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WO2019009369A1 - Dérivé d'imine - Google Patents

Dérivé d'imine Download PDF

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Publication number
WO2019009369A1
WO2019009369A1 PCT/JP2018/025563 JP2018025563W WO2019009369A1 WO 2019009369 A1 WO2019009369 A1 WO 2019009369A1 JP 2018025563 W JP2018025563 W JP 2018025563W WO 2019009369 A1 WO2019009369 A1 WO 2019009369A1
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WO
WIPO (PCT)
Prior art keywords
group
oxy
azetidin
carboxylic acid
methyl
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PCT/JP2018/025563
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English (en)
Japanese (ja)
Inventor
利夫 金井
仁志 須田
真吾 水嶋
祥子 小池
惇一郎 上杉
孝幸 深谷
雄貴 水上
砂塚　敏明
Original Assignee
大日本住友製薬株式会社
学校法人北里研究所
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Application filed by 大日本住友製薬株式会社, 学校法人北里研究所 filed Critical 大日本住友製薬株式会社
Publication of WO2019009369A1 publication Critical patent/WO2019009369A1/fr

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    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to imine derivatives useful as pharmaceuticals, or pharmaceutically acceptable salts thereof. More particularly, the present invention relates to a pharmaceutical composition containing the novel imine derivative, or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic agent containing the imine derivative or a pharmaceutically acceptable salt thereof.
  • ⁇ -lactams eg penicillins, cephalosporins, carbapenems
  • ⁇ -lactams are the most widely used drugs in the treatment of bacterial infections because of their strong bactericidal activity and high safety.
  • ⁇ -lactam drugs the emergence and spread of pathogens that have acquired resistance to ⁇ -lactam drugs has become a global problem.
  • Mechanisms of resistance of these pathogens include production of ⁇ -lactamase, structural change of target molecules of ⁇ -lactam drugs, reduction of drug permeability into cells, enhancement of drug excretion, etc.
  • ⁇ -lactams The production of ⁇ -lactamase, which degrades and inactivates the drugs of the family, is one of the most influential in maintaining the efficacy of the ⁇ -lactam drugs.
  • Various bacteria have evolved beta-lactamases that counter the efficacy of various beta-lactam drugs.
  • ⁇ -lactamases can be classified into four classes based on their amino acid sequences, namely, Ambler class A, B, C and D types. Class A, C, and D enzymes have a serine residue at the center of the enzyme activity and are called serine- ⁇ -lactamase, and class B enzymes do not have a serine residue at the center of the enzyme activity. Because they have zinc (Zn 2+ ), which is a metal ion, they are called metallo- ⁇ -lactamases (zinc- ⁇ -lactamases).
  • a combination of a ⁇ -lactamase inhibitor and a ⁇ -lactam drug is effective for solving the problem of tolerance by the production of ⁇ -lactamase
  • the commercially available ⁇ -lactamase inhibitor clavulanic acid , Sulbactam, and tazobactam mainly inhibit class A ⁇ -lactamases except KPC (Klebsiella pneumoniae Carbapenemase), and avibactam contains KPC including class A, class C and some class D including OXA-48 It is known to inhibit ⁇ -lactamase of (Non-patent Document 1).
  • ⁇ -lactamase inhibitors can not effectively and extensively inhibit all ⁇ -lactamases produced by various bacteria, and show an effect on, for example, metallo- ⁇ -lactamases of class B type. Absent.
  • ⁇ -lactamases which are generically referred to as ESBLs (Extended Spectrum ⁇ -Lactamases) capable of decomposing more substrates ( ⁇ -lactam drugs) compared to conventional ones, have been separated and have new resistance in Western countries Microorganisms, in particular, have become a problem as causes of nosocomial infections, and in addition to this, in Japan, the appearance and spread of metallo- ⁇ -lactamase-producing bacteria are becoming problems.
  • the problem to be solved by the present invention is to find a novel compound having an excellent ⁇ -lactamase inhibitory activity, and provide a useful preventive or therapeutic agent for bacterial infection in combination or as a single agent with a ⁇ -lactam drug. It is to do.
  • diseases such as secondary infections, urinary tract infections, genital infections, eye infections or dental infections in combination with a ⁇ -lactam drug. .
  • the present inventors have found that a compound represented by the following formula (1a), (1b) or (2), or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention” Have found that the above problems can be solved, and completed the present invention. That is, the present invention is as follows.
  • X is an oxygen atom, a sulfur atom, or -NR a1 Represents-
  • Z is a hydroxyl group, optionally substituted C 1-6 Alkoxy or -NR a2
  • R b1 Represents R a1 , R a2 , R b1
  • R a1 , R a2 , R b1 Are each independently the same or different, 1) Hydrogen atom, 2) C 1-6 An alkyl group, 3) C 3-10 Alicyclic group, 4) C 6-10 Aryl 5) 5- or 6-membered heteroaryl, 6) 4- to 10-membered non-aryl heterocycle, 7) C 1-6 An alkylcarbonyl group, 8) C 3-10 Alicyclic carbonyl group, 9) C 6-10 An arylcarbonyl group, 10) 5- or 6-membered heteroarylcarbonyl group, 11) C 1-6 An alkylsulfonyl group, 12) C 3-10 Alicyclic sulfonyl group
  • R c1 Is 1) Hydrogen atom, 2) C 1-6 An alkyl group, 3) C 3-10 Alicyclic group, 4) C 6-10 Aryl, 5) 5- or 6-membered heteroaryl, or 6) 4- to 10-membered non-aryl heterocycle (Wherein each substituent of 2) to 6) may be substituted),
  • Y is 1) Hydrogen atom, 2) hydroxyl group, 3) cyano group, 4) Carboxyl group, 5) C 3-10 Alicyclic group, 6) C 6-10 Aryl, 7) 5- or 6-membered heteroaryl, 8) 4- to 10-membered non-aryl heterocycle, 9) C 1-6 An alkoxy
  • R 4 Is 1)-COR 5 , 2)-SO 2 -L 6 -R 5
  • R 5 Is -NR a5 R b4 , -NR a5 -L 7 -B (OR m1 ) 2 , -OR m1 Or C which may be substituted 1-6
  • [Section 6] 5. The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 4, wherein X is an oxygen atom or a sulfur atom.
  • [Section 7] 7. The compound or a pharmaceutically acceptable salt thereof according to any one of the items 1 to 6, wherein X is an oxygen atom.
  • [Section 8] Z is a hydroxyl group, C 1-6 Alkoxy or -NR a2 R b1 8. The compound according to any one of items 1 to 7, which is: or a pharmaceutically acceptable salt thereof.
  • [Section 9] Z is a hydroxyl group or C 1-6 Item 9. The compound according to any one of Items 1 to 8, which is an alkoxy group, or a pharmaceutically acceptable salt thereof.
  • R 6 Is 1) Hydrogen atom, 2) hydroxyl group, 3) C 1-3 An alkyl group (the group may be substituted with a hydroxyl group or an amino group), or 4) Amino group Is either L 5 Is a single bond or C 1-2 An alkylene group (the group may be substituted with 1 to 2 methyl groups), G is 1) Hydrogen atom (but in this case L 5 Is C 1-2 An alkylene group (which may be substituted with 1 to 2 methyl groups), 2) C 6 Aryl, 3) 5- or 6-membered heteroaryl, 4) C 1-3 An alkoxy group, 5) C 1-3 An alkylthio group, 6) 5-membered heteroarylthio group, (Wherein each substituent of the above 2) to 6) is C 1-3 Alkyl group (the C 1-3 The alkyl group may be substituted with an amino group), a hydroxyl group, an amino group or -NR
  • R 4 The following formulas (7A), (7B), (7C), (7D), (7E), (7F), (7G), (7H), (7I), (7J), (7K), (7L) ), (7M), (7N), (7O), (7P), (7Q) or (7R): [In the formulas (7Q) and (7R), R s But hydrogen atom, C 1-6 Alkyl group or C 3-10 Alicyclic group (the C 1-6 Alkyl group or C 3-10 An alicyclic group is optionally substituted by 1 to 5 halogen atoms), R t But hydrogen atom, C 1-6 Alkyl group, C 1-6 Alkoxy group (the C 1-6 Alkyl group, C 1-6 The alkoxy group may be substituted by 1 to 5 halogen atoms), C 3-10 Alicyclic group, C 3-10 An alicyclic oxy group, a phenyl group, a phenoxy group, a pyr
  • L 1 Is a sulfur atom
  • L 2 Is a single bond
  • Y is 5-membered heteroaryl
  • the 5-membered heteroaryl is an amino group or C 1-3 Alkyl group (the C 1-3 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 24, wherein the alkyl group may be substituted with an amino group).
  • deca-1 (6), 7, 9-trien-7-carboxylic acid 2-hydroxy-7-( ⁇ 1-[(hydroxyimino) (pyridin-2-yl) methyl] azetidin-3-yl ⁇ oxy) -3,4-dihydro-2H-1,2-benzoxaborin- 8-carboxylic acid , 4,4-Dihydroxy-8-( ⁇ 1-[(hydroxyimino) (pyridin-2-yl) methyl] azetidin-3-yl ⁇ oxy) -5-oxa-4-boranidabicyclo [4.4.
  • Item 31 The compound according to Item 30, or a pharmaceutically acceptable salt thereof, which is represented by the following compound name or structural formula: 8-[(1-Ethanimidoylazetidin-3-yl) oxy] -4,4-dihydroxy-5-oxa-4-bora nida bicyclo [4.4.0] deca-1 (6), 7 , 9- Lien-7-carboxylic acid .
  • Item 32 Item 32.
  • the compound according to item 31 represented by the following compound name or structural formula: 8-[(1-Ethanimidoylazetidin-3-yl) oxy] -4,4-dihydroxy-5-oxa-4-bora nida bicyclo [4.4.0] deca-1 (6), 7 , 9-Trien-7-carboxylic acid disodium salt .
  • the compound according to item 30 represented by the following compound name or structural formula: 2-hydroxy-7-( ⁇ 1-[(2-hydroxyphenyl) (imino) methyl] azetidin-3-yl ⁇ oxy) -3,4-dihydro-2H-1,2-benzoxaborinin-8- Carboxylic acid hydrochloride .
  • a ⁇ -lactamase inhibitor comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to Item 44 further comprising an additional drug.
  • the additional agent is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent or an antiallergic agent.
  • the additional drug is a ⁇ -lactam drug.
  • ⁇ -lactam drug preferably amoxicillin, ampicillin (piampicillin, hetacillin, bacampicillin, methampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azulocillin, piperacillin, mezlocilin, mesilinam ( Pibumesillinum), sulfenicillin, benzylpenicillin (G), clomethocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocilin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxasi Phosphorus), oxacillin, methicillin, nafcillin, faropenem, beer Neem, doripenem, er
  • composition according to clause 51 wherein the additional agent is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent or an antiallergic agent.
  • the additional agent is a ⁇ -lactam agent.
