WO2010064705A1 - Nouveau dérivé de dihydropyranopyrimidine substitué en position 7 ayant une activité antagoniste du récepteur h4 - Google Patents

Nouveau dérivé de dihydropyranopyrimidine substitué en position 7 ayant une activité antagoniste du récepteur h4 Download PDF

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WO2010064705A1
WO2010064705A1 PCT/JP2009/070389 JP2009070389W WO2010064705A1 WO 2010064705 A1 WO2010064705 A1 WO 2010064705A1 JP 2009070389 W JP2009070389 W JP 2009070389W WO 2010064705 A1 WO2010064705 A1 WO 2010064705A1
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克巳 久保田
成宏 浅野
貴士 高田
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大日本住友製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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
    • A61P37/08—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 has an excellent H4 receptor antagonistic action, allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, Novel dihydropyranopyrimidine derivatives useful as therapeutic or preventive agents for neurological diseases, chronic obstructive pulmonary disease, cancer, sepsis and the like, more specifically, novel dihydropyrano [4,3- d] Pyrimidine derivatives and their pharmaceutical use.
  • Allergic diseases such as allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, or chronic bronchitis are mainly caused by allergic effects, but eosinophils over time Inflammatory cells mainly composed of infiltrate the affected area and show an inflammatory image, and in some cases, it becomes more painful and itchy.
  • antiallergic agents such as antihistamines (H1 receptor antagonists) are widely used as symptomatic therapeutic agents.
  • conventional antiallergic agents often do not provide a sufficient therapeutic effect on inflammation itself. For this reason, in addition to antiallergic agents, treatments using steroidal agents that are anti-inflammatory agents are often performed.
  • Steroids that are anti-inflammatory agents are also used for inflammatory diseases such as ulcerative colitis, Crohn's disease, rheumatism, and chronic obstructive pulmonary disease.
  • conventional steroids have side effects that cause problems such as infectivity, adrenal atrophy, osteoporosis, diabetes, and childhood growth disorders.
  • steroids do not have analgesic action or anti-pruritic action, they are not effective against itching in atopic dermatitis. Therefore, development of an antiallergic agent having both anti-inflammatory and anti-pruritic effects and a new anti-inflammatory agent is desired.
  • H4 receptor H4 receptor having histamine as a ligand has been identified, and this H4 receptor is expressed in blood cells such as eosinophils, mast cells, dendritic cells, and Th2 cells. It has become clear. Further, as an action of an H4 receptor antagonist, it inhibits migration of inflammatory cells such as eosinophils and mast cells (see, for example, Non-Patent Document 1), and acts on the antigen presentation process of T cells, thereby causing IgE of B cells. Has been reported to suppress the production of (see, for example, Non-Patent Document 2). Therefore, H4 receptor antagonists are expected to have antiallergic and / or anti-inflammatory effects. In addition, H4 receptor antagonists have been reported to have analgesic action and anti-pruritic action (see, for example, Non-Patent Document 3) and action to stop the cell cycle (see, for example, Non-Patent Document 4).
  • Dihydropyranopyrimidine derivatives have been reported in several references.
  • the compound is represented by the formula (A):
  • Patent Document 2 Has been reported (see Patent Document 2). However, these literatures do not report derivatives having substituents on the 5-position, 7-position and 8-position on dihydropyranopyrimidine and the influence of the substituents. On the other hand, recently, monocyclic and tricyclic pyrimidine derivatives having an action on the H4 receptor have been reported in several documents (Patent Documents 3, 4, 5, 6, 7, 8, 9, 10). , 11, and 12). However, these documents do not disclose bicyclic pyrimidine derivatives.
  • the problem to be solved by the present invention is to provide a novel compound having an H4 receptor antagonistic activity and useful as a therapeutic or prophylactic agent for allergic diseases, inflammatory diseases, pain, cancer, sepsis and the like. .
  • the present invention relates to a dihydropyranopyrimidine derivative having an H4 receptor antagonistic activity, or a pharmaceutically acceptable salt thereof, represented by the following items 1 to 40. That is, the present invention is as follows.
  • R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or an unsubstituted alkanoyl group having 1 to 11 carbon atoms.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and h are (i) h is an integer of 1 to 2, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted carbon.
  • h is an integer of 1 to 2
  • k is an integer of 1 to 2
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 15 and R 16 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted carbon atom of 3
  • the plurality of R 11 and R 12 are each independently the same or different.
  • n is an integer of 1 to 3
  • p, q and r are each independently an integer of 0 to 2
  • R 17 , R 18 , R 19 and R 20 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms
  • p is 2
  • R 17 and R 18 are each independently the same or different
  • R 8 is the same as described above.
  • R 8a1 and R 8a2 are (i) each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or (ii) together with the nitrogen atom to which each is bonded, may form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring; p is an integer from 0 to 2, s is an integer from 1 to 4, and t is an integer from 0 to 4. Here, when p is 0, t is an integer from 1 to 4.
  • R 17 , R 18 , R 19 and R 20 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms;
  • p is 2
  • s is an integer of 2 to 4
  • a plurality of R 17 , R 18 , R 19 and R 20 are all independently the same or different.
  • R 21 and R 22 are a hydrogen atom, and the other is —N (R 8a1 ) (R 8a2 );
  • R 8a1 and R 8a2 are (i) each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or (ii) together with the nitrogen atom to which each is bonded, may form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring; u is an integer of 0-2.
  • Yf a group represented by formula (Yf)
  • R 2 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms, substituted or unsubstituted Unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted A substituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group, or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic group An unsaturated
  • R 2 and R 3 together with the carbon atom to which they are attached may form a 3-8 membered carbon ring or a 5-8 membered heterocycle containing an oxygen atom
  • R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms.
  • Item 2 The compound according to item 1, wherein R 8 in formula (Ya) is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms. Or a pharmaceutically acceptable salt thereof.
  • R 1 is a group represented by the formula (Ya), Formula (Yc1) Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and p ′ is an integer of 1 to 2 And q ′ is an integer of 1 to 2.)
  • a group represented by formula (Yc2) (Wherein, r ′ is each independently an integer of 1 to 2, and p ′ and R 8 are the same as described above.)
  • a group represented by formula (Yd1) wherein R 8a1 and R 8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, p ′ Is the same as described above, s ′ is an integer of 1 to 3, and R 17 , R 18 , R 19 and
  • R 1 is the formula (Ya1) (Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms; h is an integer of 1 to 2. )
  • a group represented by formula (Ya2) (In the formula, g is an integer of 1 to 2, and R 8 and h are the same as described above.)
  • a group represented by formula (Ya3) (Wherein R 8 is the same as described above.)
  • a group represented by formula (Ya4) (Wherein R 8 is the same as described above.)
  • R 8a1 and R 8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, p ′ Is an integer from 1 to 2, and s ′ is an integer from 1 to 3.
  • a group represented by R 2 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms, substituted or Unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or un
  • Item 5 The compound according to Item 4, wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or a pharmaceutical thereof Acceptable salt.
  • R 1 represents the formula (Ya1) (Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, h is an integer of 1 to 2. )
  • Item 5 The compound according to Item 4, which is a group represented by: or a pharmaceutically acceptable salt thereof.
  • Item 7 The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 8 is an unsubstituted alkyl group having 1 to 10 carbon atoms.
