WO2008059373A1 - Dérivés d'imidazo [1,2-a] pyrazine et leur utilisation comme antagonistes de la pompe à protons - Google Patents

Dérivés d'imidazo [1,2-a] pyrazine et leur utilisation comme antagonistes de la pompe à protons Download PDF

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WO2008059373A1
WO2008059373A1 PCT/IB2007/003835 IB2007003835W WO2008059373A1 WO 2008059373 A1 WO2008059373 A1 WO 2008059373A1 IB 2007003835 W IB2007003835 W IB 2007003835W WO 2008059373 A1 WO2008059373 A1 WO 2008059373A1
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group
reaction
alkyl group
compound
hydroxy
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PCT/IB2007/003835
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Spanish (es)
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Hirohisa Shimokawa
Tatsuya Yamagishi
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Raqualia Pharma Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • This invention relates to imidazopyrazine derivatives. These compounds have selective acid pump inhibitory activity.
  • the present invention also relates to a pharmaceutical composition, method of treatment and use, comprising the above derivatives for the treatment of disease conditions mediated by acid pump modulating activity; in particular acid pump inhibitory activity.
  • PPIs proton pump inhibitors
  • acid pump antagonists inhibit acid secretion via reversible potassium-competitive inhibition of H + /K + -ATPase.
  • SCH28080 is one of such reversible inhibitors and has been studied extensively.
  • acid pump antagonists are found to be useful for the treatment of a variety of diseases, including gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, cancer, heartburn, nausea, esophagitis, dysphagia, hypersalivation, airway disorders or asthma (hereinafter, referred as "APA Diseases", Kiljander, Toni O, American Journal of Medicine, 2003, 115 (Suppl. 3A), 65S-71 S.).
  • APA Diseases Kiljander, Toni O, American Journal of Medicine, 2003, 115 (Suppl. 3A), 65S-71 S.
  • WO04/074289 discloses compounds reported to be acid pump antagonists. They refer to certain compounds having imidazo[1 ,2-a]pyrazine structure.
  • acid pump antagonists that are good drug candidates and address unmet needs by PPIs for treating diseases.
  • preferred compounds should bind potently to the acid pump whilst showing little affinity for other receptors and show functional activity as inhibitors of acid-secretion in stomach. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic.
  • the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • the new class of compounds having a chromane moiety and imidazo[1 ,2-a]pyrazine structure showed acid pump inhibitory activity and favorable properties as drug candidates, and thus are useful for the treatment of disease conditions 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, wherein:
  • -A-B- represents -0-CH 2 -, -CH 2 -O-; -S-CH 2 -, or -CH 2 -S-;
  • R 1 represents a hydrogen atom or a d-C 6 alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 2 represents a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 3 and R 4 independently represent a C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group, said C 1 -C 6 alkyl group and said C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group and a C 3 -C 7 cycloalkyl group; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 4 to
  • R 5 , R 6 , R 7 and R 8 independently represent a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound. Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, further comprising other pharmacologically active agent(s)..
  • the present invention provides a method for the treatment of a condition mediated by acid pump modulating activity in a mammalian subject including a human, which comprises 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 modulating activity include, but are not limited to,
  • 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.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in medicine.
  • 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 diseases selected from APA Diseases.
  • the compounds of the present invention may show good acid pump inhibitory activity, less toxicity, good absorption, good distribution, good solubility, less protein binding affinity other than acid pump, less drug-drug interaction and good metabolic stability.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 and R 8 are the C 1 -C 6 alkyl group
  • this C 1 -C 6 alkyl group may be a straight or branched chain group having one to six 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.
  • C 1 -C 2 alkyl is more preferred; methyl is more preferred.
  • R 3 , R 4 and the substituent of R 3 and R 4 are the C 3 -C 7 cycloalkyl group
  • C 3 -C 5 cycloalkyl group is preferred; cyclopropyl is more preferred.
  • substituent of R 3 , R 4 and the 4 to 7 membered heterocyclic group are the C 1 -C 6 alkoxy group
  • examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • a C 1 -C 4 alkoxy is preferred; a C 1 -C 2 alkoxy is preferred; methoxy is more preferred.
  • this 4 to 7 membered heterocyclic group represents a saturated heterocyclic group having three to six ring atoms selected from carbon atom, nitrogen atom, sulfur atom and oxygen atom other than said nitrogen atom, and examplesinclude, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pipehdyl, piperazinyl, hexahydroazepinyl, hexahydrodiazepinyl, morpholino, thiomorpholino and homomorpholino. Of these, azetidinyl, pyrrolidinyl, morpholino and homomorpholino are preferred; morpholino is more preferred.
  • substituent of the 4 to 7 membered heterocyclic group is a hydroxy-CrC ⁇ alkyl group
  • examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-1-methylpropyl, 5-hydroxypentyl and 6-hydroxyhexyl.
  • hydroxy-d-Cs alkyl is preferred; hydroxymethyl is more preferred.
  • R 5 , R 6 , R 7 , R 8 and the substituent of R 3 and R 4 are the halogen atom, it may be a fluorine, chlorine, bromine or iodine atom. Of these, a fluorine atom and a chlorine atom are preferred.
  • moiety convertible into a hydroxy group in vivo means a moiety transformable in vivo by e.g. hydrolysis and/or by an enzyme, e.g. an esterase, into a hydroxy group.
  • the moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo.
  • moieties have known to those skilled in the art as 'pro-moieties' as described, for example, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).
  • Preferred moieties convertible in vivo into a hydroxy group are e.g. a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl-carbonyl-oxy group and a C 1 -C 6 alkyl-carbonyl-oxy-methyl-oxy group.
  • treating refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • Preferred classes of compounds of the present invention are those compounds of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, in which:
  • (a) -A-B- is -0-CH 2 - or -CH 2 -O-;
  • R 1 is a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 substituent selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 1 is a hydroxy-CrC ⁇ alkyl group, C 1 -C 6 8IkOXy-C 1 -C 6 alkyl group, C 1 -C 6 alkyl-carbonyl-oxy-Ci-C ⁇ alkyl group or a C 1 -C 6 alkyl group;
  • R 1 is a hydroxy-C ⁇ Ce alkyl group or a C 1 -C 6 alkyl group
  • R 1 is a hydroxymethyl group or a C 1 -C 6 alkyl group
  • R 1 is a hydroxymethyl group or a methyl group
  • R 1 is a hydroxymethyl group
  • R 2 is a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 substituent selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 2 is a hydroxy-C r C 6 alkyl group, C 1 -C 6 8IkOXy-C 1 -C 6 alkyl group, C 1 -C 6 alkyl group or a C 1 -C 6 alkyl group;
  • (k) R 2 is a hydroxy-C r C 6 alkyl group or a C 1 -C 6 alkyl group;
  • R 2 is a hydroxymethyl group or a C 1 -C 6 alkyl group;
  • (m) R 2 is a C 1 -C 2 alkyl group;
  • R 2 is a methyl group;
  • R 3 is a C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group, said C 1 -C 6 alkyl group and said C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a CrC 6 alkoxy group and a C 3 -C 7 cycloalkyl group;
  • R 3 is a C 1 -C 6 alkyl group;
  • (q) R 3 is a C 1 -C 2 alkyl group;
  • (r) R 3 is a methyl group;
  • (s) R 4 is a C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group, said C 1 -C 6 alkyl group and said C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group and a C 3 -C 7 cycloalkyl group;
  • (t) R 4 is a C 1 -C 6 alkyl group;
  • (u) R 4 is a C 1 -C 2 alkyl group;
  • (v) R 4 is a methyl group;
  • R 3 and R 4 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a morpholino group or a homomorpholino group, said azetidinyl group, said pyrrolidinyl group, said morpholino group and said homomorpholino group being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group and a hydroxy-C r C 6 alkyl group;
  • R 3 and R 4 taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group, a morpholino group or a homomorpholino group, said pyrrolidinyl group, said morpholino group and said homomorpholino group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group and a hydroxy-CrC ⁇ alkyl group;
  • R 5 , R 6 , R 7 and R 8 are independently a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group;
  • R 5 and R 7 are independently a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group;
  • (aa)R 5 and R 7 are independently a hydrogen atom, a halogen atom or a C 1 -C 2 alkyl group;
  • R 5 and R 7 are independently a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group;
  • R 6 and R 8 are independently a hydrogen atom or a halogen atom.