  • ⁇ -lactam drug preferably amoxicillin, ampicillin (piampicillin, hetacillin, bacampicillin, methampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azulocillin, piperacillin, mezlocilin, mesilinam ( Pibumesillinum), sulfenicillin, benzylpenicillin (G), clomethocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocilin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxasi Phosphorus), oxacillin, methicillin, nafcillin, faropenem, beer Neem, doripenem, er
  • composition according to item 52 or 53 selected from ME 1036, BAL 30072, SYN 2416, ceftiofur, cefquinome, cefobecin, aztreonam, chigenonam, carmonum, RWJ-442831, RWJ-333441, or RWJ-333442.
  • ⁇ -lactam drug is selected from ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipenem.
  • the compound of the following formula (2) or a pharmaceutically acceptable salt thereof (In the formula (2), Q represents a hydroxyl group, a thiol group, -NHR a1 Represents Z, L 1 , L 2 , Y, R 1 , R 2 , R 3 , R 4 , R a1 Is synonymous with the definition as described in the item 1, and the formula (1a) is as defined in the item 1. ).
  • the compound of formula (2) has the following formula (9): [In the formula (9), Z, R 4 Is the same as the definition described in item 1, and L 1 , L 2 , Y, R 1 , R 2 , W, A, L 3 , L 4 , L 5 58. A compound of Item 57, or a pharmaceutically acceptable salt thereof, wherein G is as defined in Item 2, and Q is as defined in Item 57.
  • the compound of formula (9) has the following formula (10): [In the formula (10), Z, R 4 Is the same as the definition described in item 1, and L 1 , L 2 , Y, R 1 , R 2 , W, L 5 , G is as defined in Section 2, Q is as defined in Section 57, R is 6 60.
  • the compound of formula (9) has the following formula (11): [In the formula (11), Z and R 4 Is the same as the definition described in item 1, and L 1 , L 2 , Y, R 1 , R 2 , W is as defined in Section 2, Q is as defined in Section 57, G a The compound according to Item 57 or Item 58, or a pharmaceutically acceptable salt thereof, wherein m, n, p, J are as defined in Item 4. [Item 61] 73. The compound or a pharmaceutically acceptable salt thereof according to any one of the items 57 to 60, wherein Q is a hydroxyl group or a thiol group. [Section 62] 72.
  • the compound according to Item 57 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 3- [2- (Dihydroxyboranyl) ethyl] -6-[(1-ethaneimidoylazetidin-3-yl) oxy] -2-hydroxybenzoic acid , 3- [2- (Dihydroxyboranyl) ethyl] -6- ⁇ [(3R) -1-ethanimidoylpiperidin-3-yl] oxy ⁇ -2-hydroxybenzoic acid , 3- [2- (Dihydroxyboranyl) ethyl] -6- ⁇ [(3S) -1-ethanimidoylpyrrolidin-3-yl] oxy ⁇ -2-hydroxybenzoic acid , 3- [2- (Dihydroxyboranyl) ethyl] -6-[(1-ethaneimide Ylpiperidin-4-yl) oxy] -2-hydroxybenzoic acid , 3- [2- (Dihydroxy
  • the compound according to Item 57 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 3- (2-boronoethyl) -2-hydroxy-6-( ⁇ 1- [N-hydroxyethanimidoyl] azetidin-3-yl ⁇ oxy) benzoic acid . [Item 84] 58.
  • the compound according to Item 57 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 3-[(2R) -2- ⁇ [2- (3-aminopyrrolidin-1-yl) -2-oxoethyl] sulfanyl ⁇ -2-boronoethyl] -6- ⁇ [1- (4,5-dihydro-1) , 3-thiazol-2-yl) azetidin-3-yl] oxy ⁇ 2-hydroxybenzoic acid . [Section 85] 58.
  • the compound according to Item 57, or a pharmaceutically acceptable salt thereof which is selected from the following compounds: 6-( ⁇ 1-[(3-Aminophenyl) (imino) methyl] azetidin-3-yl ⁇ oxy) -3- (2-boronoethyl) -2-hydroxybenzoic acid .
  • the compound according to Item 57, or a pharmaceutically acceptable salt thereof which is selected from the following compounds: 6-( ⁇ 1-[(4-Aminophenyl) (imino) methyl] azetidin-3-yl ⁇ oxy) -3- (2-boronoethyl) -2-hydroxybenzoic acid .
  • a pharmaceutical composition comprising a compound of the formula (2) according to any one of items 57 to 87 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the additional agent is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent or an antiallergic agent.
  • the additional agent is a ⁇ -lactam agent.
  • ⁇ -lactam drug preferably amoxicillin, ampicillin (piampicillin, hetacillin, bacampicillin, methampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azulocillin, piperacillin, mezlocilin, mesilinam ( Pibumesillinum), sulfenicillin, benzylpenicillin (G), clomethocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocilin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxasi Phosphorus), oxacillin, methicillin, nafcillin, faropenem, beer Neem, doripenem,
  • the therapeutic agent according to Item 96 or 97 which is a secondary infection, urinary tract infection, genital infection, eye infection or dental infection.
  • Item 99 The use of a compound of any one of Items 1 to 32 and 57 to 87 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for bacterial infections.
  • Item 100 100. The use according to Item 99, wherein the bacterial infection is a bacterial infection involving bacteria which may have ⁇ -lactamase.
  • Item 99 or Item 100 which is a secondary infection, urinary tract infection, genital infection, eye infection or dental infection.
  • the compound or pharmaceutically acceptable salt thereof according to item 111 or 112, which is a secondary infection, urinary tract infection, genital infection, eye infection or dental infection.
  • the compound or the pharmaceutically acceptable salt thereof according to any one of the items 1 to 32, and the items 57 to 87, sepsis, pyrogenic neutropenia, bacterial meningitis, bacterial Endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection with chronic respiratory disease, pharyngeal and laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, bile duct
  • a pharmaceutical comprising a combination of at least one drug selected from:
  • composition according to item 115 which comprises at least one selected from BAL 30072, SYN 2416, ceftiofur, cefquinome, cefobecin, aztreonam, chigenonam, carmonum, RWJ-442831, RWJ-333441, or RWJ-333442.
  • ⁇ -lactam drug is selected from ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipenem.
  • composition according to clause 115 or clause 116, wherein the beta-lactam drug is selected from aztreonam, tigenonum, BAL30072, SYN2416 or carmonam.
  • item 119 The composition according to any one of paragraphs 115 to 118, which is for treating a bacterial infection.
  • sample 120 120.
  • a composition according to item 119, wherein said bacterial infection is a bacterial infection involving bacteria which may have ⁇ -lactamase.
  • the composition according to item 119 or 120 which is a secondary infection, urinary tract infection, genital infection, eye infection or dental infection.
  • the compound of formula I ′ ′ is a compound of formula (Ia ′): [In the formula, N is 0 or 1 and J, L and M are each independently CR 5 And N, and the compound of the formula I ′ is a compound of the formula (Ia): 124.
  • a method according to item 122 which is a compound represented by [wherein the substituent in the formula (Ia) is the same as the substituent in the formula (Ia ')].
  • A is C 3-10 Carbocyclyl, C 6-10 Selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; M is 0, 1 or 2; Y 7 Is -CH 2 -, -O-, -S- and -NR 1 Selected from the group consisting of N 1 Is 1, 2 or 3; Q 1 And Q 2 Is H; Each R 7 Is independently OH, optionally substituted -O-C 1-6 Alkyl, -NR 1 R 2 , And -N (OR 1 ) R 2 Selected from the group consisting of Y 4 Are -O-, -S-, and -NR 1 Selected from the group consisting of Y 5 Are -OH, -SH, and -NHR 1 Selected from the group consisting of Y 6 Is -OH or -O-C, which may be substituted 1-6 Alkyl, -NR
  • the compound of the formula (III ′ ′) is [Wherein, m is 0, 1 or 2 and J, L and M are each independently CR] 5 And N], and the compound of the formula (III ′) is 126.
  • Formula (I '): [In formula (I '), A is C 3-10 Carbocyclyl, C 6-10 Aryl, 5-10 members C 6-10 Selected from the group consisting of heteroaryl and 5-10 membered heterocyclyl; X A Is -C (R e R f ), -O-, -S-, -S (O)-, -S (O) 2 -Or-NR 1 -Is; R a Is -H, halogen, optionally substituted -C 1-6 Alkyl, -OH, -C ( O) OR, optionally substituted -O-C 1-6 Alkyl, -NR 1 R 2 ,
  • a method according to item 126 which is [Section 128]
  • the compound of the above formula (I ') is a compound of the formula (I-1') [Wherein, J, L and M each independently represent CR 7 And N is selected, and formula (I) is represented by formula (I-1) 127.
  • a method according to item 126 which is [Section 129] Formula (1b): [In the formula (1b), X, Z, L 1 , L 2 , Y, R 1 , R 2 , R 3 , And R 4 Is as defined in item 1]
  • the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium ethoxide, and lithium diisopropylamide 130.
  • the compounds of the present invention have an excellent inhibitory effect on serine- ⁇ -lactamase having a serine residue in the enzyme active center. Moreover, a more excellent embodiment of the compound of the present invention is expected to have a broad ⁇ -lactamase inhibitory action against multiple ⁇ -lactamases and a metallo- ⁇ -lactamase inhibitory action having zinc (Zn 2+ ) at the enzyme activity center .
  • the compound of the present invention can be used alone or in combination with a ⁇ -lactam drug to cause bacterial infections involving bacteria that may have ⁇ -lactamase, specifically, sepsis, pyrogenic neutrophils Decreased disease, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, pyothorax, secondary infection of chronic respiratory disease, pharyngopharyngitis, tonsillitis, osteomyelitis, arthritis , Peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic and lymphadenitis, secondary infection such as trauma / burn and surgical wound, urinary tract infection, genital infection It is useful as a therapeutic and / or prophylactic agent for eye infections or dental infections.
  • a ⁇ -lactam drug to cause bacterial infections involving bacteria that may have ⁇ -lactamase, specifically
  • the number of substituents in the group defined as “optionally substituted” or “substituted” is not particularly limited as long as it can be substituted. Also, unless otherwise indicated, the description of each group also applies where the group is part of or is a substituent of another group.
  • group means a monovalent group.
  • group may be omitted.
  • the substituent in “optionally substituted” is selected from the substituent group ⁇ consisting of the following, and may be substituted with the same or different 1 to 5 substituents.
  • the type of substituent is not particularly limited, but in the case where the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the atom to be bonded from among the following substituents is limited to carbon atoms.
  • Substituent group ⁇ is 1) a halogen atom 2) a hydroxyl group 3) a carboxyl group 4) a cyano group 5) C 1-6 alkyl group 6) C 2-6 alkenyl group 7) C 2-6 alkynyl group 8) C 1-6 alkoxy group 9)
  • Substituent group ⁇ is preferably 1) a halogen atom 2) a hydroxyl group 3) a carboxyl group 4) a cyano group 5) C 1-6 alkyl group 6) C 1-6 alkoxy group 7) C 1-6 alkylthio group 8) C 1-6 alkylcarbonyl group (provided that , 5) to 8) may be substituted with the same or different 1 to 5 substituents selected from the substituent group ⁇ ) 9) C 3-10 alicyclic group 10) C 3-10 alicyclic oxy group 11) C 6-10 aryloxy group 12) 5- or 6-membered heteroaryloxy group 13) 4- to 10-membered non-membered Aryl heterocyclic oxy group 14) C 3-10 alicyclic thio group 15) C 6-10 arylthio group 16) 5- or 6-membered heteroarylthio group 17) 4 to 10-membered non-ary
  • substituents in the “optionally substituted” include the following substituents.
