WO2004094424A1 - 含窒素複素環化合物およびその用途 - Google Patents
含窒素複素環化合物およびその用途 Download PDFInfo
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- WO2004094424A1 WO2004094424A1 PCT/JP2004/005610 JP2004005610W WO2004094424A1 WO 2004094424 A1 WO2004094424 A1 WO 2004094424A1 JP 2004005610 W JP2004005610 W JP 2004005610W WO 2004094424 A1 WO2004094424 A1 WO 2004094424A1
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- KHVCOYGKHDJPBZ-WDCZJNDASA-N tetrahydrooxazine Chemical compound OC[C@H]1ONC[C@@H](O)[C@@H]1O KHVCOYGKHDJPBZ-WDCZJNDASA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- RWXZKKKYLRFREK-UHFFFAOYSA-N thiadiazepane Chemical compound C1CCSNNC1 RWXZKKKYLRFREK-UHFFFAOYSA-N 0.000 description 1
- BXVYJQULAWJPSR-UHFFFAOYSA-N thiadiazepine Chemical compound S1C=CC=CN=N1 BXVYJQULAWJPSR-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- ZFEAMMNVDPDEGE-LGRGJMMZSA-N tifuvirtide Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(C)=O)[C@@H](C)CC)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 ZFEAMMNVDPDEGE-LGRGJMMZSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940098802 viramune Drugs 0.000 description 1
- 229940100050 virazole Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- 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
- A61K31/499—Spiro-condensed pyrazines or piperazines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Definitions
- Nitrogen-containing heterocyclic compounds and uses thereof are Nitrogen-containing heterocyclic compounds and uses thereof
- the present invention relates to (1) General formula (I) Akita (0,1
- Chemokines are known as basic proteins that have endogenous leukocyte chemotaxis and activation, and have strong heparin binding properties. Chemokines are now involved not only in controlling inflammation, specific leukocyte infiltration during the immune response, but also in the development, lymphocyte homing under physiological conditions, blood cell progenitor cells, and somatic cell migration. It is considered.
- the differentiation, proliferation and cell death of blood cells are controlled by various cytokines. Inflammation is localized in the body, and lymphocyte differentiation, maturation, etc. are performed at specific sites. That is, various necessary cellular forces move to a specific site and accumulate to generate a series of inflammation and immune reactions. Therefore, in addition to cell differentiation, proliferation and death, cell migration is also necessary for the immune system This is an essential phenomenon.
- hematopoiesis begins in the AGM (aorta gonad mesonephros) area, passes through the fetal liver to permanent hematopoiesis in the bone marrow.
- AGM aorta gonad mesonephros
- T cells and progenitor cells of thymic dendritic cells migrate from the fetal liver and bone marrow to the thymus, and differentiate in the thymic environment.
- T cells that have undergone clonal selection migrate to secondary lymphoid tissues and participate in peripheral immune responses.
- Activated and differentiated skin Langerhans cells that have captured the antigen migrate to the local lymph node T cell region, and activate naive T cells as dendritic cells.
- the memory T cells home via the lymph vessels and blood vessels to the lymph nodes again.
- B cells, intestinal intraepithelial T cells, ⁇ / ⁇ cells, ⁇ ⁇ ⁇ cells, and dendritic cells migrate and migrate from the bone marrow without passing through the thymus, and are involved in the immune response.
- Chemokines are deeply involved in such various cell migration.
- MI ⁇ 3 j3 (.macrophage mtlammatorv protein 3 ⁇ )
- SLC ⁇ secondary lymphoid tissue chemokine and its receptor, CCR 7, are mature dendritic cells that capture antigens, and are na ⁇ ⁇ ve T cells and memory T cells.
- These cells play an important role in the migration and homing of these cells to the local lymphoid tissues in order to meet them efficiently.
- few T cells and dendritic cells are required to control an antigen-specific immune response (J. Exp. Med .. 189 (3), 451 (1999)).
- MDC macroohage-derived chemokine
- TARC thymus and activation-regulated chemokine
- CCR4 its receptor, CCR4
- anti-TARC antibody increases the blood ALT level and increases the liver TNF a; and Fas L expression levels.
- further improved rat mortality J. Clin. Invest. 102, 1933 (1998)
- anti-MDC antibodies accumulated in the lung interstitium. It reduced the number of eosinophils and suppressed airway hyperresponsiveness (J. Immunology, 163, 403 (1999)).
- MCP-1 monocyte chemoattractant protein-l
- CCR2 CCR2
- Anti-MCP-1 antibody showed an inhibitory effect on infiltration of monocytes and macrophages into glomeruli in a rat anti-Thy 1.1 antibody nephritis model (Kidney Int., 51, 770 (1997)).
- chemokine receptors are expressed in various specific cells at specific times, and their effector cells accumulate at the locations where chemokines are produced, thereby controlling inflammatory and immune responses. He is heavily involved.
- AIDS acquired immunodeficiency syndrome
- HAV human immunodeficiency virus
- CD4 positive cells the major target cells
- T cells which are responsible for immune function.
- various immunodeficiency states such as fever, diarrhea, and swelling of the lymph nodes are exhibited, and various opportunistic infections such as Kali pneumonia are easily caused. It is well known that such a condition is the onset of AIDS and induces malignant lupus ulcers such as cystic sarcoma and becomes serious.
- various methods of preventing and treating AIDS include, for example, (1) suppression of HIV proliferation by administration of reverse transcriptase inhibitors and protease inhibitors, and (2) opportunistic infections by administration of immunostimulatory drugs. Prevention, mitigation, etc. are being attempted.
- HIV mainly infects helper T cells, which play a central role in the immune system.
- the use of the membrane protein CD4 expressed on the membrane of T cells at that time has been known since 1985 (Cell, 52, 631 (1985)).
- CD4 expressed on the membrane of T cells at that time
- CD4 expressed on the membrane of T cells at that time
- CD4 vascular endothelial cells
- Langerhans cells in skin tissues
- dendritic cells in lymphoid tissues dendritic cells in lymphoid tissues
- glial cells in the central nervous system and the like.
- Fusin a cell membrane protein called Fusin was identified as a factor other than the CD4 molecule involved in HIV infection (Science. 272.872 (1996).
- This Fusin molecule is a stromal cell-derived factor 1 (1).
- Stromal Derived Factor-1 (abbreviated as SDF-1) has been proved to be a receptor (ie, CXCR4.)
- SDF-1 has T cell tropism in vitro (X4) HIV (Nature, 382, 829 (1996), Nature, 382, 833 (1996)), which means that SDF-1 binds to CXCR4 before HIV. It is thought that HIV has lost a foothold for infecting cells, and HIV infection has been inhibited.
- CCR5 chemokine receptor
- MIP-1 o a receptor for RANTE S, MIP-1 o; and MIP-1] 3
- CXCR4 a receptor for RANTE S, MIP-1 o; and MIP-1] 3
- R5 macrophage tropism
- those that can compete for HIV with CXCR4 or CCR5, or those that bind to HIV virus and render the virus incapable of binding to CXCR4 or CCR5 could be HIV infection inhibitors.
- low-molecular-weight compounds initially discovered as inhibitors of HIV infection have been shown to be actually antagonists of CXCR4 (Nature Medicine, 4, 72 (1998)).
- chemokine receptors are deeply involved in various inflammatory diseases, autoimmune diseases, immune diseases such as allergic diseases, and HIV infection.
- asthma nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis, transplant rejection, immunosuppression, psoriasis, multiple sclerosis, human immunodeficiency virus infection (later Acquired immunodeficiency syndrome, etc.), Atopic dermatitis, Jungle rash, Allergic bronchopulmonary aspergillosis, Allergic eosinophilic gastroenteropathy, Ischemic reperfusion injury, Acute respiratory distress syndrome, Shock accompanying bacterial infection, Diabetes Or, it is considered to be involved in cancer metastasis and the like.
