WO2016140136A1 - キヌクリジン誘導体 - Google Patents
キヌクリジン誘導体 Download PDFInfo
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- WO2016140136A1 WO2016140136A1 PCT/JP2016/055637 JP2016055637W WO2016140136A1 WO 2016140136 A1 WO2016140136 A1 WO 2016140136A1 JP 2016055637 W JP2016055637 W JP 2016055637W WO 2016140136 A1 WO2016140136 A1 WO 2016140136A1
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- UKXSKSHDVLQNKG-UHFFFAOYSA-N OC(C(O)=O)(c1ccccc1)c1ccccc1 Chemical compound OC(C(O)=O)(c1ccccc1)c1ccccc1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a quinuclidine derivative and a medicine containing the same.
- Chronic obstructive pulmonary disease is a general term for diseases conventionally referred to as chronic bronchitis and emphysema. It is a chronic disease of the lung caused by long-term inhalation exposure to harmful substances, mainly cigarette smoke, and is said to be a lifestyle-related disease that develops in the middle and old age against the background of smoking habits.
- bronchodilators anticholinergic drugs, ⁇ 2 stimulants, theophylline drugs
- inhaled anticholinergic drugs and inhaled ⁇ 2 stimulants that mainly expand the bronchi for a long time are used.
- inhaled steroids are used.
- Patent Document 1 quinuclidine derivatives as muscarinic M 3 receptor antagonists (Patent Document 1), N-phenylbenzamide having bronchodilator action (Patent Document 2), and chondroitin sulfate proteoglycan as a pulmonary emphysema inhibitor are effective as drugs for treating COPD.
- Patent Document 3 the substance (patent document 3) etc. which inhibit accumulation
- the quinuclidine derivatives and N-phenylbenzamide have a bronchodilating action for a long period of time, they cannot be said to have a sufficient therapeutic effect on COPD. Therefore, the subject of this invention is providing the new compound excellent in the therapeutic effect with respect to COPD.
- the present inventor has studied to develop a new therapeutic agent for COPD, and a long-term bronchodilating action alone is not sufficient as a therapeutic agent for COPD, and a drug having an inhibitory effect on chronic lung inflammation is also useful.
- the compound represented by the following general formula (1) has a longer bronchodilating action than the compound described in Patent Document 1, and further, inflammation of the lungs Therefore, the present invention has been found to be particularly useful as a therapeutic agent for COPD.
- the present invention provides the following [1] to [12].
- R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a haloalkyl group, a lower alkoxy group or a haloalkoxy group
- M represents an integer of 1 to 5
- Z represents an oxygen atom or a sulfur atom
- l represents a number of 0 or 1
- n represents an integer of 0 to 4
- X ⁇ represents an anion
- the substituent on the quinuclidine ring represents a 1,3-bond or a 1,4-bond, provided that when m is 3, 1 is 1, and n is 0, R 1 is a halogen atom, a lower alkyl group, or a haloalkyl.
- a medicament comprising the quinuclidine derivative according to any one of [1] to [5] as an active ingredient.
- the medicament according to [6] which is a therapeutic agent for chronic obstructive pulmonary disease.
- a pharmaceutical composition comprising the quinuclidine derivative according to any one of [1] to [5] and a pharmaceutically acceptable carrier.
- the use according to [9], wherein the medicament is a therapeutic agent for chronic obstructive pulmonary disease.
- the quinuclidine derivative according to any one of [1] to [5] for treating chronic obstructive pulmonary disease.
- a method for treating chronic obstructive pulmonary disease comprising administering an effective amount of the quinuclidine derivative according to any one of [1] to [5].
- the quinuclidine derivative (1) of the present invention has a longer bronchodilating action and also suppresses inflammation of the lung, and thus is useful as a therapeutic agent for COPD, and is particularly effective for COPD with inflammation such as chronic bronchitis. Useful for treatment.
- the quinuclidine derivative of the present invention is represented by the following general formula (1).