  • (dd)R 6 and R 8 are independently a hydrogen atom, a fluorine atom or a chlorine atom.
  • (ee)R 5 is a hydrogen atom, a fluorine atom or a methyl group;
  • R 6 is a hydrogen atom;
  • (gg)R 7 is a hydrogen atom or a fluorine atom
  • (hh)R 8 is a hydrogen atom
  • Preferred compounds of the present invention are those compounds of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, in which:
  • (A) -A-B- is -0-CH 2 - or -CH 2 -O-;
  • R 1 and R 2 are independently a hydroxy-d-C 6 alkyl group, C 1 -C 6
  • R 3 and R 4 are independently a C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group, said CrC 6 alkyl group and said
  • C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group and a
  • R 3 and R 4 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a morpholino group or a homomorpholino group, said azetidinyl group, said pyrrolidinyl group, said morpholino group and said homomorpholino group being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group and a hydroxy-CrC 6 alkyl group; and R 5 , R 6 , R 7 and R 8 are independently a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group; (B) -A-B- is -CH 2 -O-; R 1 and R 2 are independently a hydroxymethyl group or a C 1
  • (C) -A-B- is -0-CH 2 - or -CH 2 -O-;
  • R 1 is a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 substituent selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 2 is a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 substituent selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 3 and R 4 are independently a C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group, said C 1 -C 6 alkyl group and said C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1
  • R 6 , R 7 and R 8 are independently a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group
  • (D) -A-B- is -0-CH 2 - or -CH 2 -O-;
  • R 1 is a hydroxymethyl group or a C 1 -C 6 alkyl group;
  • R 2 is a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 substituent selected from the group consisting of a hydroxy group or a moiety convertible into a hydroxy group in vivo;
  • R 3 and R 4 are independently a
  • C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group said C 1 -C 6 alkyl group and said C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group and a C 3 -C 7 cycloalkyl group; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a morpholino group or a homomorpholino group, said azetidinyl group, said pyrrolidinyl group, said morpholino group and said homomorpholino group being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a Ci-C 6 alkyl group, a
  • the compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.
  • compositions of a compound of formula (I) include the acid addition salts (including disalts) thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • a pharmaceutically acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Pharmaceutically acceptable salts of the compounds of the invention include both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • solvates in accordance with the invention include hydrates and' solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, cVacetone,
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • the compounds of formula (I) may exist in one or more crystalline forms. These 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 can exist as two or more stereoisomers.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled 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.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled 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 and preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. All of the compounds of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the examples section and the preparations section, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein.
  • the compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following Method A.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A and B in the following methods are as defined above. All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A and B are each as defined above;
  • Hal is a halogen atom, preferably a bromine atom;
  • AIk is a C 1 -C 6 alkyl group, preferably a methyl group;
  • R 1a is R 1 as defined above or R 1 wherein hydroxy group may be protected by a hydroxy-protecting group;
  • R 2a is R 2 as defined above or R 2 wherein hydroxy group may be protected by a hydroxy-protecting group;
  • R 3a is R 3 as defined above or R 3 wherein hydroxy group may be protected by a hydroxy-protecting group;
  • R 4a is R 4 as defined above or R 4 wherein hydroxy group may be protected by a hydroxy-protecting group.
  • hydroxy-protecting groups signifies a protecting group capable of being cleaved by various means to yield a hydroxy group, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such hydroxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). Such as for example, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, W-C 1 -C 4 alkylsilyl or tri-C r C 4 alkylarylsilyl groups, and C 1 -C 4 alkoxy- C 1 -C 4 alkyl groups.
  • Suitable hydroxy-protecting groups include benzyl, 4-methoxybenzyl and tert-butyldimethylsilyl.
  • the compound of formula (IV) is prepared by nucleophilic substitution of the compound of formula (II), which is commercially available or may be prepared by the methods as described in J. Med. Chem., 1983, 26, 357. with the compound of formula (III), which is commercially available or may be prepared by the methods described in the following Method B and C.
  • the reaction is carried out under the same conditions as described in WO2005/004607 and WO2004/074289.
  • the reaction is normally and preferably effected in the presence or absence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: ethers, such as tetrahydrofuran (THF), ethylene glycol dimethyl ether and dioxane; amides, such as ⁇ /, ⁇ /-dimethylformamide (DMF), ⁇ /, ⁇ /-dimethylacetamide (DMA) and ⁇ /-methyl-2-pyrrolidinone (NMP); nitriles, such as acetonitrile; alcohols, such as 2-methyl-2-propanol, 1-butanol, 1-propanol, 2-propanol, ethanol and methanol; and sulfoxide, such as dimethyl sulfoxide (DMSO). Of these solvents, amides and nitriles are preferred.
  • ethers such as tetrahydrofuran (THF), ethylene glycol dimethyl ether and dioxane
  • amides such as ⁇ /, ⁇ /-dimethylformamide (DMF), ⁇ /, ⁇ /-dimethylacet
  • ⁇ /-methyl-2-pyrrolidinone and acetonitrile are more preferred.
  • a base can accelerate the reaction.
  • the reaction may be carried out with or without a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • Examples of such bases include: alkali metal alkoxides, such as potassium ferf-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate (Na 2 CO 3 ), cesium carbonate and potassium carbonate (K 2 CO 3 ); alkali metal hydrogencarbonates, such as sodium hydrogencarbonate (NaHCO 3 ) and potassium hydrogencarbonate; and organic amines, such as triethylamine, tripropylamine, tributylamine, dicyclohexylamine, ⁇ /, ⁇ /-diisopropylethylamine, ⁇ /-methylpiperidine, ⁇ /-methylmorpholine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN). Of these, triethylamine is preferred.
  • alkali metal alkoxides such as potassium ferf-butoxide
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 250 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 72 hours will usually suffice.
  • the reaction at a temperature may be from about 50 °C to about 250 "C.and the reaction time from about 5 minutes to about 12 hours will usually suffice.
  • the compound of formula (Vl) is prepared by cyclization of the compound of formula (IV) and the compound of formula (V), which may be commercially available or may be prepared by the methods described in Synthetic communications., 1994, 24, 2557, Synthetic communications., 1995, 25, 3923, Synthetic communications., 1995, 25, 1045, Tetrahedron Letters., 1993, 34, 1733. or Tetrahedron Letters., 1999, 40, 2231.
  • the reaction is normally and preferably effected in the presence or absence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone and hexamethylphosphoric triamide; amines, such as ⁇ /-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, ⁇ /-methylpiperidine, pyridine, 4-pyrrolidinopyridine, ⁇ /, ⁇ /-dimethyl
  • the reaction may be carried out in the presence or absence of reagent, such as an acid or a base.
  • reagent such as an acid or a base.
  • acids or bases there is likewise no particular restriction on the nature of the acids or bases used, and any acid or base commonly used in reactions of this type may equally be used here.
  • acids include: acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid and p-toluenesulfonic acid. Of these, p-toluenesulfonic acid or the absence of acid is preferred.
  • bases examples include: alkali metal hydrogencarbonates, such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal carbonates, such as sodium carbonate and potassium carbonate; and amines, such as triethylamine, pyridine and diisopropylethylamine. Of these, triethylamine or the absence of base is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 0 C to about 180 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 120 hours, will usually suffice.
  • Step A3 the compound of formula (VII) is prepared by the ester formation reaction of the compound of formula (Vl) with alcohol under the carbon monoxide atmosphere.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone, and hexamethylphosphohc triamide; nitriles, such as acetonitrile and benzonitrile; and ketones, such as acetone and diethylketone. Of these solvents, ⁇ /, ⁇ /-dimethylformamide is preferred.
  • the reaction is carried out in the presence of a palladium catalyst.
  • a palladium catalyst there is no particular restriction on the nature of the palladium catalyst to be employed, and any palladium catalyst commonly used in reactions of this type may equally be used here.
