MHz)δ：7.92(s，1H)，7.83(s，1H)，7.53-7.33(m，5H)，7.39(s，1H)，5.21(s，2H)，2.21(s，3H)ppm。
MS(ESI)m/z：312(M+H)+，310(M-H)-。
And step 3: 2-methyl-4- [ (phenylmethyl) oxy]-1H-benzimidazole-6-carbonitrile
A mixture of N- { 4-cyano-2-nitro-6- [ (benzyl) oxy ] phenyl } acetamide (5.5g, 17.7mmol, step 2) and iron powder (2.96g, 53.0mmol) formulated in acetic acid (90mL) was refluxed with stirring for 2 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was poured into water, and the aqueous layer was extracted with ethyl acetate/methanol (20: 1). The organic layers were combined, washed with brine (brine), dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a brown solid (3.82g, 82%).
1H NMR(DMSO-d6，300MHz)δ：7.64(s，1H)，7.64-7.27(m，6H)，7.19(s，1H)，5.34(s，2H)，2.50(s，3H)ppm。
MS(ESI)m/z：264(M+H)+，262(M-H)-。
And 4, step 4: 2-methyl-4- [ (phenylmethyl) oxy]-1H-benzimidazole-6-carboxylic acid
A solution of 2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole-6-carbonitrile (3.82g, 14.5mmol, step 3) and potassium hydroxide (85%, 10.2g, 15.4mmol) in ethylene glycol (50mL) was heated to 170 ℃ for 20 min in a microwave synthesizer (Biotage, Emrys Optizer). After cooling to room temperature, the mixture was acidified with 2M aqueous hydrochloric acid (pH 3). The precipitated solid was collected by filtration to obtain the title compound (3.83g, 93%) as a white solid.
1H NMR(DMSO-d6，270MHz)δ：12.68(br.s，1H)，7.74(s，1H)，7.64-7.01(m，7H)，5.33(s，2H)，2.50(s，3H)ppm。
MS(ESI)m/z：283(M+H)+，281(M-H)-。
And 5: n, N, 2-trimethyl-4- [ (phenylmethyl) amino group]-1H-benzimidazole-6-carboxamide
A solution of 2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxylic acid (5.0g, 17.7mmol, step 4), dimethylamine hydrochloride (4.33g, 53.1mmol), 2- [ 1H-benzotriazol-1-yl ] -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (10.1g, 26.6mmol) and triethylamine (10.7g, 106mmol) prepared in N, N-dimethylformamide (80mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate/methanol (20: 1) and washed with saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column purification on silica gel (eluting from a gradient of ethyl acetate alone to ethyl acetate: methanol 5: 1) to give the title compound as a white solid (4.90g, 89%).
1H NMR(CDCl3270MHz) δ: 7.47-7.23(m, 5H), 7.20(s, 1H), 6.75(s, 1H), 5.22(s, 2H), 2.95(br.s, 6H), 2.54(s, 3H) ppm (no-NH observed).
MS(ESI)m/z：310(M+H)+，308(M-H)-。
Step 6: n, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl]-4- [ (phenylmethyl) oxy group]-1H-benzimidazole-6-carboxamide
To a suspension of N, N, 2-trimethyl-4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxamide (928mg, 3.0mmol, step 5) formulated in N, N-dimethylformamide (20mL) at 0 deg.C was added sodium hydride (60% in mineral oil, 180mg, 4.50 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was cooled to 0 ℃. 4-Methylbenzenesulfonyl chloride (572mg, 3.00mmol) was added to the mixture at 0 ℃ and then the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution from dichloromethane only to ethyl acetate only) to give the title compound as a white solid (1.00g, 72%).
1H NMR(CDCl3，270MHz)δ：7.80(d，J＝8.1Hz，2H)，7.70(s，1H)，7.45(d，J＝8.1Hz，2H)，7.40-7.22(m，5H)，6.86(s，1H)，5.32(s，2H)，3.11(br.s，3H)，2.89(br.s，3H)，2.81(s，3H)，2.40(s，3H)ppm。
MS(ESI)m/z：464(M+H)+。
And 7: 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl]-1H-benzimidazole-6-carboxamide
A mixture of N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl ] -4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxamide (350mg, 0.756mmol, step 6) and 20% palladium hydroxide (1.20g) formulated in acetic acid (20mL) under hydrogen (4 atm) with stirring was carried out for 4 hours. The resulting mixture was then filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting from a gradient of ethyl acetate alone to ethyl acetate: methanol 5: 1) to give the title compound (131mg, 36%) as a white solid.
1H NMR(CDCl3270MHz) δ: 7.82(d, J ═ 8.1Hz, 2H), 7.63(s, 1H), 7.31(d, J ═ 8.1Hz, 2H), 6.92(s, 1H), 3.14(br.s, 3H), 3.01(br.s, 3H), 2.79(s, 3H), 2.40(s, 3H) ppm (no-OH observed).
MS(ESI)m/z：374(M+H)+，372(M-H)-。
And 8: 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl group]-1H-benzimidazole-6-carboxamide
Step 8-1: 5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol
To a solution of 5, 7-difluoro-2, 3-dihydro-4H-chromen-4-one (14.2g, 77.0mmol, U.S. Pat. No. 4, 20050038032) in methanol (200mL) at 0 deg.C was added sodium borohydride (3.50g, 92.5 mmol). The reaction mixture was stirred at the same temperature for 1 hour, and then evaporated to remove methanol. The residue was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate 3: 1 as eluent) to give the title compound (9.64g, 67%) as a white grey solid.