- R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a haloalkyl group, a lower alkoxy group or a haloalkoxy group
- M represents an integer of 1 to 5
- Z represents an oxygen atom or a sulfur atom
- l represents a number of 0 or 1
- n represents an integer of 0 to 4
- X ⁇ represents an anion
- the substituent on the quinuclidine ring represents a 1,3-bond or a 1,4-bond, provided that when m is 3, 1 is 1, and n is 0, R 1 is a halogen atom, a lower alkyl group, or a haloalkyl.
- Z represents an oxygen atom or a sulfur atom, and an oxygen atom is more preferable.
- Examples of the halogen atom represented by R 1 include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, Examples thereof include a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group.
- a methyl group and an ethyl group are more preferable, and a methyl group is particularly preferable.
- the haloalkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms. Specific examples include a chloromethyl group, a trifluoromethyl group, and a trichloromethyl group. Etc.
- Examples of the lower alkoxy group represented by R 1 include linear or branched alkoxy groups having 1 to 6 carbon atoms, and specifically include methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n -Butyloxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group, n-pentyloxy group, n-hexyloxy group and the like.
- a methoxy group and an ethoxy group are more preferable, and a methoxy group is particularly preferable.
- haloalkoxy group examples include a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, and specific examples include a trifluoromethoxy group and a trichloromethoxy group. .
- R 1 is preferably a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halo-C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a halo-C 1 -C 6 alkoxy group.
- substitution position of R 1 is not particularly limited, and includes ortho-position, meta-position or para-position, but ortho-position or para-position is preferable, and para-position is more preferable.
- n represents an integer of 0 to 4, more preferably an integer of 0 to 2, and still more preferably 0 or 1. More preferably, m is an integer from 2 to 5, l is 0 or 1, and n is 0 or 1; m is an integer from 2 to 5, l is 0 or 1, and n is More preferably, it is 0; more preferably, m is 3, and l and n are 0.
- X ⁇ represents an anion, and examples thereof include a halogen anion, a trifluoroacetate anion, a sulfate anion, a nitrate anion, an acetate anion, an oxalate anion, and a succinate anion.
- a halogen anion and a trifluoroacetate anion are more preferable.
- the bonding position of the substituent on the quinuclidine ring is 1,3-bond or 1,4-bond, and 1,3-bond is more preferable.
- Preferred embodiments of the quinuclidine derivative (1) of the present invention are as follows.
- (1) Y is —C ( ⁇ O) —O—, Z is an oxygen atom,
- R 1 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halo-C 1 -C 6 alkyl A group, a C 1 -C 6 alkoxy group or a halo-C 1 -C 6 alkoxy group,
- m is an integer of 2 to 5, l is 0 or 1, n is 0 or 1, and
- Y is —C ( ⁇ O) —O—
- Z is an oxygen atom
- R 1 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halo-C 1 -C 6 alkyl A C 1 -C 6 alkoxy group or a halo-C 1 -C 6 alkoxy group
- m is an integer of 2 to 5
- l 0 or 1
- n 0,
- Y is —C ( ⁇ O) —O—
- Z is an oxygen atom
- R 1 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halo-C 1 -C 6 alkyl A group, a C 1 -C 6 alkoxy group or a halo-C 1 -C 6 alkoxy group
- m is an integer of 2 to 5
- l and n are 0, and
- X ⁇ is a halogen ion.
- the quinuclidine derivative (1) of the present invention has an optical isomer since the 3-position carbon atom of the quinuclidine skeleton is an asymmetric carbon atom. Both an optically active form and a racemic form are included, and the (R) form is particularly preferred.
- the quinuclidine derivative (1) of the present invention can be produced, for example, according to the following reaction formula.
- Hal represents a halogen atom
- Y, Z, R 1 , l, m and n are the same as above.
- the quinuclidine derivative (1) can be produced by reacting the compound (2) with the compound (3).
- the reaction of the compound (2) and the compound (3) proceeds easily by heating to room temperature to about 100 ° C.
- the reaction solvent dioxane, acetonitrile and the like can be used.
