WO2004104000A1 - Compose cyclique condense tricyclique et son utilisation medicale - Google Patents

Compose cyclique condense tricyclique et son utilisation medicale Download PDF

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Publication number
WO2004104000A1
WO2004104000A1 PCT/JP2004/007212 JP2004007212W WO2004104000A1 WO 2004104000 A1 WO2004104000 A1 WO 2004104000A1 JP 2004007212 W JP2004007212 W JP 2004007212W WO 2004104000 A1 WO2004104000 A1 WO 2004104000A1
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WIPO (PCT)
Prior art keywords
group
compound
pharmaceutically acceptable
acceptable salt
hydrogen atom
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PCT/JP2004/007212
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English (en)
Japanese (ja)
Inventor
Hisashi Kawasaki
Tetsudo Kaya
Hiroto Imai
Tomoya Miura
Yukihiro Nomura
Hiroshi Chatani
Yoshifumi Ueda
Takayuki Mimura
Hiroyuki Iwamura
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Japan Tobacco Inc.
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Publication of WO2004104000A1 publication Critical patent/WO2004104000A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • 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

Definitions

  • Tricitral fused ring compounds and their pharmaceutical uses
  • the present invention relates to a 2-oxoquinoline compound, which is a novel tricyclic fused ring compound, and a pharmaceutical use thereof.
  • the present invention also relates to a novel use of a certain tricyclic fused ring compound. More specifically, a novel tricitalic condensed ring 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
  • 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, alcoholic solvents for cannabis were recognized as drugs for rheumatism, asthma, and tonsillitis in the Pharmacopoeia from 1850 to 1942.
  • ⁇ 9-tetrahydrid cannabinol which is considered to be a major component of cannabis or its psychoactive manifestations, has visual and auditory abnormalities, temporal and spatial cognitive abnormalities, and darkness. It is known that if the proficiency is large, the ability to think and the spontaneity decrease, it can cause memory impairment and cause significant changes in mental function. 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 biodistribution is detected in many tissues other than brain, such as human testis, human prostate, ovary, uterus 'bone marrow, thymus', tonsils, pituitary gland, adrenal gland, heart, lungs, stomach, large intestine, bile duct, leukocytes, etc. But its level is much lower than the brain.
  • CB2 was absent in rat brain but found in monocytes in the marginal zone of the spleen. In human spleen, leukocytes, tonsils, thymus, and knees, CB2 is present at much higher levels than CB1.
  • CB1 and CB2 The existence of two subtypes of receptors (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 effects observed with cannabinoid administration.
  • Various findings are being obtained, such as the lack of suppression of helper T cell activation by cannabinoid in knockout mice with deficiency.
  • 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 Have been.
  • cannapinoids 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 cannapinoid receptor ligands include ⁇ 9-THC, CP55940, WIN55212-2, HU-243, HU-210, etc.
  • CBl-selective ligands include SR141716A, LY320135, and arachidonol-2.
  • -Cloethylethylamide, CP56667 and the like and CB2 selective ligands such as SR144528, AM630, HU-308, JWH-051, L-768242 and the like are known (for example, see Non-patent Document 1 and Non-patent Document 2). )).
  • the allergic reaction is recognized as a hypersensitivity reaction of the living body based on the antigen-antibody reaction, which is different from the usual inflammatory response characterized by accumulation of monocytes, macrophages, neutrophils, etc. Eosinophils, basophils, and mast cells contribute greatly.
  • the antigen-presenting cells such as macrophages Is taken up by the vesicles.
  • Antigen presenting cells transmit the information of the taken-in antigen to T cells.
  • T cells instruct B cells to produce antigen-specific IgE antibodies.
  • IgE antibodies bind to mast cells, which renders mast cells sensitized.
  • the mast cell When the antigen re-enters and the IgE antibody on the mast cell binds to the antigen, the mast cell releases various chemical mediators such as histamine, eosinophil chemotactic factor, leukotriene and cytokines such as interleukin.
  • various chemical mediators such as histamine, eosinophil chemotactic factor, leukotriene and cytokines such as interleukin.
  • bronchial smooth muscle contracts, swelling of mucous membranes, secretion of sputum, etc., narrowing the airway and causing asthma attacks. Acts on the skin, causing inflammation, swelling and itching, and skin diseases such as rash. When it acts on the mucous membrane of the nose, it increases vascular permeability, collects water in the blood and swells the nasal mucosa, causing nasal congestion, and allergic rhinitis, which produces a large amount of sneezing and nasal discharge due to nerve stimulation. When this reaction occurs in the gastrointestinal tract, intestinal smooth muscle contracts and intestinal movement (peristalsis) abnormally increases, resulting in gastrointestinal allergies such as abdominal pain, vomiting, and diarrhea.
  • This reaction occurs within 30 minutes after the antigen has entered, and is called an immediate allergic reaction or a type I allergic reaction. Usually, an immediate reaction can be settled in about an hour. Representative diseases include anaphylaxis, allergic rhinitis, hay fever, jungle rash, and allergic gastroenteropathy. However, after several hours to several days, eosinophils, which are released from mast cells, are attracted to eosinophil chemotactic factors and cytokines, and eosinophils, which have highly toxic chemicals, gather at sites of allergic reactions. Releases and causes tissue damage.
  • late-onset allergic reaction When this reaction occurs in the bronchi, the mucosal epithelium detaches, making it easier for antigen to penetrate, prolonging allergic reactions, increasing airway irritability, and making asthma intractable. This is called a late asthmatic reaction. For example, this late-onset response occurs mainly after 4-8 hours in asthma and mainly 12-48 hours in atopic dermatitis.
  • Type II allergic reaction is also called cytolytic type, and IgM or IgG anti- This is a reaction in which a captor acts on the body to make holes in the cell membrane and lyse the cells. Separately, there is also a reaction in which macular phage ⁇ killer cells act on cells that have received antibody binding to release damaging substances and break cells and tissues. Representative diseases include hemolytic anemia, thrombocytopenic purpura, myasthenia gravis, and Goodpathia's syndrome.
  • an antigen-antibody complex in which an antigen and an antibody (IgG antibody) are bound cannot be processed by phagocytic cells and deposits in tissues, where traps, macrophages, and neutrophils collect and inflame.
  • Representative diseases include acute glomerulonephritis due to streptococcus, rheumatoid arthritis, collagen disease, serum sickness, viral hepatitis, and allergic alveolitis.
  • Type IV allergic reactions unlike types 1-3, do not involve antibodies.
  • the T cells When sensitization is established and the antigen re-enters, the T cells release cytotoxicity, migrate immune cells such as lymphocytes, neutrophils, and macrophages to break down the antigen, but at the same time cause inflammation. Causes tissue rupture. If the invading antigen is a cell, killer T cells break down the antigen. The reaction usually takes one to two days to complete and is also called a "delayed allergic response.” Tuberculin reaction, tuberculosis lesions, rejection after organ transplantation, dermatitis such as irritation, cosmetic rash, etc. are type IV allergic reactions.
  • 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.
  • Airway inflammation are thought to involve many inflammatory cells such as eosinophils, T cells, mast cells, mast cells for immediate response, eosinophils for late response, eosinophils and CD4 positive helper for delayed response T cell involvement may be important.
  • 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 i3 2 agonists, short-acting theophylline drugs, inhaled anticholinergics, injection 'oral steroids, or the like are used.
  • Xan A2 inhibition antagonists, ⁇ ⁇ ⁇ 2- site force-in inhibitors have been used.
  • side effects such as suppression of adrenal function seen in steroids, as well as symptoms with low effects (resistance) such as steroids and leukotriene antagonists are also known, and further antiasthmatics are expected.
  • Atopic asthma or atopic dermatitis is a symptom of an allergic disorder with a family or medical history. Since atopic asthma and dermatitis often occur in children, a drug with fewer side effects is particularly desirable.
  • Atopic dermatitis is a disease in which pruritus eczema is the main lesion, with repeated exacerbations and remissions. Many patients have atopic predisposition.
  • Atopic predisposition (1) Family history, medical history (one or more diseases of bronchial asthma, allergic rhinitis, conjunctivitis, atopic dermatitis), or (2) Predisposition to easily produce IgE antibodies " It is distinguished from other inflammatory skin diseases.
  • Symptoms include irritability of the skin and dryness, and the 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 IgE * mast cells
  • the delayed allergic reaction by Langerhans cells and T cells is considered to be involved in addition to the type allergic reaction.
  • the treatment is based on the removal of foods, mites and other causes and exacerbation factors, and skin care (keeping the skin clean, using a moisturizer to prevent dry skin, etc.), and using drug therapy depending on the symptoms.
  • Antihistamines are used for pruritus, but their effect is not as pronounced as in the case of juniper.
