WO2012008565A1 - Dérivés imidazoline - Google Patents

Dérivés imidazoline Download PDF

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WO2012008565A1
WO2012008565A1 PCT/JP2011/066188 JP2011066188W WO2012008565A1 WO 2012008565 A1 WO2012008565 A1 WO 2012008565A1 JP 2011066188 W JP2011066188 W JP 2011066188W WO 2012008565 A1 WO2012008565 A1 WO 2012008565A1
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imidazoline
compound
isopropyl
subtype
methyl
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PCT/JP2011/066188
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English (en)
Japanese (ja)
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高橋俊弘
金久保紀子
小林正
西宗敦史
村松郁延
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日本ケミファ株式会社
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Priority claimed from JP2010161431A external-priority patent/JP2013199431A/ja
Priority claimed from JP2011034325A external-priority patent/JP2013199432A/ja
Application filed by 日本ケミファ株式会社 filed Critical 日本ケミファ株式会社
Publication of WO2012008565A1 publication Critical patent/WO2012008565A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

  • the present invention relates to an imidazoline derivative.
  • Urinary incontinence is defined as a state of involuntary urinary leakage that is not directly life-threatening, but significantly impairs quality of life (QOL) and hurts patients' self-esteem and makes them unwilling to live Psychological influence is also great.
  • QOL quality of life
  • the prevalence of urinary incontinence is high in the elderly, and the frequency of occurrence of urinary tract infections and pressure ulcers is increased, which is a matter of course for elderly people who suffer from urinary incontinence, and also for carers. Therefore, the need for measures against urinary incontinence is increasing. Stress urinary incontinence is caused by an increase in abdominal pressure during daily life activities such as physiological reactions such as coughing and sneezing, emotional expressions such as laughing loudly and angry, and lifting heavy objects.
  • the urine will cause an unintentional overflow of urine.
  • stress urinary incontinence has a significant impact on spontaneous activity and emotional expression from the stage of not losing autonomous activity, leading to anatomically short urethral women, especially childbirth. Incidence is high in women who have experienced it.
  • Treatment for urinary incontinence includes lower urinary tract rehabilitation, medication, and surgical treatment.
  • drugs used for drug treatment vary depending on the type of urinary incontinence, ephedrine, clenbuterol, imipramine, and the like are used in stress urinary incontinence.
  • each of these drugs is known to have harmful side effects, and it is known that there are cases where it is not possible to take an amount that is expected to have a sufficient effect.
  • ⁇ 1 adrenergic receptors are classified into four subtypes, ⁇ 1A subtype, ⁇ 1B subtype, ⁇ 1D subtype and ⁇ 1L subtype, of which ⁇ 1L subtype is the same as ⁇ 1A subtype. It was known to be derived from the gene. However, a method for specifically expressing the ⁇ 1L subtype on the cell membrane has not been known.
  • Non-patent document 1, Patent document 1 Unlike other subtypes, the ⁇ 1L subtype is known to be selectively involved in urethral contraction. The ⁇ 1L subtype is also known to be involved in the contraction of the dilated pupil and the contraction of some peripheral blood vessels.
  • the ⁇ 1A subtype expressed from the same gene as the ⁇ 1L subtype is not only involved in aqueous humor production but also maintains vasoconstriction and vascular tone, similar to the ⁇ 1B subtype and ⁇ 1D subtype. It is said to be mainly involved. Therefore, a drug that selectively acts on the ⁇ 1L adrenergic receptor is expected to treat stress urinary incontinence without causing side effects such as an increase in blood pressure.
  • the present inventors have the following formula (A),
  • the imidazolidine derivative (ESR1150CL) represented by the formula (1) is an agonist of the ⁇ 1L receptor and has been found to be useful as a therapeutic agent for urinary incontinence.
  • Patent Documents 2 to 5 Furthermore, the inventors have the following formula (B),
  • trazoline hydrochloride (2-benzyl-2-imidazoline hydrochloride) or clonidine hydrochloride (2- (2,6-dichlorophenylimino) imidazolidine monohydrochloride) is included. It is included in the broad sense.
  • Trazoline hydrochloride is known as an ⁇ receptor antagonist, and clonidine hydrochloride is marketed as an ⁇ 2 receptor agonist as a therapeutic agent for various hypertensions, but ⁇ 2 receptor on which clonidine acts is a compound of the present invention. It is a completely different receptor from the target receptor ⁇ 1L receptor (as described above, ⁇ 1L receptor is one of ⁇ 1 receptors).
  • Patent Documents 7 and 8 describe imidazoline derivatives having the use as therapeutic agents for urinary incontinence, but they are clearly different from the compounds of the present invention in that they have a sulfonamide group as a phenyl group substituent. Further, in Patent Document 9, the following formula (C) similar in structure to the imidazoline derivative of the present invention represented by the following general formula (I):
  • An object of the present invention is to provide an imidazoline derivative useful as a therapeutic agent for urinary incontinence.
  • one of X and Y represents a hydrogen atom, and the other represents NR 1 R 2 ;
  • R 1 and R 2 may be the same or different and each represents hydrogen or methyl, Z represents chloro or methyl.
  • a pharmacologically acceptable salt thereof
  • the present invention also relates to a therapeutic agent for dysuria, which contains an imidazoline derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also relates to an ⁇ 1L adrenergic receptor agonist containing, as an active ingredient, an imidazoline derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention also relates to a disease in which ⁇ 1L adrenergic receptor is highly involved as compared with ⁇ 1B adrenergic receptor containing as its active ingredient an imidazoline derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. It relates to a therapeutic agent.
  • the present invention relates to a disease in which ⁇ 1L adrenergic receptor is more involved than ⁇ 1A adrenergic receptor containing as its active ingredient an imidazoline derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. It is related with the therapeutic agent for.
  • FIG. 1 is a graph showing a concentration-response curve of noradrenaline in cells in which the ⁇ 1 adrenergic receptor subtype was forcibly expressed.
  • FIG. 2 is a graph showing a concentration-response curve of the compound of the present invention described in Example 2 in cells in which the ⁇ 1 adrenergic receptor subtype was forcibly expressed.
  • FIG. 3 is a graph showing a concentration-response curve of the compound of the present invention described in Example 4 in cells in which the ⁇ 1 adrenergic receptor subtype was forcibly expressed.
  • FIG. 1 is a graph showing a concentration-response curve of noradrenaline in cells in which the ⁇ 1 adrenergic receptor subtype was forcibly expressed.
  • FIG. 2 is a graph showing a concentration-response curve of the compound of the present invention described in Example 2 in cells in which the ⁇ 1 adrenergic receptor subtype was for
  • FIG. 4 is a graph showing a concentration-response curve of Comparative Compound A in cells in which the ⁇ 1 adrenergic receptor subtype was forcibly expressed.
  • FIG. 5 is a graph showing a concentration-response curve of Comparative Compound B in cells in which the ⁇ 1 adrenergic receptor subtype was forcibly expressed.
  • FIG. 6 is a graph showing noradrenaline concentration-response curves via four types of ⁇ 1 adrenergic receptor subtypes using isolated rat tissues.
  • FIG. 7 is a graph showing the concentration-response curves of the compound of the present invention described in Example 2 via four ