TW201925201A - Diazabicyclooctane derivatives - Google Patents

Abstract

It is intended to provide a compound that exhibit having widely potent inhibitory activity against various beta-lactamase, a pharmaceutically acceptable salt thereof, or a prodrug form thereof.

Description

 Diazabicyclooctane derivative  

The present invention relates to a novel diazabicyclooctane derivative having a β-endosaminolase inhibitory action, a pharmaceutically acceptable salt thereof or a carboxylic acid pre-drug agent at the 6-position thereof.

To date, various β-endoxime antibacterial agents have been developed, which are one of the most important therapeutic drugs for bacterial infections in clinical practice. On the other hand, Gram-negative bacteria which are resistant to β-neutamine antibacterial agents are increased due to the production of β-endo-amphetase which decomposes the β-indoleamine antibacterial agent. According to the molecular classification of Ambler, β-endoprolinase is divided into four categories. That is, category A (TEM type, SHV type, CTX-M type, KPC type, etc.), category B (NDM type, IMP type, VIM type, L-1 type, etc.), category C (AmpC type, CMY type, ADC type, etc.), category D (OXA type, etc.). It is known that these are divided into two categories, roughly classified into category A, type C and type D are serine type β-endoprolinase, and type B is metal type β-endoaminase, according to different action machines. The β-neutamine antibacterial agent is hydrolyzed (Non-Patent Document 1).

To date, several β-endoprostanase inhibitors have been developed to support the effectiveness of the β-endoxime antibacterial agent. However, clavulanic acid, tazobactam and sulbactam, which are now most commonly used in clinical practice, are serine-type β-endoprostanase inhibitors only for category A. The specific enzyme has an inhibitory activity and its usefulness is limited. Further, avibactam mainly inhibits the enzymes of the categories A and C of Klebsiella pneumoniae carbapenemase (KPC) (Non-Patent Document 2) which are currently clinically problematic. Avidabatin is used clinically as a mixture with ceftazidime (AVYCAZ) which is a cefem antibacterial agent, but Klebsiella is a part of KPC which is produced as a class A enzyme. There is a report (see Non-patent Document 3) which is a plant that has acquired patience. Also, the effectiveness of the enzyme of category D is also limited. In the future, in order to meet the challenge of significant β-endoxime tolerance, it is urgent to expect a broad and strong inhibition of the class A, C and D of the serine type β-endoprotonase by either alone or with various β-endoamines. The combination of antibacterial agents not only shows the effectiveness of the existing β-indoleamine antibacterial agent, but also the gram-negative bacteria showing resistance to the combination of the existing β-endoxime antibacterial/β-endosaminolase inhibitor. A serine type beta-endoprostanase inhibitor.

 [Previous Technical Literature]    [Non-patent literature]  

[Non-Patent Document 1] Antimicrobial Agents and Chemotherapy, 54(3), 969-976, 2010

[Non-Patent Document 2] The Lancet Infraction diseases, 13(9), 785-796, 2013

[Non-Patent Document 3] Antimicrobial Agents and Chemotherapy, 61(3), 1-11, 2017

It is an object of the present invention to provide a compound which has broad and potent inhibitory activity against various β-endoguanamine enzymes. It is preferred to provide a compound which has broad and potent inhibitory activity against various β-endosaminolase and which can be administered orally. Further, another object of the present invention is to preliminarily administer a compound having a broad and effective inhibitory activity against various β-endoprostanases, and to be efficiently absorbed in the body after administration, thereby exhibiting a high pharmacological effect. Compound. Another object of the present invention is to provide a compound, a pharmaceutically acceptable salt thereof or a prodrug thereof, alone or in combination with a β-nadeamine antibacterial agent, for use in the treatment and/or prevention of bacterial infections (including A pharmaceutical composition of an infectious disease caused by a drug-resistant bacteria of a drug-resistant bacteria. It is preferred to provide a pharmaceutical composition which can be administered orally and which can be used for the treatment of bacterial infections (including infections caused by drug-resistant bacteria including a plurality of drug-resistant bacteria). Further, it is preferred to provide a broad inhibitory effect on the β-endoprostanase belonging to the classes A, C and D produced by Gram-negative bacteria, especially for the representative TEM type, SHV type, KPC type, etc. ESBL (matrix) A specifically-expanded β-endoprostanase has a compound which has an effective inhibitory action. In particular, it is provided that it exhibits an effective inhibitory effect on the serine-type β-endoprostanase belonging to the class A, C or D, alone or in combination with a β-endoxime antibacterial agent, for the inclusion of cephalosporin or carbapenem Various agents of carbarenem are also effective compounds resistant to Gram-negative bacteria. Further provided because it also exhibits an effective inhibitory effect on the serine-type β-endoprolinase belonging to the class A, C or D, either alone or in combination with a β-endoxime antibacterial agent, for the inclusion of cephalosporin or carbapenem The various β-endoxime antibacterial resistant Gram-negative bacteria are also effective compounds.

The present invention provides a pharmaceutical composition capable of solving the above problems or a pharmaceutical composition for treating a bacterial infection (including an infection caused by a drug-resistant bacteria including a plurality of drug-resistant bacteria) by having at least the following structural features.

1) A linking group having a sulfur atom at the 2-position of the diazabicyclooctane skeleton.

2) The group represented by -OCR ²¹ R ²² COOH or -OS(=O) ₂ OH at the 6-position of the diazabicyclooctane skeleton.

The present invention provides the invention shown below.

(Item 1) A compound, a pharmaceutically acceptable salt thereof or a carboxylic acid or a sulfonic acid precursor drug at the 6 position thereof, which is of the formula: Any of them.

(Item 2) A compound according to item 1, a pharmaceutically acceptable salt thereof or a carboxylic acid or a sulfonic acid precursor drug at the 6 position thereof, which is of the formula: Among the responsibilities.

(Item 3) A β-endoprostanase inhibitor comprising the compound according to Item 1 or 2, a pharmaceutically acceptable salt thereof or a 6-position carboxylic acid or sulfonic acid precursor drug.

(Item 4) A pharmaceutical composition comprising the compound according to Item 1 or 2, a pharmaceutically acceptable salt thereof or a 6-position carboxylic acid or sulfonic acid precursor drug.

(Item 5) The pharmaceutical composition according to Item 4, which is for use in combination with a β-neutamine antibacterial agent.

(Item 6) A pharmaceutical composition containing a β-neutamine antibacterial agent for administration in combination with the β-endoprostanase inhibitor described in Item 3.

(Item 7) A pharmaceutical composition comprising the β-endosaminolase inhibitor and the β-namidamide antibacterial agent according to item 3.

The pharmaceutical composition according to any one of items 5 to 7, wherein the β-nadehydeamine antibacterial agent is any one selected from the group consisting of Ampicillin, Piperacillin, and A. Amoxicillin, Carbenicillin, Sulbactam, Cefepime, Ceftazidime, Cefixime, Ceftibuten, Cefpod Cefpodoxime, Cefiderocol, Cefaclor, Cefdinir, Cefditore, Cefuroxime, Cefcapene, Ceftriaxone (Ceftriaxone), Imipenem, Meropenem, Doripenem, Tebipenem, Ertapenem, Aztreonam, Card Carumonam, Latamoxef, Flomoxef, Faropenem, Sulopenem, Cefmetazole, Cexixitin, and Cefotaxime a compound of Cefotetan, such pharmaceutically acceptable salts or such precursors Thereof.

(Item 9) A compound according to item 1 or 2, a pharmaceutically acceptable salt thereof, or a 6-position thereof, for use in combination with a β-namidamine antibacterial agent for administration, treatment and/or prevention of a bacterial infection A carboxylic acid or a sulfonic acid precursor drug.

(Item 10) One for use with any one selected from the group consisting of ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam, cefepime, cefotaxime, cefixime, ceftibuten, cefpodoxime , cefadidime, cefaclor, cefdinir, ceftal, cefuroxime, cefaclor, ceftriaxone, imipenem, meropenem, doripenem, tibepine, ertape Compounds of south, aztreonam, carumol, oxycephalosporin, fluoxetine, faropenem, thiopenem, cefmetazole, cefoxitin and cefotetan, such pharmaceutically acceptable salts or A compound such as the compound of item 1 or 2, a pharmaceutically acceptable salt thereof or a 6-position thereof, or a 6-position of a carboxylic acid or a compound of the above-mentioned drug, which is administered in combination with a drug for the treatment and/or prevention of a bacterial infection. Sulfonic acid precursor drugs.

The compound of the present invention can be used as a pharmaceutical product alone or in combination with a β-namidamide antibacterial agent having at least one of the following characteristics.

A) shows potent inhibitory activity against various β-endoprolinases (especially serine type β-endoguanases (e.g., classes A, C, D)).

B) A good antibacterial spectrum is shown for various bacteria of Gram-negative bacteria.

C) shows strong antibacterial activity against Gram-negative bacteria producing β-endosaminolase.

D) Strong antibacterial activity is exhibited for a plurality of dose-tolerant bacteria, particularly Gram-negative bacteria producing a serine-type β-endosaminolase.

E) Strong antibacterial activity against matrix-specific expanded β-endoprolinase (ESBL)-producing bacteria.

F) shows strong antibacterial activity against Gram-negative bacteria producing the β-endoprolinase of class A, C and/or D.

G) shows strong antibacterial activity against carbapenem resistant bacteria.

H) Strong antibacterial activity against enterobacteriaceae bacteria which are commercially available.

I) Carbon for carbapenemase producing Klebsiella pneumoniae Carbapenemase (KPC) or New Delhi metallo-beta-lactamase (NDM) Penicillin-resistant enterobacteriaceae bacteria (CRE) showed strong antibacterial activity.

J) does not show cross-resistance with existing β-endoxime antibacterials, especially cephalosporin antibacterials and/or carbapenem antibacterials.

K) No side effects (such as fever, anaphylaxis, drug eruption, etc.) were observed after administration in vivo.

L) The stability of the compound (for example, solution stability in various liquid properties, light stability, etc.) and/or high solubility in water.

M) It has the characteristics of high drug concentration, high oral absorption, high membrane permeability, long duration of effect, long duration of blood, high bioavailability or high tissue migration.

N) The inhibitory effect on CYP enzymes (eg CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.

O) High metabolic stability.

P) does not cause digestive tract disorders (such as diarrhea, hemorrhagic enteritis, peptic ulcer, gastrointestinal bleeding, etc.).

Q) Does not cause nephrotoxicity, hepatotoxicity, cardiotoxicity (such as prolonged QTc), sputum, etc.

Hereinafter, embodiments of the invention will be described. The expressions of the singular forms in the full text of the present specification (for example, "a", "an", "the" in English, etc., corresponding articles in other languages, adjectives, etc., unless otherwise stated, may also be construed as including the plural. concept. Further, the terms used in the specification are to be understood as meanings commonly used in the field unless otherwise specified. Therefore, unless otherwise defined, all the specific terms and technical terms used in this specification have the same meaning as those generally understood by those skilled in the art to which the invention belongs, and in the case of contradiction, the present specification (including definition) is preferred. . Hereinafter, specific definitions of terms specifically used in the present specification are described.

The term "constituting" means having only the constituent elements.

The term "including" means not only the constituent elements but also the undocumented elements.

Unless otherwise stated, each term in this specification is used alone or in combination with other terms and is defined as follows. The substituent "substituted or unsubstituted" may be substituted by one or more of the groups exemplified below. Further, when substituted with a plural substituent, the substituents may be the same or different.

The "precursor drug" in the compound of the present invention means "the 6-position compound of the formula is a carboxylic acid precursor drug" or "the 6th compound of the formula is a sulfonic acid precursor drug".

The "parent compound" in the compound of the present invention means, for example, when the compound of the present invention is represented by the formula (IA) or (IB), as shown in the formula (IA) or (IB), having a carboxylic acid at the terminal of the 6-position side chain or Sulfonic acid compounds: (wherein, -L- is -S-, -S(=O)-, -S(=O) ₂ - or -S(=O)(=NH)-; R ¹ is a substituted or unsubstituted alkane Alkenyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted An aromatic heterocyclic group, a substituted or unsubstituted amino group or R ¹³ R ¹⁴ C=N-; wherein R ¹³ and R ¹⁴ a) R ¹³ and R ¹⁴ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group a substituted or unsubstituted amino group or b) R ¹³ and R ¹⁴ together with an adjacent carbon atom form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; with respect to R ²¹ and R ²² a) R ²¹ and R ²² are each independently a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group or b) R ²¹ and R ²² together with an adjacent carbon atom form a substituted or unsubstituted methylene group, a substituent or Unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted non-aromatic heterocyclic ring).

The "carboxylic acid at the 6-position of the compound represented by the formula" means a substituent -COOH group bonded to the nitrogen atom at the 6-position of the parent nucleus (diazabicyclooctane) of the compound represented by the formula.

