WO2004103974A1 - Compose 2-oxoquinoline substitue et utilisation medicale de celui-ci - Google Patents

Compose 2-oxoquinoline substitue et utilisation medicale de celui-ci Download PDF

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WO2004103974A1
WO2004103974A1 PCT/JP2004/007219 JP2004007219W WO2004103974A1 WO 2004103974 A1 WO2004103974 A1 WO 2004103974A1 JP 2004007219 W JP2004007219 W JP 2004007219W WO 2004103974 A1 WO2004103974 A1 WO 2004103974A1
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group
substituted
pharmaceutically acceptable
acceptable salt
ring
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PCT/JP2004/007219
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English (en)
Japanese (ja)
Inventor
Tetsudo Kaya
Hisashi Kawasaki
Shizue Watanabe
Noboru Nagahashi
Noriaki Matsumoto
Yukihiro Nomura
Hiroshi Chatani
Yoshifumi Ueda
Takayuki Mimura
Hiroyuki Iwamura
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Japan Tobacco Inc.
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Publication of WO2004103974A1 publication Critical patent/WO2004103974A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel substituted 2-oxoquinoline compounds and their pharmaceutical uses. It also relates to novel uses of certain substituted 2-oxoquinoline compounds. More specifically, a novel substituted 2-oxoquinoline compound that selectively acts on cannabinoid receptors, particularly peripheral receptors, has few central side effects, has antiallergic, immunomodulatory and anti-inflammatory effects, and its pharmaceutical use About. Background art
  • THC tetrahydrocannabinol
  • ⁇ 91-THC the major component contained in cannabis. It has been reported that this ⁇ 9-THC has effects such as motor tone, increased irritability, antiemetic, analgesic, hypothermia, respiratory depression, stimulatory action, vasodilatory action, and immunosuppressive action. ing.
  • Cannabis has been used since ancient times for pain relief, antipyretics, hypnosis, etc., and as a medicine. In Japan, it was listed as Indian Cannabis in the Pharmacopoeia from 1886 to 1951, and was used as an analgesic and anesthetic. In the United States of America, alcoholic solvents for cannabis were recognized as drugs for rheumatism, asthma, and tonsillitis in the Pharmacopoeia from 1850 to 1942.
  • ⁇ 9-tetrahide oral cannabinol which is considered to be the main component of cannabis or its psychoactive effects, has visual and auditory abnormalities, temporal and spatial cognitive abnormalities, increased detectability, thinking ability, and spontaneity. Induces sexual decline and memory impairment, prominent in mental function Is known to cause significant changes.
  • Other pharmacological effects are also extremely diverse, including reports on ataxia, increased irritability, decreased body temperature, respiratory depression, increased heart rate, stimulatory effects on blood pressure, increased blood pressure, vasodilatory effects, immunosuppressive effects, and the like At present, there are restrictions on its use.
  • cannobinoids A series of hallucinogenic substances contained in cannabis are collectively called cannobinoids, and more than 60 cannabinoids including THC have been found at present.
  • CB1 The distribution of CB1 is detected in many tissues other than the brain, such as human testis, human prostate, ovary, ovary, bone marrow, and thymus. But its level is much lower than the brain. In contrast, CB2 was absent in rat brain but found in monocytes in the marginal zone of the spleen. In human spleen, leukocytes, emulsions, thymus, and knees, CB2 is present at much higher levels than CB1.
  • CB1 and CB2 The existence of two subtypes of receptor (CB1 and CB2) and endogenous ligands such as anandamide and 2-arachidonylglycerol were confirmed, and their physiological roles were examined.
  • CB2 suppressed the proliferation of T cells and B cells, induced apoptosis and exhibited immunosuppressive effects
  • CB1 deficient knockout mice did not show the central effect seen with cannabinoid administration
  • CB2 deficiency Various findings are being obtained, such as the lack of suppression of helper T cell activation by cannapinoids in knockout mice.
  • CB1-related Parkinson's disease Alzheimer's disease, memory impairment, senile dementia, multiple sclerosis, loss of appetite, pain, etc.Immune diseases, rheumatism, inflammation, etc. related to CB2 are considered for drug development ing.
  • drugs that selectively act on CB2 that is, modulators that are selective for the peripheral cell type (also referred to as peripheral type or peripheral type) cannabinoid receptor are expected to be safe drugs without central action
  • cannabinoids show a central effect on CB1 at extremely low concentrations, it is desirable that the CB1 effect be lower among CB2-selective modulators.
  • non-selective cannabinoid receptor ligands include A9-THC, CP55940, WIN55212-2, HU-243, HU-210, etc.
  • CBl-selective ligands include SR141716A, LY320135 N arachidonol-2,- black port Echiruamido, etc.
  • CP56667 is a CB2 selective ligands, SR144528, AM630, HU - 308 , Jlffl-051 N L-768242 and the like that have been known (for example, non-patent documents 1 and 2 reference.) .
  • an antigen enters the body, it is first taken up by antigen presenting cells such as macrophages. Antigen presenting cells transmit the information of the taken-in antigen to T cells. In addition, T cells instruct B cells to produce antigen-specific IgE antibodies. IgE antibodies bind to mast cells, which renders mast cells sensitized.
  • mast cells When the antigen re-enters and the IgE antibody on the mast cell binds to the antigen, mast cells release cytokins such as histamine, eosinophil chemotactic factor, leukotriene, and various other chemical mediators, interleukin. Is done.
  • cytokins such as histamine, eosinophil chemotactic factor, leukotriene, and various other chemical mediators, interleukin. Is done.
  • bronchial smooth muscle contracts, swelling of mucous membranes, secretion of sputum, etc., narrowing the airway and causing asthma attacks. Inflammation, swelling and itching occur on the skin, causing skin diseases such as measles.
  • skin diseases such as measles.
  • it acts on the nasal mucosa it increases vascular permeability, collects water in the blood and swells the nasal mucosa, causing nasal congestion, and allergic rhinitis with sneezing and a large amount of nasal discharge due to nerve stimulation. .
  • intestinal smooth muscle contracts and intestinal movement (peristalsis) abnormally increases, resulting in gastrointestinal allergies such as abdominal pain, vomiting, and diarrhea.
  • allergic asthma atopic dermatitis
  • allergic rhinitis atopic dermatitis
  • allergic conjunctivitis a chronic inflammation
  • Asthma is known as “allergic asthma” induced by allergens and non-allergic asthma induced by cold, exercise, etc., regardless of the specific allergen.
  • Anti-asthmatics have shifted from a bronchodilator-centered treatment for reversible airway obstruction to an anti-inflammatory-centered treatment for chronic inflammation.
  • the treatment time of seizure depending on the symptoms, short-acting 0 2 agonists, short-acting theophylline drugs, inhaled anticholinergics, injection, oral, steroids, or the like are used.
  • sustained-release theophylline drugs, long-acting 2- stimulants, and antiallergic agents immediate-release inhibitors, histamine antagonists, leukotriene antagonists, tropoxanes
  • ⁇ 2 inhibition antagonist, Th2 site force-in inhibitor
  • side effects such as suppression of adrenal function seen in steroids, as well as symptoms (resistance) of less effective steroids and leukotriene treatments are known, and further antiasthmatics are expected.
  • Atopic predisposition (1) Family history, medical history (either bronchial asthma, allergic rhinitis, conjunctivitis, or atopic dermatitis, or multiple diseases), or (2) Predisposition to produce IgE antibodies " It is distinguished from other inflammatory skin diseases.
  • Symptoms include skin irritation and dryness, and characteristic rash (erythema, papule, crust, scale, lichenified lesion, prurigo, etc.) has a chronic and repetitive course. It also causes complications such as rash for varicella, rash for varicella, viral infection (simple herpes virus infection, etc.), impetigo, and infectious molluscs (cataract, retinal detachment, etc.).
  • the lesions include immediate and delayed allergic reactions by IgE * mast cells, and delayed allergic reactions by Langernon's cells and T cells. It is thought that response is involved.
  • Treatment is based on food, 'causes of mites' and other factors, and skin care (keeping the skin clean, using moisturizers to prevent dry skin, etc.). Used.
  • Antihistamines are used for pruritus, but their effect is not as pronounced as in the case of erythema.
  • Topical steroids are used for inflammation in principle.
  • Oral medications of antihistamines or antiallergic drugs are used to assist, but it is considered difficult to control dermatitis by using them alone.
  • atopic dermatitis is intractable, and there are many voices that avoid steroids due to side effects, so the development of new drugs is desired.
  • tacrolimus ointment an immunosuppressant, has been used and has been effective, but there are concerns about its side effects, and its use is restricted. It is also used for the treatment of severely damaged skin lesions that are difficult to apply externally, symptoms that occur in sensitive areas where the epidermis is originally thin and sensitive, such as the inner layer of the epidermis and diseases that cover a wide range of the body.