  • palladium catalysts include: palladium metal, palladium-carbon, palladium (II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1 ,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(thphenylphosphine) palladium, dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium, or a catalyst produced in solution by adding a ligand into the reaction solution of these.
  • the ligand added into the reaction solution may be a phosphoric ligand such as 1 ,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl) ether, 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthol, 1 ,3-bis(diphenylphosphino)propane, 1 ,4-bis(diphenylphosphino)butane, tri-o-toluylphosphine, triphenylphosphine, 2-diphenylphosphino-2'-methoxy-1 ,1'-binaphthyl or 2,2- bis
  • a phosphoric ligand such as 1 ,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl) ether, 2,2'-bis(diphenylphosphino)-1
  • the above palladium catalysts are preferably tetrakis(triphenylphosphine) palladium and palladium (II) acetate - triphenylphosphine.
  • the reaction may be carried out with or without a base.
  • bases there is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • bases include: amines, such as ⁇ /-methylmorpholine, triethylamine, diisopropylethylamine, ⁇ /-methylpiperidine and pyridine. Of these, triethylamine is preferred.
  • the reaction can take place over a wide range of temperatures, and the precise reaction ' temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 0 C to about 180 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction- is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 72 hours, will usually suffice. (Step A4)
  • the compound of formula (I) is prepared by (A4a1 ) hydrolysis of the compound of formula (VII), prepared as described in Step A3, followed by (A4a2) condensing reaction with the compound of formula (VIII) or (A4b) substituting the reaction of the compound of formula (VII) with the compound of formula (VIII). (A4a1 ) hydrolysis
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: ether, such as tetrahydrofuran and dioxane; amides, such as ⁇ /, ⁇ /-dimethylformamide; alcohols, such as ethanol and methanol; and water; or mixed solvents thereof. Of these solvents, methanol, tetrahydrofuran, and water are preferred.
  • the reaction is carried out in the presence of a base.
  • bases include: alkali metal hydroxides, such as lithium hydroxide (LiOH), sodium hydroxide (NaOH) and potassium hydroxide (KOH). Of these, sodium hydroxide is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 100 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 12 hours will usually suffice. (A4a2) condensing reaction
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, and 1 ,2-dichloroethane; ethers, such as tetrahydrofuran and dioxane; amides, such as ⁇ /, ⁇ /-dimethylformamide and ⁇ /, ⁇ /-dimethylacetamide; and nitriles, such as acetonitrile.
  • halogenated hydrocarbons and amides are preferred.
  • Dichloromethane and ⁇ /, ⁇ /-dimethylformamide are more preferred.
  • the reaction is carried out in the presence of a condensing agent.
  • a condensing agent There is likewise no particular restriction on the nature of the condensing agents used, and any condensing agents commonly used in reactions of this type may equally be used here.
  • condensing agents include: azodicarboxylic acid di-lower alkyl ester-triphenylphosphines, such as diethyl azodicarboxylate- triphenylphosphine; 2-halo-1 -lower alkyl pyridinium halides, such as 2-chloro-1 -methyl pyridinium iodide and 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP); diarylphosphorylazides, such as diphenylphosphorylazide (DPPA); chloroformates, such as ethyl chloroformate and isobutyl chloroformate; phosphorocyanidates, such as diethyl phosphorocyanidate (DEPC); imidazole derivatives, such as N, N'- carbonyldiimidazole (CDI); carbodiimide derivatives, such as ⁇ /, ⁇ /'-dicyclohexyl
  • Reagents such as 4-( ⁇ /, ⁇ /-dimethylamino)pyridine (DMAP), and ⁇ /-hydroxybenztriazole (HOBt), may be employed for this step. Of these, HOBt is preferred.
  • DMAP 4-( ⁇ /, ⁇ /-dimethylamino)pyridine
  • HOBt ⁇ /-hydroxybenztriazole
  • the reaction may be carried out with or without a base.
  • bases there is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • bases include: amines, such as ⁇ /-methylmorpholine, triethylamine, diisopropylethylamine, ⁇ /-methylpiperidine and pyridine. Of these, triethylamine and ⁇ /-methylmorpholine are preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 0 C to about 80 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours will usually suffice. (A4b) substituting reaction
  • the reaction can be carried out by heating the reactants in the neat amino compound or in an inert solvent under standard condition.
  • solvents such as ethylene glycol dimethyl ether, tetrahydrofuran and dioxane; amides, such as ⁇ /, ⁇ /-dimethylformamide and ⁇ /, ⁇ /-dimethylacetamide; nithles, such as acetonitrile; and alcohols such as 2-methyl-2-propanol, 1-butanol, 1-propanol, 2-propanol, ethanol and methanol. Of these solvents, ethers and alcohols are preferred. Tetrahydrofuran is more preferred.
  • the reaction may be carried out with or without a catalyst.
  • a catalyst there is likewise no particular restriction on the nature of the catalysts used, and any catalysts commonly used in reactions of this type may equally be used here. Examples of such catalysts include: sodium cyanide or potassium cyanide. Of these, sodium cyanide is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 40 °C to about 200 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours will usually suffice. (Deprotection of hydroxy-protecting group)
  • the deprotection reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include, but are not limited to: alcohol, such as methanol, ethanol or mixed solvents thereof.
  • the deprotection reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 100 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 24 hours, will usually suffice. (Introduction of hydroxymethyl) In the case of the compound of wherein R 1a is H and R 1 is hydroxymethyl, the following reaction will be carried out to yield a hydroxymethyl group of formula (I).
  • the hydroxymethyl reaction is carried out with formaldehyde, paraformaldehyde or 1 ,3,5-thoxane.
  • the reaction is carried out in the presence or absence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; 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, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and hexamethylphosphoric thamide; amines, such as ⁇ /-methylmorpholine, triethylamine, thpropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, ⁇ /-methylpiperidine, pyridine, 4-pyrroli
  • the reaction is carried out in the presence of reagent, such as an acid or a base.
  • reagent such as an acid or a base.
  • acids include: carboxylic acids, such as acetic acid and propionic acid; inorganic acids, such as hydrochloric acid and sulfuric acid; organic acids, such as p-toluenesulfonic acid and thfluoro acetic acid; and Lewis acids, such as BF 3 , AICI 3 , FeCI 3 , AgCI, ZnI 2 , Fe(NO 3 ) 3 , CF 3 SO 3 Si(CH 3 ) 3 , Yb(CF 3 SO 3 ) 3 and SnCI 4 .
  • acetic acid is preferred.
  • bases include: alkali metal acetates, such as lithium acetate, sodium acetate, potassium acetate and cesium acetate; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium f-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogen carbonate and potassium hydrogencarbonate; and amines, such as ⁇ /-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, ⁇ /-methylpipehdine, pyridine, 4-pyrrolidinopyridine, picoline, 4-( ⁇ /, ⁇ /-dimethylamino)pyridine, 2,6
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 0 C to about 250 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 72 hours will usually suffice. (Step A5)
  • the compound of formula (I) is prepared by the amidation of the compound of formula (Vl) with the compound of formula (VIII) under the carbon monoxide atmosphere.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /, ⁇ /-dimethylformamide, /V, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone, and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonithle; and ketones, such as acetone and diethylketone. Of these solvents, tetrahydrofuran is preferred.
  • the reaction is carried out in the presence of a palladium catalyst.
  • a palladium catalyst there is no particular restriction on the nature of the palladium catalyst to be employed, and any palladium catalyst commonly used in reactions of this type may equally be used here.
  • palladium catalysts include: palladium metal, palladium-carbon, palladium (II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1 ,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(thphenylphosphine) palladium, dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium, or a catalyst produced in solution by adding a ligand into the reaction solution of these.
  • the ligand added into the reaction solution may be a phosphoric ligand such as 1 ,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl) ether, 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthol,
  • the above palladium catalysts are preferably tetrakis(triphenylphosphine) palladium and palladium (II) acetate - triphenylphosphine.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 °C to about 120 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 72 hours, will usually suffice. (Deprotection of hydroxy-protecting group)
  • Hal is a halogen atom
  • R alk is a hydrogen atom or a Ci-C 6 alkyl group and the same shall apply hereinafter.