1H NMR(CDCl3，270MHz)δ：6.47-6.36(m，2H)，5.05-4.97(m，1H)，4.36-4.20(m，2H)，2.16-1.92(m，3H)ppm。
Step 8-2: 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl group]-1H-benzimidazole-6-carboxamide
To a stirred mixture of 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl ] -1H-benzimidazole-6-carboxamide (110mg, 0.294mmol, step 7), 5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol (164mg, 0.884mmol, step 8-1), and triphenylphosphine (232mg, 0.884mmol), formulated in toluene (5mL) at room temperature was added diisopropyl azodicarboxylate (DIAD) (179mg, 0.884 mmol). The reaction mixture was stirred at room temperature for 6 hours, then concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution from ethyl acetate: hexane 1: 20 to 10: 1) to obtain a mixture of the title compound and triphenylphosphine oxide (280mg, crude) as a white solid, which was used in the next step without further purification.
1H NMR(CDCl3，270MHz)δ：7.81(d，J＝8.1Hz，2H)，7.51(s，1H)，7.31(d，J＝8.1Hz，2H)，7.07(s，1H)，6.54-6.22(m，2H)，5.93(br.s，1H)，4.40(t，J＝10.8Hz，1H)，4.27(t，J＝10.8Hz，1H)，3.15(br.s，3H)，3.03(br.s，3H)，2.79(s，3H)，2.39(s，3H)，2.40-2.21(m，1H)，2.19-1.73(m，1H)ppm。
MS(ESI)m/z：542(M+H)+，540(M-H)-。
And step 9: 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
To a solution of 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1- [ (4-tolyl) -sulfonyl ] -1H-benzimidazole-6-carboxamide (280mg, crude, step 8) in tetrahydrofuran (8mL) and methanol (4mL) was added sodium hydroxide (165mg, 4.1mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium dihydrogenphosphate solution, followed by extraction with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting from a gradient of ethyl acetate to ethyl acetate: methanol 10: 1 only) to give the title compound (74mg, 65% for 2 steps) as a white solid.
1H NMR(CDCl3270MHz) δ: 7.27(s, 1H), 6.95(s, 1H), 6.51-6.33 (m, 2H), 5.87-5.69(m, 1H), 4.41-4.25(m, 2H), 3.10(br.s, 6H), 2.56(s, 3H), 2.44-2.34(m, 1H), 2.14-1.98(m, 1H) ppm (no-NH observed).
MS(ESI)m/z：388(M+H)+，386(M-H)-。
Example 2
(-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide and
example 3
(+) -4- [ ((4R) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
Example 2Example 3
Fraction 1(582mg) and fraction 2(562mg) were prepared by HPLC from racemic 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 1, 2-trimethyl-1H-benzimidazole-6-carboxamide (1.63g, step 9 in example 1) as follows.
Separation conditions
Column: CHIRALCEL OJ-H (20mm X250 mm, DAICEL)
Mobile phase: n-hexane/ethanol/diethylamine (95/5/0.1)
Flow rate: 18.9 mL/min
(-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide (fraction 1)
1H NMR: the spectral data are the same as those of the racemic compound
Optical rotation: [ alpha ] to]D 231.1 ° (c ═ 1.00, methanol)
Retention time: 14 minutes
(+) -4- [ ((4R) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide (fraction 2)
1H NMR: the spectral data were in agreement with those of the racemic compound
Optical rotation: [ alpha ] to]D 23Equal to +104.2 ° (c equal to 1.00, methanol)
Retention time: 18 minutes
The following are alternative methods for the synthesis of (-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide.
Step 1: 6-bromo-2-methyl-4- [ (phenylmethyl) oxy]-1H-benzimidazole
A mixture of N- { 4-bromo-2-nitro-6- [ (benzyl) oxy ] phenyl } acetamide (120g, 329mmol, step 1 in example 1) and iron powder (55.1g, 986mmol) formulated in acetic acid (500mL) was refluxed with stirring for 6 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was eluted with ethyl acetate (1.5L). The resulting precipitate was filtered through a pad of Celite, then washed with ethyl acetate (500 mL). The filtrate was concentrated in vacuo and the residue was eluted with ethyl acetate (200 mL). Brine (800mL) was added to the organic mixture, the resulting white precipitate was collected by filtration, and the precipitate was washed with water (200mL) and diethyl ether (200 mL). The white solid was dissolved in dichloroethane/methanol (10: 1, 1.0L), dried over magnesium sulfate, and concentrated. The solid was triturated with diethyl ether (300mL), collected by filtration and then dried in vacuo to give the title compound as a white solid (54.7g, 53%).
1H NMR(DMSO-d6270MHz) δ: 7.63-7.28(m, 7H), 5.38(s, 2H), 2.69(s, 3H) ppm. (no NH observed).
MS(ESI)m/z：317(M+H)+，315(M-H)-。
Step 2: 6-bromo-2-methyl-1- [ (4-tolyl) sulfonyl]-4- [ (phenylmethyl) oxy group]-1H-benzimidazole
To a suspension of 6-bromo-2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole (79.2g, 250mmol, step 1) in N, N-dimethylformamide (500mL) was added sodium hydride (60% in mineral oil, 12.0g, 300mmol) at 0 ℃. After stirring at room temperature for 20 minutes, the reaction mixture was cooled to 0 ℃. 4-Methylbenzenesulfonyl chloride (47.6g, 250mmol) was added to the mixture at 0 ℃ and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water (800mL), and the white precipitate was collected by filtration, washed with diisopropyl ether (500mL), and then dried under vacuum at 70 ℃ for 7 hours to obtain the title compound (116g, 98%) as a white solid.