  • Topical steroids are used for inflammation in principle.
  • Oral medications of antihistamines or antiallergic drugs are used as supplements, 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 Literatures 1 to 3 Pyrazole derivatives (Patent Literatures 1 to 3), THC Ning conductor (Patent Literature 4), benzoxazine derivatives (Patent Literature 5), indole derivatives (Patent Literatures 2, and 6, Patent Literature 6) include modulators of cannabinoid receptors.
  • Fatty acid derivatives (Patent Document 7), indazole derivatives (Patent Document 2) and the like are known. :: ⁇ The tricitral 2 oxoquinoline compound, which is a feature of the compound of the present invention, is not known.
  • Non-Patent Document 3 6,7-dimethoxy-12-oxo-1,1,2-dihydroquinoline-13-butyronic acid benzylamide (compound A), which is useful as a central nervous system stimulant.
  • Non-Patent Document 4 4-hydroxy-21-oxo-1,1,2-dihydroquinoline-13-potassium ribonate (pyridine-12-yl) amide (compound B below) useful as an anti-inflammatory agent has been shown (Non-Patent Document 4), Pharmaproject and others include 4-hydroxy-2-oxo-11-methyl-1,2-dihydroquinoline-13-carboxylate N-methyl-N-phenylamide (compound C), known as roquini mex, as an anti-inflammatory agent, It has been shown that it can be used for various diseases including immunosuppressants and antirheumatic drugs.
  • Non-Patent Document 5 2-oxo-1,2-dihydroquinoline_3-capillonic acid cyclohexylamide
  • Patent Document 9 useful quinoline compounds as immunomodulators
  • Patent Document 10 useful quinoline compounds as analgesics
  • Patent Document 1 5-HT 4 useful quinoline compounds as receptor agonists
  • N- (3,4-methylenedioxyphenyl) _1,2-dihydro4 —Hydroxy-11-methyl-2-oxoquinoline-13-potassium lipoxamide (the following compound E) has been disclosed (Patent Document 12).
  • Compound E Compound F
  • a compound having a quinoline structure is useful as an immunomodulator, an anti-inflammatory agent, an anti-allergic agent, etc. (Patent Document 14 ) .
  • the quinoline compound disclosed in the literature is simply a quinoline substituted with a hydroxyl group, and there is no description suggesting 2-oxoquinoline having a tricyclic fused ring as in the present compound.
  • quinoline compounds having an adhesion-inhibiting action are known as quinoline compounds having an adhesion-inhibiting action, and their indications include allergic diseases, inflammatory diseases, and autoimmune diseases (Patent Document 15) .
  • an immunomodulator comprising a cannabinoid receptor agonist and an antagonist as active ingredients
  • a compound having a 2-oxoquinoline structure which is one of the features of the compound of the present invention.
  • 7-methoxy-12-oxo-8-pentynoleoxy-1,2-dihydroquinoline-13-forcenolevonic acid (4-aminophenyl) amide is disclosed (Patent Document 16).
  • Patent Document 16 only specifically discloses, in addition to the compound H, three other compounds, for example.
  • compound L compound ⁇ , compound ⁇ , compound 0, and compound ⁇ ⁇ are known as tricital 2-oxoquinoline compounds, and have tachykinin receptor antagonistic activity, and are used for various diseases including inflammation and allergy. It has been shown that it can be used as a therapeutic agent (Patent Document 20, Patent Document 21, Patent Document 22, Patent Document 23, Patent Document 24, respectively).
  • Non-Patent Document 6 The following compound Q is known as a tricital 2-oxoquinoline compound (Non-Patent Document 6).
  • Non-Patent Documents 7 and 8 are known as tricyclic 2-oxoquinoline compounds.
  • Non-patent Document 1 Shozo Yamamoto et al., Biology and Chemistry, vol. 39, No. 5, pp. 293-300, 2001
  • Non-Patent Document 2 E p art O i n i o n o n Th e r a p e u t i c P a t e n t ss, Vo l. 12, No. 10, 1475—1489, 2002
  • Non-Patent Document 3 J. Pharm. Sci., 73, 11, 1652-1653 (1984)
  • Non-Patent Document 5 Synthesis, 11, 1362-1364 (1995) (Non-Patent Document 6) J ournalof He terocyc 1
  • Non-Patent Document 7 CAS Reg. No. 400631— 70— 1
  • Non-Patent Document 8 CAS Reg. No. 400631—54—1
  • Patent Document 1 JP-A-6-173014
  • Patent Document 2 EP 65 6 3 5 4
  • Patent Document 3 EP 65 8 5 4 6
  • Patent Document 4 Japanese Patent Application Laid-Open No. 3209377
  • Patent Document 5 US 51 1 2 8 20
  • Patent Document 6 US 50 8 1 1 2 2
  • Patent Document 7 WO 94/1 2 4 66
  • Patent Document 8 Japanese Examined Patent Publication No. 471-1414 107
  • Patent Literature 9 Tokuhyohei 4-1 500 373
  • Patent Document 10 French Patent Publication No. 2377400
  • Patent Document 11 Re-publication publication WO 96/05166
  • Patent Document 12 JP-A-57-171975 (EP 59698)
  • Patent Document 13 Japanese Translation of International Patent Application No. 6-506925 (WO 92Z18483)
  • Patent Document 14 WO 97Z29079
  • Patent Document 15 WO 2000/37429 (Table, page 44, page 5, line 5 to line 27)
  • Patent Document 16 Japanese Patent Application Laid-Open No. H11-180124 (WO 99/02499)
  • Patent Document 17 Japanese Patent Application Laid-Open No. 2000-256323 (Compounds 3-10 on pages 26, 27 and 42) (WO00 / 40562)
  • Patent Document 18 WO02 / 53543 (pages 23 to 24, 221)
  • Patent Document 19 JP-A-2003-12667 (page 5, Table 1: Compound No. 24); WO 2003/681 6-
  • Patent Document 20 WO 2001/85732 (1 page, 88 pages)
  • Patent Document 21 JP-A-2000-44560 (pages 8 to 9, 18); WO 2000/6572
  • Patent Document 22 JP-A-2000-44561 (pages 8 to 9, 16); WO 2000/6571
  • Patent Document 23 JP-A-2000-103792 (pages 8 to 9, 17); WO 2000/6578
  • Patent Document 24 JP-A-2000-103793 (pages 6 and 19); WO20 00/6580
  • Patent Document 25 Patent No. 31 75164 (pages 23 to 24, page 27, column 54, compound (7) of Example 4); WO 93/1 5083
  • Patent Document 26 JP-T-Hei 6-506925 (p. 24, p. 35, compound of Example 10 (10)); WO 92/18483
  • Patent Document 27 JP-A-57-171975 (page 12, lower left column example 12 on page 20); US4738971 Disclosure of 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.
  • cannabinoid receptors especially peripheral cell receptors
  • effects on the central nervous system ie, excitement, hallucinations, motor dynamism, increased irritability, body temperature.
  • Compounds with low side effects such as lowering of blood pressure, respiratory depression, stimulative action of tallepsy, lowering of blood pressure, etc., low toxicity, and therapeutic effects such as antiallergic action, immunomodulatory action and anti-inflammatory action, and pharmaceutical compositions thereof It is to provide things.
  • the present inventors have conducted intensive studies to achieve the above object, and as a result, have obtained Disease areas, which have selective affinity for receptor, especially peripheral cell-type receptors, and are therefore known to involve cannabinoid receptors, especially disease areas involving peripheral cell-type tissues (immune diseases, various inflammations, allergies) 2-oxoquinoline compounds having a tricyclic fused ring useful as pharmaceuticals in sexual diseases and the like have been found, and the present invention has been completed.
  • X is one CR 81 R 82 —, _0—, one S— or one NR 83 —,
  • Y is one CRUR 12 —, one 0_, _S— or one NR 13 —
  • R 83 , R 13 and R 14 are the same or different and are each a hydrogen atom, A 1 k or —CO—A 1 k, wherein Alk is one to three selected from the following group A A C- 8 alkyl group which may be substituted by a substituent of
  • R 81 , R 82 , R 11 and R 12 are the same or different and are each a hydrogen atom, A 1k, a substituent selected from the following group A, or R 81 and R 82 , or R 11 connexion R 12 is a together form a C 3 6 cycloalkyl group; '
  • n and n are the same or different and are each 0 or an integer of 1 to 4 Yes,
  • R 14 may be the same or different;
  • R 5, R 6 and R 7 are the same or different and each is a hydrogen atom, a hydroxyl group, a halogen atom, Al k, -0_Al k, one O- heterocyclic group, One OCO- Al k one OS0 2 - Al k , NR ql — Al k, _NR q2 CO_A 1 k or _ S — A 1 k,
  • R 2 is the same or different and is a hydrogen atom or a Ci- 4 alkyl group.