  • the compound of formula (XIII) is prepared by Michael reaction (B1a) of the compound of formula (IX) with the compound of formula (X), by alkylation reaction (B1 b) of the compound of formula (IX) with the compound of formula (Xl), or by coupling reaction (B1 c) of the compound of formula (IX) with the compound of formula (XII) followed by the hydrogenation (Bid).
  • Michael reaction (B1a) of the compound of formula (IX) with the compound of formula (X) by alkylation reaction (B1 b) of the compound of formula (IX) with the compound of formula (Xl), or by coupling reaction (B1 c) of the compound of formula (IX) with the compound of formula (XII) followed by the hydrogenation (Bid).
  • the compound of formula (IX), (X), (Xl) and (XII) are commercially available.
  • the reaction is normally and preferably effected in the presence or the absence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone, and hexamethylphosphohc thamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof. Of these, the reaction in the absence of solvent is preferred.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
  • amides such as formamide, ⁇ /, ⁇ /-dimethylform
  • the reaction is carried out in the presence of a base.
  • 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 fert-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; amines, such as ⁇ /-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, ⁇ /-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-( ⁇ /, ⁇ /-dimethylamino)pyridine, 2,
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 °C to about 120 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 48 hours, will usually suffice.
  • hydrolysis is carried out by adding an acid in a solvent to produce the compound of formula (XIII), and may be carried out in a usual hydrolysis condition.
  • 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 fert-butanol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diethoxymethane and dioxane; or mixed solvents thereof. It is preferably water.
  • reaction temperature varies depending on the starting compound, the reagent and the solvent, however, it is usually from 20 0 C to the reflux temperature.
  • reaction time varies depending on the starting compound, the reagent, the solvent and the reaction temperature, however, it is usually from 60 minutes to 24 hours.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone, and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, .2-propanol and butanol; nitriles, such as acetonitrile and benzonithle; sulfoxides, such as dimethyl sulfoxide and sulfolane; ketones, such as acetone and diethylketone; water; or mixed solvents thereof.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydr
  • the reaction is carried out in the presence of a base.
  • 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 ferf-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 diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.
  • sodium hydroxide is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 0 C to about 100 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 24 hours, will usually suffice. (B1c) coupling reaction
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and hexamethylphosphoric triamide; amines, such as ⁇ /-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, ⁇ /-methylpiperidine, pyridine, 4-pyrrolidinopyridine, ⁇ /, ⁇ /-dimethylaniline and ⁇ /, ⁇ /-diethylaniline; alcohols, such as
  • acetonitrile and tetrahydrofuran are preferred.
  • the reaction is carried out in the presence of a base.
  • a base There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • 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 f-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; amines, such as ⁇ /-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, ⁇ /-methylpiperidine, pyridine, 4-( ⁇ /, ⁇ /-dimethylamino)pyridine and DBU; and tetraalkylammonium fluorides, such as tetra-n-butylammonium fluoride (TBAF).
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 100 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 72 hours will usually suffice.
  • (Bid) hydrogenation The reaction is normally and preferably effected in the presence of solvent.
  • solvents there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: aromatic hydrocarbons, such as toluene; alcohols, such as methanol and ethanol; esters, such as ethyl acetate; and carboxylic acids, such as acetic acid. Of these solvents, alcohols and carboxylic acids are preferred.
  • the reaction is carried out under hydrogen atmosphere and in the presence of a catalyst.
  • a catalyst there is likewise no particular restriction on the nature of the catalysts used, and any catalysts commonly used in reaction of this type may equally be used here. Examples of such catalysts include: palladium on carbon, palladium hydroxide, platinum and Raney nickel. Of these catalysts, palladium on carbon is preferred.
  • hydrodehalogenation of substituent "Hal” in Reaction Scheme B
  • the reaction may be carried out in the presence of an additive, which reduces activity of the catalyst employed.
  • the additive is selected from substances known to show poisonous effect in some extent against the catalyst.
  • additives examples include: halide ion source, such as tetra-n-butylammonium bromide and sodium bromide; and sulfoxides, such as dimethyl sulfoxide. Of these, sodium bromide is preferred.
  • the reaction can take place under a wide range of pressures, and precise pressure is not critical to the invention.
  • the preferred pressure will depend upon such factors as the nature of the starting materials, and the solvent. However, in general, it is convenient to carry out the reaction at a pressure of from 1 atm to about 10 atm.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 0 C to about 50 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the pressure of hydrogen, the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred condition outlined above, a period of from about 30 minutes to about 12 hours will usually suffice. (Step B2)
  • the compound of formula (XIV) is prepared by Friedel Crafts reaction (B2a) after halogenation (B2b) or by cyclization (B2c) of the compound of formula (XIII) when R alk is a hydrogen atom, or by acidic cyclization (B2d) of the compound of formula (XIII) when R alk is a C 1 -C 6 alkyl group.
  • B2a Friedel Crafts reaction
  • the reaction is normally and preferably effected in the presence or the absence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, ⁇ provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, 1 ,1 ,2,2-tetrachloroethane and 1 ,2-dichloroethane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; carbon disulfide; or mixed solvents thereof. Of these, dichloromethane or carbon disulfide is preferred.
  • the reaction is carried out in the presence of an acid.
  • an acid there is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here.
  • examples of such acids include: Lewis acids, such as BF 3 , AICI 3 , AIBr 3 , FeCI 3 , AgCI, ZnI 2 , ZnCI 2 , Fe(NO 3 ) 3 , CF 3 SO 3 Si(CHs) 3 , Yb(CF 3 SO 3 ) 3 and SnCI 4 .
  • Lewis acids such as BF 3 , AICI 3 , AIBr 3 , FeCI 3 , AgCI, ZnI 2 , ZnCI 2 , Fe(NO 3 ) 3 , CF 3 SO 3 Si(CHs) 3 , Yb(CF 3 SO 3 ) 3 and SnCI 4 .
  • AICI 3 is preferred.
  • reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 0 C to about 150 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours, will usually suffice. (B2b) halogenation
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and hexamethylphosphoric triamide; and nitriles, such as acetonitrile and benzonitrile; or mixed solvents thereof. Of these, 1 ,2-dichloroethane or dichloromethane is preferred.
  • the reaction is carried out in the presence of a halogenating agent.
  • a halogenating agent there is likewise no particular restriction on the nature of the halogenating agents used, and any halogenating agent commonly used in reactions of this type may equally be used here.
  • halogenating agents include: thionyl chloride, oxalyl chloride and phosphorus oxychloride. Of these, thionyl chloride is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 80 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 12 hours will usually suffice. (B2c) cyclization
  • the reaction is normally and preferably effected in the presence or absence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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; and amides, such as formamide, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone, and hexamethylphosphoric triamide; or mixed solvents thereof.
  • dichloromethane or the absence of solvent is preferred.
  • the reaction is carried out in the presence of an acid.
  • an acid there is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here.
  • acids include: acids, such as hydrochloric acid, sulfuric acid, or hydrobromic acid; acids, such as trifluoro acetic acid, or polyphosphoric acid. Of these, polyphosphohc acid is preferred.
  • reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 0 C to about 150 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours, will usually suffice.
  • (B2d) acidic cyclization The reaction is normally and preferably effected in the presence of an acid, which functions as solvent and reagent.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 150 °C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours, will usually suffice. (Step B3)
  • the compound (XV) is prepared by reduction of the carbonyl group of the compound of formula (XIV).
  • the resulting compound of formula (XV) may be obtained as an optically active compound.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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; sulfoxides, such as dimethyl sulfoxide and sulfolane; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; or mixed solvents thereof. Of these, methanol is preferred.
  • the reaction is carried out in the presence of a reducing agent.
  • reducing agents used, and any reducing agent commonly used in reactions of this type may equally be used here.
  • reducing agents include: metal borohydrides, such as sodium borohydride, lithium borohydhde and sodium cyanoborohydhde; hydride compounds, such as lithium aluminum hydride and diisobutyl aluminum hydride; and borane reagents, such as boran-tetrahydrofuran complex, boran-dimethyl sulfide complex (BMS) and 9-borabicyclo[3,3,1]nonane (9-BBN).