  • R 1 is the formula (Yd2)
  • R 8a1 and R 8a2 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, p ′ is an integer of 1 to 2, s ′ is 1 to The compound of claim
  • R 2 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted cyclohexane having 3 to 10 carbon atoms
  • R 2 represents an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group, or an unsubstituted carbon atom having 7 to Item 14.
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms. .
  • Item 12 The compound according to any one of Items 1 to 8, wherein R 2 and R 3 together with the carbon atom to which each is bonded form a 3- to 8-membered ring, or a pharmaceutical product thereof Acceptable salt.
  • R 4 and R 5 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, substituted or unsubstituted, Item 13.
  • Item 14 The compound according to Item 13, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
  • Item 15 The compound according to Item 14, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are a hydrogen atom.
  • Item 16 The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein X is a hydrogen atom.
  • Item 17 The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein X is an amino group.
  • R 1 is a group represented by the formula (Ya) (wherein R 8 is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are all hydrogen atoms, and h is an integer of 1.) Or a group represented by the formula (Yd) (wherein R 8a1 and R 8a2 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, and p is 1 to 2).
  • R 2 is an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 10 carbon atoms, an unsubstituted aryl group, or an unsubstituted aralkyl group having 7 to 14 carbon atoms.
  • R 3 is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, or R 2 and R 3 together with the carbon atom to which each is bonded form a 3- to 8-membered carbocyclic ring.
  • R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms;
  • Item 2 The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein X is an amino group.
  • Item 19 The compound according to Item 18, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group represented by the formula (Ya).
  • Item 20 The compound of Item 18, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group represented by the formula (Yd).
  • Item 21 Item 18 to Item 20, wherein R 2 is an unsubstituted alkyl group having 1 to 10 carbon atoms, and R 3 is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
  • R 2 is an unsubstituted alkyl group having 1 to 10 carbon atoms
  • R 3 is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
  • Item 22 The compound according to any one of Items 18 to 20, wherein R 2 and R 3 together with the carbon atom to which each is bonded form a 3- to 8-membered carbocyclic ring, or a pharmaceutical thereof Acceptable salt.
  • Item 23 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 18 to 22, wherein R 4 , R 5 , R 6 and R 7 are all hydrogen atoms.
  • R 1a represents the formula (Ya5) (Wherein R 8a is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms.) Or a group represented by formula (Yd3) ( Wherein R 8a1 and R 8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms; Is an integer from 1 to 3.)
  • a group represented by R 2a is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group having 7 to 14 carbon atoms
  • R 3a is a hydrogen atom, a substituted or un
  • Item 25 The compound according to Item 24 or a pharmaceutically acceptable salt thereof, wherein R 8a is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
  • R 1a is represented by formula (Ya5) (wherein R 8a is a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms) or formula (Yd3) (wherein R 8a1 and R 8a2 each independently represents a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms, and s ′ is 1 or 2, and R 2a represents an unsubstituted carbon atom number.
  • R 3a is a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms, or R 2a and R 3a may form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring together with the carbon atom to which each is bonded, and X is a hydrogen atom or an amino group.
  • R 1a is a formula (Ya5) (wherein R 8a is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or an isobutyl group) or a formula (Yd3) (formula R 8a1 and R 8a2 are each independently a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group, and s ′ is 1 or 2.
  • R 2a is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, benzyl group or 2-phenylethyl group
  • R 3a is a hydrogen atom, methyl group, ethyl group, propyl group group, isopropyl group, butyl group, or an isobutyl group or pentyl group
  • R 2a and R 3a is cyclopentyl or cycloalkyl together with the carbon atoms bonded thereto May have built a cyclohexyl ring
  • X is hydrogen atom or an amino group.
  • Item 28 A pharmaceutical composition comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 29 A medicament comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 30 An H4 receptor antagonist comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 31 An antiallergic agent comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 32 An anti-inflammatory agent comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 33 A therapeutic agent for pain comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 34 An allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient, A therapeutic or prophylactic agent for asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, cancer, sepsis or chronic obstructive pulmonary disease.
  • Item 35 Use of the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of an antiallergic agent.
  • Item 36 Use of the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-inflammatory agent.
  • Item 37 Allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, cancer, sepsis or chronic obstructive pulmonary disease Alternatively, use of the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic agent.
  • Item 38 An antiallergic disease and / or an antiinflammatory disease characterized by administering an effective amount of the compound according to any one of Items 1 to 27, or a pharmaceutically acceptable salt thereof. Prevention or treatment method.
  • Item 39 The method for prevention or treatment according to Item 38, wherein the antiallergic disease is allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, or chronic bronchitis.
  • Item 40 The method for prevention or treatment according to Item 38, wherein the anti-inflammatory disease is ulcerative colitis, Crohn's disease, rheumatism, chronic obstructive pulmonary disease, or pain.
  • a novel therapeutic or preventive agent for allergic diseases, inflammatory diseases, pain, cancer, sepsis, which exhibits an antiallergic action and / or an antiinflammatory action as an H4 receptor antagonist Offering became possible.
  • Alkyl group means a linear or branched alkyl group having 1 to 10 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- Examples thereof include a butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Among them, preferred is an alkyl group having 1 to 8 carbon atoms.
  • Alkenyl group means a straight or branched alkenyl group having 2 to 10 carbon atoms, and specifically includes a vinyl group, 1-propenyl group, allyl group (2-propenyl group), isopropenyl group. (1-methylvinyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methylallyl group, 1-ethylvinyl group A 1-pentenyl group or a 1-hexenyl group can be exemplified. Among them, preferred is an alkenyl group having 2 to 6 carbon atoms.
  • alkynyl group represents a linear or branched alkynyl group having 2 to 10 carbon atoms, and specifically includes an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-butynyl group, Examples thereof include a methyl-2-propynyl group, a 2-butynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynyl group. Among them, preferred is an alkynyl group having 2 to 6 carbon atoms.
  • the “cycloalkyl group” represents a 3 to 10-membered saturated cycloalkyl group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. be able to. Of these, a 3- to 6-membered saturated cycloalkyl group is preferable.
  • cycloalkenyl group refers to a 4- to 8-membered cycloalkenyl group containing 1 to 2 double bonds in the ring, and specifically includes a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cyclohexyl group, and the like.
  • a ptenyl group or a cyclooctenyl group can be exemplified, and the bonding position is not particularly limited as long as it is chemically stable. Among them, preferred is a 5- to 6-membered cycloalkenyl group.
  • the “aryl group” represents an aryl group having 6 to 10 carbon atoms, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • “Aralkyl group” refers to an aralkyl group having 7 to 14 carbon atoms. Specific examples include a benzyl group, a phenethyl group, a 1-phenylethyl group, and a 2-phenylethyl group. Among them, preferred is an aralkyl group having 7 to 9 carbon atoms.
  • heteroaryl group also called an aromatic heterocyclic group, is 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms. It represents a monocyclic 5- or 6-membered heteroaryl group or a bicyclic 9- or 10-membered heteroaryl group containing an atom.
  • the bonding position is not particularly limited as long as it is chemically stable.
  • Halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • alkoxy group represents a straight or branched alkoxy group having 1 to 10 carbon atoms, and specifically includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec -Butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group or A decyloxy group etc. can be mentioned. Among them, preferred is an alkoxy group having 1 to 6 carbon atoms.