  • Substituent group ⁇ is more preferably 1) a halogen atom 2) a hydroxyl group 3) a cyano group 4) C 1-6 alkyl group 5) C 1-6 alkoxy group 6) C 1-6 alkylthio group 7) C 1-6 alkylcarbonyl group (provided that 4)
  • Each substituent of 7) may be substituted with the same or different 1 to 5 substituents selected from Substituent group ⁇ ) 8) 5- or 6-membered heteroaryloxy group 9) 4- to 10-membered non-aryl heterocyclic oxy group 10) 5- or 6-membered heteroarylthio group 11) 4- to 10-membered non-aryl heterocyclic thio group 12) C 6-10 aryl 13) 5- or 6-membered heteroaryl 14) 4 to 10-membered non-aryl heterocyclic ring (provided that 4 to 14) each substituent has 1 to 5 substituent groups
  • C 1-6 means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, “C 1-4 ” means that the number of carbon atoms is 1 to 4.
  • hetero atom means an oxygen atom, a nitrogen atom, a sulfur atom and the like.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably it is a fluorine atom or a chlorine atom. More preferably, it is a fluorine atom.
  • the “C 1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • the “C 1-6 alkyl group” preferably “C 1-4 alkyl group” is mentioned, more preferably “C 1-3 alkyl group”, still more preferably “C 1-2 alkyl group” is there.
  • Specific examples of the “C 1-6 alkyl group” include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl and the like.
  • C 2-6 alkenyl group means a linear or branched C 2 -C 6 unsaturated hydrocarbon group containing one or more carbon-carbon double bonds Do.
  • C 2-6 alkenyl group preferred is a "C 2-4 alkenyl group”.
  • Specific examples of “C 2-6 alkenyl group” include, but are not limited to, vinyl group, 1-propynyl group, 2-propynyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, for example. Examples include 2-methyl-1-propynyl group, 2-methyl-2-propynyl group and the like.
  • the “C 2-6 alkynyl group” means a linear or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds.
  • preferred is a "C 2-4 alkynyl group”.
  • ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group etc. are mentioned.
  • C 3-20 alicyclic group means a monocyclic or bicyclic non-aromatic hydrocarbon ring having 3 to 20 carbon atoms, which has a partially unsaturated bond, a portion Also included are those having a crosslinked structure, those that are partially spiroylated and those that have one or two carbonyl structures.
  • Alicyclic group includes cycloalkyl group, cycloalkenyl group, and cycloalkynyl group.
  • the “C 3-20 alicyclic group” is preferably a “C 3-10 alicyclic group”, and more preferably a “C 3-6 alicyclic group”.
  • C 3-20 alicyclic group examples include, but are not limited to, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclohexazinyl group, And cycloheptazinyl group, cyclooctazinyl group, adamantyl or norbornyl and the like.
  • Specific examples of the “C 3-20 alicyclic group” having a partially crosslinked structure include, but are not limited to, those having the structures shown below, and the like.
  • the “C 3-20 alicyclic group” also includes compounds which are fused with an aromatic ring. As a specific example, the group etc. which are represented below are mentioned, for example.
  • the “C 3-10 alicyclic group” means a substituent in which the “C 3-10 alicyclic group” is a monovalent group among the above “C 3-20 alicyclic groups”.
  • C 6-10 aryl means a monocyclic or bicyclic aromatic hydrocarbon ring having 6 to 10 carbon atoms, and specifically, a phenyl group, a 1-naphthyl group, a 2-naphthyl group Groups and the like.
  • the C 6-10 aryl preferably includes C 6 or C 10 aryl.
  • the “5- or 6-membered heteroaryl” is a 5- to 6-membered single ring containing the same or different 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. Means an aromatic heterocycle of
  • the “5- or 6-membered nitrogen-containing heteroaryl” includes, in addition to one nitrogen atom, the same or different 0 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, A single ring aromatic heterocycle consisting of 5 to 6 atoms is meant.
  • 6-membered heteroaryl include, but are not limited to, for example, pyridine, pyridazine, pyrimidine, pyrazine and the like.
  • 5-membered heteroaryl include, but are not limited to, for example, thiophene, pyrrole, thiazol, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole And the like, preferably triazole, tetrazole or thiadiazole.
  • 5- or 6-membered heteroaryl means a substituent in which the above-mentioned “5-membered heteroaryl” or “6-membered heteroaryl” is a monovalent group.
  • a 4- to 20-membered non-aryl heterocycle is composed of 4 to 20 atoms including the same or different 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom
  • a monocyclic or bicyclic non-aromatic heterocycle including those having a partially unsaturated bond, those having a partially bridged structure, and those having a partially spirated structure.
  • the nonaryl heterocycle may form a fused ring with aryl or heteroaryl. For example, when fused with a C 6-10 aryl or 5- or 6-membered heteroaryl, it is also included in the heterocycle.
  • one or two carbonyl, thiocarbonyl, sulfinyl or sulfonyl may be included to constitute the non-aryl heterocycle, and for example, lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate
  • a cyclic group such as cyclic thiocarbamate is also included in the non-aryl heterocycle.
  • oxygen atoms of carbonyl, sulfinyl and sulfonyl and sulfur atoms of thiocarbonyl are not included in the number of 4 to 20 members (ring size) and the number of hetero atoms constituting the ring.
  • 4 to 20 membered non-aryl heterocycle include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran and the like. The thing of the structure shown below etc. are mentioned. Further, specific examples of the “4 to 20-membered non-aryl heterocycle” having a partial bridge and a spiro structure are not limited thereto, and examples thereof include those having the structures shown below.
  • the “4 to 20-membered nitrogen-containing non-aryl heterocycle” contains, in addition to one nitrogen atom, the same or different 0 or 1 hetero atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom Or a monocyclic or bicyclic non-aromatic heterocyclic ring composed of 4 to 20 atoms, having a partially unsaturated bond, having a partially bridged structure, or a portion Including spiro-ized ones.
  • the “4- to 10-membered non-aryl heterocycle” is a substituent in which “4- to 10-membered non-aryl heterocycle” is a monovalent group among the above-mentioned “4- to 20-membered non-aryl heterocycle”. means.
  • the “4- to 7-membered non-aryl heterocycle” is a substituent in which “4- to 7-membered non-aryl heterocycle” is a monovalent group among the above “4- to 20-membered non-aryl heterocycle”. means.
  • the "four-membered non-aryl heterocycle” include, but are not limited to, azetidine, oxetane, thietane and the like.
  • specific examples of the "four-membered non-aryl heterocycle” having a partially unsaturated bond are not limited thereto, and examples thereof include those having the structures shown below.
  • Specific examples of the "5-membered non-aryl heterocycle” include, but are not limited to, pyrrolidine, pyrrolidone, oxazolidinone, tetrahydrofuran, tetrahydrothiophene and the like.
  • specific examples of the “5-membered non-aryl heterocycle” having a partially unsaturated bond are not limited thereto, and examples thereof include those having the structures shown below.
  • specific examples of the “5-membered non-aryl heterocycle” having a partially crosslinked structure are not limited thereto, and examples thereof include those having the structures shown below.
  • specific examples of the “5-membered non-aryl heterocycle” containing carbonyl, thiocarbonyl and the like are not limited thereto, and examples thereof include those having the structures shown below.
  • 6-membered non-aryl heterocycle examples include, but are not limited to, for example, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrothiopyran and the like.
  • specific examples of the “6-membered non-aryl heterocycle” having a partially unsaturated bond are not limited thereto, and examples thereof include those having the structures shown below.
  • specific examples of the “six-membered non-aryl heterocycle” having a partially crosslinked structure are not limited thereto, and examples thereof include those having the structures shown below.
  • the “C 1-6 alkoxy group” means a “C 1-6 alkyloxy group”, and the C 1-6 alkyl moiety has the same meaning as the above C 1-6 alkyl group.
  • the “C 1-6 alkoxy group” is preferably a “C 1-4 alkoxy group”, more preferably a “C 1-3 alkoxy group”, still more preferably a “C 1-2 alkoxy group” .
  • C 1-6 alkoxy group include, but are not limited to, for example, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group And isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1,2-dimethylpropoxy group and the like.
  • C3-6 alicyclic oxy group means a ( C3-6 alicyclic group) -O- group, and said C3-6 alicyclic part is a C3-6 alicyclic group It is synonymous with Preferred as the "C 3-6 alicyclic oxy group” is a "C 3-5 alicyclic oxy group”.
  • Specific examples of the “C 3-6 alicyclic oxy group” include, but are not limited to, for example, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group and the like.
  • the C 6-10 aryl moiety of the “C 6-10 aryloxy group” has the same meaning as the above C 6-10 aryl.
  • Preferred examples of the “C 6-10 aryloxy group” include “C 6 or C 10 aryloxy group”.
  • Specific examples of the "C 6-10 aryloxy group” include, but are not limited to, for example, phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group and the like.
  • the 5- or 6-membered heteroaryl moiety of the "5- or 6-membered heteroaryloxy group” has the same meaning as the above-mentioned "5-membered heteroaryl” or "6-membered heteroaryl".
  • Specific examples of "5- or 6-membered heteroaryloxy group” include, but are not limited to, for example, pyrazolyloxy group, triazolyloxy group, thiazoyloxy group, thiadiazoyloxy group, pyridyloxy group And pyridazoyloxy groups.
  • the 4- to 10-membered non-aryl heterocyclic portion of the "4- to 10-membered non-aryl heterocyclic oxy group” is the same as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring".
  • the “4 to 10-membered non-aryl heterocyclic oxy group” preferred is a “4 to 6-membered non-aryl heterocyclic oxy group”.
  • 4- to 10-membered non-aryl heterocyclic oxy group include, but are not limited to, for example, tetrahydrofuranyloxy group, tetrahydropyranyloxy group, azetidinyloxy group, pyrrolidinyloxy group, pi Peridinyloxy group etc. are mentioned.
  • the C 1-6 alkyl moiety of the “C 1-6 alkylthio group” has the same meaning as the above C 1-6 alkyl.
  • the “C 1-6 alkylthio group” is preferably a “C 1-4 alkylthio group”, more preferably a “C 1-3 alkylthio group”.
  • Specific examples of “C 1-6 alkylthio group” include, but are not limited to, methylthio group, ethylthio group, propylthio group, butylthio group, isopropylthio group, isobutylthio group, tert-butylthio group, sec-butylthio group. Groups, isopentylthio group, neopentylthio group, tert-pentylthio group, 1,2-dimethylpropylthio group and the like.
  • the "C 3-10 alicyclic thio group” means a (C 3-10 alicyclic group) -S- group, and the C 3-10 alicyclic moiety is the above C 3-10 alicyclic group. It is synonymous with group.