1H NMR(DMSO-d6，270MHz)δ：7.98(d，J＝8.1Hz，2H)，7.64(d，J＝1.9Hz，1H)，7.53-7.34(m，7H)，7.22(d，J＝1.9Hz，1H)，5.28(s，2H)，2.74(s，3H)，2.38(s，3H)ppm。
MS(ESI)m/z：471(M+H)+，469(M-H)-。
And step 3: n, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl]-4- [ (phenylmethyl) oxy group]-1H-benzimidazole-6-carboxamide
A mixture of 6-bromo-2-methyl-1- [ (4-tolyl) sulfonyl ] -4- [ (benzyl) oxy ] -1H-benzimidazole (53.0g, 112mmol, step 2) and tetrakis (triphenylphosphine) palladium (0) (25.9g, 22.4mmol) formulated in 2M dimethylamine tetrahydrofuran solution (580mL) was stirred under carbon monoxide gas (1 atm) at 65 ℃ for 32H. The mixture was cooled to room temperature and then diluted with ethyl acetate (600 mL). The organic mixture was washed with saturated ammonium chloride solution (800mL) and brine (500mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient from 1: 2 to 1: 3 hexane: ethyl acetate) to give the title compound as a white solid (21.8g, 42%).
1H NMR: the spectroscopic data were the same as in step 6 of example 1.
And 4, step 4: 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl]-1H-benzimidazole-6-carboxamide
A mixture of N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl ] -4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxamide (29.0g, 62.6mmol, step 3) and 10% palladium on carbon (6.0g), formulated in tetrahydrofuran (200mL), was stirred at room temperature under nitrogen (1 atmosphere) for 24 hours. An additional 4.0g of 10% palladium on carbon was added and the mixture was stirred under hydrogen (1 atmosphere) at room temperature for an additional 6 hours. The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give the title compound as a white solid (23.0g, 98%).
1H NMR: the spectral data were the same as in step 7 of example 1.
And 5: 3- (3, 5-Difluorophenoxy) acrylic acid methyl ester
To a solution of 3, 5-difluorophenol (35.5g, 273mmol) and methyl propiolate (25.0mL, 300mmol) in acetonitrile (109mL) at room temperature was added a solution of tetrabutylammonium fluoride (1.0M commercial solution, 109mL, 109mmol) in tetrahydrofuran over a period of 2 hours. After complete addition of the solution, the mixture was stirred for 1 hour. The reaction mixture was diluted with toluene (350mL) and the organic mixture was washed 2 times with water (250mL × 2), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on aminated gel (hexane: ethyl acetate 3: 2 as eluent) to give the title compound (60.0g, quantitative, 1: 1 mixture of cis and trans isomers) as a yellow solid.
1H NMR(CDCl3，270MHz，)δ：7.72(d，J＝10.8Hz，0.5H)，6.83(d，J＝5.4Hz，0.5H)，6.74-6.49(m，3H)，5.68(d，J＝10.8Hz，0.5H)，5.28(d，J＝5.4Hz，0.5H)，3.76(s，3H)ppm。
Step 6: 3- (3, 5-Difluorophenoxy) propionic acid methyl ester
A mixture of methyl 3- (3, 5-difluorophenoxy) acrylate (60.0g, 280mmol, step 5) and 10% palladium on carbon (1.0g) in methanol (300mL) was stirred under hydrogen (1 atmosphere) at room temperature for 18 hours. The reaction mixture was passed through a pad of Celite, followed by washing with toluene (100 mL). The filtrate was concentrated in vacuo to give the title compound (61.0g, quant) as a colorless oil, which was used in the next step without further purification.
1H NMR(CDCl3，270MHz)δ：6.56-6.21(m，3H)，4.21(t，J＝5.4Hz，2H)，3.74(s，3H)，2.80(t，J＝5.4Hz，2H)ppm。
And 7: 5, 7-difluoro-2, 3-dihydro-4H-chromen-4-one
A mixture of methyl 3- (3, 5-difluorophenoxy) propionate (11.6g, 53.7mmol, step 6) and trifluoromethanesulfonic acid (23.2mL, 2.0mL/g of substrate) was stirred at 80 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (120mL) and then extracted with toluene (120 mL). The organic layer was successively washed with an aqueous potassium carbonate solution (50mL) and water (50mL), and then dried over magnesium sulfate. The organic mixture was concentrated in vacuo to give the title compound as a white solid (8.75g, 88%), which was used in the next step without further purification.
1H NMR(CDCl3，270MHz)δ：6.51-6.40(m，2H)，4.55-4.50(m，2H)，2.86-2.75(m，2H)ppm。
And 8: (+) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol
To a mixture of 1M(s) -tetrahydro-1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo [1, 2-c ] [1, 3, 2] oxazaborole tolumene (oxazaborole) solution (5.43mL, 5.43mmol) and tetrahydrofuran (40mL) at 0 ℃ was added 2M borane-methyl sulfide tetrahydrofuran solution (29.8mL, 59.7mmol), and the mixture was stirred for 20 minutes. To the mixture was added a solution of 5, 7-difluoro-2, 3-dihydro-4H-chromen-4-one (10.0g, 54.3mmol, step 7) formulated in tetrahydrofuran (70mL) at 0 ℃ over 1 hour, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with methanol (50mL) and stirred at room temperature for 30 min. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (hexane: ethyl acetate 4: 1 as eluent) to give a crude white solid (8.85g, 86% ee). The solid was recrystallized from hexane (300mL) to give the title compound (5.90g, 58%, > 99% ee) as colorless needle crystals.