  • the 1-O-heterocyclic group is substituted by 1 to 5 substituents selected from the following group B) It may be.
  • Group A Halogen atom, — OR al , _OCOR a2 , one COOR a3 , one NR a4 COR a5 , one NR a6 R a7 , one CONR a8 R a9 , one SR al0 , — SOR all , one S0 2 R al2 , — OS0 2 R AL3, one S0 2 NR al4 R al5, 1 to 5 substituents which may be substituted by a substituent carbocyclic group selected from the following group B, ⁇ Pi, 1 to 5 substituents selected from the following group B A heterocyclic group which may be substituted by a substituent;
  • R al , R a3 , R a4 , R a6 , R a7 , R a8 , R a9 , R al0 , R al4 and R al5 are the same or different, respectively, a hydrogen atom, C— 4 An alkyl group or a hydroxy d- 4 alkyl group, and R a2 , R a5 , R all , R al2 and R al3 are alkyl groups.
  • Group B halogen atom,. 4 alkyl groups, one OR bl , — COOR b2 , one
  • R bl , R b2 , R b3 and R b4 are the same or different and are each independently a hydrogen atom or an alkyl group which may be substituted by 1 to 3 substituents selected from the following group C) Is.
  • Group C hydroxyl and phenyl groups
  • R 2 , R 21 , R 22 and R 23 are a hydrogen atom or A 1 k; R 3 is
  • R 31 , R 32 and R 33 are the same or different and are each a hydrogen atom, a cyano group, Alk, one COOR 36 , one CONR 37 R 38 , and 1 to 5 selected from the above group B Or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the above group B (where R 36 , R 37 R 38 and R 38 are the same or different and each is a hydrogen atom ⁇ or Alk, and R 37 and R 38 may form a heterocycle together with an adjacent nitrogen atom.
  • R 31 and R 32 may be taken together to form a cycloalkyl group, a saturated heterocyclic group or a bridged ring group, and the cycloalkyl group may be condensed with a benzene ring.
  • the cycloalkyl group, saturated heterocyclic group or bridged ring group may be substituted with 1 to 5 Alk or hydroxyl groups.
  • pl, p4, p5, p6 , p7, P 8 and P 9 are 0 or an integer der of 1 to 4 Ri
  • p2 ⁇ Pi P 3 is an integer of 1 to 4
  • the carbon The ring may be replaced by one to five A 1 k. ⁇ Or
  • R 34 and R 35 are a hydrogen atom, A lk, a carbocyclic group which may be substituted by 1 to 5 substituents selected from the above group B, or R 34 and R 35 35 may form a heterocyclic ring together with an adjacent nitrogen atom, and the heterocyclic ring may be substituted by 1 to 5 substituents selected from the following group D.) ,
  • R 2 and R 3 may be combined with an adjacent nitrogen atom to 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 by 1 to 5 substituents selected from the following group D;
  • R 3 ° is the same substituent as R 3 except for a hydrogen atom ;
  • Group D halogen atom, A lk, one OR dl , one COOR d2 , one CON R d3 R d4 , one NR d5 R d6 , even if substituted by 1 to 5 substituents selected from the above group B A good carbocyclic group, and a heterocyclic group which may be substituted by 1 to 5 substituents selected from the above group B;
  • R dl , R d2 , R d3 , R d4 , R d5 and R ds are the same or different, It is a hydrogen atom or A 1 k. ):]
  • R 3Z is Al 3 ⁇ 4, a carbocyclic group which may be substituted by 1 to 5 substituents selected from the above group B, and 1 to 5 carbon atoms selected from the above group B
  • the tricyclic condensed ring compound or a pharmaceutically acceptable salt thereof according to [12] which is a heterocyclic group which may be substituted by a substituent.
  • one of R 31 and R 33 is a hydrogen atom, and the other is —COOR 36 or one CONR 37 R 38 ; (13) the tricyclic fused ring compound or a pharmaceutically acceptable compound thereof; salt.
  • R 31 and R 32 together form a cycloalkyl group (the cycloalkyl group may be condensed with a benzene ring or may be substituted with 1 to 5 A 1 k
  • the tricyclic fused ring compound of [12] or a pharmaceutically acceptable salt thereof may be used to form a cycloalkyl group (the cycloalkyl group may be condensed with a benzene ring or may be substituted with 1 to 5 A 1 k.
  • R 31 is a hydrogen atom
  • R 32 is A 1k or a carbocyclic group which may be substituted by 1 to 5 substituents selected from the above group B.
  • R 31 and R 32 are each the same or different and Ru carbocyclic ring group Der be substituted with 1 to 5 substituents selected from Al k or the Group B [12], wherein Or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the tricyclic fused ring compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a cannabinoid receptor modulator comprising, as an active ingredient, the tricitral fused ring compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof.
  • the cannabinoid receptor modulator is an inverse agonist [22]
  • a therapeutic agent for an allergic disease comprising the tricyclic fused ring compound according to any one of [1] to [19] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • an immunomodulator comprising a tricyclic fused ring compound according to any one of (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient, and a therapeutic agent for autoimmune disease And anti-inflammatory agents.
  • Alkyl is a straight or branched chain having 1 to 10 carbon atoms (may be referred to as. The same applies to the following.), Specifically, methyl, ethyl And propyl, isopropyl, butynole, isobutynole, s-butyl, t-butynole, pentinole, isopenentole, neopentinole, t-pentyl, hexinole, isohexyl, neohexyl, heptyl and the like.
  • it has 1 to 7 carbon atoms.
  • methyl, ethyl, propyl, isopropyl, petit / le, t-pentinole, pliers / le, isopentinole, and t-pentyl are exemplified.
  • . ⁇ 6 alkyl group means an alkyl group having 1 to 6 carbon atoms.
  • R 2 preferably has 1 to 6 carbon atoms, and more preferably has 1 to 4 carbon atoms. Specifically, preferably, it is methyl, ethyl, propyl, isopropyl, butyl, isoptyl, pentyl, isopentyl or t-pentyl.
  • R 3 preferably has 1 to 6 carbon atoms, and more preferably has 1 to 4 carbon atoms. Specifically, it is preferably methyl, ethyl, propyl, isopropyl, butyl, t-pentinole, pentyl, isopentyl, or t-pentyl, and more preferably ethyl, propyl, isopropyl, butyl, t-butyl. Tyl, pentyl, isopentyl and t-pentyl, and particularly preferably butyl.
  • R 31 , R 32 and R 33 preferably have 1 to 6 carbon atoms, and more preferably have 1 to 4 carbon atoms. Specifically, it is preferably methyl, ethyl, propyl, butyl or pentyl, more preferably methyl, ethyl, propyl or butyl, and particularly preferably methyl or ethyl.
  • R 34 , R 35 , R 36 , R 37 , and R 38 preferably have 1 to 6 carbon atoms, and more preferably have 1 to 4 carbon atoms. Specifically, it is preferably methyl, ethyl, propyl, isopropyl, butyl or pentyl, more preferably methyl, ethyl, propyl, isopropyl or butyl, and particularly preferably methyl, ethyl or isopropyl.
  • R 5 , R 6 , R 7 , R ", R 12 , R 81 , R 82 , and R 83 preferably have 1 to 6 carbon atoms, and more preferably have 1 to 4 carbon atoms. .
  • Alkoxy means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above, and “_OAlk” includes alkoxy. Specifically, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, t_butyloxy and the like are preferred, and methoxy is more preferred.
  • R 7 preferably include main butoxy.
  • “Cycle mouth alkyl” is a cyclic alkyl having 3 to 10 carbon atoms and is saturated, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclootatyl and the like.
  • R u , R 12 , R 81 , R 82 , R 31 , and R 32 preferably have 3 to 9 carbon atoms, and more preferably have 3 to 8 carbon atoms.
  • R ", in R 12 is preferably a 3 to 6 carbon atoms, and more preferably from 5 3 carbon. Specifically, preferably cyclopropyl, and cyclopentyl. R 31 and R 32 preferably have 5 to 8 carbon atoms. Specifically, preferably, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are mentioned.
  • Hydroalkyl is a group in which any hydrogen atom of the above-defined alkyl group having 14 to 14 carbon atoms has been replaced with a hydroxyl group.
  • a hydroxymethyl group a 2-hydroxyethyl group, a 4-hydroxybutyl group, or a 2-hydroxy-t-butyl group is preferred, and a hydroxymethyl group is more preferred.
  • Aryl is an aromatic hydrocarbon having 6 to 16 carbon atoms, specifically, phenyl, naphthyl, biphenyl, anthracenyl, indenyl, azulenyl, fluorenyl, phenanthryl, pyrenyl and the like. Preferably it is 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 benzyl / phenyl, pheninole, feninolepropynole, phenylinolebutinole, naphthinolemethyl, biphenylmethyl, and the like, with benzyl being preferred.