The "6-position of the compound represented by the formula is a carboxylic acid precursor drug" means, for example, a compound represented by the formula (II-A) when the compound of the present invention is represented by the formula (IA): (wherein, ^{R R} is a group forming a prodrug, and other symbols have the same meaning as the above).

In the present specification, the "6-position of the compound represented by the formula is a carboxylic acid precursor drug" means a compound represented by the formula (II-A) in the following reaction formula or a pharmaceutically acceptable salt thereof. (wherein, each symbol has the same meaning as the above) means a decomposition reaction caused by a drug metabolizing enzyme, a hydrolyzing enzyme, a gastric acid, an intestinal bacterium, or the like under physiological conditions in a living body, and is converted into a formula (IA). A compound which exhibits β-inactamase inhibitory activity as a parent compound. The precursor drug has its own activity.

Preferably, the 6-position of the compound represented by the formula (I) is a carboxylic acid pre-drug drug, and the bioavailability and/or AUC (curved blood concentration area) ratio when expressed in a living body is expressed as a formula (IA). a compound that enhances the compound.

Therefore, the prodrug is administered to a living body (for example, orally), and is absorbed in the stomach and/or the intestines, and is preferably absorbed in the body, and then converted into a parent compound represented by the formula (IA), preferably Oral administration can be a more effective β-endosinase inhibitor and/or antibacterial agent than the parent compound represented by formula (IA).

The 6-position of the compound of the present invention is a carboxylic acid pre-drug, and for example, a pro-compound represented by the formula (IA) having a carboxyl group is introduced into an active intermediate such as a mercapto halide, an acid anhydride or a mixed acid anhydride, and then reacted with an appropriate alcohol, or a substituted or unsubstituted alkoxycarbonyl derivative, a substituted or unsubstituted alkoxycarbonyl derivative, which is produced by reacting a condensing agent with a suitable alcohol or by reacting with a suitable alkyl halide in the presence of a base, A prodrug such as a substituted or unsubstituted cycloalkoxycarbonyl derivative, a substituted or unsubstituted non-aromatic heterocyclic derivative.

Or a compound represented by the formula (I') having a hydroxyl group represented by the following formula may be produced by reacting a suitable alkyl halide in the presence of a base, and examples thereof include a substituted or unsubstituted alkoxycarbonyl derivative, and a substitution. Or an unsubstituted alkenyloxycarbonyl derivative, a substituted or unsubstituted cycloalkoxycarbonyl derivative, a substituted or unsubstituted non-aromatic heterocyclic derivative, and the like. The substituents in the "substituted or unsubstituted alkoxycarbonyl derivative" and the "substituted or unsubstituted oxycarbonyl derivative" may, for example, be a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group or a non-aromatic group. Ring base, etc. The substituents in the "substituted or unsubstituted alkenyloxycarbonyl derivative", the "substituted or unsubstituted cycloalkoxycarbonyl derivative" and the "substituted or unsubstituted non-aromatic heterocyclic derivative" can be enumerated Halogen, alkyl, alkoxy, and the like.

For example, the P ^R O- group in the formula (II-A) may, for example, be CH ₃ O-, C ₂ H ₅ O-, iso-Pro-, tert-BuO-, sec-BuO-, PhO-, tert-BuCH ₂ O-, (C ₂ H ₅ ) ₂ CH ₂ O-, tert-BuCOOCH ₂ O-, MeCOOCH(CH ₃ )O-, iso-ProCOCH(CH ₃ )O-, cyclohexyl O-, dimethyl ring Hexyl O-, 2-isopropyl-5-methyl-cyclohexyl O-, cyclohexyl CH ₂ O-, cyclopentyl CH ₂ O-, cycloheptyl O-, cyclooctyl O-, tetrahydroper O-, 4-((5-methyl-2-oxo-1,3-dioxol-4-yl)CH ₂ O-, cyclohexyl OCOOCH(CH ₃ )O-, CF ₃ CH ₂ O-, FCH ₂ CH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, CH ₃ CH(CH ₃ )=CHCH ₂ O-, CH ₃ CH(CH ₃ )=CHCH ₂ CH ₂ CH(CH ₃ ) = CHCH ₃ O- and so on.

In the present specification, the "6-position of the compound represented by the formation formula is the base of the carboxylic acid precursor drug" means the "P ^R " group in the formula (II-A) of the following reaction formula: (where the symbols have the same meaning as the above)

- The part of the COOP ^R group is converted to the base of the -COOH group in the formula (IA) by the decomposition reaction caused by the drug metabolizing enzyme, hydrolyzing enzyme, gastric acid, intestinal bacteria, etc. under physiological conditions in the living body.

The "precursor-forming drug-based group" preferably means increasing the bioavailability and/or AUC of the parent compound represented by the formula (IA) by addition to the parent compound represented by the formula (IA) (under the blood concentration curve) The basis of the area).

The "sulfonic acid at the 6-position of the compound represented by the formula" means an -S(=O) ₂ OH group bonded to the side chain of the nitrogen atom at the 6-position of the compound nucleus (diazabicyclooctane) represented by the formula.

The "6-position of the compound represented by the formula is a sulfonic acid precursor drug" means a compound of the formula (II-B), for example, when the compound of the present invention is represented by the formula (IB): (wherein, ^{R R1} is the group forming the precursor drug, and other symbols have the same meaning as the above)

In the present specification, the "6-position of the compound represented by the formula is a sulfonic acid precursor drug" means a compound represented by the formula (II-B) in the following reaction formula or a pharmaceutically acceptable salt thereof: (where the symbols have the same meaning as the above)

a compound which exhibits β-endoprostase inhibitory activity by a decomposition reaction caused by a drug metabolizing enzyme, a hydrolyzing enzyme, a gastric acid, an intestinal bacterium, etc. under physiological conditions in a living body, and converted into a parent compound represented by the formula (IB) . The precursor drug also has its own activity.

Preferably, the compound represented by the formula is a sulfonic acid pre-drug agent, and the bioavailability and/or AUC (curved area of blood concentration) ratio is higher than that of the compound (IB). Compound.

Therefore, the prodrug is absorbed in the body and/or the intestines after being administered in vivo (for example, orally), and then converted into a pro-compound represented by the formula (IB), preferably Oral administration can be a β-endoprotinase inhibitor and/or an antibacterial agent which is more effective than the parent compound represented by the formula (IB).

The compound 6 represented by the formula is a sulfonic acid precursor drug. For example, an affinity compound represented by the formula (IB) having a sulfonic acid group is introduced into an active intermediate such as a sulfonium halide, an acid anhydride or a mixed acid anhydride, and an appropriate alcohol. A substituted or unsubstituted alkoxysulfonate derivative precursor drug produced by the reaction.

Alternatively, a substituted or unsubstituted alkoxylate prepared by reacting a compound represented by the formula (I') having a hydroxyl group represented by the following formula with a suitable sulfonium halide, a sulfonic anhydride or a mixed acid anhydride in the presence of a base may be exemplified. A prosthetic drug derived from a sulfonium derivative. The substituent in the "substituted or unsubstituted alkoxysulfonyl derivative" may, for example, be a halogen, an alkoxy group, a cycloalkyl group, a non-aromatic heterocyclic group, a substituted or unsubstituted alkoxycarbonyl group (substituent group) Examples: halogen, alkoxy, cycloalkyl, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group (example of substituent: halogen, alkyl, pendant oxy group), alkylcarbonyl thiol group, etc. .

(where the symbols have the same meaning as the above)

For example, the P ^R1 O- group in the formula (II-B) may, for example, be CH ₃ O-, C ₂ H ₅ O-, iso-PrO-, sec-BuO-, PhO-, tert-BuCH ₂ O-, ( C ₂ H ₅ ) ₂ CH ₂ O-, tert-BuCOOCH ₂ O-, MeCOOCH(CH ₃ )O-, iso-PrOCOCH(CH ₃ )O-, cyclohexyl O-, cyclopentyl CH ₂ O-, 4 -((5-Methyl-2-oxo-1,3-dioxol-4-yl)CH ₂ O-, cyclohexyl OCOOCH(CH ₃ )O-, CF ₃ CH ₂ O- , FCH ₂ CH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, and the like.

In the present specification, the "6-position of the compound represented by the formation formula is the base of the sulfonic acid precursor drug" means the "P ^R1 " group in the formula (II-B) of the following reaction formula: (wherein, each symbol has the same meaning as the above), and the -S(=O) ₂ OP ^R1 group is caused by a drug metabolizing enzyme, a hydrolyzing enzyme, a gastric acid, an intestinal bacteria, etc. under physiological conditions in the living body. The decomposition reaction is converted to a group of the -S(=O) ₂ OH group in the formula (IB).

Preferably, the "formation of a prodrug-forming group" refers to a bioavailability and/or AUC (a blood concentration curve) of a parent compound represented by the formula (IB) by addition of a parent compound represented by the formula (IB). The basis of the area).

Examples of the group forming the precursor drug include those described in, for example, Prog. Med. 5: 2157-2161 (1985) and Supplied by The British Library - "The world's Knowledge".

The "P ^R " group in the -COOP ^R group of the formula (II-A) may be a group which can be converted into a -COOH group in the living body, and preferably a substituted or unsubstituted alkyl group (example of a substituent) Halogen, hydroxy, alkoxy, alkylcarbonyloxy, alkoxycarbonyloxy, aromatic carbocyclic, non-aromatic carbocyclic, aromatic carbocyclic, non-aromatic carbosiloxane, An aromatic heterocyclic group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group (examples of a substituent: a pendant oxy group, an alkyl group, etc.), a non-aromatic carbocyclic oxycarbonyl group, etc., substituted or not Substituted non-aromatic carbocyclic groups (examples of substituents: halogen, alkyl, alkoxy, pendant oxy, etc.), substituted or unsubstituted aromatic carbocyclic groups (examples of substituents: halogen, alkyl, Alkoxy, nitro, etc.), substituted or unsubstituted non-aromatic heterocyclic group (examples of substituents: halogen, alkyl, alkoxy, pendant oxy, etc.), substituted or unsubstituted aromatic heterocyclic ring a group (an example of a substituent: a halogen, an alkyl group, an alkoxy group, a nitro group, etc.). More preferably, a substituted or unsubstituted alkyl group (an example of a substituent: a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a non-aromatic heterocyclic group or the like), a substituted or unsubstituted alkenyl group (an example of a substituent) may be exemplified. : halogen, hydroxy, alkoxy, cycloalkyl, non-aromatic heterocyclic group, etc., substituted or unsubstituted non-aromatic heterocyclic group (example of substituent: halogen, alkyl, alkoxy, etc.) .

The "P ^R1 " group in the -S(=O) ₂ OP ^R1 group of the formula (II-B) may be converted into a base of the -S(=O) ₂ OH group in the living body, preferably. A substituted or unsubstituted alkyl group (Examples of substituents: halogen, alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl (examples of substituents: halogen, alkoxy, non-aromatic carbocyclyl, non- Aromatic heterocyclic group, substituted non-aromatic heterocyclic group (example of substituent: alkyl group, pendant oxy group), alkylcarbonyl thiol group), alkylcarbonyloxy group, alkoxycarbonyloxy group, aromatic group Carbocyclic group, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group (substituent Examples: pendant oxy, alkyl, etc., non-aromatic carbo oxycarbonyl, etc., substituted or unsubstituted non-aromatic carbocyclic groups (examples of substituents: halogen, alkyl, alkoxy, side oxygen Or a substituted or unsubstituted aromatic carbocyclic group (examples of substituents: halogen, alkyl, alkoxy, nitro, etc.), substituted or unsubstituted non-aromatic carbocyclic groups (examples of substituents : halogen, alkyl, alkoxy, pendant oxy, etc.), substituted or not taken The aromatic heterocyclic group (examples of the substituent of: halogen, alkyl, alkoxy, nitro, etc.) and the like. More preferably, a substituted or unsubstituted alkyl group is exemplified (Examples of a substituent: a halogen, an alkoxy group, a cycloalkyl group, a non-aromatic heterocyclic group, a substituted or unsubstituted alkoxycarbonyl group (Example of a substituent: halogen) An alkoxy group, a cycloalkyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group (examples of a substituent: a halogen, an alkyl group, a pendant oxy group), an alkylcarbonylthiol group), and the like.

In the present specification, "the 6-position of the compound represented by the formula is a carboxylic acid pre-catalyzed" means a conversion of the -COOH group of the parent compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof as shown in the following reaction formula. For the meaning of -COOP ^R : (wherein, each symbol has the same meaning as the above).

In the present specification, "the 6th position of the compound represented by the formula is a sulfonic acid pre-drugification" means a parent compound represented by the formula (IB) or a pharmaceutically acceptable salt thereof as shown in the following reaction formula. (=O) ₂ OH group is converted to -S(=O) ₂ OP ^R1 base meaning: (wherein, each symbol has the same meaning as the above).

