WO2007072782A1 - Derive d’acide carboxylique ou sel derive - Google Patents

Derive d’acide carboxylique ou sel derive Download PDF

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Publication number
WO2007072782A1
WO2007072782A1 PCT/JP2006/325197 JP2006325197W WO2007072782A1 WO 2007072782 A1 WO2007072782 A1 WO 2007072782A1 JP 2006325197 W JP2006325197 W JP 2006325197W WO 2007072782 A1 WO2007072782 A1 WO 2007072782A1
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Prior art keywords
methyl
amino
benzoic acid
lower alkyl
ylmethyl
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PCT/JP2006/325197
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English (en)
Japanese (ja)
Inventor
Hideki Kubota
Issei Tsukamoto
Koji Kato
Yuta Fukuda
Kazunori Kamijo
Kei Ohnuki
Yusuke Hirano
Toru Watanabe
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Astellas Pharma Inc.
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Publication of WO2007072782A1 publication Critical patent/WO2007072782A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is useful as a medicine, particularly as a therapeutic agent for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc.
  • the present invention relates to a novel carboxylic acid derivative.
  • 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.
  • it has been reported that it is difficult to use for patients with benign prostatic hyperplasia and the elderly because of the known side effects such as rheumatoid arthritis, constipation, and blurred vision and the risk of urinary retention. .
  • 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
  • Non-Patent Document 4 abnormal urinary function in urethral stricture model mice is EP1 receptor Disappeared by KO and abnormal urination due to intravesical injection of PGE
  • EP1 Receptor Antagonist is a frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis It is considered useful as a therapeutic agent for lower urinary tract diseases such as prostatitis.
  • EP1 receptor antagonists have different mechanisms of action, side effects unique to anticholinergic drugs This can be expected to be avoided, and it can be expected to be effective for patients who have not shown efficacy with anticholinergic treatment. In addition, this drug acts on sensory nerves and is expected to have a stronger effect of improving subjective symptoms. Furthermore, it has been reported that it has an effect of improving the pathological condition without lowering the urination efficiency of rats with spinal cord injury (Non-Patent Document 5), and it can be expected that it can 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.
  • 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).
  • Non-patent Document 9 the clinical effect of EP1 receptor antagonist administration on acetic acid-induced visceral pain has also been reported. Based on the above, EP1 receptor antagonists are considered to be useful as therapeutic agents for various pains.
  • an EP1 receptor antagonist has an action of suppressing abnormal formation of colonic mucosa abnormal crypts and intestinal polyps (Patent Document 2), and EP1 receptor antagonists are used for colon cancer, bladder It is considered useful as a therapeutic agent for cancer, prostate cancer and the like.
  • Patent Document 3 discloses a compound represented by the formula (A)!
  • R 4 there is no disclosure of a substituted lower alkyl substituted with a heterocyclic group, which is a feature of the compound of the present invention.
  • Patent Document 4 discloses a compound represented by the formula (B).
  • R1 represents isopropyl, isobutyl, 2-methyl-2-propyl, cyclopropylmethyl, methyl, ethyl, propyl, 2-propenyl, or 2-hydroxy-2-methylpropyl. (See the official gazette for the symbol.)
  • Patent Document 5 discloses compounds represented by the formula (C) including a wide range of compounds.
  • X or Q may be an optionally substituted phenylene or an optionally substituted single.
  • the chemical structure is different from the compound of the present invention in that it does not have a cyclic structure such as cyclic heteroarylene.
  • Patent Document 6 published after the priority date of the present application discloses a compound represented by the formula (D).
  • ring A represents an optionally substituted 5- to 8-membered heterocycle. For other symbols, refer to this publication.
  • the chemical structure is different from that of the compound of the present invention in that the ring A is a 5- to 8-membered heterocyclic ring which may be substituted.
  • 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, No. 97, 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 US Patent Application Publication No. 2005Z0020646 Specification
  • Patent Document 2 Pamphlet of International Publication No. 00Z069465
  • Patent Document 3 Pamphlet of International Publication No. 98Z027053
  • Patent Document 4 International Publication No. 02Z072564 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 00Z020371
  • Patent Document 6 International Publication No. 06Z121097 Pamphlet
  • An 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 an 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 can be substituted as a substituent on the N atom of the sulfonamide, but may have a lower alkyl group substituted with a heterocyclic group. The present invention was completed by discovering that the novel carboxylic acid derivative shown has a potent EP1 receptor antagonistic action.
