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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4192—1,2,3-Triazoles
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  • A61K31/4196—1,2,4-Triazoles
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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  • A61P39/00—General protective or antinoxious agents
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  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/28—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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Definitions

• the present invention relates to a medicament that suppresses (or mitigates) various neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) due to peripheral nerve disorders induced by anti-cancer agents.
• various neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• Neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• side effects such as nausea (vomiting), hair loss, anorexia, diarrhea, constipation, limb numbness, pain, stomatitis, leucopenia and the like are known as the side effects of anti-cancer agents such as paclitaxel (taxol) and the like.
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• peripheral nerve disorders lack an effective improving method.
• Acute symptoms of such peripheral nerve disorders include muscular pain and neuralgia, and these symptoms accompany numbness and pain in the fingers and toes as the treatment proceeds.
• QOL quality of life
• non-patent document 1 and non-patent document 2 neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) by peripheral nerve disorders caused by the administration of an anti-cancer agent form a dose limiting factor of various anti-cancer agents, and the development of a therapeutic drug for mitigating these neurological symptoms associated with a treatment with an anti-cancer agent has been desired (non-patent document 1 and non-patent document 2).
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• neuropathic pain is a severe pain that continues even after a complete cure of an injured tissue including peripheral and central nervous systems, which includes hyperalgesia in which even a mild pain stimulation is felt as a severe pain, spontaneous pain accompanying uncomfortable dysesthesia, allodynia in which even a light contact stimulation that does not develop a pain in itself causes a pain and the like.
• neuropathic pain animal models have been developed in recent years, and the elucidation of the onset mechanism thereof is ongoing.
• the representative models include the spinal cord nerve ligation model by Kim and Chung (non-patent document 3), the sciatic nerve partial ligation model by Seltzer et al. (non-patent document 4), the model with gentle ligation of the sciatic nerve at several sites by Bennett et al.
• non-patent document 5 the model with ligation and cleavage of tibial nerve and whole sural nerve, leaving the sural nerve, by Decosterd and Woolf (non-patent document 6) and the like, all of which creates pathology similar to human chronic neuropathic pain by causing peripheral nerve disorders.
• neuropathic pain includes one caused by changes in the peripheral nerve such as a sustained increase in the sensitivity or spontaneous firing and the like of the peripheral nerve starting from a peripheral nerve disorder (non-patent document 7), and one caused by changes in the spinal cord or highest center (non-patent document 8).
• the changes in the spinal cord are caused by activation of microglia, and factors such as cytokine and the like produced and liberated from the activated microglia are considered to stimulate secondary neuron and enhance pain sensitivity.
• Patent document 1 describes that (i) a compound represented by the formula:
• R is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group represented by the formula: —OR 1 wherein R 1 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group represented by the formula:
• R 1b is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and R 1c is the same as or different from R 1b , a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), R 0 is a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0 in combination form a bond
• ring A is a cycloalkene substituted by 1 to 4 substituents selected from (1) an aliphatic hydrocarbon group optionally having substituent(s), (2) an aromatic hydrocarbon group optionally having substituent(s), (3) a group represented by the formula: —OR 11 wherein R 11 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (4) a halogen atom
• Ar is an aromatic hydrocarbon group optionally having substituent(s), a group represented by the formula:
• n is an integer of 1 to 4, and (ii) a compound represented by the formula:
• R a is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group represented by the formula: —OR 1a wherein R 1a is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group represented by the formula:
• R 4a and R 5a are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), R 0a is a hydrogen atom or an aliphatic hydrocarbon group, or R a and R 0a in combination form a bond, Ar a is an aromatic hydrocarbon group optionally having substituent (s), a group represented by the formula:
• n is an integer of 1 to 4
• a salt thereof and a prodrug thereof have a nitric oxide (NO) production-inhibiting effect and an inhibitory effect on the production of inflammatory cytokines, such as TNF- ⁇ , IL-1, IL-6 and the like, and are useful as an agent for the prophylaxis or treatment of diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like; and
• Patent document 2 describes that a compound represented by the formula:
• R 1 is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group represented by the formula: —OR 1a wherein
• R 1a is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group represented by the formula:
• R 1b and R 1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s)
• X is methylene, NH, a sulfur atom or an oxygen atom
• Y is methylene optionally having substituent(s) or NH optionally having substituent(s)
• ring A is a 5- to 8-membered ring optionally having 1 to 4 substituents selected from the group consisting of (1) an aliphatic hydrocarbon group optionally having substituent(s), (2) an aromatic hydrocarbon group optionally having substituent(s), (3) a group represented by the formula: —OR 2 wherein R 2 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (4) a halogen atom, Ar is an aromatic hydrocarbon group optionally having substituent(s), a group represented by the formula:
• n is an integer of 0 to 2
• n is an integer of 1 to 3
• the total of m and n is 4 or less; provided that when X is a methylene group, then Y should be a methylene group optionally having substituent(s), a salt thereof and a prodrug thereof have a nitric oxide (NO) production-inhibiting effect and an inhibitory effect on the production of inflammatory cytokines, such as TNF- ⁇ , IL-1, IL-6 and the like, and are useful as an agent for the prophylaxis or treatment of diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like.
• diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like.
• Patent document 11 describes that the compounds described in the above-mentioned patent document 1 and/or patent document 2 have a TLR (particularly, TLR4) signal inhibitory action, and are useful as an agent for suppressing production or expression of a factor selected from IL-2 (Interleukin-2), IL-3, IL-8, IL-10, IL-12, IL-17, MIP-2 (macrophage inflammatory protein-2), KC (keratinocyte derived-chemokine), GM-CSF (granulocyte-macrophage colony-stimulating factor), IFN (interferon)- ⁇ and prostaglandin E2 and the like, and the like.
• IL-2 Interleukin-2
• IL-3 interleukin-2
• IL-8 interleukin-10
• IL-12 interleukin-12
• IL-17 MIP-2
• MIP-2 microphage inflammatory protein-2
• KC keratinocyte derived-chemokine
• GM-CSF granulocyte-ma
• Patent documents 3-13 describe that the compounds described in the above-mentioned patent document 1 and/or patent document 2 can be used for the treatment of pain.
• patent documents 1-13 do not describe that the compounds described in the above-mentioned patent document 1 and/or patent document 2 can suppress peripheral nerve disorders induced by anti-cancer agents.
• the present invention aims to provide a medicament for suppressing (or mitigating) neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) due to peripheral nerve disorders which are one of the side effects caused by the administration of anti-cancer agents.
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• the present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that the compounds represented by the below-mentioned formula (I), formula (II) and formula (III) unexpectedly suppress (or mitigate) neurological symptoms of peripheral nerve disorders caused by anti-cancer agents. Further studies made by the present inventors based on these findings have resulted in the completion of the present invention.
• the present invention relates to
• An agent for suppressing a peripheral nerve disorder induced by an anti-cancer agent which comprises a compound represented by the formula (I):
• R 1b and R 1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), R 0 is a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0 in combination may form a bond, ring A 1 is a cycloalkene optionally substituted by 1 to 4 substituents selected from the group consisting of (i) an aliphatic hydrocarbon group optionally having substituent(s), (ii) an aromatic hydrocarbon group optionally having substituent(s), (iii) a group represented by the formula: —OR 11 wherein R 11 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (iv) a halogen atom, Ar is an aromatic hydrocarbon group optionally having substituent(s), a group represented by the formula:
• n is an integer of 1 to 4, or a salt thereof or a prodrug thereof, or a compound represented by the formula (II):
• R 1b′ and R 1c′ are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s)
• X is methylene, NH, a sulfur atom or an oxygen atom
• Y is methylene optionally having substituent(s) or NH optionally having substituent(s)
• ring A′ is a 5- to 8-membered ring optionally having 1 to 4 substituents selected from the group consisting of (i) an aliphatic hydrocarbon group optionally having substituent(s), (ii) an aromatic hydrocarbon group optionally having substituent(s), (iii) a group represented by the formula: —OR 2′ wherein R 2′ is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (iv) a halogen atom, Ar′ is an aromatic hydrocarbon group optionally having substituent (s), a group represented by the formula:
• an agent for suppressing a peripheral nerve disorder induced by an anti-cancer agent comprising a compound represented by the formula (III):
• R 1aa is C 1-6 alkyl
• X aa is methylene or an oxygen atom
• Ar aa is phenyl optionally having 1 or 2 substituents selected from a halogen atom, C 1-6 alkyl and C 1-6 alkoxy, or a salt thereof or a prodrug thereof
• the agent of the above-mentioned [1] or [2] comprising ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof or a prodrug thereof
• the agent of the above-mentioned [1] or [2] comprising ethyl (3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate or a salt thereof or a prod
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• peripheral nerve disorders which are one of the side effects caused by the administration of an anti-cancer agent
• a treatment at a high dose which has been impossible heretofore, can be enabled by controlling the side effects of the administration of an anti-cancer agent.