1H NMR: the spectral data agreed with those of the racemic compound (step 8-1 in example 1).
Optical rotation: [ alpha ] to]D 24+143.6 ° (c-1.00, methanol).
And step 9: (-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl group]-1H-benzimidazole-6-carboxamide
To a stirred mixture of 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl ] -1H-benzimidazole-6-carboxamide (21.2g, 56.8mmol, step 4), (+) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol (15.86g, 85.1mmol, step 8) and tributylphosphine (22.9g, 113mmol) formulated in toluene (840mL) at room temperature was added 1, 1' - (azodicarbonyl) dipiperidine (ADDP) (19.3g, 76.5 mmol). After stirring at room temperature for 2 hours, the reaction mixture was filtered through a pad of Celite, then washed with ethyl acetate (300 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution from 1: 20 to 20: 1 ethyl acetate: hexane) to obtain a crude solid (27.0 g). The solid was recrystallized from 2-propanol (130mL) to give the title compound (23.2g, 75%, > 99% ee) as colorless crystals.
1H NMR: the spectral data agreed with those of the racemic compound (step 8-2 in example 1).
Optical rotation: [ alpha ] to]D 24-80.4 ° (c-0.50, methanol).
Step 10: (-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
To a solution of (-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, N, 2-trimethyl-1- [ (4-tolyl) -sulfonyl ] -1H-benzimidazole-6-carboxamide (24.2g, 44.7mmol, step 9) formulated in tetrahydrofuran (65mL) and 2-propanol (220mL) was added aqueous 2M sodium hydroxide (220mL, 440mmol) at room temperature. After stirring at room temperature for 4 hours, the mixture was diluted with ethyl acetate (1.20L) and washed with saturated aqueous ammonium chloride (500 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on aminated gel (gradient elution of ethyl acetate: methanol from 50: 1 to 20: 1) to give the title compound as a white solid (15.2g, 87%, > 99% ee).
1H NMR: the spectroscopic data agree with those of the racemic compound (step 9 in example 1).
The optical rotation and the retention time were the same as above.
Example 4
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole
Step 1: 2-methyl-4- [ (phenylmethyl) oxy]-1H-benzimidazole-6-carboxylic acid methyl ester
A mixture of 2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxylic acid (10.0g, 35.4mmol, step 4in example 1) and thionyl chloride (5.2mL, 7.1mmol) prepared in methanol (300mL) was stirred at 80 ℃ for 3 hours. The mixture was diluted with ethyl acetate and then washed with saturated aqueous ammonium chloride solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was diluted with methanol, filtered to remove the precipitate, and the filtrate was concentrated in vacuo. The resulting solid was washed with dichloromethane to yield the title compound as a brown solid (29.8g, crude) which was used in the next step without further purification.
MS(ESI)m/z：297(M+H)+，295(M-H)-。
Step 2: 1- (1, 1-Dimethylethyl) 6-methyl-2-methyl-4- [ (phenylmethyl) oxy]-1H-benzimidazole-1, 6-dicarboxylic acid ester
A mixture of methyl 2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxylate (29.8g, crude, step 1), di-tert-butyl-pyrocarbonate (69g, 315mmol), 4-dimethylaminopyridine (366mg, 3.0mmol), and triethylamine (100mL, 717mmol) formulated in N, N-dimethylformamide (100mL) was stirred at room temperature for 2 hours. The mixture was washed with ethyl acetate and with saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution from 1: 20 to 3: 2 ethyl acetate: hexane) to give the title compound (12.1g, crude) as a white solid which was used in the next step without further purification.
1H NMR(CDCl3，270MHz)δ：8.29(s，1H)，7.54(s，1H)，7.60-7.50 (m，2H)，7.40-7.31(m 3H)，5.37(s，2H)，3.92(s，3H)，2.86(s，3H)，1.73(s，9H)ppm。
MS(ESI)m/z：397(M+H)+。
And step 3: 1- (1, 1-dimethyl)Ethyl) 6-methyl-4-hydroxy-2-methyl-1H-benzimidazole-1, 6-dicarboxylate
A mixture of 1- (1, 1-dimethylethyl) 6-methyl-2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole-1, 6-dicarboxylate (12.1g, crude, step 2) and 20% palladium hydroxide (6.0g) formulated in tetrahydrofuran (250mL) was stirred under hydrogen for 2 hours. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was washed with hexane/diethyl ether (10: 1) to give the title compound (3.02g, 28% for step 3) as a white solid.
1H NMR(CDCl3，270MHz)δ：10.38(br.s，1H)，8.21(s，1H)，7.62(s，1H)，3.94(s，3H)，2.87(s，3H)，1.73(s，9H)ppm。
MS(ESI)m/z：307(M+H)+，305(M-H)-。
And 4, step 4: 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid
To a stirred mixture of 1- (1, 1-dimethylethyl) 6-methyl-4-hydroxy-2-methyl-1H-benzimidazole-1, 6-dicarboxylate (1.50g, 4.90mmol, step 3), 5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol (1.82g, 9.79mmol, step 1 in example 1) and triphenylphosphine (2.57g, 9.79mmol), formulated in toluene (50mL) was added diisopropyl azodicarboxylate (DIAD) (1.98g, 4.90mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was dissolved in methanol (20mL) and tetrahydrofuran (5mL), and 4M aqueous lithium hydroxide (20mL, 80mmol) was added to the mixture at room temperature. After stirring at 80 ℃ for 4 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in water, washed with ethyl acetate and acidified with 2M aqueous hydrochloric acid (pH 6). The precipitated solid was filtered and dried in vacuo to give the title compound (1.67g, crude) as a white solid, which was used in the next step without further purification.
