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WO2006121097A1 - Derive heterocyclique bicyclique ou son sel - Google Patents

Derive heterocyclique bicyclique ou son sel Download PDF

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Publication number
WO2006121097A1
WO2006121097A1 PCT/JP2006/309447 JP2006309447W WO2006121097A1 WO 2006121097 A1 WO2006121097 A1 WO 2006121097A1 JP 2006309447 W JP2006309447 W JP 2006309447W WO 2006121097 A1 WO2006121097 A1 WO 2006121097A1
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Prior art keywords
methyl
dihydro
oxy
benzofuran
lower alkylene
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English (en)
Japanese (ja)
Inventor
Hideki Kubota
Issei Tsukamoto
Daisuke Suzuki
Hiroyuki Koshio
Kazunori Kamijo
Kei Ohnuki
Koji Kato
Yuta Fukuda
Yusuke Hirano
Toru Watanabe
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Astellas Pharma Inc
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Astellas Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a bicyclic heterocycle useful as a therapeutic agent for lower urinary tract diseases such as urinary incontinence, cystitis, interstitial cystitis, and prostatitis, which is associated with urinary frequency associated with overactive bladder.
  • urinary tract diseases such as urinary incontinence, cystitis, interstitial cystitis, and prostatitis, which is associated with urinary frequency associated with overactive bladder.
  • Overactive bladder is a pathological condition complaining of urgency regardless of incontinence, and is usually accompanied by frequent urination and nocturia (Non-patent Document 1).
  • anticholinergic drugs are mainly used for the treatment, and some treatment results have been shown.
  • side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people.
  • side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people.
  • side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people.
  • there are patients who do not show efficacy with anticholinergic treatment Based on the above, there are great expectations for
  • Prostaglandin E is a bioactive substance with arachidonic acid as a precursor.
  • EP1, EP2, EP3 and EP4 which are G protein-coupled receptors.
  • Patent Document 3 suggests that PGE may affect lower urinary tract function.
  • spine In recent years, spine
  • EP1 receptor antagonists are frequently used in overactive bladder, It is thought to be useful as a therapeutic agent for lower urinary tract diseases such as urgency, urinary incontinence, cystitis, interstitial cystitis, and prostatitis.
  • EP1 receptor antagonists have different mechanisms of action, they can be expected to avoid the side effects peculiar to anticholinergic drugs, and can also be expected to be effective in patients who do not show efficacy with anticholinergic treatment. In addition, this drug is expected to improve the subjective symptoms by acting on sensory nerves. it can. Furthermore, it has been reported that the effect of improving the pathological condition is exhibited without reducing the urination efficiency of rats with spinal cord injury (Non-patent Document 5), and it can be expected to be safely administered to patients with benign prostatic hyperplasia and the elderly.
  • PGE is produced locally with inflammation and tissue damage, and enhances the inflammatory response.
  • Non-patent Document 9 Pain ⁇ It is widely known that it is also involved in fever. In recent years, EP1 receptor antagonists have shown efficacy in inflammatory pain (Non-patent document 6), postoperative pain (Non-patent document 7), and neuropathic pain (Non-patent document 8). In addition, the clinical effect of EP1 receptor antagonist administration on acetic acid-induced visceral pain has also been reported (Non-patent Document 9).
  • EP1 receptor antagonists are known to have an inhibitory effect on colonic mucosal abnormal crypts and intestinal polyp formation (Patent Document 1). EP1 receptor antagonists are used for colon cancer, bladder cancer, It is considered useful as a therapeutic agent for prostate cancer and the like.
  • Patent Document 2 discloses a compound represented by the formula (A)!
  • B represents a C5-15 carbocyclic ring, or a 5- to 7-membered heterocyclic ring having one or two oxygen, sulfur, or nitrogen atoms.
  • B represents a C5-15 carbocyclic ring, or a 5- to 7-membered heterocyclic ring having one or two oxygen, sulfur, or nitrogen atoms.