For example, when the pro-compound of the present invention or the 6-position carboxylic acid or sulfonic acid prodrug is represented by the formula (IA), (IB), (II-A) or (II-B), the moiety represented by the following formula structure:

A preferred embodiment of the present invention includes a partial configuration represented by the following formula: (wherein, each symbol has the same meaning as the above). For example, a preferred embodiment of the compound represented by the formula may be a compound represented by the formula (I-1): (wherein R ² is -OCR ²¹ R ²² COOH or -OS(=O) ₂ OH; other symbols have the same meaning as described above).

For example, when the compound of the present invention is represented by the formula (IA), (IB), (I-1), (II-A) or (II-B), the parent formula represented by the following formula (diaza-divalent) The nomenclature of the substitution position on cyclooctane) is as follows:

The substituent at the 2 position and the substituent at the 6 position in the present specification mean a group which is bonded to the 2 and 6 positions of the parent core described below.

In this manual, the formula: The number indicated is the position of substitution of the diazabicyclooctane skeleton which is the mother nucleus.

The compounds of the present invention are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers) , rotamer, etc.), racemate or a mixture of such.

More than one hydrogen, carbon and/or other atoms of the compounds of the invention may be substituted with isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of such equivalents are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ³⁶ Cl, respectively. Contains hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine. The compounds of the invention also include compounds substituted with such equivalents. Compounds substituted with such isomers can also be used as pharmaceuticals, including all radioactive labels of the compounds of the invention. Moreover, the "radioactive labeling method" for manufacturing the "radioactive label" is also included in the present invention, and the "radioactive label" can be used as a tool for dynamic research of metabolic drugs, research and/or diagnostic tools in combined analysis. .

The radioactive label of the compound of the invention can be prepared by methods well known in the art. For example, the oxime labeling compound of the compound of the present invention can be prepared by introducing hydrazine into a specific compound of the present invention by dehalogenation using a catalyst of hydrazine. The process comprises reacting a suitable catalyst, for example, in the presence of Pd/C, in the presence or absence of a base, in the presence of a base, in the presence of a base, with a suitable halogen prior to the reaction of the precursor and the hydrazine gas. Other suitable methods for formulating hydrazine-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ¹⁴ C-labeled compounds can be used by using ¹⁴ C carbon raw materials are prepared.

The pharmaceutically acceptable salt of the compound of the present invention may, for example, be a compound of the present invention and an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkaline earth metal (e.g., calcium, barium, etc.), magnesium, a transition metal (e.g., zinc, iron, etc.), Ammonia, organic base (such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, methylglucamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acid a salt or an inorganic acid (such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and an organic acid (such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid) , oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc. The salt made. In particular, a salt formed with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid or methanesulfonic acid can be mentioned. These salts can be formed by the usual methods.

The compounds of the present invention or pharmaceutically acceptable salts thereof may be formed as solvates (e.g., hydrates, etc.), co-crystals, and/or crystalline polymorphs, and the present invention also encompasses various solvates, co-crystals, and crystalline polymorphs. "Solvate" is such that the compound of the invention can be coordinated to any number of solvent molecules (e.g., water molecules, etc.). The compound of the present invention or a pharmaceutically acceptable salt thereof can be placed in the atmosphere to absorb water and adsorb water or form a hydrate. Further, there is a case where the compound of the present invention or a pharmaceutically acceptable salt thereof is recrystallized to form a crystalline polymorph. "Co-crystal" means that the compound or salt of the present invention is present in the same crystal lattice as the opposite molecule, and may be formed with any number of opposing molecules.

The "β-endoprostanase inhibitor" may be any one having a β-endoprostanase inhibitory action. The "β-endoprostanase inhibitor" contains a drug which has a β-endoprostase inhibitory action due to a decomposition reaction caused by a physiological condition in a living body. Specifically, for example, in the evaluation method described below, the IC ₅₀ is preferably 5 μM or less, more preferably 1 μM or less, and still more preferably 0.5 μM or less. The optimum is 0.1 μM or less. Preferably, it has a β-endoprostanase inhibitory action which can be used as a medicine.

The general synthetic method of the compound of the present invention is shown below. The starting materials and reaction reagents used in such syntheses are all commercially available or commercially available as a commercially available compound, and are manufactured according to methods well known in the art. Further, extraction, purification, and the like may be carried out by a usual treatment by an organic chemical experiment.

In the following steps, when there are substituents which may become reaction defects (for example, a hydroxyl group, a mercapto group, an amine group, a decyl group, a carbonyl group, a carboxyl group, etc.), it is possible to use Protective Groups in Organic Synthesis, Theodora W Greene, John Wiley & Sons. The method described in (hereinafter, referred to as Document A) and the like is protected in advance, and the protecting group is removed at a desired stage. Further, the order of the steps to be carried out may be appropriately changed in all the steps described below, and the respective intermediates may be separated and used in the next step. The reaction time, the reaction temperature, the solvent, the reagent, the protecting group, and the like are all exemplified, and there is no particular limitation as long as the reaction is unobstructed.

When the compound of the present invention is represented by the formula (I-A), (I-B), (I-1), (II-A) or (II-B), the compound of the present invention can be produced by the synthetic route shown below. The compounds shown below may also be their pharmaceutically acceptable salts.

(Method A-1)

(wherein R ¹ , R ²¹ and R ²² have the same meanings as defined above, and A ¹ is a phenyl group which has the same meaning as R ¹ or is substituted or unsubstituted, and E ¹ is a substituent which can also be used in a precursor drug, m An integer from 0 to 2, n is an integer from 1 to 2.)

 step 1  

The compound (III) or the compound (III) is converted into an ester body, and then decarbonated by light irradiation or the like and reacted with the compound (IV) to obtain a compound (V). The reaction solvent may, for example, be an ether (for example, anisole, two Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Representative examples of the ester body include 2-sided thiopyridine-1(2H)-ester. The ester body can be obtained by reacting the compound (III) with a 2-sided oxy group in the presence of a base - [1, 4, 2] The thiazolo[2,3-a]pyridin-4-indene chloride is reacted or condensed with 1-hydroxypyridine-2(1H)-thione to form. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide. The base may, for example, be an organic base or the like. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like. Preferred is triethylamine. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 48 hours.

 Step 2  

Compound (VI) is obtained by oxidizing compound (V). The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrate Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the oxidizing agent include peracetic acid, m-chloroperoxybenzoic acid, hydrogen peroxide, sodium tungstate, and N-bromosinium iminoamine. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -50 to 60 ° C, more preferably from about -50 to 30 ° C. The reaction time varies depending on the reagent to be used, the solvent or the reaction temperature, and is usually from 0.5 to 48 hours.

Here, when R ^{1 of the} compound (VI) is, for example, an amine group, a hydroxyl group, a carboxyl group or a protective agent thereof, if necessary, it is subjected to deprotection according to a known method, followed by alkylation and hydrazine according to a known method. Chemical modification by radical, imidolation, guanylation, cyclization, oxidation, and/or reduction reactions. After chemical modification, if there is a substituent which becomes a reaction disorder in the subsequent step, it can be used in the next step after being protected by a known method.

 Step 3  

Compound (VII) is obtained by reduction in the presence of a catalyst in the presence of a catalyst in a hydrogen atmosphere. The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrate Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. The catalyst may be 5% palladium carbon or 10% palladium carbon. Palladium hydroxide, platinum oxide, and the like. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. The pressure of the hydrogen atmosphere is usually from about 1 to 20 atmospheres, preferably from about 1 to 5 atmospheres. The reaction time varies depending on the reagent to be used, the solvent or the reaction temperature, and is usually from 0.5 to 48 hours.

 Step 4  

Compound (VII) is reacted with compound (VIII) in the presence of a base to obtain compound (IIa). The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the base include an inorganic base and an organic base. For example, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, triethylamine, diisopropylethylamine, and the like. Potassium carbonate is preferred. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 24 hours. In E ¹ 'in the prodrug can enjoy a substituent "group include groups shown above P ^R of the embodiment. Preferred are substituted or unsubstituted alkyl groups (examples of substituents: halogen, alkoxy group, aromatic carbocyclic ring, non-aromatic carbocyclic ring, etc.), substituted or unsubstituted non-aromatic carbocyclic rings (substituents) Examples: halogen, alkyl, alkoxy, etc.).

Here, when R ^{1 of the} compound (IIa) is, for example, an amine group, a hydroxyl group, a carboxyl group or a protective agent thereof, if necessary, it is subjected to deprotection according to a known method, followed by alkylation and hydrazine according to a known method. Chemical modification by radical, imidolation, guanylation, cyclization, oxidation, and/or reduction reactions. After chemical modification, if there is a substituent which becomes a reaction disorder in the subsequent step, it can be used in the next step after being protected by a known method.

 Step 5  

The compound (IIa) is subjected to hydrolysis to obtain a compound (Ia). The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the inorganic base used in the hydrolysis reaction include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and the like. Preferred is sodium hydroxide. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about -10 to 10 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 24 hours.

(Method B-1)

(wherein R ¹ , R ²¹ and R ²² have the same meanings as defined above, and A ¹ and R ^{1 have the} same meaning or are substituted or unsubstituted phenyl groups, and E1 is a substituent which can also be utilized in the precursor drug, m is 0. An integer of 2, E ¹ is a protecting group for a carboxylic acid, and is a substituent which can also be utilized as a precursor. For example, diphenylmethyl, trimethyldecylethyl, tert-butyl, p-methoxy Benzyl)

 step 1  

The compound (III) is obtained by a condensation reaction with the compound (IX) or a reaction with an esterifying agent in the presence of a base. The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrate Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, phosphonium chloride, methanesulfonium chloride, dicyclohexylcarbodiimide, and carbonyldiimidazole. Phenyl dichlorophosphate and the like. The base may, for example, be triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine or dimethylaminopyridine. These bases may be used singly or in combination of two or more. Further, examples of the esterifying agent to be used alone include diphenyldiazomethane and tert-butyl-1,3-diisopropylisourea. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 30 ° C, more preferably from about -20 to 30 ° C. The reaction time varies depending on the reagent to be used, the solvent or the reaction temperature, and is usually from 0.5 to 24 hours.

 Step 2  

The same procedure as in Process 3 of Process A-1 was carried out from Compound (X) to obtain Compound (XI).

 Step 3  

The compound (XI) is subjected to the same operation as in the step 4 of Process A-1, and reacted with the compound (VIII) to obtain the compound (XII).

 Step 4  

The compound (XIII) is obtained by subjecting the compound (XII) to a deprotection reaction. The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg: dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrate Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the deprotecting agent include tetra-n-butylammonium fluoride, fluorohydrogen pyridine complex, difluorotrimethyldecanoic acid tris(dimethylamino)phosphonium, trifluoroacetic acid, aluminum chloride, and titanium tetrachloride. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. The reaction time varies depending on the reagent to be used, the solvent or the reaction temperature, and is usually from 0.5 to 24 hours.

 Step 5  

The compound (IIb) is obtained by reacting with the compound (IV) from the compound (XIII) in the same manner as in the step 1 of Process A-1.

Here, when R ^{1 of the} compound (IIb) is, for example, an amine group, a hydroxyl group, a carboxyl group or a protective agent thereof, if necessary, it is subjected to deprotection according to a known method, followed by alkylation and hydrazine according to a known method. Chemical modification by radical, imidolation, guanylation, cyclization, oxidation, and/or reduction reactions. After chemical modification, if there is a substituent which becomes a reaction disorder in the subsequent step, it can be used in the next step after being protected by a known method.

 Step 6  

The same procedure as in Process A-1, Step 5 was carried out from Compound (IIb) to give Compound (Ic).

(Method B-2)

(wherein R ¹ , R ²¹ and R ²² have the same meanings as defined above, and E1 is a substituent which can also be used in the precursor drug, and n is an integer of 1 to 2.)

 step 1  

From the compound (IIb), the same operation as in the step 2 of Process A-1 is carried out to obtain the compound (IIc).

Here, when R ^{1 of the} compound (IIc) is, for example, an amine group, a hydroxyl group, a carboxyl group or the like, or the like, if necessary, deprotection according to a known method, followed by alkylation and hydrazine according to a known method. Chemical modification is carried out by radical, iminoation, guanylation, cyclization, oxidation, and/or reduction reactions. After chemical modification, if there is a substituent which becomes a reaction disorder in the subsequent step, it can be used in the next step after being protected by a known method.

 Step 2  

The same procedure as in Process A-1 Step 5 was carried out from Compound (IIc) to obtain Compound (Id).

(Method C-1)

(wherein R ²¹ and R ²² have the same meanings as defined above, and R ¹¹ and R ¹² are each independently, and are a hydrogen atom, a decyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, and a substitution. Or unsubstituted alkynyl group, substituted or unsubstituted alkylcarbonyl group, substituted or unsubstituted alkenylcarbonyl group, substituted or unsubstituted alkynylcarbonyl group, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic ring Carbocyclic, substituted or unsubstituted carbocycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted carbocyclic carbonyl or substituted or unsubstituted heterocyclic carbonyl, or R ¹¹ and R ¹² adjacent thereto The nitrogen atom together forms a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted imido group. E ¹ is a substituent which may also be utilized in the precursor drug)

 step 1  

The compound (III) is converted into a 2-sided thiopyridine-1(2H)-ester and then decarboxylated by light irradiation or the like and reacted with two sulfur oxides to obtain a compound (XIV). The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. The intermediate ester can be obtained by combining the compound (III) with a 2-sided oxy group in the presence of a base - [1, 4, 2] The thiazolo[2,3-a]pyridine-4-indene chloride is reacted or formed by condensation with 1-hydroxypyridine-2(1H)-thione. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide. The base may, for example, be an organic base or the like. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine, etc. are mentioned. Preferred is triethylamine. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -40 to 40 ° C, more preferably from about -20 to 20 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 48 hours.