- a halogen atom (Hal) of a compound (2) a bromine atom, a chlorine atom, etc. are used.
- Raw material compound (2) (the following compounds (2-a), (2-b), (2-c)) can be produced, for example, according to the following reaction formula.
- R 2 represents an alkyl group
- the compound (2-a) is obtained by condensing benzylic acid (4) and quinuclidinol (5).
- the reaction of benzylic acid (4) and quinuclidinol (5) is preferably carried out in the presence of a condensing agent such as carbonyldiimidazole (CDI).
- a condensing agent such as carbonyldiimidazole (CDI).
- CDI carbonyldiimidazole
- the reaction is preferably carried out in the presence of a polar organic solvent such as dimethylformamide or diethylformamide.
- the reaction is preferably carried out with stirring at room temperature to the boiling point of the solvent for 1 to 24 hours.
- Compound (2-b) is obtained by reacting compound (6) with compound (7).
- the reaction between the compound (6) and the compound (7) is a Cranard reaction, and is preferably carried out in a solvent such as tetrahydrofuran, for example, with stirring at room temperature to the boiling point of the solvent for 30 minutes to 24 hours.
- Compound (2-c) is obtained by reacting compound (8) with quinuclidinol (5).
- the reaction between compound (8) and quinuclidinol (5) is carried out in the presence of a base such as sodium hydride in a polar organic solvent such as dimethylformamide and diethylformamide at room temperature to the boiling point of the solvent for 1 to 24 hours. It is preferable to do so.
- Compound (2) may be used after isolation, but may be used for the next reaction without isolation. After completion of the reaction, it can be purified by extraction, solvent evaporation, and chromatography. Moreover, the refinement
- (+) quinuclidinol, ( ⁇ ) quinuclidinol, (+) quinuclidine acetate or ( ⁇ ) quinuclidine acetate may be used.
- the quinuclidine derivative (1) of the present invention has a persistent and strong bronchodilator action as well as an excellent anti-inflammatory action as shown in the examples below, and therefore COPD exhibiting symptoms of emphysema and chronic bronchitis It is useful as a therapeutic agent. In particular, it is useful as a therapeutic agent for COPD accompanied by inflammation.
- Examples of the administration form of the COPD therapeutic agent of the compound (1) of the present invention include inhalants, respiratory tract agents, nasal drops, injections, oral preparations (tablets, granules, powders, capsules), ointments, creams, Examples include patches and suppositories. Of these, inhalants, respiratory tract agents, nasal drops, and oral agents are particularly preferable. These pharmaceutical compositions can be formulated with a pharmaceutically acceptable carrier.
- Such carriers include water, ethanol, propylene glycol, polyethylene glycol, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl Pyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium salt, magnesium stearate, talc, acetylcellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant , White sugar, simple syrup, citric acid, distilled water, ethanol, glycerin, propylene glycol, macrogol, phosphoric acid-water Sodium, sodium dihydrogen phosphate, sodium phosphate, dextrose, sodium chloride, phenol, thimerosal, p-hydroxybenzoic acid esters, and sodium hydrogen sulfite
- Inhalants and transrespiratory agents mean pharmaceutical compositions for reaching each tissue such as trachea, bronchi, lungs, and preferably nasal drops or compositions suitable for nasal or pulmonary administration. Is effective when administered with a nebulizer, atomizer, dropper, pipette, cannula, etc.
- the compound (1) of the present invention is a drug having an anticholinergic action such as ipratropium, scopolamine, pirenzepine, tiotropium, oxitropium, acridinium, glycopyrronium, umeclidinium, or ⁇ 2 stimulant such as indacaterol, birantrol, salmeterol, It can be effectively used by co-administering with formoterol and the like. In addition, when used in combination with a steroid, it effectively exhibits a therapeutic effect.
- an anticholinergic action such as ipratropium, scopolamine, pirenzepine, tiotropium, oxitropium, acridinium, glycopyrronium, umeclidinium, or ⁇ 2 stimulant such as indacaterol, birantrol, salmeterol
- the content of the active ingredient of the present invention (quinuclidine derivative (1)) in the pharmaceutical composition preparation of the present invention varies greatly depending on the form of the preparation and is not particularly limited.