  • Patent Document 3 discloses a compound represented by the formula (B).
  • R 3 and R 4 are (1) methyl and methyl, (2) methyl and black mouth, (3) black mouth and methyl, (4) a combination of trifluoromethyl and hydrogen, or R 3 and R 4 is bonded to V and carbon atoms to form (5) cyclopentene or (6) a benzene ring.
  • Patent Document 4 discloses a compound represented by the formula (C) including a wide range of compounds!
  • Non-patent document 1 “Neurourology and Urody namics” (UK), 2002, 21st pp.167-78
  • Non-Patent Document 2 “Urological Research” (USA), 1990, No. 18 ⁇ No. 5, P.349- 52
  • Non-Patent Document 3 “The Journal of Urology” (USA), June 1995, No. 153, No. 6, p.2034-8
  • Non-Patent Document 4 "Journal of the Japanese Urological Association", February 2001, No. 92, No. 2, p. 304
  • Non-Patent Document 5 "Proceedings of the 89th Annual Meeting of the Japanese Urological Association", Kobe, 2001 , MP-305
  • Non-Patent Document 6 “Anesthesiology” (USA), November 2002, 97th Sakai, No. 5, p.1254-62
  • Non-Patent Document 7 “Anesthesia and Analgesia” (USA), December 2002, No. 95, No. 6, p.1708-12
  • Non-Patent Document 8 “Anesthesia and Analgesia” (USA), October 2001, No. 93, No. 4, p.1012-7
  • Non-Patent Document 9 “Gastroenterology”, January 2003, No. 124, No. 1, p.18-25
  • Patent Document 1 International Publication No. 00Z69465 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 98Z27053
  • Patent Document 3 Pamphlet of International Publication No. 02Z72564
  • Patent Document 4 Pamphlet of International Publication No. 00Z20371
  • the EP1 receptor antagonist can be expected to be a highly safe therapeutic agent for lower urinary tract disease with few side effects such as phlegm and urinary retention. Accordingly, the present inventors have intensively studied compounds having EP1 receptor antagonistic activity for the purpose of providing novel compounds useful for the treatment of lower urinary tract diseases and the like. As a result, it was found that a novel bicyclic heterocycle derivative represented by the following general formula (I) has a strong EP1 receptor antagonistic action, and the present invention was completed.
  • Ring B cycloalkyl, benzene ring, or hetero ring
  • R 1 substituted, optionally lower alkyl, or heterocyclic group
  • R 2 C alkyl, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloa
  • R 3 - OH, - C (O) - OR °, - C (O) - NR 5 R 5a, 1H- tetrazol - 5 I le, or 5 Okiso 4,5-dihydro - 1,2, 4-oxadiazol-3-yl,
  • R ° and R °° the same or different, H or lower alkyl
  • R 5 and R 5a the same or different, -R °, -lower alkylene-NR ° R °°, -lower alkylene-C 0 R °, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloalkyl -Low
  • R 4 nanogen, lower alkyl, halogeno lower alkyl, nitro-nitro, -0R °, -0-halogeno lower alkyl, -C (0) R °, or -NR ° C (0) R °°,
  • J lower alkylene, lower alkylene, -0-lower alkylene-, -lower alkylene-0-,- 0-lower alkylene, -lower alkylene-0-, -C (0) NR °-, or -NR ° C (0)-
  • X single bond, lower alkylene, lower alkylene, -0-lower alkylene-, -0-lower alkylene-, -NR ° -lower alkylene-, -S (O) -lower alkylene-, or- S (O) -lower alkenylene-,
  • n 0, 1, or 2.
