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WO2002034719A1 - Composes heterocycliques azotes satures - Google Patents

Composes heterocycliques azotes satures Download PDF

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Publication number
WO2002034719A1
WO2002034719A1 PCT/JP2000/007345 JP0007345W WO0234719A1 WO 2002034719 A1 WO2002034719 A1 WO 2002034719A1 JP 0007345 W JP0007345 W JP 0007345W WO 0234719 A1 WO0234719 A1 WO 0234719A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
acceptable salt
bis
fluorophenyl
Prior art date
Application number
PCT/JP2000/007345
Other languages
English (en)
Japanese (ja)
Inventor
Akio Shiraishi
Tohru Tatsuta
Takahide Nishi
Original Assignee
Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2000120206A priority Critical patent/JP2001011050A/ja
Priority claimed from JP2000120206A external-priority patent/JP2001011050A/ja
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU2000279529A priority patent/AU2000279529A1/en
Priority to PCT/JP2000/007345 priority patent/WO2002034719A1/fr
Publication of WO2002034719A1 publication Critical patent/WO2002034719A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a nitrogen-containing saturated heterocyclic compound having a selective immunosuppressive activity, a pharmacologically acceptable salt thereof, an ester thereof, or an excellent TH1 (refers to TH1 cells which are one of a subset of helper T cells).
  • TH1 cells which are one of a subset of helper T cells.
  • anti-inflammatory drugs such as steroids have been used for inflammatory reactions caused by abnormal immune responses.
  • Th1 cells type 1 helper T cells
  • Th2 cells type 1 helper T cells
  • Th1 cells produce cytokines such as interleukin 2 (hereinafter, IL-2), interferon-a (hereinafter, IFN), and TNF--, and are mainly involved in cell-mediated immunity.
  • Th2 cells produce cytokines such as IL-4 and IL-10 and are mainly involved in humoral immunity (J. Immunol., Vol. 136, 2348-2357, 1986). Images produced by Th1 cells ⁇ inhibits the function of Th2 cells. Conversely, IL-4 and IL-10 produced by Th2 cells inhibit the function of Th1 cells. It is considered that the balance between Th1 cells and Th2 cells via these cytokines is important for normal immune function in vivo.
  • Th1 / Th2 cells imbalance of Th1 / Th2 cells is involved in the development of various immune-related diseases.
  • the balance bias toward Th1 cells is used for organ-specific autoimmune diseases such as rheumatoid arthritis, diabetes, multiple sclerosis, inflammatory bowel disease, and glomerulonephritis. It has been reported to be involved in allergic diseases and systemic autoimmune diseases (hmmmol. Today, Vol. 16, 34-38, 1995; Science Vol. 260, 547-549, 1993; Immunity, Vol. 3, 171-174, 1995; J. Exp. Med., Vol. 190, 995-1003, 1999; Kidney Int., Vol. 52, 52-59, 1997; J. Exp. Med., Vol.
  • JP-A-50-100052 (US Pat. No. 3,959,475) JP-A-50-89363 discloses the following general formula (A)
  • the compound (A) is a Jifuenirume Toki Shiarukiru group represented by the formula (C3 ⁇ 4) nOCHPh 2, Y is CH 2 or O0. ] Is disclosed,
  • JP-A-50-100052 discloses the following general formula (B)
  • a compound having a structure similar to that of the powerful prior art includes a 5- to 8-membered saturated heterocyclic ring including R 3 and R 4 together and the carbon atom to which they are bonded.
  • the compound (I) of the present invention is different from the above compounds (A) and (B) because tetrahydrofuran is excluded from the saturated heterocycle.
  • the present publication discloses a compound having a structure similar to that of the compound (I) of the invention. None is specifically disclosed, and even if a compound closest to the structure of the compound (I) of the present invention is selected, at most only the following compounds are disclosed.
  • the compounds (A) and (B) are disclosed as antidepressants, tranquilizers, and analgesics, and their use as TH1-selective immunosuppressive effects is not described or suggested.
  • A is the following general formula (A-1)
  • the compound (I) of the present invention a compound of the prior art having the general formula (A_l) described above.
  • R 3 and R 4 are bonded together to form a bond.
  • the compound (I) of the present invention is the same as the compound (C) in that imidazolidin is excluded from the saturated heterocyclic ring, except that imidazolidin is removed from the saturated heterocyclic ring. Is different from
  • a compound having a structure similar to that of the prior art compound (C) having the general formula (A_2) includes an aryl and a formula COR 5 at the 4-position of piperidine. It has a group, but is different from the compound (C) in the substituent at the 4-position of piperidin.
  • this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and describes a compound closest to the structure of the compound (I) of the present invention. Even if selected, at best, only the following compounds are disclosed
  • R represents the following general formula (R-1)
  • the compound (I) of the present invention those having a structure close to that of the powerful prior art include a 5 'to 8 membered saturated heterocyclic ring including a carbon atom to which R 3 and R 4 are bonded together.