  • alkanoyl group is also called an acyl group or an alkylcarbonyl group, and represents a linear or branched alkanoyl group having 1 to 11 carbon atoms, and specifically includes a formyl group, an acetyl group, a propionyl group, a butyryl group.
  • preferred is an alkanoyl group having 1 to 6 carbon atoms.
  • alkanoyloxy group represents a straight or branched alkanoyloxy group having 1 to 11 carbon atoms, and specifically includes formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryl group. Examples thereof include an oxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, hexanoyloxy group, heptanoyloxy group, octanoyloxy group, nonanoyloxy group and decanoyloxy group. Among them, preferred is an alkanoyloxy group having 1 to 6 carbon atoms.
  • alkoxycarbonyl group represents a straight or branched alkoxycarbonyl group having 2 to 11 carbon atoms, and specifically includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxy group.
  • Carbonyl group isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, 1-methylbutoxycarbonyl group Hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group, decyloxycarbonyl group and the like. Among them, preferred is an alkoxycarbonyl group having 2 to 7 carbon atoms.
  • alkylthio group represents a linear or branched alkylthio group having 1 to 10 carbon atoms, specifically, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1-methylbutylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, decylthio group, etc. Can be mentioned. Among them, preferred is an alkylthio group having 1 to 6 carbon atoms.
  • Alkylsulfinyl group means a linear or branched alkylsulfinyl group having 1 to 10 carbon atoms, and specifically includes a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group.
  • Alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 10 carbon atoms, specifically, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl Group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, tert-pentylsulfonyl group, 1-methylbutylsulfonyl group, hexylsulfonyl group, heptyl A sulfonyl group, an octyl sulfonyl group,
  • a “saturated aliphatic heterocyclic group”, also referred to as a saturated aliphatic heterocyclic group, is selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms. Represents a 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group containing 1 to 4 heteroatoms.
  • the bonding position is not particularly limited as long as it is chemically stable.
  • an “unsaturated aliphatic heterocyclic group”, also called an unsaturated aliphatic heterocyclic group, consists of 0-4 nitrogen atoms, 0-2 oxygen atoms, and 0-2 sulfur atoms. It represents a 4- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group containing 1 to 4 heteroatoms and containing 1 to 2 double bonds. Specific examples include 2-pyrrolinyl group, 3-pyrrolinyl group, 2-imidazolinyl group, 3-imidazolinyl group, 2-pyrazolinyl group and 3-pyrazolinyl group.
  • the bonding position is not particularly limited as long as it is chemically stable.
  • aryloxy group represents an aryloxy group having 6 to 10 carbon atoms, and specific examples include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.
  • heteroaryl part of the “heteroaryloxy group” is the same as the “heteroaryl group”. Specific examples include a furyloxy group, a thienyloxy group, and a pyrrolyloxy group.
  • the substituent is selected from the following groups (Ii) to (Iv), and 1 to 5 identical or different substituents: Has replaced: (Ii) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group; (I-ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (I-iii) an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group [each group in the group (I-iii) is a halogen atom, a hydroxyl
  • (I-iv) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group
  • the groups (I-iv) are represented by the following groups (1) to ( 5) may be substituted with the same or different 1 to 5 substituents selected from: (1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group; (2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in
  • each group (Iv) is the same or different from 1 to 5 selected from the following groups (1) to (5) May be substituted with: (1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group; (2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (each group in group (3) is a halogen atom, a hydroxyl group, a carboxyl group, They may be substituted with 1 to 5 identical or different substituents
  • the substituent is selected from the following groups (II-i) to (II-v), and the same or different substituents are 1 to 5 Is replaced: (II-i) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group; (II-ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (II-iii) alkyl group, alkenyl group, alkynyl group, alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group [each group in the group (II-
  • (II-iv) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group
  • the groups in the group (II-iv) are represented by the following groups (1) to ( 3) may be substituted with the same or different 1 to 5 substituents selected from: (1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group; (2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl
  • each group in group (II-v) is the same or different selected from the following groups (1) to (3) Optionally substituted with 1 to 5 substituents: (1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group; (2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, It may be substituted with the same or
  • the substituent is selected from the following groups (III-i) to (III-v), 1 to 5 different substituents are substituted: (III-i) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group; (III-ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (III-iii) alkyl group, alkenyl group, alkynyl group, alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group [each group in the group (III-iii) is , Halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group; (III-ii) a substituted or un
  • each group (III-iv) is the same or selected from the following groups (1) to (3)]
  • substituents (1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group; (2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl
  • each group in group (III-v) is the same or different selected from the following groups (1) to (4) Optionally substituted with 1 to 5 substituents: (1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group; (2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group; (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, They may be substituted with the same or different
  • the substituent is selected from the following groups (IV-i) to (IV-iii), and the same or different substituents are 1-2 replacements: (IV-i) an alkyl group, an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group [each group in group (IV-i) is a substituent selected from a halogen atom, a hydroxyl group, a carboxyl group, and an unsubstituted alkoxy group May be the same or different and 1 to 5 may be substituted.
  • (IV-ii) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group
  • the groups (IV-ii) are represented by the following groups (1) to ( 5) optionally substituted with 1 to 5 substituents selected from the same or different: (1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group; (2) Amino group optionally substituted with the same or different 1 to 2 alkyl groups, carbamoyl group optionally substituted with the same or different 1 to 2 alkyl groups, 1 to 2 identical or different A sulfamoyl group optionally substituted with an alkyl group of (3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfiny
  • each group (IV-iii) is the same or different selected from the following (1) to (4)]
  • the “sulfonic acid ester group” is selected from the group consisting of, for example, an alkylsulfonyloxy group (such as methanesulfonyloxy group), a halogenoalkylsulfonyloxy group (such as trifluoromethanesulfonyloxy group), a methyl group, a methoxy group, and a halogen atom.
  • an alkylsulfonyloxy group such as methanesulfonyloxy group
  • a halogenoalkylsulfonyloxy group such as trifluoromethanesulfonyloxy group
  • R 2 and R 3 together with the carbon atom to which each is bonded is a 3- to 8-membered carbon ring or a 5- to 8-membered heterocycle containing an oxygen atom.
  • “Constructed” means that the carbon atom to which R 2 and R 3 are bonded is the carbon atom at the 7-position of the 7,8-dihydro-5H-pyrano [4,3-d] pyrimidine ring (R 2 and R 3 are (Bonded carbon atom) is a spiro atom and means a spiro bond with a 3-8 membered carbon ring or a 5-8 membered heterocycle containing an oxygen atom.
  • the 3- to 8-membered carbocycle include a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cycloheptyl ring, and a cyclooctyl ring, and a 5- to 8-membered heterocycle containing an oxygen atom.
  • Specific examples of the ring include a tetrahydrofuran ring and a tetrahydropyran ring. Examples of the compound represented by the definition include the following:
  • R 4 and R 5 together may be either an oxo group, or R 6 and R 7 together may be an oxo group, and R 4 and R 5 and R 6 and R 7 together may be an oxo group. It may be a group.