• a long-term treatment with an anti-cancer agent while maintaining the QOL of patients, can be enabled by controlling the side effects of the administration of an anti-cancer agent.
• R 1b and R 1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or R and R 0 in combination form a bond, with particular preference given to the group represented by the formula: —OR 1 wherein R 1 is as defined above.
• R 0 is a hydrogen atom or an aliphatic hydrocarbon group.
• R 2 is a hydrogen atom or an aliphatic hydrocarbon group, and other symbols are as defined above, and specifically can be represented by the formula:
• aliphatic hydrocarbon group of the “aliphatic hydrocarbon group optionally having substituent(s)” for R, R 1 , R 11 , R 1b or R 1c and the “aliphatic hydrocarbon group” for R 0 or R 2 , for example, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, etc. are preferable.
• alkyl for example, linear or branched alkyl having 1 to 20 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl) and the like are preferable, and particularly, for example, lower alkyl having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) and the like are preferable.
• lower alkyl having 1 to 6 carbon atoms e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, iso
• cycloalkyl for example, cycloalkyl having a carbon number of 3 to 10 (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl) and the like are preferable and, in particular, for example, cycloalkyl having a carbon number of 3 to 6 (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and the like are preferable.
• cycloalkyl having a carbon number of 3 to 10 e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
• cycloalkyl having a carbon number of 3 to 6 e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
• cycloalkylalkyl for example, cycloalkylalkyl having a carbon number of 4 to 12 (e.g., cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl) and the like are preferable and, in particular, for example, cycloalkylalkyl having a carbon number 4 to 8 (particularly 4 to 7) (e.g., cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl) and the like are preferable.
• alkenyl for example, lower alkenyl having a carbon number of 3 to 6 (e.g., propenyl, butenyl, pentenyl) and the like are preferable and, in particular, for example, lower alkenyl having a carbon number of 3 or 4 (e.g., propenyl, butenyl) and the like are preferable.
• alkynyl for example, lower alkynyl having a carbon number of 3 to 6 (e.g., propynyl, butynyl, pentynyl) and the like are preferable and, in particular, for example, lower alkynyl having a carbon number of 3 or 4 (e.g., propynyl, butynyl) and the like are preferable.
• lower alkynyl having a carbon number of 3 or 4 e.g., propynyl, butynyl
• substituents are substituted at substitutable positions of the aforementioned “aliphatic hydrocarbon group”. They are not limited to a single substituent, but may be the same or different, and more than one substituent (preferably 2 to 4) may be used.
• C 1-6 alkoxy for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and the like are used.
• C 3-10 cycloalkyloxy for example, cyclopropyloxy, cyclohexyloxy and the like are used.
• C 6-10 aryloxy for example, phenoxy, naphthyloxy and the like are used.
• C 7-19 aralkyloxy for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, 1-naphthylmethyloxy and the like are used.
• C 1-6 alkylthio (the sulfur atom is optionally oxidized)”, for example, methylthio, ethylthio, n-propylthio, n-butylthio, methylsulfinyl, methylsulfonyl and the like are used.
• C 3-10 cycloalkylthio (the sulfur atom is optionally oxidized)”, for example, cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl, cyclohexylsulfonyl and the like are used.
• C 6-10 arylthio (the sulfur atom is optionally oxidized)”, for example, phenylthio, naphthylthio, phenylsulfinyl, phenylsulfonyl and the like are used.
• C 7-19 aralkylthio (the sulfur atom is optionally oxidized)
• benzylthio, phenylethylthio, benzhydrylthio, benzylsulfinyl, benzylsulfonyl and the like are used.
• halogen atom for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.
• C 1-10 alkoxy-carbonyl for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like are used.
• C 3-6 cycloalkyloxy-carbonyl for example, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like are used.
• C 6-10 aryloxy-carbonyl for example, phenoxycarbonyl, naphthyloxycarbonyl and the like are used.
• C 7-19 aralkyloxy-carbonyl for example, benzyloxycarbonyl, benzhydryloxycarbonyl, 2-phenethyloxycarbonyl and the like are used.
• C 6-10 aryl-carbonyl for example, benzoyl group, naphthoyl group and the like are used.
• C 1-6 alkanoyl for example, formyl, acetyl, propionyl, butyryl group, valeryl group, pivaloyl group and the like are used.
• C 3-5 alkenoyl for example, acryloyl, crotonoyl and the like are used, as the “C 6-10 aryl-carbonyloxy”, for example, benzoyloxy, naphthoyloxy and the like are used.
• C 2-6 alkanoyloxy for example, acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy and the like are used.
• C 3-5 alkenoyloxy for example, acryloyloxy, crotonoyloxy and the like are used.
• carbamoyl optionally having substituent(s) for example, carbamoyl or cyclic amino (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl)carbonyl or the like, which is optionally substituted by one or the same or different two substituents selected from
• C 1-7 acyl e.g., acetyl, propionyl, benzoyl
• C 1-4 alkoxy-phenyl e.g., methoxyphenyl
• C 1-4 alkoxy-phenyl e.g., methoxyphenyl
• carbamoyl N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl and the like are used.
• thiocarbamoyl optionally having substituent(s)
• thiocarbamoyl optionally substituted by one or the same or different two substituents selected from
• phenyl and the like is used, and specifically, for example, thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl and the like are used.
• carbamoyloxy optionally having substituent(s) for example, carbamoyloxy optionally substituted by one or the same or different two substituents selected from
• phenyl and the like are used, and specifically, for example, carbamoyloxy, N-methylcarbamoyloxy, N,N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy and the like are used.
• C 1-6 alkanoylamino for example, an acetamido group, a propionamido group, a butyramido group, a valeramido group, a pivalamido group and the like are used.
• C 6-10 aryl-carbonylamino for example, a benzamido group, a naphthamido group, a phthalimido group and the like are used.
• C 1-10 alkoxy-carboxamido for example, methoxycarboxamido (CH 3 OCONH—), ethoxycarboxamido, tert-butoxycarboxamido and the like are used.
• C 6-10 aryloxy-carboxamido for example, phenoxycarboxamido (C 6 H 5 OCONH—) and the like are used.
• C 7-19 aralkyloxy-carboxamido for example, benzyloxycarboxamido (C 6 H 5 CH 2 OCONH—), benzhydryloxycarboxamido and the like are used.
• C 1-10 alkoxy-carbonyloxy for example, methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-butoxycarbonyloxy, n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy and the like are used.
• C 6-10 aryloxy-carbonyloxy for example, phenoxycarbonyloxy, naphthyloxycarbonyloxy and the like are used.
• C 7-19 aralkyloxy-carbonyloxy for example, benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, benzhydryloxycarbonyloxy and the like are used.
• C 3-10 cycloalkyloxy-carbonyloxy for example, cyclopropyloxycarbonyloxy, cyclohexyloxycarbonyloxy and the like are used.
• ureido optionally having substituent(s) for example, ureido optionally substituted by 1 to 3 (particularly 1 or 2) substituents selected from
• phenyl, and the like is used and, for example, ureido, 1-methylureido, 3-methylureido, 3,3-dimethylureido, 1,3-dimethylureido, 3-phenylureido and the like are used.
• substituents When two or more substituents are present, they may be the same or different.
• the heterocyclic group is a group obtained by removing one hydrogen atom bonded to the heterocycle, which is, for example, a 5- to 8-membered ring (particularly 5- or 6-membered ring) group containing 1 to several, preferably 1 to 4, hetero atoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom and the like, or a fused ring group thereof.
• heterocyclic groups may be substituted at substitutable positions by 1 to 3 substituents selected from
• C 6-10 aryl of the “C 6-10 aryl optionally having substituent(s)”, for example, phenyl, naphthyl, etc. can be used.
• the C 6-10 aryl may be substituted at a substitutable position by a substituent selected from those exemplified as the “substituent” (except for C 6-10 aryl optionally having substituent(s)) of the “aliphatic hydrocarbon group optionally having substituent(s)” described above.
• substituent is not limited to a single substituent, but the same or different, more than one (preferably 2 to 4) substituents may be used.
• the substituent may form, together with the aliphatic hydrocarbon group, an optionally substituted fused ring group, and as such fused ring group, indanyl, 1,2,3,4-tetrahydronaphthyl, etc. can be used.
• This fused ring group may be substituted at a substitutable position by a substituent selected from those exemplified as the “substituent” of the “aliphatic hydrocarbon group optionally having substituent(s)” described above.
• substituent substitutes at a substitutable position of the fused ring group wherein the substituent is not limited to a single substituent, but the same or different, more than one (preferably 2 to 4) substituents may be used.
• R, R 1 , R 11 , R 1b and R 1c include lower alkyl having a carbon number of 1 to 6 which may have substituent(s) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butoxycarbonylmethyl, hydroxyethyl, phenylmethyl, carboxymethyl) and the like.
• C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like are preferable, methyl, ethyl, n-propyl and the like are more preferable, and ethyl and the like are particularly preferable.
• an aromatic hydrocarbon group having a carbon number of 6 to 14 e.g., phenyl, naphthyl, anthryl, indenyl
• aryl having a carbon number of 6 to 10 e.g., phenyl, naphthyl
• phenyl and the like are particularly preferable.
• a halogen atom e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
• lower (C 1-4 ) alkyl e.g., methyl, ethyl, propyl, butyl
• lower (C 1-4 ) alkoxy e.g., methoxy, ethoxy, propoxy, butoxy
• lower (C 1-4 ) alkoxy-carbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl
• acylamino e.g., alkanoylamino having a carbon number of 1 to 4 such as acetylamino, propionylamino, butyrylamino and the like
• cycloalkyl having a carbon number of 3 to 6
• a halogen atom e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
• lower (C 1-4 ) alkyl e.g., methyl, ethyl, propyl, butyl
• a fluorine atom, a chlorine atom and methyl are used.
• substituents substitute at substitutable positions of the aromatic hydrocarbon group, and the number of the substituents is preferably 1 to 5, more preferably 1 to 3, most preferably 1 or 2. When two or more of such substituents are present, they may be the same or different.
• heterocyclic group of the “heterocyclic group optionally having substituent(s)” for R is, for example, a 5 to 8-membered ring (particularly a 5 or 6-membered ring) group containing 1 to several, preferably 1 to 4, hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom and the like, and a fused ring group thereof.
• heterocyclic groups are optionally substituted by 1 to 3 substituents selected from C 1-4 alkyl (e.g., methyl, ethyl), hydroxy, oxo, C 1-4 alkoxy (e.g., methoxy, ethoxy) and the like at substitutable positions.
• substituents selected from C 1-4 alkyl (e.g., methyl, ethyl), hydroxy, oxo, C 1-4 alkoxy (e.g., methoxy, ethoxy) and the like at substitutable positions.
• substituents selected from C 1-4 alkyl (e.g., methyl, ethyl), hydroxy, oxo, C 1-4 alkoxy (e.g., methoxy, ethoxy) and the like at substitutable positions.
• C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like is preferable.
• methyl, ethyl, n-propyl and the like are more preferable, and methyl and the like are particularly preferable.
• R 0 or R 2 in particular, a hydrogen atom and methyl are preferable.
• an aromatic hydrocarbon group having a carbon number of 6 to 14 e.g., phenyl, naphthyl, anthryl, indenyl
• aryl having a carbon number of 6 to 10 e.g., phenyl, naphthyl
• phenyl and the like are particularly preferable.
• a halogen atom e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
• lower (C 1-4 ) alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
• lower (C 1-4 ) alkoxy e.g., methoxy, ethoxy, propoxy, butoxy
• (4) lower (C 1-4 ) alkoxy-carbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl
• acylamino e.g., alkanoylamino having a carbon number of 1 to 4 such as acetylamino, propionylamino, butyrylamino and the like
• a halogen atom e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
• lower (C 1-4 ) alkyl e.g., methyl, ethyl, propyl, butyl
• a fluorine atom, a chlorine atom and methyl are used.
• substituents substitute at substitutable positions of the aromatic hydrocarbon group, and the number of the substituents is preferably 1 to 5, more preferably 1 to 3, most preferably 1 or 2. When two or more of such substituents are present, they may be the same or different.
• phenyl optionally having substituent(s) is preferable.
• halogenophenyl, lower (C 1-4 ) alkylphenyl, phenyl substituted by a halogen atom and lower (C 1-4 ) alkoxycarbonyl, phenyl substituted by a halogen atom and lower (C 1-4 ) alkyl and the like are preferably used.
• R 4 and R 5 are the same or different and each is a halogen atom or lower (C 1-4 ) alkyl, and n is an integer of 0 to 2, is more preferable, and one wherein at least one of R 4 and R 5 is a halogen atom is further preferable.
• halogen atom for R 4 or R 5 a fluorine atom or a chlorine atom is preferable.
• halogenophenyl for example, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophen
• lower (C 1-4 ) alkylphenyl for example, 2-ethylphenyl, 2,6-diisopropylphenyl and the like are preferably used.
• lower (C 1-4 ) alkoxyphenyl for example 4-methoxyphenyl and the like are preferably used.
• lower (C 1-4 ) alkoxy-carbonylphenyl for example, 2-ethoxycarbonylphenyl, 2-methoxycarbonylphenyl, 4-methoxycarbonylphenyl and the like are preferably used.
• halogeno lower (C 1-4 ) alkylphenyl for example, 2-trifluoromethylphenyl and the like are preferably used.
• halogeno lower (C 1-4 ) alkoxyphenyl for example, 2-trifluoromethoxyphenyl, 4-(2,2,3,3,3-pentafluoropropoxy)phenyl and the like are preferably used.
• lower (C 1-4 ) alkanoylphenyl for example, 2-acetylphenyl and the like are preferably used.
• phenyl substituted by a 5-membered aromatic heterocyclic group for example, 4-(2H-1,2,3-triazol-2-yl)phenyl, 4-(2H-tetrazol-2-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(1H-1,2,3-triazol-1-yl)phenyl and the like are preferably used.
• lower (C 1-4 ) alkoxy-carbonyl-lower (C 1-4 ) alkyl-carbamoylphenyl for example, 4-(N-ethoxycarbonylmethylcarbamoyl)phenyl and the like are preferably used.
• 1,3-diacylguanidino-lower (C 1-4 ) alkylphenyl for example, 4-(1,3-bis-tert-butoxycarbonylguanidinomethyl)phenyl and the like are preferably used.
• phenyl substituted by a halogen atom and lower (C 1-4 ) alkyl for example, 2-fluoro-4-methylphenyl, 2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl and the like are preferably used.
• phenyl substituted by a halogen atom and lower (C 1-4 ) alkoxy-carbonyl for example, 2-chloro-4-methoxycarbonylphenyl and the like are preferably used.
• phenyl substituted by a halogen atom and cyano 2-chloro-4-cyanophenyl and the like are preferably used.
• phenyl substituted by a halogen atom and 5-membered aromatic heterocyclic group for example, 2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl and the like are preferably used.
• phenyl substituted by a halogen atom and lower (C 1-4 ) alkoxy-carbonyl-lower (C 1-4 ) alkyl-carbamoyl for example, 2-chloro-4-(N-tert-butoxycarbonylmethylcarbamoyl)phenyl, 2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl)phenyl and the like are preferably used.
• phenyl, phenyl substituted by 1 to 3 (particularly 1 or 2) halogen atoms may be the same or different; e.g., 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 4-bromo-2-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl
• phenyl substituted by 1 to 3 (particularly 1 or 2) halogen atoms may be the same or different; e.g., 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,5-trifluorophenyl), phenyl substituted by a halogen atom and lower (C 1-4 ) alkyl (e.g., 2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl) and the like are preferable.
• halogen atoms when substituted by plural halogen atoms, these halogen atoms may be the same or different; e.g., 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-d
• 2,4-difluorophenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methylphenyl and the like are preferable, and 2,4-difluorophenyl, 2-chloro-4-fluorophenyl and the like are preferable.
• ring A 1 is preferably cycloalkene optionally substituted by 1 to 4 substituents selected from
• R 11 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (iv) halogen atoms.
• cycloalkene optionally substituted by 1 to 4 substituents selected from (i) an aliphatic hydrocarbon group optionally having substituent(s), (ii) an aromatic hydrocarbon group optionally having substituent(s), and (iv) halogen atoms are preferable.
• substituents (i) to (iv) substitute on substitutable carbon atoms in the ring A 1 , and when the ring A 1 is substituted by two or more of such substituents, the substituents may be the same or different.
• a single carbon atom may be substituted by two substituents, and different carbon atoms may be substituted by two or more substituents.
• aliphatic hydrocarbon group optionally having substituent(s) as the substituent on the ring A 1 , for example, those similar to the “aliphatic hydrocarbon group optionally having substituent(s)” for R and the like described above may be used.
• aromatic hydrocarbon group optionally having substituent(s) as the substituent on the ring A 1 , for example, those similar to the “aromatic hydrocarbon group optionally having substituent(s)” for Ar described above may be used.