 Step 2  

The compound (XIV) is reacted with a thiolate, and then reacted with the compound (XV) in the presence of a base to obtain a compound (XVI). The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the thiolate include sodium hydrosulfide, sodium methylthiolate, sodium thiophenolate, and the like. Preferred is sodium thiophenolate. Examples of the base include inorganic and organic bases. For example, potassium carbonate, sodium carbonate, sodium hydride, potassium butoxide, sodium acetate, triethylamine, diisopropylethylamine, etc. are mentioned. Preferred is sodium acetate. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -40 to 40 ° C, more preferably from about -20 to 20 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 48 hours.

Here, when R ¹¹ and/or R ^{12 of the} compound (VI) is present, for example, an amine group, a hydroxyl group, a carboxyl group or the like, or the like, if necessary, deprotection according to a known method, followed by a known method. The alkylation, thiolation, imidolation, guanylation, cyclization, oxidation and/or reduction reactions are chemically modified. Or when R ¹¹ and R ¹² of the compound (VI) are hydrogen, the alkylation, thiolation, imidization, guanylation, cyclization, oxidation and/or reduction reaction can be carried out according to a known method. Modification. After chemical modification, if there is a substituent which becomes a reaction disorder in the subsequent step, it can be used in the next step after being protected by a known method.

 Step 3  

The same procedure as in Process 3 of Process A-1 was carried out from Compound (XVI) to give Compound (XVII).

 Step 4  

The compound (XVII) is subjected to the same operation as in the step 4 of Process A-1, and reacted with the compound (VIII) to obtain the compound (IId).

Here, when R ¹¹ and/or R ^{12 of the} compound (IId) is present, for example, an amine group, a hydroxyl group, a carboxyl group or the like, and the like, if necessary, deprotection according to a known method, followed by a known method. The alkylation, thiolation, imidolation, guanylation, cyclization, oxidation and/or reduction reactions are chemically modified. Or when R ¹¹ and R ¹² of the compound (VI) are hydrogen, the alkylation, thiolation, imidization, guanylation, cyclization, oxidation and/or reduction reaction can be carried out according to a known method. Modification. After chemical modification, if there is a substituent which becomes a reaction disorder in the subsequent step, it can be used in the next step after being protected by a known method.

 Step 5  

The same procedure as in Process A-1, Step 5 was carried out from Compound (IId) to give Compound (Ig).

(Method C-3)

(R ¹¹ and R ¹² have the same meaning as the above)

 step 1  

From the compound (XVII), the same operation as in Step 1 of Process A-2 was carried out to obtain (Ih).

(Method A-3)

(wherein R ¹ and L have the same meaning as the above, and E ² is a substituent which can also be utilized in the sulfonic acid precursor)

 step 1  

Compound (IIe) is obtained by reacting compound (XVIII) with compound (XIX) in the presence of a base. The reaction solvent can be exemplified by an ether such as anisole or two. Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Examples of the base include inorganic and organic bases. For example, potassium carbonate, sodium carbonate, sodium hydride, potassium butoxide, triethylamine, diisopropylethylamine, etc. are mentioned. Preferred is triethylamine. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 100 hours. The "substituent which may be used in the precursor drug" of E ² is preferably exemplified by the above-mentioned P ^R1 . More preferably, a substituted or unsubstituted alkyl group (substituted substituent: halogen, alkoxy group, aromatic carbocyclic group, non-aromatic carbocyclic group, etc.), substituted or unsubstituted non-aromatic carbocyclic group (substituted) Base examples: halogen, alkyl, alkoxy, etc.).

 Step 2  

The compound (Ij) is obtained by subjecting the compound (IIe) to dealkylation using a salt of a thiol. The reaction solvent can be listed as an ether such as anisole, Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, tetra Carbon chloride), hydrocarbons (eg, n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrate) Base benzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. The mercaptan used may be methanethiol, thiophenol, pyridinethiol, 5-methyl-1,3,4-thiadiazole-2-thiol, 1-methyl-1H-tetrazole-5- Examples of the salt include a sodium salt, a potassium salt, a lithium salt, an ammonium salt, and a triethylamine salt. Preferred is the sodium salt of 5-methyl-1,3,4-thiadiazole-2-thiol. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 0 to 30 ° C. The reaction time varies depending on the solvent or the reaction temperature, and is usually from 0.5 to 24 hours.

The compound of the present invention has inhibitory activity against various β-endosinases and/or has broad-spectrum antibacterial activity, and can be used alone or in combination with β-neutamine antibacterial agents for preventing or treating various mammals including humans due to pathogenic bacteria. Various diseases, such as tracheal infection, urinary tract infection, respiratory infection, sepsis, nephritis, cholestitis, intraoral infection, endocarditis, pneumonia, myelitis, otitis media, enteritis, empyema, traumatic infection Opportunistic infections, etc.

The compound of the present invention exhibits a broad inhibitory effect on the β-endoprostanase belonging to the classes A, C and D produced by Gram-negative bacteria, especially for ESBL represented by TEM type, SHV type, KPC type and the like. effect. Since it exhibits an effective inhibitory effect on the serine type β-endo-aminease belonging to the class A, C or D, it is antibacterial to various β-indoleamines containing a cephalosporin antibacterial or a carbapenem antibacterial. Drug-resistant Gram-negative bacteria are also effective. Further, the compound of the present patent application is alone or in combination with a β-indoleamine antibacterial agent, and for Gram-negative bacteria, a Gram-negative bacteria (Escherichia coli, Klebsiella) of the enterobacteriaceae is preferred. , Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc., fixed to the respirator Gram-negative bacteria (Haemophilus, Moraxella, etc.) and non-fermented Gram-negative bacteria (Pseudomonas, Pseudomonas, Pseudomonas) Stenotrophomonas, Burkholderia, Acinetobacter, etc. show high antibacterial activity. Since it also exhibits an effect on the serine-type β-endoprolinase belonging to the class A, C or D, various β-endoxime antibacterial resistant leathers containing a cephalosporin antibacterial or a carbapenem antibacterial agent Ran-negative bacteria are also effective. More preferred compounds also have high blood concentration in the body, high oral absorbability, high membrane permeability, long duration of action, long lasting blood, and/or high tissue migration. Further, a preferred compound is safe in that it does not show fever, does not show digestive tract disorders, and does not exhibit side effects such as nephrotoxicity. Further, preferred compounds are high in water solubility and good in vivo dynamics, and are suitable as injection medicines and/or oral medicines.

The pharmaceutical composition of the present invention can be administered by any one of oral and parenteral methods. Non-oral administration methods include percutaneous, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye, ear, intravaginal administration, and the like.

For oral administration, the compound of the present invention can be used as a usual preparation, for example, a solid preparation such as a tablet, a powder, a granule or a capsule; or a liquid preparation such as a liquid preparation, an oily suspension, a syrup or an expectorant. A dosage form is used. For parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or a nasal spray. When it is prepared, a conventional excipient, a binder, a lubricant, an aqueous solvent, an oily solvent, an emulsifier, a suspending agent, a preservative, a stabilizer, etc. can be used arbitrarily. The formulations of the present invention can be made by combining (e.g., mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.

The compound of the present invention can be administered as an injection, a capsule, a tablet, or a granule, parenterally or orally, preferably as an injection. The dose is about 0.1 to 100 mg/day, preferably about 0.5 to 50 mg/day, per 1 kg of the body weight of the patient or animal, and it may be divided into 2 to 4 times on the 1st as desired. The carrier for use as an injection is, for example, distilled water, physiological saline or the like, and a base for adjusting the pH or the like can also be used. The carrier used as a capsule, granule or lozenge is a known excipient (for example, starch, lactose, white sugar, calcium carbonate, calcium phosphate, etc.), a binder (for example, starch, gum arabic, carboxymethyl cellulose, Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (such as magnesium stearate, talc, etc.).

When necessary, an effective amount of the compound of the present invention can be mixed with various pharmaceutical additives such as an excipient, a binder, a cleaving agent, and a lubricant which are suitable for the dosage form to prepare a pharmaceutical composition. The pharmaceutical composition can be used as a pharmaceutical composition for pediatric, elderly, critically ill or surgical use by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention. Pediatric medicinal compositions are preferably administered to patients 12 years of age or younger than 15 years of age. In addition, pediatric pharmaceutical compositions can be administered to patients who have not reached 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, 12 to 17 years old, or 18 years old. The pharmaceutical composition for elderly people is preferably administered to patients over 65 years of age.

The administration amount of the compound of the present invention is preferably set in consideration of the age, body weight, type or degree of the disease, administration route, etc., and is usually 0.5 to 300 mg/kg/day for oral administration, preferably. Within the range of 1 to 50 mg/kg/day. In the case of parenteral administration, there is a large difference depending on the route of administration, and it is usually in the range of 0.5 to 300 mg/kg/day, preferably 1 to 50 mg/kg/day. This can be divided into one to several administrations per day.

The compound of the present invention can be used in combination with a β-neutamine antibacterial agent (hereinafter referred to as a concomitant agent) for the purpose of enhancing the antibacterial action, reinforcing or reducing the administration amount of the compound, that is, in combination. In this case, the administration period of the compound of the present invention and the concomitant drug is not particularly limited, and it may be administered at the same time as the administration target, or may be administered with a time difference. One or two or more kinds of agents can be used together with the drug. Preferably, one or two combined pharmaceutical agents are used in combination with the compound of the present invention. More preferably, one combination of the agents is used in combination with the compound of the present invention. The compound of the present invention and the concomitant drug can be administered as a preparation containing two or more of the respective components, or can be administered as a single preparation containing the compound of the present invention and the active ingredient of the concomitant drug.

The dosage of the pharmaceutical agent can be appropriately selected based on the amount of the clinical use. Further, the ratio of the compound of the present invention to the concomitant agent can be appropriately selected depending on the administration target, the administration route, the target disease, the symptom, the combination, and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight may be used for the compound of the present invention in an amount of 1 part by weight.

The β-indoleamine antibacterial agent comprises an antibacterial agent having a β-indoleamine structure (for example, penicillin, cephalosporin, carbapenem, monobactam, and oxacephem). a compound, a pharmaceutically acceptable salt thereof, or such a precursor drug. Examples of the β-endoxime antibacterial agent include penicillin-based antibacterial agents (for example, ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam), and cephalosporin-based antibacterial agents (for example, cefepime, cephalosporin). Qiding, ceftriaxone, cefixime, ceftibuten, cefpodoxime, cefdibut, cefaclor, cefdinir, ceftime, cefuroxime, cefaclor, ceftriaxone, carbapenem Ethylene-based antibacterials (eg, imipenem, meropenem, doripenem, tibepine, ertapenem), monocyclic guanamine-based antibacterials (eg, aztreonam, carumonam) ), oxygen cephem antibacterials (eg, cephalosporin, fluoxetine), penem-based antibacterials (eg, faropenem, thiopenem), cephamycine (eg cephalosporin) Methazole, cefoxitin, cefotetan, and the like, include such pharmaceutically acceptable salts or such prodrugs. A preferred example of the β-namidoxime antibacterial agent is any one or two selected from the group consisting of ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam, cefepime, ceftazidime, and cefixime. , ceftibuten, cefpodoxime, cefadidime, cefaclor, cefdinir, ceftriaxone, cefuroxime, cefaclor, ceftriaxone, imipenem, meropenem, doripenem, Compounds such as tibepine, ertapenem, aztreonam, carumonam, oxycephalosporin, fluoxetine, faropenem, thiopenem, cefmetazole, cefoxitin and cefotetan, these Pharmaceutically acceptable salts or such prodrugs. More preferably, any one selected from the group consisting of ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam, cefepime, ceftazidime, cefixime, ceftibuten, cefpodoxime, cefdibutime , cefaclor, cefdinir, ceftibutin, cefuroxime, cefaclor, ceftriaxone, imipenem, meropenem, doripenem, tibepine, ertapenem, ammonia Compounds of south, carumol, cephalosporin, fluoxetine, faropenem, thiopenem, cefmetazole, cefoxitin and cefotetan, such pharmaceutically acceptable salts or such precursor drugs .