  • metal borohydrides such as sodium borohydride, lithium borohydhde and sodium cyanoborohydhde
  • hydride compounds such as lithium aluminum hydride and diisobutyl aluminum hydride
  • borane reagents such as boran-tetrahydrofuran complex, boran-dimethyl sulfide complex (BMS) and 9-borabicyclo[3,
  • optically active reducing agent there is likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type may equally be used here.
  • reducing agents include: the combination of (S) or (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1 ,2-c][1 ,3,2]oxazaborole and BMS; the combination of the optically active ruthenium catalyst and hydrogen gas.
  • optically active ruthenium catalyst examples include; dichloro[(S)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl][(S)-1 ,1'-bis(p-methoxyphenyl)-2-isopropyl-1 ,2-et hanediamine]ruthenium(ll), dichloro[(R)-2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl][(R)-1 ,1 '-bis(p-methoxyphenyl)-2-isopropyl-1 ,2-et hanediamine]ruthenium(ll).
  • the ruthenium catalyst is used in the presence of a catalytic amount of potassium fert-butoxide. Of these, the combination of (S) or
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about -78 °C to about 80 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 8 hours will usually suffice.
  • the compound of formula (XVI) is prepared by the azide displacement of the hydroxy group of the compound of formula (XV).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, ⁇ /, ⁇ /-dimethylformamide, ⁇ /./V-dimethylacetamide, /V-methyl-2-pyrrolidinone and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; and ketones, such as acetone and diethylketone; Of these solvents, tetrahydrofuran is preferred.
  • aliphatic hydrocarbons such as hexane, heptane and petroleum
  • the reaction is carried out in the presence of an azide agent such as diphenylphosphorylazide (DPPA).
  • an azide agent such as diphenylphosphorylazide (DPPA).
  • a base can accelerate the reaction.
  • the reaction may be carried out with or without a base.
  • bases include: organic amines, such as triethylamine, tripropylamine, tributylamine, dicyclohexylamine, ⁇ /, ⁇ /-diisopropylethylamine, ⁇ /-methylpipehdine, ⁇ /-methylmorpholine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN). Of these, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about -20 0 C to about 150 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 24 hours will usually suffice. (Step B5)
  • the compound (Ilia) is prepared by the hydrogenation of the azide moiety of the compound of formula (XVI).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; esters, such as ethyl acetate; amides, such as formamide, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone and hexamethylphosphoric triamide; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, methanol is preferred.
  • the reaction is carried out under hydrogen atmosphere and in the presence of a catalyst.
  • a catalyst there is likewise no particular restriction on the nature of the catalysts used, and any catalysts commonly used in reaction of this type may equally be used here. Examples of such catalysts include: palladium on carbon, palladium hydroxide, platinum and Raney nickel. Of these catalysts, palladium on carbon is preferred.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 0 C to about 80 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 8 hours will usually suffice.
  • the compound of formula (XVIII) is prepared by halogenation of the methyl group of the compound of formula (XVII).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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; and sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof. Of these, carbon tetrachloride or 1 ,2-dichloroethane is preferred. The reaction is carried out in the presence of a halogenating agent.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1 ,2-dichloroethane
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and diox
  • halogenating agents used, and any halogenating agent commonly used in reactions of this type may equally be used here.
  • halogenating agents include: succinimides, such as ⁇ /-bromosuccinimide (NBS), /V-chlorosuccinimide (NCS); bromine. Of these, NBS is preferred.
  • Reagents such as benzoyl peroxide and 2,2'-azobis(isobutyronitrile) (AIBN) may be employed for this step. Of these, benzoyl peroxide is preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 100 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours will usually suffice. (Step C2)
  • the compound of formula (XX) is prepared by ether formation reaction of the compound of formula (XVIII) with the compound of formula (XIX), which is commercially available.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • 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, ⁇ /,/V-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonithle; and sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
  • aromatic hydrocarbons such as benzene, toluene and nitrobenzene
  • amides such as formamide, ⁇ /,/V-dimethylformamide, ⁇ /, ⁇
  • the reaction is carried out in the presence of a base.
  • 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 terf-butoxide; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 20 °C to about 150 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 48 hours, will usually suffice. (Step C3)
  • the compound of formula (XXI) is prepared by cyclization (Dieckmann Condensation) of the compound of formula (XX).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene and nitrobenzene; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; or mixed solvents thereof. Of these, toluene is preferred.
  • the reaction is carried out in the presence of a base.
  • bases include: alkali metal, such as lithium and sodium; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium terf-butoxide; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, potassium fert-butoxide and sodium are preferred.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0 °C to about 150 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours, will usually suffice.
  • Step C4 the compound of formula (XXVI) is prepared by decarboxylation of the compound of formula (XXI).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide, ⁇ /-methyl-2-pyrrolidinone, and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; and water; or mixed solvents thereof.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
  • amides such as formamide, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇
  • the reaction may be carried out in the presence of a base.
  • 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. Of these, sodium hydroxide is preferred.
  • the reaction may be carried out in the presence of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here.
  • Such acids include: carboxylic acids, such as acetic acid or propionic acid; and acids, such as hydrochloric acid, sulfuric acid, or hydrobromic acid. Of these, hydrochloric acid is preferred.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, Jn general, it is convenient to carry out the reaction at a temperature of from about 20 °C to about 120 °C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 48 hours, will usually suffice.
  • the compound of formula (XXVII) is prepared by reduction of the compound of formula (XXVI).
  • the reaction may be carried out under the same condition as described in Step B3 of
  • the compound of formula (XXVIII) is prepared by the azide displacement of the hydroxy group of the compound of formula (XXVII).
  • the reaction may be carried out under the same condition as described in Step B4 of Method B.
  • reaction may be carried out under the same condition as described in Step B5 of Method B.
  • Step C8 the compound of formula (XXIV) is prepared by ether formation reaction of the compound of formula (XXII) with the compound of formula (XXIII), which is commercially available.
  • the reaction may be carried out under the same condition as described in Step C2 of Method C.
  • the compound of formula (XXV) is prepared by hydrolysis of the compound of formula (XXIV).
  • the reaction may be carried out under the same condition as described in Step A4 of Method A.
  • the compound of formula (XVI) is prepared by cyclization (C10a) of the compound of formula (XXV) or by formation of acid halide (C10b) followed by Friedel Crafts reaction (C10c) of the compound of formula (XXV).
  • the reaction may be carried out under the same condition as described in Step B2 of Method B.
  • the preparation/isolation of individual enantiomers can be prepared by conventional techniques, such as chiral synthesis from a suitable optically pure precursor which may be prepared according to the Method C or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC) and supercritical fluid chromatography (SFC).
  • HPLC high-pressure liquid chromatography
  • SFC supercritical fluid chromatography
  • a method of optical resolution of a racemate can be appropriately selected from conventional procedures, for example, preferential crystallization, or resolution of diastereomeric salts between a basic moiety of the compound of formula (I) and a suitable optically active acid such as tartaric acid.
  • the compounds of formula (I), and the intermediates in the above-mentioned preparation methods can be isolated and purified by conventional procedures, such as distillation, recrystallization or chromatographic purification.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. s
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as, for example, tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include, for example, suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one . or more emulsifying agents and/or suspending agents. Liquid formulations ' may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents. H (6), 981-986 by Liang and Chen (2001 ).
  • the drug may make up from about 1 wt% to about 80 wt% of the dosage form, more typically from about 5 wt% to about 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from about 1 wt% to about 25 wt%, preferably from about 5 wt% to about 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface-active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from about 0.25 wt% to about 10 wt%, preferably from about 0.5 wt% to about 3 wt% of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line. 25(2), 1-14 (2001 ). The use of chewing gum to achieve controlled release is described in WO00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from about 3 to about 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • a suitable propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • comminuting method such as spiral jet milling, fluid 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 for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from about 1 ⁇ g to about 20mg of the compound of the invention per actuation and the actuation volume may vary from about 1 ⁇ l to about 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from about 1 to about 100 ⁇ g of the compound of formula (I).