1H NMR(DMSO-d6270MHz) δ: 7.76(s, 1H), 7.51(s, 1H), 6.79(t, J ═ 10.8Hz, 1H), 6.66(t, J ═ 10.8Hz, 1H), 5.99(br.s, 1H), 4.39-4.17(m, 2H), 2.46(s, 3H), 2.28-2.05(m, 2H) ppm (no observation of-COOH and-NH).
MS(ESI)m/z：361(M+H)+，359(M-H)-。
And 5: 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole
The title compound (70mg, 56% yield for 3 steps) was prepared as a white solid from 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-1H-benzimidazole-6-carboxylic acid (100mg, crude, step 4) and pyrrolidine (59mg, 0.832mmol) according to the same method as in step 5 of example 1.
1H NMR(CDCl3270MHz) δ: 7.33(s, 1H), 7.03(s, 1H), 6.47-6.07(m, 2H), 5.90-5.66(m, 1H), 4.40-4.18(m, 2H), 3.73-3.40(m, 4H), 2.48(s, 3H), 2.37-2.22(m, 1H), 2.11-1.78(m, 5H) ppm (no-NH observed).
MS(ESI)m/z：414(M+H)+，412(M-H)-。
Example 5
(+) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole and
example 6
(-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole
Fraction 1(152mg) and fraction 2(146mg) were prepared by HPLC from the racemic compound 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole (0.35g, step 5in example 4) as follows.
Separation conditions
Column: CHIRALPAK AD-H (20mm X250 mm, DAICEL)
Mobile phase: n-hexane/isopropanol/diethylamine (85/15/0.1)
Flow rate: 20 mL/min
(+) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole (fraction 1)
1H NMR: the spectral data are in agreement with those of the racemic compound.
Optical rotation: [ alpha ] to]D 23Plus 105.0 ° (c is 0.50, methanol)
Retention time: 12 minutes
(-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole (fraction 2)
1H NMR: the spectral data are in agreement with those of the racemic compound.
Optical rotation: [ alpha ] to]D 23-106.5 ° (c ═ 0.50, methanol)
Retention time: 14 minutes
Example 7
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N- (2-hydroxyethyl) -N, 2-dimethyl-1H-benzimidazole-6-carboxamide
The title compound was prepared as a white solid (50mg, 40% yield for 3 steps) according to the same method as in step 5 of example 1 from 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-1H-benzimidazole-6-carboxylic acid (100mg, crude, step 4 of example 4) and 2- (methylamino) ethanol (63mg, 0.83 mmol).
1H NMR(CDCl3270MHz) δ: 6.91(br.s, 2H), 6.49-6.23(m, 2H), 5.88-5.65(m, 1H), 4.37-4.11(m, 2H), 3.99-3.60(m, 3H), 3.07(s, 3H), 2.41(s, 3H), 2.36-2.17(m, 1H), 2.08-1.89(m, 2H) ppm (no-OH and-NH observed).
MS(ESI)m/z：418(M+H)+，416(M-H)-。
Example 8
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N- [2- (dimethylamino) ethyl group]-N, 2-dimethyl-1H-benzimidazole-6-carboxamide
The title compound was prepared as a white solid (10mg, 13% yield for 3 steps) from 4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-1H-benzimidazole-6-carboxylic acid (100mg, crude, step 4in example 4) and N, N' -trimethyl-1, 2-ethylenediamine (45mg, 0.44mmol) according to the same method as in step 5 of example 1.
1H NMR(CDCl3 270MHz)δ：7.27(s，1H)，6.94(s，1H)，6.50-6.31(m，2H)，5.76 (br.s，1H)，4.44-4.24(m，2H)，3.76-3.32(m，2H)，3.09(s，3H)，2.56(s，3H)，2.61-1.94(m，10H)ppm (no-NH observed).
MS(ESI)m/z：445(M+H)+，443(M-H)-。
Example 9
4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
Step 1: 1, 1-Dimethylethyl 6- [ (dimethylamino) carbonyl group]-2-methyl-4- [ (phenylmethyl) oxy group]-1H-benzimidazole-1-carboxylic acid ester
The title compound was prepared as a white solid in 67% yield (5.68g) from N, 2-trimethyl-4- [ (benzyl) oxy ] -1H-benzimidazole-6-carboxamide (6.4g, 20.7mmol, step 5in example 1) and di-tert-butyl-pyrocarbonate (6.77g, 31.0mmol) according to the same method as in step 2 of example 4.
1H NMR(CDCl3 270MHz)δ：7.64(s，1H)，7.47(d，J＝8.1Hz，2H)，7.38-7.28(m，3H)，6.83(s，1H)，5.38(s，2H)，2.97(br.s，6H)，2.83(s，3H)，1.69(s，9H)ppm；
MS(ESI)m/z：410(M+H)+。
Step 2: 1, 1-Dimethylethyl 6- [ (dimethylamino) carbonyl group]-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylic acid ester
The title compound was prepared as a white solid in 92% yield (4.10g) from 1, 1-dimethylethyl 6- [ (dimethylamino) carbonyl ] -2-methyl-4- [ (benzyl) oxy ] -1H-benzimidazole-1-carboxylate (5.68g, 13.9mmol, step 1) and 20% palladium hydroxide (2.4g) in the same manner as in step 3 of example 4.