  • R 1 and R 2 the same or different, H, halogen, lower alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, or a carbon atom to which R 1 and R 2 are bonded.
  • a 5- to 8-membered cycloalkene ring or a benzene ring may be formed.
  • A: substituted ! may be a heterocyclic group
  • substituted ! may, file, or substituted, may be monocyclic heteroaryl
  • substituted ! may, phenylene, substituted !, may! /, Monocyclic heteroalkylene
  • X lower alkylene, lower alkylene, -0-lower alkylene-, or -lower alkylene -o-,
  • Y a single bond, lower alkylene, lower alkylene, or -o-lower alkylene
  • A is oxygen-containing 4- to 6-membered saturated heterocyclic group or nitrogen-containing 5- to 6-membered heteroaryl
  • B is a ring, or N or O.
  • A is a group selected from the group consisting of oxetal, tetrahydrofuryl, tetrahydrobiral, pyridyl, pyrajur, imidazolyl, and virazolylca
  • B is selected from phenyl, thiazolyl, furyl, and pyridyl
  • A is selected from the group power in which A is also oxetanyl and pyridylca.
  • R 3 is —OH, R 1 and R 2 are the same or different, and H, halogen, lower alkyl, halogeno lower alkyl, ⁇ 0-lower alkyl, or R 1 and R 2 are bonded.
  • the method includes administering to a patient a therapeutically effective amount of the compound according to [1], frequent urination with overactive bladder, urinary incontinence, lower urinary tract symptoms with prostatic hypertrophy, interstitial cystitis, A method for treating lower urinary tract disease comprising prostatitis,
  • the compound of the present invention has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, It is useful as a therapeutic agent for lower urinary tract diseases such as interstitial cystitis and prostatitis.
  • lower means 1 to 6 carbon atoms (hereinafter abbreviated as C) unless otherwise specified.
  • “Lower alkyl” means C alkyl. Specifically, methyl, ethyl, n-propyl
  • Mouth pill isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like can be mentioned.
  • it is C alkyl, more preferably methyl,
  • “Lower alkylene” is a divalent group formed by removing one hydrogen from any position of C alkyl.
  • Means group Specific examples include methylene, ethylene, methylmethylene, dimethylmethylene, trimethylene, tetramethylene, and propylene. Preferred are methylene, ethylene and trimethylene, and more preferred are methylene and ethylene.
  • “Lower alkellene” is formed by removing one hydrogen atom at any position of the C alkell 2
  • Means a valent group include beylene, probelene, 1-butylene, 2-butene. Biylene is preferred.
  • Halogen means a halogen atom. Specific examples include fluoro, black mouth, bromo and iodine. Fluoro and black mouth are preferred.
  • halogeno lower alkyl means a group substituted with the above “halogen” in the same or different one or more arbitrary hydrogen atom forces of the “lower alkyl”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Trifluoromethyl is preferred.
  • “5- to 8-membered cycloalkene ring” means carbonization of C having 1 or 2 double bonds in the ring.
  • Specific examples include cyclopentene, cyclopentagen, cyclohexene, cyclohexagen, cycloheptene, cyclootaten and the like. Cyclopentene is preferred.
  • “Monocyclic heteroaryl” is a monocyclic 5- to 6-membered aromatic ring group containing 1 to 4 heteroatoms selected from 0, S and N forces, and S or a ring atom N may be oxidized to form an oxide.
  • Specific examples include pyridyl, pyridazyl, pyrimidyl, pyrajyl, triazinyl, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. .
  • Nitrogen-containing 5- to 6-membered heteroaryl refers to the ring structure in the above “monocyclic heteroaryl”. It means a cyclic group containing at least one N as a constituent atom. Specific examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • Pyridyl, pyrazyl, thiazolyl, imidazolyl, pyrazolyl and oxadiazolyl are preferable, and pyridyl, pyrazinyl, thiazolyl, imidazolyl and pyrazolyl are more preferable.
  • “5- to 6-membered heteroaryl containing at least one N or 0” means that the above “monocyclic heteroaryl” always contains one N and / or 0 as a ring-constituting atom, Furthermore, it means a cyclic group which may contain one S. Specific examples include pyridyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl and the like. Pyridyl, thiazolyl and furyl are preferred.
  • the “monocyclic heteroarylene” means a divalent group formed by removing one arbitrary hydrogen on the ring atom of the “monocyclic heteroaryl”. Specifically, pyridine, pyridazine, pyrimidine, pyrazine, triazine, flanged, thiophene, pyrrole, oxazole, isoxazole, oxadiazol, thiazole, and thiadiazole Imidazole dil, triazole dil, tetrazol dil and the like. Pyridine diyl and thiophen diyl are preferable.