- Oyopi 5 3 sigma independently are carbon, nitrogen, oxygen or sulfur or al chosen, (provided that at least one atom of A 1 z is carbon, and at least one B j Z is carbon.
- the spiro bicycle formed by A i Z and B jz may each be optionally partially unsaturated
- p Z and q Z are each independently numbers from 2 to 6.
- m Z is a number from 0 to p Z
- n Z is a number from 0 to q Z,
- -(L z ) is a bond or a divalent substituted or unsubstituted chain consisting of 1 to 10 atoms selected from carbon, nitrogen, sulfur and oxygen, and Q z is 1 or It is a basic group containing two or more basic radicals, and R 3Z is an acidic group containing one or more acidic radicals.
- mY or 1 ⁇ independently represents 0, 1, 2, 3, 4, or 5;
- R 1Y represents a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group,
- W Y represents a single bond, a C 1-3 alkyl group, a C 1-3 alkyl group substituted with oxo, etc.
- Q Y represents one NR 2 —, one O—, one S—, one S (O) —, or _SO 2 —
- ⁇ represents a single bond, a C 1-3 alkyl group, a C 1-3 alkyl group substituted with oxo, etc.
- Y Y —Z Y ring represents phenyl, naphthyl, or heteroaryl. However, the definition of each symbol is partly excerpted. ) Have been reported to be useful as chemokine receptor modulators (see WO98 / 25605).
- triazaspiro [5.5] indecan derivative compounds their quaternary ammonium salts, their N-oxides, or their non-toxic salts control the action of the chemokinin-Z chemokine receptor (CCR).
- CCR chemokinin-Z chemokine receptor
- An object of the present invention is to provide a compound which is useful as a prophylactic and therapeutic agent for human immunodeficiency virus infection or the like and which antagonizes a chemokine receptor against a chemokine.
- the present inventors have conducted intensive studies to find a compound that antagonizes a chemokine. As a result, they have found that the compound of the present invention represented by the general formula (I) meets this purpose, and have completed the present invention.
- the compound of the present invention is suitable as a CCR5 receptor antagonist.
- ring A represents an optionally substituted 3- to 15-membered nitrogen-containing monocyclic, bicyclic, or tricyclic heterocyclic ring,
- Ring B is an aliphatic hydrocarbon group which may have a substituent, a cyclic group which may have a substituent, a hydroxyl group which may be protected, a carboxyl group which may be protected, Optionally a rubamoyl group, or
- Q 1 and Q 2 are each independently a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, a cyclic group which may have a substituent, A good hydroxyl group, an optionally protected carboxy group, or an optionally substituted carpamoyl group.
- R 1 represents a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group or a substituted or unsubstituted cyclic group
- R 2 and R 3 are each independently a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, a cyclic group which may have a substituent, a hydroxyl group which may be protected, Represents an optionally protected carboxy group or an optionally substituted carbamoyl group.
- ring A is a 4- to 8-membered nitrogen-containing monocyclic heterocyclic ring or a 9 to 15-membered nitrogen-containing bicyclic or tricyclic heterocyclic ring which may have a substituent, Their salts, their solvates, or their prodrugs,
- R 1 is an aliphatic hydrocarbon group which may have a substituent, a salt thereof, a solvate thereof, or a prodrug thereof; 5.
- ring B is The compound according to the above 1, which has an aliphatic hydrocarbon group which may have a substituent, a salt thereof, a solvate thereof, or a prodrug thereof,
- a drug a composition comprising the compound according to 1 above, a salt thereof, a solvate thereof, or a prodrug thereof as an active ingredient.
- composition according to the above 7 which is a preventive and / or therapeutic agent for CCR5-mediated disease
- composition according to the above 7 which is a prophylactic and / or therapeutic agent for human immunodeficiency virus infection,
- composition according to the above 7 which is an agent for preventing and / or treating acquired immunodeficiency syndrome
- One or more agents selected from antagonists, CCR4 antagonists, CXCR4 antagonists, fusion inhibitors, HIV integrase inhibitors, antibodies to HIV-1 surface antigens, and HIV-1 vaccines A medicine comprising a combination of
- a CCR 5 in a mammal which comprises administering to the mammal an effective amount of the compound represented by the general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof according to the above 1.
- An immunodeficiency in a mammal comprising administering to the mammal an effective amount of the compound represented by the general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof according to the above 1.
- prodrugs Regarding the use of prodrugs.
- the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having substituent (s)” for R 1 may be a “linear or branched C 1 to 18
- a "linear or branched C1-18 hydrocarbon group” includes, for example, a C1-18 alkyl group, a C2-18 alkenyl group, a C2-18 18 alkynyl groups and the like.
- the C 1-18 alkyl group includes, for example, methinole, ethyl, propyl, isopropyl, butyl, isoptinole, sec-butyl, tert-butylinole, pentinole, hexyl, heptinole, octinole, noninole, decyl, pentadecyl , Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and isomers thereof
- the C2-18 alkenyl group includes, for example, butyl, propeninole, buteninole, pentenyl Nore, Hexeninole, Hepteninole, Octeninole, Nonenyl, Decenyl, Pendesenyl, Dodecenyl, Trideceninole
- Tininole Pentul, Hexchel, Heptinole, Octyl, Nonininole, Desininole, Pendecinyl, Dodecinyl, Tridecinyl, Tetradecinyl, Pentadeshul, Hexadesinole, Heptadecinyl, Neptinyl, Butadidinyl, Butadidinyl , Heptazinyl, Octadinyl, Nonadinyl, Decadinyl, Pindecadinyl, Dodecadinyl, Tridecadinyl, Tetradecadinyl, Pentadecadinyl, Hexadecadinyl, Heptadecadinyl, Hoctadinyl, Hexadinyl, Hexadrinyl , Decatrinil, pendecatrinil, dodecatrilinyl, tridecatrilinyl, tetradecatrilinyl, pen Dekatoryinir
- the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” for R 1 is preferably an aliphatic hydrocarbon group of C 1 to L 0 And more preferably a C1-6 alkyl group and a C2-6 alkenyl group, particularly preferably a C1-6 alkyl group. Especially, a methyl or ethyl group is preferable.
- examples of the "substituent" in the "optionally substituted aliphatic hydrocarbon group” represented by R 1 include, for example, a substituent selected from the following first group, Examples include a substituent selected from the two groups, a cyclic group which may have a substituent, and the like, and 1 to 5 of these may be substituted at substitutable positions.
- R a , R a , R b and R b each independently represent a hydrogen atom, an optionally substituted cyclic group (ring 1), or an optionally substituted substituent.
- R b and R b ′ together with the adjacent nitrogen atom represent a good aliphatic hydrocarbon radical, or (1) —C 2-6 alkylene (eg, methylene, ethylene, trimethylene, tetramethylene, pentane) Methylene, hexamethylene and isomers thereof), (2)-(C2-6 alkylene) one O_ (C2-6 alkylene) one, (3) — (C2-6 alkylene) one S— ( (C2-6 alkylene) one, (4) one (C2-6 alkylene) one NR N1 — (C2-6 alkylene) — (wherein R N1 is a hydrogen atom, even if it has a substituent) A C 1-8 alkyl group which may be substituted by a good cyclic group (ring 1)
- aliphatic hydrocarbon group in the “aliphatic hydrocarbon group which may have a substituent” represented by R a , R a , R b , and R b ′, Or a linear or branched C1-8 hydrocarbon group ".
- substituents represented by R a , R a , R b , and R b ′
- linear or branched C1-8 hydrocarbon group include a C1-8 alkyl group and a C2-8
- examples thereof include an 8 alkenyl group and a C2-8 alkynyl group.
- Examples of the C1-8 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
- Examples of the C2-8 alkenyl group include, for example, butyl, propenyl, butyr, pentenyl, hexenyl, heptenyl, octyl, ptageninole, pentageninole, hexageninole, heptageninole, octagenil, hexatrienyl, heptatrienyl, Octatrienyl group and C2-8 alkynyl groups include, for example, echul, propyninole,NICyl, pentininole, hexinole, heptininole, octininole, butadininole, pentazininole, hexazininole, heptazinyl, Octadinyl, hexatriynyl, heptatriynyl, octatriynyl group and isomers thereof.