1H NMR(CDCl3 270MHz)δ：10.39(s，1H)，7.56(s，1H)，6.97(s，1H)，3.13(br.s，3H)，3.04(br.s，3H)，2.82(s，3H)，1.69(s，9H)ppm。
MS(ESI)m/z：320(M+H)+，318(M-H)-。
And step 3: 4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
Step 3-1: 5-fluoro-3, 4-dihydro-2H-chromen-4-ol
The title compound was prepared as black oil in quantitative yield (0.9g) from 5-fluoro-2, 3-dihydro-4H-chromen-4-one (0.9g, 5mmol, GB 2355264) according to the same method as in step 8-1 of example 1.
1H NMR(CDCl3，300MHz)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 3-2: 4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
To a stirred mixture of 1, 1-dimethylethyl 6- [ (dimethylamino) carbonyl ] -4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (1.00g, 3.13mmol, step 2), 5-fluoro-3, 4-dihydro-2H-chromen-4-ol (948mg, 5.64mmol, step 3-1) and triphenylphosphine (2.57g, 9.79mmol), formulated in toluene (50mL) at room temperature was added diisopropyl azodicarboxylate (DIAD) (1.98g, 4.90 mmol). The reaction mixture was stirred at room temperature for 2 hours and the reaction was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (30mL) and methanol (15mL), and then sodium hydroxide (750mg, 18.8mmol) was added to the mixture at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium dihydrogenphosphate solution, followed by extraction with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (starting with dichloromethane only, then ethyl acetate: methanol 10: 1 as eluent) to give the title compound (510mg, 50%) as a white solid.
1H NMR(CDCl3270MHz) δ: 7.20-7.11(m, 1H), 7.13(s, 1H), 6.90(s, 1H), 6.64(d, J ═ 8.1Hz, 1H), 6.52(d, J ═ 8.1Hz, 1H), 5.76(br.s, 1H), 4.28-4.07(m, 2H), 3.04(br.s, 6H), 2.38(s, 3H), 2.29-2.18(m, 1H), 2.04-1.90(m, 1H) ppm (no-NH observed).
MS(ESI)m/z：370(M+H)+，368(M-H)-。
Example 10
(-) -4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide and
example 11
(+) -4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
Fraction 1(126mg) and fraction 2(114mg) were prepared from the racemic compound 4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 1, 2-trimethyl-1H-benzimidazole-6-carboxamide (510mg, step 3-2 in example 9) by HPLC as follows.
Separation conditions
Column: CHIRALCEL OJ-H (20mm X250 mm, DAICEL)
Mobile phase: n-hexane/ethanol/diethylamine (90/10/0.1)
Flow rate: 20.0 mL/min
(-) -4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide(fraction 1)
1H NMR: the spectral data are consistent with those of racemic compounds
Optical rotation: [ alpha ] to]D 23-106.8 ° (c ═ 0.50, methanol)
Retention time: 7 minutes
(+) -4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide (fraction 2)
1H NMR: the spectral data are consistent with those of racemic compounds
Optical rotation: [ alpha ] to]D 23103.6 ° (c ═ 0.50, methanol)
Retention time: 9 minutes
Example 12
4- (3, 4-dihydro-2H-chromen-4-yloxy) -N, 2-trimethyl-1H-benzimidazole-6-carboxamide
The title compound (58mg, 53% yield for 2 steps) was prepared as a white solid from 1, 1-dimethylethyl 6- [ (dimethylamino) carbonyl ] -4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (100mg, 0.313mmol, step 2 of example 9) and 3, 4-dihydro-2H-chromen-4-ol (141mg, 0.939mmol) in the same manner as in step 3-2 of example 9:
1H NMR(CDCl3270MHz) δ: 7.22-7.12(m, 3H), 6.90-6.75(m, 3H), 5.62-5.57(m, 1H), 4.29-4.08(m, 2H), 3.12-2.95(m, 6H), 2.40(s, 3H), 2.28-2.07(m, 2H) ppm (no-NH observed).
MS(ESI)m/z：352(M+H)+，350(M-H)-。
Example 13
4- [ (8-fluoro-5-methyl-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
Step 1: 8-fluoro-5-methylchroman-4-ol
Step 1-1: 3- (2-fluoro-5-methylphenoxy) propionic acid
To a solution of sodium hydroxide (3.2g, 79mmol) in water (16mL) at room temperature was added 2-fluoro-5-methylphenol (5.0g, 40 mmol). After stirring the solution for 5 minutes, 3-iodopropionic acid (7.9g, 40mmol) was added to the pale yellow solution, and the mixture was refluxed with stirring for 18 minutes. The mixture was cooled to room temperature, poured into 2M aqueous hydrochloric acid (100mL) at 0 ℃, and then the mixture was extracted with ethyl acetate (60mL × 2). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution from hexane/ethyl acetate 3: 1 to ethyl acetate only). The resulting pale yellow solid was triturated with hexane, collected by filtration, and then dried in vacuo to obtain the title compound (2.45g, 31%) as a pale yellow.
1H NMR(CDCl3270MHz) δ: 6.95(dd, J ═ 11.2, 8.6Hz, 1H), 6.81(dd, J ═ 7.9, 2.0Hz, 1H), 6.75-6.66(m, 1H), 4.30(t, J ═ 6.6Hz, 2H), 2.89(t, J ═ 6.6Hz, 2H), 2.30(s, 3H) ppm. (no-OH was observed).
Step 1-2: 8-fluoro-5-methyl-2, 3-dihydro-4H-chromen-4-one
The mixture of 3- (2-fluoro-5-methylphenoxy) propionic acid (2.45g, 12.4mmol, step 1-1) formulated in polyphosphoric acid (35g) was stirred at 100 ℃ for 2 hours. After cooling to room temperature, the mixture was diluted with water (150mL) and then extracted with ethyl acetate (60 mL. times.2). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (2.30g, quant.) as a white solid.