  • h is an integer of 1 to 2
  • R 9 , R 10 , R 11 , R 12 , R 14 , R 15 and R 16 are each independently , A hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and R 13 and R 15 together represent — (CH 2 ) 2 — Or to form — (CH 2 ) 3 —
  • h is an integer of 1 to 2
  • R 10 , R 11 , R 12 , R 14 , R 15 and R 16 are all hydrogen atoms; 9 and R 13 together form — (CH 2 ) g — (wherein g is an integer of 1 to 2).
  • R 8a1 and R 8a2 are combined with the nitrogen atom to which each is bonded to form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or A group forming a perhydroazocine ring will be described.
  • R 8a1 and R 8a2 together with the nitrogen atom to which each is bonded to form an aziridine ring include the following:
  • R 21 and R 22 are a hydrogen atom, and the other is —N (R 8a1 ) (R 8a2 ), wherein R 8a1 and R 8a2 , together with the nitrogen atom to which each is bonded, describes a group that forms an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring.
  • R 8a1 and R 8a2 together with the nitrogen atom to which they are bonded form the aziridine ring
  • R 1 Preferable specific examples of R 1 include the following groups (R 8 has the same meaning as in item 1).
  • R 1 is preferably a group represented by the above formula (Ya) and a group represented by the formula (Yd), more preferably a group represented by the formula (Ya1) and It is a group represented by the formula (Yd2). Even more preferred are a group represented by the formula (Ya5) and a group represented by the formula (Yd3).
  • R 8 , R 8a1 and R 8a2 are preferably each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms. More preferably a hydrogen atom or a methyl group.
  • R 2 is preferably a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted group.
  • 9 is an aralkyl group, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a benzyl group, or a 2-phenylethyl group.
  • R 3 is preferably a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, more preferably an unsubstituted alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom, A methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group; It is also preferred when R 2 and R 3 together with the carbon atom to which each is bonded form a 3- to 8-membered carbocycle (preferably a cyclopentane ring or cyclohexane ring).
  • R 4 , R 5 , R 6 and R 7 are preferably each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, and more preferably a hydrogen atom.
  • R 8 is preferably a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom or a methyl group.
  • R 8b1 and R 8b2 are preferably a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom or a methyl group. is there.
  • X is preferably a hydrogen atom or an amino group, particularly preferably an amino group.
  • R 9 , R 10 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are preferably hydrogen atoms.
  • R 11 , R 12 , R 13 and R 14 are preferably each independently a hydrogen atom or a methyl group. When a substituent such as R 8 is present on the adjacent nitrogen atom, R 11 , R 12 , R 13 and R 14 are preferably hydrogen atoms.
  • This invention compound represented by Formula (1) is manufactured by the manufacturing method shown below using the compound which can be manufactured by combining a commercially available compound, a well-known compound, or a compound which can be manufactured from a commercially available compound or a well-known synthesis method from a well-known compound. can do.
  • Lv represents a leaving group (for example, a halogen atom, a sulfonate group, an alkylsulfinyl group, an alkylsulfonyl group, etc.).
  • Compound (1) can be obtained by reacting compound (1-1) with compound (1-2) in the presence or absence of a base.
  • the base include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride and the like.
  • Metal hydrides, metal alkoxides such as sodium methoxide, organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, halogen solvents such as dichloromethane and chlorobenzene, methanol, ethanol, and 2-propanol. And an aprotic solvent such as hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperidone, and the like. Alternatively, a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • R 23 and R 24 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 3 to 10 carbon atoms, a substituted or unsubstituted group.
  • the ketoester (1-1-2) can be obtained by treating the ketone (1-1-1) with a base and subsequently reacting it with a carbonate ester or a cyanoformate ester.
  • a base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, metal amides such as lithium diisopropylamide, lithium hexamethyldisilazide, and potassium hexamethyldisilazide.
  • This reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, And aprotic solvents such as N-methylpiperazine. Alternatively, a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • Ketone (1-1-1) is, for example, J. Chem.Soc. Perkin Trans.2, 1992, 799-803., J. Med. Chem. 1993, 36, 295-296., Chem. Ber., 1955, 1053-1059., J. Am. Chem.Soc. 1982, 104, 4666-4671, J. Fluorine Chem. 1983, .1-18., U.S. published patent US2007 / 173508 A1, U.S. published patent US5208259 A1, etc. Can be synthesized by the methods described in 1) and methods analogous thereto, or can be purchased.
  • Ketoester (1-1-2) can also be synthesized by treating diester (1-1-4) with a base.
  • the base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide, and potassium hexamethyldisilazide.
  • metal hydrides such as sodium hydride
  • metal alkoxides such as sodium methoxide and potassium tert-butoxide
  • metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide
  • potassium hexamethyldisilazide can be used. This reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, And aprotic solvents such as N-methylpiperazine. Alternatively, a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about -90 ° C to 100 ° C.
  • Diesters (1-1-4) are, for example, J. Am. Chem. Soc. 1960, 82. 2050-2052. Zhurnal Obshchei Khimii, 1954, 24, 319-327., J. Am. Chem. Soc. 1997 , 119, 4285-4291. And the like and methods based thereon, or can be purchased.
  • Compound (1-1-3) can be obtained by reacting ketoester (1-1-2) with a guanidine derivative or a salt thereof in the presence or absence of a base.
  • a base include alkali metal carbonates such as sodium carbonate and potassium carbonate cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metals such as sodium hydride Metal alkoxides such as hydride, sodium methoxide and potassium tert-butoxide, organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, hexane, Examples include aprotic solvents such as heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile and N-methylpiperazine, halogen solvents such as chloroform and chlorobenzene, and water. Alternatively, a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • Compound (2) is compound (1-1-3) obtained by reacting sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesylate acid chloride, sulfonic acid anhydride such as trifluoromethanesulfonic anhydride, phosphorus oxychloride , Thionyl chloride and the like in the presence or absence of a base. This reaction can be carried out in a solvent or without a solvent.
  • sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesylate acid chloride
  • sulfonic acid anhydride such as trifluoromethanesulfonic anhydride, phosphorus oxychloride , Thionyl chloride and the like
  • examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, halogen solvents such as chloroform, dichloromethane, chlorobenzene, acetonitrile, hexane , Aprotic solvents such as heptane and toluene.
  • a mixed solvent thereof may be used.
  • examples of the base include organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, N, N-dimethylaniline, and the like.
  • the reaction temperature is selected, for example, from the range of about -78 ° C to 250 ° C.
  • Compound (1-2-2) can be synthesized by reducing compound (1-2-1) according to a conventional method.
  • Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc or Raney nickel, organophosphorus compound reagents such as triphenylphosphine, boron reagents such as diborane, metal hydrides such as silane and tin hydride.
  • the catalyst that can be used include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, and catalysts placed on a carrier such as a polymer. The reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about -90 ° C to 200 ° C.
  • Ketone (3) can be synthesized by oxidizing compound (1-2-2) according to a conventional method.
  • oxidizing agents include metal oxides such as chromic acid and salts thereof, sulfur trioxide / pyridine complexes, chloric acid, hypochlorous acid and salts thereof, and the like, and combinations of oxalyl chloride and dimethyl sulfide used in Swern oxidation. Can be used. This reaction can be carried out in a solvent.
  • the solvent examples include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperazine, and the like.
  • ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperazine, and the like.
  • Aprotic solvents halogen solvents such as chloroform, dichloromethane and chlorobenzene, water and the like.