- R c , R c ′, R d , and R d ′ have the same meanings as R a , R a ′, R b , and R b , provided that R c , R c ⁇ R d , R d ′ does not represent an aliphatic hydrocarbon group substituted by a substituent selected from the present group (third group).
- R a , R a ′, R b , R b ′ an optionally substituted cyclic group (ring 1) ”represented by R N1 , and a“ substituent represented by R a , R a , R b , R b ”
- Examples of the carbocycle include C 3 to C 15 monocyclic, bicyclic, or tricyclic carbocyclic arylene, which may be partially or wholly saturated.
- the "one" Examples of the C 3 to C 15 monocyclic, bicyclic, or tricyclic carbocyclic aryl which may be partially or entirely saturated include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexane, Cycloheptane, Cyclobutane, Cyclononane, Cyclodecane, Cycloundecane, Cyclododecane, Cyclotridodecane, Cyclotetradecane, Cyclopentapentane, Cyclopentene, Cyclohexene, Cyclohepten, Cyclootaten, Cyclopentapentagen, Cyclohexene Hexadiene, cycloheptadiene, cyclobutadiene, benzene
- C3-15 monocyclic, bicyclic or tricyclic carbocyclic aryl which may be partially or wholly saturated includes a spiro-bonded bicyclic carbocycle and a bridged bicyclic Also included are formula carbocycles such as spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] pendecane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] ] Hepta-2-ene, bicyclo [3.1.1] heptane, bicyclo [3.1.1] Hepta-2-ene, bicyclo [2.2.2] octane, bicyclo [2.2.2] ] Otter 2-ene, adamantane, noradamantan and the like.
- the heterocyclic ring may be, for example, a 3- to 5-membered monocyclic or bicyclic ring containing 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms, Z or 1 to 3 sulfur atoms.
- the above “3- to 15-membered monocyclic, bicyclic, or tricyclic (1 to 4 nitrogen atoms, 1 to 3 oxygen atoms_ or 1 to 3 sulfur atoms containing 1 to 3 sulfur atoms include, for example, pyrroline, pyrrolidine, imidazoline, imidazolidin, pyrazoline, virazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, tetrahydropyridine, Piperidin, dihydrobirazine, tetrohydrobirazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine,
- the “cyclic group” of the “cyclic group (ring 1) optionally having substituent (s)” is preferably a 5- to 10-membered monocyclic or bicyclic cyclic group, more preferably Benzene, cyclohexane, cyclohexene, thiophene, pyrazonole, isothiazonole, thiazonole, imidazonole, furan, dihydropyrazoneole, quinoline, benzodioxane, dioxindan, benzofuran, pyridine, and particularly preferably benzene, pyridine, pyrazin .
- Examples of the “substituent” in the “optionally substituted cyclic group (ring 1)” include, for example, an optionally substituted aliphatic hydrocarbon group and a substituted group.
- the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” as the “substituent” refers to the aforementioned “linear or branched C 1-8 carbon atom”.
- substituted in the “aliphatic hydrocarbon group optionally having substituent (s)” has the same meaning as “hydrogen group”, and is, for example, a cyclic group optionally having substituent (s) ), A substituent selected from the first group, a substituent selected from the following fourth group, and the like. These may be substituted at 1 to 5 positions that can be substituted.
- R e , R e ′, R f and R f ′ each independently represent a hydrogen atom, an optionally substituted cyclic group (ring 2), or an optionally substituted substituent.
- R f and R “together with the adjacent nitrogen atom represent a good aliphatic hydrocarbon group; (1) one C2-6 alkylene, (2) _ (C2-6 alkylene) one O— (C2-6 alkylene) one, (3) — (C2-67 norylene) one S— (J2-6 anorylene) one, (4)-(C2-6 alkylene) — NR N2 _ (C2 in (group, R N2 is hydrogen atom, phenylene Honoré represents group, or a phenylene Honoré represent good C 1 to 8 alkyl group optionally substituted by a group)] - 6 alkylene).
- the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having substituent (s)” represented by R e , R e , R f , and R ” is the aforementioned“ linear chain ”.
- R e , R e ', R f , R is an "optionally substituted aliphatic hydrocarbon group”
- the “substituent” in the above include a cyclic group (ring 2) which may have a substituent and a substituent selected from the following fifth group, and these are substituted with 1 to 5 substituents at substitutable positions. I'm doing it.
- R g , R e ⁇ R h , and R h ′ have the same meanings as R e , R e ′, R f , and R ′′.
- R g , R g ′, R h , R h ' is selected from this group (fifth group) It does not represent an aliphatic hydrocarbon group substituted by a substituent.
- substituted cyclic group (ring 2) examples include, for example, an optionally substituted aliphatic hydrocarbon group and a substituted group.
- the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having substituent (s)” as the “substituent” is the same as the “linear or branched C 1 to 8 hydrocarbon group '', and the ⁇ substituent group '' in the ⁇ aliphatic hydrocarbon group optionally having substituent (s) '' may be a 3- to 8-membered substituent.
- RR, R j and R j ′ each independently represent a hydrogen atom, a 3- to 8-membered monocyclic carbocyclic or heterocyclic ring which may have a substituent, or a substituent.
- R j and R j ′ together with an adjacent nitrogen atom form (1) —C 2-6 alkylene (e.g., methylene, ethylene, trimethylene, tetra Methylene, pentamethylene, hexamethylene, etc.), (2) — (C2-6 alkylene) mono O— (C2-6 alkylene) —, (3) — (C2-6 (Anoalkylene) 1 S— (C 2-6 alkylene) 1, (4) — (C 2-6 alkylene) 1 NR N2 — (C 2-6 alkylene) 1 (wherein R N2 has the same meaning as described above) ).
- —C 2-6 alkylene e.g., methylene, ethylene, trimethylene, tetra Methylene, pentam
- the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having substituent (s)” represented by RR, R j and R ” is the aforementioned“ linear or branched ”.
- C 1-8 hydrocarbon group ”, Ri, Ri, R j , R” represented by “optionally substituted aliphatic hydrocarbon group” represented by “substituent” A 3- to 8-membered monocyclic carbocyclic or heterocyclic ring, which may have a substituent, and a substituent selected from the following group 7; these are substituted at 1 to 5 at substitutable positions. It may be.
- R k , R k ′, R m , and R m ′ have the same meaning as Ri, R, R j , and R ′′. However, R k , R k ′, R m , and R ra ′ Does not represent an aliphatic hydrocarbon group substituted by a substituent selected from the group (seventh group).
- the term “optionally substituted 3 Examples of the "3- to 8-membered monocyclic carbocyclic or heterocyclic ring" in the "to 8-membered monocyclic carbocyclic or heterocyclic ring” include the following: For example, a C 3-8 monocyclic carbocyclic aryl, which may be partially or completely saturated, or 1-4 nitrogen atoms, 1-2 oxygen atoms, and / or 1-2 Examples thereof include a 3- to 8-membered monocyclic heterocyclic aryl containing a sulfur atom, and a partially or entirely saturated heterocyclic ring.
- Examples of the ⁇ C 3-8 monocyclic carbocyclic aryl which may be partially or completely saturated '' include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclooctane, Pen mouth pentene, mouth hexene, mouth heptene, cyclo octene, pen pentagen, mouth hexadiene, cyclohexadiene, cyclooctadiene, benzene, and the like.