• substituents for the ring A 1 , 1 or 2 C 1-6 alkyl groups e.g., methyl, tert-butyl
• phenyl e.g., phenyl, a halogen atom (e.g., fluorine, chlorine, bromine, iodine atoms), etc.
• a halogen atom e.g., fluorine, chlorine, bromine, iodine atoms
• n 1 to 3 is preferable, and 2 is particularly preferable.
• the compound represented by the formula (I) the compound represented by the formula (Ibb′) is preferable, and the compound represented by the formula (Inn) is more preferable.
• R 1 is lower alkyl optionally having substituent(s) (more preferably R 1 is C 1-6 alkyl)
• R 2 is a hydrogen atom or lower (C 1-6 ) alkyl
• Ar is phenyl optionally having substituent(s) (more preferably Ar is phenyl substituted by 1 or 2 halogen atoms)
• n is 1, 2 or 3 (more preferably n is 2).
• R 1a is C 1-6 alkyl
• R 2a is a hydrogen atom or C 1-6 alkyl
• Ara is phenyl substituted by 1 or 2 halogen atoms.
• aliphatic hydrocarbon group optionally having substituent(s) “aromatic hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” for R 1′ , those similar to these substituents for R can be used.
• R 1b′ and R 1c′ for example, those similar to the aforementioned “aliphatic hydrocarbon group optionally having substituent(s)” for R can be used.
• R 1b′ and R 1c′ for example, lower alkyl having 1 to 6 carbon atoms optionally having substituent(s) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butoxycarbonylmethyl, hydroxyethyl) and the like are preferably used.
• methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like are preferably used.
• methyl, ethyl, n-propyl and the like are preferable, and ethyl and the like are specifically preferable.
• R 1′ a group represented by the formula: —OR 1a′ wherein R 1′ is as defined above is preferable.
• R 1a′ a group represented by the formula: —OR 1a′ wherein R 1′ is as defined above is preferable.
• R 1a′ a group represented by the formula: —OR 1a′ wherein R 1′ is as defined above.
• R 1a′ a group represented by the formula: —OR 1a′ wherein R 1′ is as defined above is preferable.
• R 1a′ a group represented by the formula: —OR 1a′ wherein R 1′ is as defined above is preferable.
• substituent(s) e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butoxycarbonylmethyl, hydroxyethyl
• substituent(s) e.g., methyl, ethyl, n-propyl, is
• C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like are preferably used.
• methyl, ethyl, n-propyl and the like are preferable, and ethyl and the like are preferable.
• C 1-6 alkyl e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
• hydroxyl substituted-C 1-6 alkyl e.g., hydroxymethyl, hydroxyethyl
• C 1-4 alkoxy-carbonyl-C 1-4 alkyl e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, tert-butoxycarbonylethyl
• methyl is preferable.
• Y unsubstituted methylene is particularly preferable.
• C 1-6 alkyl e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
• hydroxyl substituted-C 1-6 alkyl e.g., hydroxymethyl, hydroxyethyl
• C 1-4 alkoxy-carbonyl-C 1-4 alkyl e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, tert-butoxycarbonylethyl
• methyl is preferable.
• Y unsubstituted NH is particularly preferable.
• aromatic hydrocarbon group optionally having substituent(s) for Ar′, those similar to the aforementioned “aromatic hydrocarbon group optionally having substituent(s)” for Ar can be used.
• R 3′ is a halogen atom or a lower alkyl group, and ring B′ is optionally further substituted by 1 or 2 halogen atoms is preferable, and a group represented by the formula (c1):
• R 3a′ and R 3b′ are the same or different and each is a halogen atom is more preferable.
• a halogen atom for R 3 and a halogen atom which is a substituent of ring B′ and a halogen atom for R 3a′ and R 3b′ in the formula (c1) a fluorine atom or a chlorine atom is preferable.
• the lower alkyl for R 3′ in the formula (c) for example, C 1-4 alkyl such as methyl, ethyl, propyl and the like can be mentioned.
• 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-chlorophenyl and the like are preferable.
• 2,4-difluorophenyl, 2-chloro-4-fluorophenyl and the like are preferable.
• X is methylene, NH, a sulfur atom or an oxygen atom, and methylene or an oxygen atom is particularly preferable.
• Ring A′ is a 5- to 8-membered ring substituted by a group represented by the formula: —CO—R 1′ wherein R 1′ is as defined above and a group represented by the formula: —SO 2 —Y—Ar′ wherein Y and Ar′ are as defined above, and optionally further substituted by 1 to 4 substituents selected from the group consisting of
• R 2′ is as defined above and (iv) a halogen atom.
• a 5- to 8-membered ring optionally substituted by 1 to 4 substituents selected from (i) an aliphatic hydrocarbon group optionally having substituent(s), (ii) an aromatic hydrocarbon group optionally having substituent(s) and (iv) a halogen atom are preferable.
• substituents are present at substitutable positions on the ring A′.
• X constituting the ring is NH or methylene, they can substitute the NH and methylene.
• ring A′ is substituted by plural substituents, the kinds of such substituents may be the same or different. In addition, two substituents may substitute on the same carbon atom.
• aliphatic hydrocarbon group optionally having substituent(s) and “aromatic hydrocarbon group optionally having substituent(s)”, which are substituents of ring A′, for example, those similar to the aforementioned group for R can be mentioned.
• substituent for ring A′ 1 or 2 C 1-6 alkyl (e.g., methyl, tert-butyl), phenyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and the like are preferably used. When two substituents are present, they may be the same or different.
• the “s” is an integer of 0 to 2
• “t” is an integer of 1 to 3
• the total of “s” and “t” is 4 or less, with preference given to “s” being 1 and “t” being 1.
• R 1′ is a group represented by the formula: —OR 1a′ wherein R 1a′ is C 1-6 alkyl, a group represented by the formula:
• X is methylene or an oxygen atom
• Y is methylene or —NH—
• Ar′ is phenyl optionally having 1 or 2 substituents selected from a halogen atom and C 1-4 alkoxy, that is, a compound represented by the formula (IIa):
• R 1a′′ is C 1-6 alkyl
• X a is methylene or an oxygen atom
• Y a is methylene or —NH—
• Ar a ′ is phenyl optionally having 1 or 2 substituents selected from a halogen atom and C 1-4 alkoxy, provided when X a is methylene, then Y a is methylene optionally having substituent(s).
• R 1′ is a group represented by the formula: —OR 1a′ (R 1a′ is C 1-6 alkyl), a group represented by the formula:
• X and Y are both methylene, or X is an oxygen atom and Y is —NH—, and Ar′ is phenyl optionally having two halogen atoms (e.g., 2-chloro-4-fluorophenyl).
• R 1aa is C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl etc.). Of these, ethyl is preferable.
• X aa is methylene or an oxygen atom.
• Ar aa is phenyl optionally having 1 or 2 substituents selected from a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.), C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl etc.) and C 1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy,
• phenyl optionally having 1 or 2 substituents selected from a halogen atom (particularly, a fluorine atom, a chlorine atom) and C 1-6 alkyl (particularly, methyl, ethyl, isopropyl) is preferable.
• substituents particularly, a fluorine atom, a chlorine atom
• C 1-6 alkyl particularly, methyl, ethyl, isopropyl
• R 1aa is ethyl
• X aa is methylene or an oxygen atom
• Ar aa is phenyl optionally having 1 or 2 substituents selected from a halogen atom (particularly, a fluorine atom, a chlorine atom) and C 1-6 alkyl (particularly, methyl, ethyl, isopropyl).
• a halogen atom particularly, a fluorine atom, a chlorine atom
• C 1-6 alkyl particularly, methyl, ethyl, isopropyl
• each stereoisomer and a mixture of these stereoisomers are both encompassed in the present invention.
• the compound represented by the formula (I) is a compound represented by the formula (Icc) or (Inn)
• the formula (b) of the compound represented by the formula (II) is the formula (b1)
• s and t are 1 and the compound represented by the formula (III)
• each has an optical isomer based on the asymmetric carbon in cycloalkene or cyclohexene ring.
• Such optical isomer and a mixture of such optical isomers are both encompassed in the present invention.
• the compounds represented by the formulas (I), (II) and (III) may be converted into a salt with an inorganic base, organic base, inorganic acid, organic acid, basic or acidic amino acid, and the like.
• an alkali metal salt such as sodium and potassium salts, etc.
• an alkaline earth metal salt such as calcium and magnesium salts, etc.
• aluminum salt such as calcium and magnesium salts, etc.
• ammonium salt and the like
• the salt with an organic base for example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc can be used.