  • a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the
  • Ketone (3) can also be synthesized by selectively reducing the olefin in compound (1-2-1) according to a conventional method.
  • Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc, and Raney nickel, organophosphorus compound reagents such as triphenylphosphine, boron reagents such as diborane, and metal hydrides such as silane and tin hydride.
  • the catalyst that can be used include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, and catalysts placed on a carrier such as a polymer. The reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about ⁇ 90 to 200 ° C.
  • Compound (1-2-1) can be synthesized by, for example, the method described in Chemistry Letters, 2003, 608-609., Synlett, 1997, 79-80. Is possible.
  • R 25 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms.
  • m is an integer of 1 to 2.
  • Compound (1-3-2) can be obtained by treating ketone (1-1-1) with a base, reacting with carbon disulfide, and subsequently alkylating with an alkyl halide reagent.
  • the base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide, and potassium hexamethyldisilazide.
  • This reaction can be carried out in a solvent or without a solvent.
  • alkyl halide reagent examples include alkyl iodide reagents such as methyl iodide, ethyl iodide, allyl bromide, and benzyl bromide, and alkyl bromide.
  • examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, And aprotic solvents such as N-methylpiperazine. Alternatively, a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about ⁇ 90 to 100 ° C.
  • Compound (1-3-3) can be obtained by reacting compound (1-3-2) with a guanidine derivative or a salt thereof in the presence or absence of a base.
  • reaction conditions the same conditions as in the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • Compound (4) can be synthesized by oxidizing compound (1-3-3) with a peroxide such as m-chloroperbenzoic acid, peracetic acid or hydrogen peroxide, or a metal oxide such as chromic acid. .
  • a peroxide such as m-chloroperbenzoic acid, peracetic acid or hydrogen peroxide, or a metal oxide such as chromic acid.
  • This reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, halogen solvents such as dichloromethane and chlorobenzene, methanol, ethanol, and 2-propanol.
  • alcoholic solvents such as butanol, aprotic solvents such as hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile and N-methylpiperidone, and water.
  • a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • Lv ′ represents a leaving group (for example, a halogen atom, a sulfonate group, an alkylsulfinyl group, an alkylsulfonyl group, etc.).
  • Compound (5) can be synthesized by reacting compound (2-1) with ammonia or a salt thereof in the presence or absence of a base.
  • reaction conditions the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.
  • Compound (5) can also be synthesized by reacting compound (2-1) with sodium azide, a hydrazine derivative or a salt thereof, a hydroxylamine derivative or a salt thereof in the presence or absence of a base, and then reducing the compound. it can.
  • a base include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride and the like.
  • Metal hydrides metal alkoxides such as sodium methoxide
  • organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine
  • This reaction can be carried out in a solvent or without a solvent.
  • the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, halogen solvents such as dichloromethane and chlorobenzene, methanol, ethanol, and 2-propanol.
  • an aprotic solvent such as hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperidone, and the like.
  • a mixed solvent thereof may be used.
  • the reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc, and Raney nickel, organophosphorus compound reagents such as triphenylphosphine, boron reagents such as diborane, and metal hydrides such as silane and tin hydride.
  • Examples of the catalyst that can be used include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, polymers and the like.
  • the reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • m ′ is an integer of 1 to 2.
  • Compound (2-1-3) can be synthesized by reacting compound (2-1-1) and compound (2-1-2) in the presence or absence of a base.
  • reaction conditions the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.
  • Compound (2-1-4) can be synthesized by oxidizing compound (2-1-1).
  • reaction conditions conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.
  • Compound (6) can be synthesized by oxidizing compound (2-1-3).
  • reaction conditions conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.
  • Compound (6) can also be synthesized by reacting compound (2-1-4) and compound (2-1-2) in the presence or absence of a base.
  • reaction conditions the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.
  • R 2, R 3, R 4, R 5, R 6, R 7, R 23, R 25 and Lv a are as defined above.
  • Compound (2-2-2) can be obtained by reacting compound (1-1-2) with thiourea or a salt thereof in the presence or absence of a base.
  • reaction conditions conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • Compound (2-2-3) is obtained by reacting Compound (2-2-2) with a halogenated alkyl compound such as methyl iodide, ethyl iodide, allyl bromide, benzyl bromide or the like in the presence or absence of a base. Can be obtained by reacting under.
  • a halogenated alkyl compound such as methyl iodide, ethyl iodide, allyl bromide, benzyl bromide or the like in the presence or absence of a base.
  • the base examples include alkali metal carbonates such as sodium carbonate and potassium carbonate cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metals such as sodium hydride Metal alkoxides such as hydride, sodium methoxide and potassium tert-butoxide, organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent.
  • alkali metal carbonates such as sodium carbonate and potassium carbonate cesium carbonate
  • alkaline earth metal carbonates such as calcium carbonate
  • metal hydroxides such as sodium hydroxide and potassium hydroxide
  • metals such as sodium hydride
  • Metal alkoxides such as hydride, sodium methoxide and potassium tert-butoxide
  • organic bases such as triethylamine, diisopropylethy
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, hexane, Examples include aprotic solvents such as heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile and N-methylpiperazine, halogen solvents such as chloroform and chlorobenzene, and water. Alternatively, a mixed solvent thereof may be used.
  • ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme
  • alcohol solvents such as methanol, ethanol, 2-propanol and butanol
  • hexane examples include aprotic solvents such as heptane, toluene, dimethylformamide, dimethyl
  • Compound (2-2-3) can be obtained by reacting compound (1-1-2) with alkylisothiourea or a salt thereof in the presence or absence of a base.
  • reaction conditions conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • Compound (7) is obtained by converting compound (2-2-3) from sulfonic acid chlorides such as p-toluenesulfonic acid chloride and mesylic acid chloride, sulfonic acid anhydrides such as trifluoromethanesulfonic anhydride, phosphorus oxychloride , Thionyl chloride and the like in the presence or absence of a base.
  • sulfonic acid chlorides such as p-toluenesulfonic acid chloride and mesylic acid chloride
  • sulfonic acid anhydrides such as trifluoromethanesulfonic anhydride, phosphorus oxychloride , Thionyl chloride and the like in the presence or absence of a base.
  • the reaction conditions the same conditions as in the synthesis of compound (2) in formula (A-1-1) can be used.
  • R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 23 and Lv a are as defined above.
  • Lv b represents a halogen or sulfonate group.
  • Compound (2-3-2) can be obtained by reacting compound (1-1-2) with urea or a salt thereof in the presence or absence of a base.
  • reaction conditions conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • the compound (2-3-3) is obtained by converting the compound (2-3-2) into a sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesyl acid chloride, or a sulfonic acid anhydride such as trifluoromethanesulfonic anhydride. , Phosphorus oxychloride, thionyl chloride and the like in the presence or absence of a base.
  • the same conditions as in the synthesis of compound (2) in formula (A-1-1) can be used.
  • Compound (8) can be obtained by reacting compound (2-3-3) and compound (2-3-4) in the presence or absence of a base.
  • reaction conditions the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.
  • R 26 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms.
  • Compound (2-4-2) can be obtained by reacting compound (1-3-2) with thiourea or a salt thereof in the presence or absence of a base.