Another preferred example of the β-indoleamine antibacterial agent is any one or more selected from the group consisting of ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam, cefepime, cefotaxime, Cefixime, ceftibuten, cefpodoxime, cefpodoxime proxetil, cefadidime, cefaclor, cefdinir, cefetacrom, cefprozil, cefuroxime, cefuroxime axetil (cefuroxime axetil), cefocaine, cefcapene pivoxil, ceftriaxone, imipenem, meropenem, doripenem, tibepine, tibeapram, ertapenem Aztreonam, carumol, deoxycephalosporin, fluoxetine, faropenem, thiopenem, cefmetazole, cefoxitin and cefotetan. More preferably, any one is selected from the group consisting of ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam, cefepime, cefotaxime, cefixime, ceftibuten, cefpodoxime, cefpod Oxime ester, cefadidime, cefaclor, cefdinir, cefoperon, ceftalil, cefuroxime, cefuroxime axetil, cefaclor, cefaclor, ceftriaxone, imipenem , meropenem, doripenem, tibepine, tibeparam, ertapenem, aztreonam, carumonam, oxycephalosporin, fluoxetine, faropenem, thiopenem, cephalosporin Methazole, cefoxitin and cefotetan.

 [Examples]  

The invention is illustrated in more detail below by way of examples and test examples, but the invention is not limited to the examples.

In addition, the short form used in this specification has the following meaning.

Bn: benzyl group

Boc: third butoxycarbonyl

DMAP: N,N-dimethyl-4-aminopyridine

DMF: N,N-dimethylformamide

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

Et: ethyl

mCPBA: m-chloroperoxybenzoic acid

Me: methyl

ODS: octadecyl fluorenyl

Ph: phenyl

TFA: trifluoroacetic acid

TMS: trimethyl fluorenyl

To each of the embodiments NMR 400MHz analysis carried out in line, using DMSO-d _6, CDCl ₃ was measured. Further, when the NMR value is indicated, there is a case where all the peaks of the measurement are not described.

When there is RT in the specification, the retention time (residence time) by LC/MS: liquid chromatography/mass analysis is measured under the following conditions.

LC/MS (Liquid Chromatography / Mass Analysis) conditions

Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm i.d.2.1x50mm) (Waters)

Flow rate: 0.8mL/min

UV detection wavelength: 254nm

Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

Gradient: 100% solvent [B] was maintained for 0.5 minutes after a linear gradient of 5%-100% solvent [B] over 3.5 minutes.

Further, the descriptions of MS, MS (m+1) or MS (m-1) in the specification indicate values observed by mass analysis.

 (Example 1)  

Synthesis of Compound II-001 and I-001

 Step 1 Synthesis of Compound 1b  

Compound 1a (3.00 g, 10.9 mmol) was dissolved in dichloromethane (78 mL) under a nitrogen atmosphere, and 2- oxy-[1,4,2] was added. Thiazolo[2,3-a]pyridine-4-indole chloride (2.47 g, 13.0 mmol), triethylamine (2.26 ml, 16.3 mmol) was stirred at room temperature for 1 hour under light. 1,2-Disulfide disulfide (7.35 g, 33.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour under light irradiation. The solvent was evaporated under reduced pressure, and the residue obtained was purified to silica gel column chromatography (hexane-ethyl acetate) to afford compound 1b (1.61 g, yield 44%).

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.78 (2H, m), 2.01-2.08 (1H, m), 2.36-2.47 (1H, m), 2.90 (1H, dt, J = 11.5, 3.0 Hz) , 3.35-3.36 (1H, m), 3.82 (1H, d, J = 11.7 Hz), 4.90 (1H, d, J = 11.5 Hz), 5.03-5.06 (2H, m), 7.20-7.49 (10H, m ).

 Step 2 Synthesis of Compound 1c  

Compound 1b (500 mg, 1.47 mmol) was dissolved in dichloromethane (10 mL) and evaporated. 72% aqueous mCPBA (880 mg, 3.67 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was ice-cooled, and a 5% aqueous sodium thiosulfate solution and a saturated aqueous It was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 1c (509 mg, yield 93%).

¹ H-NMR (CDCl ₃ ) δ: 1.84-1.93 (1H, m), 2.05-2.22 (2H, m), 2.44-2.48 (1H, m), 3.02 (1H, d, J = 11.9 Hz), 3.42 -3.43(1H,m),3.73(1H,d,J=12.0Hz), 4.40-4.42(1H,m),4.81(1H,d,J=11.5Hz),4.94(1H,d,J=11.4 Hz), 7.35-7.37 (5H, m), 7.56 (2H, t, J = 7.7 Hz), 7.67 (1H, t, J = 7.4 Hz), 7.91 (2H, d, J = 7.2 Hz).

 Step 3 Synthesis of Compound 1d  

Compound 1c (258 mg, 0.693 mmol) was dissolved in tetrahydrofuran/methanol (v/v = 1/1) (10 mL), 5% palladium carbon (50 mg, 0.023 mmol) was added and stirred at room temperature under a 1 atmosphere of hydrogen atmosphere 2 hour. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure to give Compound 1d (218 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.98-2.01 (1H, m), 2.18-2.21 (2H, m), 2.47-2.58 (1H, m), 3.17 (1H, d, J = 10.8 Hz), 3.83 -3.86 (2H, m), 4.41 (1H, t, J = 7.6 Hz), 7.58 (2H, t, J = 7.7 Hz), 7.68 (1H, t, J = 7.5 Hz), 7.93 (2H, d, J=7.3Hz).

 Step 4 Synthesis of Compound II-001  

Compound 1d (98.0 mg, 0.347 mmol) was dissolved in DMF (2.0 mL), ethyl 2-bromo-2,2-difluoroacetate (106 mg, 0.521 mmol), potassium carbonate (62.4 mg, 0.451 mmol) Stir at room temperature for 3 hours. Ethyl acetate and a 10% aqueous citric acid solution were added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the organic layer was washed twice with water. It was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound II-001 (93.0 mg, yield 66%).

1H-NMR (CDCl3) δ: 1.35 (3H, t, J = 7.2 Hz), 2.27-2.04 (3H, m), 2.57-2.47 (1H, m), 3.29 (1H, d, J = 12.3 Hz), 3.90 (1H, d, J = 12.4 Hz), 4.05 (1H, d, J = 3.4 Hz), 4.36 (2H, q, J = 7.1 Hz), 4.50 (1H, t, J = 8.0 Hz), 7.58 ( 2H, t, J = 7.7 Hz), 7.69 (1H, t, J = 7.5 Hz), 7.92 (2H, d, J = 7.3 Hz).

 Step 5 Synthesis of Compound I-001  

Compound II-001 (92.0 mg, 0.228 mmol) was dissolved in tetrahydrofuran / water (v / v = 2 / 1) (3 mL). A 1.0 mol/L aqueous sodium hydroxide solution (0.228 mL) was added, and the mixture was stirred at 0 ° C for 30 minutes. Diisopropyl ether was added to carry out liquid separation, and the aqueous layer was concentrated, and subjected to ODS column chromatography (water-acetonitrile), and the desired fraction was concentrated and freeze-dried to obtain Compound I-001 (55.4 mg, yield 61%). ).

1H-NMR (D2O) δ: 2.20-2.06 (3H, m), 2.40-2.34 (1H, m), 3.33 (1H, dd, J = 12.5, 2.5 Hz), 3.56 (1H, d, J = 12.4 Hz) ), 4.19 (1H, d, J = 3.3 Hz), 4.89 (1H, t, J = 8.3 Hz), 7.73 (2H, t, J = 7.8 Hz), 7.87 (1H, t, J = 7.5 Hz), 8.00 (2H, d, J = 7.7 Hz).

 (Reference example 2)  

Synthesis of Compound I-004

 Step 1 Synthesis of Compound I-004  

Compound 1d (98.0 mg, 0.347 mmol) was dissolved in dichloromethane (4 mL), 2,6-dimethylpyridine (0.121 mL, 1.04 mmol), sulfur trioxide-pyridine (138 mg, 0.868 mmol), Stir at night. After the insoluble material was filtered, a saturated aqueous solution of sodium hydrogencarbonate was added, and the aqueous layer was washed twice with dichloromethane. Dichloromethane (4 mL) and tetrabutylammonium hydrogen sulfate (134 mg, 0.396 mmol) were added to the aqueous layer and stirred at room temperature for 30 min. After extracting three times with dichloromethane, it was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in water, and the cation exchange resin which had been treated with an aqueous sodium hydroxide solution in advance was concentrated and freeze-dried to obtain I-004 (104 mg, yield: 77%).

1H-NMR (D2O) δ: 2.08-2.04 (2H, m), 2.19-2.11 (1H, m), 2.40-2.35 (1H, m), 3.33 (1H, dd, J = 12.4, 3.1 Hz), 3.57 (1H, d, J = 12.3 Hz), 4.27 (1H, q, J = 3.3 Hz), 4.85 (1H, t, J = 8.2 Hz), 7.73 (2H, t, J = 7.9 Hz), 7.87 (1H , t, J = 7.5 Hz), 8.00 (2H, d, J = 7.4 Hz).

 (Reference Example 3)  

Synthesis of Compound I-006

 Step 1 Synthesis of Compound 3a  

Compound 1a (3.00 g, 10.9 mmol) was dissolved in dichloromethane (30 mL) and pyridine (1.75 mL, 21.7 mmol) and 2-(trimethyldecyl)ethane-1-ol (1.28 g) 10.9 mmol), DMAP (0.133 g, 1.09 mmol), and EDC hydrochloride (2.45 g, 13.0 mmol) were stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added and washed three times with a 1.0 mol/L hydrochloric acid aqueous solution. It was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to yield Compound 3a (3.93 g, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.99-1.07 (2H, m), 1.62-1.71 (1H, m), 2.04-2.12 (4H, m), 2.93 (1H, d, J=11.9 Hz), 3.06 (1H, d, J = 12.0 Hz), 3.31 (1H, s), 4.07-4.10 (1H, m), 4.25-4.28 (2H, m), 4.90 (1H, d, J = 11.3 Hz), 5.06 (1H, d, J = 11.4 Hz), 7.35-7.40 (3H, m), 7.43 (2H, dd, J = 7.6, 1.9 Hz).

 Step 2 Synthesis of Compound 3b  

Using Compound 3a (3.93 g, 10.4 mmol), Compound 3b (2.95 g, yield: 99%) was obtained by the same procedure as Step 3 of Reference Example 2.

 Step 3 Synthesis of Compound 3c  

Using Compound 3b (2.95 g, 10.3 mmol), Compound 3c (1.21 g, yield 29%) was obtained by the same procedure as in Step 3 of Example 1.

¹ H-NMR (CDCl ₃ ) δ: 0.06 (9H, s), 1.04-1.07 (2H, m), 1.39 (3H, t, J = 7.2 Hz), 1.85-1.90 (1H, m), 2.12-2.21 (3H,m), 3.16 (1H, d, J = 12.2 Hz), 3.30 (1H, dd, J = 12.2, 2.4 Hz), 3.95-3.96 (1H, m), 4.18 (1H, t, J = 4.5) Hz), 4.27-4.34 (2H, m), 4.35-4.45 (2H, m).

 Step 4 Synthesis of Compound 3d  

Compound 3c (8.31 g, 20.3 mmol) was dissolved in DMF (40 mL), and tris(dimethylamino)phosphonium difluorotrimethyl decanoate (6.73 g, 24.4 mmol) was added and the mixture was stirred at room temperature for 1 hour. . Ethyl acetate and a 10% aqueous citric acid solution were added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the organic layer was washed twice with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield Compound 3d (5.6 g, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.2 Hz), 1.85-1.89 (1H, m), 2.11-2.31 (3H, m), 3.11 (1H, d, J = 12.3 Hz) ), 3.37 (1H, d, J = 12.3 Hz), 3.99-4.00 (1H, m), 4.23-4.25 (1H, m), 4.34-4.46 (2H, m).

 Step 5 Synthesis of Compound 3e  

Using Compound 3d (562 mg, 1.82 mmol), Compound 3e (176 mg, yield 26%) was obtained by the same procedure as in Step 1 of Example 1.

¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.2 Hz), 1.81 (1H, dd, J = 15.6, 7.0 Hz), 1.89-1.97 (1H, m), 2.14-2.21 (1H) , m), 2.40-2.50 (1H, m), 3.10-3.14 (1H, m), 3.99-4.00 (1H, m), 4.04 (1H, d, J = 11.9 Hz), 4.39 (2H, q, J = 7.2 Hz), 5.14 (1H, d, J = 6.3 Hz), 7.25 (3H, t, J = 7.3 Hz), 7.31 (2H, t, J = 7.4 Hz), 7.48 (2H, d, J = 7.2) Hz).

 Step 6 Synthesis of Compound I-006  

Compound I-006 (16.6 mg, yield: 47%) was obtained by the same procedure as in the step 5 of Example 1 using Compound 3e (35.6 mg, 0.096 mmol).

1H-NMR (D2O) δ: 2.01-1.92 (2H, m), 2.15-2.13 (1H, m), 2.37-2.23 (1H, m), 3.09 (1H, d, J = 12.0 Hz), 4.14 (1H) , d, J = 12.0 Hz), 4.18 (1H, s), 5.18 (1H, d, J = 7.0 Hz), 7.46-7.38 (3H, m), 7.60 (2H, dd, J = 7.8, 1.3 Hz) .