  • R 3 is —CO 2 H or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl
  • a 1 ring: substituted with lower alkyl! May be 2,3-dihydrofuran, 2,3-dihydrothiophene, or 2,3-dihydrothiophene 1,1-dioxide,
  • B 1 ring benzene ring or thiophene ring
  • R 1A (1) -OH, (2) halogen, (3) lower alkyl, -O-lower alkyl, or halogen substituted
  • the pyridylca group force may be substituted with a selected group, which may be a lower alkyl,
  • R 2A (1) halogen, (2) lower alkyl, (3) 0-lower alkyl group power is also selected
  • R 3A -CO H, or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
  • R 4A H, halogen, lower alkyl, or -0-lower alkyl.
  • a pharmaceutical composition comprising the compound according to [1] as an active ingredient,
  • the culture medium was loaded with a loading buffer (fluorescent labeling reagent (trade name: Fluo3- AM, Dojindo), 4 ⁇ of washing solution: Nontas balanced salt solution (HBSS), 20 mM 2- [4- (2-hydroxyl Chill) -1-piperadyl-ethane] sulfonic acid (HEPES) -sodium hydroxide (NaOH), 2.5 mM probenecid, 0.1% ushi serum albumin (BSA)) and left at room temperature for 3 hours, The cells are washed with a plate washer (trade name: ELx405, BIO-TEK Instruments, Inc.) in which a washing solution is set.
  • HBSS Nontas balanced salt solution
  • HEPES 2- [4- (2-hydroxyl Chill) -1-piperadyl-ethane] sulfonic acid
  • NaOH sodium hydroxide
  • BSA 0.1% ushi serum albumin
  • the concentration that inhibits 50% is the IC value.
  • the compound of the present invention showed a strong EP1 receptor antagonistic activity.
  • Table 1 shows the test results of the representative compounds. Ex represents an Example compound number described later.
  • the rat EP1 receptor was introduced into the expression vector (trade name: pCEP4, Invitrogen) after introducing a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) and a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) at the N-terminus. .
  • This rat EP1 expression vector was transformed into HEK293EBNA cells (American's type culture ⁇ ⁇ ⁇ American Type Culture) using transfection reagent (trade name: Fugene-6, Roche Diagnostics). Collection)), then 10% FB at 37 ° C, 5% CO
  • the cells were cultured in a medium containing S (trade name: DMEM, Invitrogene) for 2 days.
  • the cultured cells are collected, treated with a cell lysate (20 mM Tris (hydroxymethyl) aminomethane (Tris) buffer pH 7.5, 5 mM ethylenediamine tetraacetic acid (EDTA)), and ultracentrifuged (23,000 rpm, 25 The membrane preparation was roughly adjusted by min x 2).
  • MES ethanesulfonic acid
  • KOH potassium hydroxide
  • ImM EDTA ImM EDTA
  • MgCl lOmM salt ⁇ magnesium
  • the filter is trapped on a filter 1-96, GF / B, Perkin Elma Co., Ltd., and the combined radioactivity is microplate (trade name: Micro Cinch 20, Perkin Elma Co.) using a microplate scintillation counter (product) Name: Top Count, Notcard Inc.).
  • -PGE binding inhibitory activity is measured by adding 2.5 nM 3 H-PGE and the compound of the present invention.
  • Ki IC / (1 + ([C] / Kd))
  • [C] represents the 3 H-PGE concentration used in the reaction system.
  • the compound of the present invention showed strong EP1 receptor binding activity.
  • Table 2 The test results of representative compounds are shown in Table 2 below.
  • Wistar male rats (Charles River Inc.) weighing 200 to 450 g were used for the experiment. Under anesthesia with pentobarbital (50 mg / kg, i.p.), a midline incision was made in the abdomen to expose the bladder, and residual urine in the bladder was removed with a syringe equipped with a 27G needle. Thereafter, 0.5% to 0.7 mL of 1% acetic acid solution was injected into the bladder and closed. The experiment was conducted two days later. Rats were placed in metabolic cages and acclimated for 1 hour, then the test drug was administered, and changes in urinary weight were measured continuously for 6 hours immediately thereafter. The effective bladder capacity was calculated by dividing the total urination volume by the total number of urinations.