  • reaction conditions conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • Compound (2-4-3) is obtained by reacting Compound (2-4-2) with a halogenated alkyl compound such as methyl iodide, ethyl iodide, allyl bromide, benzyl bromide or the like in the presence or absence of a base. Can be obtained by reacting under.
  • a halogenated alkyl compound such as methyl iodide, ethyl iodide, allyl bromide, benzyl bromide or the like.
  • Compound (2-4-3) can also be synthesized by reacting compound (1-3-2) with alkylisothiourea or a salt thereof in the presence or absence of a base.
  • reaction conditions conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • Compound (9) can be synthesized by oxidizing compound (2-4-3).
  • reaction conditions conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.
  • Compound (2-5-2) can be obtained by reacting compound (1-3-2) with urea or a salt thereof in the presence or absence of a base.
  • reaction conditions conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.
  • the compound (2-5-3) is obtained by converting the compound (2-5-2) into a sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesyl acid chloride, or a sulfonic acid anhydride such as trifluoromethanesulfonic anhydride. , Phosphorus oxychloride, thionyl chloride and the like in the presence or absence of a base.
  • the same conditions as in the synthesis of compound (2) in formula (A-1-1) can be used.
  • Compound (2-5-4) can be synthesized by oxidizing compound (2-5-3).
  • reaction conditions conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.
  • Compound (10) can be synthesized by reacting compound (2-5-4) with compound (2-5-5).
  • reaction conditions the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.
  • Compound (2-6-2) can be obtained by reacting compound (2-5-3) with ammonia or a salt thereof in the presence or absence of a base.
  • reaction conditions the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.
  • Compound (2-6-2) is obtained by reacting compound (2-5-3) with sodium azide, a hydrazine derivative or a salt thereof, a hydroxylamine derivative or a salt thereof in the presence or absence of a base, It can also be synthesized by reduction.
  • reaction conditions the same conditions as in the synthesis of compound (5) in formula (B-1) can be used.
  • Compound (11) can be synthesized by oxidizing compound (2-6-2).
  • reaction conditions conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.
  • Compound (2-7-2) can be synthesized by reducing compound (2-5-3).
  • Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc or Raney nickel, boron reagents such as borane tetrahydrofuran complex, and hydrides such as sodium borohydride or sodium cyanoborohydride.
  • Reagents can be used, and examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, polymers and the like. This reaction can be carried out in a solvent or without a solvent.
  • examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.
  • Compound (12) can be synthesized by oxidizing compound (2-7-2).
  • reaction conditions conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Lv b are as defined above].
  • the compound (13) can be obtained by reducing the compound (2-1).
  • reaction conditions conditions similar to those for the synthesis of compound (2-7-2) in formula (B-5-2) can be used.
  • compound (1-2), compound (2-1-2), compound (2-3-4) and compound (2-5-5) are all the same or different and have the formula: A compound represented by R 1 —H (wherein R 1 is as defined above).
  • the compound of the present invention represented by the formula (1), an intermediate thereof, or a raw material compound thereof has a functional group
  • a person skilled in the art can use the production method 1, the production method 2 or the production method 3 as necessary.
  • a substituent introduction reaction or a functional group conversion reaction can be performed. These were described in “Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen)” or “Comprehensive Organic Transformation, RC Rallock, (VCH Publishers, Inc, 1989)”. A method or the like can be used.
  • functional group conversion reactions include acylation or sulfonylation using acid halides or sulfonyl halides, reactions involving alkylating agents such as alkyl halides, hydrolysis reactions, Friedel-Crafts (Friedel -Crafts reaction and Wittig reaction, carbon-carbon bond formation reaction, reductive amination reaction, carbon-nitrogen bond formation reaction such as amine alkylation reaction, oxidation or reduction reaction and the like.
  • the compound of the present invention represented by the formula (1) and the intermediate thereof have a functional group such as an amino group, a carboxyl group, a hydroxyl group, or an oxo group
  • protection or deprotection is performed as necessary. Can be done. Suitable protecting groups, protecting methods and deprotecting methods are described in detail in “Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc .; 1990)”.
  • the compound of the present invention represented by the formula (1) and its intermediate can be separated and purified by methods known to those skilled in the art. Examples thereof include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography, preparative liquid chromatography, etc.), recrystallization and the like.
  • the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • Ketone solvents such as dichloromethane and chloroform
  • hydrocarbon solvents such as hexane
  • aprotic solvents such as dimethylformamide and acetonitrile
  • water or a mixed solvent thereof.
  • the methods described in Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) Vol. 1 can be used.
  • the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular two-spectrum spectroscopy, and mass. It can be easily done by analytical methods.
  • the compound of the present invention represented by the formula (1) and the pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon.
  • Optical isomers exist.
  • the compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage.
  • optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process.
  • the solvent is an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol). , Ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, and mixed solvents thereof), optically active acids (for example, mandelic acid, N-benzyloxyalanine, monocarboxylic acid such as lactic acid, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acid such as malic acid, sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.) to form a salt
  • an inert solvent for example, an alcohol solvent such as methanol, ethanol, 2-propanol.
  • Ether solvents such as diethyl ether, ester solvents such as ethyl acetate
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.
  • the optical resolution can also be carried out by forming a salt using an organic amine or the like.
  • the temperature for forming the salt is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield.
  • the amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate.
  • Crystals in an inert solvent as necessary for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc.
  • an inert solvent for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc.
  • a high purity optically active salt can be obtained.
  • the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.
  • an optically active acid for example, mandelic acid, N— A monocarboxylic acid such as benzyloxyalanine or lactic acid, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acid such as malic acid, sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.
  • Optical resolution can be performed by a diastereomer method.
  • an optically active alcohol such as l-menthol
  • an optically active amine such as 1-phenylethylamine
  • the compound or intermediate of the present invention can be optically resolved by HPLC using a chiral column.
  • the compound of the present invention represented by the formula (1) can form a pharmaceutically acceptable salt thereof as a medicine if necessary. Since the compound of the present invention represented by formula (1) has a basic secondary or tertiary amino group, it can form salts with various acids.
  • the pharmaceutically acceptable salt in this case include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, fumarate, maleate , Succinate, oxalate, citrate, malate, tartrate, aspartate, salt with organic carboxylic acid such as glutamate, methanesulfonic acid, benzenesulfonate, p-toluenesulfonate And salts with sulfonic acids such as hydroxybenzene sulfonate and dihydroxybenzene sulfonate.
  • inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, formate, a
  • salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (1) with an acid.
  • compound represented by Formula (1) has acidic functional groups, such as a carboxyl group
  • various bases and salts can be formed.
  • the pharmaceutically acceptable salt in this case include alkali metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt, ammonium salt and the like.
  • These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (1) with a base.
  • the present invention also includes solvates such as a hydrate or ethanol solvate of the compound of the present invention represented by formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention includes all existing stereoisomers such as tautomers, optical isomers and geometric isomers of the compound of the present invention represented by the formula (1), and crystal forms of all embodiments. Yes.
  • the compound of the present invention represented by the formula (1) and a pharmaceutically acceptable salt thereof can act as an antagonist of the H4 receptor. Therefore, the compounds and the salts are useful as therapeutic or preventive agents for allergic diseases or inflammatory diseases or pain or cancer or sepsis, that is, antiallergic agents or antiinflammatory agents or analgesics or anticancer agents.