  • Heterocyclic group means a saturated, unsaturated or partially unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N forces, 8 Means a 14-membered bicyclic heterocyclic group or an 11-20 membered tricyclic heterocyclic group.
  • the ring atom S or N may be acidified to form an oxide or dioxide, or a bridged ring or spiro ring may be formed.
  • the monocyclic heterocyclic group examples include pyridyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, furyl, dihydrofuryl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, and pyrazol.
  • Examples include ryl, triazolyl, tetrazolyl, oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and the like.
  • bicyclic heterocyclic group examples include indolyl, Examples include benzofuranyl, dihydrobenzofuranyl, benzocenyl, benzoid oxazolinole, benzoimidazolyl, benzothiazolyl, indazolyl, quinolyl, quinazolinyl, quinoxalinyl, cinnoyl and the like.
  • Specific examples of the tricyclic heterocyclic group include force rubazolyl and attalizyl.
  • it is a 4- to 6-membered monocyclic heterocyclic group, more preferably oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, and still more preferably oxetanyl, Tetrahydrofuryl, pyridyl, pyrajur, thiazolyl, imidazolyl, pyrazolyl.
  • Oxygen-containing 4- to 6-membered saturated heterocyclic group is a 4- to 6-membered saturated hetero group containing at least one or more 0 as a ring constituent atom in the "heterocyclic group”. Means a cyclic group.
  • Examples include oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, morpholinyl, oxazepanyl, dioxol, and dioxal. Preferred are oxetal, tetrahydrofuryl and tetrahydroviral, and more preferred are oxetal and tetrahydrofuryl.
  • substituent in the “optionally substituted heterocyclic group” of A preferably lower alkyl, halogen, halogeno lower alkyl, —OH, —O-lower alkyl, —O-halogeno lower alkyl, -Troca and the like, more preferably lower alkyl, halogen, and -O-lower alkyl, still more preferably lower alkyl.
  • B “Substituted, may be a monocyclic heteroaryl”, and the same “Substituted !, may be As a substituent in the ⁇ monocyclic heteroarylene '', preferably a lower alkyl, a halogen, a halogeno lower alkyl, a -0-lower alkyl, a -o-halogeno lower alkyl, a cyanide and a -tro force, More preferred are lower alkyl, halogen and -0-lower alkyl, and even more preferred are lower alkyl and halogen.
  • A is preferably an optionally substituted oxetanyl, tetrahydrofuryl, tetrahydroviral, pyridyl, pyrajyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, more preferably each substituted. May be oxetal, tetrahydrofuryl, pyridyl, pyrajyl, imidazolyl, pyrazolyl, and more preferably oxetanyl and pyridyl which may be substituted.
  • the substituent on A the substituents described above are preferable.
  • B is preferably an optionally substituted thiazolyl, furyl, pyridyl, or phenol, and more preferably an optionally substituted thiazolyl or vinyl.
  • substituent on B the substituents described above are preferable.
  • C is preferably an optionally substituted phenylene, thiopheneyl, or pyridinezyl, and more preferably an optionally substituted phenylene.
  • substituent on C the substituent described above or unsubstituted is more preferable, and unsubstituted is more preferable.
  • R 2 is preferably the same or different and is H, lower alkyl, halogen, —O-lower alkyl, or halogeno lower alkyl.
  • Another preferred embodiment of R 2 is the case of forming a cyclopentene ring together with the carbon to which R 1 and R 2 are attached.
  • Luka lower alkyl optionally substituted with a selected group), more preferably-
  • X is preferably -0-lower alkylene-, more preferably -0-methylene-.
  • Y is preferably a single bond.
  • Z is preferably methylene, methylmethylene, or ethylene, more preferably Tylene.
  • a particularly preferred embodiment of the present invention is a compound capable of combining each preferred group described in the above (1) to (8).
  • compound (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers such as (R) and (S) isomers may exist based on this.
  • optical isomers such as (R) and (S) isomers may exist based on this.
  • the present invention includes all of these optical isomers and mixtures thereof.
  • the present invention includes pharmacologically acceptable prodrugs of Compound (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, OH, COH, or the like of the present invention by solvolysis or under physiological conditions.
  • Shape prodrug is a compound having a group that can be converted to an amino group, OH, COH, or the like of the present invention by solvolysis or under physiological conditions.