- Examples of the aforementioned “3- to 8-membered monocyclic heterocyclic aryl containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms Z or 1 to 2 sulfur atoms” include, for example, pyro Ichinore, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, xixin, jixianfen, chiopyran, chepin, oxoxinolole, isoxoxazo Nore, thiazonole, isothiazonole, furazan, oxaziazol, oxazine, oxaziazine, oxazepine, oxaziazepine, thiadiazole, thiazine, thiadiazine, thiazepine
- heterocyclic ring saturated with are: aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidin, triazoline, triazolidine, tetrazoline, tetrazolidine, villazolin, villazolidine, dihydropyridine, tetrahydropyridine, piperididine, dihydrovirazine, Tetrahydrovirazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydrodropyridazine, dihydroazepi , Tetrahydroazepine, perhydroazepine, dihydrodiazepine,
- ⁇ 3- to 8-membered monocyclic carbocyclic or heterocyclic ring '' in the ⁇ 3- to 8-membered monocyclic carbocyclic or heterocyclic ring which may have a substituent '', preferably a 5- to 6-membered And more preferably tetrahydropyran, tetrahydrothiopyran, piperidine, benzene, pyridine, pyrimidine, pyrazine, fura And oxazonole, thisaifen, pyrrole, thiazole and imidazonole, and particularly preferably benzene.
- examples of the “substituent” in the “optionally substituted 3- to 8-membered monocyclic carbocyclic or heterocyclic ring” include, for example, a C 1-8 alkyl group, selected from the first group. And a substituent selected from Group 8 below.
- R n, R. And R. Each independently represents a hydrogen atom, a phenyl group, or a C 1-8 alkyl group which may be substituted with a phenyl group; And R. , Together with the adjacent nitrogen atom, (1) —C 2-6 alkylene,
- cyclic group as “substituent” of the "aliphatic hydrocarbon group optionally having a substituent” for R 1, the R a , R a ′, R b , R b ′ and R N1 have the same meaning as the “cyclic group optionally having substituents (ring 1)”.
- the "cyclic group” of the “cyclic group optionally having substituent (s)” is preferably a 5- to 10-membered monocyclic or bicyclic cyclic group, more preferably benzene or cyclohexane.
- the R 1 group is preferably an aliphatic hydrocarbon group which may have a substituent, and more preferably a 3- to 15-membered monocyclic or dicyclic group which may have a substituent.
- a C 1-6 alkyl group which may have a cyclic cyclic group as a substituent.
- Cl-6 alkyl group which may have a 3- to 15-membered monocyclic or bicyclic cyclic group which may have a substituent
- C 1-6 alkyl group) 1 (benzene which may have a substituent), 1 (C 1-6 alkyl group)-(virazole which may have a substituent), 1 ′ (C 1 -6 alkyl group)-(pyridinine optionally having substituent (s)), (C1-6 alkyl group) one (C3-6 cycloalkyl optionally having substituent (s)), One (Cl-6 alkyl group) one (C4-6 cycloalkenyl optionally having substituent (s)),-(Cl-6 alkyl group) one (thiazole optionally having substituent (s)) , 1 (Cl-6 alkyl group)-(furan optionally having substituent (s)), 1 (Cl-6 alkyl group) 1 (isoxazole optionally having substituent (s)) ), (C 1-6 alkyl group) 1
- Y A is preferably a bond, one O—, one CH 2 —, one CO— or the like.
- Preferred examples of ring 1 and ring 2 include “5-: carbon ring aryl or heterocyclic aryl of LO member” and the like.
- Examples include "5- to 6-membered carbocyclic aryl or heterocyclic aryl", and particularly preferred are, for example, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, Furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxaziazole, thiadiazole ring and the like.
- these cyclic groups may have a substituent, and in particular, those in which ring 2 is substituted with an acidic group such as a carboxy group, an amide group or a sulfonamide group which may be protected.
- an acidic group such as a carboxy group, an amide group or a sulfonamide group which may be protected.
- substituent of ing 1 and ring 2 include, for example, an aliphatic hydrocarbon group which may have a substituent, an alkoxy group, a carboxy group, an alkanoylamide group, and the like.More preferred substituents include, for example, And an aliphatic hydrocarbon group and an alkoxy group. In the present invention, the R 1 group having these combinations is more preferable.
- Benzyl) monopropyl group 2,4,6-trimethoxybenzinole group, 2,4-dimethoxybenzyl group, 2,6-dimethoxybenzinole group, 2-phenylimidazole-5-ylmethyl group, 2-phenylenoletinol 2, 2-benzyloxy, 2-methoxybenzyl, 3- (2-furan-2-yl)-2-propanol, 3,5-dimethyl-1-phenyl-1H- Pyrazole-1-4-ylmethyl group, 3-cyanobenzyl group, 3-phenylvirazole_4_ylmethyl group, 3-phenylpropyl group, 3-phenyloxybenzyl group, 4- (3--(N, N— Dimethylamino) propyl Xy) benzyl group, 4- (4-hydroxyl 4-methylpentyl) cyclohexyl 3-en-l ⁇ remethyl group, 4- (4-methylsulfonylamino) phenoxy Benzyl group, 4-
- a ⁇ 3- to 5-membered nitrogen-containing nitrogen atom which may have a substituent '' As the ⁇ 3- to 5-membered nitrogen-containing monocyclic, bicyclic or tricyclic heterocyclic ring '' of the ⁇ monocyclic, bicyclic or tricyclic heterocyclic ring '', at least one nitrogen atom other than a carbon atom
- a monocyclic, bicyclic or tricyclic heterocyclic ring which may further contain 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
- Examples of the "3- to 5-membered nitrogen-containing monocyclic, bicyclic or tricyclic heterocyclic ring” include “3- to 15-membered nitrogen-containing unsaturated heterocyclic ring” and “3- to 15-membered nitrogen-containing saturated heterocyclic ring”. ].
- Examples of the “3- to 15-membered nitrogen-containing unsaturated heterocyclic ring” include, for example, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydrovirazine, tetrahydrovirazine, dihydropyrimidine, tetrahydropyrimidine, Dihydropyridazine, Tetrahydropyridazine, Dihydroazepine, Tetrahydroazepine, Dihydrodiazepine, Tetrahydrodiazepine, Dihydroxazonole, Dihydroisoxazonole, Dihydrothiazol, Dihydroisothiazole / Dihydroisoflazozan, Dihydrooxa Diazole, dihydrooxazine, dihydrooxazine diazine, dihydroxoxazepine, tetrahydrooxaze
- Examples of the "3- to 15-membered nitrogen-containing saturated heterocycle” include aziridine, azetidin, azocan, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, virazolidine, piperidine, piperazine, perhydropyrimidine, and phenol.
- ring A may have a substituent other than R 1
- Shall have. That is, when ring A is piperidine, ring A has a substituent at at least one of positions 2, 3, 5, and 6.
- a dotted line bonded to a nitrogen atom represents an R 1 binding site, and the other dotted lines represent a spiro bond to ring B.
- Ring A may have 1 to 5 substituents at substitutable positions.
- substituents in ring A include a substituent selected from the following ninth group or a linear group optionally having 1 to 5 substituents selected from the following ninth group: Or a branched C1-8 hydrocarbon group.
- R x and R x ′ each independently represent a hydrogen atom, a linear or branched C 1-8 hydrocarbon group, and R y is a linear or branched C 1-8 Represents an 8 hydrocarbon group, and Rt represents a hydrogen atom, a linear or branched C 1-8 hydrocarbon group, or an optionally protected hydroxyl group.
- linear or branched C 1-8 hydrocarbon group has the same meaning as described above.
- the hydroxy group which may be protected has the same meaning as one OR a (the symbols in the group have the same meanings as described above), which are listed in the second group.
- the substituent on ring A is preferably methyl, methoxy, or norreoxy.
- examples of the "substituent" in the ring B which may have a substituent include, for example, an aliphatic hydrocarbon group which may have a substituent, and a ring which may have a substituent An optionally protected hydroxyl group, an optionally protected carboxyl group, an optionally substituted canolebamoyl group, or
- Q 1 and Q 2 are each independently a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, a cyclic group which may have a substituent, A good hydroxyl group, a carboxy group which may be protected, or a carpamoyl group which may be substituted.).