  • the overall daily dose will typically be in the range about 50 ⁇ g to about 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in. WO91/11172, WO94/02518 and WO98/55148.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range of about 0.05 mg to about 500 mg depending, of course, on the mode of administration, preferred in the range of about 0.1 mg to about 400 mg and more preferred in the range of about 0.5 mg to about 300 mg.
  • oral administration may require a total daily dose of from about 1 mg to about 300 mg, while an intravenous dose may only require from about 0.5 mg to about 100 mg.
  • the total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65 kg to about
  • the physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • a compound of the invention exhibits acid pump inhibitory activity.
  • An acid pump antagonist of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of gastroesophageal reflux disease.
  • an acid pump antagonist particularly a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from: (i) histamine H 2 receptor antagonists, e.g. ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine;
  • proton pump inhibitors e.g. omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole
  • oral antacid mixtures e.g. Maalox ® , Aludrox ® and Gaviscon ® ;
  • mucosal protective agents e.g. polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper and plaunotol;
  • anti-gastric agents e.g. Anti-gastrin vaccine, itriglumide and Z-360;
  • 5-HT 3 antagonists e.g. dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron;
  • 5-HT 4 agonists e.g. tegaserod, mosapride, cinitapride and oxtriptane;
  • laxatives e.g. Trifyba ® , Fybogel ® , Konsyl ® , Isogel ® , Regulan ® , Celevac ® and Normacol ® ;
  • GABA 8 agonists e.g. baclofen and AZD-3355;
  • GABAB antagonists e.g. GAS-360 and SGS-742
  • calcium channel blockers e.g. aranidipine, lacidipine, falodipine, azelnidipine, clinidipine, lomerizine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine and fasudil;
  • dopamine antagonists e.g. metoclopramide, domperidone and levosulpiride
  • NK Tachykinin
  • N K-3, NK-2 and NK-1 antagonists e.g.
  • Helicobacter pylori infection agents e.g. clarithromicyn, roxithromycin, rokitamycin, flurithromycin, telithromycin, amoxicillin, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, piperacillin, lenampicillin, tetracycline, metronidazole, bithmuth citrate and bithmuth subsalicylate;
  • nitric oxide synthase inhibitors e.g. GW-274150, tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen;
  • vanilloid receptor 1 antagonists e.g. AMG-517 and GW-705498;
  • muscarinic receptor antagonists e.g. trospium, solifenacin, tolterodine, tiotropium, cimetropium, oxitropium, ipratropium, tiquizium, dalifenacin and imidafenacin;
  • calmodulin antagonists e.g. squalamine and DY-9760
  • potassium channel agonists e.g. pinacidil, tilisolol, nicorandil, NS-8 and retigabine
  • beta-1 agonists e.g. dobutamine, denopamine, xamoterol, denopamine, docarpamine and xamoterol;.
  • beta-2 agonists e.g. salbutamol; terbutaline, arformoterol, meluadrine, mabuterol, ritodrine, fenoterol, clenbuterol, formoterol, procaterol, tulobuterol, pirbuterol, bambuterol, tulobuterol, dopexamine and levosalbutamol;
  • beta agonists e.g. isoproterenol and terbutaline;
  • alpha 2 agonists e.g. clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine;
  • endthelin A antagonists e.g. bonsetan, atrasentan, ambrisentan, clazosentan, sitaxsentan, fandosentan and darusentan;
  • opioid ⁇ agonists e.g. morphine, fentanyl and loperamide
  • opioid ⁇ antagonists e.g. naloxone, buprenorphine and alvimopan;
  • motilin agonists e.g. erythromycin, mitemcinal, SLV-305 and atilmotin;
  • ghrelin agonists e.g. capromorelin and TZP-101
  • AchE release stimulants e.g. Z-338 and KW-5092
  • CCK-B antagonists e.g. itriglumide, YF-476 and S-0509;
  • glucagon antagonists e.g. NN-2501 and A-770077;
  • Glucagon-like peptide-1 (GLP-1 ) antagonists e.g. PNU-126814;
  • SK-3 small conductance calcium-activated potassium channel 3 antagonists, e.g. apamin, dequalinium, atracurium, pancuronium and tubocurarine
  • mGluR ⁇ anatagonists e.g. ADX-10059 and AFQ-056;
  • 5-HT3 agonists e.g. pumosetrag(DDP733);
  • microlitter(s) Kg (kirogram(s)), g (gram(s)), mg (milligram(s)), ⁇ g (microgram(s)), pmol (pico molar(s)), mmol (milli molar(s)), M (molar mass (m 3 /mol)), mM (milli molar mass), ⁇ M (micro molar mass), quant.
  • porcine gastric vesicles for Porcine gastric H + /K + -ATPase inhibition assays were prepared from mucous membrane in fresh porcine stomachs by homogenization with a tight-fitted polytetrafluoroethylene (Teflone®) homogenizer in 0.25 M sucrose at 4 0 C.
  • Teflone® polytetrafluoroethylene
  • the crude pellet was removed with centrifugation at 20,000 g for 30 min. Then supernatant was centrifuged at 100,000 g for 30 min.
  • the resulting pellet was re-suspended in 0.25 M sucrose, and then subjected to density gradient centrifugation at 132,000 g for 90 min.
  • the gastric vesicles were collected from interface on 0.25 M sucrose layer containing 7% FicollTM PM400(Amersham Biosciences). This procedure was performed in a cold room.
  • Ion-leaky Porcine gastric H*/K*-ATPase inhibition Ion-leaky porcine gastric H + /K + -ATPase inhibition was measured according to the modified method described in Biochemical Pharmacology, 1988, 37, 2231-2236.
  • lyophilized vesicles were reconstituted with 3 mM MgSO 4 containing 40 mM Bis-tris (pH 6.4 at 37 0 C).
  • Enzyme reaction was performed incubating 5 mM KCI , 3 mM Na 2 ATP, 3 mM MgSO 4 and 1.0 ⁇ g of reconstituted vesicles for 30 minutes at 37 0 C in a final 60 ⁇ l of reaction mixture (40 mM Bis-tris, pH 6.4) with or without the test compound. Enzyme reaction was stopped by adding 10% sodium dodecyl sulphate
  • Ion-tight porcine gastric H + /K + -ATPase inhibition was measured according to the modified method described in Biochemical Pharmacology, 1988, 37, 2231-2236.
  • vesicles were kept in deep-freezer until use.
  • vesicles were diluted with 3 mM MgSO 4 containing 5 mM Tris (pH 7.4 at 37 0 C).
  • Enzyme reaction was performed incubating 150 mM KCI, 3 mM Na 2 ATP, 3 mlyl MgSO 4, 15 ⁇ M valinomycin and 3.0 ⁇ g of vesicles for 30 minutes at 37 0 C in a final 60 ⁇ l of reaction mixture ( 5mM Tris, pH 7.4) with or without the test compound. Enzyme reaction was stopped by adding 10% SDS. Released inorganic phosphate from ATP was detected by incubating with mixture of 1 part of 35 mM ammonium molybdate tetrahydrate in 15 mM Zinc acetate hydrate and 4 parts of 10% ascorbic acid (pH 5.0), resulting in phosphomolybdate, which has optical density at 750 nm.
  • the powdered canine kidney Na7K + -ATPase (Sigma) was reconstituted with 3 mM MgSO 4 containing 40 mM Tris (pH 7.4 at 37 0 C). Enzyme reaction was performed incubating 100 mM NaCI, 2 mM KCI, 3 mM Na 2 ATP, 3 mM MgSO 4 and 12 ⁇ g of enzyme for 30 minutes at 37 0 C in a final 60 ⁇ l of reaction mixture (40 mM Tris, pH 7.4) with or without the test compound. Enzyme reaction was stopped by adding 10% SDS.
  • Acid secretion in the gastric lumen-perfused rat was measured according to Watanabe ef a/. [Watanabe K et al., J. Physiol. (Paris) 2000; 94: 111-116].
  • the acid secretion was stimulated by a continuous intravenous infusion of pentagastrin (16 ⁇ g/kg/h).
  • the test compounds were administered by an intravenous bolus injection or intraduodenal administration after the stimulated acid secretion reached a plateau phase.
  • the acid secretion was monitored after the administration.