  • Alkylenedioxy is a divalent group represented by one O—R—O— (R is an alkylene group having preferably 1 to 6, more preferably 1 to 4 carbon atoms).
  • R is an alkylene group having preferably 1 to 6, more preferably 1 to 4 carbon atoms.
  • alkylenedioxy group include, for example, preferably methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy, one O—CH (CH 3 ) — 0—, one O—C (CH 3 ) 2 — O—, and more preferably methylenedioxy.
  • 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 ⁇ Pi P 19 is 0 or an integer of 1 to 4
  • pl2 ⁇ Pi pl3 is an integer of 1 to 4
  • the carbocycle It may be substituted with 1 to 5 A 1 k.
  • Such a group examples include adamantyl, norbornyl, polnanyl, fentanyl, and pinanyl. Of these, adamantyl, 2-norbornyl and 2-phenfenyl are preferred.
  • 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.
  • Heterocycle refers to a ring containing from 1 to 4 heteroatoms in the atoms that constitute the ring, which may contain double bonds in the ring, a non-aromatic ring or an aromatic ring. Means a ring.
  • heterocyclic ring examples include, for example, pyrimigel, pyrazur, pyrrolyl, chenyl, furyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, triazolyl, tetrazolyl, pyrrolidiel, imidazolidinyl, piperidyl, 2,6,2,6 Tetramethyl-4-piperidyl, piperazur, morpholinyl, azepael, and diazepanil ([1,4-diazepanyl]) And piperidyl and pyridyl are preferred.
  • “Saturated heterocyclic group” means a saturated group among the groups contained in the heterocycle as defined above.
  • piperidyl, piperazur, 2,2,6,6-tetramethyl-14-piperidyl, and the like, and 2,2,6,6-tetramethyl-14-piperidinole are preferred.
  • cycloalkyl fused to a benzene ring for R 3 means a structure in which the cycloalkyl portion is ortho-fused to a benzene ring, and cycloalkyl is cycloalkyl as defined above, specifically, tetrahydronaphthalene, Indane and the like are mentioned, and preferred is tetrahydronaphthalene.
  • Heterocycle fused to a benzene ring means a cyclic structure in which the heterocyclic portion is ortho-condensed with a benzene ring, and the heterocyclic portion is a heterocycle as defined above.
  • 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 perhydroindolyl, perhydroisoindolyl, perhydroquinolyl, and perhydroisoquinolyl.
  • each of the optionally substituted groups may be substituted with one or more substituents, preferably one or two substituents. The group used as the substituent will be described below.
  • 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, propoxycarbon, butoxycarbonyl, and the like, preferably methoxycarbon or ethoxycarbon, and more preferably methoxycarboninole.
  • Group C is a hydroxyl group and a phenyl group.
  • Group B is a halogen atom, as defined above.
  • R bl , R b2 , R b3 and R b4 are the same or different and are each independently a hydrogen atom, or may be substituted with 1 to 3 substituents selected from the above group C-4. Is an alkyl group as defined.
  • Group A is a halogen atom, one OR al , one OCOR a2 , one COOR a3 , —NR a4 COR a5 , _NR a6 R a7 , —CONR a8 R a9 , one SR al as defined above.
  • R al , R a3 , R a4 , R a6 , R a7 , R a8 , R a9 , R al0 , R al4, and R al5 are the same or different and are each a hydrogen atom, an alkyl group, or a hydroxy group.
  • an alkyl group, R a2, R a5, R all, R aI2 and R AL3 is - 4 alkyl der You.
  • a lk is an alkyl group as defined above, which may be substituted by 1 to 3 substituents selected from the above group A.
  • Group D means a halogen atom as defined above, A lk, one OR dl , one COOR d2 , _CO NR d3 R d4 , one NR d5 R d6 as defined above, and the following group: B A carbocyclic group as defined above which may be substituted by 5 substituents; and a heterocyclic group as defined above which may be substituted by 1 to 5 substituents selected from group B above. .
  • R dl , R d2 , R d3 , R d4 , R d5 and R d6 are the same or different and are each a hydrogen atom or A 1k 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].
  • 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, roscorbic acid, methylsulfonic acid, benzylsulfonic acid
  • inorganic bases such as sodium hydroxide, hydroxylating lime, calcium hydroxide, magnesium hydroxide, hydroxylammonium, etc .; or chilamine, getylamine, triethylamine, triethanolamine, ethylenediamine, tris
  • Organic bases such as methylamine, guanidine, choline, and cinchonine; or lysine , Arg
  • Autoimmune diseases include diseases associated with cannapinoid receptors, and include systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, and the like. 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. Examples include agonists, antagonists, inverse agonists, and other substances that enhance or reduce the sensitivity of cannapinoid receptors, and the latter include substances that enhance or suppress cannabinoid receptor gene expression. No. Inverse agonists have the opposite effect to that of the receptor agonist. For example, in terms of the level of cyclic AMP (cAMP) at the cannapinoid receptor, it indicates a compound that increases cAMP levels as compared to cannapinoids that suppress the increase.
  • cAMP cyclic AMP
  • Allergic diseases include anaphylaxis, gastrointestinal allergy, allergic gastroenteropathy, allergic dermatitis, dermatitis such as rash, rash and cosmetic rash, rash, measles, atopic dermatitis, asthma, allergic asthma, atopic Asthma, allergic bronchopulmonary aspergillosis, hay fever, allergic rhinitis, allergic conjunctivitis, allergic granulomatous vasculitis, drug allergy, serum sickness, tuberculosis lesions, rejection after organ transplantation, tuberculosis lesions, Examples include, but are not limited to, rejection after organ transplantation, and can be applied to any disease related to allergy.
  • allergic dermatitis More preferred are allergic dermatitis, atopic dermatitis, asthma, allergic asthma, atopic asthma, allergic rhinitis, and allergic conjunctivitis. Particularly preferred are skin and respiratory organs. Allergic diseases can be cited, and more specific indications are allergic dermatitis, atopic dermatitis, allergic asthma, and atopic asthma. "Allergic dermatitis” refers to dermatitis associated with an allergic reaction, including, for example, atopic dermatitis. It is classified as non-allergic dermatitis such as dermatitis due to a wound. As the "agent for treating atopic dermatitis", a drug which enhances the therapeutic effect by acting on an allergic reaction of atopic dermatitis is preferable.
  • a delayed type reaction it is preferable to have an effect on the delayed type reaction, the delayed type reaction, or the delayed type reaction and the delayed type reaction of the allergy reaction. More preferably, in addition to the immediate type reaction, a delayed type reaction, It is a delayed response or a therapeutic agent that has an effect on delayed response and delayed response.
  • 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.
  • a drug which enhances the therapeutic effect by acting on the allergic reaction of asthma is preferable.
  • Antipruritic effect refers to the effect of reducing itching or removing itching, thereby reducing the itching 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. Further, it preferably has an antipruritic effect on the above allergic 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 can be used, for example, to improve absorption in oral administration or to target Used for position targeting.
  • modification site examples include highly reactive functional groups such as a hydroxyl group, a carboxyl 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 propionyl group, an isobutylinole group, a bivaloyl 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, an 11- (acetyloxy) ethyl group, a 1- (ethoxycarbo-loxy) ethynole group, and an 11- (cyclohexynoleoxycanolevoni).
  • Roxy ethyl group, propyloxylmethyl group, (5-methyl-2-oxo-11,3-dioxol-14-yl) methyl group, phenyl group, o-tolyl group and the like.
  • 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-1-oxo-1,3-dioquil—4T) methyl group and the like.
  • Preferred embodiments of the compound of the present invention include compounds having good pharmacological activity (for example, compounds having high binding activity to CB 2, compounds having high CB 2 selectivity for CB 1 in CB binding activity, compounds having high anti-allergic activity, Compounds with high gonist 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.).
  • compounds having good pharmacological activity for example, compounds having high binding activity to CB 2, compounds having high CB 2 selectivity for CB 1 in CB binding activity, compounds having high anti-allergic activity, Compounds with high gonist 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.
  • compounds with high safety
  • those having a CZ S of 10 times or more are preferable, those having a C / S of 100 times or more are more preferable, and those having a CZ S of 300 times or more are more preferable. Those having a C / S of 100 times or more are particularly preferred.
  • R 5 and R 6 are preferably hydrogen atoms.
  • R 7 is preferably a hydrogen atom and —O—A 1 k, and one O—A lk Preferred is an alkyloxy group having 1 to 4 carbon atoms, and among them, a methoxy group is particularly preferred.