- hydroxyl group which may be protected, optionally protected carboxy group may force Rubamoiru group which may be substituted, listed in the second group, one OR a, One COOR a, one CONR b R b '[The symbols in the group have the same meanings as above. I forgot. ] Has the same meaning as Further, as the "aliphatic hydrocarbon group" in the "aliphatic hydrocarbon group optionally having substituent (s)", a “linear or branched C1-8 hydrocarbon group” may be mentioned. . The “linear or branched C 1-8 hydrocarbon group” has the same meaning as described above.
- the “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)” represented by R 1 Represents the same meaning as ".”
- “linear or branched C 1-8 hydrocarbon group” has the same meaning as described above.
- the “optionally substituted cyclic group” has the same meaning as the “optionally substituted cyclic group (ring 1)” in the second group.
- R 2 and R 3 each independently represent a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group, a substituted or unsubstituted cyclic group, And an optionally protected hydroxyl group, an optionally protected carboxy group, and an optionally substituted carbamoyl group.
- hydroxyl group which may be protected, optionally protected carboxy group may force Rubamoiru group which may be substituted, listed in the second group, - OR ⁇ _ COOR a, one CONR b R b ′ (the symbols in the group have the same meanings as described above.).
- the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” includes a “linear or branched C 1-8 hydrocarbon group”. .
- the “linear or branched C 1-8 hydrocarbon group” has the same meaning as described above.
- the “substituent” of the “aliphatic hydrocarbon group optionally having a substituent” the “substituent” in the “aliphatic hydrocarbon group optionally having a substituent” represented by R 1 Has the same meaning as "substituent”.
- linear or branched C 1-8 hydrocarbon group has the same meaning as described above.
- the “cyclic group optionally having a substituent” has the same meaning as the “cyclic group optionally having a substituent (ring 1)” in the second group.
- the substituent of ring B is preferably a 4- to 6-membered carbon ring which may have a substituent, or a C 1-6 aliphatic hydrocarbon group which may have a substituent.
- the “optionally protected carboxy group”, which is mentioned as a preferable substituent of the optionally substituted cyclic group (ring 2), is One COOR a listed in the group (the symbols in the group have the same meanings as described above.) Can be mentioned up.
- the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylthio group, the alkylene group, the alkenylene group and the alkynylene group include straight-chain and branched-chain ones.
- isomers E, Z, cis, trans
- isomers due to the presence of asymmetric carbon R, S, ⁇ ,] 3 configuration, enantiomers, diastereomers
- Optically active substance with optical activity D, L, d, 1 body
- polar form by chromatographic separation high polar form, low polar form
- equilibrium compound rotamer, mixture of any ratio of these All racemic mixtures are included in the present invention.
- the compound represented by the general formula (I) is converted into a salt by a known method.
- a salt a pharmacologically acceptable salt is preferable.
- Examples of pharmacologically acceptable salts include metal salts of alkali metal, earth metal salts of alkali metal, ammonium salts, amine salts, acid addition salts and the like.
- the pharmacologically acceptable salt is preferably a water-soluble salt.
- Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (quaternary ammonium salts, etc.), pharmaceutically acceptable organic amines (Tetramethinoammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylenamine, piperidine, monoethanolanolamine, diethanol Lamine, tris (hydroxymethyl) amino, lysine, arginine,
- the acid addition salt is preferably water-soluble.
- Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, Organic salts such as benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesnoleonate, toluenesulfonate, isethionate, glucuronate, and dalconate.
- inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate
- Organic salts such as benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesnoleonate, toluenesulfonate, isethionat
- the compound represented by the general formula (I) and a salt thereof can also be converted to a solvate.
- the solvate is non-toxic and water-soluble.
- Suitable solvates include, for example, water and solvates such as alcoholic solvents (eg, ethanol and the like).
- the compounds represented by the general formula (I) or pharmacologically acceptable salts thereof are all preferred. Specific examples include the compounds described in the examples or pharmacologically acceptable salts thereof.
- Salts also include quaternary ammonium salts.
- the R ° group represents a C1-8 alkyl group or a C1-8 alkyl group substituted by a phenyl group.
- N-oxo refers to a compound represented by the general formula (I) in which a nitrogen atom is oxidized.
- a prodrug of the compound represented by the general formula (I) is converted into the compound (I) in vivo by a reaction with an enzyme, gastric acid, or the like.
- a compound. As a prodrug of compound (I), when compound (I) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, the amino group of compound (I) is eicanosyl) , Alanylation, pentylaminocarbonylation, (5-methyl-12-oxo-1,1,3-dioxolen_4-inole) methoxycarbonylation, tetrahydrofuranylation, pyro-V-dilmethylation, bivaloyloxymethylation , Acetoxymethylated, tert-butylated compounds, etc.); when the compound (I) has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkyl
- R 2 and R 3 both represent a hydrogen atom.
- T is a C 1-4 alkyl group, a C 5-6 monocyclic carbocycle, or a C 5-6 monocyclic carbocycle or 1-2 nitrogen atoms and / or 1 represents C. 1 to 4 alkyl groups had it occurred substituted monocyclic heterocyclic ring 5-6 membered ring containing SansoHara child, R ", ring a 'each represent the same meaning as R 1 ring a. However, If R 1 'or ring A' contains a carboxyl, hydroxyl, amino, or thiol group, those groups shall be protected if necessary.
- the compound represented by) is subjected to a cyclization reaction and, if necessary, to a deprotection reaction of a protecting group.
- This cyclization method is known.
- a tertiary amine triethylamine, disopropyle
- an organic solvent dichloroethane, toluene, ethyl acetate, etc.
- the reaction is carried out by heating to 60 to 120 ° C. with or without using an acid (acetic acid, trifluoroacetic acid, etc.).
- This reaction is a reaction that is simultaneously cyclized cleavage of T group P
- an operation for converting into the desired salt may be carried out by a known method.
- the deprotection reaction of a protecting group is known and can be performed by the following method.
- the carboxyl-protecting group include a methyl group, an ethyl group, an aryl group, a t-butyl group, a trichloroethyl group, a benzyl (Bn) group, and a phenacyl group.
- hydroxyl-protecting group examples include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyxetinole (EE) group, a methoxyethoxymethyl (MEM) group, and a 2-tetrahydroviranyl (THP).
- TMS Trimethylsilyl
- TES triethylsilyl
- TDMS t-butyldimethylsilyl
- TDPS t-butyldiphenylsilyl
- acetyl Ac
- piperoyl benzoyl, benzyl (Bn) group, p-methoxybenzyl group, aryloxycarbonyl (Al1oc) group, 2,2,2-trichloromouth ethoxycarbonyl (Troc) group and the like.
- Examples of the protecting group for the amino group include benzyloxycarbonyl group, t-butoxycarbonyl group, aryloxycarbonyl (A1 1 oc) group, 1-methyl 1 _ (4-biphenyl ) Ethoxycarbonyl (B poc) group, trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) groups.
- benzyloxycarbonyl group t-butoxycarbonyl group
- aryloxycarbonyl (A1 1 oc) group 1-methyl 1 _ (4-biphenyl ) Ethoxycarbonyl (B poc) group
- trifluoroacetyl group 9-fluorenylmethoxycarbonyl group
- benzyl (Bn) group p-
- Examples of the thiol protecting group include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydroviranyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.
- the protecting group for the carboxyl group, hydroxyl group, amino group, or thiol group is not particularly limited as long as it is a group other than those described above that can be easily and selectively eliminated. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.
- the deprotection reaction by alkali hydrolysis includes, for example, alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.),
- the reaction is carried out at a temperature of 0 to 40 ° C using an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution or a mixture thereof. It is.
- the deprotection reaction under acid conditions is performed, for example, in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisol, etc.), in an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.). ) Or in an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromoacetate, etc.) at a temperature of 0 to 100 ° C.
- the deprotection reaction by hydrogenolysis is carried out, for example, by using a solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, etc.)) Norecone (methanolone, ethanolone, etc.), benzene (benzene, tonorenene, etc.), ketone (acetone, methylethylketone, etc.), nitrile (acetonitrile, etc.), amide (dimethylformamide, etc.), water , Ethyl acetate, acetic acid, or a mixed solvent of two or more of them) in the presence of a catalyst (palladium carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), hydrogen at normal pressure or under pressure
- a catalyst palladium carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.
- the deprotection reaction of the silyl group is carried out, for example, by using tetrabutylammonium fluoride in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) at a temperature of 0 to 40 ° C. It is done in.
- a water-miscible organic solvent tetrahydrofuran, acetonitrile, etc.
- the deprotection reaction using a metal is carried out, for example, by the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution of ⁇ 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran). Below, it is carried out at a temperature of 0 to 40 ° C while applying ultrasonic waves if necessary.
- an acidic solvent acetic acid, a buffer solution of ⁇ 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran.
- the deprotection reaction using a metal complex may be carried out, for example, in a trapping reagent in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixed solvent thereof.
- organic solvent dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.
- Tributyltin hydride triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.
- organic acids acetic acid, formic acid, 2-ethylhexanoic acid, etc.
- organic acid salts sodium 2-ethylhexanoate, 2 Metal complex (tetrakistriphenyl phosphine palladium (0), dichlorotribis bis (triphenyl phosphine) in the presence or absence of a phosphine-based reagent (triphenyl phosphine, etc.) ) Palladium (II), palladium acetate (I I), tris (tripheninolephosphine) rhodium (I) or the like) at a temperature of 0 to 40 ° C.
- R 1 represents an optionally substituted aliphatic hydrocarbon
- R 2 and R 3 both represent a hydrogen atom
- R 1 represents a nitrogen atom.
- R 1 — A represents an optionally substituted aliphatic hydrocarbon, provided that R 1 -A represents an aliphatic hydrocarbon (R 1 — in which the number of carbon atoms in the main chain of R 1 is reduced by one) represents the backbone of carbon number ⁇ R 1 of the main chain carbon number one 1) of a. other symbols are the same meaning as above.) the general formula (III)
- ring B ′ has the same meaning as ring B. However, ring B ′ is a carboxyl group, If it contains hydroxyl, amino, or thiol groups, those groups shall be protected if protection is required. Other symbols have the same meaning as described above.
- Reductive amination is known in the art. For example, a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride) in an organic solvent (dichloroethane, dichloromethane, dimethylformamide, acetic acid, etc.) is used. , Sodium borohydride, etc.) at a temperature of 0 to 40 ° C.
- X represents a leaving group (for example, a halogen atom, a mesylate, or a tosylate), and the other symbols have the same meanings as described above).
- the compound can be produced by reacting the compound of the formula (IV) and, if necessary, subjecting the compound to deprotection of a protecting group.
- This reaction is known.
- an organic solvent for example, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, etc.
- an alkali carbonic acid, sodium carbonate, etc.
- sodium or sodium iodide The reaction is performed at a temperature of 100 to 150 ° C. in the presence or absence of potassium chloride.
- R 1 is a partially or completely saturated monocyclic, bicyclic or tricyclic carbocyclic aryl of C 3 to 15, or a partially or fully saturated 1 3- to 15-membered monocyclic, bicyclic, or tricyclic containing up to 4 nitrogen atoms, 1-2 oxygen atoms and a heteroatom selected from Z or 1-2 sulfur atoms
- R 1 —B represents ring 1 and is partially or wholly saturated C 3 to 15 monocyclic, bicyclic or tricyclic carboaryl, or partially or wholly saturated 3- to 15-membered mono-, bi-, or tri-ring containing a heteroatom selected from up to 4 nitrogen atoms, 1 to 2 oxygen atoms or 1 to 2 sulfur atoms
- a compound represented by the formula: is a heterocyclic aryl, and the other symbols are as defined above.
- Reductive amination is known in the art.
- a reducing agent sodium triacetoxyborohydride, sodium cyanoborohydride
- an organic solvent diichloroethane, dichloromethane, dimethylformamide, acetic acid, etc.
- Sodium borohydride, etc. at a temperature of 0 to 40 ° C.
- At least one nitrogen atom represents a quaternary ammonium salt, ie, a compound represented by the general formula (1-2)
- R represents a C 1-4 alkyl group or a C 1-4 alkyl group substituted by a phenyl group, and Q represents a halogen atom.
- This reaction is known and is carried out, for example, in an organic solvent (acetone, dimethylformamide, methylethylketone, etc.) at a temperature of 0 to 40 ° C.
- organic solvent acetone, dimethylformamide, methylethylketone, etc.
- At least one nitrogen atom represents N-oxide, ie, a compound of the general formula (1-3)
- N 3 represents a nitrogen atom, provided that at least one nitrogen atom is N- Okishido
- the compound represented by the general formula (I) can be produced by subjecting the compound represented by the general formula (I) to an oxidation reaction.
- This oxidation reaction is known.
- an appropriate organic solvent dichloromethane, chloroform, benzene, hexane, t-butyl alcohol, etc.
- excess oxidizing agent hydrogen peroxide, sodium periodate, Acyl nitrate, sodium perborate, peracid (for example, 3-chloroperbenzoic acid, peracetic acid, etc.), oxone (trade name of potassium peroxymonosulfate), potassium permanganate
- the reaction is carried out at a temperature of 20 to 60 ° C in the presence of chromic acid or the like.
- the compounds represented by the general formulas (II) and (IV) can be prepared by the following reaction step formula (1).
- reaction in the reaction step formula (1) is performed by a known method.
- the general formula (VIII) and the general formula (I) The compounds represented by X), the general formula (X) and the general formula (XI) can be prepared by a method known per se or a known method, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) can be easily used in combination.
- a solid-phase-supported reagent supported on a high-molecular polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like
- a high-molecular polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like
- the reaction product is purified by conventional purification means, for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, or column chromatography. It can be purified by a method such as chromatography, washing, or recrystallization. Purification may be performed for each reaction, or may be performed after completion of several reactions.
- conventional purification means for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, or column chromatography. It can be purified by a method such as chromatography, washing, or recrystallization. Purification may be performed for each reaction, or may be performed after completion of several reactions.
- the other starting materials and reagents in the present invention are known per se or can be produced by known methods.
- the toxicity of the compound of the present invention is extremely low, and it can be determined that the compound is sufficiently safe for use as a medicament.
- the compound of the present invention represented by the general formula (I) antagonizes chemokine receptors, and therefore, can be used for various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, chronic Rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis, etc.), immune diseases (treatment of autoimmune diseases, transplant rejection, immunosuppression, psoriasis, Multiple sclerosis, etc.), human immunodeficiency virus infection (acquired immunodeficiency syndrome, etc.), allergic disease (atopic dermatitis, juniper, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastrointestinal tract It is useful for preventing and / or treating ischemia-reperfusion injury, acute respiratory distress syndrome, shock associated with bacterial infection, diabetes, or cancer metastasis.
- ischemia-reperfusion injury acute respiratory distress syndrome, shock associated with bacterial infection,
- CCR5 mediated diseases include all diseases caused or related to CCR5 or the CCR5 gene.
- Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, in the range of lmg to 100mg, once orally several times a day It is administered orally or parenterally (preferably intravenously) once to several times a day, in the range of lmg to 100 mg per adult per day. It is administered intravenously over a period ranging from 24 hours to 24 hours.
- a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range.
- Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like.
- Capsules include hard capsules and soft capsules.
- one or more of the active substances As it is or as excipients (latatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, poly (vinylpyrrolidone), magnesium metasilicate aluminate, etc.) Calcium, etc.), lubricants (magnesium stearate, etc.), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc., and used in the form of pharmaceuticals according to the usual methods.