  • the "C 3-10 alicyclic thio group” is preferably a "C 3-6 alicyclic thio group”. Specific examples of “C 3-6 alicyclic thio group” include, but are not limited to, for example, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group and the like.
  • the C 6-10 aryl moiety of the “C 6-10 arylthio group” has the same meaning as the above C 6-10 aryl.
  • the “C 6-10 arylthio group” preferably “C 6 or C 10 arylthio group” is mentioned.
  • Specific examples of the “C 6-10 aryloxy group” include, but are not limited to, for example, phenylthio group, 1-naphthylthio group, 2-naphthylthio group and the like.
  • the 5- or 6-membered heteroaryl moiety of the "5- or 6-membered heteroarylthio group” has the same meaning as the above-mentioned "5-membered heteroaryl” or "6-membered heteroaryl".
  • Specific examples of "5- or 6-membered heteroarylthio group” include, but are not limited to, for example, pyrazolylthio group, triazolylthio group, thiazolylthio group, thiadiazoylthio group, pyridylthio group, pyridazoylthio group and the like. It can be mentioned.
  • the 4- to 10-membered non-aryl heterocyclic portion of the "4- to 10-membered non-aryl heterocyclic thio group” has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring".
  • the "4- to 10-membered non-aryl heterocyclic thio group” preferred is a "4- to 6-membered non-aryl heterocyclic thio group”.
  • Specific examples of “4 to 10-membered non-aryl heterocyclic thio group” include, but are not limited to, for example, tetrahydropyranyl thio group, piperidinyl thio group and the like.
  • C 1-6 alkylcarbonyl group means a carbonyl group substituted by the above “C 1-6 alkyl group”.
  • C 1-6 alkylcarbonyl group preferred is a "C 1-4 alkylcarbonyl group”.
  • Specific examples of the “C 1-6 alkylcarbonyl group” include, but are not limited to, for example, an acetyl group, a propionyl group, a butyryl group and the like.
  • the “C 3-10 alicyclic carbonyl group” means a carbonyl group substituted by the above “C 3-10 alicyclic group”. As the “C 3-10 alicyclic carbonyl group”, preferred is a “C 3-6 alicyclic carbonyl group”. Specific examples of “C 3-10 alicyclic carbonyl group” include, but are not limited to, for example, cyclopropylcarbonyl group, cyclopentylcarbonyl group and the like.
  • the “C 6-10 arylcarbonyl group” means a carbonyl group substituted by the above “C 6-10 aryl”.
  • Specific examples of the "C 6-10 arylcarbonyl group” include, but are not limited to, for example, benzoyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group and the like.
  • the "5- or 6-membered heteroarylcarbonyl group” means a carbonyl group substituted by the above-mentioned "5- or 6-membered heteroaryl”.
  • Specific examples of "5- or 6-membered heteroarylcarbonyl group” include, but are not limited to, for example, pyrazolylcarbonyl group, triazolylcarbonyl group, thiazolylcarbonyl group, thiadiazoylcarbonyl group, pyridylcarbonyl group, and the like. Pyridazoyl carbonyl group etc. are mentioned.
  • the “4- to 10-membered non-aryl heterocycle carbonyl group” means a carbonyl group substituted by the above-mentioned “4- to 10-membered non-aryl heterocycle”.
  • the "4- to 10-membered non-aryl heterocycle carbonyl group” preferred is a "4- to 6-membered non-aryl heterocycle carbonyl group”.
  • Specific examples of "4- to 10-membered non-aryl heterocyclic carbonyl group” include, but are not limited to, azetidinyl carbonyl group, pyrrolidinyl carbonyl group, piperidinyl carbonyl group, morpholinyl carbonyl group, etc. Can be mentioned.
  • the “C 1-6 alkylsulfonyl group” means a sulfonyl group substituted by the above “C 1-6 alkyl group”.
  • the “C 1-6 alkylsulfonyl group” preferred is “C 1-4 alkylsulfonyl group”.
  • Specific examples of the “C 1-6 alkylsulfonyl group” include, but are not limited to, methylsulfonyl group, propionylsulfonyl group, butyrylsulfonyl group and the like.
  • the “C 3-10 alicyclic sulfonyl group” means a sulfonyl group substituted by the above “C 3-10 alicyclic group”.
  • Preferred as the "C 3-10 alicyclic sulfonyl group” is a "C 3-6 alicyclic sulfonyl group”.
  • Specific examples of “C 3-10 alicyclic sulfonyl group” include, but are not limited to, cyclopropyl sulfonyl group, cyclobutyl sulfonyl group, cyclopentyl sulfonyl group, cyclohexyl sulfonyl group and the like.
  • the “C 6-10 arylsulfonyl group” means a sulfonyl group substituted by the above “C 6-10 aryl”.
  • the "C 6-10 arylsulfonyl group” preferred is a "C 6 or C 10 arylsulfonyl group”.
  • Specific examples of “C 6-10 arylsulfonyl group” include, but are not limited to, phenylsulfonyl group, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group and the like.
  • the "5- or 6-membered heteroarylsulfonyl group” means a sulfonyl group substituted by the above-mentioned "5- or 6-membered heteroaryl".
  • Specific examples of "5- or 6-membered heteroarylsulfonyl group” include pyrazolylsulfonyl group, triazolylsulfonyl group, thiazoylsulfonyl group, thiadiazoylsulfonyl group, pyridylsulfonyl group, pyridazoylsulfonyl group, etc. Etc. can be mentioned.
  • the “C 1-6 alkylene group” means a substituent in which the saturated hydrocarbon group having 1 to 6 carbon atoms is a divalent group.
  • the “C 1-3 alkylene group” means a substituent in which a saturated hydrocarbon group having 1 to 3 carbon atoms is a divalent group.
  • carboxylic acid equivalent means a bioisostere of carboxylic acid, and other partial structures (functional groups) that play the same biological role in drug molecules are referred to as biological equivalents (this document). In the invention, prodrug structures are also included as a concept of biological equivalents).
  • Examples of the carboxylic acid equivalent include, but are not limited to, for example, -SO 3 H, -SO 2 NHR 19a , -B (OR m1 ) 2 , -PO (OR m1 ) (OR m2 ), -CONHR 19a ,- CONHSO 2 R 19a , -CONR 19a CN, -CONHNHSO 2 R 19a and the following formulas (8A), (8B), (8C), (8D), (8E), (8F), (8G), (8H), (8I), (8J), (8K), (8L), (8M), (8N), (8O), (8P), (8Q), (8R), (8S), (8T), (8U) ), (8 V) and (8 W) (The respective substituents may be further substituted with 1 to 3 R 19 b , which may be the same or different at the chemically substitutable positions) Is mentioned, [In the formulas (8 V) and (8 W), R s is a hydrogen atom, a C 1-6 alkyl group or a C
  • R s is a hydrogen atom or a C 1-6 alkyl group
  • R t is any of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-10 alicyclic group or a C 3-10 alicyclic oxy group.
  • R 19a and R 19 b are each independently the same or different and are a hydrogen atom, a hydroxyl group or a C 1-6 alkyl group.
  • R m1 and R m2 are each independently the same or different and are a hydrogen atom, a C 1-6 alkyl group, or a C 3-10 alicyclic group.
  • R 1 , R 2 and R 3 is —O—R AL
  • R AL is a substituent selected from A 1 to A 33, and the remaining two are hydrogen atoms
  • R 1 and R 2 are hydrogen atoms
  • R 3 is —O—R AL
  • R AL is a substituent selected from the above A 1 to A 33
  • a further preferred embodiment of the compound of the present invention can be exemplified as a compound of the following Table (1) or a pharmaceutically acceptable salt thereof.
  • stereoisomers such as tautomers, geometric isomers and optical isomers may be present in the compound of the present invention, and the present invention also includes them. That is, when one or more asymmetric carbon atoms are present in the compound of the present invention, diastereomers and optical isomers exist, but a mixture of these diastereomers and optical isomers or those isolated Are also included in the compounds of the present invention.
  • the structures thereof are stereoisomers (geometric isomers) in E form and Z form (E configuration and Z configuration)
  • E form and Z form E configuration and Z configuration
  • R 6 is a cyano group, a hydroxyl group, a methoxy group, a Boc group, etc.
  • the notation of the bond between R 6 and the nitrogen atom to which it is attached is the partial structure (i)
  • the E form, the Z form, or the E / Z mixture is represented and may be contained, and the E form only, the Z form alone, or the E / Z mixture only
  • the compound of the present invention may exist in a structure represented by the following formula (2) in an equilibrium state or the like depending on environmental conditions such as temperature and humidity, or physical factors such as solid, liquid or in solution.
  • the compounds of the present invention are also included.
  • Q represents a hydroxyl group, a thiol group, or —NHR a1 ;
  • Z, L 1 , L 2 , Y, R 1 , R 2 , R 3 , R 4 , R a1 represent the term 1 It is synonymous with the definition of a statement, Formula (1a) is synonymous with term 1.).
  • the structure of the compound of the present invention is based on a proton nuclear magnetic resonance spectrum ( 1 H-NMR), liquid chromatography-mass spectrometry (LCMS), etc., and based on an estimation that is considered most appropriate for those skilled in the art.
  • the structure of the formula (1a), the structure of the formula (1b) and the structure of the formula (2) are specific characteristics of the individual compound, temperature, humidity. And the like, or may be mutually converted due to physical factors such as in solid, liquid, or in solution.
  • the compounds of the present invention also include various hydrates, solvates and crystalline polymorphs.
  • the compounds of the present invention may be substituted with isotopes (eg, D, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I, etc.) These compounds are also included in the compounds of the present invention.
  • isotopes eg, D, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I, etc.
  • a prodrug refers to a derivative which is decomposed in vivo by acid hydrolysis or enzymatically to give a compound of the above formula (1) or (2).
  • a prodrug refers to a derivative which is decomposed in vivo by acid hydrolysis or enzymatically to give a compound of the above formula (1) or (2).
  • the compound of the above formula (1a), (1b) or (2) has a hydroxyl group, an amino group or a carboxy group, these groups can be modified according to a conventional method to produce a prodrug.
  • a compound having a carboxy group a compound in which the carboxy group is an alkoxycarbonyl group, a compound in which an alkylthiocarbonyl group is formed, or a compound in which an alkylaminocarbonyl group is formed.
  • a compound having an amino group a compound in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group, a compound substituted with an alkoxycarbonyl group to form an alkoxycarbonylamino group, and an alkanoyloxymethylamino group Or compounds which have become hydroxylamine.
  • examples of the compound having a hydroxyl group include a compound in which the hydroxyl group is substituted by the alkanoyl group to form an alkanoyloxy group, a compound in which a phosphoric acid ester is formed, or a compound in which an alkanoyloxymethyloxy group is formed.
  • alkyl moiety of the groups used for forming these prodrugs include the aforementioned alkyl groups, which may be substituted by, for example, an alkoxy group.
  • Preferred examples include the following.