  • the development of an easy and safe oral preparation is also desired.
  • Patent Documents 1 to 3 Pyrazole derivatives (Patent Documents 1 to 3), THC derivatives (Patent Document 4), benzoxazine derivatives (Patent Document 5), indole derivatives (Patent Documents 2 and 6, Patent Documents 6), fatty acid derivatives (Patent Document 7) and indazole derivatives (Patent Document 2) are known.
  • roqinimex 4-hydroxy-2-oxo-1-methyl-1,2-dihydroquinoline-13-carboxylic acid N-methyl-N-phenylamide (compound C below) known by the name of roqinimex is an anti-inflammatory agent and an immunosuppressant It has been shown that it can be used for various diseases including anti-rheumatic drugs.
  • Patent Document 12 4-Hydroxy-l-methyl-l-oxoquinoline-l-hexalpoxamide (the following compound F) has been disclosed (Patent Document 12).
  • Patent Document 13 4-Hydroxy-l-methyl-l-oxoquinoline-l-hexalpoxamide (the following compound F) has been disclosed (Patent Document 12).
  • a compound having an immunomodulatory action, an anti-inflammatory action, and an analgesic action 1-methyl-2-oxo-13- ⁇ N- (1,3-benzodioxol-5-yl) -1-N-methylcarbamoyl ⁇
  • a quinoline having 1,4-hydroxy-6-methylthio-1,1,2-dihydroxyl mouth compound G below
  • Patent Document 14 a compound having a quinoline structure is useful as an immunomodulator, an anti-inflammatory agent, an anti-allergic agent, etc.
  • the quinoline compound disclosed in the literature is simply a quinoline substituted with a hydroxyl group, and there is no description suggesting a substituted 2-oxoquinoline as in the present conjugate.
  • Patent Document 15 the following compound H and the like are known as quinoline compounds having an adhesion inhibitory action, and allergic diseases, inflammatory diseases, autoimmune diseases and the like are listed as indications thereof (Patent Document 15).
  • compound i and compound J are known as 2-oxoquinoline compounds, which have an inhibitory effect on autoantibody production and have been shown to be useful as anti-inflammatory agents and immunomodulators (each of which is described in Patent Documents). 16, Patent Document 13).
  • Patent Document 13 also discloses the following compound K, compound L, etc. as anti-inflammatory agents and immunomodulators having an inhibitory action on autoantibody production (Patent Document 13).
  • the following compound M is known, and has been shown to have an autoantibody production inhibitory effect and to be useful as an anti-inflammatory agent and an immunomodulator (Patent Document 17).
  • the following compound N is known as a 2-oxoquinoline compound, and has been shown to be useful as an antibacterial agent (Patent Document 18).
  • the following compound O is known as a 2-oxoquinoline compound, has an antagonistic action against leukotriene and an inhibitory action on production, and has been shown to exert a therapeutic effect on diseases such as inflammation, allergy and asthma. (Patent Document 19).
  • Compound P The following compound Q is also known as a 2-oxoquinoline compound and has been shown to have immunomodulatory activity (Patent Document 20).
  • Patent Document 21 the following compound R is known as a 21-oxoquinoline compound, and has been shown to be useful as a herbicide.
  • the following compound S is known as a 2-oxoquinoline compound, and has been shown to be useful for treating diseases caused by autoimmune immunity and pathological inflammation (Patent Document 22).
  • Patent Document 24 only specifically discloses, for example, the other three compounds of the compound G.
  • Non-patent Document 1 Shozo Yamamoto et al., Biology and Chemistry, vol. 39, No. 5, pp 293-300, 2001
  • Patent Document 2 EP 656354
  • Patent Document 3 EP 658546 [Patent Document 4] JP-A-3-209377
  • Patent Document 6 US 5081122
  • Patent Document 7 W094 / 12466
  • Patent Document 11 Re-publication publication WO 96Z05166
  • Patent Document 13 Japanese Patent Application Publication No. 6-506925 (page 24, page 30 Example 3 (Compound J), page 33 Example 8 (3) (Compound K), page 36 Example 12 (Compound) (W 092 // 18483)
  • Patent Document 14 WO 97/29079
  • Patent Document 16 JP-T-Hei 8-511514 (pages 28 to 29, 39 (11)); WO 94/29295
  • Patent Document 20 Tokuhyohei 4-500373 (2 pages, 2 pages, Example 1); WO 90 Z15052
  • Patent Document 24 JP-A-11-110124 (WO 99/02499)
  • Patent Document 25 JP-A-2000-256323 (Page 26, Page 42: 3-10); W000 / 40562
  • Patent Document 26 WO 02/53543 (pages 23 to 24, page 221) Disclosure of the Invention ''
  • An object of the present invention is to provide a novel compound that selectively acts on a cannapinoid receptor, particularly a peripheral receptor, and a pharmaceutical composition thereof.
  • R 1 is a hydrogen atom or A 1 k, where Al k is from 1-3 may be by connexion substituted with a substituent C 8 selected from the following group A An alkyl group;
  • R 5 , R 6 , R 7 and R s are the same or different and are each a hydrogen atom, a hydroxyl group, a halogen atom, Al k, one O-Al k, one O-heterocyclic group, one OCO-Al k, OS0 2 — A 1 k, -NR 9l -A 1 k, one NR q2 CO—A 1 3 ⁇ 4 :, one S—A 1 k, one lipoxyl group, one COO—Al k, or one CONR q3 R q4 ,
  • n represents an integer of 0 to 4
  • R sl and R s2 are the same or different and each represents a hydrogen atom or A 1 k.
  • R ql, R q2, IT 3 and R 94 are the same or different and each is a hydrogen atom or CI_ 4 alkyl group.
  • Group A a halogen atom, one OR al, One OCOR a2, One COOR a3, - NR a4 C OR a5, one NR a6 R a7, one CONR a8 R a9, One SR AL0, One SOR a Interview 1, One S0 2 R al2, one OS0 2 R al3, one S0 2 NR al4 R al5, - S0 2 OR al6, one COR AL7, one NR al8 S0 2 R al9, substituted by 1 to 5 substituents selected from the following group B A carbocyclic group, and the following groups: substituted by 1 to 5 substituents selected from B A heterocyclic group which may be
  • R al , R a3 , R a4 , R a6 , R a7 , R a8 , R a9 , R al0 , R al4 , R al5 , R al6 , R al7 , R al8 and R al9 are the same or Differently, a hydrogen atom, a Ci- 4 alkyl group, a carbocyclic group which may be substituted by 1 to 5 substituents selected from the following group B, or 1 to 5 substituents selected from the following group B And R a2 , R a5 , R all , R al2 and R al3 are Ci-4 alkynole groups.)
  • Group B halogen atom, C ⁇ 4 alkyl group, one OR bl , one COOR b2 , -CONR b3 R b4 , alkylenedioxy group;
  • R bl, R b2, R M and R b4 are the same or different and each is but it may also be due connection substituted 1 to 3 substituents selected from hydrogen atom or the following group C - 4 is an alkyl group.
  • R 2 is a hydrogen atom or A 1 k
  • R 31 and R 33 are the same or different and are each a hydrogen atom, a cyano group, A lk, one COOR 36 , one CONR 37 R 38 , and 1 to 5 substituents selected from the above group B.
  • R 32 is Alk, a carbocyclic group which may be substituted by 1 to 5 substituents selected from the group B, or 1 to 5 substituents selected from the group B.
  • R 31 and R 32 may be taken together to form a cycloalkyl group or a bridged ring, and the cycloalkyl group may be condensed with a benzene ring, and the cycloalkyl group or the bridged ring may be formed.
  • the ring or benzene ring may be substituted by 1 to 5 A 1 k or hydroxyl groups;
  • pl, p4, p5, p6 , p7, p8 ⁇ Pi p9 is 0, or an integer der of 1 to 4 Ri, P 2 and P 3 is an integer from 1 to 4, the carbon
  • the ring may be replaced by 1 to 5 A 1 k.
  • R 31 or R 33 is a hydrogen atom, the other is one COOR 36 or one CO NR 37 R 38 ;
  • n is an integer of 0 to 3
  • R 6Q is a hydrogen atom or A.lk. ⁇
  • R 2 and R 3 may form a heterocyclic ring together with an adjacent nitrogen atom, and the heterocyclic ring may be condensed with a benzene ring, a pyridine ring or cycloalkyl,
  • the ring, benzene ring, pyridine ring or cycloalkyl may be substituted by 1 to 5 substituents selected from Group D below:
  • Group D halogen atom, A lk, one OR dl , one COOR d2 ,-COR d3 R d4 -1 NR d5 R d6 , a carbocyclic group which may be substituted by 1 to 5 substituents selected from the above group B And a heterocyclic group which may be substituted by 1 to 5 substituents selected from the above group B; (Here, R dl , R d2 , R d3 , R d R d5 and R d6 are the same or different and are each a hydrogen atom or A 1k.)].