- a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcenolol phthalate, etc.
- a coating agent such as gelatin.
- Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, Includes L, syrup, elixir, etc.
- a commonly used diluent such as purified water, ethanol, or a mixture thereof.
- this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
- Injections for parenteral administration include all injections. Examples include injections into muscle, intravenous injections, intravenous infusions, and the like.
- Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
- the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used.
- this injection contains a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysonolate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. You may go out. These are produced by sterilization or aseptic processing in the final step.
- a sterile solid preparation for example, a lyophilized product, can be manufactured and dissolved in aseptic or sterile distilled water for injection or other solvents before use.
- parenteral administration examples include topical solutions, ointments, salves, inhalants, sprays, suppositories and vagina which contain one or more active substances and are formulated in a conventional manner. Pessaries for internal administration, etc. are included.
- Sprays may be used in addition to commonly used diluents, as well as buffering agents which provide isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium salt sodium, sodium tenoate or citric acid.
- An agent may be contained.
- Methods for producing spray agents are described in detail, for example, in U.S. Pat. Nos. 2,868,691 and 3,095,355.
- the compound of the present invention represented by the general formula (I) or a salt thereof is combined with other drugs, for example, a prophylactic or therapeutic agent for HIV infection (particularly, a prophylactic and / or Z or therapeutic agent for AIDS). May be used.
- these drugs may be mixed separately or simultaneously with pharmacologically acceptable excipients, binders, disintegrants, lubricants, stabilizers, solubilizing agents, diluents, etc. It can be formulated and administered orally or parenterally as a pharmaceutical composition for the prevention and treatment or prevention of HIV infection.
- the compound represented by the general formula (I) or a salt thereof of the present invention can be used for HIV- acquired resistance to other preventive and / or therapeutic agents for HIV infection (particularly, preventive and / or therapeutic agents for AIDS). 1 has an inhibitory effect on infection. Therefore, it can be used for HIV-infected patients for whom other preventive and / or therapeutic agents for HIV infection have become ineffective.
- the compound of the present invention may be used as a single agent, or may be used in combination with a preventive and / or therapeutic agent for HIV infection in which the infected HIV-1 strain has acquired resistance or with other agents. good.
- the present invention also includes a compound comprising the compound represented by the general formula (I) or a salt thereof and a drug that does not inhibit HIV infection, and which has a more prophylactic and / or therapeutic effect on HIV infection than a single agent.
- prophylactic or therapeutic agents for HIV infection used in combination with the compound represented by the general formula (I) of the present invention or a salt thereof include reverse transcriptase inhibitors, protease inhibitors, chemokines Antagonists (eg, CCR2 antagonists, CCR3 antagonists, CCR4 antagonists, CCR5 antagonists, CXCR4 antagonists, etc.), fusion inhibitors, HIV integrase inhibitors, antibodies to HIV-1 surface antigen, and HIV -1 vaccine and the like.
- chemokines Antagonists eg, CCR2 antagonists, CCR3 antagonists, CCR4 antagonists, CCR5 antagonists, CXCR4 antagonists, etc.
- fusion inhibitors eg, HIV integrase inhibitors, antibodies to HIV-1 surface antigen, and HIV -1 vaccine and the like.
- reverse transcriptase inhibitors include (1) nucleic acid-based reverse transcriptase inhibitors zidovudine (trade name: retrovir), didanosine (trade name: Videx), zalcitabine (trade name: hybrid), stavudine (trade name) Name: Zelit), Lamivudine (trade name: Epivir), Aba Riki Building (trade name: Ziadzion), Adefofi ⁇ ⁇ , Adefovir Jipipoxyl, Entrycitabine (trade name: Kobiracil), ⁇ (trade name: Tenofovir), etc.
- nucleic acid-based reverse transcriptase inhibitors zidovudine (trade name: retrovir), didanosine (trade name: Videx), zalcitabine (trade name: hybrid), stavudine (trade name) Name: Zelit), Lamivudine (trade name: Epivir), Aba Riki Building (trade name: Ziadzion), Adefofi ⁇ ⁇ , Adefovir Jipi
- Non-nucleic acid reverse transcriptase inhibitors nevirapine (trade name: viramune), delavidin (trade name: rescripter), efavirenz (trade names: Sustiva, Stocklin), capravirin (AG1549) and the like .
- protease inhibitors include indinavir (trade name: Clixipane), ritonavir (trade name: Novia), nelfinavir (trade name: Viracebut), saquinavir (trade names: Invirase, Fort Base), and amprinavir (Trade name: ezinelaser), mouth pinavir (trade name: Kaletra), tibranavir and the like.
- Chemokine antagonists include endogenous ligands of the chemokine receptor, or derivatives thereof and non-peptidic low molecular weight compounds, or antibodies to the chemokine receptor.
- Specific examples of endogenous ligands for chemokine receptors include MIP-1, MIP_l j3, RANTE S, SDF-1 ⁇ , SDF-1, MCP-1, MCP-2, MCP-4, Eotaxin, MDC and the like.
- derivative of the endogenous ligand examples include AOP-RANTES, Met-SDF-1 ⁇ , Met-SDF-l] 3 and the like.
- chemokine receptor antibody examples include Pro-140.
- CCR5 antagonist specifically, W099 / 17773, WO99 / 32100, WO00 / 06085, WOOO / 06146, WOOO / 10965, WOOO / 06153, WOOO / 21916, WO00 / 37455 EP1013276, WO00 / 38680, WO00 / 39125, WO00 / 40239, WO00 / 42045, WO00 / 53175, WO00 / 42852, WO00 / 66551, WO00 / 66558, WO00 / 66559, WO00 / 66141, WO00 / 68203, JP2000-309598, WO00 / 51607, WO00 / 51608, WO00 / 51609, WOOO / 51610, WOOO / 56729, WOOO / 59497, WOOO / 59498, WOOO / 59502,
- CXCR4 antagonist examples include AMD-3100, T-22, KRH-1120, and the compounds described in WO00 / 66112.
- fusion inhibitor examples include T-20 (pentafuside), T-1249 and the like.
- HIV integrase inhibitor examples include L-ticolic acid, Zintevir, L-870810, PL-2500, Component B, c-2507, and the like.
- Typical clinical doses of typical reverse transcriptase inhibitors and protease inhibitors are, for example, as shown below, but the present invention is not limited thereto.
- Zidovudine 100 mg force capsule, 200 mg at a time, 3 times a day;
- Didanosine 25-200 mg tablet, 125-200 mg at a time, twice a day;
- Zalcitabine 0.375 mg to 0.75 mg tablet, 0.75 mg at a time, 3 times a day; Stavudine: 15 to 40 mg capsule, 30 to 40 mg at a time, 1 ⁇ 2 times;
- Lamipudine 150 mg tablet, 150 mg at a time, twice a day;
- Nevirapine 200 mg tablet, 200 mg at a time, once a day for 14 days, then twice a day; Delavirdine: 100 mg tablet, 400 mg at a time, 3 times a day; Favirenz: 50-200 mg capsule, 600 mg at a time, once a day; indinavir: 200-400 force capsules, 800 mg at a time, 3 times a day;
- Ritonavir 100 mg capsenolle, 600 mg at a time, twice daily;
- Nelfinavir 250mg tablet, 750mg at a time, 3 times a day;
- Saquinavir 200mg force pseudonore, once l, 200mg, 3 times a day;
- Amprenavir 50-150 mg tablet, 1,200 mg at a time, twice a day.
- the compound of the present invention represented by the general formula (I), a salt thereof, or a prodrug thereof antagonizes a chemokine receptor (particularly, CCR5), and therefore can be used for various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis).
- the solvent in the kakkou indicated by the chromatographic separation point and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
- compounds with smaller R f values can be converted to higher polar compounds and larger compounds by thin-layer silica gel chromatography.
- the substance may be represented as a low-polar substance.