  • allergic diseases and / or inflammatory diseases include allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis and the like.
  • inflammatory diseases include ulcerative colitis, Crohn's disease, rheumatism, chronic obstructive pulmonary disease, and sepsis.
  • the antiallergic agent, anti-inflammatory agent, analgesic agent or anticancer agent of the present invention can be administered orally or parenterally.
  • it can be administered in a commonly used dosage form, such as a tablet, capsule, pill, granule, fine granule, powder, liquid, syrup, suspension, etc.
  • parenteral administration include aqueous injections, oily injections, suppositories, nasal preparations, transdermal absorption agents [lotions, emulsions, ointments, creams] , Jelly preparations, gel preparations, patches (tape preparations, transdermal patch preparations, poultice preparations, etc.), powders for external use, etc.].
  • preparations can be prepared using a conventionally known technique, and can contain a nontoxic and inert carrier or excipient usually used in the pharmaceutical field. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, eye drops and the like.
  • a pharmaceutical carrier a substance which is commonly used in the pharmaceutical field and does not react with the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used. That is, the pharmaceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof includes an excipient, a binder, a lubricant, a stabilizer, a disintegrant, a buffer, and a solubilizing agent.
  • Tonicity agent solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier, gelling agent, soothing agent, preservative , Plasticizers, percutaneous absorption accelerators, anti-aging agents, moisturizers, preservatives, fragrances and the like, and can contain two or more types of pharmaceutical carrier additives as appropriate. it can.
  • carrier additives for pharmaceutical preparations include lactose, inositol, glucose, sucrose, fructose, mannitol (mannit), dextran, sorbitol (sorbit), cyclodextrin, starch (potato starch, corn starch, amylopectin, etc.) , Partially pregelatinized starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, sodium alginate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, Hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , Hydroxyethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, gelatin, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium steacetate
  • antiallergic agents or anti-inflammatory agents include ketotifen, epinastine, fexofenadine, cetirizine antihistamines, leukotriene antagonists such as montelukast, zafirlukast, pranlukast, and the like.
  • anti-inflammatory agent include NSAIDs such as diclofenac, aspirin and loxoprofen, and COX-2 inhibitors such as celecoxib.
  • analgesics include paracetamol and the like in addition to the NSAIDs listed above.
  • anticancer agents include taxol, cyclophosphamide, methotrexate, doxorubicin and the like.
  • the dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, and the like.
  • the range of about 300 mg can be administered in one or several divided doses.
  • the range of about 0.1 to about 500 mg, preferably about 1 to about 100 mg can be administered once or divided into several times.
  • methyl cyanoformate (5.00 mmol) was added and stirred for 2 hours. After completion of the reaction, the mixture was extracted with an ethyl acetate-ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Guanidine carbonate (5.00 mmol) was added to a solution of the resulting residue in ethanol (14 ml), and the mixture was stirred for 2 hours with heating under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and methanol was added to the resulting residue and filtered.
  • Lithium diisopropylamide prepared from a solution of compound 8B 897 mg (7.00 mmol) in tetrahydrofuran (12 ml) at -78 ° C from 1.66 M n-butyllithium in hexane (7.70 mmol) and diisopropylamine (7.70 mmol) Of tetrahydrofuran (6 ml) was added dropwise. After 1 hour, ethyl cyanoformate (7.70 mmol) was added and stirred for 2 hours.
  • the title compound was obtained by reacting and treating in the same manner as in Reference Example 8 using cyclohexanecarbaldehyde, diethyl ketone, cyclohexanone, dihydrocinnamaldehyde or acetaldehyde.
  • Example 1 (Production method A) 7,7-Dimethyl-4- (4-methylpiperazin-1-yl) -7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (compound of Reference Example 1) 100 mg (0.512 mmol) was added to phosphorus oxychloride ( 2.0 ml) was added and the mixture was stirred at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure.
  • Example 2 7,7-Dimethyl-4- [3- (methylamino) azetidin-1-yl] -7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine
  • Phosphorous oxychloride (1.3 ml) was added to 65 mg (0.333 mmol) of the compound of Reference Example 1, and the mixture was stirred at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue and azeotropic distillation was performed, and then azeotropic distillation was performed again using methanol.
  • Example 3 4- (4-Methylpiperazin-1-yl) -7-phenyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine 2-Amino-7-phenyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (compound of Reference Example 2) 50 mg (0.206 mmol) and phosphorus oxychloride (1.0 ml) ) was added and stirred at 100 ° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure.
  • Example 4-10 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 2 (Production Method B) or Example 3 (Production Method C) to obtain the compound of Example 4-10 below.
  • 4- (4-Methylpiperazin-1-yl) -7 By optically resolving 81 mg (0.278 mmol) of 2-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine with chiral HPLC, (+)-form (26.1 mg, Yield 32%, 98.2% ee) and ( ⁇ )-isomer (21.7 mg, yield 27%, 94.3% ee) were obtained as white solids, respectively.
  • Example 9 4- (4-Methylpiperazin-1-yl) -7-cyclohexyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; Process C (45% yield); 1 H NMR (300 MHz, CDCl 3 , ⁇ ppm): 4.62 (2H, s), 4.53 (2H, s), 3.41 (1H, m), 3.31 (4H, m), 2.66 (2H, m), 2.51 (2H , m), 2.43 (2H, m), 2.32 (3H, s), 2.01 (1H, m), 1.74 (4H, m), 1.48 (1H, m), 0.97-1.30 (5H, m).
  • Examples 11-13 The corresponding starting materials were used and reacted and treated in the same manner as in Example 2 (Production Method B) or Example 3 (Production Method C) to give the following Examples 11-13.
  • Examples 15 and 16 The corresponding starting materials were used and reacted and treated in the same manner as in Example 14 (Production D) to give the compounds of Examples 15 and 16 below.
  • (Example 15) (R) -4 '-[3- (Dimethylamino) pyrrolidin-1-yl] -5', 8'-dihydrospiro (cyclopentane-1,7'-pyrano [4,3-d] pyrimidine) -2 '-Amine; (51% yield);
  • Examples 17b, 18 The corresponding starting materials were used and reacted and treated in the same manner as in Example 17a (Production E) to give the compounds of Examples 17a and 18 below.
  • H4 Receptor Binding Inhibition Test The H4 receptor binding inhibitory activity of histamine of the compound of the present invention was determined by (2,5- [ 3 H]) in a buffer solution (50 mM TrisHCl pH 7.5) for 1 hour at 25 ° C. Assayed by competitive displacement of histamine (Amersham TRK.631) to 100 ⁇ g membrane prepared from recombinant CHO-K1 (in-house constructed stable expression cell line) expressing human H4 receptor. For some example compounds, IC 50 values (nM), the concentration of compound required to inhibit 50% of the specific binding of (2,5- [ 3 H])-histamine, are shown in Table 1. It was.
  • the compounds of the present invention were shown to inhibit Ca 2+ influx induced by histamine stimulation on the H4 receptor. That is, it was revealed that the compound of the present invention is an antagonist of H4 receptor.
  • Formulation Example 1 Manufacture of tablets 4- (4-Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine (5 g), lactose (80 g), corn starch (30 g ), Crystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g) were mixed and granulated by a conventional method, and 145 mg per tablet. Lock and make 1000 tablets.