 (Reference example 4)  

Synthesis of Compounds II-009 and I-009

 Step 1 Synthesis of Compound II-009  

Compound 3e (136 mg, 0.366 mmol) was dissolved in dichloromethane (4.0 mL) and cooled at -78. mCPBA (96.0 mg, 0.403 mmol) was added and the temperature was slowly raised to room temperature. After completion of the reaction, a 5% aqueous sodium thiosulfate solution and a saturated aqueous It was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound II-009 (110 mg, yield 77%).

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2 Hz), 1.46-1.55 (1H, m), 1.98-2.01 (1H, m), 2.07-2.15 (1H, m), 2.34 -2.38 (1H, m), 3.40 (1H, d, J = 12.3 Hz), 3.80 (1H, d, J = 12.3 Hz), 4.02 (1H, s), 4.24 (1H, t, J = 7.2 Hz) , 4.35-4.41 (2H, m), 7.52-7.54 (3H, m), 7.60-7.62 (2H, m).

 Step 2 Synthesis of Compound I-009  

Compound II-009 (23.3 mg, 0.060 mmol) was dissolved in tetrahydrofuran / water (v / v = 2 / 1) (l. A 1.0 mol/L aqueous sodium hydroxide solution (0.060 mL) was added, and the mixture was stirred at 0 ° C for 30 minutes. After diisopropyl ether was added, the aqueous layer was purified by reverse phase column chromatography (ODS) (water-acetonitrile) to afford I-009 (20.9 mg, yield 91%).

1H-NMR (D2O) δ: 1.95-1.93 (1H, m), 2.13-2.06 (2H, m), 2.33-2.26 (1H, m), 3.36 (1H, d, J = 12.4 Hz), 3.46 (1H) , d, J = 12.0 Hz), 4.20 (1H, s), 4.51 (1H, t, J = 7.3 Hz), 7.70-7.66 (3H, m), 7.77 (2H, d, J = 6.3 Hz).

 (Example 11)  

Synthesis of Compound II-012 and I-027

 Step 1 Synthesis of Compound 11a  

Compound 1a (10.00 g, 36.2 mmol) was dissolved in dichloromethane (50 mL) under a nitrogen atmosphere, and 2- oxy-[1,4,2] was added. Thiazolo[2,3-a]pyridin-4-indene chloride (8.24 g, 43.4 mmol), triethylamine (7.53 ml, 54.3 mmol) was stirred at room temperature for 1 hour under light to give solution A. On the other hand, dichloromethane (200 mL) prepared in a separate vessel was cooled to -40 ° C under a nitrogen atmosphere, and liquid sulfurous acid (70 mL) was added. The solution was warmed to -10 ° C, and solution A was added dropwise under light irradiation. After completion of the dropwise addition, the mixture was stirred for 1 hour while warming to room temperature under light irradiation conditions. The liquid sulfurous acid and dichloromethane were removed by passing nitrogen through the solution, and the residual solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 11a (1.18 g, yield 8.0%).

¹ H-NMR (CDCl ₃ ) δ: 1.79-1.84 (1H, m), 2.08-2.15 (1H, m), 2.17-2.25 (1H, m), 2.31-2.37 (1H, m), 3.13 (1H, d, J = 12.3 Hz), 3.46-3.47 (1H, m), 3.53 (1H, d, J = 12.0 Hz), 4.88 (1H, d, J = 11.4 Hz), 5.00 (1H, d, J = 11.4) Hz), 5.09 (1H, t, J = 8.1 Hz), 7.35-7.39 (6H, m), 7.74 - 7.79 (2H, m), 8.67 (1H, d, J = 4.6 Hz).

 Step 2 Synthesis of Compound 11b  

Compound 11a (250 mg, 0.617 mmol) was dissolved in tetrahydrofuran (2.5 mL) and water (0.25 mL) under a nitrogen atmosphere, and sodium thiophenol (91 mg, 0.617 mmol, purity 90%) was added. After stirring at room temperature for 5 hours, ethyl acetate was added to the obtained solution, and extracted with water. The aqueous layer was washed with ethyl acetate and the aqueous solution was concentrated under reduced pressure to about 3 mL. The obtained aqueous solution was diluted with water (9.8 mL) and tetrahydrofuran (3.9 mL), and sodium acetate (127 mg, 1.543 mmol) and hydroxylamine-O-sulfonic acid (87 mg, 0.771 mmol) were added under ice cooling. After the mixture was stirred at room temperature for one night, a 10% aqueous sodium thiosulfate solution was added, and ethyl acetate was evaporated. The organic layer was washed with 0.5 N aqueous hydrochloric acid, 8.4% aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous sodium sulfate. The inorganic matter was removed by filtration and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 11b (128.5mg, yield: 66.9%).

¹ H-NMR (CDCl ₃ ) δ: 1.79-1.83 (1H, m), 2.06-2.33 (3H, m), 3.07 (1H, dt, J = 12.1, 1.5 Hz), 3.46 (1H, dd, J = 5.5, 3.2 Hz), 3.55 (1H, d, J = 12.2 Hz), 4.37 (1H, t, J = 8.2 Hz), 4.82 (2H, s), 4.88 (1H, d, J = 11.5 Hz), 5.01 (1H, d, J = 11.4 Hz), 7.38-7.42 (5H, m).

 Step 3 Synthesis of Compound 11c  

Using a compound 11b (128.5 mg, 0.413 mmol), Compound 11c (91 mg, yield: 100%) was obtained by the same procedure as in Step 3 of Example 1.

MS(m+1)=222.12, hold time: 0.30

 Step 4 Synthesis of Compound II-012  

Using Compound 11c (91 mg, 0.413 mmol), Compound II-012 (12.9 mg, yield 9.1%) was obtained by the same procedure as in Step 4 of Example 1.

¹ H-NMR (CDCl ₃ ) δ: 1.34-1.39 (3H, m), 1.57-1.88 (1H, m), 2.07-2.43 (3H, m), 3.34 (1H, d, J = 12.3 Hz), 3.75 (1H,d,J=12.4Hz), 4.08-4.10(1H,m),4.34-4.44(3H,m),5.00(2H,s).

 Step 5 Synthesis of Compound I-027  

Using the compound II-012 (12.9 mg, 0.038 mmol), Compound I-027 (5.6 mg, yield 44.2%)

1H-NMR (D2O) δ: 2.05-2.17 (2H, m), 2.26-2.30 (2H, m), 3.39-3.42 (1H, m), 3.71 (1H, d, J = 12.4 Hz), 4.22-4.25 (1H, br m), 4.64 - 4.67 (1H, m).

MS(m+1)=316.98, hold time: 0.43

 (Embodiment 12)  

Synthesis of Compound I-028

 Step 1 Synthesis of Compound I-028  

Using Compound 11c (119 mg, 0.538 mmol), Compound I-028 (133.1 mg, yield: 76.

1H-NMR (D2O) δ: 2.04-2.10 (2H, m), 2.24-2.30 (2H, m), 3.41 (1H, dd, J = 12.0, 2.1 Hz), 3.72 (1H, d, J = 12.3 Hz) ), 4.29-4.32 (1H, br m), 4.60 (1H, t, J = 8.1 Hz).

MS (m-1) = 299.99, hold time: 0.29 minutes

 (Embodiment 16)  

Synthesis of Compound II-016, I-036

 Step 1 Synthesis of Compound 16a  

Compound 7b (508 mg, 1.83 mmol) was dissolved in dichloromethane (10 mL). The solution was cooled at -78 ° C, and 72% aqueous Mcpba (459 mg, 1.92 mmol) was added and stirred at -78 ° C for one hour. A 10% aqueous sodium thiosulfate solution and a 5% aqueous sodium hydrogencarbonate solution were added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to afford compound 16a (360 mg, yield 67%).

¹ H-NMR (CDCl ₃ ) δ: 1.73-1.83 (1H, m), 2.10-2.15 (2H, m), 2.33-2.42 (1H, m), 2.67 (3H, s), 3.02 (1H, d, J = 11.6 Hz), 3.18 (1H, d, J = 11.9 Hz), 3.40 - 3.41 (1H, m), 4.02 (1H, dd, J = 7.6, 4.5 Hz), 4.90 (1H, d, J = 11.4) Hz), 5.03 (1H, d, J = 11.4 Hz), 7.38-7.41 (5H, m).

 Step 2 Synthesis of Compound 16b  

The compound 16a (630 mg, 2.14 mmol) was dissolved in methanol (63 mL), 5% palladium carbon (4.56 g, 2.14 mmol) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere of 1 atmosphere. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure to give Compound 16b (403mg, yield: 92%).

¹ H-NMR (D ₂ O) δ: 1.96-1.99 (1H, m), 2.15-2.20 (2H, m), 2.34-2.37 (1H, m), 2.79 (3H, s), 3.29-3.38 (2H , m), 3.95-3.95 (1H, m), 4.21 (1H, t, J = 5.9 Hz).

 Step 3 Synthesis of Compound II-016  

Compound 16b (3.50 g, 17.1 mmol) was dissolved in DMF (70 mL), and ethyl (R)-2-bromo-2-fluoroacetate (3.81 g, 20.6 mmol), potassium carbonate (2.84 g, 20.6 mmol), stirred at -20 ° C for 3 hours. Ethyl acetate and a 10% aqueous citric acid solution were added to the reaction solution, and the mixture was extracted with ethyl acetate for 4 times, and then the organic solvent was evaporated under reduced pressure. The residue obtained was purified by ODS column chromatography (water-acetonitrile) to give compound II- 016 (2.26 g, yield 43%).

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.1 Hz), 1.94-2.02 (1H, m), 2.11-2.29 (2H, m), 2.39-2.48 (1H, m), 2.68 (3H, s), 3.20 (1H, d, J = 12.1 Hz), 3.36 (1H, d, J = 12.1 Hz), 4.06-4.11 (2H, m), 4.29-4.35 (2H, m), 5.88 ( 1H, d, J = 52.5Hz).

 Step 4 Synthesis of Compound I-036  

Using the compound II-016 (100 mg, 0.324 mmol), Compound 1-036 (97.0 mg, yield: 89%)

¹ H-NMR (D ₂ O) δ: 1.98-2.07 (1H, m), 2.16-2.22 (2H, m), 2.33-2.37 (1H, m), 2.78 (3H, s), 3.32 (1H, d , J = 12.1 Hz), 3.44 (1H, d, J = 12.1 Hz), 4.23-4.26 (1H, m), 4.33 (1H, t, J = 6.3 Hz), 5.82 (1H, d, J = 58.9 Hz) ).

 (Reference Example 18)  

Synthesis of Intermediates (3): Synthesis of Compound 7

 Step 1 Synthesis of Compound 7  

Compound 6 (Tetrahedron: Asymmetry, 2002, 13, 975.) (17.6 g, 112 mmol) was dissolved in dichloromethane (225 mL), and ethanol (32.7 mL, 560 mmol), WSCD HCl (23.6 g, 123 mmol) Stir at 0 ° C for 30 minutes. The organic layer was washed with a 0.3 mol/L aqueous solution of sulfuric acid, water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give Compound 7 (21.4 g, yield: 100%).

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.2 Hz), 4.36 (2H, q, J = 7.2 Hz), 6.57 (1H, d, J = 50.6 Hz).

Synthesis of Intermediates (4): Synthesis of Compound 8

 Step 1 Synthesis of Compound 8  

The compound 6 (4.71 g, 30.0 mmol) was used to carry out the same procedure as the intermediate compound (3) step 1 to obtain compound 8 (5.85 g, yield 98%).

¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, d, J = 2.6 Hz), 1.34 (3H, d, J = 2.6 Hz), 5.13-5.22 (1H, m), 6.53 (1H, d, J =50.8Hz).

 (Embodiment 19)  

Synthesis of Compound II-017

 Step 1 Synthesis of Compound II-017  

The same procedure as in Step 4 of Example 1 was carried out using Compound 16b (3.50 g, 17.1 mmol) to give Compound II-017 (2.66 g, yield 48%).

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 6.3 Hz), 1.33 (3H, d, J = 6.3 Hz), 1.96-2.00 (1H, m), 2.11-2.28 (2H, m ), 2.42 - 2.45 (1H, m), 2.68 (3H, s), 3.19 (1H, d, J = 12.3 Hz), 3.36 (1H, d, J = 12.2 Hz), 4.06 - 4.11 (2H, m) , 5.11-5.19 (1H, m), 5.85 (1H, d, J = 52.3Hz).