- the reaction solution was concentrated, diluted with dichloromethane, and neutralized with a 1N aqueous solution of sodium hydroxide.
- the reaction solution was extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and concentrated.
- Example 1 The same operation as in Example 1 was carried out using 1-benzyl-13-methyl-4-piperidone or a corresponding compound to obtain the following compound of the present invention.
- the entire procedure was based on basic genetic engineering techniques, producing high gene expression cells, and utilizing the usual methods.
- the measurement method of the present invention is obtained by improving the measurement accuracy and improving the Z or measurement sensitivity in order to evaluate the compound of the present invention as described below.
- the detailed experimental method is shown below.
- Human placenta cDNA was prepared using Marathon cDNA amplification kit (Clontech). PCR primers hCCR5XbaI-Fl: 5, one AGCTAGTC No. 1) and hCCR5XbaI-Rl: 5, AGCTAGTCTAGAGTGC A CAACTCTGACTGGGTCACCA—3, (SEQ ID NO: 2) are GenBank
- the amplified PCR product was purified using a QIAquick Gel Extraction Kit (QIAGEN) after 1% agarose gel electrophoresis, and cut with a restriction enzyme Xbal. Insert the cut fragment into the expression vector pEF-BOS-bsr using DNA Ligation Kit Ver.2. (Takara) and transformed into E. coli DH5a.
- the plasmid P EF-BOS-bsr / hCCR5 was prepared and confirmed DN A sequences.
- CHO-dhfr (-) was cultured using Ham's F-12 (containing fetal bovine serum (10%), penicillin (50 U / ml), and streptomycin (50 mg / ml)).
- the transduced cells were cultivated by adding blasticidin (5 mg / ml) as described above.
- the plasmid pEF-BOS-bsr / hCCR5 was transduced into CHO-dhfr (-) cells using DMRIE-C reagent (Gibco BRL). Forty-eight hours later, the medium was replaced with a medium containing 5 mg / m1 blastsidine, and selection was performed to establish stable overexpressed cells.
- the established human CCR 5 stably over-expressing CHO cells (CCR5 / CHO cell) was suspended in Ham's F-12 medium, and FB S (10%), as a 3.0 X 10 6 cells / well in 96-well plates Got involved. After culturing at 37 for 1 day, the culture supernatant was removed, and Ham's F-12 medium (Fura-2AM (5 ⁇ ), Probenecid (2.5 mM) and HE PES (20 mM; pH 7.4) was contained. ) was incubated at 37 ° C for 1 hour in a light-shielded state. After washing twice with 1 XHanksZH EPE S (20 mM; pH 7.4) solution, 100 ⁇ l / well of the same solution was added.
- Ham's F-12 medium Fura-2AM (5 ⁇ ), Probenecid (2.5 mM) and HE PES (20 mM; pH 7.4
- the compound of the present invention showed 50% or more inhibition at 10 ⁇ 10.
- the compound produced in Example 1 has IC 5 .
- the value was 0.76 ⁇ .
- the following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 5 Omg of the active ingredient.
Description
Claims
Priority Applications (3)
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EP04728443A EP1621540A4 (en) | 2003-04-21 | 2004-04-20 | HETEROCYCLIC COMPOUNDS CONTAINING NITROGEN AND USE THEREOF |
JP2005505741A JPWO2004094424A1 (ja) | 2003-04-21 | 2004-04-20 | 含窒素複素環化合物およびその用途 |
US10/554,096 US20070155713A1 (en) | 2003-04-21 | 2004-04-20 | Nitrogen-containing heterocyclic compounds and use thereof |
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JP2003/116235 | 2003-04-21 | ||
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US (1) | US20070155713A1 (ja) |
EP (1) | EP1621540A4 (ja) |
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WO (1) | WO2004094424A1 (ja) |
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WO2010009196A1 (en) * | 2008-07-15 | 2010-01-21 | Temple University Of The Commonwealth System Of Higher Education | Synthesis of bis-peptides oligomers comprising at least one n-substituted diketopiperazine as structural moiety |
RU2477478C1 (ru) * | 2011-11-23 | 2013-03-10 | Олег Владимирович Князев | Способ оценки эффективности лечения воспалительных заболеваний кишечника |
KR20210068422A (ko) * | 2018-08-31 | 2021-06-09 | 싸이토키네틱스, 인코포레이티드 | 심장 근절 억제제 |
CA3209557A1 (en) | 2021-03-04 | 2022-09-09 | Bradley P. Morgan | Cardiac sarcomere inhibitors |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001040227A1 (fr) * | 1999-12-03 | 2001-06-07 | Ono Pharmaceutical Co., Ltd. | Derives triazaspiro[5.5]undecane et medicaments contenant ces derives en tant que principe actif |
WO2002074770A1 (fr) * | 2001-03-19 | 2002-09-26 | Ono Pharmaceutical Co., Ltd. | Derives de triazaspiro[5.5]undecane et medicaments les contenant en tant que principe actif |
WO2002074769A1 (fr) * | 2001-03-19 | 2002-09-26 | Ono Pharmaceutical Co., Ltd. | Medicaments contenant comme principe actif des derives du triazaspiro [5.5] undecane |
JP2002348288A (ja) * | 2001-05-28 | 2002-12-04 | Ono Pharmaceut Co Ltd | スピロ複素環誘導体およびそれらを有効成分とする薬剤 |
WO2003035074A1 (fr) * | 2001-10-23 | 2003-05-01 | Ono Pharmaceutical Co., Ltd. | Medicaments comprenant une combinaison de derives de triazaspiro[5,5]undecane et d'un inhibiteur 3a4 d'isoenzyme p450 cytochrome et/ou d'un inhibiteur de p-glycoproteine |
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TW200413372A (en) * | 2002-09-18 | 2004-08-01 | Ono Pharmaceutical Co | Derivatives of triazaspiro [5.5] undecane and medicants using such derivatives as effective ingredient |
-
2004
- 2004-04-20 WO PCT/JP2004/005610 patent/WO2004094424A1/ja active Application Filing
- 2004-04-20 EP EP04728443A patent/EP1621540A4/en not_active Withdrawn
- 2004-04-20 US US10/554,096 patent/US20070155713A1/en not_active Abandoned
- 2004-04-20 JP JP2005505741A patent/JPWO2004094424A1/ja not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001040227A1 (fr) * | 1999-12-03 | 2001-06-07 | Ono Pharmaceutical Co., Ltd. | Derives triazaspiro[5.5]undecane et medicaments contenant ces derives en tant que principe actif |
WO2002074770A1 (fr) * | 2001-03-19 | 2002-09-26 | Ono Pharmaceutical Co., Ltd. | Derives de triazaspiro[5.5]undecane et medicaments les contenant en tant que principe actif |
WO2002074769A1 (fr) * | 2001-03-19 | 2002-09-26 | Ono Pharmaceutical Co., Ltd. | Medicaments contenant comme principe actif des derives du triazaspiro [5.5] undecane |
JP2002348288A (ja) * | 2001-05-28 | 2002-12-04 | Ono Pharmaceut Co Ltd | スピロ複素環誘導体およびそれらを有効成分とする薬剤 |
WO2003035074A1 (fr) * | 2001-10-23 | 2003-05-01 | Ono Pharmaceutical Co., Ltd. | Medicaments comprenant une combinaison de derives de triazaspiro[5,5]undecane et d'un inhibiteur 3a4 d'isoenzyme p450 cytochrome et/ou d'un inhibiteur de p-glycoproteine |
Non-Patent Citations (2)
Title |
---|
MAEDAA K. ET AL.: "Novel low molecular weight spirodiketopiprazin derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 276, no. 37, 2001, pages 35194 - 35200, XP002951814 * |
See also references of EP1621540A4 * |
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US20070155713A1 (en) | 2007-07-05 |
EP1621540A1 (en) | 2006-02-01 |
EP1621540A4 (en) | 2008-07-23 |
JPWO2004094424A1 (ja) | 2006-07-13 |
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