  • R 31 and R 32 are taken together to form a cycloalkyl group or a bridge Forming a formula ring (the cycloalkyl group may be condensed with a benzene ring, and the cycloanorexyl group, a bridged ring or a benzene ring may be substituted with 1 to 5 A 1 k atoms; ) The substituted 2-oxoquinoline compound according to [3] or [4] or a pharmaceutically acceptable salt thereof.
  • R 31 is a hydrogen atom
  • R 32 is A 1 k or a carbocyclic group which may be substituted by 1 to 5 substituents selected from the above group B (3) or (4) The substituted 2-oxoquinoline compound described above, or a pharmaceutically acceptable salt thereof.
  • R 31 and R 32 are the same or different and are each a carbocyclic group which may be substituted by A 1 k or 1 to 5 substituents selected from the above group B (3) or [4] The substituted 2-oxoquinoline compound according to the above or a pharmaceutically acceptable Its salt.
  • the carbocycle may be substituted with 1 to 5 A 1k;
  • R 31 and R 32 may together form a cycloalkyl group or a bridged ring, the cycloalkyl group may be condensed with a benzene ring, the cycloalkyl group, the bridged
  • the formula ring or the benzene ring may be substituted by 1 to 5 A 1 k or hydroxyl groups;
  • R ⁇ R 2, R 36, R 7, R 8 ⁇ Pi Al k is [1] as described. )
  • R 31 ′′ is a carbocyclic group that may be substituted by 1 to 5 substituents selected from A 1 k or group B;
  • R ⁇ R 2 , R 32 , R 36 , R 7 , R 8 , A 1k and group B are as described in (1) c ))
  • heterocyclic ring may be condensed with a benzene ring, a pyridine ring or a cycloalkyl, and the heterocyclic ring, the benzene ring, the pyridine ring or the cycloalkyl is substituted with 1 to 5 substituents selected from Group D. May be done. ;
  • each Al k may be the same or different and is as described in [1].
  • each Alk may be the same or different and is as described in [1].
  • each Alk may be the same or different and is as described in [1].
  • a cannabinoid receptor modulator comprising the substituted 2-oxoquinoline compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Inverse agonist is a cannabinoid receptor modulator
  • An agent for treating an allergic disease comprising the substituted 2-oxoquinoline compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • an immunomodulator comprising a substituted 2-oxoquinoline compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof as an active ingredient; ⁇ Anti-inflammatory agent.
  • Alkyl is a straight or branched chain having 1 to 10 carbon atoms. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, s-butynole, t-butynole, Pentinole, isopenpentole, neopentinole, t-pentyl, hexyl, isohexyl, neohexyl, heptyl and the like. Preferably it has 1 to 7 carbon atoms.
  • 0 ⁇ 6 alkyl group j means an alkyl group having 1 to 6 carbon atoms.
  • Alkyl moiety means that the alkyl moiety thereof is preferably an alkyl having the above-defined alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and "1-OAlk” includes alkoxy. Is methoxy, ethoxy, propoxy, isopropyl Xy, butynoleoxy, t-butyloxy, isopentyloxy, pentyloxy and the like.
  • Cycloalkyl is a monocyclic saturated cyclic alkyl having 3 to 10 carbon atoms, specifically, cyclopropyl, cyclobutyl / cyclohexyl, cyclopentyl, cyclohexynole, cyclohexyl, cyclooctyl, etc. No.
  • R 31 and R 32 preferably have 3 to 9 carbon atoms, and more preferably have 3 to 8 carbon atoms.
  • Aryl refers to an aromatic hydrocarbon having 6 to 16 carbon atoms, and specifically includes phenyl, naphthyl, biphenyl, anthracenole, indul, azure'nyl, fluorenyl, phenanthrenyl, pyrenyl and the like. And is preferably phenyl or naphthyl, particularly preferably phenyl.
  • Arylalkyl means that the aryl moiety is an aryl as defined above, and the alkyl moiety is an alkyl having the above definition having 1 to 4 carbon atoms. Specific examples include benzinole, phenethyl, phenylpropyl, phenylbutyl, naphthinolemethyl, biphenylmethyl and the like, and preferably benzyl.
  • R sl includes a hydrogen atom or Alk, preferably a hydrogen atom, a methyl group or an ethylenol group. And more preferably a hydrogen atom or a methyl group.
  • n is an integer of 0 to 4, preferably 1 to 3.
  • R sl includes a hydrogen atom and Alk, preferably a hydrogen atom, a methyl group, and an ethyl group, and more preferably a hydrogen atom or a methyl group.
  • R s2 includes a hydrogen atom and Alk, preferably a hydrogen atom and a 4- alkyl group, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an n-butyl group.
  • n is an integer of 0-4, preferably '1-2.
  • Such groups include, for example, one O—CH 2 —NH—, one O— (CH 2 ) 2-NH—, -0- (CH 2 ) 2-N (CH 3 ) one, —O— ( CH 2) 2 - N (C 2 H 5) -, -0- (CH 2) 2-N (C 3 H off) one, -O- (CH 2) 2- N (C 4 H 9) one such Are listed.
  • Bridged ring means a group having two or more rings that share two or more atoms. Examples of the bridged ring include a group represented by the following formula.
  • pll, pl4, pl5, pl6 , pl7, pl8 and pl9 is 0 or an integer of 1 to 4
  • pl2 ⁇ Pi P 13 is an integer of 1 to 4
  • the carbocycle 1 And may be substituted with up to 5 A 1 k.
  • Carbocycle means a non-aromatic ring or an aromatic ring in which all atoms constituting the ring are carbon atoms. It includes a cycloalkyl group as defined above, an aryl group as defined above, a bridged ring as defined above, and a partially saturated ring.
  • cyclopent pinole cyclobutyl / cyclohexene, pentopenole, cyclohexenole, cyclohepty / phenyl, phenyl, cyclopropeninole, cyclobutenyl, cyclopenteninole, cyclopentagenenole, cyclopentageninole, Cyclohexeninole group, cyclohexageninole group (2,4-cyclohexadiene 1-yl group, 2,5-cyclohexadiene 1-yl group, etc.), adamantyl, norpolnil, ponanil, phennyl, pinanil, etc.
  • Heterocycle refers to a ring that contains 1 to 2 heteroatoms in the atoms constituting the ring, may contain a double bond in the ring, and may have a non-aromatic ring or an aromatic ring. Means a ring.
  • heterocyclic ring examples include, for example, pyrimidinyl, pyrazinyl, pyrrolyl, chenyl, furyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidinyl / piperazineridinyl, piperidinyl / piperazinylidinyl Nore, diazepaninole ([1,4—dazepal)], tetrahydrofuryl and the like.
  • Cycloalkyl fused to a benzene ring means a structure in which the cycloalkyl portion is ortho-fused to a benzene ring.
  • Cycloalkyl is a cycloalkyl as defined above, specifically, tetrahydronaphthalene, indane, etc. And preferably tetrahydronaphthalene, 2- ⁇ fdanil, and 2-hydroxyl- ⁇ -danidole.
  • the heterocyclic ring fused with the benzene ring includes 2,3-dihydroisoindolinole, 3,4-dihydro-2H-quinoline-1-yl, and 3,4-dihydro-1H-isoquinoline — 2-yl, 2, 3, 4, 5-tetrahydro-1H-benzo [b] azepinil or 2,3,4,5-tetrahydro-1H-benzo [c] azepier New
  • heterocycle fused with cycloalkyl means a cyclic structure in which the heterocyclic moiety is ortho-fused with cycloalkyl, and cycloalkyl excludes one hydrogen atom at any position in the above cycloalkyl group.
  • the bicyclic group is a heterocyclic ring as defined above. Specific examples include octahydridoindolyl, octahydroisoindolyl, octahydroquinolyl, and octahydroisoquinolyl.
  • octahydroquinolyl and octahydroisoquinolyl / are preferred.
  • Halogen atom is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • Alkoxycarbonyl means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like, and preferably methoxycanoleponyl and ethoxycanoleponinole.
  • Group C is a hydroxyl group and a phenyl group.
  • Group B is defined as halogen, as defined above, alkyl as defined above, One OR bl , one COOR b2 , one CONR b3 R M , an alkylenedioxy group as defined above.
  • R bl , R b2 , R b3 and R b4 are each the same or different and each may be substituted by a hydrogen atom or 1 to 3 substituents selected from the above group C.
  • Group A means a halogen atom as defined above, one OR al , one OCOR a2 , one COOR a3 , one NR a4 COR a5 , one NR a6 R a7 , one CONR a8 R a9 , one SR al0 , one SOR al ⁇ 1 S0 2 R al2 , 1 OS0 2 R al3 , —S0 2 NR al4 R al5 , 1 S0 2 OR al6 , 1 COR al 7, 1 NR al8 S0 2 R al9 , selected from group B below 1 to 5 And a heterocyclic group which may be substituted by 1 to 5 substituents selected from Group B below.