• a salt with an inorganic acid for example, a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc can be used.
• a salt with an organic acid for example, a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like can be used.
• a salt with a basic amino acid for example, a salt with arginine, lysine, ornithine, etc can be used.
• a salt with acidic amino acid for example, a salt with aspartic acid, glutamic acid, and the like can be used.
• a prodrug of the compound represented by the formula (I), (II) or (III) or a salt thereof is a compound which is converted into a parent compound (that is, the compound represented by the formula (I), (II) or (III)) as a result of a reaction with an enzyme, gastric acid etc. under physiological conditions in vivo.
• the compound is converted into a parent compound by enzymatical oxidation, reduction, hydrolysis etc., by hydrolysis due to gastric acid etc.
• a prodrug of a parent compound may be a compound obtained by subjecting an amino group of a parent compound to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group of a parent compound to an eicosanoylation, alanylation, pentylaminocarbonylation, 2-hydroxypropionylation, 2-acetoxypropionylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, etc.); a compound obtained by subjecting a hydroxy group of a parent compound to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting a hydroxy group of a parent compound to an acetylation, palmitoylation, propanoylation, pivaloy
• a prodrug of the compound represented by the formula (I), (II) or (III) may also be one which is converted into a parent compound (that is, the compound represented by the formula (I), (II) or (III)) under a physiological condition, such as those described in “IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).
• the compound represented by the formula (I), a salt thereof or a prodrug thereof can be produced according to a method known per se, for example, a production method described in WO99/46242 and WO02/32859 or a method analogous thereto.
• the compound represented by the formula (II), a salt thereof or a prodrug thereof can be produced according to a method known per se, for example, a production method described in WO01/10826 or a method analogous thereto.
• a compound represented by the formula (III) or a salt thereof or a prodrug thereof can be produced according to a method known per se.
• X aa in the formula (III) when X aa in the formula (III) is methylene, it can be produced by the production methods described in WO99/46242 and WO02/32859 or the method analogous thereto, and when X aa is an oxygen atom, it can be produced by the production methods described in WO01/10826, the below-mentioned Reference Example 1 and Reference Example 2 or a method analogous thereto.
• optically active compound or a salt thereof contains an enantiomer
• general separation means may be applied such as diastereomeric salt methods wherein a salt with an optically active acid (e.g., camphor sulfonic acid) or optically active base (e.g., 1-methylbenzylamine) is formed, inclusion compound methods using an optically active host molecule (e.g., 1,6-bis(2-chlorophenyl)-1,6-diphenylhexa-2,4-diyn-1,6-diol), various chromatographies (e.g., liquid chromatography using an optically active column), fractional recrystallization and the like, whereby an optically pure compound can be obtained.
• optically active acid e.g., camphor sulfonic acid
• optically active base e.g., 1-methylbenzylamine
• inclusion compound methods using an optically active host molecule e.g., 1,6-bis(2-chlorophenyl)-1,6
• a compound represented by the formula (I), (II) or (III), or a salt thereof or a prodrug thereof may be any of hydrate, non-hydrate, solvate and non-solvate.
• compound A may be labeled with an isotope (e.g., 3 H, 14 C, 3 S, 125 I) and the like.
• an isotope e.g., 3 H, 14 C, 3 S, 125 I
• compound A may be a deuterated compound wherein 1 H is converted to 2 H(D).
• Compound A is useful for suppressing (or mitigating) various neurological symptoms (e.g., dysesthesia such as numbness, pain (e.g., muscular pain, neuralgia), anesthesia, ache and the like) caused by peripheral nerve disorders that may be developed as the side effects of the administration of chemotherapeutic agents such as anti-cancer agent and the like.
• various neurological symptoms e.g., dysesthesia such as numbness, pain (e.g., muscular pain, neuralgia), anesthesia, ache and the like
• chemotherapeutic agents such as anti-cancer agent and the like.
• Compound A is useful for the suppression (or mitigation) of numbness from among the above-mentioned neurological symptoms.
• Compound A is also useful for the suppression (or mitigation) of pain from among the above-mentioned neurological symptoms.
• lung cancer e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, colorectal cancer (e.g., colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer (e.g.,
• anti-cancer agent examples include taxane anti-cancer agents (e.g., paclitaxel (taxol), docetaxel), vinca alkaloid anti-cancer agents (e.g., vincristine, vinblastine), platinum preparations (e.g., cisplatin, carboplatin, oxaliplatin), molecular targeted drugs (e.g., bortezomib) and the like.
• taxane anti-cancer agents e.g., paclitaxel (taxol), docetaxel
• vinca alkaloid anti-cancer agents e.g., vincristine, vinblastine
• platinum preparations e.g., cisplatin, carboplatin, oxaliplatin
• molecular targeted drugs e.g., bortezomib
• paclitaxel, vincristine, cisplatin, carboplatin and bortezomib are known as the agents having numbness and/or pain (e.g., muscular pain, neuralgia) as remarkable side effects (J. Clin Oncol. 24:1633-1642, 2006; Neurotoxicology, 27:992-1002, 2006; British Journal of Haematology, 127, 165-172, 2004).
• compound A is particularly useful for suppressing (or mitigating) dysesthesia such as numbness and/or pain (e.g., muscular pain, neuralgia) and the like caused by paclitaxel, vincristine, cisplatin, carboplatin and/or bortezomib.
• compound A is useful for suppressing (or mitigating) dysesthesia such as numbness and/or pain (e.g., muscular pain, neuralgia) and the like caused by paclitaxel.
• the dose of the aforementioned anti-cancer agents can be appropriately determined based on the clinical dose of each of the agents. As long as compound A can suppress the side effects, a dose higher than the conventional dose can also be administered.
• the dose is administered by drip infusion according to the schedule of an administration at 60-70 mg/m 2 every 3 weeks, or at 210 mg/m 2 once a week for 3 weeks and one week cessation of the drug.
• Such preparation can be produced by the method conventionally used in the technical field of preparations, for example, the method described in the Japanese Pharmacopoeia and the like.
• the dose of compound A can be appropriately determined in consideration of the dose and dosing period of the above-mentioned anti-cancer agents, age, body weight and symptom of the subject of administration, dosage form, administration method and the like.
• the dose of compound A is, for example, generally 0.1-10 mg/kg/day, preferably 0.6-2.4 mg/kg/day, of compound A in a free form for an adult patient (body weight 60 kg).
• This mount is orally or parenterally administered in one to several portions (e.g., 1-3 portions) a day. It is needless to say that an amount smaller than the aforementioned dose may be sufficient or an administration beyond the above level may be necessary, since the dose changes under various conditions as mentioned above.
• Compound A can be safely administered to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) orally or parenterally.
• mammals e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey
• Examples of the dosage form of compound A include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet), capsule (including soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparations, pulmonary preparation (inhalant), eye drop and the like.
• oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet), capsule (including soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g.
• these preparations may be release control preparations (e.g., sustained-release microcapsule) such as immediate-release preparations, sustained-release preparations and the like.
• release control preparations e.g., sustained-release microcapsule
• immediate-release preparations sustained-release preparations and the like.
• sustained-release preparations can be produced by the method conventionally used in the technical field of preparations, for example, the method described in the Japanese Pharmacopoeia and the like.
• Compound A is used in combination with the aforementioned anti-cancer agents to suppress (or mitigate) various neurological symptoms caused by peripheral nerve disorders that may be developed as the side effects of the administration of the aforementioned anti-cancer agents.
• the present invention relates to kit of parts for suppressing a peripheral nerve disorder induced by an anti-cancer agent comprising compound A and the anti-cancer agent.
• the present invention relates to a medicament comprising compound A and the anti-cancer agent.
• one or more kinds of the aforementioned anti-cancer agents may be combined.
• paclitaxel it may be combined with cisplatin and/or carboplatin and administered.
• the timing of the administration of compound A and an anti-cancer agent is not particularly limited.
• Compound A (or a pharmaceutical composition thereof) and an anti-cancer agent (or a pharmaceutical composition thereof) may be administered to an administration subject simultaneously or in a staggered manner.
• each of compound A (or a pharmaceutical composition thereof) and one or more kinds of anti-cancer agents (or a pharmaceutical composition thereof) may be administered to an administration subject simultaneously or in a staggered manner.
• the mode of administration of compound A and an anti-cancer agent is not particularly limited as long as compound A and an anti-cancer agent are combined.
• the mixing ratio of compound A and the aforementioned anti-cancer agent in the combination drug of the present invention can be appropriately determined according to the subject of administration, administration route, disease and the like.
• the content of compound A in the combination agent of the present invention differs depending on the form of a preparation, and is usually from about 0.01 to 99.8% by weight, preferably from about 0.1 to 50% by weight, further preferably from about 0.5 to 20% by weight, based on total of the preparation.