  • the compound (I) of the present invention is different from the above-mentioned compound (D) in that imidazolidin is excluded from the saturated heterocyclic ring.
  • this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and describes a compound closest to the structure of the compound (I) of the present invention. Even if selected, at best only the following compounds are disclosed:
  • the compound (D) is disclosed as a compound having a psychotropic effect, and its use as a TH1-selective immunosuppressive effect is not described or suggested.
  • R 5 represents an optionally substituted phenyl group.
  • the compound (I) of the present invention a compound whose structure is close to that of the powerful prior art is that R 3 and R 4 together form a 5- to 8-membered saturated heterocycle including a carbon atom to which they are bonded.
  • the compound (I) of the present invention differs from the compound (E) in that dioxepane is excluded from the saturated heterocycle.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and the compound closest to the structure of the compound (I) of the present invention is not disclosed. Even if is selected, at most, only the following compounds are disclosed.
  • the above compound (E) is disclosed as a therapeutic agent for hypertension and a therapeutic agent for analgesia, and its use as a TH1-selective immunosuppressive effect is neither described nor suggested.
  • the compound (I) of the present invention those having a structure close to that of the prior art include 5 to 5 carbon atoms including R 3 and R 4 together at the 4-position of piperidine, including the carbon atom to which they are bonded.
  • the compound (F) forms an 8-membered saturated heterocycle
  • the compound (F) has a 5- to 7-membered heterocycle including a carbon atom other than the 4-position of piperidine, and thus the present invention Has a structure different from that of compound (I).
  • this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compound is disclosed.
  • the above compound (F) is disclosed as a compound useful for the treatment of "depression, impulsive threat, panic attack, memory disorder, schizophrenia, Parkinson's disease, dependence, etc.” The use as an immunosuppressive effect is neither described nor suggested.
  • Y may have a substituent, and may be a saturated or unsaturated aliphatic or aromatic heterocyclic amine radical (the substituent may be a C 6 alkyl, And at least one group selected from the group consisting of a group consisting of norebone, ketone, estenole, cyclohexynole, cyclohexeneol and aryl.)
  • the substituent may be a C 6 alkyl, And at least one group selected from the group consisting of a group consisting of norebone, ketone, estenole, cyclohexynole, cyclohexeneol and aryl.
  • the saturated or unsaturated aliphatic or aromatic heterocyclic amine radical in Y is azetidine, pyrrolidine, pyrroline, pyrrole, piperidine, pyridine, imidazole and unsubstituted or substituted.
  • the compound is selected from pyrimidine radicals, and no compound having a spiro bond has been disclosed.
  • the compound (I) of the present invention has a structure similar to that of the prior art.
  • a group having aryl and a formula CO—R 5 at the 4-position of piperidine can be mentioned.
  • Cf Csanolekyl or canolepo2 As a substituent for a heterocyclic amine radical, Cf Csanolekyl or canolepo2 There is only a statement that the compound has at least one group selected from the group consisting of phenol, ketone, estenole, cyclohexynole, cyclohexeninole and aryl, and no specific description or examples of each substituent are given. Not disclosed.
  • this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if a compound is selected, at most only the following compounds are disclosed.
  • the above compound (G) is disclosed as a compound having a dopamine uptake inhibitory effect, and its use as a TH1-selective immunosuppressive effect is not described or suggested.
  • Z is a cyano group, an alkoxycarbonyl group, an acyl group, Indicates an aminomethyl group.
  • a compound having a structure close to the powerful prior art includes a group having an aryl and a CO—R 5 at the 4-position of piperidine (wherein R 5 is And a substituent at the 4-position of piperidine is different between compound (I) and compound (J) of the present invention.
  • this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and the compound closest to the structure of the compound (I) of the present invention is not disclosed. Even if you choose, at most, only the following compounds are disclosed
  • R 4 represents a group having (aryl) 2 CH-0-.
  • a compound whose structure is close to that of the powerful prior art is that R 3 and R 4 together form a 5- to 8-membered saturated heterocycle including a carbon atom to which they are bonded.
  • the compound (I) of the present invention is different from the compound (K) in that imidazolidin is removed from the saturated heterocyclic ring.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if a compound is selected, at most only the following compound is disclosed.
  • the above compound (K) is disclosed as a compound having a central nervous system inhibitory effect, and its use as a TH1-selective immunosuppressive effect is not described or suggested.
  • R 3 is a phenyl group.
  • radical (R 5 having Ariru and Shikiichi CO- R 5 in the 4-position of the pin Perijin is an Amin residue like Show. )
  • the substituent at the 4-position of piperidine is different between the compound (I) of the present invention and the above compounds (L) and (M).
  • the present inventors have conducted intensive studies on derivatives having a TH1-selective immunosuppressive effect, and have found that nitrogen-containing saturated heterocyclic compounds, pharmacologically acceptable salts thereof, esters or other derivatives thereof, The present inventors have found that they have an excellent TH1-selective immunosuppressive action, and have completed the present invention.
  • Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient.
  • Another object of the present invention is to use the above-mentioned nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof for producing a pharmaceutical composition, and Provided is a method for preventing or treating an autoimmune disease, which comprises administering to a warm-blooded animal a pharmacologically effective amount of the nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. That is.
  • the nitrogen-containing saturated heterocyclic compound of the present invention has the following general formula (I).
  • R 1 and R 2 are the same or different and each represents an aryl group, a heteroaryl group, a substituent group an aryl group substituted by 1 to 3 groups with a group selected from a, or a heteroaryl group substituted by 1 to 3 groups with a group selected from a substituent group a,
  • Y represents a C i-Cs alkylene or C 2 _ C 8 7 Rukeeren group.
  • L is a group having the formula C (R 3 ) (R 4 )
  • R 3 is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from the substituent group a, or a heteroaryl substituted 1 to 3 groups with a group selected from the substituent group a. Represents a group,
  • R 4 is a group having the formula: CO—R 5 (wherein R 5 is an aryl group substituted by 1 to 3 groups selected from an amide residue, an aryl group, a heteroaryl group, and a substituent group a ) Or a heteroaryl group substituted by 1 to 3 groups selected from a substituent group a).
  • R 3 and R 4 are taken together to form a group including the carbon atom to which they are bonded, and are substituted with 1 to 3 5- to 8-membered saturated heterocycles or a group selected from substituent group c. Or a 5- to 8-membered saturated heterocyclic ring (provided that the saturated heterocyclic ring excludes tetrahydrofuran, imidazolidine or dioxepane), or
  • R 3 and R 4 are taken together to form a 3- to 10-membered saturated carbocyclic ring formed by including the carbon atom to which they are bonded, or 1 to 3 substituted with a group selected from the group of substituents a and c. 3 to 10-membered saturated carbocycle. ]. ]
  • Halogen atom lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano group
  • Substituent group b Lower alkyl group, aryl group, aralkyl group, lower alkyl group substituted with 1 to 3 groups selected from substituent group a, aryl group substituted with 1 to 3 groups selected from substituent group a Groups, an aralkyl group substituted by 1 to 3 groups selected from the substituent group a, a lower aliphatic acyl group, and a lower alkylsulfonyl group
  • preferred compounds include
  • R 1 and R 2 are the same or different, and are an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a,
  • R 1 and R 2 are the same or different and are an aryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a,
  • R 1 and R 2 the same or different, an aryl group or an aryl group substituted by 1 to 3 (the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group)
  • the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group
  • R 1 and R 2 are the same or different and are an aryl group or an aryl group substituted by one halogen atom,
  • R 1 and R 2 i are the same aryl group substituted by one halogen atom.
  • Y is a ⁇ " ⁇ 8 alkylene group compound
  • R 3 is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from substituent group a, or a heteroaryl group substituted with 1 to 3 groups selected from substituent group a.
  • R 4 is a group having the formula CO—R 5 .
  • (1 9) is a group having the formula C (R 3 ) (R 4 ) 1, wherein R 3 and R 4 are taken together to form a carbon atom to which they are bonded,
  • L is a 5- to 6-membered saturated heterocyclic ring or a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from substituent group c,
  • (21) a compound that is a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from L group substituent group c,
  • (22) a compound wherein L is a 5- or 6-membered saturated heterocyclic ring which may be substituted by one oxo group and further substituted by 1 or 2 groups selected from substituent group c,
  • L is the following formula (L-1) ( ⁇ 1)-
  • G and J are the same or different and each represent an oxygen atom, a sulfur atom or a group having the formula NR—. However, G and J each represent a group having the same formula NR—. No.
  • L is a group having the formula _C (R 3 ) (R 4 ) —, wherein R 3 and R 4 are taken together to form the carbon atom to which they are attached;
  • the TH1-selective immunosuppressant of the present invention further comprises a compound having the general formula (II): Products, pharmacologically acceptable salts, esters or other derivatives thereof as active ingredients. '
  • R 1 and R 2 are the same or different and are selected from an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from a substituent group a, or a substituent group a Represents a heteroaryl group substituted by 1 to 3 groups,
  • X represents an oxygen atom, a sulfur atom, or a group having the formula —NR—, wherein R is a hydrogen atom or a group selected from substituent group b.
  • Y represents an C 8 Arukiren group or C 2 _ ⁇ 8 Aruke two alkylene groups
  • L 1 is a group having the formula C (R 3a ) (R 4a )
  • R 3a is a hydrogen atom, an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from substituent group a, or 1 to 3 groups selected from substituent group a Indicates a substituted heteroaryl group,
  • R 4a is a group having the formula —D—E—R 6 [wherein
  • D represents a single bond or a group having the formula —C (R 7 ) H— (wherein R 7 is a hydrogen atom or a group selected from substituent group a);
  • E represents a single bond or a C 8 alkylene group
  • R 6 is a hydrogen atom, a hydroxyl group, an amino group, a lower aliphatic acylamino group, an aromatic acylamino group, or a group having the formula CO—R 5a (wherein
  • R 5a is a lower alkyl group, a lower alkoxy group, an amine residue, a hydroxyl group, an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from a substituent group a , or a substituent group a heteroaryl group substituted by 1 to 3 groups selected from a. ).