  • R al , R a3 , R a4 , R a6 , R a7 , R a R a9 , R al0 , R al4 , R al5 , R al6 , al7 , R al8 and R al9 are the same or different, respectively.
  • a hydrogen atom, a C- 4 alkyl group, a carbocyclic group which may be substituted by 1 to 5 substituents selected from the following group B, or a 1 to 5 substituents selected from the following group B a heterocyclic group which may be, R a2, R a5, R all, R al2 ⁇ Pi R AL3 is
  • Al k is an alkyl group as defined above, which may be substituted by 1 to 3 substituents selected from Group A.
  • Group D is a halogen atom as defined above, Al k as defined above, one OR dl , one COOR d2 , one CONR d3 R d4 , — NR d5 R d6 , 1 to 5 selected from the above group B
  • R dl , R d2 , R d3 , R d R d5 and R d6 are the same or different and are each a hydrogen atom or A 1 k as defined above.
  • the “pharmaceutically acceptable salt” may be any salt that forms a nontoxic salt with the compound represented by the above general formula [I]. For example, hydrochloric acid, sulfuric acid, phosphoric acid, odor, etc.
  • Inorganic acids such as hydrofluoric acid; or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, dalconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid
  • inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; or methylamine, getylamine, triethylamine, triethanolanolamine, ethylenediamine, tris
  • Organic bases such as methylamine, guanidine, choline, and shinkyouyun; Lysine, ⁇ arginine, can be obtained by reacting with amino acids such Araen.
  • a hydrate, a hydrate and a solvate of each compound are also included.
  • Autoimmune diseases include cannapinoid receptor-related diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis.
  • Inflammatory diseases include acute and chronic knee inflammation.
  • Cannabinoid receptor modulators and “cannabinoid receptor modulators” are substances that regulate the biological activity of cannapinoid receptors or substances that regulate the expression of cannabinoid receptors. , Agonists, antagonists, inverse agonists, and other substances that enhance or reduce the sensitivity of the cannabinoid receptor, and the latter include substances that enhance or suppress gene expression of the cannabinoid receptor.
  • Impersago Nist is an action that is the opposite of the original action of the receptor's agogoest. For example, in terms of cyclic AMP (cAMP) levels at the cannabinoid receptor, it indicates compounds that increase cAMP levels as compared to cannapinoids, which suppress the increase.
  • cAMP cyclic AMP
  • Allergic diseases include anaphylaxis, gastrointestinal allergies, allergic gastroenteropathy, allergic dermatitis, dermatitis such as rash, rash and cosmetic rash, rash, atopic dermatitis, asthma, allergic asthma, atopy Asthma, allergic bronchopulmonary aspergillosis, hay fever, allergic rhinitis, allergic conjunctivitis, allergic granulomatous vasculitis, drug allergies, serum sickness, tuberculosis lesions, rejection after organ transplantation, tuberculosis lesions Examples include, but are not limited to, rejection reactions after organ transplantation, and can be applied to any allergy-related disease.
  • allergic dermatitis More preferably, mention may be made of allergic dermatitis, atopic dermatitis, asthma, allergic asthma, atopic asthma, allergic rhinitis and allergic conjunctivitis. Particularly preferred are allergic diseases relating to the skin or the respiratory tract, and more specific indications are allergic dermatitis, atopic dermatitis, allergic asthma and atopic asthma.
  • Allergic dermatitis refers to dermatitis associated with an allergic reaction and includes, for example, atopic dermatitis. It is distinguished from non-allergic dermatitis such as dermatitis due to a wound.
  • a drug which enhances the therapeutic effect by acting on an allergic reaction of atopic dermatitis is preferable.
  • Allergic asthma refers to the allergic aspect of asthma symptoms and includes, for example, mixed asthma and atopic asthma. It is distinguished from non-allergic asthma such as aspirin asthma. Acts as an asthma remedy on allergic reactions of asthma It is preferable to increase the therapeutic effect thereby. Further, it is preferable to have an effect on chronic bronchitis or airway hypersensitivity, and more preferably a therapeutic agent having an effect on chronic bronchitis and airway hypersensitivity. In addition, it is preferable to have an effect on the delayed type reaction, delayed type reaction, or delayed type and delayed type reaction of the allergic reaction. More preferably, in addition to the immediate type reaction, a delayed type reaction, delayed type It is a therapeutic agent that has an effect on type reaction or delayed type reaction and delayed type reaction.
  • Antipruritic effect refers to an effect of reducing itching or removing itching, thereby reducing the pruritic response and reducing mental stress from itching. It is preferable to eliminate the cause of pain, for example, antihistamine action, antisubstance P action, rather than central action. In addition, it preferably has an antipruritic effect on the above-mentioned arrenolegic diseases, especially on atopic dermatitis.
  • prodrugs and metabolites of each compound are also included.
  • a “prodrug” is a derivative of a compound of the present invention that has a group that can be chemically or metabolically degraded, and that, after being administered to a living organism, reverts to the original compound and exhibits its original efficacy, Conjugates and salts.
  • Prodrugs are used, for example, to improve absorption in oral administration or to target a target site.
  • modification site examples include a highly reactive functional group such as a hydroxyl group, a hydroxyl group, an amino group, and a thiol group in the compound of the present invention.
  • the modifying group for the hydroxyl group include an acetyl group, a propioyl group, an isobutylyl group, a pivaloyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, and a sulfo group.
  • Specific examples of the carboxyl group-modifying group include an ethyl group, a piperyloxymethyl group, a 1- (acetyloxy) ethyl group, a 1- (ethoxycarponyloxy) ethyl group, and a 1- (cyclohexyloxyl-loxycarbonyl group).
  • Specific examples of the modifying group for the amino group include a hexylcarbamoyl group, 3-methylthio-11- (acetylamino) propylcarbonyl group, 1-sulfo-11- (3-ethoxy-4-hydroxyphenyl) methyl group, (5 —Methyl-2-oxo-1,3-dioctyl-4-yl) A methyl group and the like.
  • Preferred embodiments of the compound of the present invention include a compound having good pharmacological activity (for example, a compound having high CB 2 binding activity, a compound having high CB 2 selectivity for CB1 in CB binding activity, a compound having high anti-allergic activity, and inverse agonist).
  • a compound having good pharmacological activity for example, a compound having high CB 2 binding activity, a compound having high CB 2 selectivity for CB1 in CB binding activity, a compound having high anti-allergic activity, and inverse agonist.
  • Compounds with high activity, etc.) compounds with good bioavailability (eg, compounds with high oral absorption, compounds with high cell membrane permeability, compounds that are stable against metabolic enzymes, etc.), and compounds with high safety (eg, And compounds having low binding activity to CB1, compounds having low inhibitory activity to P450 (CYP), etc.).
  • a compound having high CB 2 selectivity a compound having a CZS of 10 times or more is preferable, a compound having a CZS of 100 times or more is more preferable, a compound having a C / S of 300 times or more is more preferable, and C / S is 1000 times.
  • the above are particularly preferred.
  • R 5 and R 6 are preferably hydrogen atoms.
  • R 3 is preferably, for example,
  • Such groups may further comprise from 1 to 4 methylene groups, specifically
  • m is an integer of 0 to 3
  • R 6Q is a hydrogen atom or A 1 k.
  • a substituted 2-oxoquinoline compound represented by the following general formula (1-1) can be preferably used.
  • RR 2 , R 31 , R 32 , R 33 , 17 and 18 are the same as described above.
  • R 31 and R 32 may be taken together to form a cycloalkyl group or a bridged ring. Of these, a cycloalkyl group is preferred.
  • the cycloalkyl group may be condensed with a benzene ring.
  • the cycloalkyl group, the bridged ring or the benzene ring may be substituted with 1 to 5 A 1k.
  • a 1 k is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms. Among the alkyl groups having 1 to 3 carbon atoms, a methyl group is more preferred. As the cycloalkyl group fused to the benzene ring, tetrahydronaphthalyl and indanyl are preferable.
  • the cycloalkyl group is more preferably a 3- to 8-membered ring. Specific examples include cyclopropynole, cyclopentinole, cyclopentinole, cyclohexinole, cycloheptyl, and cyclooctyl.
  • cycloalkyl group having a substituent preferably include 4-methylcyclohexyl and 4,4-dimethylcyclohexyl.
  • Specific examples of the cycloalkyl group condensed with a benzene ring preferably include 2-indanyl, 2-hydroxy-1-indanyl and the like.
  • the bridged ring preferably includes adamantyl, 2-norpornyl, 2-phencanyl and the like.