- the content is 0.01 to 100% by mass, preferably 1 to 100% by mass, based on the total amount.
- the dose of the therapeutic agent for COPD of the present invention varies depending on the symptom, age and administration method of the patient to be administered, but is preferably 1.0 ⁇ g to 10 mg per day for an adult as the quinuclidine derivative (1).
- the dose can be divided into 1 to 4 times per day, but preferably once a day.
- Test Example 1 human M 3 receptor antagonist activity
- the receptor binding ability was measured using a CHO cell membrane expressing 1- [N-methyl- 3 H] scopolamine methyl bromide ([ 3 H] NMS, specific activity of 82 Cimmol) expressing human M 3 receptor transfected. I went.
- the protein concentration of the cell membrane was 2 ⁇ g per well, and the [ 3 H] NMS concentration was 1.0 nM.
- the range of antagonist concentrations (10 ⁇ 4 to 10 ⁇ 11 M) was tested by creating a comparison curve. Unspecific binding was measured in the presence of 1 ⁇ M atropine.
- the reagent was a binding buffer (phosphate buffer / saline) so that the total amount was 100 ⁇ L.
- the Ki value (nM) of the obtained compound is shown in each example.
- Example 2 to Example 41 In the same manner as in Example 1, the compounds of Examples 2 to 41 were obtained. The Ki value for the M 3 receptor of the obtained compound was also shown.
- the precipitated crystals are collected by filtration, washed with 20 mL of water 3 times, and dried under reduced pressure at 50 ° C. to 55 ° C. for 4 hours to obtain quinuclidinol benzyl acid.
- the ester was obtained as white crystals.
- the precipitated crystals were collected by filtration, washed with 20 mL of H 2 O ⁇ 3, and dried under reduced pressure at 50 ° C. to 55 ° C. for 4 hours to obtain the target product (c) As a pale brown solid, 4.22 g was obtained.
- the obtained treated crude product (4.22 g) was recrystallized with THF-IPE to obtain 2.21 g of the desired product (a) as white crystals.
- Test example 2 (effect on methacholine-induced airway constriction) ⁇ Method> The increase in airway resistance induced by methacholine was measured.
- Four to six week-old ICR mice were given five 20 second spray doses of 1 mg / mL methacholine. After completion of administration of methacholine, airway resistance was measured by a snap shot technique. All data was analyzed using FlexiVent software. 47.9 ⁇ g / kg of the test compound was administered via the respiratory tract, 1 hour, 96 hours, and 120 hours after administration, the mice were exposed to nebulized methacholine 5 times, and the airway resistance at that time was measured. The results are shown in FIG. 1, FIG. 2, and FIG.
- Test Example 3 (Effect on porcine pancreatic elastase-induced inflammation) ⁇ Method> Test compounds were administered once by airway to 4-6 week-old ICR mice. One hour after administration of the test compound, 100 ⁇ g / mouse of porcine pancreatic elastase was administered. Bronchoalveolar lavage fluid (BALF) was collected from the lung 24 hours after administration of porcine pancreatic elastase, and the total number of cells was measured. The results are shown in FIG.
- BALF Bronchoalveolar lavage fluid
- the compound of the present invention has a long-lasting bronchodilating action and is effective against inflammatory symptoms caused by porcine pancreatic elastase, which is a COPD model, and is therefore extremely useful as a COPD therapeutic agent having both bronchodilating action and anti-inflammatory action. It is.