  • the effective bladder capacity decreased in the acetic acid intravesical treatment group compared to the sham-operated group, resulting in frequent urination.
  • the compound of the present invention improved the frequent urination state well.
  • the compound of the present invention has a strong EP1 receptor antagonistic action and satisfactorily improves frequent urination.
  • the compound of the present invention has excellent metabolic stability with few concerns about drug interaction, etc. It is preferred as a medicine and has properties.
  • the compound of the present invention is expected as a therapeutic agent for lower urinary tract diseases such as frequent urination, urinary incontinence, cystitis, interstitial cystitis, prostatitis power associated with overactive bladder with less side effects.
  • lower urinary tract diseases such as frequent urination, urinary incontinence, cystitis, interstitial cystitis, prostatitis power associated with overactive bladder with less side effects.
  • lower means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms unless otherwise specified.
  • “Lower alkyl” means C alkyl. Specifically, methyl, ethyl,
  • Examples include normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like. Preferred are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl and tert-butyl.
  • “Lower ark” means a C alkell. Double bond can be at any position
  • it may have a plurality of double bonds.
  • Specific examples include ethenyl, probe, butyr, pentale, hexyl, butagel and the like.
  • Preferred are etule, 1-probe, and 2-probe.
  • “Lower alkylene” is formed by removing one hydrogen at any position of alkyl of C 2
  • Means a valent group means methylene, ethylene, methylmethylene, dimethylmethylene, propylene and the like. Preferred are methylene, ethylene and propylene.
  • “Lower alkylene” refers to the removal of one hydrogen atom at any position of the C alkenyl.
  • Means a divalent group means a divalent group. Specific examples include beylene, probelene, 1-butylene, 2-butylene. Biylene is preferred.
  • Cycloalkyl means a non-aromatic hydrocarbon ring of C, and the bridged ring is a spiro ring.
  • Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexenole, cycloheptinole, cyclooctyl, cyclohexenyl, cyclooctanegel, adamantyl and norbol.
  • Halogen means a halogen atom. Specific examples include fluoro, black mouth, bromo and iodine. Fluoro and black mouth are preferred.
  • halogeno lower alkyl means one or more arbitrary hydrogen atoms of the “lower alkyl” which are the same or different from each other and substituted with the “halogen”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Preferred is trifluoromethyl.
  • Aryl means a monocyclic to tricyclic C aromatic hydrocarbon ring group, specifically
  • the 5-8 cycloalkyl ring may be condensed.
  • indanyl or tetrahydronaphthyl may be formed.
  • Heterocyclic group means a saturated or unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N forces, and 8 to 14 It means a membered bicyclic heterocyclic group or an 11-20 membered tricyclic heterocyclic group.
  • the ring atom S or N may be oxidized to form an oxide or a bridged ring or a spiro ring.
  • the monocyclic heterocyclic group examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazinyl, furyl, dihydrofuryl, chenyl, dihydrochenyl, pyrrolinole, pyrrolinyl, oxazolinole, isoxazolyl, oxadiazolyl , Thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, virazolinyl, virazolidinyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidyl, piperazil, morpholinyl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl -Le.
  • bicyclic heterocyclic group examples include indolyl, indolyl, benzofuran, dihydrobenzofuranore, benzocenore, dihydrobenzocenore, indazolinole, benzoxazolyl, benzoimidazolyl, benzothiazolyl, Examples include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, cinnolinyl and the like.
  • tricyclic heterocyclic group examples include carbazolyl and attalidinyl.
  • Heterocycle means the above “heterocyclic group” as a ring.
  • the heterocyclic groups pyridyl, chenyl, dihydrofuryl and pyrrolinyl are pyridine, thiophene, Corresponds to dihydrofuran and pyrroline (2,3-dihydro-1H-pyrrole).
  • all of the above “heterocyclic groups” may be divalent or higher polyvalent groups depending on the force structure described as a monovalent group for convenience.