  • R 3a and R 4a are taken together and include 1 to 3 substituted 5- to 8-membered saturated heterocycles or a group selected from substituent group c, including the carbon atom to which they are attached. Forms an 8-membered saturated heterocycle, or
  • R 3a and R 4a are taken together and are substituted by 1 to 3 3-membered saturated carbocycles or a group selected from substituent groups a and c, including the carbon atom to which they are attached. To form a 3- to 10-membered saturated carbocycle. ]
  • R 4b represents a group having the formula D_E—R 6 (wherein D, E and R 6 have the same meanings as described above)].
  • Halogen atom lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano group
  • R 1 and R 2 force are the same or different, aryl group, heteroaryl group or Is a compound which is an aryl group substituted by 1 to 3 groups selected from a substituent group a,
  • R 1 and R 2 are the same or different and are aryl groups or aryl groups substituted by 1 to 3 aryl groups or groups selected from substituent group a;
  • R 1 and R 2 are an aryl group or a compound which is an aryl group substituted by one halogen atom,
  • R 3a is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from a substituent group a, or a heteroaryl group substituted with 1 to 3 groups with a group selected from a substituent group a.
  • R 4a is a group having the formula —D—E—R 6 .
  • R 3a is a hydrogen atom
  • R 4a is a group having the formula D—E—R 6 . ).
  • R 6 is a compound having the formula _CO_R 5a ,
  • L 1 is a group having the formula _C (R 3a ) (R 4a ) —, wherein R 3a and R 4a are linked together to form the carbon atom to which they are bonded, A compound, which is a 5- to 8-membered saturated heterocyclic ring substituted with 1 to 3 member (s) or a group selected from substituent group c,
  • L 1 is a 5- to 6-membered saturated heterocyclic ring or a compound which is a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 substituents with a group selected from substituent group c,
  • L 1 force S a compound which is a 5- or 6-membered saturated heterocyclic ring substituted by 1 to 3 groups selected from a substituent group c,
  • (59) L is substituted with one oxo group and further selected from a substituent group c.
  • G person J (Le 1) '' (Wherein G and J are the same or different and are an oxygen atom, a sulfur atom or a group having the formula NR_).
  • L 1 is a group having the formula C (R 3a ) (R 4a ) —, wherein R 3a and R 4a together form the carbon atom to which they are attached, A 3 to 10-membered saturated carbon ring or a compound which is a 3 to 10-membered saturated carbon ring substituted by 1 to 3 groups with a group selected from substituent groups a and c,
  • (63) L 1 a compound having 5 to 6 membered saturated carbocycle or a 5 to 6 membered saturated carbocyclic ring substituted by 1 to 3 members with a group selected from substituent groups a and c,
  • L 1 force A compound which is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent),
  • the aryl moiety of the “substituted aryl group” includes, for example, aromatic hydrocarbon groups having 6 to 10 carbon atoms such as fuel, indul, and naphthyl, and is preferably a phenyl group.
  • the teloaryl moiety may be, for example, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiaziazolyl, pirael,
  • An aromatic heterocyclic group such as pyridyl, pyridazinyl, pyrimidiel, and pyrazinyl; and the above-mentioned heteroaryl group may be condensed with another cyclic group such as a benzene ring, for example, benzothienyl
  • one C B alkylene group in the definitions of Y and E, for example, methylcarbamoyl Ren, Mechinoremechiren, ethylene, propylene, trimethylene, 1-Mechinoreechire , Tetramethylene, 1-methylinoletrimethylene, 2-methinoletrimethylene, 3_methinoletrimethylene, 1-methinolepropylene, 1,1-dimethyleneethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methinoletetramethylene, 1,1-dimethinoletrimethylene, 2,2-dimethinoletrimethylene, 3,3-dimethinoletrimethylene, hexamethylene, 1- Meth
  • C 2 - ⁇ 8 Arukeeren group in the definition of Y are, for example, Eteyure down, 2-propenylene, 1-Mechinore 2 propenylene, 2-methyl 'single 2- propenyl two Len , 2-Echinolene 2-Probelene, 2-Phtenylene, 1-Methynole 2-butenylene, 2-Methizole-1-butenylene, 1-Echinolene 21-butenylene, 3-butenylene, 1-Methynole 3 _ Butenylene, 2-Methynole 3- 3-ptenelen, 1-et / re
  • the 5-xenon - Ren 9 from 2 to 8 carbon atoms, such as one to Kisadeseniren group or a linear or branched Aruke two alkylene groups, preferably a ⁇ one C 5 Aruke There, more suitably C 2 -.