  • Examples of the group to be formed include groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), No. 7 Molecular design 163-198. .
  • the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid , Lactic acid, Malic acid, Tartaric acid, Chenic acid, Methanesulfonic acid, Ethanesulfonic acid, P-Toluenesulfonic acid, Aspartic acid, Carboxylic acid with organic acids such as glutamic acid, sodium, potassium, magnesium, calcium, aluminum And inorganic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortho salts, and ammonium salts.
  • the present invention also includes various hydrates and solvates of the compound of the present invention and pharmaceutically acceptable salts thereof, and polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • an appropriate protecting group a group that can be easily converted into the functional group
  • functional groups include amino groups, hydroxyl groups, and carboxyl groups
  • protecting groups include Greene and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999). And the like, and these may be appropriately selected and used according to the reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.
  • the prodrug of compound (I) can be produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound (I).
  • the reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • This step is a step for producing the compound (I) of the present invention by alkylating the compound (II) with the compound (III) having a leaving group.
  • the leaving group represented by Lv can be any leaving group commonly used in nucleophilic substitution reactions. Sulfonoxy such as tansulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., sulfonyl such as lower alkyl sulfole, arylsulfol and the like are preferably used.
  • an alkyl iodide usually used by those skilled in the art can be employed.
  • esters such as ethyl acetate, ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane, dichloromethane, 1,2-dichloroethane , Halogenated hydrocarbons such as black mouth form, ⁇ , ⁇ -dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), acetonitrile
  • the reaction can be carried out in a solvent inert to the reaction, or a solvent such as alcohols at room temperature to heating under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used
  • metal salt bases potassium carbonate, In the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy, etc. may be advantageous for the smooth progress of the reaction. is there.
  • Aromatic hydrocarbons such as toluene and benzene, triphenylphosphine, tri-n-butylphosphine, tris (dimethylamino) phosphine, triphenylphosphite, diphenoxyphenylphosphine, diphenyl (2-pyridyl) in solvents such as DMF )
  • phosphine such as (4-dimethylamino) diphenylphosphine
  • azodicarboxylate such as jetylazodicarboxylate, diisopropylpropyl dicarboxylate, dimethylazodicarboxylate, etc. It can also be performed at room temperature.
  • R represents lower alkyl, and other symbols have the same meanings as described above.
  • a compound of the invention which is R 3 months OR by hydrolysis from (Ia), R 3 is - a step for producing a OH der Ru present compound (Ib).
  • the hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in “Protective Groups in Organic Synthesis (3rd edition, 1999)”.
  • the starting compound used for the production of the compound (I) of the present invention can be easily produced, for example, using the following method, a known method, or a modified method thereof.
  • This step is a step for producing compound (VI) by alkylating compound (IV) with compound (V) having a leaving group.
  • the alkylation in this step can be performed in the same manner as in Production Method 1.
  • This step is a step for producing compound (VII) by -trolation of compound (VI).
  • Nitration can be carried out by a method that can be generally 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 (vm) by reducing the nitro compound ( ⁇ ).
  • a nitro group reduction reaction that can be generally employed by those skilled in the art can be used for the reduction reaction of the nitro group. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride, and a hydrogenation reaction using palladium-carbon or the like as a catalyst.
  • This step is a step of producing compound (VII) by alkylating compound (IX) with compound (V) having a leaving group.
  • the alkylation in this step can be carried out by the same method as Production method 1.
  • This step is a step for producing the compound (vm) by reducing the nitro compound ( ⁇ ). This reduction of the -tro group can be carried out in the same manner as in the third step of raw material synthesis 1. [0039] (Raw material synthesis 3)
  • This step is a step of producing compound (II) by sulfonating compound (X) with compound (XI).
  • halogen such as black mouth and bromo is preferably used.
  • the reaction for example, the conditions of sulfoniru ⁇ described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” can be applied. Specifically, the reaction can be carried out in the absence of a solvent or in a solvent such as tetrahydrofuran, methylene chloride, and acetonitrile, in the presence of a base such as triethylamine and pyridine, if necessary, under cooling or under reflux with heating.
  • a base such as triethylamine and pyridine
  • the compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphic substance thereof.
  • the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • optical isomers can be separated by selecting an appropriate raw material compound or by utilizing the difference in physical and physical properties between isomers.
  • optical isomers can be obtained by stereochemically pure isomers by general optical resolution methods (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Can lead to. It can also be produced from a suitable optically active raw material compound.