  • R 31 is a hydrogen atom
  • R 32 is A 1 k or a carbocyclic group which may be substituted by 1 to 5 substituents selected from the above group B.
  • Alk is substituted with an alkyl group having 1 to 6 carbon atoms, a benzyl group, a benzoyl benzene group, an alkyl group having 1 to 6 carbon atoms having a hydroxyl group as a substituent, or a heterocyclic group.
  • alkyl group having 1 to 6 carbon atoms in the group examples include an alkyl group having 1 to 6 carbon atoms in the group.
  • Examples of the carbocyclic group include a phenyl group.
  • alkyl group having 1 to 6 carbon atoms preferably, a methyl group, an ethyl group, an isopropynole group, an isoptyl group, a t-pentynole group, a neopentyl group, a 2-hydroxy-t-butyl group, and a 3-hydroxyneopentyl group , A 3,3-dimethyl-butyl group, and more preferably a methyl group, an ethyl group, an isopropyl group, and an isobutyl group.
  • alkyl group having 1 to 6 carbon atoms having a hydroxyl group as a substituent examples include a 2,2-dimethyl-3-hydroxy-1-propyl group.
  • alkyl group having 1 to 6 carbon atoms having a heterocyclic group as a substituent examples include a 2-tetrahydrofuryl monomethyl group.
  • the benzoyl nodogenated group a fluo benzyl group and a chloro benzyl group are more preferable, and a p-fluoro benzyl group and a p-chloro benzyl group are more preferable.
  • the carbocyclic group is preferably a phenyl group.
  • R 31 and R 32 are the same or different and are each a carbocyclic group which may be substituted by 1 to 5 substituents selected from Alk or the above-mentioned group B. . In this case, Alk is more preferred.
  • Alk is preferably an alkyl group having 1 to 6 carbon atoms which may have a substituent, a benzyl group or a benzyl halide group.
  • alkyl groups having 1 to 6 carbon atoms which may have a substituent an alkyl group having 1 to 3 carbon atoms which may have a substituent is more preferable. More specifically, a methyl group, an ethyl group and a hydroxymethyl group are preferred, and a methyl group and an ethyl group are still more preferred.
  • benzyl halide group a fluorobenzyl group and a benzobenzyl group are more preferred, and a p-fluorobenzyl group and a p-chlorobenzyl group are more preferred.
  • carbon ring group which may be substituted by 1 to 5 substituents selected from the above group B, a phenyl group and a halogenated phenyl group are preferable, and among the halogenated phenyl groups, p-chlorophenyl is preferred.
  • the radical, o-chlorophenyl is preferred.
  • the R 33 is preferably a hydrogen atom, a cyano group, Alk, one COOR 36 , —CONR 37 R 38 , a carbon which may be substituted by 1 to 5 substituents selected from the above group B.
  • a ring group or a heterocyclic group which may be substituted by 1 to 5 substituents selected from the above group B, more preferably Al k, one COOR 36 or one CONR 37 R 38 It is more preferably one COOR 36 or —CONR 37 R 38 , and particularly preferably one COOR 36 .
  • R 33 is Al k, preferably a C ⁇ 4 alkyl group, hydroxy. 4 Alkyl groups and aminoalkyl groups.
  • the C 1-4 alkyl group preferably includes a methyl group and an ethyl group.
  • the hydroxyalkyl group includes a hydroxymethyl group.
  • Examples of the aminoalkyl group include a ⁇ , ⁇ -dimethylaminomethyl group.
  • a phenyl halide group and a phenyl group are preferable.
  • the halogenated phenyl group include an o-chloro phenyl group and a ⁇ -chloro phenyl group.
  • the R 36 of one COOR 36 is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent of Group A.
  • the alkyl groups having 1 to 6 carbon atoms which may have a substituent in the group A preferably an alkyl group having 1 to 3 carbon atoms, and specific examples of the alkyl group include a methyl group, An ethyl group is more preferred.
  • Specific examples of such a single COOR 36 preferably include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, and a pentinoleoxycarbon group.
  • R 37 and R 38 are the same or different and are each preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent of group A.
  • the alkyl group specifically, a methyl group, an ethyl group, and an isopropyl group are more preferable.
  • the substituent in Group A is preferably a hydroxyl group.
  • a 1-pyrrolidyl group and a 1-piperidyl group can be more preferably employed.
  • C ON R 37 R 38 include, preferably, an aminocarbonyl group, an N-methylaminocarbonyl group, a ⁇ , ⁇ -dimethylaminocarbonyl group, and a ⁇ -isopropylaminophenol- And benzyl-aminopropyl group, 11-pyrrolidinylcarbonyl group, 11-pyridylcarbonyl group, 2-hydroxyethylaminocarbonyl group and the like.
  • the carbocycle may be substituted with 1 to 5 A 1k.
  • pl, 2, p3, p4, p5, p6, p7, p8, p9 and Alk are the same as described above.
  • an adamantyl group and norpolnane are preferred.
  • R 1 R 2, R 32 , R 3 1 7 ⁇ Pi 1 8 are the same as defined above.
  • R 32 may be substituted by A 1 k or 1 to 5 substituents selected from the above group B as described above! /, Preferably a carbocyclic group.
  • Alk includes an alkynole group having 1 to 6 carbon atoms, a benzyl group, and a benzyl benzene group.
  • the alkyl group is preferably a methyl group, an ethyl group, an isopropyl group, or an isopropyl group.
  • the benzoyl nodogenate group a fluorobenzyl group and a chlorobenzyl group are more preferable, and a p-fluoropentyl group and a p-chlorobenzyl group are more preferable.
  • the carbocyclic group is preferably a phenyl group.
  • R 36 is preferably a hydrogen atom or an alkyl group having preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and specific examples of the alkyl group include: Preferred are a methyl group and an ethyl group, and more preferred is a methyl group.
  • R 31 ′ and R 32 ′ together form a cycloalkyl group
  • the cycloalkyl group may be condensed with a benzene ring
  • the cycloalkyl group or the benzene ring is 1 to 5
  • a 1 k may be substituted with a hydroxyl group.
  • R 36 , R 7 , R 8 and Alk are the same as described above.
  • a 1 k is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms. Among the alkyl groups having 1 to 3 carbon atoms, a methyl group is more preferred.
  • the cycloalkyl group is more preferably a 3- to 8-membered ring.
  • Specific examples include cyclopropyl, cyclobutynole, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl group having a substituent preferably include 4-methylcyclohexyl and 4,4-dimethylcyclohexyl.
  • cycloalkyl group fused to the benzene ring specifically, preferably 2
  • R 36 is preferably a hydrogen atom, the number of carbon atoms which may have a substituent in Group A
  • COOR 36 is preferably a carboxyl group or a methoxy group.
  • a ponyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group is a ponyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group.
  • R 31 ′′ is a carbocyclic group that may be substituted by 1 to 5 substituents selected from A 1 k or group B, and RRR 32 , R 36 , R 7 , and R 8 , A lk and group B are the same as above.
  • R 31 ′′ Alk is more preferred.
  • an alkyl group having 1 to 6 carbon atoms preferably an alkyl group having 1 to 3 carbon atoms is more preferable, and more specifically, a methyl group and an ethyl group are more preferable. preferable.
  • R 32, A lk is more preferable.
  • Alk an alkyl group having 1 to 6 carbon atoms is preferable, and an alkyl group having 1 to 3 carbon atoms is more preferable. More specifically, a methyl group and an ethyl group are more preferable.
  • R 36 is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and specific examples of the alkynole group include a methyl group and an ethyl group. Is more preferred.
  • R 6Q is preferably a hydrogen atom, and m is preferably 0 or 1.
  • Specific examples include the following groups. 2,2-dimethylethyl group, 3,3-dimethylbutyl group, 2,2-dimethyl-3-hydroxypropyl group, 2-tetrahydrofuranylmethyl group.
  • R 2 is preferably a methyl group or a hydrogen atom, and more preferably a hydrogen atom.
  • a substituted 2-oxoquinoline compound represented by the following general formula (1-5) can also be preferably used.
  • R 2 ′ and R 3 ′ together with an adjacent nitrogen atom form a heterocyclic ring, and the heterocyclic ring may be condensed with a benzene ring, a pyridine ring, or a cycloalkyl;
  • the heterocycle, benzene ring, pyridine ring or cycloalkyl may be substituted with 1 to 5 substituents selected from Group D. I 1 , R 7 , R 8 and group D are the same as described above.
  • the heterocyclic ring formed together with the adjacent nitrogen atom is preferably a 5-membered ring or a 6-membered ring, and includes, for example, a 1-pyrrolidinyl group and a 1-piperidyl group.
  • the substituents selected from group D include a halogen atom, an alkyl group having preferably 1 to 6, more preferably 1 to 3, carbon atoms, an alkyloxy group, a carboxyl group, a hydroxyl group, an alkoxyalkyl group.