 (Example 24)  

Synthesis of Compound II-028, I-133

 Step 1 Synthesis of Compound II-028  

Compound 16b (200 mg, 0.979 mmol) was suspended in tetrahydrofuran (4 mL), EtOAc (EtOAc) Stir at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and solvent was evaporated under reduced pressure. Hexane/diisopropyl ether was added to the residue, and the powder was obtained, and the obtained powder was filtered to give Compound II-028 (42.3 mg, yield 12%).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (9H, s), 2.08-1.99 (1H, m), 2.11-2.29 (2H, m), 2.43-2.52 (1H, m), 2.69 (3H, s) , 3.34 (1H, d, J = 12.1 Hz), 3.45 (1H, d, J = 12.1 Hz), 4.10 (1H, dd, J = 7.3, 5.1 Hz), 4.18 (1H, d, J = 8.8 Hz) , 4.26 (1H, br s), 4.42 (1H, d, J = 8.8 Hz).

MS=355 (M+H), hold time: 1.80 min.

 Step 2 Synthesis of Compound I-133  

Compound II-028 (286 mg, 0.807 mmol) was dissolved in dimethylformamide (2.9 mL), and 5-methyl-1,3,4-thiadiazole-2-thiol sodium salt was added under a nitrogen atmosphere. (187 mg, 1.21 mmol), stirred at room temperature for 5 hours and then allowed to stand overnight at 5 ° C. The reaction solution was concentrated to dryness under reduced pressure, and the obtained residue was dissolved in water/acetonitrile. After concentration of HP20SS was added to the obtained solution, HP20SS was then purified by column chromatography coupled to ODS. The mixture was washed with water, and a mixture of the desired compound was collected, concentrated under reduced pressure, and then freeze-dried to obtain Compound I-133 (188 mg, yield 76%).

¹ H-NMR (D ₂ O) δ: 2.01-2.07 (1H, m), 2.13-2.21 (2H, m), 2.42-2.29 (1H, m), 2.80 (3H, s), 3.35-3.49 (2H , m), 4.27-4.35 (2H, m).

MS=285 (M+H), hold time: 0.25min.

 (Reference example 25)  

Synthesis of Intermediates (1): Synthesis of Compound 3

 Step 1 Synthesis of Compound 2  

Compound 1 (10.0 g, 44.2 mmol) was dissolved in (50 mL), ethyl iodide (5.36 mL, 66.3 mmol) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 2 (9.49 g, yield 99%).

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.5 Hz), 2.45 (3H, s), 3.01 (2H, q, J = 7.5 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8.2 Hz).

 Step 2 Synthesis of Compound 3  

Compound 2 (9.49 g, 43.9 mmol) was dissolved in acetonitrile / water (v / v = 2 / 1) (75 mL), and sodium thiophenol (6.76 g, 46.1 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, saturated brine was added thereto, and the mixture was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 3 (6.78 g, yield 91%).

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 2.75 (2H, q, J = 7.3 Hz), 7.21. (1H, t, J = 7.3 Hz), 7.32 (2H, t, J = 7.7 Hz), 7.54 (2H, d, J = 7.4 Hz).

Synthesis of Intermediates (2): Synthesis of Compound 5

 Step 1 Synthesis of Compound 5  

Compound 4 (3.00 g, 15.5 mmol) was dissolved in diethyl ether (30 mL), MeOH (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; Water was added to the reaction solution, and the mixture was extracted twice with diethyl ether and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 5 (2.44 g, yield: 59%).

¹ H-NMR (CDCl ₃ ) δ: 5.36 (2H, s), 7.38-7.40 (5H, m).

Synthesis of Intermediates (3): Synthesis of Compound 9

 Step 1 Synthesis of Compound 9  

Compound 1 (10.0 g, 44.2 mmol) was dissolved in DMF (50 mL), bromoacetonitrile (5.30 g, 44.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water, dried over anhydrous sodium sulfate and evaporated. The obtained solid was washed with diisopropyl ester to give Compound 9 (5.93 g, yield 59%).

¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 3.87 (2H, s), 7.41 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz).

 (Example 26)  

Synthesis of Compound I-095

Synthesis of intermediates Synthesis of compound 10

 Step 1 Synthesis of Compound 10  

Compound 10A (116 g, 493 mmol, JACS. 2008, 130, 14942) was dissolved in DMF (826 mL). Stir at 50 ° C for 1.5 hours. After the reaction solution was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and concentrated to give Compound 10 (115 g, yield 67%).

¹ H-NMR (CDCl ₃ ) δ: 0.03 (9H, s), 0.89-0.94 (2H, m), 2.45 (3H, s), 3.78 (2H, s), 4.07-4.11 (2H, m), 7.35 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8.2 Hz).

Synthesis of intermediates Synthesis of compound 11

 Step 1 Synthesis of Compound 11  

Compound 11A (82 g, 383 mmol) was dissolved in dichloromethane (1 L), EtOAc (EtOAc) After stirring at -20 ° C for 15 minutes, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and concentrated to give Compound 11 (109 g, yield: 88%).

¹ H-NMR (CDCl ₃ ) δ: 6.66 (1H, d, J = 50.4 Hz), 6.98 (1H, s), 7.31-7.37 (10H, m).

Synthesis of Compound I-095

 Step 1 Synthesis of Compound 95b  

Using a compound 95a (30 g, 109 mmol) and Compound 10 (113 g, 326 mmol), Compound 95b (21.5 g, yield 47%) was obtained by the same procedure as Step 1 of Example 1.

¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 1.00-1.04 (2H, m), 1.60-1.69 (2H, m), 1.94-2.01 (1H, m), 2.25-2.35 (1H, m), 2.79-2.83 (1H, m), 3.25 (1H, d, J = 15.6 Hz), 3.32-3.34 (1H, m), 3.47 (1H, d, J = 15.6 Hz), 3.73 (1H, d , J=11.5Hz), 4.18-4.23(2H,m), 4.76(1H,d,J=7.2Hz), 4.90(1H,d,J=11.5Hz),5.04(1H,d,J=11.5Hz ), 7.34-7.44 (5H, m).

 Step 2 Synthesis of Compound 95c  

Using a compound 95b (21.3 g, 50.4 mmol), Compound 95c (18.7 g, yield: 85%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.05 (9H, s), 1.02-1.07 (2H, m), 1.60-1.62 (1H, m), 1.74-1.83 (1H, m), 2.11-2.21 (2H, m), 2.30-2.39 (1H, m), 3.02 (1H, d, J = 11.9 Hz), 3.15 (1H, d, J = 11.9 Hz), 3.39-3.41 (1H, m), 3.65 (1H, d , J = 14.4 Hz), 3.99 (1H, d, J = 14.4 Hz), 4.24 - 4.33 (2H, m), 4.89 (1H, d, J = 11.5 Hz), 5.03 (1H, d, J = 11.5 Hz) ), 7.37-7.42 (5H, m).

 Step 3 Synthesis of Compound 95d  

The compound 95c (1.0 g, 2.28 mmol) was dissolved in tetrahydrofuran (5 ml), and the mixture was evaporated. Ethyl acetate, a 10% aqueous citric acid solution and a salt were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, and then the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. Compound 95d was used in the next step without purification.

 Step 4 Synthesis of Compound 95e  

Compound 95d (1.00 g, equivalent to 1.87 mmol) was dissolved in dichloromethane (20 ml), and HOBt (479 mg, 3.55 mmol), 28% aqueous amine (0.40 ml, 5.91 mmol), EDC (680 mg, 3.55 mmol), Stir at room temperature for 2 hours. Methylene chloride, a 10% aqueous citric acid solution, and a salt were added to the reaction solution, and the mixture was extracted twice with dichloromethane, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and concentrated, and then isopropyl acetate and diisopropyl ether to afford compound 95e (448.8 mg, yield 71%).

¹ H-NMR (CDCl ₃ ) δ: 1.74-1.84 (1H, m), 2.12-2.36 (3H, m), 3.04 (1H, d, J = 12.7 Hz), 3.10 (1H, d, J = 12.7 Hz) ), 3.41 (1H, br s), 3.57 (1H, d, J = 14.1 Hz), 3.86 (1H, d, J = 14.1 Hz), 4.29 - 4.32 (1H, m), 4.89 (1H, d, J) =11.4 Hz), 5.03 (1H, d, J = 11.4 Hz), 5.54 (1H, br s), 6.57 (1H, br s), 7.37-7.43 (5H, m).

 Step 5 Synthesis of Compound 95f  

Compound 95e (448.8 mg, 1.33 mmol) was dissolved in DMF / methanol (v / v = 1 / 1) (10 mL), palladium hydroxide carbon (93 mg, 0.067 mmol), DABCO (2.98 mg, 0.027 mmol), 1 atmosphere under a hydrogen atmosphere, stirring at room temperature for 1 hour. Palladium hydroxide carbon (374 mg, 0.266 mmol) was added, and the mixture was further stirred at room temperature for 1 hour under a hydrogen atmosphere of 1 atmosphere. Palladium hydroxide carbon (374 mg, 0.266 mmol) was added and stirred at room temperature for 1 hour under a 1 atmosphere of hydrogen atmosphere. After filtering the reaction solution with diatomaceous earth, the solvent was distilled off under reduced pressure to obtain a solution of about 5 g to obtain a solution of the compound 95f. Compound 95f was used in the next step without purification.

 Step 6 Synthesis of Compound 95g  

To a solution of compound 95f (about 5 g, corresponding to 1.33 mmol) was added a solution of compound 11 (473 mg, 1.46 mmol) in DMF (5 ml). After ice cooling, DBU (0.20 ml, 1.33 mmol) was added and stirred for 10 min. Ethyl acetate, 2 mol/L hydrochloric acid (2 ml, 4 mmol), and water were added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol), and concentrated to afford compound 95 g (510 mg, yield 78%).

¹ H-NMR (CDCl ₃ ) δ: 1.88-1.97 (1H, m), 2.13 - 2.35 (3H, m), 2.67 (1H, d, J = 12.2 Hz), 3.09 (1H, d, J = 12.2 Hz) ), 3.53 (1H, d, J = 14.1 Hz), 3.80 (1H, d, J = 14.1 Hz), 3.99 (1H, br s), 4.35 (1H, t, J = 6.3 Hz), 5.56 (1H, s), 5.98 (1H, d, J = 53.2 Hz), 6.53 (1H, s), 6.95 (1H, s), 7.28-7.41 (10H, m).

 Step 7 Synthesis of Compound I-095  

Compound I-095 (261 mg, yield 73%) was obtained by the same procedure as in the step 5 of Example 1 using the compound 95 g (510 mg, 1.04 mmol).

¹ H-NMR (D ₂ O) δ: 2.04-2.08 (1H, m), 2.16-2.26 (2H, m), 2.32-2.39 (1H, m), 3.33 (1H, d, J = 12.4 Hz), 3.42 (1H, d, J = 12.4 Hz), 4.26 (1H, s), 4.58 (1H, t, J = 6.3 Hz), 5.81 (1H, d, J = 58.6 Hz).

MS(m+1)=325, hold time: 0.25

Elemental analysis: C10H13FN3O6SNa(H2O)1.5(NaHCO3)0.07

Calculated: C, 31.98; H, 4.28; F, 5.02; N, 11.11; S, 8.48; Na, 6.50 (%)

Found: C, 32.03; H, 4.27; F, 4.92; N, 11.30; S, 8.08; Na, 6.49 (%)

The following compounds were obtained based on the usual production methods and the methods described in the examples. The structure and physical properties (LC/MS value and/or NMR) are shown in the following table. In the table below, "min" means minutes.

Test Example 1 β-endoprostanase inhibitory activity (IC50)

(experiment method)

The IC50 values for inhibition of KPC-2 and CMY-2 were determined by spectrophotometry using nitrocefin as the reporter matrix. Various concentrations of the evaluation compound, cephalosporin (final concentration 50 μg/ml), and each crude refined enzyme were sequentially added to the 96-well plate, and the mixture was incubated at 35 ° C for 20 minutes. Thereafter, the absorbance at 492 nm was measured, and the concentration of the compound (IC50 value) at which the decomposition of cephalosporin was reduced by 50% was calculated from the measured value.

(result)

The test results are shown below. The unit of inhibitory activity (IC50) in the table is μM.

From the above test results, it is understood that the compound of the present invention has high β-endoprostase inhibitory activity.

Test Example 2 Effect of Combination with β-Indoleamine Antibacterial Agent (MIC)

Test Example 2-1: Effect with cefixime (CFIX) (MIC)

(experiment method)

The effect of the combination with the β-endoxime antibacterial agent for the bacteria of the test substance was evaluated. Using Cefixime (CFIX) as a β-indoleamine antibacterial agent, the minimum developmental inhibition concentration of CFIX was determined by a micro-liquid dilution method based on the Clinical and Laboratory Standards Institute (CLSI method). (MIC). That is, a cation-adjusted Muller-Hinton broth (CAMHB) containing CFIX having a final concentration of 4 μg/mL and adjusted to a concentration of 2 times the dilution series was prepared. The bacteria cultured on the agar medium for one night were adjusted with CAMHB, and inoculated into a liquid medium containing the drug to make about 5 × 10 ⁵ CFU/mL. The medium was cultured at 35 ° C for 16 hours to 20 hours, and the minimum drug concentration at which no bacteria developed was visually observed was taken as the MIC.