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Abstract
Description
従って、本発明の課題は、COPDに対する治療効果に優れた新たな化合物を提供することにある。
(式中、R1は水素原子、ハロゲン原子、低級アルキル基、ハロアルキル基、低級アルコキシ基又はハロアルコキシ基を示し;Yは-C(=O)-O-、-CH2-又は-CH2O-を示し;mは1~5の整数を示し;Zは酸素原子又は硫黄原子を示し;lは0又は1の数を示し;nは0~4の整数を示し;X-はアニオンを示し;キヌクリジン環の置換基は1,3-結合又は1,4-結合を示す。ただし、mが3、lが1、かつnが0の場合、R1はハロゲン原子、低級アルキル基、ハロアルキル基、低級アルコキシ基又はハロアルコキシ基を示す。)
〔2〕mが2~5の整数であり、lが0又は1の数であり、nが0又は1の数である〔1〕記載のキヌクリジン誘導体。
〔3〕mが2~5の整数であり、lが0又は1であり、nが0である〔1〕又は〔2〕記載のキヌクリジン誘導体。
〔4〕mが3であり、l及びnが0である〔1〕~〔3〕のいずれかに記載のキヌクリジン誘導体。
〔5〕(R)体である〔1〕~〔4〕のいずれかに記載のキヌクリジン誘導体。
〔6〕〔1〕~〔5〕のいずれかに記載のキヌクリジン誘導体を有効成分とする医薬。
〔7〕慢性閉塞性肺疾患治療剤である〔6〕記載の医薬。
〔8〕〔1〕~〔5〕のいずれかに記載のキヌクリジン誘導体及び薬学的に許容される担体を含有する医薬組成物。
〔9〕〔1〕~〔5〕のいずれかに記載のキヌクリジン誘導体の医薬製造のための使用。
〔10〕医薬が、慢性閉塞性肺疾患治療剤である〔9〕記載の使用。
〔11〕慢性閉塞性肺疾患を治療するための〔1〕~〔5〕のいずれかに記載のキヌクリジン誘導体。
〔12〕〔1〕~〔5〕のいずれかに記載のキヌクリジン誘導体の有効量を投与することを特徴とする慢性閉塞性肺疾患の治療方法。
(式中、R1は水素原子、ハロゲン原子、低級アルキル基、ハロアルキル基、低級アルコキシ基又はハロアルコキシ基を示し;Yは-C(=O)-O-、-CH2-又は-CH2O-を示し;mは1~5の整数を示し;Zは酸素原子又は硫黄原子を示し;lは0又は1の数を示し;nは0~4の整数を示し;X-はアニオンを示し;キヌクリジン環の置換基は1,3-結合又は1,4-結合を示す。ただし、mが3、lが1、かつnが0の場合、R1はハロゲン原子、低級アルキル基、ハロアルキル基、低級アルコキシ基又はハロアルコキシ基を示す。)
一般式(1)中、Yは、-C(=O)-O-、-CH2-又は-CH2O-を示すが、-C(=O)-O-がより好ましい。
mが2~5の整数であり、lが0又は1であり、nが0又は1であるのがより好ましく;mが2~5の整数であり、lが0又は1であり、nが0であるのがさらに好ましく;mが3であり、l及びnが0であるのがさらに好ましい。
本発明のキヌクリジン誘導体(1)の好ましい態様は、次のとおりである。
(1)Yが-C(=O)-O-であり、Zが酸素原子であり、R1が、水素原子、ハロゲン原子、C1-C6アルキル基、ハロ-C1-C6アルキル基、C1-C6アルコキシ基又はハロ-C1-C6アルコキシ基であり、mが2~5の整数であり、lが0又は1であり、nが0又は1であり、X-がハロゲンイオンである(ただし、R1が水素原子のとき、m=3、l=1、かつn=0ではない)。
(2)Yが-C(=O)-O-であり、Zが酸素原子であり、R1が、水素原子、ハロゲン原子、C1-C6アルキル基、ハロ-C1-C6アルキル基、C1-C6アルコキシ基又はハロ-C1-C6アルコキシ基であり、mが2~5の整数であり、lが0又は1であり、nが0であり、X-がハロゲンイオンである(ただし、R1が水素原子のとき、m=3、l=1、かつn=0ではない)。