1H NMR(CDCl3，270MHz)δ：7.15(dd，J＝9.9，8.6Hz，1H)，6.73(dd，J＝8.6，5.3Hz，1H)，4.59(t，J＝6.6Hz，2H)，2.85(t，J＝6.6Hz，2H)，2.59(s，3H)ppm。
Step 1-3: 8-fluoro-5-methylchroman-4-ol
The title compound was prepared as a white solid in 93% yield (2.16g) from 8-fluoro-5-methyl-2, 3-dihydro-4H-chromen-4-one (2.30g, 12.8mmol, step 1-2) according to the same method as in step 8-1 of example 1.
1H NMR(CDCl3，270MHz)δ：6.94(dd，J＝11.2，7.9Hz，1H)，6.68(dd，J＝7.9，4.6Hz，1H)，4.90-4.82(m，1H)，4.47-4.36(m，1H)，4.30-4.17(m，1H)，2.38(s，3H)2.15-2.00(m，2H)1.85-1.75(m，1H)ppm。
Step 2: 4- [ (8-fluoro-5-methyl-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
The title compound was prepared as a white solid in 32% yield (38mg) from 1, 1-dimethylethyl 6- [ (dimethylamino) carbonyl ] -4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (100mg, 0.31mmol, step 2 of example 9) and 8-fluoro-5-methylchroman-4-ol (0.23g, 1.2mmol, steps 1-3) according to the same method as in step 3-2 of example 9.
1H NMR(CDCl3，270MHz)δ：9.61(br.s，1H)，7.45-7.22(m，1H)，7.08-6.90(m，2H)，6.75-6.60(m，1H)，5.70-5.50(m，1H)，4.43-4.05(m，2H)，3.11(br.s，6H)，2.55(s，3H)2.50-2.33(m，1H)，2.28-2.05(m，1H)，2.20(s，3H)ppm。
MS(ESI)m/z：384(M+H)+，382(M-H)-。
Example 14
4- [ (5, 8-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
Step 1: 5, 8-difluoro-chroman-4-ols
Step 1-1: 3- (2, 5-Difluorophenoxy) propionic acid
The title compound was prepared as a white solid in 37% yield (4.6g) from 2, 5-difluorophenol (8.0g, 61mmol) according to the same method as in step 1-1 of example 13.
1H NMR(CDCl3300MHz) δ: 7.10-6.95(m, 1H), 6.80-6.68(m, 1H), 6.67-6.55(m, 1H), 4.29(t, J ═ 6.3Hz, 2H), 2.91(t, J ═ 6.3Hz, 2H) ppm. (no-OH was observed).
Step 1-2: 5, 8-difluoro-2, 3-dihydro-4H-chromen-4-one
The title compound was prepared as a brown oil in 91% yield (3.8g) from 3- (2, 5-difluorophenoxy) propionic acid (4.6g, 23mmol, step 1-1) according to the same method as in step 1-2 of example 13.
1H NMR(CDCl3，270MHz)δ：7.30-7.18(m，1H)，6.72-6.60(m，1H)，4.65(t，J＝6.3Hz，2H)，2.87(t，J＝6.3Hz，2H)ppm。
Step 1-3: 5, 8-difluoro-chroman-4-ols
The title compound was prepared as a brown oil in 91% yield (3.3g) from 5, 8-difluoro-2, 3-dihydro-4H-chromen-4-one (3.8g, 21mmol, step 1-2) according to the same method as in step 8-1 of example 1.
1H NMR(CDCl3，270MHz)δ：7.05-6.93(m，1H)，6.62-6.52(m，1H)，5.10-5.02(m，1H)，4.47-4.38(m，1H)，4.35-4.23(m，1H)，2.33-2.03(m，3H)ppm。
Step 2: 4- [ (5, 8-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide
The title compound was prepared as a white solid in 48% yield (87mg) from 1, 1-dimethylethyl 6- [ (dimethylamino) carbonyl ] -4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylic acid (150mg, 0.47mmol, step 2 in example 9) and 5, 8-difluorochroman-4-ol (0.26g, 1.4 mmol, steps 1-3) according to the same method as in step 3-2 of example 9.
1H NMR(CDCl3270MHz) δ: 7.33-7.18(m, 1H), 7.08-6.90(m, 2H), 6.58-6.48(m, 1H), 5.90-5.75(m, 1H), 4.45-4.30(m, 2H), 3.12(br.s, 3H), 3.06(br.s, 3H), 2.52(s, 3H)2.44-2.34(m, 1H), 2.18-2.00(m, 1H) ppm (no-NH observed).
MS(ESI)m/z：388(M+H)+，386(M-H)-。
The following examples 15 to 21 were prepared according to the method described in example 1 or example 2.
Example 22
(-) -6- (azetidin-1-ylcarbonyl) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-1H-benzimidazole
Step 1: (-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid
To a stirred mixture of 1- (1, 1-dimethylethyl) 6-methyl-4-hydroxy-2-methyl-1H-benzimidazole-1, 6-dicarboxylate (1.33g, 4.34mmol, step 3 in example 4), (+) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol (1.82g, 9.79mmol, step 8in example 2) and triphenylphosphine (2.28g, 8.69mmol) formulated in toluene (50mL) was added diisopropyl azodicarboxylate (DIAD) (1.76g, 8.70mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo. The residue was dissolved in methanol (20mL) and tetrahydrofuran (5mL), and 4M aqueous aluminum hydroxide (18.0mL, 90.0mmol) was added to the mixture at room temperature. After stirring at 80 ℃ for 1 hour, the reaction mixture was concentrated in vacuo. The residue was dissolved with water (200mL), acidified with 2M aqueous hydrochloric acid (50mL) and extracted with ethyl acetate (200 mL. times.3). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting from a gradient of ethyl acetate to ethyl acetate: methanol and 1 wt% acetic acid ═ 3: 1 only) to give the title compound (1.15g, 73%, > 99% ee) as a white solid.