  • the activity was evaluated either inhibition of total acid secretion from 0 hours to 1.5 or 3.5 hours after administration or the maximum inhibition after administration.
  • the compound of Example 2 and 4 showed a good inhibitory activity.
  • Human ether a-go-go related gene (HERG) transfected HEK293S cells were prepared and grown in-house.
  • Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25 0 C with 2 M HCI containing 1 mM MgCI 2 , 10 mM KCI.
  • the cells were homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,000 g for 20 minutes at 4°C. The pellet was resuspended, homogenized and centrifuged once more in the same manner.
  • the resultant supernatant was discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds.
  • the membrane homogenate was aliquoted and stored at -8O 0 C until use. An aliquot was used for protein concentration determination using a Protein Assay Rapid Kit (wako) and Spectra max plate reader (Wallac). All the manipulation, stock solution and e ⁇ uiDiment were keDt on ice at all times. For saturation assays, experiments were conducted in a total volume of 200 ⁇ l.
  • Saturation was determined by incubating 36 ⁇ l of [ 3 H]-dofetilide, and 160 ⁇ l of membrane homogenates (20-30 ⁇ g protein per well) for 60 minutes at room temperature in the absence or presence of 10 ⁇ M dofetilide at final concentrations (4 ⁇ l) for total or nonspecific binding, respectively. All incubations were terminated by rapid vacuum filtration over PEI soaked glass fiber filter papers using Skatron cell harvester followed by two washes with 50 mM Tris buffer (pH 7.4 at 25 0 C). Receptor-bound radioactivity was quantified by liquid scintillation counting using Packard LS counter.
  • the assay was initiated by addition of YSi poly-L-lysine SPA beads (50 ⁇ l, 1 mg/well) and membranes (110 ⁇ l, 20 ⁇ g/well). Incubation was continued for 60 minutes at room temperature. Plates were incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity was quantified by counting Wallac MicroBeta plate counter.
  • PAMPA parallel artificial membrane permeation assay
  • the donor plate Transport Receiver plate (MATRNPS50, Millipore) was filled with 300 ⁇ L of MES buffered HBSS (pH 6.5) containing 10 ⁇ M of the test compounds.
  • the acceptor plate was placed onto the donor plate to form a "sandwich" and was incubated at 30° C for 2.5 hours. After the incubation period, acceptor, donor and initial donor solution (reference) were analyzed via LC-MS/MS. Data were reported as the effective permeability value in cm X 106/sec and the membrane retention value.
  • Test compounds (1 ⁇ M) were incubated with 1 mM MgCI 2 , 1 mM NADP+, 5 mM isocithc acid, 1 U/mL isocithc dehydrogenase and 0.8 mg/mL HLM in 100 mM potassium phosphate buffer (pH 7.4) at 37°C on a number of 384-well plates. At several time points, a plate was removed from the incubator and the reaction was terminated with two incubation volumes of acetonitrile. The compound concentration in supernatant was measured by LC/MS/MS system. The intrinsic clearance value was calculated using following equations:
  • Clin t (ul/min/mg protein) k x incubation volume Protein concentration
  • k - slope of ln(concentration) vs. time (min-1 )
  • HEK293 cells stably expressing the hERG channel were used in whole-cell patch clamp electrophysiology studies at ambient temperature (26.5-28.5°C). The methodology for stable transfection of this channel in HEK293 cells can be found elsewhere (Zhou et al 1998, Biophysical Journal, 74, pp230-241 ).
  • the solutions used for experimentation were standard extracellular solution of the following composition (mM); NaCI, 137; KCI, 4; CaCI 2 , 1.8; MgCI 2 , 1 ; Glucose, 10; HEPES, 10; pH 7.4 ⁇ 0.05 with NaOH/HCI; and standard intracellular solution of the following composition (mM); KCI, 130; MgCI 2 , 1 ; HEPES, 10; EGTA , 5; MgATP, 5; pH 7.2 ⁇ 0.05 with KOH.
  • the voltage protocol applied was designed to activate the hERG channel and allow the measurement of drug block of the channel and is as follows. First the membrane potential was stepped from a holding potential of -8OmV to +3OmV for 1 s.
  • Rats of the Sprague-Dawley strain were used. One to two days prior to the experiments all rats were prepared by cannulation of the right jugular vein under anesthesia. The cannula was exteriorized at the nape of the neck. Blood samples (0.2-0.3 mL) were drawn from the jugular vein at intervals up to 24 hours after intravenous or oral administrations of the test compound. The samples were frozen until analysis. Bioavailability was assessed by calculating the quotient between the area under plasma concentration curve (AUC) following oral administration or intravenous administration.
  • AUC area under plasma concentration curve
  • Plasma protein binding of the test compound (1 ⁇ M) was measured by the method of equilibrium dialysis using 96-well plate type equipment. Spectra-Por®, regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm x 120 mm) were soaked for over night in distilled water, then for 20 minutes in 30% ethanol, and finally for 15 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, pH7.4). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs were used.
  • the dialysis equipment was assembled and added 150 ⁇ l_ of compound-fortified plasma to one side of each well and 150 ⁇ L of dialysis buffer to the other side of each well. After 4 hours incubation at 37 0 C for 150 r.p.m, aliquots of plasma and buffer were sampled. The compound in plasma and buffer were extracted with 300 ⁇ L of acetonitrile containing internal standard compounds for analysis. The concentration of the compound was determined with LC/MS/MS analysis.
  • Aqueous solubility in the mediums (a)-(c) was determined by following method: Whatman mini-UniPrep chambers (Clifton, NJ, USA) containing more than 0.5 mg of compound and 0.5 mL of each medium were shaken overnight (over 8 hours) at room temperature. All samples were filtered through a 0.45 ⁇ m Polyvinylidene Difluoride (PVDF) membrane into the Whatman mini-UniPrep plunger before analysis. The filtrates were assayed by HPLC.
  • PVDF Polyvinylidene Difluoride
  • PBS Phosphate buffer saline
  • PBS Phosphate buffer saline
  • NaTC sodium taurocholate
  • POPC 1-palmitoyl-2-oleyl-L- phosphatidylcholine
  • gliver weight /kg body weight is 21
  • Cells / g liver is 1.2 x 10 8
  • ml incubation/ number of cells in incubation is 2.0 x 10 "6
  • Q h is 20 ml/min/kg.
  • Tested compounds (100 ⁇ M) were incubated with 5 mM glutathione (GSH) and human liver microsomes (HL ' 101 : 2.0 mg/mL) in 100 mM phosphate buffer (pH 7.4).
  • the reaction was initiated by addition of cofactors (3.3 mM glucose 6-phosphate, 3.3 mM MgCI 2 , 10 unit/mL glucose 6-phosphate dehydrogenase, 1.3 mM NADP + and 0.93 mM NADH).
  • the final incubation volume was 1.5 mL.
  • MCA monochloroacetic acid
  • Flash column chromatography was carried out using Biotage KP-SIL (40-63 ⁇ m), Biotage KP-NH (an amine coated silica gel) (40-75 ⁇ M) or Wako silica gel 300HG (40-60 ⁇ M).
  • Preparative TLC was carried out using Merck silica gel 60 F 254 precoated TLC plates (0.5 or 1.0 mm thickness). All Mass data was obtained in Low-resolution mass spectral data (ESI) using ZMDTM or ZQTM (Waters) and mass spectrometer.
  • IR spectra were measured by a Fourier transform infrared spectrophotometer (Shimazu FTIR-8300). Optical rotations were measured using a P-1020 Digital Polarimeter (Japan Spectroscopic CO, Ltd.). Microwave irradiation was carried out using Initiator 60 (Biotage).
  • N-methylpyrrolidinone (8 mL) in a sealed tube was irradiated in a microwave-oven for 1.5 hours. After cooled to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated aqueous ammonium chloride solution
  • 6-bromo- ⁇ /-(5,7-difluoro-3,4-dihydro-2/-/-chromen-4-yl)-2-methylimidazo[1 ,2-a]pyrazin-8-amine (1.50 g, 3.80 mmol, STEP 5) and tetrakis(triphenylphosphine)palladium(0) (877 mg, 0.76 mmol) in 2M dimethylamine tetrahydrofuran solution (60 mL) was stirred at 65 °C under carbon monoxide gas (1 atm) for 16 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate (200 mL).