  • R 5 and R 5a definition are, for example, amino An amino group substituted by one or two “lower alkyl groups” such as methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, acetylamino, diisopropylamino, dibutylamino; cyclopentylamino, cyclohexylamino, diamino Amino groups substituted by 1 or 2 "cycloalkyl groups having 5 to 7 carbon atoms” such as cyclopentylamino and dicyclohexylamino; pyrrolidino, pipe Saturated cyclic amine residues having a nitrogen atom in the ring, such as dino, piperazino, N-methylbiperazino, morpholino, thiomorph
  • the 5- to 8-membered saturated heterocyclic moiety of the ⁇ 5 to 8-membered saturated heterocyclic substituted with 3 to 3 carbon atoms '' is a 5- to 8-membered saturated heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms, and 1 to 3 Z or nitrogen atoms. .
  • Such 5- to 8-membered saturated heterocycles include, for example, tetrahydrobiranyl, morpholine Groups such as nil, thiomorpholinyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, piperidinyl, piperadiel, oxazolidiel, isoxazolidinyl, thiazolidinyl, and pyrazolidinyl; and further, the 5- to 8-membered saturated heterocyclic group is It may be condensed with another cyclic group such as a benzene ring. In such a 5- to 8-membered saturated heterocyclic ring, a 5- to 6-membered saturated heterocyclic group is preferable.
  • the 5- to 8-membered saturated heterocyclic group substituted by 3 to 3 membered 5- to 8-membered saturated heterocyclic ring, excluding tetrahydrofuran, imidazolidine or dioxepane, is the same as the above R 3a and R 4a together.
  • 3- to 10-membered saturated carbocycle and “substituent group” formed by including R 3 and R 4 , or carbon atoms to which R 3a and R 4a are bonded together
  • the 3- to 10-membered saturated carbocyclic moiety of the 3- to 10-membered saturated carbocyclic ring substituted by 1 to 3 groups selected from a and c is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Examples thereof include groups such as Xinole, Cycopenia, Puchinore, Nonolepornyl, Adamantyl, and Indanore, and may be condensed with another cyclic group such as a benzene ring.
  • Such a 3- to 10-membered saturated carbocycle is preferably a 5- to 6-membered saturated cyclic hydrocarbon group which may be condensed with a benzene ring, and most preferably an indanyl group.
  • the “halogen atom” in the definition of the substituent group “a” is fluorine, chlorine, bromine or iodine atom, preferably fluorine atom or chlorine atom, and most preferably fluorine atom.
  • R 5a represents a lower alkyl group of “lower alkyl group” in the definition of the substituent groups a and b and “lower alkyl group substituted by 1 to 3 groups selected from the substituent group a”.
  • the parts are, for example, methyl, ethyl, propyl, isopropyl, butyl, isopti , S-butyl, t_butylinole, pentinole, isopentyl / le, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentinole, 3-methylpentyl, 2-methylpentyl, 1-Methynolepentinole, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethynolebutyl, 1,2-dimethynolebutyl, 1,3-dimethylbutyl, 2,3-dimethyl,
  • the “halogeno lower alkyl group” in the definition of the substituent group a represents a group in which the above “lower alkyl group” has been substituted with a halogen atom, for example, trifluoromethyl, trichloromethyl, difluoromethino.
  • a lower alkyl group having 1 to 6 carbon atoms such as 2-ethyl ethynole, 3-chloropropyl, 4-fluorobutyl, 6-hexylhexyl, and 2,2-dibutyl moethyl.
  • lower alkoxy group in the definition of R 5a and the substituent group a represents a group in which the above “lower alkyl group” is bonded to an oxygen atom, and is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy.
  • a straight chain with 1 to 6 carbon atoms such as toxic, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy
  • a branched chain alkoxy group preferably a 1 C 4 alkoxy group, more preferably a 1 C 2 alkoxy group, Most preferably, it is a methoxy group.
  • a "lower alkoxy group” represents a group bonded to a carboxyl group, for example, methoxy canolebonyl, ethoxycarbur, propoxypropyl, isopropoxycarbonyl, butoxycarbol, isobutoxycarbel, sbutoxy Carbonyl, t-butoxycarbonyl, pentoxycarbol, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonel, hexyloxycarbel, 4-methylpentoxycarbonyl, 3-methylpen Toxicylcarbonyl, 2-Methyl grepentoxy force / report, 3,3-Dimethynolebutoxy force / Repotinole, 2,2-Dimethylbutoxycarbonyl, 1,1-Dimethylbutoxycarbol, 1,2-Dimethylbutane Toxicylcarbonyl, 1,3-dimethylbutoxycarbur, 2,3-dimethyl Help butoxy carbonyl having 2 to 7 amino lower alkoxycarbon
  • the “lower aliphatic acyl group” in the definition of the substituent groups a and b represents a hydrogen atom or a group in which a saturated or unsaturated chain hydrocarbon group is bonded to a carboel group, for example, formyl Acetyl, propionyl, butyryl, isoptyryl, norrelyl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, and octyl tonnyl. Or a propioel group, most preferably an acetyl group.