  • A is preferably one CONR 2 R 3 , -NR 21 CON R 2 R 3 , one NR 22 COR 3 . , One NR 22 COOR 3 , _NR 23 SO 2 R 3 . Or one COCH 2 —R 2 , more preferably one CONR 2 R 3 .
  • the group represented by the formula, one A lk, or R 2 and R 3 form a heterocyclic ring together with the adjacent nitrogen atom.
  • R 31 , R 32 and R 33 are the same or different, each is selected from a hydrogen atom, a cyano group, Alk, one COOR 36 , —CONR 37 R 38 , and the group B group A carbocyclic group which may be substituted by 1 to 5 substituents; or a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group B.
  • R 32 is preferably Alk, and 1 to 5 substituents selected from the group B Or a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group B.
  • one of R 31 and R 33 is preferably a hydrogen atom, and the other is preferably —COOR 36 or —CON R 37 R 38 .
  • R 31 and R 32 may combine to form a cycloalkyl group, a saturated heterocyclic group or a bridged ring group, preferably a cycloalkyl group or a saturated heterocyclic group, more preferably Preferably forms a cycloalkyl group.
  • the cycloalkyl group may be condensed with a benzene ring, and may be substituted with 1 to 5 A 1k.
  • R 31 is a hydrogen atom
  • R 32 is A 1k or a carbocyclic group which may be substituted by 1 to 5 substituents selected from the aforementioned Group B forces.
  • R 31 and R 32 are the same or different and are each a carbocyclic group which may be substituted with Alk or 1 to 5 substituents selected from the above group B.
  • R 33 is one COOR 36 or one CONR 37 R 38 , and in this, one COOR 36 is more preferred.
  • R 3 R 32 and R 33 include, for example, the following embodiments.
  • R 31 , R 32 and R 33 are all the same or different and are Alk. ⁇
  • R 31 , R 32 and R 33 are the same or different and each is Al k, and the other one is a hydrogen atom, one COOR 36 or one CONR 37 R 38
  • R 31 and R 32 together form a cycloalkyl group or a saturated heterocyclic group
  • R 33 is a hydrogen atom, Alk, -COOR 36 , one CONR 37 R 38 , or When it is a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group B
  • R 31 , R 32 and R 33 in the embodiments (1) to (5) include, for example, the following embodiments.
  • R 31 , R 32 and R 33 are the same or different and are each more preferably a C 4 alkyl group which may have one or two hydroxyl groups as a substituent, more preferably An alkyl group which may have one or two hydroxyl groups as a substituent, or
  • R 31 and R 32 are Ci- 4 alkyl groups and R 33 is HOCH 2 CONHCH 2 —.
  • R 31 and R 32 are the same or different and are each a C ⁇ 4 alkyl group and R 33 is —COOR 36 , more preferably R 36 is a hydrogen atom or an alkyl group ,
  • R 31 and R 32 are the same or different and each is an alkyl group, and R 33 is one CONHR 38 ; in this case, more preferably, R 38 is a Ci- 4 alkyl group; or
  • R 31 and R 32 may be the same or different and each may have 1 to 2 hydroxyl groups as substituents, or 4 alkynole groups or 1 to 2 alkyloxy groups as substituents.
  • a C 4 alkyl group, and R 33 is a hydrogen atom.
  • R 31 is a C 2-5 alkyl group which may have a hydroxyl group or a phenyl group as a substituent, and R 32 is one COOR 36 ; in this case, more preferably, R 36 is A hydrogen atom, an alkyl group or a benzyl group, and R 33 is a hydrogen atom If it is
  • R 31 is a d- 4 alkyl group optionally having 1 to 2 substituents selected from group A, and the substituent is preferably a phenyl group, a phenyl halide group, or a pyridinole group , hydroxyl, C 5 - 8 a cyclohexyl group, or a HO CH 2 CONH- (hydroxymethyl Cal Poni Rua amino group), R 32 ⁇
  • 'And R 33 are hydrogen atoms
  • R 31 and R 32 and are together a connexion, 1-4 alkyl groups which may have a substituent C 5 have the substituent to form a good piperidyl group
  • R 33 is a hydrogen atom, water acid groups or HOCH 2 CONHCH 2 - which may have a substituent CI_ 4 ⁇ alkyl group
  • one COOR 36 more preferably R 36 is a hydrogen atom or an 0 2 alkyl group,
  • -CONR 37 R 38 R 37 R 38 are each independently preferably a hydrogen atom, 2 an alkyl group or HOC 2 H 4 - is Or in the case of a piperidyl group which may be substituted by 1 to 5 C ⁇ s alkyl groups. More specifically, such R 3 includes, for example, the following groups.
  • R 3 examples include groups having the following structures.
  • —NR 2 R 3 of CONR 2 R 3 preferably includes the following groups.
  • R 21 and R 2 are preferably hydrogen atoms, and R 3 is all An benzyl group is preferred.
  • R 22 is a hydrogen atom or a C- 4 alkyl group. Of the ⁇ 4 alkyl groups, an isopropyl group is preferred.
  • R 30 examples include 1 C (CH 3 ) 3 and —CH 2 C (CH 3 ) 3 .
  • R 22 is a hydrogen atom
  • R 3 include a hydrogen atom and an alkyl group having 1 to 4 carbon atoms.
  • the alkyl group a methyl group, an ethyl group, and a t-butyl group are preferable, and a t-butyl group is more preferable.
  • - NR 23 S0 2 R 3 ° of, R 23 is preferably a hydrogen atom.
  • R 3. Examples include a p-tolyl group.
  • R 2 is preferably a hydrogen atom.
  • R 3 include a hydrogen atom, a benzyl group, and a 2,2,6,6-tetramethyl-4-piberidinole group.
  • R 2 is preferably a hydrogen atom.
  • R 2 includes one CH 2 C (CH 3 ) 3 .
  • X is preferably one CR 81 R 82 —, one O— or one NR 83 —,
  • the R 81, R 82, each independently, lay preferred is hydrogen atom or C _ 4 alkyl group, more preferably a hydrogen atom or a methyl group.
  • R 83 is preferably a hydrogen atom, a C 4 alkyl group or 1 CO—A 1 k.
  • a C 4 alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, or an n-butyl group.
  • One CO—Alk is preferably one CO——4 alkyl group, and among the alkyl groups, an n-propyl group is preferred.
  • Such X include, for example, one CH 2 —, —CH (CH 3 ) one O—, —NH—, —N (CH 3 ) one, and —N (nC 4 H 9 ) -, One N (COC 3 H 7 )-and the like.
  • the Y, one CR U R 12 - one O- one NR 13 _ is rather preferable one CR "R 12 - one O- is more preferred.
  • R u and R 12 are each independently preferably a hydrogen atom or Alk—COOR a3 .
  • a 1 k Alkyl groups or hydroxymethyl groups are more preferred,
  • alkyl groups are more preferred.
  • alkyl groups a methyl group, an ethyl group, an n-propyl group, and an n_butyl group are preferable.
  • R a3 is a hydrogen atom.
  • a ⁇ 4 alkyl group is more preferred. Examples of the alkyl group include a methyl group and an ethyl group.
  • I 11 and R 12 are preferably both hydrogen atoms or both alkyl groups, and more preferably both hydrogen atoms, methyl groups or ethyl groups, is mentioned. Further, an embodiment in which either R u or R 12 is a hydrogen atom, and the remainder is an alkyl group or one COOR a3 is also preferable.
  • R " may be R 12 together form a C 3 _ 6 cycloalkyl group.
  • Al k and one CO—A 1 k are preferable.
  • Alk an alkyl group, a methoxycarbonyl-4 alkyl group, or a carboxylalkyl group is more preferred. Specific examples include an n-butyl group, a methoxycarbonylmethyl group, a carboxylmethyl group, and the like.
  • a -42-alkylcarbonyl group is more preferred. Specific examples include a methylcarbonyl group and a propyloxypropyl group.
  • n and n are the same or different and are each preferably an integer of 1 to 4, and more preferably an integer of 1 to 2.
  • R “R 12 is a hydrogen atom, and any one is an alkyl group having 1 to 6 carbon atoms, and 1 to 3 carbon atoms. It is desirable that the alkyl group be an alkylcarbonyl group or a hydroxyalkyl group having 1 to 3 carbon atoms.
  • the alkyl group having 1 to 3 carbon atoms is preferably a methyl group, an ethyl group, or a propyl group.
  • the alkylcarbonyl group having 1 to 3 carbon atoms is preferably an ethoxycarbonyl group, and the hydroxyalkyl group having 1 to 3 carbon atoms is preferably a hydroxymethyl group.
  • any of R "R 12 is a hydrogen atom and any one is an alkyl group having 1 to 4 carbon atoms, or R" R 12 is the same or different, and includes an alkyl group having 1 to 4 carbon atoms.