  • examples of compounds in which the carboxyl group is an alkoxycarbonyl group include alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, or methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or Examples include alkoxycarbonyl substituted by an alkoxy group such as valoyloxymethoxycarbonyl.
  • “pharmaceutically acceptable salts” mean acid addition salts and base addition salts which are accepted for pharmaceutically use.
  • pharmaceutically acceptable salts include, but are not limited to, for example, acetates, propionates, butyrates, formates, trifluoroacetates, maleates, fumarates, tartrates, etc.
  • the compounds of the present invention can be administered orally or parenterally, directly or in suitable dosage forms, in preparations, medicaments or pharmaceutical compositions.
  • suitable dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and patches.
  • these preparations can be manufactured by known methods using additives used as conventional pharmaceutical additives.
  • excipients As these additives, according to the purpose, excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers Sweeteners, flavors and the like can be used.
  • additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low substituted hydroxypropyl cellulose, corn starch, partially gelatinized starch, carmellose calcium, croscarmellose sodium, hydroxy Propyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc and the like can be mentioned.
  • the dose of the compound of the present invention is appropriately selected depending on the administration subject, administration route, disease, patient's age, weight and condition.
  • the lower limit is 0.01 mg (preferably 100 mg) per day and the upper limit 10000 mg (preferably 6000 mg), and this amount may be once or several times a day It can be divided and administered.
  • the compounds of the present invention are compounds having inhibitory activity against serine- ⁇ -lactamase having a serine residue in the active center. Therefore, when used in combination with an antimicrobial agent, it can be a useful prophylactic or therapeutic agent for bacterial infections.
  • bacterial infections include sepsis, pyrogenic neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, pyothorax, chronic respiratory tract Secondary infection of the lesion, pharyngeal and laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic and lymphadenitis, trauma, Secondary infections such as burns and surgical wounds, urinary tract infections, genital infections, eye infections or dental infections etc. may be mentioned.
  • the compounds of the invention are at least selected from antibacterial agents, antifungal agents, antiviral agents, antiinflammatory agents or antiallergic agents to treat one or more bacterial infections described herein. It can be used in combination with one or more agents.
  • antimicrobial agents and more preferred are ⁇ -lactam drugs, and more specifically amoxicillin, ampicillin (picampicillin, hetacillin, bacampicillin, methampicillin, talampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin , Azurocil, piperacillin, mezlocillin, mesilinam (pibumesilinam), sulfenicillin, benzylpenicillin (G), clomethocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocilin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, Pheneticillin, clo
  • the administration time of the compounds of the present invention and their therapeutic agents is not limited, and they may be administered simultaneously to the administration subject, or may be administered with a time lag. In addition, they may be a combination of the compound of the present invention and their therapeutic agents.
  • the dose of the therapeutic agent can be appropriately selected based on the dose clinically used.
  • the compounding ratio of the compound of the present invention to the therapeutic agent thereof can be appropriately selected depending on the administration subject, administration route, target disease, condition, combination and the like.
  • compositions comprising such beta-lactam agents, such as sepsis, pyrogenic neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, Pneumonia, lung abscess, pyothorax, secondary infection of chronic respiratory disease, pharyngeal and laryngitis, tonsillitis, osteoarthritis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection ,
  • bacterial infections such as lymphatics / lymphadenitis
  • secondary infections such as trauma / burn and surgical wound, urinary tract infections, genital infections, eye infections or dental infections be able to.
  • Such medicaments, formulations, pharmaceutical compositions may be combined with the compounds of the present invention and / or additional agents (eg, anti-microbial agents such as ⁇ -lactam agents) using any technique known in the art. Or separately, as a combination or as separate agents, by mixing with appropriate optional ingredients, using any technique known in the art, suitable formulations such as tablets, It can be formulated as capsules, powders, granules, solutions, suspensions, injections, patches, and patches.
  • agents eg, anti-microbial agents such as ⁇ -lactam agents
  • the compound of the invention and / or the additional agent e.g., an anti-microbial agent such as a beta-lactam agent
  • the additional agent e.g., an anti-microbial agent such as a beta-lactam agent
  • it may be provided as a kit of two agents, one component of Provided as a single agent, the other component (in the case of the compound of the present invention, an additional agent (eg, an antibacterial agent such as a ⁇ -lactam agent, an additional agent (eg, an antibacterial agent such as a ⁇ -lactam agent))
  • the compound of the present invention may be provided together with instructions (such as package insert) instructing to be administered simultaneously or in combination.
  • the compound of the present invention When used as an active ingredient of a medicament, it is not intended to be used only for humans, but is also used for other non-human animals (cat, dog, cow, chicken, fish, etc.) It is possible.
  • the compounds of the present invention can be produced, for example, by the production methods described below, but not limited thereto. These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry. In the following production methods, compounds used as raw materials may be used as their salts as long as they do not interfere with the reaction.
  • the desired compound can be obtained by protecting other than the reaction point as necessary, and deprotecting after completion of the reaction or after performing a series of reactions.
  • protecting groups used in these processes are generally described in the literature (TW Greene and PGM Wuts, “Protective Group in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999)), etc. Can be used.
  • the introduction and removal of the protective group can be carried out by a method commonly used in organic synthetic chemistry (for example, the method described in the above literature) or a method analogous thereto.
  • Starting materials and intermediates in the following production methods can be purchased as commercial products, or can be obtained by synthesizing from methods described in known documents or known compounds according to known methods. In addition, these starting materials and intermediates may be used as their salts as long as they do not interfere with the reaction.
  • the intermediates and target compounds in the following production methods can also be converted into other compounds included in the present invention by converting their functional groups appropriately. Conversion of functional groups in that case, a method (e.g., conventionally used in organic synthetic chemistry, R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Is described in New York (1999) Or the like, or a method according to them.
  • a method e.g., conventionally used in organic synthetic chemistry, R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Is described in New York (1999) Or the like, or a method according to them.
  • the inert solvent in the following production method means a solvent which does not react with the starting materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (hereinafter sometimes referred to as "the starting materials used in the reaction"). means.
  • the solvent used in each step reacts with the raw material used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds to obtain the target compound.
  • Manufacturing method 1 The compound represented by following formula (1-7) among the compounds of Formula (1a) can be manufactured, for example with the following manufacturing method.
  • a is a hydroxyl group or a C 1-6 alkoxy group
  • H is a hydrogen atom
  • LG is a leaving group (eg, a halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy)
  • a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, an arylsulfonyloxy group such as p-toluenesulfonyloxy and the like
  • PG 1 represents a hydroxyl protecting group (eg, tert.
  • PG 2 and PG 3 is a protective group of the boronic acid (e.g., optionally substituted C 1-6 alkyl group, or a structure like) represented by the following formula Represent
  • PG 4 is a hydrogen atom, a protecting group of a hydroxyl group (for example, tert-butoxycarbonyl group, acetyl group, methoxymethyl group, p-methoxybenzyl group, tert-butyldimethylsilyl group, trimethylsilyl group etc.
  • a protecting group of a hydroxyl group for example, tert-butoxycarbonyl group, acetyl group, methoxymethyl group, p-methoxybenzyl group, tert-butyldimethylsilyl group, trimethylsilyl group etc.
  • thiol group Protecting group for example, acetamidemethyl group or trityl group
  • protecting group for amino group for example, ethoxycarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group , 3- or 4-chlorobenzyloxycarbonyl, triphenylmethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, benzyloxycarbonyl, 3- or 4-chlorobenzyloxycarbonyl, benzyl And sulfonyl group, benzyl group, 4-nitrobenzyl group, 4-methoxybenzyl group, methyl group, ethyl group and the like.
  • the compound (1-1) which is a starting material those commercially available can be used, or those produced by known methods (for example, WO2016 / 003929, WO2016 / 149393, etc.) can be used.
  • Step 1-1 The compound (1-3) is reacted with the compound (1-2) in an inert solvent, in the presence of a base, under normal pressure or under pressure relative to the compound (1-1).
  • a base under normal pressure or under pressure relative to the compound (1-1).
  • the inert solvent include ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), Aprotic solvents such as dimethyl sulfoxide (DMSO) and the like can be mentioned.
  • the base include potassium tert-butoxide, sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like.
  • the equivalent of the base can be 0.001 to 100 equivalents, preferably 0.5 to 10 equivalents, relative to compound (1-1).
  • the equivalent of the compound (1-2) can be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to the compound (1-1).
  • the reaction temperature is selected from the range of about -10 ° C to about 100 ° C.
  • Step 1-2 The compound (1-4) can be produced by deprotecting the protecting group PG 1 of the compound (1-3). This process can be performed according to the method etc. which are described in literature (T. W. Greene and P. G. M. Wuts, "Protective Group in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)).
  • Step 1-3 With respect to the compound (1-4), compound (1-6) can be added to an inert solvent in the presence of an azo compound analog and an organic phosphorus compound / or in the presence of a phosphorane compound under normal pressure or pressure. Can be produced by reacting the compound (1-5) under Mitsunobu conditions.
  • the inert solvent include ether solvents such as THF and DME, and hydrocarbon solvents such as toluene and benzene.
  • the azo compound analogues include diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like.
  • the equivalent of the azo compound analog may be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (1-4).
  • Examples of the organic phosphorus compound include triphenyl phosphine, tributyl phosphine and the like.
  • the equivalent weight of the organic phosphorus compound can be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to the compound (1-4).
  • Examples of the phosphorane compound include (cyanomethylene) tributylphosphorane, (cyanomethylene) trimethylphosphorane and the like.
  • the equivalent of the phosphorane compound can be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (1-4).
  • the reaction temperature is selected from the range of about -10 ° C to about 100 ° C.
  • Step 1-4 This reaction can be produced from the corresponding compound (1-6) according to a known method (eg, WO2014 / 151958, WO2015 / 191907, WO2016 / 003929, etc.). Preferably, it can be produced using the production method (1-4-1) or the production method (1-4-2) shown below.
  • Compound (1-7) can be produced by reacting compound (1-6) as a starting material with boronic acid in an inert solvent under acidic conditions .
  • boronic acids include phenylboronic acid and 2-methylpropylboronic acid.
  • the equivalent of boronic acid can be used in the range of 0.001 to 100 equivalents, preferably 1 to 3 equivalents, relative to compound (1-6).
  • the acid include hydrochloric acid, trifluoroacetic acid and the like.
  • the equivalent of the acid can be used in the range of 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (1-6).
  • the inert solvent include, for example, halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, hydrocarbon solvents such as hexane or heptane, ether solvents such as THF or DME, acetonitrile or propionitrile, etc.
  • a nitrile type solvent and water are mentioned, It can use individually or as a mixed solvent.
  • the acid shown above can also be used as a solvent as it is.
  • a mixed solvent of hexane / acetonitrile is used as the solvent.
  • the reaction temperature is selected from the range of about -10 ° C to about 100 ° C.
  • Compound (1-7) can be produced by reacting compound (1-6) as a starting material with triethylsilane in a trifluoroacetic acid solvent.
  • the equivalent of triethylsilane can be used in the range of 0.001 to 100 equivalents, preferably 1 to 50 equivalents, relative to compound (1-6).