  • the present invention includes those structures. Specific embodiments of the divalent group correspond to those obtained by converting the above-mentioned “heterocyclic group” suffix into a dil according to the organic compound nomenclature.
  • the permissible substituent of the word “substituted or may be used” is usually used in the art as a substituent of each group. Any substituent may be used. In addition, each group may have at least one identical or different substituent.
  • the substituent in the “substituted or lower alkyl” of R 1 is preferably a group selected from the following G group forces.
  • cycloalkyl, aryl, and heterocyclic groups in Group G may be substituted with halogen, lower alkyl, halogeno lower alkyl, -OR ° or -0-norogeno lower alkyl!
  • R 2 may preferably be a substituent in “C alkyl”.
  • p group neurogen, -OR 0 ,-0- SiR ° R °° (Areel), -NR ° R °°, -CO R. And -C (0) NR ° R. .
  • Lower alkyl optionally substituted by a group selected from the group consisting of halogen, sirene-to, -OR °, -0-halogeno lower alkyl, -C (0) R °, -CO R °,- NR ° C (0) R °°,-C (0) NR ° R °
  • a ring is preferably furan, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3-dihydrothiophene 1,1-dioxide, pyrroline, 3,4-dihydro-2H-pyran, 1,3 -Dioxol or 2,3-dihydro-1,4-dioxin, which are fused together!
  • the ring B is preferably benzene, thiophene, pyridine or thiazole, more preferably benzene, thiophene or thiazole, and still more preferably benzene or thiophene.
  • R 1 is preferably halogen, -OR 0 , cycloalkyl, aryl, or lower alkyl optionally substituted with a heterocyclic group, and more preferably halogen, -OR °, or heterocyclic.
  • Lower alkyl which may be substituted with a group, more preferably isobutyl, 2-fluoropropyl, 3-hydroxy-2-methylpropyl or (pyridin-2-yl) methyl.
  • R 2 is preferably each independently substituted or unsubstituted or more preferably a heterocyclic group, and more preferably one or more lower alkyl, -0-lower alkyl or halogen each being the same or different.
  • a aryl group or a heterocyclic group more preferably Each is the same or different phenyl, pyridyl, furyl or thiazolyl substituted with one or more lower alkyl or halogen.
  • R 3 is preferably -C (0) -OR °, 1H-tetrazol-5-yl or 5-oxo-4,5-dihydride-1,2,4-oxadiazol-3-yl, More preferably, -CO H or 5-oxo-4,5-
  • R 4 is preferably halogen, lower alkyl, halogeno lower alkyl, -0-lower alkyl, or -0-nitrogeno lower alkyl, and more preferably halogen or lower alkyl.
  • m is 0 or 1.
  • X is preferably a single bond, lower alkylene, lower alkylene, or 0-lower alkylene-, more preferably a single bond or lower alkylene, and still more preferably a single bond.
  • J is preferably -0-lower alkylene-, more preferably -0-methylene-.
  • L is preferably -S (O)-.
  • a particularly preferred embodiment of the present invention is a compound comprising a combination of each preferred group described above.
  • the compound of the present invention may have a geometric isomer or a tautomer depending on the kind of the substituent, but the present invention includes a separated or a mixture of these isomers.
  • the compound of the present invention may have an asymmetric carbon atom, and optical isomers such as (R) isomer and (S) isomer based on this may exist.
  • optical isomers such as (R) isomer and (S) isomer based on this may exist.
  • the present invention includes all of these optical isomers and isolated ones.
  • the compounds of the present invention include pharmacologically acceptable prodrugs.
  • a pharmacologically acceptable prodrug is a compound having a group that can be converted to NH, OH, COH or the like of the present invention by solvolysis or under physiological conditions. Form a prodrug
  • the compound of the present invention may form a salt with a base depending on the type of acid addition salt or substituent.
  • strong salts are pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propion.
  • Acid addition salts with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid
  • organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid
  • Inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum
  • salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortin, and ammonium salts.