  • Formulation Example 2 Production of powder 4- (4-Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine (10 g), lactose (960 g), hydroxypropylcellulose (25 g) and light anhydrous silicic acid (5 g) are mixed by a conventional method and then made into a powder.
  • the 7-substituted dihydropyranopyrimidine derivative of the present invention represented by formula (1) and a pharmaceutically acceptable salt thereof act as an antagonist of H4 receptor, and are allergic diseases, inflammatory diseases, neurogenic It can be used as a therapeutic agent or preventive agent for diseases, cancer, and sepsis.

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention porte sur un dérivé de dihydropyranopyrimidine qui s’utilise comme produit pharmaceutique tel qu'un agent antiallergique ou un agent anti-inflammatoire. L'invention porte sur un composé représenté par la formule (1) ou sur un sel de qualité pharmaceutique de celui-ci. Dans la formule (1), R1 est un groupe représenté par la formule (Ya), un groupe représenté par la formule (Yd) (R8 étant un atome d'hydrogène, un groupe alkyle ou autre ; R8a1 et R8a2 étant chacun un atome d'hydrogène, un groupe alkyle ou autre ; R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 et R20 étant chacun indépendamment un atome d'hydrogène ou autre ; h étant un entier de 1 à 2 ; p étant un entier de 0 à 2; s étant un entier de 1 à 4, et t étant un entier de 1 à 4), R2 et R3 sont chacun un groupe alkyle substitué ou non substitué ou autre, ou peuvent être reliés ensemble par l'atome de carbone auquel ils sont liés pour former un noyau de carbone de 3 à 8 chaînons ou autre ; R4, R5, R6, et R7 représentent chacun indépendamment un atome d'hydrogène ou autre ; X représente un atome d'hydrogène ou un groupe amino.
PCT/JP2009/070389 2008-12-05 2009-12-04 Nouveau dérivé de dihydropyranopyrimidine substitué en position 7 ayant une activité antagoniste du récepteur h4 WO2010064705A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021109737A1 (fr) * 2019-12-02 2021-06-10 上海璎黎药业有限公司 Composé hétérocyclique contenant de l'oxygène, son procédé de préparation et son utilisation
CN112979664A (zh) * 2019-12-02 2021-06-18 上海璎黎药业有限公司 一种含氧杂环化合物、其制备方法及应用
WO2022251576A1 (fr) * 2021-05-28 2022-12-01 Merck Sharp & Dohme Corp. Petites molécules inhibitrices du mutant g12c kras
US11518750B2 (en) * 2019-08-06 2022-12-06 Northwestern University 3-methylideneoxan-4-one compounds and substituted derivatives thereof as inhibitors of telomerase
WO2023154766A1 (fr) * 2022-02-09 2023-08-17 Quanta Therapeutics, Inc. Modulateurs de kras et leurs utilisations
WO2024073502A1 (fr) * 2022-09-28 2024-04-04 Accutar Biotechnology Inc. Composés hétérocycliques utilisés en tant qu'inhibiteurs de ligase e3

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WO2000012487A1 (fr) * 1998-08-27 2000-03-09 Sumitomo Pharmaceuticals Co., Ltd. Derives de pyrimidine
WO2008008359A2 (fr) * 2006-07-11 2008-01-17 Janssen Pharmaceutica, N.V. Modulateurs benzofuro et benzothiénopyrimidine du récepteur histamine h4
WO2008031556A2 (fr) * 2006-09-12 2008-03-20 Ucb Pharma, S.A. Nouveaux dérivés de la 2-amino-pyrimidine, procédés pour les préparer, compositions pharmaceutiques les contenant
WO2008100565A1 (fr) * 2007-02-14 2008-08-21 Janssen Pharmaceutica N.V. 2-aminopyrimidines en tant que modulateurs du récepteur h4 de l'histamine
WO2009047255A1 (fr) * 2007-10-09 2009-04-16 Ucb Pharma, S.A. Composés hétérobicycliques utiles comme antagonistes du récepteur h4 de l'histamine
WO2009114575A1 (fr) * 2008-03-11 2009-09-17 Abbott Laboratories Dérivés de spiropyrimidine tricyclique en tant que ligand d'histamine h4
WO2009123967A1 (fr) * 2008-04-03 2009-10-08 Abbott Laboratories Dérivés de 5,6,7,8-tétrahydroquinazolin-2-amine et composés associés en tant que modulateurs du récepteur d’histamine h4 pour le traitement de l’asthme

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Publication number Priority date Publication date Assignee Title
WO2000012487A1 (fr) * 1998-08-27 2000-03-09 Sumitomo Pharmaceuticals Co., Ltd. Derives de pyrimidine
WO2008008359A2 (fr) * 2006-07-11 2008-01-17 Janssen Pharmaceutica, N.V. Modulateurs benzofuro et benzothiénopyrimidine du récepteur histamine h4
WO2008031556A2 (fr) * 2006-09-12 2008-03-20 Ucb Pharma, S.A. Nouveaux dérivés de la 2-amino-pyrimidine, procédés pour les préparer, compositions pharmaceutiques les contenant
WO2008100565A1 (fr) * 2007-02-14 2008-08-21 Janssen Pharmaceutica N.V. 2-aminopyrimidines en tant que modulateurs du récepteur h4 de l'histamine
WO2009047255A1 (fr) * 2007-10-09 2009-04-16 Ucb Pharma, S.A. Composés hétérobicycliques utiles comme antagonistes du récepteur h4 de l'histamine
WO2009114575A1 (fr) * 2008-03-11 2009-09-17 Abbott Laboratories Dérivés de spiropyrimidine tricyclique en tant que ligand d'histamine h4
WO2009123967A1 (fr) * 2008-04-03 2009-10-08 Abbott Laboratories Dérivés de 5,6,7,8-tétrahydroquinazolin-2-amine et composés associés en tant que modulateurs du récepteur d’histamine h4 pour le traitement de l’asthme

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11518750B2 (en) * 2019-08-06 2022-12-06 Northwestern University 3-methylideneoxan-4-one compounds and substituted derivatives thereof as inhibitors of telomerase
WO2021109737A1 (fr) * 2019-12-02 2021-06-10 上海璎黎药业有限公司 Composé hétérocyclique contenant de l'oxygène, son procédé de préparation et son utilisation
CN112979664A (zh) * 2019-12-02 2021-06-18 上海璎黎药业有限公司 一种含氧杂环化合物、其制备方法及应用
CN112979664B (zh) * 2019-12-02 2024-03-01 上海璎黎药业有限公司 一种含氧杂环化合物、其制备方法及应用
JP7480298B2 (ja) 2019-12-02 2024-05-09 シャンハイ インリー ファーマシューティカル カンパニー リミテッド 酸素含有複素環化合物、その製造方法及び使用
WO2022251576A1 (fr) * 2021-05-28 2022-12-01 Merck Sharp & Dohme Corp. Petites molécules inhibitrices du mutant g12c kras
WO2023154766A1 (fr) * 2022-02-09 2023-08-17 Quanta Therapeutics, Inc. Modulateurs de kras et leurs utilisations
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024073502A1 (fr) * 2022-09-28 2024-04-04 Accutar Biotechnology Inc. Composés hétérocycliques utilisés en tant qu'inhibiteurs de ligase e3

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