  • R 11 and R 12 are the same or different alkyl groups having 1 to 4 carbon atoms, for example, the alkyl group is preferably methyl. group, Echiru group, a propyl group, and butyl group, more preferably a Echiru group, a propyl group or a butyl group. it is more preferred R U R 12 are the same alkyl group.
  • one CR 11 R 12 - as preferably include cycloalkylene group 3-6 carbon atoms, Preferably, a cyclopropylene group and a cyclobutylene group are used.
  • 1 C (cyclopropylene group) 1 indicates that a cyclopropyl group is formed including the C atom (the same shall apply hereinafter in this specification).
  • the alkyl group, methyl group, is Echiru group preferably, Of these, more methyl group It is preferable.
  • R U R 12 are the same alkyl group.
  • R “R 12 with each other may also be connexion bond such together R “R 12 with each other, for example, one CR 11 R 12 - as preferably include cycloalkylene group 3-6 carbon atoms, preferably cyclopropylene Group, cyclobutylene group and cyclopentylene group.
  • R 12 is preferably any one of R n R 12 is a hydrogen atom and any one is an alkyl group having 1 to 3 carbon atoms, or R U R 12 can be mentioned the same or different alkyl group having a carbon number of 1-3 together. Of these, R "shall either one is a hydrogen atom of R 12 is an alkyl group having 1 to 3 carbon atoms are preferred. For example, the alkyl group, methyl group, Echiru group, propyl And among these, a propyl group is preferred.
  • R U R 12 preferably, R "R 12 caries Chiizure or either an alkyl group from 1 to 3 carbon atoms with hydrogen atoms, Or an alkyl group having 1 to 3 carbon atoms in which R 11 and R 12 are the same or different from each other, and among these, any of RUR 12 is a hydrogen atom and any of RUR 12 is a hydrogen atom having 1 to 3 carbon atoms.
  • R U R 12 preferably, R "R 12 caries Chiizure or either an alkyl group from 1 to 3 carbon atoms with hydrogen atoms, Or an alkyl group having 1 to 3 carbon atoms in which R 11 and R 12 are the same or different from each other, and among these, any of RUR 12 is a hydrogen atom and any of RUR 12 is a hydrogen atom having 1 to 3 carbon atoms.
  • Preferred is an alkyl group of 3.
  • the alkyl group includes a methyl group, an ethyl group, and a propyl group, and among
  • R ⁇ R 12 is a hydrogen atom and any one is an alkyl group having 1 to 3 carbon atoms, or, RHR 12 and the like are the same or different alkyl group having a carbon number of 1-3 together. of these, R "one of R 12 is a hydrogen atom or is a carbon atom number of from 1 to 3 Those which are alkyl groups are preferred.
  • examples of the alkyl group include a methyl group, an ethyl group, and a propyl group. Of these, a methyl group is preferable. Specifically, for example, the following groups may be mentioned.
  • R 81 R 82 CR 8i R82 _ (CH 2 ) 2 - of, as the R 81 R 82, preferably, either one is an alkyl group having 1-3 carbon atoms in the hydrogen atom of R 81 R 82 or, And R 81 and R 82 are the same or different and are alkyl groups having 1 to 3 carbon atoms. Among them, it is preferable that any one of R 81 R 82 is a hydrogen atom and any one of them is an alkyl group having 1 to 3 carbon atoms.
  • examples of the alkyl group include a methyl group, an ethyl group, and a propyl group. Of these, a methyl group is preferable.
  • R 81 R 82 is a hydrogen atom and any one is an alkyl group having 1 to 3 carbon atoms, or R 81 and R 82 are the same or different, and are each an alkyl group having 1 to 3 carbon atoms.
  • R 81 R 82 is a hydrogen atom and any one of them is an alkyl group having 1 to 3 carbon atoms.
  • examples of the alkyl group include a methyl group, an ethyl group, and a propyl group. Of these, a methyl group is preferable.
  • R 83 preferably includes an alkyl (Ci-s alkyl) group having 1 to 6 carbon atoms and a C 6 alkyl monocarbonyl group.
  • alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Of these, a methyl group, an ethyl group, a propyl group, and a butyl group are preferable.
  • the C ⁇ e alkyl monocarbonyl group is preferably And a pillcarboel group.
  • R 13 is preferably Al k or CO 1 A 1 k.
  • — 4 alkyl groups methoxycarbonylalkyl groups, or hepoxyl.
  • ⁇ 4 alkyl groups are more preferred. Specific examples include an n-butyl group, a methoxycarbonylmethyl group, and a carboxylmethyl group.
  • a C 1-4 alkylcarbonyl group and a carboxyl C 1-4 alkylcarbonyl group are more preferred. Specific examples include a methylcarbonyl group and a carboxylpropylcarbonyl group.
  • R 83 is a hydrogen atom or a C 4 alkyl group preferable.
  • alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group.
  • R "R 12 either a hydrogen atom, it is preferred that one is CI_ 4 alkyl group.
  • the tricyclic fused ring compound represented by the general formula (I) according to the present invention (hereinafter referred to as “the compound”) Below it is sometimes referred to as "Compound I”. ) Can be produced, for example, as in the following production method A or production method B, but is not limited thereto. [Production method A]
  • Step A 3 R p10 2 cA CO R P2 AV]
  • R 2 , R 3 , R 5 , R 6, RR ”, t , X , Y , m , and n have the same meanings as in the above formula ( I)
  • R P1 and R P2 are the same or different, respectively.
  • Al k represents a methyl group, an ethyl group, a benzyl group or the like, or a carboxylic acid protecting group (for example, a toshimethylsilyl group)
  • Z represents a protecting group (for example, a methyl group, an ethyl group, a benzyl group, a trimethylsilyl group, a methoxymethyl group).
  • Ha 1 is chlorine atom, bromine. Indicates a halogen atom such as an atom.
  • Y is —O—
  • one S— or one NR 81 —, m and n are the same or different and are each an integer of 1 to 4. ⁇ .
  • R 2 , R 3 , R 5 , R 6 , R 7 , R 14 , t, X, Y, m, n, and P 1 have the same meanings as in the above-mentioned Production Method A.
  • the nitro compound can be obtained by reacting the compound [All] 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 ethyl acetate.
  • Ester solvents such as acetic acid, methyl acetate and butyl acetate; alcohol solvents such as methanol, ethanol, isopropyl alcohol and t-butanol; acid solvents such as acetic acid and acetic anhydride; and acetic acid is preferable.
  • the reaction temperature is usually from 15 to 200 ° C, preferably from 10 to 60 ° C.
  • the reaction time is usually from 15 minutes to 48 hours, preferably from 1 to 8 hours. It is.
  • the compound [AIII] can be obtained by reacting the obtained nitro compound with an alkylpromide such as promopentane in a suitable solvent in the presence of a base.
  • Suitable bases include, for example, sodium carbonate, Potassium carbonate, lithium carbonate Sodium bicarbonate, sodium bicarbonate, sodium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydride, n-butyl lithium, s-butyl lithium t-butyl lithium, lithium diisopropylamide, etc. And preferably potassium carbonate.
  • Suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, xylene, and hexane; getyl ether, 1,2-dimethoxetane, and tetrahydrogen.
  • Ether solvents such as furan and diglyme; halogen solvents such as dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane and the like; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; dimethylformamide And polar solvents such as dimethylsulfoxide acetonitrile and acetone; alcoholic solvents such as methanol, ethanol, isopropyl alcohol and t-butanol; and the like, preferably dimethylformamide.
  • halogen solvents such as dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane and the like
  • ester solvents such as ethyl acetate, methyl acetate and butyl acetate
  • dimethylformamide And polar solvents such as dimethylsulfoxide acetonitrile and acetone
  • alcoholic solvents such
  • the reaction temperature is usually from 110 to 200 ° C, preferably from 0 to 60 ° C.
  • the reaction time is usually from 15 minutes to 48 hours, preferably from 1 to 8 hours.
  • the compound [AIV] can be obtained by reducing the nitro group of the compound [AIII] by a conventional method.
  • Compound [AIV] can be obtained by condensing compound [AIV] with malonic acid derivative [AV] in the presence of an appropriate acid or base.
  • the malonic acid derivative 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 ethoxide, sodium methoxide, ammonium acetate, sodium acetate, piperidine, pyridine, pyrrolidine, n-methylmorpholine, morpholine-triethylamine and the like. And preferably 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; dimethylformamide, dimethylsulfoxide, acetate Polar solvents such as nitrile and acetone; alcoholic solvents such as methanol, ethanol, isopropyl alcohol and t-butanol; and the like, preferably toluene.
  • 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.
  • Compound [AVII] can be obtained by hydrolyzing compound [AVII] in a solvent in the presence of a suitable acid or 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, lithium hydroxide, lithium hydroxide, and the like, with preference given to lithium carbonate.