  • HEK293 cells stably expressing rat EP1 receptor (American type culture) • Collection (American Type Culture Collection), 96-well poly-D-lysine-coated plate (trade name: Biocoat PDL96W Black / Clear) to be 2 X 10 4 cells / well the day before the experiment First, it was dispensed to Nippon Betaton Dickinson Co., Ltd., and the medium containing 10% urinary fetal serum (FBS) at 37 ° C and 5% carbon dioxide (CO) (trade name: DMEM, Invito
  • 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.
  • Control Compound J Compound disclosed in Patent Document 4, Example 2 (71) Test Example 2 Receptor binding experiment using cells expressing EP1 receptor
  • Rat EP1 receptor has a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) at the N-terminus. ) And a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) and subcloned into an expression vector (trade name: pCEP4, Invitrogen) (the amino acid sequences of the signal peptide and the FLAG sequence are described in Patent Document 6) See).
  • This rat EP1 expression vector was transformed into HEK293EBNA cells (Ameri can Type) using a transfer reagent (trade name: Fugene-6, Roche Diagnostics). Culture Collection)), then 37 ° C, 5% CO, 1
  • the cells were cultured in a medium containing 0% FBS (trade name: DMEM, Invitrogen) 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 centrifuged (23000 rpm, 25
  • the membrane preparation was roughly adjusted by min x 2).
  • MES ethanesulfonic acid
  • KOH potassium hydroxide
  • ImM EDTA ImM EDTA
  • MgCl lOmM magnesium chloride
  • 0.02% 3-[(3-Colamidopropyl) dimethylammonio] propane
  • 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.
  • Test Example 3 Effects of compounds on changes in intravesical pressure in rats treated with sulprostone
  • sulprostone (0.3 mg / kg, sc) was administered to the rat, and the intravesical pressure curve 1 hour later was used as the pre-test compound administration value. Thereafter, the test compound was administered to the femoral vein, and the intravesical pressure was measured for up to 90 minutes. The inhibition rate by the test compound was calculated when the difference between the pre-test compound administration value and the sulprostone pre-administration value was 100%.
  • sulprostone administration resulted in bladder overactivity such as decreased urination interval, increased basal pressure, increased maximum urinary pressure, and decreased compliance.
  • the compound of the present invention improved the bladder overactivity.
  • Test Example 4 Effects of compounds on acetic acid-induced frequent urination rats
  • 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. Two days later, the experiment was conducted. Rats were placed in metabolic cages and acclimated for 1 hour, then the test compound 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.
  • Inhibitory activity 1 (%) 100—V / V X 100
  • control compound J (the compound disclosed in Patent Document 4, Example 2 (71)) has an inhibitory activity I power of S37% and an inhibitory activity II of 71%, whereas for example the compound of Example 51 Inhibitory activity I was 6% and inhibitory activity II was 7%.
  • 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 favorable properties as a pharmaceutical product, such as being excellent in metabolic stability and causing little drug interaction.
  • the compound of the present invention is highly safe and useful as a therapeutic agent for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc. It is.
  • a preparation containing one or more of the compounds (I) or a salt thereof of the present invention as an active ingredient is usually used using a pharmaceutical carrier, excipient, etc. that are usually used in the art. It can be prepared by this method.
  • Administration is oral by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intraarticular, intravenous, intramuscular, suppositories, eye drops, eye ointments, transdermal solutions. , Ointment, transdermal patch, transmucosal liquid, transmucosal patch, parenteral administration by inhalation, etc. It may be a form.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch. , Polybulurpyrrolidone, and / or magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as carboxymethyl starch sodium, a stabilizer, and a solubilizing agent according to a conventional method. Good.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, etc., commonly used inert diluents such as purified Contains water or ethanol.
  • the liquid composition may contain solubilizers, wetting agents, suspending agents and other adjuvants, sweeteners, flavors, fragrances and preservatives.
  • Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • aqueous solvent include distilled water for injection or physiological saline.
  • water-insoluble solvent include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emollients, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a pacteria retention filter, blending of a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointment or lotion bases include: polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol Cole, cetyl alcohol, lauromacrogol, sorbitan sesquioleate and the like.
  • 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.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • 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 alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like can use a dry powder or a powder-containing capsule which can be used for single or multiple administrations.
  • a dry powder or a powder-containing capsule which can be used for single or multiple administrations.