  • Group, carboxyl-alkyl group, hydroxyalkyl group having 1 to 3 carbon atoms, phenyl group, benzyl group, alkylaminocarbyl group, 1-pyrrolidinyl group and 1-piperidyl group are preferred.
  • the alkyloxy moiety of one carbonyl group is preferably an alkyloxy group having 1 to 3 carbon atoms or a benzyl group.
  • the alkoxy portion of the alkoxyalkyl group is an alkyl of 1-3 carbon atoms
  • the alkyl moiety of the alkoxyalkyl group is preferably an alkyl having 1 to 3 carbon atoms.
  • the alkyl of the alkylaminocarbonyl group is preferably an alkyl group having 1 to 6 carbon atoms.
  • the heterocyclic ring is condensed with a benzene ring, a pyridine ring or a cycloalkyl, among these, it is preferable that the heterocyclic ring is condensed with a benzene ring or a cycloalkyl, and the cycloalkyl group is a cyclohexyl ring. preferable.
  • 3 ⁇ 4 of the substituent is preferably 1 to 3, more preferably 1 to 2.
  • One such NR 2 'R 3 ' has the following structure, for example. 50
  • n is an integer of 1 to 3, preferably 1 or 2, and more preferably 2.
  • R 41, R 42 are each independently a hydrogen atom, A lk, One COOR 45, one C ON R 4 6 R 47, a halogen atom, one OR 48, or 1 to 5 substituents selected from the group B It is a carbocyclic group which may be substituted by a substituent.
  • R 45 , R 46 , and R 47 are each independently a hydrogen atom or A 1k, and R 48 is a hydrogen atom or a 4- alkyl group.
  • R 41 and R 42 examples include a methyl group, an ethyl group, a propyl group, a hydroxyl group, a methoxy group, a methoxymethyl group, a hydroxymethyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group.
  • R 43 and R 44 are each independently a hydrogen atom, Alk, a halogen atom, or
  • R 43 and R 44 include a methyl group, a methoxy group, a trifluoromethyl group, a chlorine atom, a fluorine atom and the like. .
  • R 49 and R 5Q are each independently a hydrogen atom or Alk, preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom.
  • R 2 is a hydrogen atom and R 3 is a group represented by the following formula, more specific examples include the following groups. However, R 31 , R 32 and R 33 are the same as described above.
  • Me methyl group, Et: ethyl group, i-propyl: isopropyl group, Bn: benzyl group, 1-Pyrrolidinyl: 1-pyrrolidinyl group, 1-Piperridyl: 1-piperidyl group, 4-Me-cHex: 4 Hexinole group, 4,4-diMe-cHex: 4,4-dimethinyl hexyl group, p-F-Ben group: p-fluorobenzyl group, p-C1-Ben group: p-chlorobenzyl group , I-butyl: isobutyl group, p-chloro mouth phenol group: p-Cl-Ph group, o-neck mouth phenyl group: o-Cl-Ph group.
  • R 31, R 32 is due if number R 31 R 32 1 which forms a cycloalkyl group together
  • R 2 and R 3 are linked together with an adjacent nitrogen atom More specifically, the following groups may be mentioned.
  • Heterocycles include 1-piperidyl, 2-methyl-1-piperidyl, 3-methyl-11-piperidyl, 4-methyl to 1-1-piridyl, 2-ethyl-11-piperidyl, 3- 1-piperidyl group, 4-ethyl-1-piperidyl group, 2-propyl-11-piperidyl group, 3-propyl-11-piperidyl group, 4-propyl-1-piperidyl group, 2-propyloxy group 1-piperidyl group, 3-piperidyl group, 4-piperidyl group, 4-piperoxyl to 1-piperidyl group, 2-ethoxycarbo 2-l 1-piperidyl group, 3-ethoxycarbol-l 1-piperidyl group , 4-ethoxycarbone 1-piperidyl group, 2-hydroxy-11-piperidyl group, 3-hydroxy-1-piperidyl group, 4-hydroxy-1-piperidyl group, 2-hydroxymethyl-1-piperidyl group, 3-hydroxy Mud 1-piperidyl group, 4-hydroxymethyl-1-pipe
  • groups having the following structures such as octahydro-11-quinolyl, octahydro-2-isoquinolyl, and 31-tert-butylaminocarbonyl-2-octahydro-2f soquinolyl, can also be preferably used.
  • t-Bu represents a t-butyl group.
  • R 7 is preferably a hydrogen atom, a halogen atom, an alkoxy group, or a hydroxyl group.
  • halogen atom a chlorine atom is preferable.
  • alkoxy group examples include an alkyloxy group having 1 to 3 carbon atoms, and among these, a methoxy group is preferable.
  • the R 8 preferably a hydrogen atom, a hydroxyl group, a halogen atom, One O- Al k, one NR ql - Al k, -O- carbocyclic group one O- heterocyclic group, One OS0 2 - A 1 k, carboxyl group, 1 COOA 1 k.
  • a chlorine atom is preferred among the halogen atoms.
  • -0-A 1 k includes an alkoxy group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms having a halogen atom as a substituent, and a carbon atom having 1 carbon atom having a carbocyclic group as a substituent.
  • 1 to 6 carbon atoms having 1 to 6 alkoxy groups and hydroxyl groups as substituents A alkoxy group, an alkoxy group having 1 to 6 carbon atoms having a carbocyclic group and a hydroxyl group in the substituent, an alkoxy group having 1 to 6 carbon atoms having an alkoxy group having 1 to 6 carbon atoms in the substituent, the above group A carbocyclic group which may be substituted with 1 to 5 substituents selected from B, 1- O-substituted alkoxy group having 1 to 6 carbon atoms, and alkylamino group having 1 to 6 carbon atoms substituted An alkoxy group having 1 to 6 carbon atoms in the group; — an alkoxy group having 1 to 6 carbon atoms having OCOA 1 k as a substituent; — an alkoxy group having 1 to 6 carbon atoms having CON RaSR 39 in a substituent.
  • the group is an alkoxy group having 1 to 6 carbon atoms having a substituent of COR al7 and an alkoxy group having 1 to 6 carbon atoms having one NR al8 S02R a19 as a substituent. .
  • alkoxy groups having 1 to 6 carbon atoms having a carbocyclic group as a substituent a cyclic propylmethyloxy group and the like can be mentioned.
  • the alkoxy group having 1 to 6 carbon atoms having a hydroxyl group as a substituent preferably includes a 2-hydroxyethyloxy group.
  • a cycloalkyl group is preferable as the carbocyclic group.
  • a 3-hydroxy-2-cyclopropylpropyloxy group is preferable.
  • alkoxy groups having 1 to 6 carbon atoms having an alkoxy group having 1 to 6 carbon atoms as a substituent ethoxyxetoxy groups and the like can be mentioned.
  • a phenyl group is used as the carbon ring group.
  • the substituent of the carbocyclic group is preferably a halogen atom, more preferably a chlorine atom. Specific examples include a phenyloxy ethoxy group and a p-chloro phenyloxy ethoxy group.
  • a dialkylaminoalkyloxy group is preferable, for example, a getylaminoethyloxy group and the like. Is mentioned.
  • A1k is preferably an alkyl group having 1 to 6 carbon atoms, and among them, a methyl group is preferred.
  • a specific example is a methylcarbonyloxyethoxy group.
  • R a 8 R a9 are independently of each other, preferably a hydrogen atom or A 1 k.
  • Alk is preferably an alkyl group having 1 to 6 carbon atoms, and among them, a methyl group, an ethyl group, a butyl group and an isopropyl group are preferable.
  • Ral8 is preferably a hydrogen atom
  • Ral9 is preferably a methyl / le group.
  • R ql is preferably a hydrogen atom
  • Al k is preferably an alkyl group having 16 carbon atoms. Examples thereof include a butylamino group and a pentylamino group.
  • the —O— carbocyclic group is preferably a cyclopentyloxy group or the like.
  • a 4-piperidyloxy group and the like are preferable.
  • One OS0 2 - The A 1 k of the A 1 k, an alkyl group having a carbon number of 1 to 6, preferably an alkyl group having a carbon number of 1 to 6 having a substituent Ha androgenic atom, the halogen atom fluorine atom Is preferred. Specifically CF 3 (CH 2) 3 S0 3 - , and the like.
  • Alk is preferably an alkyl group having 16 carbon atoms, and among them, a methyl group is preferable. Specifically, a methoxycarbonyl group is preferred.
  • R sl include a hydrogen atom and Alk, preferably a hydrogen atom, a methyl group and an ethyl group, and more preferably a hydrogen atom or a methyl group.
  • n is an integer of 04, preferably 13.
  • alkylenedioxy examples include methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, mono-O—CH (CH 3 ) —O——OC (CH 3 ) 2 —O— .