(3)Yが-C(=O)-O-であり、Zが酸素原子であり、R1が、水素原子、ハロゲン原子、C1-C6アルキル基、ハロ-C1-C6アルキル基、C1-C6アルコキシ基又はハロ-C1-C6アルコキシ基であり、mが2~5の整数であり、l及びnが0であり、X-がハロゲンイオンである。
(4)Yが-C(=O)-O-であり、Zが酸素原子であり、R1が水素原子であり、mが2~5の整数であり、l及びnが0であり、X-がハロゲンイオンである場合。
なお、本発明化合物(1)の光学活性体を得るには、(+)キヌクリジノール、(-)キヌクリジノール、(+)キヌクリジン酢酸エステル又は(-)キヌクリジン酢酸エステルを用いればよい。
受容体結合能の測定は、遺伝子導入したヒトM3受容体発現したCHO細胞膜、1-[N-メチル-3H]スコポラミンメチルブロマイド([3H]NMS、82Cimmolの特異的な活性)を用いて行った。細胞膜のタンパク質濃度は1wellあたり2μg、[3H]NMS濃度は、1.0nMであった。
拮抗剤濃度の範囲(10-4~10-11M)は、比較曲線を作成することにより試験した。不特定な結合は1μMのアトロピンの存在下で測定した。
試薬は結合緩衝液(リン酸バッファー/食塩水)にて、全量が100μLになるようにした。平衡になるように室温で2時間インキュベーションを行った後、反応混合液は0.05%ポリエチレンイミンを含有する洗浄バッファーで1時間前処理したGF/Cフィルタープレートに移植した。
結合した[3H]NMS及び遊離な[3H]NMSを、迅速真空濾過により分離し、リンスバッファー(50mMトリス、100mM食塩水、pH7.4)で3回洗浄した。得られたフィルターを乾燥後、固形シンチレーターMeltiLexA(PerkinElmer))を融着させてβ-カウンター(MicroBeta microplate scintillation counter(Trilux))を用いて測定し、定量した。
Ki値は以下の式により算出した。([L];[3H]NMS濃度,Kd;[3H]NMSの解離定数)
(数1)
Ki=IC50/(1+[L]/Kd)
mp 219.2-220.4℃
Ki(M3receptor)=4.12nM
実施例1と同様にして実施例2~41の化合物を得た。得られた化合物のM3受容体に対するKi値も示した。
mp 223.2-223.9℃
Ki(M3receptor)=0.083nM
mp 213.5-214.2℃
Ki(M3 receptor)=0.13nM
mp 223.4-224.1 ℃
Ki (M3 receptor) = 0.114 nM
mp 211.4-212.2 ℃
Ki (M3 receptor) = 2.39 nM
mp 202.9-203.9 ℃
Ki (M3 receptor) = 0.458nM
mp 182-184 ℃
mp 188-190 ℃
mp 150-153 ℃
mp 169-173 ℃
mp 155-157 ℃
mp 211-213 ℃
mp 205-207 ℃
mp 195-196 ℃
mp 185-188 ℃
mp 203-204 ℃
mp 176-177 ℃
mp 243.1-244.4℃
Ki(M3 receptor)=0.014nM
mp 243.2-244.1℃
Ki(M3 receptor)=2.09nM
mp 210.5-211.1℃
Ki(M3receptor)=0.029nM
mp 131-133 ℃
mp 194-195 ℃
mp 168-169 ℃
mp 211.5-212.1 ℃
Ki (M3 receptor) = 0.31nM
mp 219.5-219.9 ℃
Ki (M3 receptor) = 1.26nM
mp 184-185 ℃
mp 221.5-221.9 ℃
Ki (M3 receptor) = 0.67nM
mp 218.3-218.9 ℃
Ki (M3 receptor) = 1.29nM
mp 211.1-212.0℃
Ki(M3 receptor)=0.19nM
mp 208.8-210.0℃
Ki(M3 receptor)=0.084nM