  • STEP 2 (-VS-rfSJ-Difluoro-S ⁇ -dihvdro ⁇ H-chromen ⁇ -vDaminoi-S-fhvdroxymethvD-N.N ⁇ -trimethylimida zoH .2-alpyrazine-6-carboxamide and (+)-8-f(5.7-Difluoro-3.4-dihvdro-2H-chromen-4-yl)amino1-3-(hvdrox vmethyl)-N,N,2-trimethylimidazo[1.2-alpyrazine-6-carboxamide
  • fraction-1 (59 mg) and fraction-2 (61 mg) were prepared from racemic 8-[(5,7-difluoro-3,4-dihydro-2/-/-chromen-4-yl)amino]-3-(hydroxymethyl)- ⁇ /, ⁇ /,2-trimethylimidazo[1 ,2-a]pyra zine-6-carboxamide (130 mg, STEP 1 ) by HPLC as follows.
  • STEP 2 (SH- )-3-(Hvdroxymethyl)-/V. ⁇ /,2-trimethyl-8-r(5-methyl-3.4-dihvdro-2H-chromen-4-yl)amino1imid azo[1.2-alpyrazine-6-carboxamid6 and (f?H+)-3-(Hvdroxymethyl)- ⁇ /. ⁇ /.2-trimethyl-8-[(5-methyl-3.4-dihvd ro-2H-chromen-4-yl)aminolimidazo[1.2-aipyrazine-6-carboxamide
  • fraction-1 (74 mg) and fraction-2 (87 mg) were prepared from racemic 3-(hydroxymethyl)-/V, ⁇ /,2-trimethyl-8-[(5-methyl-3 l 4-dihydro-2H-chromen-4-yl)amino]imidazo[1 ,2-a]pyrazi ⁇ e-6-carboxamide (200 mg, STEP 1 ) by HPLC as follows.
  • Isolation condition Column: CHIRALCEL OJ-H (20 mm x 250 mm, DAICEL)
  • STEP 3 S-rfSy-Difluoro-S ⁇ -dihvdro ⁇ H-chromen ⁇ -vDaminol- ⁇ /.A/ ⁇ .S-tetramethylimidazofi ⁇ -alpyrazine- 6-carboxamide (example 5-1 )
  • STEP 4 (-VS-KS.T-Difluoro-S ⁇ -dihvdro ⁇ H-chromen ⁇ -vDaminol-Ai/. ⁇ / ⁇ .S-tetramethylimidazo ⁇ ⁇ -alpyraz ine-6-carboxamide and (+)-8-f(5.7-Difluoro-3.4-dihvdro-2H-chromen-4-v ⁇ aminol- ⁇ /. ⁇ /,2,3-tetramethylimid azoH ,2-alpyrazine-6-carboxamide
  • fraction-1 122 mg
  • fraction-2 108 mg
  • HPLC HPLC as follows. Isolation condition
  • STEP 4 amide and (+)-/V, ⁇ /,2.3-tetramethyl-8-f(5-methyl-3.4-dihvdro-2H-chromen-4-yl)aminolimidazo ⁇ .2-alpyrazine-6-carbox amide.

Abstract

Cette invention concerne des composés représentés par la formule (I) ou l'un de ses sels pharmaceutiquement admis. Dans cette formule, R1, R2, R3, R4, R5, R6, R7, R8, A et B sont tels que décrits dans les revendications. L'invention concerne également des compositions à base de tels composés et des procédés utilisant de tels composés, pour le traitement d'un état à médiation par une activité antagoniste de la pompe à protons, tel que notamment les affections gastro-intestinales et gastro-œsophagiennes, le reflux gastro-œsophagien (GERD), le reflux laryngopharyngé, les ulcères peptiques, gastriques et duodénaux, les ulcères induits par les anti-inflammatoirse non stéroïdiens (NSAID), la gastrite, l'infection par Helicobacter pylori, la dyspepsie, la dyspepsie fonctionnelle, le syndrome de Zollinger-Ellison, le reflux non érosif (NERD), la douleur viscérale, le cancer, les brûlures d'estomac, la nausée, l'œsophagite, la dysphagie, l'hypersalivation, les troubles des voies respiratoires ou l'asthme.
PCT/IB2007/003835 2006-11-17 2007-11-05 Dérivés d'imidazo [1,2-a] pyrazine et leur utilisation comme antagonistes de la pompe à protons WO2008059373A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024585A2 (fr) 2007-08-21 2009-02-26 Biofocus Dpi Limited Composés d'imidazopyrazine
US8778935B2 (en) 2009-04-16 2014-07-15 Centro Nacional De Investigaciones Oncologicas (Cnio) Imidazopyrazines for use as kinase inhibitors
WO2017023124A1 (fr) * 2015-08-04 2017-02-09 씨제이헬스케어 주식회사 Nouveau procédé de préparation d'un dérivé de chromanol
US9993554B2 (en) 2010-10-21 2018-06-12 Centro Nacional De Investigaciones Oncologicas (Cnio) Use of P13K Inhibitors for the Treatment of Obesity, Steatosis and ageing
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
CN113527272A (zh) * 2021-08-06 2021-10-22 西安淳甄新材料有限公司 一种特戈拉赞的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055706A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique
WO2003018582A1 (fr) * 2001-08-22 2003-03-06 Astrazeneca Ab Nouveaux composes d'imidazopyridine a effet therapeutique
WO2004074289A1 (fr) * 2003-02-18 2004-09-02 Altana Pharma Ag 6-imidazopyrazines substituees
WO2006064339A1 (fr) * 2004-12-17 2006-06-22 Pfizer Japan Inc. Derives de chromane utilises comme antagonistes de la pompe a acide
WO2007026218A2 (fr) * 2005-09-01 2007-03-08 Pfizer Japan Inc. Derives de 2-alkyl imidazopyridine a substitution chromane

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055706A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique
WO2003018582A1 (fr) * 2001-08-22 2003-03-06 Astrazeneca Ab Nouveaux composes d'imidazopyridine a effet therapeutique
WO2004074289A1 (fr) * 2003-02-18 2004-09-02 Altana Pharma Ag 6-imidazopyrazines substituees
WO2006064339A1 (fr) * 2004-12-17 2006-06-22 Pfizer Japan Inc. Derives de chromane utilises comme antagonistes de la pompe a acide
WO2007026218A2 (fr) * 2005-09-01 2007-03-08 Pfizer Japan Inc. Derives de 2-alkyl imidazopyridine a substitution chromane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAMINSKI J J ET AL: "ANTIULCER AGENTS 2. GASTRIC ANTISECRETORY, CYTOPROTECTIVE, AND METABOLIC PROPERTIES OF SUBSTITUTED IMIDAZOÚ1,2-APYRIDINES AND ANALOGUES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 30, no. 11, January 1987 (1987-01-01), pages 2031 - 2046, XP002008621, ISSN: 0022-2623 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024585A2 (fr) 2007-08-21 2009-02-26 Biofocus Dpi Limited Composés d'imidazopyrazine
EP2567960A2 (fr) 2007-08-21 2013-03-13 Biofocus DPI Limited Composés d'imidazo[1,2-a]pyrazine pour le traitement d'infections virales comme l'hépatite
US8778935B2 (en) 2009-04-16 2014-07-15 Centro Nacional De Investigaciones Oncologicas (Cnio) Imidazopyrazines for use as kinase inhibitors
US9993554B2 (en) 2010-10-21 2018-06-12 Centro Nacional De Investigaciones Oncologicas (Cnio) Use of P13K Inhibitors for the Treatment of Obesity, Steatosis and ageing
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
WO2017023124A1 (fr) * 2015-08-04 2017-02-09 씨제이헬스케어 주식회사 Nouveau procédé de préparation d'un dérivé de chromanol
CN113527272A (zh) * 2021-08-06 2021-10-22 西安淳甄新材料有限公司 一种特戈拉赞的合成方法
CN113527272B (zh) * 2021-08-06 2023-07-21 西安淳甄新材料有限公司 一种特戈拉赞的合成方法

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