  • the reaction temperature is selected from the range of about -10 ° C to about 70 ° C.
  • Manufacturing method 1A The compound of the formula (1a) can be produced from the corresponding starting materials which can be purchased or prepared in the same manner as the method for producing the compound (1-7). (Wherein, X, Z, L 1 , L 2 , Y, R 1 , R 2 , R 3 and R 4 are as defined in item 1)
  • the compound of formula (1b) (tetrasubstituted boron) can be reacted, for example, with a nucleophilic Z anion (Z ⁇ ), depending on the nature of the compound Can be converted to the compound).
  • the compound (1b) is usually present as a metal salt as represented by the following formula.
  • Z - is a Z anion, for example, water oxide ion (HO - or - OH and the notation), C 1-6 alkoxide (the C 1-6 alkoxide, R u O - expressed in, said R u is a said C 1-6 alkyl group ), amide anion (- NR a2 represents R b1) or the like
  • M + is a monovalent metal cation, e.g., sodium ion (Na +), lithium ion (Li +), potassium ion (K +), such as M 2 + represents an alkali metal ion
  • M 2 + is a divalent metal cation, for example, an alkaline earth metal ion such as magnesium ion (Mg 2+ ) or calcium ion (Ca 2+ ).
  • a compound of formula (1b) can be produced by adding a base as described below to the compound of formula (1a).
  • An ion pair M + Z - or M 2+ (Z -) 2 can be used for the reaction to be produced is generated by addition of a base which is in the form MZ or M (Z) 2 and (1b),
  • the base for example, when Z is a hydroxyl group, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide etc. may be mentioned, preferably lithium hydroxide, sodium hydroxide, hydroxide It is potassium, more preferably sodium hydroxide.
  • the base for example, when Z is a C 1-6 alkoxy group (R u O), metal alkoxides such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like can be mentioned.
  • metal amides such as sodium amide and lithium diisopropylamide can be mentioned.
  • M + Z - may be generated by ZH addition of another base in a reaction system consisting of present or ZH is.
  • ZH is water (H 2 O)
  • hydroxide ions and sodium ions are added to the water by adding sodium hydride or sodium carbonate, or potassium hydride or potassium carbonate is added to the water.
  • sodium hydride or sodium carbonate is added to the water.
  • potassium hydride or potassium carbonate is added to the water.
  • hydroxide ions and potassium ions are generated in the system, respectively.
  • ZH is a C 1-6 alcohol (wherein the C 1-6 alcohol is represented by R u OH and the R u is the C 1-6 alkyl group)
  • hydrogen in the R u OH the addition of sodium reduction, hydroxide ions and sodium ions, or by adding potassium hydride in R u OH, C 1-6 alkoxide and potassium ions, occurring respectively during system.
  • HNR a2 R b1 (wherein R a2 and R b1 are as defined in item 1)
  • sodium hydride is added to a reaction system containing the HNR a2 R b1
  • potassium hydride is generated in the system.
  • compounds of the formula I ′ can be converted into compounds of the formula I ′ ′, for example by reaction with the nucleophilic Z anion (Z ⁇ ).
  • the compound I ′ ′ usually exists as a metal salt as represented by the following formula. More specifically, the compound of formula I ′ ′ can be prepared by adding the same base as described in Preparation method 1B to the compound of formula I ′.
  • Z - is a Z anion (i.e., Z - represents an R 7 anion), for example, water oxide ion (HO - or - OH and the notation) represents a C 1-6 alkoxide
  • M + is a monovalent metal cation, e.g., sodium ion (Na +), lithium ion (Li +)
  • M 2+ is a divalent metal cation, and examples thereof include alkaline earth metal ions such as magnesium ion (Mg 2+ ) and calcium ion (Ca 2+ ).
  • the compound of formula III ′ can be converted to the compound of formula III ′ ′, for example by reaction with the nucleophilic Z anion (Z ⁇ ).
  • the compound III ′ ′ is usually present as a metal salt as represented by the following formula. More specifically, the compound of formula III ′ ′ can be prepared by adding the same base as described in Preparation method 1B to the compound of formula III ′.
  • Z - is a Z anion (i.e., Z - represents an R 7 anion), for example, water oxide ion (HO - or - OH and the notation) represents a C 1-6 alkoxide
  • M + is a monovalent metal cation, e.g., sodium ion (Na +), lithium ion (Li +)
  • M 2+ is a divalent metal cation, and examples thereof include alkaline earth metal ions such as magnesium ion (Mg 2+ ) and calcium ion (Ca 2+ ).
  • the compound of formula (I) can be converted to the compound of formula (I ′), for example, by reaction with the nucleophilic Z anion (Z ⁇ ).
  • the compound (I ') is usually present as a metal salt as represented by the following formula. More specifically, the compound of formula (I ') can be prepared by adding the same base as described in Preparation method 1B to the compound of formula (I). (In the formula, the group is as defined above, provided that R d is the same as Z, and Z - is a Z anion, for example, hydroxide ion (HO - or - OH) ), C 1-6 alkoxide etc.
  • M + is a monovalent metal cation, for example, sodium ion (Na + ), lithium ion (Li + ) Represents an alkali metal ion such as potassium ion (K + ), and M 2+ is a divalent metal cation, and examples thereof include alkaline earth metal ions such as magnesium ion (Mg 2+ ) and calcium ion (Ca 2+ ). Represent)
  • a disodium salt compound of the formula (1b ′ ′) can be obtained by carrying out the reaction to be obtained and then treating with an aqueous solution of sodium hydroxide.
  • X, L 1 , L 2 , Y, R 1 , R 2 and R 3 are as defined in item 1.
  • the compound (1-1) and the compound (1-5) which are starting materials those purchased as commercial products can be used, or those manufactured by the method described in the manufacturing method 1 can be used.
  • the compound (2-2) and the compound (2-3) may be commercially available products, or may be prepared from known compounds (for example, R. C. Larock, “Comprehensive Organic Transformations”, 2 nd Ed., John A compound synthesized according to the method described in Wiley and Sons, inc., New York (1999) can be used.
  • the compound (1-5), the compound (2-2), and the compound (2-3) their salts can be used as long as they do not interfere with the reaction, and the functional group is optionally protected It is also possible to use the
  • Step 2-1 The compound (2-1) can be produced by reacting the compound (1-1) with hexamethyldisilazane lithium in an inert solvent at normal pressure or under pressure.
  • the inert solvent include, for example, ether solvents such as THF or diethyl ether.
  • the equivalent of hexamethyldisilazane lithium can be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (1-1).
  • the reaction temperature is selected from the range of about -78 ° C to about 50 ° C.
  • Step 2-2 With respect to compound (2-1), compound (2-4) is a compound in an inert solvent, in the presence or absence of a condensing agent and / or a base, under normal pressure or pressure. It can be produced by reacting with (2-2) or (2-3).
  • the inert solvent include ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or chloroform, aprotic solvents such as DMF, NMP, and DMSO.
  • the equivalent of (2-2) or (2-3) can be used in an amount of 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (2-1).
  • condensing agent various condensing agents conventionally used can be used, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride), O- (7- And azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate and the like.
  • the equivalent of the condensing agent can be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to the compound (2-1).
  • the base include diisopropylethylamine, triethylamine and the like.
  • the equivalent of the base can be used 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to the compound (2-1).
  • the reaction temperature is selected from the range of about -78 ° C to about 100 ° C.
  • Step 2-3 The compound (2-5) can be produced using the compound (2-4) as a starting material and using conditions according to step 1-2 of the above production method 1.
  • Step 2-4 Compound (2-6) is prepared using Compound (2-5) as a starting material, and using the conditions according to Step 1-3 of the aforementioned Production Method 1 and Compound (1-5) with the Mitsunobu reaction It can be manufactured by doing.
  • Step 2-5 The compound (2-7) can be produced using the compound (2-6) as a starting material and using conditions according to step 1-4 of the above production method 1.
  • the intermediates and target compounds in the above-mentioned production methods can be subjected to purification methods commonly used in organic synthesis chemistry (for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.). It can be separated and refined. In addition, each intermediate can be subjected to the next reaction without particular purification.
  • purification methods commonly used in organic synthesis chemistry for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.
  • each intermediate can be subjected to the next reaction without particular purification.
  • optically active forms of the compounds of the present invention can be produced by using optically active starting materials and intermediates, or by optically resolving racemates of intermediates and final products.
  • Examples of the method of optical resolution include, but are not limited to, separation methods using an optically active column, separation methods such as fractional crystallization, and the like.
  • the diastereomers of the compound of the present invention can be produced, for example, by separation methods such as, but not limited to, column chromatography and fractional crystallization.
  • Pharmaceutically acceptable salts of the compound represented by the formula (1) are not limited to these, for example, in a solvent such as water, methanol, ethanol, 2-propanol, ethyl acetate, acetone and the like, It can be produced by mixing the compound represented by 1) with a pharmaceutically acceptable acid or base.
  • a silica gel column manufactured by Yamazen Co., Ltd., an ODS-A column manufactured by YMC, and YMC-Actus Triart C18 manufactured by YMC were used.
  • Silica gel 60F254 (Merck) was used for TLC (silica gel plate) when purified using thin layer chromatography (TLC), and TLC plate NH (FujiSilysia) was used for TLC (NH silica gel plate).
  • NMR spectrum [ 1 H-NMR] 400 MHz: JEOL JNM-AL series AL400, JEOL EX 270, or JEOL JNM-ECS series ECS 400
  • LC-MS spectrum Waters ACQUITYTM UltraPerformance LC, Waters AQUITY UPLC H-Class System
  • the measurement conditions (hereinafter also referred to as measurement method) of the high performance liquid chromatography mass spectrometer (LCMS) are as follows, and the observed mass spectrometry value [MS (m / z)] is [M + 1] + The retention time at which the mass spectrometry value was observed is indicated by Rt (minutes, min).
  • Reference Example 1 tert-Butyl [1- (3-hydroxyazetidin-1-yl) ethylidene] carbamate
  • Reference Examples 2 to 4 The compound of Reference Example 1- (i) was used as a starting material, and the reaction, post-treatment and purification were performed according to the same method as that described in Reference Example 1 to obtain the compounds shown in Table (2).
  • reaction solution is evaporated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound (0. 82 g).
  • Reference Example 6- (vi): tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-hydroxy-3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethyl Hexahydro-4,6-methano-1,3,2-benzodioxaborole-2-yl] ethyl ⁇ benzoate Pyrrolidine (0.121 mL, 1.46 mmol) was added to a solution of the compound of Reference Example 6- (v) (0.899 g, 1.46 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 3 hours.
  • the azodicarboxylic acid diisopropyl 40% toluene solution (1.02 mL, 1.94 mmol) was added dropwise.
  • the reaction solution was heated to 30 ° C. and stirred for 45 hours.
  • Reference Example 12- (i): tert-Butyl 2-[(tert-butoxycarbonyl) oxy] -6-hydroxy-3- [2- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) ethyl] benzoate Using the compound of Reference Example 6- (iv) (36 mg) as a starting material, the reaction, workup and purification were carried out according to the same method as that described in Reference Example 6- (vi) to give the title compound (9. 4 mg) was obtained.