  • the present invention includes various hydrates and solvates of the compound (I) and salts thereof, and crystalline polymorphic substances.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent.
  • a suitable protecting group at the raw material or intermediate stage, or replace it with a group that can be easily transferred to the functional group. May be effective.
  • Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups, and examples of protective groups for these functional groups include “Protective”, “Groups”, “In” and “Organic” by TW Greene and PGM Wuts. 'Protective Groups in Organic Synthesis', (USA), 3rd edition, John' Wiley & Sons, Inc. What is necessary is just to select suitably according to reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
  • R la and R 2a represent groups that are converted into R 1 and R 2 , respectively, by the reductive amination reaction described later.
  • the first step is a step of producing the compound (V) from the compound (II) by alkylation.
  • This step is a step of producing the compound (V) by reductive alkylation of the compound (II) and the carbonyl compound (III).
  • the reaction for example, the method described in “Chemical Experiment Course (20) Organic Synthesis 2” edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, p. Specifically, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, etc.
  • Ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane, alcohols such as methanol and ethanol, and solvents inert to the reaction such as acetic acid It is preferable to carry out the reaction at room temperature to reflux with heating using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • This step is a step for producing compound (V) by alkylating compound (II) with compound (IV) having a leaving group.
  • the leaving group represented by Lv may be any leaving group that is commonly used in nucleophilic substitution reactions, such as halogen, halogen such as bromo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonylo. Sulfoloxy such as xy, sulfone such as lower alkyl sulphone, aryl sulol and the like are preferably used.
  • an alkylation commonly used by those skilled in the art can be employed.
  • reaction in the absence of solvent or inert to reactions such as the aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, dimethylsulfoxide (DMSO), and acetonitrile.
  • the reaction can be carried out in a solvent or a solvent such as alcohols at room temperature or under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • metal salt bases are preferably used) or metal salt bases (potassium carbonate, In the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxypotassium, etc.), it may be advantageous for the reaction to proceed smoothly.
  • compound (V) is treated with compound (VI) by sulfo-louis, so that L is -S (O)-
  • Lv halogen such as black mouth and bromo
  • the conditions of sulfoniru ⁇ described in “Protective Groups in Organic Synthesis” can be applied. Specifically, it can be carried out in a solvent such as tetrahydrofuran, dichloromethane or acetonitrile, in the presence of a base such as triethylamine or pyridine, if necessary, under cooling to heating under reflux.
  • This step is a step for producing the compound (I-b) of the present invention in which L is —C (O) — by subjecting compound (V) to carboxylic acid (VII) or a reactive derivative thereof.
  • reactive derivatives include acid salts, logogens (acid chlorides, acid bromides, etc.), acid anhydrides (black ester carbonate, benzyl carbonate, chloroform carbonate, P-toluenesulfonic acid, isoforms).
  • the reaction is carried out by using an equimolar amount or an excess of one of the carboxylic acid compound (VII) or its reactive derivative and compound (V), aromatic hydrocarbons, halogenated hydrocarbons, ethers,
  • the reaction can be carried out under cooling to heating in a solvent inert to the reaction such as DMF, DMA, NMP, ethyl acetate or acetonitrile.
  • a solvent inert such as DMF, DMA, NMP, ethyl acetate or acetonitrile.
  • the reaction may be carried out in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.) In some cases, the reaction proceeds smoothly.
  • a base preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N
  • a condensing agent ⁇ , ⁇ '-dicyclohexyl carpositimide, (DCC), 1- [3- (dimethylamino) propyl] -3-ethyl carbodiimide (WSC), 1,1 , -Carbo-rubbisimidazole (CDI), ⁇ , ⁇ '-Disuccinimidyl carbonate, Bop reagent (Aldrich, USA), 2- (1 ⁇ -benzotriazol-1-yl) -1,1, 3,3-tetramethylu-mu-tetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1,1, 3,3-tetramethylu mouth -Umhexafluorophosphate (HBTU), diphenylphosphoric acid azide (DPPA), phosphorus oxychloride, phosphorus trichloride, triphenylphosphine ZN-bromosuccinimi
  • This step is a step for producing a compound (I-c) of the present invention in which L is a single bond by alkylating compound (V) with compound (VIII) or compound (IX).