  • Suitable acids include hydrochloric acid, sulfuric acid, etc., preferably hydrochloric acid.
  • Compound [AIX] can be obtained by converting compound [AVII] into an activated carboxylic acid derivative and reacting with compound [AVIII].
  • Examples of the activated carboxylic acid derivative include, for example, an acid halide obtained by treating a carboxylic acid with thiol chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, etc .; Condensation with benzotriazole, N-hydroxysuccinimide, etc., and condensing agents such as dicyclohexylcarpoimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride And a mixed acid anhydride obtained by reacting a carboxylic acid with ethyl ethyl carbonate, pivaloyl chloride, isobutyl carbonate, and the like.
  • DCC dicyclohexylcarpoimide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • a mixed acid anhydride obtained by
  • Examples of the base include organic amines such as triethynoleamine, tert-butylamine, pyridin, and N-methylmorpholine, and preferably tert-butynoleamine.
  • Halogen solvents such as 2-dichloromethane; ester solvents such as ethyl acetate, methyl acetate and butynole acetate; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone; and preferably dimethylform Amido.
  • the reaction temperature is usually from 0 to 100 ° C, preferably from 0 to 50 ° C.
  • the reaction time is generally 15 minutes to 24 hours, preferably 1 to 12 hours.
  • the compound [AX] can be obtained by treating the compound [AIX] with a Lewis acid in a solvent to dealkylate the ether moiety.
  • Lewis acid examples include titanium tetrachloride, aluminum chloride, aluminum bromide, trimethylsilinole iodide, boron trichloride, boron tribromide, and the like, with boron tribromide being preferred.
  • a sulfur compound such as thiophenol or ethyl mercaptan may coexist.
  • the solvent examples include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; ether solvents such as tetrahydrofuran and diglyme; halogens such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Examples include a system solvent, and dichloromethane is preferable.
  • the reaction temperature is usually from 100 to 100 ° C, preferably from 180 to 0 ° C.
  • the reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 5 hours.
  • the catalytic reduction may be carried out in a solvent in the presence of a catalyst such as palladium-activated carbon.
  • the solvent include ether solvents such as tetrahydrofuran and diglyme; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and t-butanol; and mixed solvents thereof.
  • the compound [AX] is reacted with a compound [AX I] such as an alkyl dihalide, and the compound is cyclized to obtain the target compound [I].
  • a compound [AX I] such as an alkyl dihalide
  • the reaction is preferably performed in a solvent in the presence of a base.
  • a base include sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogencarbonate, sodium hydrogencarbonate, sodium hydroxide, sodium hydroxide, lithium hydroxide, and the like, with potassium carbonate being preferred.
  • the solvent examples include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; ether solvents such as getyl ether, 1,2-dimethyloxetane, and tetrahydrofuran diglyme; dichloromethane, chloroform, and tetrachloride Hapogen-based solvents such as carbon and 12-dichloroethane; ester-based solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone; Is dimethylformamide.
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • ether solvents such as getyl ether, 1,2-dimethyloxetane, and tetrahydrofuran diglyme
  • the reaction temperature is usually 20 to: L 00 ° C, and preferably a temperature under reflux.
  • the reaction time is usually from 15 minutes to 24 hours, preferably from 30 minutes to 5 hours.
  • a compound [BIII] having a tricyclic structure is obtained from a compound [BII] having a dicyclic structure.
  • the method described in J. Heterocycle Chem. 1997 : 34, 969-972. Can be.
  • compound [BII] is heated with HC (C 0 2 R P 3 ) 3 (where R P 3 is an alkyl group such as a methyl group or an ethyl group or a benzyl group).
  • R P 3 is an alkyl group such as a methyl group or an ethyl group or a benzyl group.
  • xylene for example, xylene, mesitylene, nitrobenzene.
  • diphenyl ether for example, xylene, mesitylene, nitrobenzene.
  • dautherm mixed solution of biphenyl and diphenyl ether
  • the reaction temperature is usually from 100 to 300 ° C, preferably from 150 to 250 ° C.
  • the reaction time is generally 5 minutes to 24 hours, preferably 5 minutes to 3 hours.
  • the hydroxyl group of the compound [Bill] is converted to a leaving group T to produce the compound [BIV].
  • T halogen atom (chlorine atom, bromine atom, etc.), OS 0 2 R (where, R represents a methyl group, triflate Ruo Russia methyl, p- Toruiru group) and the like.
  • This step can be carried out, for example, when T is a halogen atom, by reacting a halogenating agent in the presence or absence of a solvent.
  • halogenating agent examples include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like.
  • a halogenating agent such as hypochlorite or N-chlorosuccinimide
  • phosphines such as triptylphosphine and triphenylphosphine may be added.
  • the solvent examples include ether solvents such as 1,4-dioxane, dimethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; Hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and polar solvents such as dimethylformamide and aceto nitrile are preferred.
  • ether solvents such as 1,4-dioxane, dimethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran
  • halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane
  • Hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • polar solvents such as dimethylform
  • the reaction temperature is usually an 7 8 ⁇ 4 0 ° C, preferably also is an 3 0 ° C ⁇ 3 0 ° C, for example, in the case of T is OS_ ⁇ 2 R, and sulfonating reagent, and a base
  • the reaction can be carried out in the presence of a solvent.
  • sulfonating reagent examples include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl anhydride, and N-phenyltrifluoromethanesulfonylimide.
  • Examples of the base include triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, lithium diisopropylamide and the like.
  • a solvent for example, dichloromethane, tetrahydrofuran and the like can be used.
  • the reaction temperature is usually from _78 to 100 ° C, and preferably from 30 to 80 ° C.
  • Normal hydrogenation may be used.
  • the compound [B IV] is subjected to catalytic reduction with hydrogen in a solvent in the presence of a catalyst such as palladium-activated carbon, palladium hydroxide, Raney nickel, oxidized platinum and the like.
  • the compound [BV] can be obtained.
  • the solvent examples include ether solvents such as tetrahydrofuran; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and t-butanol; acetic acid; or a mixed solvent thereof.
  • ether solvents such as tetrahydrofuran
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol, and t-butanol
  • acetic acid or a mixed solvent thereof.
  • the pressure of hydrogen gas can be, for example, in the range of normal pressure to about 10 atm.
  • the reaction temperature is usually 0 to 50 ° C., preferably about room temperature.
  • the reaction time is usually 30 minutes to 24 hours, preferably 1 to 10 hours.
  • Compound [BV I] can be obtained by hydrolyzing compound [BV] in a solvent in the presence of a suitable acid or base.
  • step A4 It can be carried out by the same operation as in step A4.
  • Compound [I] can be obtained by converting compound [BVI] into an activated carboxylic acid derivative and reacting with compound [BVII].
  • step A5 It can be carried out by the same operation as in step A5.
  • any of the above-mentioned production methods A and B can be adopted.
  • the production method A or B Either can be preferably employed.
  • X is bonded to an aromatic ring by a carbon atom, a nitrogen atom, or a diatom
  • Production Method B may be preferably used.
  • the tricyclic compound can be obtained by the methods described in, for example, JP-A-2000-44561, JP-A-2000-103792, JP-A-2000-103793, and JP-A-7-503248. It can also be manufactured by appropriate application.
  • the compound [I] produced as described above can be separated and purified by known means such as, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, chromatography and the like.
  • the pharmaceutically acceptable salt of compound [I] and various isomers of compound [I] can be produced by a conventionally known method.
  • the tricyclic fused ring compound of the present invention and a pharmaceutically acceptable salt thereof are useful for mammals, in which disease areas known to involve cannapinoid receptors, particularly disease areas involving peripheral cell tissues. (Pharmaceutical effects in immune diseases, various inflammations, allergic diseases, etc.)
  • the tricyclic fused ring compound and a pharmaceutically acceptable salt thereof selectively act on cannabinoid receptors, particularly peripheral receptors, have few side effects in the central system, and have excellent immunomodulatory effects. It has anti-inflammatory and anti-allergic effects.
  • the tricyclic polycondensation therapeutic compound and a pharmaceutically acceptable salt thereof include a cannabinoid receptor (particularly, peripheral cannabinoid receptor) modulator, an immunomodulator, an autoimmune disease therapeutic agent, an anti-inflammatory agent and the like. ⁇ Useful as an antiallergic agent.
  • 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 Alcohols such as benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, ratatose, starch, etc. W
  • the dosage may vary depending on the type and extent of the disease, the compound to be administered and the route of administration, the age, sex, weight, etc. of the patient.
  • oral administration usually 0.1 to 1000 mg, preferably 1 to 300 mg of the tricyclic fused ring compound per adult is administered in 1 to several times per day.