  • R 7 and R 8 are bonded to each other to form
  • R sl include a hydrogen atom and Alk, preferably a hydrogen atom, a methyl group and an ethyl group, and more preferably a hydrogen atom or a methoxy group.
  • R s2 include a hydrogen atom and Alk, preferably a hydrogen atom and a 4- alkyl group, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an n-butyl group.
  • n is an integer of 0-4, preferably 1-2.
  • R 1 examples include a hydrogen atom or A 1 k.
  • Alk is an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms having a hydroxyl group as a substituent, or an alkyl group having 1 to 6 carbon atoms having a halogen atom as a substituent.
  • an alkyl group having 1 to 8 carbon atoms an alkyl group having 1 to 6 carbon atoms is more preferable.
  • Preferred examples of the alkyl group having 1 to 8 carbon atoms having a hydroxyl group as a substituent include a hydroxyethynole group.
  • an alkyl group substituted with fluorine is preferable.
  • an alkyl group substituted with fluorine is preferable.
  • 5,5,5-trifluoropentyl group F 3 C—C 4 H 8 —
  • R al is preferably an alkyl group having 1 to 3 carbon atoms, and examples thereof include a methoxymethyl group, a methoxyxyl group, an ethoxymethyl group, and an ethoxyxyl group.
  • alkyl group having 1 to 6 carbon atoms having a substituent an OCOR a2 preferably has R a2 is an alkyl group of 1 to 3 carbon atoms, for example, Mechirukarupo Niruokishimechiru group, methylcarbonyl O key Chez Chill And the like.
  • alkyl group having 1 to 6 carbon atoms having COOR a3 as a substituent those in which Ra3 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms are preferable, and examples thereof include a carboxymethyl group and a carboxyethyl group.
  • R 1 is more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group, an n-pentyl group, an n-hexyl group, a hydroxyethyl group, Examples thereof include 4,4-trifluorobutyl group, methoxymethyl group, ethoxyxyl group, methylcarbonyloxyl group, carboxypropyl group, and ethoxycarbonylpropyl group.
  • the substituted 2-oxoquinoline compound represented by the general formula (I) according to the present invention (hereinafter sometimes referred to as “compound I” or “compound I”) can be produced, for example, as follows. However, the present invention is not limited to these.
  • R 1 R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 have the same meanings as in the formula (I), and R P1 and R P2 are the same or different, respectively, hydrogen, Alk (for example, a methynole group, an ethyl group, a benzyl group, etc.) or a carboxylic acid protecting group (for example, a toshimethylsilyl group).
  • Alk for example, a methynole group, an ethyl group, a benzyl group, etc.
  • a carboxylic acid protecting group for example, a toshimethylsilyl group.
  • a nitro compound can be obtained by reacting compound [II] with fuming nitric acid in a solvent in the presence of concentrated sulfuric acid.
  • the solvent examples include ether solvents such as getyl ether, 1,2-dimethoxetane, tetrahydrofuran, and diglyme; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and acetic acid.
  • ether solvents such as getyl ether, 1,2-dimethoxetane, tetrahydrofuran, and diglyme
  • halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane
  • acetic acid Ethyl, methyl acetate Ester solvents such as chill and butyl acetate
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol and t-butanol
  • acid solvents such as acetic acid and acetic anhydride, with acetic acid being preferred.
  • the reaction temperature is generally -50 to 200 ° C, preferably -10 to 60 ° C.
  • the reaction time is generally 15 minutes to 48 hours, preferably 1 to 8 hours.
  • the compound [III] can be obtained by reacting the obtained nitro compound with an alkyl bromide such as bromopentane in a suitable solvent in the presence of a base.
  • Suitable bases include, for example, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, hydrogen bicarbonate, sodium hydroxide, hydroxylate, lithium hydroxide, sodium hydride, n-butyllithium, Butyllithium, t-butyllithium, lithium diisopropylamide and the like, and preferably potassium carbonate.
  • Suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, xylene, and hexane; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme; dichloromethane; , Carbon tetrachloride, 1,2-dichloroethane and other halogen solvents; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone; methanol, ethanol, Examples thereof include alcohol solvents such as isopropyl alcohol and t-butanol, and dimethylformamide is preferable.
  • hydrocarbon solvents such as benzene, toluene, xylene, and hexane
  • ether solvents such as getyl ether, 1,
  • the reaction temperature is usually from 110 to 200 ° C, preferably from 0 to 60 ° C.
  • the reaction time is usually 15 minutes, preferably 1 to 8 hours.
  • Compound [IV] can be condensed with malonic acid derivative [V] in the presence of a suitable acid or base to give compound [VI].
  • suitable acid or base examples include getyl malonate, dimethyl malonate, dibenzyl malonate, ethyl cyanoacetate, methyl cyanoacetate and the like, and preferably dimethyl malonate is used.
  • Suitable acids include, for example, benzoic acid, p-toluenesulfonic acid, acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid and the like, preferably benzoic acid.
  • Examples of the base include sodium hydride, potassium t-butoxide, sodium methoxide, sodium methoxide, ammonium acetate, sodium acetate, piperidine, pyridine, pyrrolidine, n-methinolemo ⁇ holin, monorephorin, and triethylamine. Preferably it is piperidine.
  • the solvent examples include hydrocarbon solvents such as benzene, toluene, xylene, hexane, and heptane; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme; ethyl acetate, methyl acetate, Ester solvents such as butyl acetate; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetate nitrile, and acetone; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and t-butanol; and preferably toluene. It is.
  • hydrocarbon solvents such as benzene, toluene, xylene, hexane, and heptane
  • ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme
  • the reaction temperature is usually 0 to 150 ° C, preferably 120 ° C.
  • the reaction time is generally 2 hours to 48 hours, preferably 24 hours.
  • the compound [VI] can be obtained by hydrolyzing the compound [VI] in a solvent in the presence of a suitable base.
  • the solvent examples include alcoholic solvents such as methanol, ethanol, isopropyl alcohol and t-butanol, or water or a mixed solvent thereof.
  • Suitable bases include, for example, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, sodium bicarbonate, sodium hydroxide, sodium hydroxide, Examples include lithium hydroxide and the like, and preferably sodium hydroxide.
  • Compound [I] can be obtained by reacting compound [VII] with compound [VIII] as an activated carboxylic acid derivative.
  • Examples of the activated carboxylic acid derivative include, for example, an acid halide obtained by treating a carboxylic acid with thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or the like; Condensation with hydroxybenzotriazole, N-hydroxysuccinimide, etc., with condensing agents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride And a mixed acid anhydride obtained by reacting a carboxylic acid with ethyl ethyl carbonate, piperoyl lauride, isobutyl carbonate and the like.
  • DCC dicyclohexylcarbodiimide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • a mixed acid anhydride obtained by
  • Examples of the base include organic amines such as triethylamine, tert-butylamine, pyridin, and N-methylmorpholine, and preferably tert-butylamine.
  • the solvent examples include hydrocarbon solvents such as benzene, tonolene, hexane, and xylene; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme; dichloromethane, chloroform, and tetrachloride Halogen solvents such as carbon and 1,2-dichloromethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; and polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and aceton. Preferred is dimethylformamide.
  • hydrocarbon solvents such as benzene, tonolene, hexane, and xylene
  • ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme
  • the reaction temperature is usually from 0 to 100 ° C, preferably from 0 to 50 ° C.
  • the time is usually from 15 minutes to 24 hours, preferably from 1 to 12 hours.
  • alkylating agent examples include alkyl iodide such as methyl iodide, alkyl bromide such as methyl bromide, bromide tyl, propyl bromide, butyl bromide and pentyl bromide, and chloride such as pentyl chloride.
  • alkyl, dialkyl sulfate such as dimethyl sulfate and the like are used, and alkyl bromide is preferably used.
  • Examples of the base include sodium carbonate, carbonated lithium, lithium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, and n-butyl lithium. Titanium, s-butyllithium, t-butyllithium, lithium diisopropylamide, and the like are preferable, and lithium carbonate is preferably used.
  • the solvent examples include hydrocarbon solvents such as benzene, toluene, xylene and hexane; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran and diglyme; Halogen solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitril, and acetone; methanol, ethanol, and isopropyl Examples thereof include alcohol solvents such as alcohol and t-butanol, and dimethylformamide is preferably used.
  • hydrocarbon solvents such as benzene, toluene, xylene and hexane
  • ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran
  • the reaction temperature is usually from 120 to 100 ° C, preferably from 0 to 100 ° C.
  • the reaction time is usually from 15 minutes to 48 hours, preferably from 1 to 6 hours.
  • the compound [I] produced as described above is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, chromatography and the like. be able to.
  • Compound [I] or [I one pharmaceutically acceptable salt, and various isomers of compound [I] or [I] can be produced by a conventionally known method.