  • Reference Example 12 tert-Butyl 6-( ⁇ (3S) -1- [N- (tert-butoxycarbonyl) ethanimidoyl] pyrrolidin-3-yl ⁇ oxy) -2-[(tert-butoxycarbonyl) oxy] -3- [2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl] benzoate
  • the compound of Reference Example 10- (i) (250 mg) was used as a starting material, and the reaction, workup and purification were performed according to the same method as the method described in Reference Example 6, to obtain the title compound (320 mg).
  • Reference Example 14 tert-Butyl 2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR)- 3a, 5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy] azetidin-1-yl ⁇ -4,5-dihydro-1H -Imidazole-1-carboxylate
  • the compound (171 mg, 0.30 mmol) of Reference Example 13- (i) was added to a methanol solution of 2-methylthio-2-imidazoline hydrochloride (73 mg, 0.30 mmol) and triethylamine (0.125 mL, 0.90 mmol).
  • Reference Example 15-(i) A solution of the compound (158 mg, 0.50 mmol) and pyridine (0.081 mL, 1.0 mmol) in dichloromethane (2.5 mL) under nitrogen atmosphere at -20 ° C trifluoromethanesulfonic anhydride (0.101 mL, 0.60 mmol) was added dropwise. The reaction was warmed to room temperature and stirred overnight.
  • Reference Example 15 Di-tert-butyl [(3-iodoazetidin-1-yl) methylidene] biscarbamate Sodium iodide (302 mg) was added to a solution of the compound of Reference Example 15- (ii) (450 mg) in acetone (5 mL). The reaction solution was stirred at room temperature for 1 hour, and then the solvent was evaporated under reduced pressure. Chloroform was added to the obtained residue, the precipitated insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure to give the title compound (377 mg).
  • the reaction was stirred at 50 ° C. for 6 hours.
  • the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound (496 mg).
  • Reference Example 18 Methyl Pyridazinimidic Acid The reaction, work-up and purification were carried out using pyridazine-3-carbonitonyl (0.20 g) according to the same method as that described in Reference Example 17 to obtain the title compound (0.21 g).
  • Reference Example 22 tert-Butyl 6-((1-(((tert-butoxycarbonyl) imino) (4-((tert-butoxycarbonyl) oxy) phenyl) methyl) azetidin-3-yl) oxy) -2-) ((Tert-butoxycarbonyl) oxy) -3- (2-((3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioki Saborol-2-yl) ethyl) benzoate
  • the compound of Reference Example 22- (i) 100 mg, 0 mg) was added to a solution of ethyl 2-hydroxybenzimidate (54.3 mg, 0.329 mmol) and triethylamine (0.0688 mL, 0.493 mmol) in methanol (0.50 mL).
  • Reference Examples 24 to 33 Reaction, post-treatment and purification are carried out according to the same method as described in Reference Example 21, Reference Example 22 or Reference Example 23 using commercially available imidic acid esters or compounds of Reference Examples 17 to 20. The compound shown in (4) was obtained.
  • Reference example 35 tert-butyl 6-((1- (N, N'-bis (tert-butoxycarbonyl) -N-ethylcarbimidoyl) azetidin-3-yl) oxy) -2-((tert-butoxy) Carbonyl) oxy) -3- (2-((3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborol-2-yl) ethyl ) Benzoate
  • the compound of Reference Example 6- (vi) (0.100 g, 0.194 mmol) and the compound of Reference Example 35- (iii) (0.132 g, 0.291 mmol) are used to obtain the same method as described in Reference Example 16.
  • the reaction, workup and purification were carried out according to the methods to obtain the title compound (0.07 g).
  • Reference Example 36- (i): tert-butyl (S)-(1- (3-hydroxypyrrolidin-1-yl) ethylidene) carbamate It is the same as the method described in Reference Example 1 using the compound of Reference Example 1- (i) (1.62 g, 8.61 mmol) and (R) -3-pyrrolidinol (500 mg, 5.74 mmoL) as raw materials. The reaction, workup and purification were carried out according to the method of 1. to give the title compound (1.36 g).
  • Reference Example 36 tert-butyl 6-(((R) -1- (1-((tert-butoxycarbonyl) imino) ethyl) pyrrolidin-3-yl) oxy) -2-((tert-butoxycarbonyl) oxy ) -3- (2-((3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborol-2-yl) ethyl) benzoate It is the same as the method described in Reference Example 6 using the compound of Reference Example 36- (i) (442 mg, 1.94 mmol) and the compound of Reference Example 6- (vi) (500 mg, 0.968 mmol) as starting materials. The reaction, workup and purification were carried out according to the method of to obtain the title compound (810 mg).
  • the reaction solution was heated to 100 ° C. and stirred for 3 hours.
  • Reference Examples 40 and 41 The compounds of Reference Example 38 and Reference Example 39 were used as starting materials, and the reaction, post-treatment and purification were carried out according to the same method as that described in Reference Example 37- (ii) to obtain compounds shown in Table (6). .
  • Reference Examples 42 to 44 The compound of Reference Example 40, Reference Example 41, and Reference Example 13- (i) is used as a raw material, and the reaction, post-treatment and purification are carried out according to a method similar to the method described in Reference Example 37. The compound is obtained.
  • Reference Example 45 N-hydroxynicotinimidoyl chloride N-chlorosuccinimide (203 mg, 1.52 mmol) was added to a mixed solution of the compound of Reference Example 45- (i) (161 mg, 1.32 mmol) in dimethoxyethane (2 mL) / THF (2 mL), and the reaction mixture was heated to 60 ° C. The mixture was stirred for 1 hour. After cooling to room temperature, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (134 mg).
  • Reference Example 50 N-hydroxy-2- (thiophen-2-yl) acetimidoyl chloride 10% lithium methoxide methanol solution (1.45 mL, 3.82 mmol) was added to a solution of the compound of Reference Example 50- (i) (300 mg, 1.91 mmol) in dry methanol (15 mL), and then the reaction solution was cooled to room temperature. And stirred for 1 hour.
  • reaction solution is concentrated under reduced pressure, dichloromethane (27 mL) is added to the residue, cooled to -78 ° C, and titanium (IV) chloride (14% dichloromethane solution, about 1.0 M) (6.11 mL, 6.11 mmol) is added After addition and stirring for 30 minutes, it stirred at room temperature for 1 hour.
  • the reaction solution was cooled in an ice bath, water (25 mL) was added, the solid was filtered off (using Celite), washed with dichloromethane, and the filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Reference Examples 52-60 Reaction, post-treatment and purification were conducted according to the same method as that described in Reference Example 51 using commercially available imidate esters or the compounds of Reference Examples 45 to 50 to obtain the compounds shown in Table (9).
  • a solution of the compound of Reference Example 61- (i) (292.2 mg, 0.941 mmol) in N, N-dimethylformamide (0.47 mL), methyl iodide (0.118 mL, 1.88 mmol) and cesium carbonate (552 mg) , 1.69 mmol) was added and the reaction was stirred at 90 ° C. for 14 h. After cooling to room temperature, water was added to the reaction solution, and extracted with ethyl acetate.
  • Reference example 61 tert-butyl 2-((tert-butoxycarbonyl) oxy) -6-((1-((methoxyimino) (1-methyl-1H-pyrazol-4-yl) methyl) azetidin-3-yl )) Oxy) -3- (2-((3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborol-2-yl) ethyl) Benzoate Compound of Reference Example 6- (vi) (159 mg, 0.397 mmol), N, N, N ', N'-Tetramethylazodicarboxamide (106 mg, 0.615 mmol) and Compound of Reference Example 61- (ii) To a solution of 84 mg, 0.40 mmol) in toluene (1.5 mL) was added tri-n-butylphosphine (0.152 mL
  • Reference example 62 tert-butyl 2-((tert-butoxycarbonyl) oxy) -6-((1- (imino (1-methyl-1H-pyrazol-4-yl) methyl) azetidin-3-yl) oxy) -3- (2-((3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborole-2-yl) ethyl) benzoate
  • Acetic anhydride (0.016 mL, 0.171 mmol) is added to a solution of the compound of Reference Example 54 (79 mg, 0.114 mmol) in acetic acid (0.455 mL), and after stirring at room temperature, methanol (0.682 mL) , Potassium formate (191 mg, 2.275 mmol) and 10% palladium on carbon (15.4 mg) were added.
  • Reference example 63 tert-butyl 2- ⁇ (tert-butoxycarbonyl) oxy ⁇ -6-([1- ⁇ 1-imino-2- (thiophen-2-yl) ethyl ⁇ azetidin-3-yl] -3- [2- ⁇ (3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborole-2-yl ⁇ ethyl] benzoate Using the compound of Reference Example 60 (149 mg, 0.210 mmol), according to a method similar to the method described in Reference Example 62, reaction, post-treatment and purification were carried out to obtain the title compound (0.0791 g).
  • Reference example 64 tert-butyl 6-([1- ⁇ (4-aminophenyl) (imino) methyl ⁇ azetidin-3-yl] oxy) -2- ⁇ (tert-butoxycarbonyl) oxy ⁇ -3- [2 - ⁇ (3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborole-2-yl ⁇ ethyl] benzoate To a solution of the compound of Reference Example 31 (96.0 mg, 0.133 mmol) in methanol (2.0 mL) was added 10% palladium / carbon (20.0 mg), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (112 mg).
  • the reaction solution is cooled to room temperature, and the compound of Reference Example 6- (ii) (2.5 g, 5.11 mmol) and bis (tri-tert-butylphosphine) palladium (0) (0.261 g, 0.511 mmol)
  • the solution was added dropwise to a solution of (10 mL) in THF and stirred at room temperature for 1 hour.
  • the reaction solution was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the title compound (2.51 g).
  • Reference example 65 tert-butyl 3-((2R) -2-((2- (3-((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -2-oxoethyl) thio) -2-(( 3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methanobenzo-1,3,2-dioxaborol-2-yl) ethyl) -2-((tert-butoxycarbonyl) oxy ) -6-((1- (4,5-Dihydrothiazol-2-yl) azetidin-3-yl) oxy) benzoate
  • the compound (308 mg, 0.393 mmol) of Reference Example 65- (iv) and 1- (4,5-dihydrothiazol-2-yl) azetidin-3-ol (92.1 mg, 0.582 mmol) in toluene (2 mL
  • Reference example 66 tert-butyl 2- ⁇ (tert-butoxycarbonyl) oxy ⁇ -6-[ ⁇ 1- (4,5-dihydrothiazol-2-yl) azetidin-3-yl ⁇ thio] -3- ⁇ 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl ⁇ benzoate
  • Reference Example 66 tert-butyl 2- ⁇ (tert-butoxycarbonyl) oxy ⁇ -6-[ ⁇ 1- (4,5-dihydrothiazol-2-yl) azetidin-3-yl ⁇ thio] -3- ⁇ 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl ⁇ benzoate
  • the reaction, post-treatment and formation were carried out according to the same method as that described in Reference Example 6- (iv) to give the title compound 38, 3 mg).