  • the alkylation in this step can be performed in the same manner as the alkylation in the first step.
  • This step is a step of producing compound (X) from compound (II) by sulfonylation, acylation or alkylation.
  • the sulfonylation, the acylation, and the alkylation can be carried out in the same manner as in the second step 1 to the second step 3 of production method 1, respectively.
  • This step is a step for producing the present compound (I) from the compound (X) by alkylation.
  • the alkylation reaction in this step can be produced in the same manner as in the first step 2 of production method 1.
  • R represents lower alkyl
  • R 3 is —CO 2 H from the compound (Id) of the present invention in which R 3 is —CO 2 R by hydrolysis.
  • the hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in the above-mentioned “Protective Groups Inorganic Organic Synthesis”.
  • R 3 is —CONR 5a from the compound (Ie) of the present invention in which R 3 is —CO 2 H by amido.
  • the amidation reaction in this step can be carried out in the same manner as in the second step 1 and 2 of production method 1.
  • the starting compound used for the production of the compound (I) of the present invention can be produced, for example, using the following method, a known method, or a modified method thereof.
  • This step is a step for producing compound (XIII) by nitration of compound (XII).
  • Nitration can be produced by a method usually employed by those skilled in the art.
  • concentrated nitric acid can be used as a nitrating agent in a solvent such as acetic acid or concentrated sulfuric acid.
  • This step is a step for producing the compound ( ⁇ ) by reducing the nitro compound ( ⁇ ).
  • a -tro group reduction reaction that can be usually employed by those skilled in the art can be used. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride and a hydrogenation reaction using palladium-carbon as a catalyst.
  • J 1 and / represent groups that can be converted to J.
  • compound (XVI) and compound (XV) are condensed to produce compound (XVI). It is.
  • This step can be produced by amidation, alkylation or the like that can be usually employed by those skilled in the art depending on the structure of J.
  • a compound (XVI) in which J is -0-lower alkylene- is a compound (XIV) in which J 1 OH is a -lower alkylene-Lv (Lv represents a leaving group).
  • the alkylation can be carried out in the same manner as in the first step 2 of production method 1.
  • reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate.
  • the salt can be produced by subjecting it to normal salt formation treatment.
  • Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
  • optical isomers can be isolated by a conventional method using physical and physical differences between isomers.
  • optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography.
  • An optical isomer can be produced from an appropriate optically active raw material compound.
  • a preparation containing one or more of the compounds of the present invention or a salt thereof as an active ingredient is usually prepared using carriers, excipients, and other additives used for formulation.
  • Administration is oral by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral by injections such as intravenous and intramuscular injections, suppositories, transdermal, nasal or inhalants. Either form may be sufficient.
  • the dosage is appropriately determined according to the individual case, taking into account the symptoms, age of the subject, sex, etc., but in the case of oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per day for an adult. This should be administered once or in 2 to 4 divided doses.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substances are less potent. It is mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybulurpyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. Tablets or pills may be coated with sugar coating or gastric or enteric coatings if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and are generally used inert solvents such as purified water, ethanol. including.
  • the composition may contain solubilizers, wetting agents, suspending agents and other auxiliary agents, sweeteners, corrigents, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solvent include distilled water for injection and physiological saline.
  • Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can be prepared by preparing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods.
  • an excipient and as Ratatosu Ya starch furthermore, P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer, the compound is administered as a solution or suspension alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier be able to.
  • the dry powder inhaler or the like can use a dry powder or a capsule containing a powder, which may be for single or multiple administrations.