The strain used was as shown in the following table.

(result)

The test results are shown below. In the table, "cpds No." refers to the compound number, and "CFIX" refers to the result when Cefixime (CFIX) is used alone. Further, the unit of the MIC value in the table is μg/mL.

From the results of the above tests, it was confirmed that the compound of the present invention exhibits high antibacterial activity by being used in combination with cefixime.

Test Example 2-2: Effect (MIC) in combination with various β-endoxime antibacterial agents

(experiment method)

Evaluate the effect of the combination of the bacterial test substance and the β-neutamine antibacterial agent. Use ampicillin (ABPC), amoxicillin (AMPC), cefotaxime (CAZ), ceftibuten (CETB), cefpodoxime (CPDX), cefixime (CFIX), cefdinir (CFDN), ammonia Qunan (AZT), meropenem (MEPM), cefodidil (CFDC), faropenem (FRPM), fluoxetine (FMOX) and cefmetazole (CMZ) as β-endoxime antibacterial agents The minimum developmental inhibitory concentration (MIC) of each β-nadehydeamine antibacterial agent was determined by the Clinical and Laboratory Standards Institute (CLSI method). That is, a cation-adjusted Muller-Hinton broth (CAMHB) containing a test substance having a final concentration of 4 μg/mL and a β-endoxime antibacterial agent other than CFDC at a concentration of 2 times the dilution ratio was prepared. In the case of CFDC, an iron-depleted cation-adjusted Muller-Hinton broth (ID-CAMHB) containing a test substance having a final concentration of 4 μg/mL and CFDC adjusted to each concentration of a 2 fold dilution series was prepared. The bacteria cultured on the agar medium for one night were adjusted with CAMHB or physiological saline, and inoculated into a liquid medium containing the drug to make about 5 × 10 ⁵ CFU/mL. The medium was cultured at 35 ° C for 16 to 20 hours, and the minimum concentration of the drug outside the CFDC was visually observed as the MIC. For CFDC, the minimum drug concentration at which fertility was significantly reduced was compared to the growth of the bacteria when no drug was added.

The strain used was as shown in the following table.

(result)

The compound of the present invention is selected from the group consisting of ampicillin (ABPC), amoxicillin (AMPC), cefotaxime (CAZ), ceftibuten (CETB), cefpodoxime (CPDX), cefixime (CFIX), cephalosporin. Β-endoin of dexamethasone (CFDN), aztreonam (AZT), meropenem (MEPM), cefodidil (CFDC), faropenem (FRPM), fluoxetine (FMOX) and cefmetazole (CMZ) The combination of the amine antibacterial agents confirms the superior antibacterial activity, and the combination of the β-endoxime antibacterial agent and the β-endoxime antibacterial agent are superior to various β-endoprostanase-producing bacteria regardless of the type of the β-indoleamine antibacterial agent. Antibacterial activity.

Test Example 3 PK test

Review of experimental materials and methods for oral absorption

(1) Use of animals: use mice, rats, dogs or monkeys.

(2) Feeding conditions: The mice or rats are free to ingest solid feed and tap water. Dogs or monkeys give solid feed bait 1 time on the 1st, free to ingest tap water.

(3) Administration of administration amount and grouping: The parent compound of the compound of the present invention or its precursor drug is administered orally and intravenously in a prescribed dosage. Set the group as shown below. (The dosage of each compound is changed. On the hunger strike, the hunger strike is 1 night from the day before the administration, and the bait is taken after the final screening on the day of administration.)

Oral administration of 5 to 30 mg/kg (n=2 to 3)

Intravenous administration of 1 to 10 mg/kg (n=2 to 3)

(4) Preparation of a solution: Oral administration is carried out as a solution or a suspension. Intravenous administration is done for solubilization.

(5) Method of administration: Oral administration to a mouse or a rat is carried out by oral administration by an oral catheter by administering an oral probe to a dog or a monkey. Intravenous administration is carried out by a syringe attached to an injection needle, and the mouse or rat is administered from the tail vein, and the dog or monkey is administered from the forefoot or hind foot vein.

(6) Evaluation item: Time-lapse blood sampling, and the concentration of the compound of the present invention in plasma was measured using LC/MS/MS.

(7) Statistical analysis: The concentration of the compound of the present invention in plasma is calculated by the trapezoidal method to calculate the area under the concentration-time curve in the plasma (AUC), and the ratio of administration from the oral administration group to the intravenous administration group is And the AUC ratio (the AUC ratio of the corresponding parent compound when the compound is a precursor drug) is used to calculate the bioavailability (BA) of the parent compound of the compound of the present invention or its precursor drug.

As a result, it was confirmed that the drug-releasing compound was rapidly converted into a corresponding parent compound in vivo after administration of the present invention.

The results of the bioavailability (BA) by the rat PK test are shown in the following table.

As described above, the drug-releasing compound of the present invention exhibits a good bioavailability regardless of the configuration of the parent compound.

Test Example 3-1 Rat Small Intestine and Liver S9 Stability Test

Review the experimental materials and methods for S9 stability

(1) Use S9: Use the small intestine and liver S9 taken from the rat.

(2) Solution preparation: The compound of the present invention is weighed before the drug is dissolved in a suitable solvent to prepare a solution containing the compound.

(3) Preparation of reaction solution: The above-prepared compound-containing solution was added to a small intestine or liver S9 solution (0.8 mg/mL) at a concentration of 10 μM.

(4) Reaction: The above reaction solution was kept at 37 ° C for 0 and 60 minutes. The reaction was stopped by adding an appropriate solvent at the set time.

(5) Evaluation item: The prodrug of the compound of the present invention and the corresponding parent compound in the solution after the reaction was stopped were measured by LC/MS/MS.

(6) Analysis: The mass chromatographic peak area of the drug of the present invention was compared after 0 minutes and 60 minutes of incubation, and the residual rate after incubation for 60 minutes was compared with that after 0 minutes of incubation. It is confirmed whether or not the mass chromatographic peak of the corresponding parent compound is combined, and it is qualitatively confirmed to be converted into a parent compound corresponding to each precursor drug.

As a result, it was confirmed that the compound of the present invention was rapidly decomposed in the small intestine and liver S9 of the rat (especially liver S9) and converted into a corresponding parent compound.

The results of the rat small intestine and liver S9 stability test are shown in the following table.

In the table, "cpds.No." refers to the compound number, "rat intestine S9" refers to the result when the rat small intestine S9 is used, and "rat liver S9" refers to the result when the rat liver S9 is used.

Test Example 4 Clearance rate evaluation test

Experimental materials and methods

(1) Animal use: SD rats were used.

(2) Feeding conditions: SD rats were free to ingest solid feed and sterilized tap water.

(3) Administration of administration amount and grouping: The parent compound of the present invention is administered intravenously, and a prescribed administration amount is administered. Set the group as described below.

Intravenous administration of 1 to 10 mg/kg (n=2 to 3)

(4) Preparation of the administration solution: it is dissolved by using physiological saline and administered.

(5) Method of administration: administration from the tail vein by means of a syringe with an injection needle.

(6) Evaluation item: Time-lapse blood sampling, and the concentration of the compound of the present invention in plasma was measured using LC/MS/MS.

(7) Statistical analysis: The whole body clearance rate (CLtot) was calculated by moment analysis for the concentration transition of the compound of the present invention in plasma.

(Results) The compound of the present invention showed a good whole body clearance rate.

Test Example 5 hERG test

In order to evaluate the risk of prolonging the QT interval of the electrocardiogram of the compound of the present invention, the CHO cells expressing the human ether-a-go-go related gene (hERG) channel were used to study the delay of the important role of the compound of the present invention in the ventricular repolarization process. The role of rectifying K ⁺ current (I _Kr ).

Using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S), the cells were maintained at a membrane potential of -80 mV by whole cell patch clamp method, and a leakage potential of -50 mV was administered and recorded in + Depolarization stimulation of 20 mV for 2 seconds, and then I _Kr induced by repolarization stimulation of -50 mV for 2 seconds. The dimethyl sulfoxide was adjusted to 0.1% extracellular fluid (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl ₂ : ₂ mmol/L, MgCl ₂ : 1 mmol/L, glucose: 10 mmol/L, HEPES (4- (2-hydroxyethyl)-1-piper Ethanesulfonic acid), 4-(2-hydroxyethyl)-1-piper Ethyl sulfonate: 10 mmol/L, pH = 7.4) As a medium, the medium and the extracellular solution in which the compound of the present invention was dissolved at the intended concentration were used for 7 minutes or more at room temperature. From the obtained I _{Kr, the} analysis software (Qpatch Assay software; Sophion Bioscience A/S) was used to measure the absolute value of the maximum tail current for keeping the current value of the membrane potential as a reference. The effect of the compound of the present invention on I _{Kr was} evaluated by calculating the maximum tail current after use of the compound of the present invention with the maximum tail current after using the medium as the inhibition rate.

The formulation examples shown below are merely illustrative, and the scope of the present invention is not limited to the examples.

The compound of the present invention can be used in any form in the past, for example, in the form of a tablet or a capsule, for example, in the form of a parenteral solution or a suspension, for example, a lotion or a gel. The form, nasal form or suppository form of the agent, ointment or cream is administered as a pharmaceutical composition. The pharmaceutical composition of the compound of the present invention, which comprises a free form or a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be produced by a conventional method of mixing, granulating or coating. For example, as an oral composition, a tablet, a granule, or a capsule containing an excipient, a disintegrator, a binder, a lubricant, and the like, and an active ingredient can be prepared. Further, the composition for injection can be used as a solution or a suspension, and can be sterilized, and can also contain a preservative, a stabilizer, a buffering agent, and the like.

 [Possibility of industrial use]  

The compound of the present invention has broad and effective inhibitory activity against various β-endoprostanases, either alone or in combination with a β-endoxime antibacterial agent, and can be used for treating and/or preventing bacterial infections (including Pharmaceutical composition of an infectious disease caused by a drug resistant bacteria

Claims (10)

A compound, a pharmaceutically acceptable salt thereof, or a carboxylic acid or a sulfonic acid precursor drug at the 6 position thereof, which is of the formula: Any of them. A compound according to claim 1 of the patent application, a pharmaceutically acceptable salt thereof or a carboxylic acid or a sulfonic acid precursor drug at the 6th position thereof, the compound is as follows: Any of them.  A β-endoprostanase inhibitor comprising a compound as described in claim 1 or 2, a pharmaceutically acceptable salt thereof or a 6-position carboxylic acid or sulfonic acid precursor drug.    A pharmaceutical composition comprising a compound as described in claim 1 or 2, a pharmaceutically acceptable salt thereof or a 6-position carboxylic acid or sulfonic acid precursor drug.    The pharmaceutical composition according to item 4 of the patent application is for use in combination with a β-neutamine antibacterial agent.    A pharmaceutical composition comprising a β-endoamine antibacterial agent for administration in combination with a β-endosaminolase inhibitor as described in claim 3 of the patent application.    A pharmaceutical composition comprising a β-endosaminolase inhibitor and a β-neutamine antibacterial agent as described in claim 3 of the patent application.    The pharmaceutical composition according to any one of claims 5 to 7, wherein the β-namidoxime antibacterial agent is any one selected from the group consisting of Ampicillin, Piperacillin, and Piperacillin. Amoxicillin, Carbenicillin, Sulbactam, Cefepime, Ceftazidime, Cefixime, Ceftibuten, Cephalosporin Cefpodoxime, Cefiderocol, Cefaclor, Cefdinir, Cefditore, Cefuroxime, Cefcapene, Cefcime Ceftriaxone, Imipenem, Meropenem, Doripenem, Tebipenem, Ertapenem, Aztreonam, Carumonam, Latamoxef, Flomoxef, Faropenem, Sulopenem, Cefmetazole, Cexixitin, and Cephalosporin a compound of Cefotetan, such pharmaceutically acceptable salts or such The precursor drug users.    A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a 6-position thereof, for use in combination with a β-namidamine antibacterial agent for administration, treatment and/or prevention of bacterial infections It is a carboxylic acid or sulfonic acid pre-drug.    One for use with any one selected from the group consisting of ampicillin, piperacillin, amoxicillin, carbenicillin, sulbactam, cefepime, ceftazidime, cefixime, ceftibuten, cefpodoxime, cefdizime , cefaclor, cefdinir, ceftibutin, cefuroxime, cefaclor, ceftriaxone, imipenem, meropenem, doripenem, tibepine, ertapenem, ammonia Compounds of south, carumol, cephalosporin, fluoxetine, faropenem, thiopenem, cefmetazole, cefoxitin and cefotetan, such pharmaceutically acceptable salts or such precursor drugs The β-indoleamine antibacterial agent is used in combination to treat and/or prevent bacterial infection. The compound according to claim 1 or 2, the pharmaceutically acceptable salt thereof or the 6-position thereof is a carboxylic acid. Or sulfonic acid before the drug.