  • Example 1 8-[(1-Ethanimidoylazetidin-3-yl) oxy] -4,4-dihydroxy-5-oxa-4-bora nida bicyclo [4.4.0] deca-1 ( 6), 7, 9-triene-7-carboxylic acid disodium salt
  • Example 1A 7-[(1-Ethanimidoylazetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid hydrochloride
  • Phenylboronic acid (51 mg, 0.417 mmol), hexane (15 mL) and 4 mol / L hydrochloric acid / ethyl acetate solution (2.5 mL, 10 mmol) in a solution of the compound of Reference Example 8 (297 mg, 0.417 mmol) in acetonitrile (5 mL) ) was added and stirred at room temperature for 6 hours.
  • the reaction solution was allowed to stand, and the supernatant liquid (hexane layer) of the two layers separated was removed by a syringe, and the acetonitrile layer was evaporated under reduced pressure. The resulting residue was washed with acetonitrile and collected by filtration.
  • the compound of Reference Example 11 (30 mg, 0.046 mmol) was dissolved in TFA (0.5 mL), and triethylsilane (0.022 mL, 0.137 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 1.5 hours, and then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in hexane (5 mL) and acetonitrile (1 mL), 4 mol / L hydrogen chloride / dioxane (0.114 mL, 0.456 mmol) was added, and the mixture was stirred at room temperature for 3 hours.
  • reaction solution was allowed to stand, and the supernatant liquid (hexane layer) of the two layers separated was removed by a syringe, and the acetonitrile layer was evaporated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated crystals were filtered, and washed with diethyl ether and acetonitrile to give the title compound (9.0 mg).
  • Example 7 7- ⁇ [1- (4,5-Dihydro-1,3-oxazol-2-yl) azetidin-3-yl] oxy ⁇ -2-hydroxy-3,4-dihydro-2H-1, 2-Benzoxaborin-8-carboxylic acid
  • Hexane (2.5 mL), phenylboronic acid (5 mg, 0.041 mmol) and 4 mol / L hydrogen chloride / dioxane (0.105 mL) were added to a solution of the compound of Reference Example 13 (27 mg) in acetonitrile (0.5 mL). 421 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was allowed to stand, and the supernatant liquid (hexane layer) of the two layers separated was removed by a syringe, and the acetonitrile layer was evaporated under reduced pressure.
  • Example 8 7- ⁇ [1- (4,5-Dihydro-1H-imidazol-2-yl) azetidin-3-yl] oxy ⁇ -2-hydroxy-3,4-dihydro-2H-1,2- Benzoxaborin-8-carboxylic acid hydrochloride
  • Example 9 7-[(1-carbamimidoylazetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid hydrochloric acid salt
  • the compound of Reference Example 16 (244 mg, 0.30 mmol) was used as a starting material, and according to a method similar to the method described in Example 6, reaction, post-treatment and purification were carried out to obtain the title compound (4.0 mg).
  • Example X 1 8-[(1-Ethanimidoylazetidin-3-yl) oxy] -4,4-dihydroxy-5-oxa-4-bora nida bicyclo [4.4.0] deca-1 ( 6) Preparation of disodium salt of 7,9-trien-7-carboxylic acid (method for producing tetrasubstituted boron compound from trisubstituted boron compound) 2 mol of acetonitrile solution of 7-[(1-ethaneimidoylazetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid / L Add sodium hydroxide aqueous solution and stir overnight at room temperature.
  • the title compound can be obtained by purifying the reaction solution by reverse phase column chromatography (eluent: acetonitrile / water).
  • Example X2 (3R) -4,4-dihydroxy-3- (1,3,4-thiadiazol-2-ylsulfanyl) -8-methoxy-5-oxa-4-boranidabicyclo [4.4. 0] Deca-1 (6), 7,9-trien-7-carboxylate Preparation of disodium (method of preparing tetra-substituted boron compound from tri-substituted boron compound) (3R) -2-hydroxy-7-methoxy-3- (1,3,4-thiadiazol-2-ylsulfanyl) -3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid Add 2 mol / L aqueous sodium hydroxide solution to the acetonitrile solution of and stir overnight at room temperature. The title compound can be obtained by purifying the reaction solution by reverse phase column chromatography (eluent: acetonitrile / water).
  • Example 10 2-hydroxy-7-( ⁇ 1-[(2-hydroxyphenyl) (imino) methyl] azetidin-3-yl ⁇ oxy) -3,4-dihydro-2H-1,2-benzoxabori Nin-8-carboxylic acid hydrochloride
  • acetonitrile solution 1.0 mL
  • hexane 5.0 mL
  • phenylboronic acid 11.9 mg, 0.0974 mmol
  • 4 mol / L hydrogen chloride / Dioxane 0.278 mL, 1.11 mmol
  • the reaction solution was allowed to stand, and the supernatant liquid (hexane layer) of the two layers separated was removed by a syringe, and the acetonitrile layer was evaporated under reduced pressure.
  • Examples 11 to 44 The corresponding reference example compounds 21, 23 to 37, 42 to 44, 51 to 63, 65, 66 are used as starting materials, and the reaction is carried out in the same manner as the method described in Example 1, Example 2 and Example 10. The post treatment and purification were carried out to obtain the compounds shown in Table (11).
  • Example 45 7-( ⁇ 1-[(3-Aminophenyl) (imino) methyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzoxazolyl Nin-8-carboxylic acid dihydrochloride 10% Palladium / carbon (8.3 mg) was added to a solution of the compound of Example 21 (16.6 mg, 0.133 mmol) in methanol (0.7 mL), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (15.9 mg).
  • Example 46 7-( ⁇ 1-[(4-Aminophenyl) (imino) methyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzoxabori Nin-8-carboxylic acid dihydrochloride
  • the compound of Example 22 (4.0 mg, 8.94 ⁇ mol) was used as a starting material, and the reaction and post-treatment were carried out according to a method similar to the method described in Example 45 to give the title compound (2.5 mg mg) .
  • Example 47 7-[(1- ⁇ [4- (ethanimidoylamino) phenyl] (imino) methyl ⁇ azetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1, 2-Benzoxaborin-8-carboxylic acid dihydrochloride
  • acetonitrile solution 1.0 mL
  • hexane 5.0 mL
  • phenylboronic acid (15.5 mg, 0.127 mmol)
  • 4 mol / L hydrogen chloride / dioxane 0.667 mL, 2.67 mmol
  • the reaction solution was allowed to stand, and the supernatant liquid (hexane layer) of the two layers separated was removed by a syringe, the acetonitrile layer was evaporated under reduced pressure, and the obtained solid was washed with acetonitrile.
  • Test Example 1 Evaluation of Minimum Inhibitory Concentration (MIC) of MEPM against ⁇ -Lactamase-Producing Bacteria
  • MIC Minimum Inhibitory Concentration
  • Test Example 2 Evaluation of Minimum Inhibitory Concentration (MIC) of MEPM on ⁇ -Lactamase-Producing Bacteria
  • E. coli. coli ATCC BAA-2469 NDM-1
  • K. coli. pneumomiae ATCC BAA-2470 NDM-1
  • K.I. pneumomia NCTC 13439 VIM-1
  • K.I. pneumomia NCTC 13440 VIM-1
  • E. coli It is possible to evaluate the metallo- ⁇ -lactamase inhibitory activity of the test compound using E. coli NCTC 13476 (IMP) or the like.
  • the compounds of the present invention have a strong inhibitory action on ⁇ -lactamase, and are sepsis, pyrogenic neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung Abscess, pyothorax, secondary infection of chronic respiratory disease, pharyngeal and laryngitis, tonsillitis, osteoarthritis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatics It is useful as a therapeutic agent and / or preventive agent for lymphadenitis, secondary infections such as trauma / burn and surgical wounds, urinary tract infections, genital infections, eye infections or dental infections.

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Abstract

L'invention développe un nouveau composé possédant une excellente action inhibitrice de bêta-lactamase, et fournit un agent de prévention ou de traitement avantageux d'une infection bactérienne seul ou en combinaison avec un médicament à base de bêta-lactame . Plus précisément, l'invention concerne un composé représenté par la formule (1a) ou (1b) [dans la formule (1a) ou (1b), un élément parmi Ｒ１, Ｒ２ et Ｒ３ est représenté par la formule (3), Ｌ４ contient un groupe imine défini dans la description, et les autres groupes sont tels que définis dans la description] ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2018/025563 2017-07-06 2018-07-05 Dérivé d'imine WO2019009369A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020138499A1 (fr) * 2018-12-28 2020-07-02 大日本住友製薬株式会社 Composé substitué par un alkyle
WO2021079984A1 (fr) * 2019-10-25 2021-04-29 大日本住友製薬株式会社 Nouveau composé cyclique condensé substitué
JP7550421B2 (ja) 2019-10-25 2024-09-13 住友ファーマ株式会社 オキソ置換化合物からなる医薬

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JP2011503181A (ja) * 2007-11-13 2011-01-27 プロテズ・ファーマシューティカルズ・インコーポレイテッド ベータ−ラクタマーゼ阻害剤
WO2016003929A1 (fr) * 2014-07-01 2016-01-07 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
JP2016505619A (ja) * 2013-01-04 2016-02-25 レンペックス・ファーマシューティカルズ・インコーポレイテッド ボロン酸誘導体及びその治療的使用
WO2016149393A1 (fr) * 2015-03-17 2016-09-22 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
JP2017517508A (ja) * 2014-05-19 2017-06-29 レンペックス・ファーマシューティカルズ・インコーポレイテッド ボロン酸誘導体およびその治療的使用

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Publication number Priority date Publication date Assignee Title
JP2011503181A (ja) * 2007-11-13 2011-01-27 プロテズ・ファーマシューティカルズ・インコーポレイテッド ベータ−ラクタマーゼ阻害剤
JP2016505619A (ja) * 2013-01-04 2016-02-25 レンペックス・ファーマシューティカルズ・インコーポレイテッド ボロン酸誘導体及びその治療的使用
JP2017517508A (ja) * 2014-05-19 2017-06-29 レンペックス・ファーマシューティカルズ・インコーポレイテッド ボロン酸誘導体およびその治療的使用
WO2016003929A1 (fr) * 2014-07-01 2016-01-07 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
WO2016149393A1 (fr) * 2015-03-17 2016-09-22 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020138499A1 (fr) * 2018-12-28 2020-07-02 大日本住友製薬株式会社 Composé substitué par un alkyle
WO2021079984A1 (fr) * 2019-10-25 2021-04-29 大日本住友製薬株式会社 Nouveau composé cyclique condensé substitué
KR20220088736A (ko) 2019-10-25 2022-06-28 스미토모 파마 가부시키가이샤 신규 치환 축환형 화합물
JP7550421B2 (ja) 2019-10-25 2024-09-13 住友ファーマ株式会社 オキソ置換化合物からなる医薬
TWI873211B (zh) * 2019-10-25 2025-02-21 日商住友製藥股份有限公司 新穎取代縮環型化合物
JP7654554B2 (ja) 2019-10-25 2025-04-01 住友ファーマ株式会社 新規置換縮環型化合物

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