  • the substituted 2-oxoquinoline compound and the pharmaceutically acceptable salt thereof of the present invention can be used in mammals to treat disease areas known to involve cannabinoid receptors, particularly disease areas involving peripheral cell-based tissues (immunology). It has medicinal effects in diseases, various inflammations and allergic diseases.
  • substituted 2-oxoquinoline compounds and pharmaceutically acceptable salts thereof selectively act on cannabinoid receptors, particularly peripheral receptors, have few central side effects, and have excellent allergic disease-treating effects. It has an immunomodulating effect and an anti-inflammatory effect.
  • substituted 2-oxoquinoline compounds and pharmaceutically acceptable salts thereof are cannabinoid receptor (particularly peripheral cannabinoid receptor) modulators, therapeutic agents for allergic diseases, immunomodulators, therapeutic agents for autoimmune diseases, and anti-inflammatory agents. It is useful as
  • a tricyclic fused ring compound or a pharmaceutically acceptable salt thereof When used as a pharmaceutical preparation, it is usually a pharmacologically acceptable carrier, excipient, diluent, bulking agent, disintegration known per se. Agents, stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, flavoring agents, solubilizers, and other additives, specifically water, vegetable oils, ethanol or base Alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, etc., carbohydrates, magnesium stearate, talc, lanolin, petrolatum, etc.
  • the compound of the present invention can also be applied as a veterinary medicine.
  • room temperature means a temperature range of about 20 to 30 ° C.
  • the solid obtained by concentration under reduced pressure was washed with a mixed solvent of 40 ml of n-hexane and 6 ml of ethyl acetate to obtain the target substance 12 as a yellow solid (JTP-64338A, 3.30 g, yield 75%).
  • Example 6 Compound 21 (100 mg, 0.33 nimol) obtained in Reference Example 10 was suspended in dimethylformamide (lml), and 1-bromopentane (48 ⁇ l, 0.39 mmol) and potassium carbonate (137 mg, 0.37 mmol) were added. 99 mmol), and the mixture was heated and stirred at 65 ° C for 30 minutes. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.
  • dimethylformamide lml
  • 1-bromopentane 48 ⁇ l, 0.39 mmol
  • potassium carbonate 137 mg, 0.37 mmol
  • Compound 30 was produced in the same manner as in Reference Examples 1 to 3, and was hydrolyzed in the same manner as in Reference Example 4 to obtain Compound 31.
  • Table 41 and Table 42 show the NMR data of the obtained compounds (unless otherwise specified, DMSO-d 6, measured at 300 MHz).
  • Table 41 Compound No. Melting point (° c) ⁇ R data
  • the Ki value of the compound of the present invention was determined in the same manner as described below. As a result, a compound having a value of 1 M or less was obtained.
  • Human central cell cannabinoid receptor human CB 1-CHO, hereinafter hCB1
  • human peripheral cell cannabinoid receptor human CB2-CHO, hereinafter hCB2
  • Round-bottom 96-well plate specimen hCB l: 120 ⁇ g / mL s
  • h CB 2 l5 ⁇ g / mL
  • labeled ligand [3H] CP55940, InM
  • unlabeled CP55940 or test substance was added, 3 Incubated at 0 ° C for 90 minutes.
  • Assay buffer used was 50 mM Tris-HCl, 1 mM EDTA-4Na, 3 mM MgCl 2 , 0.2% Alubumin Bovine, 0.2% ethanol, H 7.4. After completion of the incubation, the mixture was filtered through a filter (Packard, Unifilter 96GF / B), dried and then added with scintilation solution (Packard, Microsint-20), and the radioactivity of the sample was measured (Packard, Top count A9912V). Non-specific binding was obtained by adding an excess amount of CP55940 (10 ⁇ ), and specific binding was calculated by subtracting non-specific binding from total binding obtained by adding only labeled ligand.
  • the test substance was dissolved in DMSO so that the final concentration of DMSO was 0.1%.
  • the IC50 value was determined from the ratio of the bound test substance to the specific binding, and the Ki value of the test substance was calculated from the IC50 value and the Kd value of [3H] CP55940.
  • the Ki value for central cell type receptors and the Ki value for peripheral cell type receptors were determined. The results are shown in Tables 43 and 44.
  • the substituted 2-oxoquinoline compounds and pharmaceutically acceptable salts thereof of the present invention selectively act on cannabinoid receptors, particularly peripheral receptors, and have side effects in the central system. It has little use and has excellent immunomodulatory, anti-inflammatory and anti-allergic effects. Therefore, it is useful as a cannabinoid receptor (particularly peripheral cannabinoid receptor 1) modulator, an allergic disease therapeutic agent, an immunomodulator, an autoimmune disease therapeutic agent or an anti-inflammatory drug. Furthermore, a modulator that acts as an impargonist can be a powerful and safe drug that is effective for chronic and refractory allergic diseases, which is ineffective with existing therapeutic agents for allergic diseases.

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Abstract

L'invention concerne un nouveau composé destiné à agir de manière sélective sur les récepteurs des cannabinoïdes, en particulier un récepteur de type périphérique, ainsi qu'une composition médicinale contenant celui-ci. Ce composé est un composé 2-oxoquinoline substitué représenté par la formule générale suivante [I] (dans laquelle les symboles sont tels que définis dans la description), ou un sel acceptable d'un point de vue pharmaceutique de celui-ci.
PCT/JP2004/007219 2003-05-23 2004-05-20 Compose 2-oxoquinoline substitue et utilisation medicale de celui-ci WO2004103974A1 (fr)

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US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
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US8048894B2 (en) 2007-04-18 2011-11-01 Amgen Inc. Quinolones and azaquinolones that inhibit prolyl hydroxylase
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8097620B2 (en) 2007-05-04 2012-01-17 Amgen Inc. Diazaquinolones that inhibit prolyl hydroxylase activity
US8178681B2 (en) 2004-10-28 2012-05-15 Shionogi & Co., Ltd. 3-carbamoyl-2-pyridone derivatives
WO2018174288A1 (fr) 2017-03-24 2018-09-27 大正製薬株式会社 Dérivé de 2(1h)-quinolinone

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US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
US8013001B2 (en) 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR
WO2005112932A3 (fr) * 2004-05-07 2006-11-23 Exelixis Inc Modulateurs de raf et methodes d'utilisation
JP2007536224A (ja) * 2004-05-07 2007-12-13 エグゼリクシス， インコーポレイテッド Ｒａｆモジュレーターおよびその使用方法
US8697737B2 (en) 2004-05-07 2014-04-15 Exelixis, Inc. Raf modulators and methods of use
JP2010006840A (ja) * 2004-05-07 2010-01-14 Exelixis Inc Ｒａｆモジュレーターおよびその使用方法
US7846959B2 (en) 2004-05-07 2010-12-07 Exelixis, Inc. Raf modulators and methods of use
WO2005112932A2 (fr) 2004-05-07 2005-12-01 Exelixis, Inc. Modulateurs de raf et methodes d'utilisation
US8367666B2 (en) 2004-10-28 2013-02-05 Shionogi & Co., Ltd. 3-carbamoyl-2-pyridone derivatives
US8178681B2 (en) 2004-10-28 2012-05-15 Shionogi & Co., Ltd. 3-carbamoyl-2-pyridone derivatives
US8012968B2 (en) 2005-12-09 2011-09-06 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
AU2006326662B2 (en) * 2005-12-09 2011-07-28 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
JP2009519249A (ja) * 2005-12-09 2009-05-14 アムジエン・インコーポレーテツド プロリルヒドロキシラーゼ阻害活性を示すキノロンベースの化合物、およびこの組成物、およびこの使用
US7728130B2 (en) 2005-12-09 2010-06-01 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity
US8017626B2 (en) 2005-12-09 2011-09-13 Amgen Inc. Quinolone based compounds exhibiting, prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US7928139B2 (en) 2006-12-18 2011-04-19 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8048894B2 (en) 2007-04-18 2011-11-01 Amgen Inc. Quinolones and azaquinolones that inhibit prolyl hydroxylase
US8349868B2 (en) 2007-04-18 2013-01-08 Amgen Inc. Azaquinolones that inhibit prolyl hydroxylase
US7569726B2 (en) 2007-04-18 2009-08-04 Amgen Inc. Indanone derivatives that inhibit prolyl hydroxylase
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
US8097620B2 (en) 2007-05-04 2012-01-17 Amgen Inc. Diazaquinolones that inhibit prolyl hydroxylase activity
WO2018174288A1 (fr) 2017-03-24 2018-09-27 大正製薬株式会社 Dérivé de 2(1h)-quinolinone
KR20190133667A (ko) 2017-03-24 2019-12-03 다이쇼 세이야꾸 가부시끼가이샤 2(1h)-퀴놀리논 유도체

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