  • lower aliphatic acylamino group in the definition of R 6 and the substituent group a represents a group in which the above “lower aliphatic acyl group” is bonded to an amino group, such as formylamino, acetylamino, propio- Lumino, butyrylamino, isopyrylamino, norrelylamino, isovalerylamino, vivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonylamino group It is preferably an acetylamino or propionylamino group, and most preferably an acetylamino group. ''
  • the aralkyl part in the “aralkyl group” and the “aralkyl group substituted by 1 to 3 groups selected from the substituent group a” in the definition of the substituent group b is benzyl.
  • ⁇ -naphthinolemethinole ⁇ -naphthinolemethyle / ⁇
  • indeninolemethinele diphenenolemethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl
  • C 7 such as 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthynolehexyl, 5-naphthylhexyl or 6-naphthylhexyl group
  • a C 16 aralkyl group preferably a benzyl group.
  • the “lower alkylsulfoyl group” in the definition of the substituent group b represents a group in which the above “lower alkyl group” is bonded to a sulfonyl group, for example, methylsulfonyl, ethynolesnorhonol, Pinores Nolehoninole, Isopropinoles Nolehoninole, Petit / Lesnole Honinore, Isobutylsulfoninole, s-Ptinoles, / Lehoninole, t-Ptylsnolehoninole, Pentylsulfonyl, Isopentylsulfur, 2-Methyl Butinolesulhoninole, Neopentylsnolejoel, 1-ethylpropinolesulhonle, hexinolesulhol, i-hexhexyl
  • the “aromatic acylamino group” in the definition of R 6 represents a group in which the aryl group is bonded to a carbonylamino group, and examples thereof include benzoylamino, 1-indancarbonylamino, and 2-indanecarbonylamino. , 1- or 2-naphthoylamino group, preferably a benzoylamino group.
  • ⁇ aryl group substituted by 1 to 3 groups selected from the substituent group a '' in the definition of RRRR 3a , R 5 , R 5a and the substituent group b include, for example, 2 —, 3— or 4—fluorophenyl, 2 _, 3— or 4 _ chlorophenol, 2 —, 3 — or 4 bromophenyl, 2-, 3 _ or 4 phenyl, 2 —, 3 — Or 4-methylphenyl, 2-, 3- or 4-methylphenyl, 2_, 3- or 4-trifluoromethylphenyl, 2_, '3
  • ⁇ 5 to 8 substituted by 1 to 3 groups selected from the substituent group c, which R 3 and R 4 together form including the carbon atom to which they are bonded
  • the ⁇ membered saturated heterocyclic ring '' is preferably a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from substituent group c, and more preferably 1-membered with an oxo group
  • a 5- or 6-membered saturated heterocyclic ring which may be further substituted by 1 or 2 groups selected from the substituent group c, and more preferably represented by the following formula (L-11)
  • G and J are the same or different, and are an oxygen atom, a sulfur atom or a formula NR. Is a group having However, G and J do not represent a group having the same formula NR—.
  • G is an oxygen atom or a sulfur atom.
  • J is a group having —N H—.
  • R 3a and R 4a are taken together to form a ⁇ 5- to 8-membered saturated group substituted by 1 to 3 groups selected from a substituent group c, including the carbon atom to which they are bonded.
  • the ⁇ complex ring '' is preferably substituted with 1 to 3 substituent groups c or a selected group.
  • a 5- or 6-membered saturated heterocyclic ring more preferably a 5- or 6-membered saturated heterocyclic ring which may be substituted by one oxo group and further substituted by 1 or 2 groups selected from substituent group c And more preferably, the following formula (L-1)
  • G and J are the same or different and each represents an oxygen atom, a sulfur atom or a group having the formula NR—). And J is a group having —NH—.
  • R 3 and R 4 , or R 3a and R 4a together form a carbon atom to which they are bonded to form a ⁇ substituent group a and c selected from 1 to
  • the ⁇ 3-substituted 3- to 10-membered saturated carbocycle '' is preferably a 5- to 6-membered saturated carbocyclic ring substituted by 1 to 3 groups with a group selected from substituent groups a and c. More preferably, it is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent), and most preferably. , 2-hydroxyindane or 2-oxoindane group.
  • “Pharmacologically acceptable salt thereof” means that the compound (I) or (II) of the present invention is reacted with an acid when it has a basic group such as an amino group, When the compound has an acidic group such as a carboxy group, it can be converted to a salt by reacting with a base.
  • the salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonates and ⁇ -toluenesulfonates.
  • Organic acid salts such as lillsulfonate, acetate, malate, fumarate, succinate, quanate, ascorbate, tartrate, oxalate and maleate; and glycine Examples include salts, amino acids such as lysine, arginine, oleetine, glutamate and aspartate, and most preferably organic acid salts.