mp 214.5-215.4℃
Ki(M3receptor)=0.32nM
mp 208.1-209.0℃
Ki(M3 receptor)=0.22nM
mp 218.1-219.3℃
Ki(M3 receptor)=0.058nM
mp 210.5-211.2℃
Ki(M3receptor)=2.7nM
mp 213.4-214.3℃
Ki(M3 receptor)=5.89nM
mp 215.1-216.9℃
Ki(M3 receptor)=0.39nM
mp 228.2-229.9℃
Ki (M3 receptor)=2.70nM
mp 224.2-224.9℃
Ki (M3 receptor)=0.63nM
mp 194.5-195.5℃
Ki(M3 receptor)=2.98nM
mp 201.1-202.4℃
Ki(M3 receptor)=2.53nM
mp 222.3?223.3 ℃
Ki (M3 receptor) = 0.12nM
次に5℃~10℃でキヌクリジノール1.23gを添加後、NaH(60%)0.351gを添加し、20℃~30℃で4日間撹拌を行った。
反応液を内温5℃~10℃まで冷却し、水120mLにゆっくりと滴下した(白色結晶析出)。内温5℃~10℃で6時間程度の熟成撹拌後、析出結晶をろ取し、水20mL×3洗浄、50℃~55℃にて4時間の減圧乾燥を行い、ベンジル酸キヌクリジノールエステルを白色結晶として得た。
反応液を4時間の氷冷撹拌後、析出結晶をろ取、IPE:30mL(20V)×3洗浄、バス温:50℃~55℃にて3時間の減圧乾燥を行い、目的物を白色結晶として、1.86g得た。
mp 231-234℃
次にキヌクリジン-3-オン4.27gのdry THE 17mL溶液を滴下し、室温で3時間撹拌後、50℃~55℃で終夜撹拌を行った。
TLCにて原料の焼失を確認後、氷水200mLおよびEtOAc 200mLに反応液を注加後、暫く撹拌を行った。
これを静置・分液後、得られた有機層を生理食塩水200mLにて順次洗浄後、無水硫酸マグネシウムで乾燥、減圧濃縮させて濃縮残渣を得た。
上記で得た濃縮残渣をシリカゲルカラムクロマト精製(NHシリカゲル:120g,Heptane/EtOAc=9/1~1/1)にて精製後、無色オイルとして3-キヌクリジリデン-酢酸エチルエステル6.43gを得た。
TLCにて原料の焼失を確認後、Pd-Cをセライトろ過、EtOH洗浄を行い、ろ液を減圧濃縮しキヌクリジン-3-酢酸エチルエステルを無色オイルとして6.05g(収率:99.8%)得た。
TLCにて原料の消失を確認後、反応液を氷冷し、飽和NH4Cl水溶液20mLをゆっくりと滴下し、反応をクエンチした。
析出固体をろ取、H2O洗浄、減圧乾燥し、目的物の処理粗体を白色結晶として、37.0g得た。これをシリカゲルカラムクロマト精製〔NHシリカゲル:37g、CHCl3/MeOH=10/1〕を行い、目的物を含むフラクションを減圧濃縮させて得た。
得られた残渣をMeOH-THF-IPEで晶析させて目的物(b)を白色結晶として、1.86g得た。
反応液を2時間の氷冷撹拌後、析出結晶をろ取、IPE 40mL×3洗浄、50℃~55℃にて3時間の減圧乾燥を行い、化合物(1-42)の処理粗体を白色結晶として、2.48g得た。この結晶2.48gをMeCN-H2Oで溶解後、MeCNにて晶析させて、化合物(1-42)を白色結晶として、0.905g得た。
mp 194-197℃
次にベンゾフェノン10.0gを分割添加し、45℃~52℃で1時間撹拌を行った。
TLCにて原料の消失を確認後、氷水200mLおよびEtOAc200mLに反応液を注加後、暫く撹拌を行った。
これを静置・分液後、得られた有機層を飽和NaHCO3水溶液200mLおよび生理食塩水200mLにて順次洗浄後、無水硫酸マグネシウムで乾燥、減圧濃縮させて濃縮残渣11.7gを得た。