• the content of the anti-cancer agent in the combination agent of the present invention varies depending on the form of the preparation, and is usually from about 0.01 to 99.8% by weight, preferably from about 0.1 to 50% by weight, further preferably from about 0.5 to 20% by weight, based on the total of the preparation.
• the content of each anti-cancer agent can be determined within the range of the above-mentioned content.
• the mixing rate of the respective anti-cancer agents can be appropriately determined according to the administration subject, administration route, disease and the like.
• the content of additives such as carrier in the combination agent of the present invention differs depending on the form of a preparation, and is usually from about 1 to 99.98% by weight, preferably from about 10 to 90% by weight, based on total of the preparation.
• compound A When compound A is administered to a human, it can be safely administered orally or parenterally as it is or in a mixture with an appropriate pharmacologically acceptable carrier, excipient and diluent, in a pharmaceutical composition such as an oral administration formulation (e.g., powder, granule, tablet, capsule etc.), a parenteral administration formulation (e.g., injection, external formulation (e.g., nasal administration formulation, percutaneous administration formulation etc.) and suppository (e.g., rectal suppository and vaginal suppository etc.).
• an oral administration formulation e.g., powder, granule, tablet, capsule etc.
• parenteral administration formulation e.g., injection, external formulation (e.g., nasal administration formulation, percutaneous administration formulation etc.)
• suppository e.g., rectal suppository and vaginal suppository etc.
• any of these formulations may be produced by any method known per se which is employed ordinarily for producing a pharmaceutical formulation.
• the amount of compound A to be incorporated into a formulation may vary depending on the dosage forms, and is preferably about 10 to 95% by weight in an oral administration formulation described above and about 0.001 to about 95% by weight in a parenteral administration formulation described above.
• compound A can be prepared into an aqueous injection together with a solubilizer (e.g., ⁇ -cyclodextrins etc.), a dispersant (e.g., Tween 80 (manufactured by ATLASPOWDER USA), HCO 60 (manufactured by NIKKO CHEMICALS), carboxymethylcellulose, sodium arginate etc.), a preservative (e.g., methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol etc.), an isotonic agent (e.g., sodium chloride, glycerine, sorbitol, glucose etc.) and the like according to a conventional method, or into an oil-based injection by appropriately dissolving, suspending or emulsifying using a vegetable oil (e.g., olive oil, sesame oil, peanut oil, cottonseed oil, corn oil etc.) and propylene glycol and the like.
• a solubilizer e.
• An oral administration formulation can be produced by, for example, compressing compound A together with an excipient (e.g., lactose, sucrose, starch etc.), a disintegrant (e.g., starch, calcium carbonate etc.), a binder (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose etc.), a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000 etc.), and the like, followed by, where necessary, a coating process known per se for the purpose of masking a taste, forming an enteric coat, or achieving a sustained release.
• an excipient e.g., lactose, sucrose, starch etc.
• a disintegrant e.g., starch, calcium carbonate etc.
• a binder e.g., starch, gum arabic, carboxymethyl cellulose, polyvinyl pyr
• a dye e.g., titanium oxide, colcothar etc.
• Compound A can also be employed as an external formulation in the form of a solid or semi-solid or a liquid.
• a solid external formulation may be compound A as it is or can be produced by mixing compound A with an excipient (e.g., glycol, mannitol, starch, microcrystalline cellulose etc.), a thickening agent (e.g., natural gums, cellulose derivatives, acrylic acid polymers etc.) which is then converted into a powder composition.
• an excipient e.g., glycol, mannitol, starch, microcrystalline cellulose etc.
• a thickening agent e.g., natural gums, cellulose derivatives, acrylic acid polymers etc.
• a semi-solid external formulation may be produced by a standard method and preferably used in the form of an aqueous or oil-based gel or ointment.
• a liquid external formulation may be produced by a method employed for producing an injection formulation or an analogous method in the form of an oil-based or aqueous suspension.
• the solid, semi-solid or liquid external formulation may be supplemented also with a pH modifier (e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide etc.), an antiseptic (e.g., p-oxybenzoate esters, chlorobutanol, benzalkonium chloride etc.) and the like, as appropriate.
• a pH modifier e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide etc.
• an antiseptic e.g., p-oxybenzoate esters, chlorobutanol, benzalkonium chloride etc.
• an ointment usually containing about 0.1 to about 100 mg of compound A per 1 g a vaseline or a lanolin etc. as a formulation base, can be used.
• Compound A may be also formulated as an oil or aqueous, solid or semi-solid or liquid suppository.
• an oil base in preparing suppository for example, a higher fatty acid glyceride (e.g., cocoa butter, WITEPSOL (manufactured by DYNAMIT NOBEL) etc.), a middle fatty acid (e.g., MYGLYOL (manufactured by DYNAMIT NOBEL) etc.), a vegetable oil (e.g., sesame oil, soybean oil, cottonseed oil etc.) and the like are used as appropriate.
• An aqueous base may be, for example, polyethylene glycol or propylene glycol
• an aqueous gel base may be, for example, a natural gums, a cellulose derivative, a vinyl polymer, an acrylic polymer and the like.
• compound A (particularly, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (compound 72), and ethyl (3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate (compound 9′)) may be used as an emulsion composition (adjusted to pH about 3.7-about 5.5) containing the compound and a buffer (hereinafter to be abbreviated as emulsion composition A).
• compound A can be effectively used as a component of a composition comprising an emulsifier.
• Compound A may be in a liquid form or a solid form in an oil phase, and emulsion composition A is formed as an oil-in-water type (O/W type) or S/O/W type emulsion composition.
• O/W type oil-in-water type
• S/O/W type emulsion composition S/O/W type emulsion composition
• Emulsion composition A can be produced by, for example, using emulsifier.
• Emulsion composition A is a composition comprising dispersion phase particles comprising an oil component, an emulsifier, and compound A, and water containing buffer wherein dispersion phase particles are dispersed.
• the dispersion phase particles mean a dispersion phase wherein one of two liquids immiscible in each other is present as fine particles in the other.
• any pharmaceutically acceptable fats and oils generally used for the preparation of fat emulsions in the pharmaceutical technical field can be used.
• fats and oils include vegetable oil, partially hydrogenated vegetable oil, fats and oils obtained by transesterification reaction (single acid group glyceride (simple glyceride) or mixed acid group glyceride (mixed glyceride)), and middle chain fatty acid glycerol ester and the like.
• the aforementioned fats and oils include fatty acid glycerol ester having a carbon number of about 6 to 30 (preferably about 6 to 22).
• fatty acid examples include saturated fatty acid such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid and the like, unsaturated fatty acid such as palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, eicosapentanoic acid, docosahexaenoic acid and the like.
• a preferable oil component contains, for example, vegetable oil such as soybean oil, cottonseed oil, rape seed oil, peanut oil, safflower oil, sesame oil, rice bran oil, corn germ oil, sunflower oil, poppy oil, olive oil and the like, and the like.
• vegetable oils soybean oil and the like are preferably used.
• a middle chain fatty acid triglyceride having a carbon number of about 6 to 14 can also be used.
• Preferable middle chain fatty acid glycerol ester includes, for example, caprylic/capric triglycerides such as “miglyol 810”, “miglyol 812” (both manufactured by Huls, available from Mitsuba Trading Co., Ltd.) and the like, caprylic acid triglycerides (glycerol tricaprylic acid ester) such as “Panacete 800” (manufactured by NOF Corporation) and the like, and the like.
• the amount of the oil component in emulsion composition A to be used is, for example, about 1 to about 30 wt %, preferably about 2 to about 25 wt %, more preferably about 2.5 to about 22.5 wt %, of the whole composition.
• any pharmaceutically acceptable emulsifier can be used.
• pharmaceutically acceptable phospholipids and non-ionic surfactants are preferable.
• the emulsifier can be used alone or as a mixture of two or more kinds thereof.
• Phospholipid includes, for example, naturally occurring phospholipids (e.g., egg-yolk lecithin, soybean lecithin etc.), hydrogenated products thereof, or synthetically obtained phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamines, phosphatidic acid, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol etc.) and the like.
• naturally occurring phospholipids e.g., egg-yolk lecithin, soybean lecithin etc.
• synthetically obtained phospholipids e.g., phosphatidylcholine, phosphatidylethanolamines, phosphatidic acid, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol etc.
• phospholipids e.g., egg-yolk lecithin, soybean le
• anionic phospholipid is preferable.