  • the salt based on the acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, Metal salts such as iron salts; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine salts, getylamine salts , Triethylamine, dihexylhexylamine, N, N'-dibenzylethylenediamine, chloroproline, proline, diethanolamine, N-benzylphenethylamine, Lazine salt, tetramethylammonium salt, tris (hydroxymethyl) a Amin salts such good Una
  • the compound having the general formula (I) or (II) of the present invention has various isomers since an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, by the general formula (I) or (II). Accordingly, the present invention includes all these isomers, as well as mixtures of these isomers in any proportion.
  • the compound represented by the general formula (I) or (II) of the present invention absorbs water, becomes adsorbed water, or becomes a hydrate when left in the air or recrystallized. Such hydrates may be included in the salts of the present invention.
  • esters in the above refers to the ester of the compound (I) or (II) of the present invention because it can be converted into an ester, and such esters include “ester of hydroxyl group” and “carboxy group”. And an ester in which each ester residue is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.
  • General protecting group refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
  • Valeryl isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethynoleoctanoyl, 3,7-dimethinole otatanyl, pentadecyl, dodecanol, tridecanol, tridecanol, tridecanol 1-methinolepentadecanoyl, 14-methylpentadecanoyl, 13, 13-dimethyltetradecanoyl, heptadecanol, 15-methylhexadecanoyl, octadecanol, 1-methylheptadecanol, Alkanoyl groups such as nonadecanoyl, eicosanoyl, henicosanoyl, halogenated alkylcarboyl groups such as chloroacetyl, dichloroacetyl, dich
  • Nitrobenzene a nitrated arylcarbonyl group such as 2-nitrobenzoyl, a lower alkoxycarbylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, "Aromatic acyl groups” such as arylated carbyl groups such as fuel benzoyl; methoxy canoleponinole, ethoxy canolebinore, propoxy canolebonore, butoxycyanoleboninole, sutoki Lower alkoxycarboyl groups such as shikanoreboninore, .t-butoxycanoleponinole, isopoxycarbonyl, 2,2 "Alkoxycarbonyl groups” such as nodogens such as 1,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl or lower alkoxycarbol groups substituted with tri-lower alkylsilyl groups; Such as 3-yl, 3-bromotetrahydropyran
  • Substituted ethyl group such as tyl group; one to three aryl groups such as benzyl, ⁇ -naphthylmethyl,] 3-naphthylmethyl, diphenylmethyl, triphenylmethyl, ⁇ -naphthyldiphenylmethinole, 9-anthrinolemethyl
  • An "aralkyl group” such as a lower alkyl group substituted with one to three aryl groups in which the aryl ring has been replaced by a lower alkyl, lower
  • the “general protecting group” for the “ester of a carboxy group” preferably, the above “lower alkyl group”; ether, 1-propyl, 2-propyl, 1-methyl-12 —Properinole, 1-methinole, 1-propernole, 2-methyl_1-prole, 2-methyl-1-propernyl, 2-ethyl-2-prole, 1-butyr, 2 — Butenyl, 1-methyl-2-butul, 1-methyl-1-butur, 3-methyl-1-buteninole, 1-ethynorre _ 2-butur, 3-buteninole, 1-methinolle 3-butur, 2-methinodia 31 Buteninole, 1-Ethylou 3 1 Buteninole, 1—Pentinole, 2—Pentinole, 1-Methinole 2—Penten / le, 2-Methinole 2—Pentennole, 3—Pentennole, 1—Mentinole 3-Pente Ninore, 2
  • a protective group that can be cleaved in vivo by a biological method such as hydrolysis means a protective group that is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof.
  • a derivative is administered to a laboratory animal such as a rat or a mouse by intravenous injection, and then the body fluid of the animal is examined to determine whether the derivative is the original compound or a pharmacologically acceptable salt thereof. Can be determined by being able to detect
  • protecting group capable of being cleaved in vivo by a biological method such as hydrolysis as the “ester of a hydroxyl group”, preferably, formyloxymethyl, acetoxmethyl, dimethylaminoacetoxymethyl , Propionyloxymethyl, petyryloxymethyl, bivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethinole, hexanoinoleoxymethinole, 1-formyloxyxethyl, 1-acetoxyethyl, 1-propionylo Kisekil.