上記で得た濃縮残渣をシリカゲルカラムクロマト精製(シリカゲル:120g,Heptane/EtOAc=60/1~40/1~20/1)にて精製後、目的物を含むカラムフラクションを減圧濃縮して、1,1-ジフェニルエチレンオキシドを無色オイルとして3.94g(収率:36.6%)得た。
次に1,1-ジフェニルエチレンオキシド3.90gのdry DMF 12mL溶液を滴下し、内温:40℃~45℃で終夜撹拌を行った。
TLCにて原料の消失を確認後、反応溶液を氷冷し、H2O 160mLをゆっくりと滴下した(白色結晶析出)。内温5℃~10℃で2時間程度の熟成撹拌後、析出結晶をろ取、H2O 20mL×3洗浄、50℃~55℃にて4時間の減圧乾燥を行い、目的物(c)の処理粗体を淡茶白色固体として、4.22g得た。
得られた処理粗体4.22gをTHF-IPEで再結晶し、目的物(a)を白色結晶として、2.21g得た。
反応液を2時間の氷冷撹拌後、析出結晶をろ取、IPE:40mL×2洗浄、50℃~55℃にて3時間の減圧乾燥を行い、化合物(1-44)を白色結晶として、3.38g得た。
<方法>
メタコリン誘発による気道抵抗(airway resistance)の上昇測定を行った。4~6週齢のICRマウスに、1mg/mLのメタコリンの20秒間の噴霧投与を5回行った。メタコリン投与終了後、スナップショット法(snap shot technique)により、気道抵抗を測定した。全てのデータは、FlexiVentソフシウエアを用いて解析した。
試験化合物の47.9μg/kgを経気道投与を行い、投与1時間後、96時間後、120時間後に、マウスを噴霧化されたメタコリンに5回曝し、その時における気道抵抗を測定した。
その結果を図1、図2、図3に示した。
図1、図2、図3に示した結果から判明するように、化合物(1-18)及び化合物(1-20)は、47.9μg/kgにおいて投与120時間後においても気道抵抗を低下させていた。一方、図2に示されるようにアクリジニウムは、96時間を超えると気道抵抗を低下させなかった。
<方法>
4~6週齢のICRマウスに、試験化合物を1回経気道投与した。試験化合物投与1時間後にブタ膵臓エラスターゼ100μg/マウスを投与した。ブタ膵臓エラスターゼ投与24時間後に気管支肺胞洗浄液(bronchoalveolar lavage fluid、BALF)を肺から採取し、細胞総数を測定した。その結果を図4に示した。
図4に示した結果から判明するように、BALF中の総細胞数が化合物(1-18)、化合物(1-19)及び化合物(1-20)の投与量依存的に減少していた。一方、アクリジニウムは有益な抗炎症作用を示さなかった。
以上の結果より、本発明化合物がブタ膵臓エラスターゼにより発症した炎症症状に対して有効であることが判明した。
Claims (12)
- mが2~5の整数であり、lが0又は1の数であり、nが0又は1の数である請求項1記載のキヌクリジン誘導体。
- mが2~5の整数であり、lが0又は1であり、nが0である請求項1又は2記載のキヌクリジン誘導体。
- mが3であり、l及びnが0である請求項1~3のいずれか1項記載のキヌクリジン誘導体。
- (R)体である請求項1~4のいずれか1項記載のキヌクリジン誘導体。
- 請求項1~5のいずれか1項記載のキヌクリジン誘導体を有効成分とする医薬。
- 慢性閉塞性肺疾患治療剤である請求項6記載の医薬。
- 請求項1~5のいずれか1項記載のキヌクリジン誘導体及び薬学的に許容される担体を含有する医薬組成物。
- 請求項1~5のいずれか1項記載のキヌクリジン誘導体の医薬製造のための使用。
- 医薬が、慢性閉塞性肺疾患治療剤である請求項9記載の使用。
- 慢性閉塞性肺疾患を治療するための請求項1~5のいずれか1項記載のキヌクリジン誘導体。
- 請求項1~5のいずれか1項記載のキヌクリジン誘導体の有効量を投与することを特徴とする慢性閉塞性肺疾患の治療方法。
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