  • a suitable propellant such as black mouth fluo It may be in the form of a caloric pressure aerosol spray using a suitable gas such as loalkane, hydrofluoroalkane or carbon dioxide.
  • Syn production method (numbers indicate that the product was produced using the corresponding raw material in the same manner as the example compound having the number as the example number. R is attached before the number)
  • the reference example number in the case of the reference example, it indicates that it was produced using the corresponding raw material in the same manner as the reference example compound.
  • reaction solution was cooled to room temperature and then concentrated under reduced pressure to about 100 ml.
  • the precipitate deposited by ice cooling was collected by filtration and dried under reduced pressure to obtain 3.49 g of 5-hydroxy-6-nitro-1,3-benzodioxole.
  • Example 13 4- ⁇ [(5- ⁇ [(5-Methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl ⁇ methyl benzoate 300 mg into 4 ml of pyridine Dissolved, 196 mg of propylene oxide was added thereto, and the mixture was stirred overnight at 100 ° C in a sealed tube. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with 1M hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate.
  • N- ⁇ 6-[(4-Cyanobenzyl) oxy] -2,3-dihydro-1-benzofuran-5-yl ⁇ -N-isobutyl-5-methylfuran-2-sulfonamide 300 mg suspended in 6 mL toluene It became cloudy and 331 mg of trimethyltin azide was added. The reaction was heated to reflux for 8 hours, then returned to room temperature and stirred overnight. To the reaction solution, 12 mL of MeOH and 16 mL of 1M hydrochloric acid were added and stirred at room temperature for 2 hours.
  • the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate.
  • the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate.
  • Example 192 4- ⁇ [(5- ⁇ Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl ⁇
  • benzoic acid was dissolved in 4.0 mL of THF, and 1.19 mL of a 1M THF solution of borane-THF complex was added thereto under ice cooling, followed by stirring at room temperature for 2 hours. A water-acetic acid mixture was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate.
  • Example compounds shown in Tables 19 to 82 to be described later were produced using the corresponding raw materials.
  • Tables 19 to 82 show the structures and physicochemical data of the example compounds.
  • Table 83 shows the structure of another compound of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in the Examples, methods obvious to those skilled in the art, or variations thereof.
  • the compound of the present invention is excellent in EP1 receptor antagonistic activity.
  • Diseases involving EP1 receptor particularly frequent urination associated with overactive bladder, urinary urgency, urinary incontinence, cystitis, interstitial cystitis, prostate It is useful as a therapeutic agent for lower urinary tract diseases such as adenitis. Sequence listing free text
  • the numerical heading ⁇ 223> in the sequence listing below describes the “Artificial Sequence”. Specifically, the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing is an artificially synthesized signal peptide sequence. The amino acid sequence represented by SEQ ID NO: 2 in the sequence listing is an artificially synthesized FLAG sequence.

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Abstract

Le problème à résoudre dans le cadre de cette invention concerne un composé pouvant être utilisé comme agent thérapeutique pour une affection dans laquelle un récepteur EP1 est impliqué, particulièrement une affection des voies urinaires inférieures telle que la pollakiurie/urgence urinaire et l’incontinence associées à une vessie hyperactive, à la cystite, à la cystite interstitielle et à la prostatite. La solution proposée consistait à découvrir qu’un dérivé hétérocyclique bicyclique dans lequel des noyaux benzéniques sont fusionnés ou son sel présente un puissant effet antagoniste du récepteur EP1. Le dérivé hétérocyclique bicyclique ou son sel peut être utilisé comme agent thérapeutique pour une affection dans laquelle un récepteur EP1 est impliqué, particulièrement une affection des voies urinaires inférieures telle que la pollakiurie/urgence urinaire et l’incontinence associée à une vessie hyperactive, à la cystite, à la cystite interstitielle et à la prostatite.
PCT/JP2006/309447 2005-05-12 2006-05-11 Derive heterocyclique bicyclique ou son sel Ceased WO2006121097A1 (fr)

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