  • it may be in the form of an appropriate propellant such as a pressurized aerosol spray using a suitable gas such as black mouth fluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Dosing once or in 2 to 4 divided doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and should be administered once to several times a day. As a transmucosal agent, administer about 0.001 to 100 mg / kg per body weight once or multiple times a day. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc.
  • the compound of the present invention can be used in combination with various therapeutic or preventive agents for diseases for which the compound of the present invention is considered effective.
  • the combination may be administered simultaneously, separately in succession, or at desired time intervals.
  • the co-administered product may be a combination drug or separately formulated.
  • Ethyl 5-[(2,3-dihydro-1H-indene-5-yloxy) methyl] thiophene-2-carboxylic acid was subjected to -trolation with acetic acid in concentrated acetic acid to give ethyl 5- ⁇ [(6- -Tro-2,3-dihydro-1H-indene-5-yl) oxy] methyl ⁇ thiophene-2-carboxylic acid was prepared.
  • the residue obtained by concentrating the reaction solution under reduced pressure was covered with 1M hydrochloric acid and chloroform, and the organic layer was separated using a Phase Separate-filter manufactured by Isotute. Hexane and ethyl acetate were added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration.
  • Example compounds shown in Tables 8 to 24 below were produced using the corresponding starting materials.
  • Tables 8 to 24 show the structures of the example compounds, and Tables 25 to 26 show the production methods and physicochemical data.
  • Tables 27 to 28 show NMR data of some example compounds.
  • Tables 29 to 32 show structures of other compounds 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 has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urinary incontinence associated with overactive bladder, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial It is useful as a therapeutic agent for lower urinary tract diseases such as cystitis and prostatitis.

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Abstract

La présente invention concerne un composé qui peut être utilisé comme agent thérapeutique pour une maladie associée à un récepteur EP1, particulièrement des troubles des voies urinaires inférieures tels qu’un besoin fréquent/fort d’uriner ou une incontinence accompagnés d’une vessie hyperactive, d’une cystite, d’une cystite interstitielle ou d’une prostatite. L’invention est un dérivé d’acide carboxylique qui se caractérise par le fait qu’il comprend une structure sulfonamide et aussi un groupe alkyle inférieur substitué par un groupe hétérocyclique qui peut être substitué comme substitut sur un atome N dans la structure sulfonamide ou un sel du dérivé. Il a été déterminé que le dérivé d’acide carboxylique ou sel en provenant a une activité antagoniste puissante sur un récepteur EP1. Par conséquent, ce composé est utile comme agent thérapeutique pour une maladie des voies urinaires inférieures telle qu’une urination fréquente/incontinence accompagnée par une vessie hyperactive, un symptôme de voie urinaire inférieure accompagnée de prostatite, de cystite interstitielle ou de prostatite.
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WO2008099907A1 (fr) 2007-02-16 2008-08-21 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour trouble de la miction
WO2009157399A1 (fr) 2008-06-23 2009-12-30 アステラス製薬株式会社 Composé de sulfonamide ou sel de celui-ci
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US8772343B2 (en) 2010-07-12 2014-07-08 Pfizer Limited Chemical compounds
US9102621B2 (en) 2010-07-12 2015-08-11 Pfizer Limited Acyl sulfonamide compounds
US9649308B2 (en) 2012-10-12 2017-05-16 H. Lundbeck A/S Benzamide-containing compounds and their use in the treatment of pain
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WO2008099907A1 (fr) 2007-02-16 2008-08-21 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour trouble de la miction
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US8772343B2 (en) 2010-07-12 2014-07-08 Pfizer Limited Chemical compounds
US9096500B2 (en) 2010-07-12 2015-08-04 Pfizer Limited Acyl sulfonamide compounds
US9102621B2 (en) 2010-07-12 2015-08-11 Pfizer Limited Acyl sulfonamide compounds
US9649308B2 (en) 2012-10-12 2017-05-16 H. Lundbeck A/S Benzamide-containing compounds and their use in the treatment of pain
US10124010B2 (en) 2012-10-12 2018-11-13 Mindimmune Therapeutics, Inc. Cyclic amines
US10238654B2 (en) 2012-10-12 2019-03-26 Mindimmune Therapeutics, Inc. Benzamides-containing compounds and their use in the treatment of epilepsy
RU2683261C2 (ru) * 2014-05-28 2019-03-27 Астеллас Фарма Инк. Производное пиридина
US10005762B2 (en) 2014-12-05 2018-06-26 Astellas Pharma Inc. Pyridine derivatives

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