  • -(Lower alkoxy group / leoxy) alkyl group such as (ethoxycarbonyloxy) hexyl; (5-phenyl-12-oxo_1,3-dioxolen-1-yl) methyl, [5- ( 4-methyl-1) 2-oxo-1, 3-dioxolen-14-yl) Methyl, [5- (4-methoxyphenyl) 1-2-oxo-1 1, '3-dioxolen-1 4-yl Methyl, [5- (4-fluoropheninole) -2-oxo-1,3-dioxolene 4-inole] Methyl, [5- (4-chlorophene) 12-year-old 1,3-dioxolene (4-yl) Methyl, (2-oxo-1,3-dioxolen-1-4-inole) Methyl, (5-methyl-2-oxo-1,3-diox
  • the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group” preferably, methoxyxyl, 1-ethoxyxyl, 1-methyl-1 1-Methoxyxetil, 1- (isopropoxy) ethyl, 2 -Methoxyxyl, 2-Ethoxytyl, 1,1-dimethyl-1-methoxethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxy
  • a lower alkoxy lower alkyl group such as methyl, a lower alkoxylated lower alkoxy lower alkyl group such as 2-methoxyxetoxymethyl, an “aryl” oxy “lower alkyl group” such as phenoxymethyl, 2, 2, 2 —Haguchigens such as trichloroethoxymethyl, bis (2-chloroethoxy) methyl
  • the compound has a carboxy group, it can be a derivative other than the above “pharmacologically acceptable salt” and the above “ester”.
  • An example of such a derivative is an amide derivative.
  • More preferred compounds include
  • the most preferred compounds include

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Abstract

Composés hétérocycliques azotés saturés de formule générale (I), sels desdits composés acceptables sur le plan pharmaceutique, ou esters ou autres dérivés de ces substances, qui possèdent un excellent effet immunosuppresseur à sélectivité pour les cellules TH1. Dans ladite formule, R1 et R2 représentent chacun aryle ou analogue, X représente oxygène ou analogue, Y représente alkylène ou analogue et L représente -C(R3)(R4)- dans laquelle R3 représente aryle, hétéroaryle ou analogue, et R4 représente -CO-R5, ou alternativement R3 et R4 peuvent former, avec l'atome de carbone auquel ils sont liés, un hétérocycle saturé comportant cinq à huit éléments, un noyau carbone saturé comportant trois à dix éléments ou analogue.
PCT/JP2000/007345 1999-04-30 2000-10-20 Composes heterocycliques azotes satures WO2002034719A1 (fr)

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JP2000120206A JP2001011050A (ja) 1999-04-30 2000-04-21 含窒素飽和複素環化合物
AU2000279529A AU2000279529A1 (en) 2000-10-20 2000-10-20 Nitrogenous saturated heterocycle compounds
PCT/JP2000/007345 WO2002034719A1 (fr) 2000-04-21 2000-10-20 Composes heterocycliques azotes satures

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084966A1 (fr) * 2002-04-05 2003-10-16 Sankyo Company, Limited Dérivés de l'oxazolidinone
EP2061780A1 (fr) * 2006-09-14 2009-05-27 Neuromed Pharmaceuticals, Ltd. Composés de diaryle piperidine utilisés en tant que bloqueurs de canaux calciques
US10106522B2 (en) * 2014-12-29 2018-10-23 Faes Farma, S.A. Benzimidazole derivatives as antihistamine agents
WO2023047107A1 (fr) * 2021-09-22 2023-03-30 The University Of Durham Composés dérivés aryles ou hétéroaryles pour traiter des infections microbiennes

Citations (3)

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Publication number Priority date Publication date Assignee Title
US3962259A (en) * 1973-12-12 1976-06-08 American Hoechst Corporation 1,3-Dihydrospiro[isobenzofuran]s and derivatives thereof
US4082755A (en) * 1977-02-14 1978-04-04 Janssen Pharmaceutica N.V. 1-[(Diarylmethyl)aminoalkyl]piperidimes
JPS56128782A (en) * 1980-03-14 1981-10-08 Yoshitomi Pharmaceut Ind Ltd Bicyclic type spiropiperidine derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962259A (en) * 1973-12-12 1976-06-08 American Hoechst Corporation 1,3-Dihydrospiro[isobenzofuran]s and derivatives thereof
US4082755A (en) * 1977-02-14 1978-04-04 Janssen Pharmaceutica N.V. 1-[(Diarylmethyl)aminoalkyl]piperidimes
JPS56128782A (en) * 1980-03-14 1981-10-08 Yoshitomi Pharmaceut Ind Ltd Bicyclic type spiropiperidine derivative

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084966A1 (fr) * 2002-04-05 2003-10-16 Sankyo Company, Limited Dérivés de l'oxazolidinone
EP2061780A1 (fr) * 2006-09-14 2009-05-27 Neuromed Pharmaceuticals, Ltd. Composés de diaryle piperidine utilisés en tant que bloqueurs de canaux calciques
EP2061780A4 (fr) * 2006-09-14 2010-12-22 Zalicus Pharmaceuticals Ltd Composés de diaryle piperidine utilisés en tant que bloqueurs de canaux calciques
US10106522B2 (en) * 2014-12-29 2018-10-23 Faes Farma, S.A. Benzimidazole derivatives as antihistamine agents
AU2015373457B2 (en) * 2014-12-29 2019-09-19 Faes Farma, S.A. New benzimidazole derivatives as antihistamine agents
WO2023047107A1 (fr) * 2021-09-22 2023-03-30 The University Of Durham Composés dérivés aryles ou hétéroaryles pour traiter des infections microbiennes

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