• anionic synthetic phospholipids such as dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, oleoylpalmitoylphosphatidylglycerol, dioctanoylphosphatidic acid, didecanoylphosphatidic acid, dilauroylphosphatidic acid, dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid, diheptadecanoylphosphatidic acid, distearoylphosphatidic acid, dioleoylphosphatidic acid, arachidonylstearoylphosphatidic acid, dipalmitoylphosphatidylserine, dioleoylphosphatidylserine, dimy
• anionic synthetic phospholipids can be chemically synthesized by a method known per se, or can also be obtained by purification.
• a polymer surfactant having a molecular weight of about 800 to 20000 for example, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, hydrogenated castor oil polyoxyethylene derivative, sorbitan polyoxyethylene derivative, polyoxyethylene sorbitol derivative, polyoxyethylene alkyl ether sulfate and the like can be mentioned.
• the emulsifiers of phospholipid and non-ionic surfactants can be used alone or as a mixture of two or more kinds thereof. Alternatively, commercially available phospholipids may be used.
• the total amount of the emulsifier in emulsion composition A to be used is generally about 0.1 to about 10% (W/V), preferably about 0.2 to about 7% (W/V), more preferably about 0.5 to about 5% (W/V), relative to the whole composition.
• the anionic synthetic phospholipid is in a proportion of about 0.0001 to about 5% (W/V) relative to the whole composition.
• the proportion of the emulsifier relative to the oil component is, for example, about 0.1 to about 150 wt %, preferably about 0.5 to about 125 wt %, more preferably about 1 to about 100 wt %.
• the emulsifier is often used in a proportion of generally about 1 to about 15 wt %, particularly about 1 to about 10 wt %, relative to the oil component.
• Water to be used in emulsion composition A is not particularly limited as long as it is acceptable as a pharmaceutical product and, for example, purified water, water for injection (distilled water for injection) and the like can be mentioned.
• purified water water for injection (distilled water for injection) and the like can be mentioned.
• water is not particularly limited.
• the amount of water in emulsion composition A to be used is generally about 40 to about 99% (W/V), preferably about 55 to about 98.8% (W/V), relative to the whole composition.
• Emulsion composition A can be prepared by mixing a dispersion phase component comprising compound A (main drug), an oil component and an emulsifier with water and emulsifying the mixture and a buffer may be added to an aqueous phase before emulsification, or may be added to the emulsion composition after emulsification.
• additives such as a stabilizer to improve the stability of the aforementioned main drug, an isotonicity agent to control the osmotic pressure, an emulsion aid to improve the emulsifying power, an emulsion stabilizer to improve stability of emulsifier and the like may be added.
• the stabilizer examples include antioxidants (e.g., ascorbic acid, tocopherol, sorbic acid, retinol etc.), chelating agents (e.g., edetic acid, citric acid, tartaric acid etc., and salts thereof) and the like.
• the amount of the stabilizer to be used is generally about 0.00001 to about 10% (W/V), preferably about 0.0001 to about 5% (W/V), relative to the whole emulsion composition A.
• An isotonicity agent contains, for example, glycerol, sugar alcohol, monosaccharides, disaccharides, amino acid, dextran, albumin and the like. These isotonicity agents can be used alone or in a mixture of two or more kinds thereof.
• Examples of the emulsion aid include fatty acid having a carbon number of about 6 to 30, salts of such fatty acid, monoglycerides of the aforementioned fatty acid and the like.
• the aforementioned fatty acid includes, for example, caproic acid, capric acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, eicosapentanoic acid, docosahexaenoic acid and the like
• salts of fatty acid include, for example, alkali metal salts such as sodium salt, potassium salt and the like, calcium salt and the like.
• emulsion stabilizer for example, cholesterol, cholesteryl ester, tocopherol, albumin, fatty acid amide derivative, polysaccharides, fatty acid ester derivative of polysaccharides and the like can be used.
• the concentration of compound A in emulsion composition A varies depending on the pharmacological activity or blood kinetics of the compound, it is generally about 0.001 to about 5% (W/V), preferably about 0.01 to about 2% (W/V), more preferably about 0.1 to about 1.5% (W/V).
• the content of compound A in emulsion composition A can also be set to about 1 to about 5000 mg, preferably about 10 to about 2000 mg, more preferably about 100 to about 1500 mg, in 100 ml of the composition.
• the content of compound A can also be adjusted to about 0.001 to about 95 wt %, preferably about 0.01 to about 30 wt %, more preferably about 0.1 to about 3 wt %, relative to the whole composition.
• the proportion (wt %) of compound A relative to the dispersion phase consisting of an oil component and an emulsifier is generally about 0.0047 to about 24%, preferably about 0.047 to about 9.4%.
• Emulsion composition A is adjusted to pH about 3.7 to about 5.5, preferably about 3.7 to about 5.0, more preferably about 4.0 to about 5.0.
• pH adjuster for example, phosphoric acid, carbonic acid, citric acid, hydrochloric acid, sodium hydroxide and the like are used and hydrochloric acid, sodium hydroxide and the like are particularly preferable.
• any pharmaceutically acceptable buffer can be used.
• respective buffers may be used in combination. Particularly, one or more buffers selected from acetate buffer, glacial acetate buffer, lactate buffer, citrate buffer and phosphate buffer are preferable.
• a combination of acetic acid or glacial acetic acid and sodium acetate (acetate buffer or glacial acetate buffer), or (ii) a combination of lactic acid and sodium lactate (lactate buffer), and the like are preferable.
• the concentration of the buffer is generally not more than about 100 mM, specifically about 0.1 mM to about 100 mM, preferably about 0.2 mM to about 50 mM, more preferably about 5 mM to about 40 mM.
• the pH adjuster is an acidic or alkaline compound to be added to adjust the pH of a solution to a desired pH.
• the amount of the pH adjuster to be generally added to an injection is trace.
• the amount of sodium hydroxide as a pH adjuster in a fatty emulsion commercially available in Japan is often not more than about 0.5 mM. While the pH can be adjusted to a desired pH during preparing the solution, the pH of the solution easily changes by the addition of an acid or alkali, and maintenance of pH is difficult.
• the buffer is a compound having an action to reduce changes in pH on addition of acid or alkali, namely, a bufferizing action. In many cases, it is a mixed solution of a weak acid and a salt thereof, or a weak base and a salt thereof.
• emulsion composition A is not influenced by the development of free fatty acid, and can maintain a constant pH of an emulsion composition during high-pressure vapor sterilization and long-term preservation.
• the amount of the buffer to be used for general injections is the aim of bufferizing action.
• the amount of an acetate buffer in a solution injection commercially available in Japan is about 0.2 mM to about 100 mM.
• Emulsion composition A is preferably used, for example, as a composition for injection.
• Emulsion composition A can be basically produced by a known method or a method according thereto. Particularly, while a conventionally used emulsion technique can be utilized for the emulsion, compound A is preferably dissolved or dispersed in advance in an oil component. To be precise, a composition containing an O/W type or S/O/W type emulsion can be produced by dispersing a mixture of dispersion phase (1) containing an oil component and an emulsifier, and compound A (2) in water. The buffer may be added to an aqueous phase before emulsification, or added to an emulsion after emulsification during production.
• the more preferable method includes, for example, a method of preparing an oil-in-water type composition comprising homogenizing an unhomogeneous mixture of a mixture of the main drug, an oil component, an emulsifier and, where necessary, an additive such as isotonicity agent and the like, and water containing a buffer using an emulsifying machine to give a crude emulsion, adding water as necessary, further homogenizing the emulsion using the above-mentioned emulsifying machine, and removing large particles by a filtration means such as a filter and the like.
• a method of preparing an oil-in-water type composition comprising homogenizing an unhomogeneous mixture of a mixture of the main drug, an oil component, an emulsifier and, where necessary, an additive such as isotonicity agent and the like, and water containing a buffer using an emulsifying machine to give a crude emulsion, adding water as necessary, further homogenizing the emulsion using
• the aforementioned mixture is often warmed to a temperature of, for example, about 30 to about 90° C., preferably about 40 to about 80° C., to dissolve or disperse the main drug.
• a temperature of, for example, about 30 to about 90° C., preferably about 40 to about 80° C. to dissolve or disperse the main drug.
• conventionally used apparatuses for example, homogenizers such as a pressurization injection type homogenizer, ultrasonication homogenizer and the like, homomixers such as high-speed rotation type mixer and the like, and the like can be used.
• homogenized emulsion is often subjected to a filtration means such as a filter and the like.
• the particle size distribution of a dispersion phase, wherein compound A is dissolved is, for example, often about 0.01 to about 7 ⁇ m, preferably about 0.02 to about 5 ⁇ m.