1H NMR: the spectral data agree with the spectral data of the racemic compound (step 4in example 4).
Optical rotation: [ alpha ] to]D 24-78.7 ° (c-0.50, methanol).
Step 2: (-) -6- (azetidin-1-ylcarbonyl) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy]-2-methyl-1H-benzimidazole
The title compound (132mg, 79%) was prepared as a white solid from (-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-1H-benzimidazole-6-carboxylic acid (150mg, step 1) and azetidine hydrochloride (117mg, 1.25mmol) according to the same method as in step 5 of example 1.
1H NMR(CDCl3270MHz) δ: 7.40(s, 1H), 7.20(s, 1H), 6.42-6.25(m, 2H), 5.87-5.62(m, 1H), 4.46-3.94(m, 6H), 2.51(s, 3H), 2.42-2.19(m, 3H), 2.19-1.78(m, 1H) ppm (no-NH observed).
MS(ESI)m/z：400(M+H)+，398(M-H)-。
Optical rotation: [ alpha ] to]D 24-98.0 ° (c ═ 1.00, methanol).
The following examples 23 and 24 were prepared from (-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-1H-benzimidazole-6-carboxylic acid (step 1 in example 22) and the corresponding various amines according to the procedure described in step 5 of example 1.
The following example 25 was prepared according to the procedure described in example 1.
All publications, including but not limited to published patents, patent applications, and journal articles cited in this application, are each incorporated by reference herein in their entirety.
While the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It will be understood that various modifications may be made without departing from the spirit of the invention. Accordingly, the invention is not to be restricted except in light of the following claims.

Claims (8)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein;
-A-B-represents-O-CH2-、-S-CH2-、-CH2-O-or-CH2-S-；
X represents an oxygen atom or NH;
R1represents unsubstituted or independently selected from hydroxy and C through 1 to 21-C6C substituted by substituents of alkoxy1-C6An alkyl group;
R2and R3Independently represents a hydrogen atom, C1-C6Alkyl radical, said C1-C6The alkyl group being unsubstituted or independently selected from halogen atom, hydroxy group, C through 1 to 31-C6Alkoxy, amino, C1-C6Alkylamino and di (C)1-C6Alkyl) amino substituted; or R2And R3Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclic group which is unsubstituted or selected from hydroxy, C1-C6Alkyl radical, C1-C6Acyl and hydroxy-C1-C6A heterocyclic group substituted with a substituent of an alkyl group;
R4、R5、R6and R7Independently represent a hydrogen atom, a halogen atom, a hydroxyl group, C1-C6Alkyl or C1-C6An alkoxy group; and
R8represents a hydrogen atom, a hydroxyl group or C1-C6An alkoxy group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom;
R2and R3Independently is C1-C6Alkyl radical, said C1-C6The alkyl group being unsubstituted or independently selected from halogen atom, hydroxy group, C through 1 to 31-C6Alkoxy and di (C)1-C6Alkyl) amino substituted; or R2And R3Together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperazinyl, or morpholino group, said azetidinyl, pyrrolidinyl, piperazinyl, and morpholino group being unsubstituted or selected from hydroxy, C1-C6Alkyl radical, C1-C6Acyl and hydroxy-C1-C6Alkyl substituents.
R4、R5、R6And R7Independently a hydrogen atom, a halogen atom or C1-C6An alkyl group; and
R8is a hydrogen atom.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein-A-B-is-O-CH2-or-CH2-O-；
X is an oxygen atom;
R1is C1-C6An alkyl group;
R2and R3Independently C unsubstituted or substituted with 1 to 3 substituents1-C6Alkyl, said substituents being selected from the group consisting of hydroxy and C1-C6An alkoxy group; or R2And R3Together with the nitrogen atom to which they are attached form an unsubstituted or substituted radical selected from hydroxy, C1-C6Alkyl and hydroxy-C1-C6Pyrrolidinyl substituted with a substituent for alkyl;
R4、R5、R6and R7Independently a hydrogen atom, a halogen atom or C1-C6An alkyl group; and
R8is a hydrogen atom.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(-) -4- [ ((4S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
(-) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
(-) -4- [ (5-fluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, N, 2-trimethyl-1H-benzimidazole-6-carboxamide.
6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. Use of a therapeutically effective amount of a compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 5in the manufacture of a medicament for the treatment of a condition mediated by acid pump inhibitory activity in a mammalian subject, including a human.
8. The use as claimed in claim 7, wherein the condition is gastrointestinal disease, gastroesophageal reflux disease GERD, laryngopharyngeal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, infection by 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.
HK09103724.8A 2005-12-19 2006-12-06 Chromane substituted benzimidazoles and their use as acid pump inhibitors HK1125368B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US75218105P 2005-12-19 2005-12-19
US60/752,181 2005-12-19
US80294406P 2006-05-23 2006-05-23
US60/802,944 2006-05-23
PCT/IB2006/003605 WO2007072146A1 (en) 2005-12-19 2006-12-06 Chromane substituted benzimidazoles and their use as acid pump inhibitors

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HK1125368A1 HK1125368A1 (en) 2009-08-07
HK1125368B true HK1125368B (en) 2012-01-06

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