  • 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 filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the target compound 10 as a colorless oil (4.1 g, yield 64%).
  • compound 7 (190 mg, 654 umol) prepared in the first 16 steps of Example 1, compound 11 (202 mg, 784 umol) obtained in the second to second steps, and sodium hydrogen carbonate ( A suspension of 165 mg (1, 96 mmol) in DMF (2 mL) was stirred at 60 ° C for 3 hours, at 90 ° C for 2 hours, and at 120 ° C for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over sodium sulfate.
  • the desiccant was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain the desired product 12 (97 mg, yield 32%) as a yellow oil. .
  • Step 3 _ 1
  • camphasulfuronic acid 113 mg, 486 g was added to a solution of compound 9 (4.9 g, 47 t ol) and benzaldehyde dimethyl acetal (6.5 mL, 42 t) in chloroform (50 mL). umol) and stirred at room temperature for 1.5 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate. After filtering the desiccant, the filtrate was concentrated under reduced pressure to obtain the target compound 16 (9.3 g, quant.) As a colorless oil.
  • the compound 17 (4.2 g, 21 mmol) obtained in the third step was treated in the same manner as in the second step to give the target compound 18 (4.3 g, yield, colorless oil). 77%).
  • the solid thus obtained was collected by filtration, washed with n-hexane, and dried under reduced pressure to obtain the desired product 26 (45 mg, yield 34%) as a white solid.
  • Example 736 The compound 7 (100 mg, 0.34 mL) obtained in Example 1 was dissolved in dimethylformamide (DMF; 5 ml) under an argon stream, and potassium carbonate (105 mg , 0.76 mmol) and 1 , 4-Dibromobutane (45 ⁇ l, 0.38 mmol) were added in sequence, and the mixture was stirred at 90 ° C for 5 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate.
  • DMF dimethylformamide
  • 4-Dibromobutane 45 ⁇ l, 0.38 mmol
  • Step 1 0-2 0 4-
  • step 10-4 Compound 4 3 (4.0 g, 8.9 mmol) obtained in step 10-4 was subjected to the same procedure as step 2-4. 0 6-The desired product 4 4 (2.6 g, 80% yield) was obtained as a yellow solid,
  • Step 10-8 0 7- Compound a-3 obtained in Preparation Example 2 was reacted with compound 46 obtained in Steps 10-7 in the same manner as in Steps 1-5 of Example 1 to obtain target compound 47. .
  • Methyl ester carboxylate was produced by applying the same method as in Steps 5_1 to 5-4 of Example 5, and the compound a-3 obtained in Preparation Example 2 was used. In the same manner as in 1, 5, the following compound 52 was produced.
  • the compound 61 (1.76 g, 5.28 mmol) obtained in the 1912 step was dissolved in tetrahydrofuran (THF; 22 ml) and methanol (22 ml), and a 2N aqueous sodium hydroxide solution (5.30 ml) was added. , 10.6 mmol) and stirred at room temperature for 0.7 hours. After neutralizing the reaction solution by adding 2 N hydrochloric acid, water was added and the mixture was stirred. The precipitated solid was collected by filtration, washed with a mixed solvent of methanol and water at a ratio of 1: 2, and dried under reduced pressure to obtain the desired product 62 (1.57 g, yield 97%) as a white solid.
  • the desiccant was filtered, the filtrate was concentrated under reduced pressure, and t-butyl methyl ether was added. The precipitated solid was collected by filtration, washed with t-butyl methyl ether, and dried under reduced pressure to obtain the target product 85 (56 mg, Yield 72%).
  • Step 2-1 step Compound 84 (13 mg, 0.050 mmol) obtained in Step 20-6 of Example 20 was dissolved in DMF (1 ml) under an argon stream, and potassium carbonate (14 mg , 0.1 OlOmmol) and sodium methane were added at room temperature. (51, 0.075 l) and stirred at 40 ° C for 1.5 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate. After filtering the drying agent, the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain the target product 88 (I2mg, yield 85%) as a yellow solid.
  • the mixture was stirred at 5 ° C for 2 hours. After allowing to cool, water and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, and the mixture was stirred. The precipitated solid was collected by filtration. The solid collected by filtration was washed with water, and dried under reduced pressure to obtain the target product 90 (2.5 mg, yield 31%) as a yellow solid.
  • the precipitated solid was separated by filtration with celite and washed with ethyl acetate.
  • Step B 2 Step 2
  • Dibromide was synthesized in the same manner as in Step B-12 of Reference Example 1 to synthesize Compound 70.
  • Step B3-1 Step 1 W
  • Human Cannabinoid Receptor human CB 1-CHO, hereinafter hCBl
  • Human Peripheral Cannabinoid Receptor human CB2-CHO, hCB 2
  • hCBl Human Cannabinoid Receptor
  • human CB2-CHO Human Peripheral Cannabinoid Receptor
  • Assay buffer used was 50 mM Tris-HC1, 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, 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 CPS5940 (10 M), 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.
  • ⁇ i values for central cell-type receptors and ⁇ i values for peripheral cell-type receptors (czs) were determined. The results are shown in Table 20. Table 20
  • the tricitral fused ring compound of the present invention and a pharmaceutically acceptable salt thereof are It selectively acts on nabinoid receptors, especially peripheral receptors, has few side effects in the central system, and has excellent immunoregulatory, anti-inflammatory and antiallergic effects. Therefore, they are useful as modulators of cannapinoids, receptors (particularly peripheral cannabinoid receptors), therapeutic agents for allergic diseases, immunomodulators, therapeutic agents for autoimmune diseases or anti-inflammatory agents. Further, a modulator that acts as an inverse agonist can be a safe and effective drug for chronic and refractory allergic diseases, which is ineffective with existing therapeutic agents for allergic diseases.

Abstract

L'invention concerne un nouveau composé capable d'agir de manière sélective sur un récepteur de cannabinoïdes, plus particulièrement un récepteur périphérique ; et une composition médicamenteuse thérapeutique associée. Plus précisément, l'invention concerne un composé cyclique condensé tricyclique de la formule générale (I), (dans laquelle les caractères sont tels que définis dans le descriptif), ou un sel de ce dernier pharmaceutiquement acceptable, ainsi que son utilisation médicale.
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WO2008120003A1 (fr) * 2007-04-03 2008-10-09 Astrazeneca Ab Pipéridines substituées destinées à être utilisées dans le traitement d'infections bactériennes
EP2080761A1 (fr) 2008-01-18 2009-07-22 Glaxo Group Limited Composés
US7569726B2 (en) 2007-04-18 2009-08-04 Amgen Inc. Indanone derivatives that inhibit prolyl hydroxylase
US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
WO2010043714A1 (fr) 2008-10-17 2010-04-22 Glaxo Group Limited Composés azotés tricycliques utilisés comme agents antibactériens
US7728130B2 (en) 2005-12-09 2010-06-01 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity
WO2010081874A1 (fr) 2009-01-15 2010-07-22 Glaxo Group Limited Composés naphthyridine-2(1h)-one utiles comme antibactériens
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
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
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WO2016027249A1 (fr) 2014-08-22 2016-02-25 Glaxosmithkline Intellectual Property Development Limited Composés contenant de l'azote tricyclique pour le traitement de l'infection à neisseria gonorrhoeae
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
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US8178681B2 (en) 2004-10-28 2012-05-15 Shionogi & Co., Ltd. 3-carbamoyl-2-pyridone derivatives
US8367666B2 (en) 2004-10-28 2013-02-05 Shionogi & Co., Ltd. 3-carbamoyl-2-pyridone derivatives
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US7728130B2 (en) 2005-12-09 2010-06-01 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity
WO2007115947A1 (fr) 2006-04-06 2007-10-18 Glaxo Group Limited Derives de pyrrolo-quinoxalinone en tant qu'agents antibacteriens
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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
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
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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
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
EP2080761A1 (fr) 2008-01-18 2009-07-22 Glaxo Group Limited Composés
WO2010043714A1 (fr) 2008-10-17 2010-04-22 Glaxo Group Limited Composés azotés tricycliques utilisés comme agents antibactériens
WO2010081874A1 (fr) 2009-01-15 2010-07-22 Glaxo Group Limited Composés naphthyridine-2(1h)-one utiles comme antibactériens
WO2016027249A1 (fr) 2014-08-22 2016-02-25 Glaxosmithkline Intellectual Property Development Limited Composés contenant de l'azote tricyclique pour le traitement de l'infection à neisseria gonorrhoeae
EP3639824A1 (fr) 2014-08-22 2020-04-22 GlaxoSmithKline Intellectual Property Development Limited Composés tricyclique contenant de l'azote pour le traitement de l'infection à neisseria gonorrhoeae
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