• the mean particle size of the dispersion phase particles, wherein compound A is dissolved is for example, about 0.025 to about 0.7 ⁇ m, more preferably about 0.05 to about 0.4 ⁇ m.
• the mean particle size used in the present specification means a mean particle size based on the volume distribution and measured by a laser diffraction particle size distribution measurement apparatus, with the laser diffraction•scattering method as a measurement principle.
• Pyrogen can be removed from emulsion composition A by a method known per se.
• emulsion composition A is sterilized and tightly sealed.
• emulsion composition A Since pH of emulsion composition A is adjusted to about 3.7 to about 5.5 by adding a buffer, pH of the composition and mean particle size of the dispersion phase particles hardly change even after sterilization by an autoclave etc. or after long-term preservation, and the composition is stable. Therefore, the stability of compound A and emulsion composition A is superior. Moreover, emulsion composition A is free of a visibly observed free oil drop even after sterilization by an autoclave etc. or after long-term preservation, and therefore, phase separation of dispersion phase particles and water wherein the dispersion phase particles are dispersed does not occur, and the composition is stable.
• emulsion composition A can increase the concentration of compound A, and control the particle size of the dispersion phase particles. Thus, it can enhance retentivity in blood, blood vessel permeability and transitivity into inflammation site. Therefore, in vivo kinetics or distribution in the body of compound A can be improved and targeting becomes possible, as a result of which administration of an effective drug with suppressed side effects becomes possible. Accordingly, emulsion composition A is particularly useful for the treatment of a target disease by an intravenous administration.
• Compound A can also be used in combination with other drugs that suppress side effects of the anti-cancer agents, such as antidepressants (e.g., amitriptyline, imipramine, clomipramine, desipramine, doxepin, nortriptyline, duloxetine, milnacipran, fluoxetine, paroxetine, sertraline, citalopram), anticonvulsants (e.g., carbamazepine, pregabalin, gabapentin, lamotrigine, phenyloin, valproic acid), antiphlogistic analgesics (e.g., loxoprofen sodium, naproxen, indomethacin, ketoprofen, ibuprofen, diclofenac, celecoxib, acetaminophen, acetylsalicylic acid), adrenal cortex hormones (e.g., dexamethasone, prednisone), narcotics (e.g
• the administration period, dose and administration mode of compound A and other drugs that suppress side effects of the anti-cancer agents are not limited, and can be appropriately determined in consideration of the age, body weight and symptom of the administration subject, dosage form, administration method, kind of side effect, combination of drugs and the like.
• the 1 H-NMR spectrum was measured using tetramethylsilane as the internal standard and a Varian Mercury 300 (300 MHz) or Varian Gemini 200 (200 MHz) spectrometer, and total 6 value was shown in ppm.
• the numerical values shown in parentheses are volume mixing ratio of each solvent. Unless particularly specified, % means weight percent.
• the ratio of solvents in silica gel chromatography is a volume ratio of the solvents to be mixed.
• High polar diastereomer means a diastereomer having a smaller Rf value when Rf values of normal phase thin layer chromatography under the same conditions (e.g., ethyl acetate/hexane and the like can be used as the solvent) are compared, and low polar diastereomer means a diastereomer having a larger Rf value.
• Reference Example A The following compounds of Reference Example A can be produced according to the Examples of WO99/46242.
• an optically active compound can be produced according to the Examples of WO02/32859.
• compound 72 can be produced according to Examples 1 and 2 or Examples 3 and 4 of WO02/32859.
• Compounds 1′-8′ of the following Reference Example B can be produced according to the Examples of WO01/10826.
• Compound 9′ can be produced according to the following Reference Example 1 or Reference Example 2.
• Compound 10′ can be produced according to the following Reference Example 1.
• the reaction mixture was stirred at room temperature for 24 hr, and extracted with ethyl acetate.
• the extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure.
• the residue was distilled under reduced pressure (110-130° C./3-4 mmHg)
• mice C57BL/6N, male, 7-week-old mice were divided into Group A (6 mice), Group B (6 mice), and Group C (6 mice).
• Group A non-treated animals were used.
• Group C was intravenously administered with compound 72 (10 mg/kg body weight) of Reference Example A dissolved in an emulsion containing soybean oil, egg-yolk lecithin, glycerol and the like immediately before and 1 and 2 weeks after intraperitoneal administration of paclitaxel (total 3 times).
• Pain threshold of each group was measured 3 weeks after paclitaxel administration to Group B and Group C. Pain threshold is a weighed value (gram) at the time when a false escape response is observed by pressurizing the plantar part of the right hindlimb using a balance type pressing device (Ugo Basile). The results are shown in the following Table 15. The values in the Table show mean ⁇ standard error of the weighed values.
• compound A has been shown to have a suppressing (or mitigating) action on neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) of peripheral nerve disorders induced by paclitaxel.
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• mice C57BL/6N, male, 8-week-old were divided into Group A, Group B, and Group C.
• Group A non-treated animals were used.
• any one of various anti-cancer agents docetaxel, vincristine, cisplatin, carboplatin, bortezomib
• saline aline
• intraperitoneal administered docetaxel at 3 mg/kg body weight, vincristine at 0.1 mg/kg body weight, cisplatin at 3 mg/kg body weight, carboplatin at 40 mg/kg body weight, bortezomib at 0.4 mg/kg body weight).
• Group C was intravenously administered with compound 72 (3 mg/kg body weight) of Reference Example A dissolved in an emulsion containing soybean oil, egg-yolk lecithin, glycerol and the like immediately before intraperitoneal administration of various anti-cancer agents. Pain threshold of each group was measured 1 week after the administration of the anti-cancer agent. Pain threshold is a weighed value (gram) at the time when a false escape response is observed by pressurizing the plantar part of the right hindlimb using a balance type pressing device (Ugo Basile). The results are shown in the following Table 16. The values in the Table show mean ⁇ standard error of the weighed values, and n is the number of the mice in each group.
• compound A has been shown to have a suppressing (or mitigating) action on neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) of peripheral nerve disorders induced by various anti-cancer agents.
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• Rat (Wistar, male, 5-week-old) were divided into Group A, Group B, and Group C.
• Group A non-treated animals were used.
• paclitaxel is diluted with saline to a given concentration, and intraperitoneally administered at 6 mg/kg body weight for a total of 3 times at intervals of 1 to 2 days.
• Group C was intravenously administered with compound 72 (10 mg/kg body weight) of Reference Example A dissolved in an emulsion containing soybean oil, egg-yolk lecithin, glycerol and the like immediately before intraperitoneal administration of paclitaxel (total 3 times). Pain threshold of each group was measured 2 weeks after first paclitaxel administration.
• Pain threshold is a weighed value (gram) at the time when an avoidance response is observed by pressurizing the plantar part of the right hindlimb using an Electronic von Frey (IITC Life Science). The results are shown in the following Table 17. The values in the Table show mean ⁇ standard error of the weighed values, and n is the number of the rats in each group.
• compound A has been shown to have a suppressing (or mitigating) action on neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) of peripheral nerve disorders induced by paclitaxel.
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• mice (C57BL/6N, male, 8-week-old) were divided into Group B and Group D.
• any one of various anti-cancer agents paclitaxel, docetaxel, vincristine, cisplatin, carboplatin, bortezomib
• saline aline
• intraperitoneally administered paclitaxel at mg/kg body weight, docetaxel at 3 mg/kg body weight, vincristine at 0.1 mg/kg body weight, cisplatin at 3 mg/kg body weight, carboplatin at 40 mg/kg body weight, bortezomib at 0.4 mg/kg body weight.
• Group D was intravenously administered with compound 9′ (1 mg/kg body weight) of Reference Example B dissolved in solution of N methyl-D( ⁇ )-glucamine (0.01 mol/L) immediately before intraperitoneal administration of various anti-cancer agents.
• Pain threshold of each group was measured 3 week after the administration for paclitaxel and 1 week after the administration for the anti-cancer agents other than paclitaxel. Pain threshold is a weighed value (gram) at the time when a false escape response is observed by pressurizing the plantar part of the right hindlimb using a balance type pressing device (Ugo Basile). The results are shown in the following Table 18. The values in the Table show mean ⁇ standard error of the weighed values, and n is the number of the mice in each group.
• compound A has been shown to have a suppressing (or mitigating) action on neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) of peripheral nerve disorders induced by various anti-cancer agents.
• neurological symptoms e.g., dysesthesia such as numbness, pain and the like
• the present invention is useful for suppressing (or mitigating) neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) of peripheral nerve disorders which are one of the side effects caused by the administration of an anti-cancer agent.
• the present invention is useful for avoiding a decrease in the dosage due to the side effects of the administration of an anti-cancer agent.

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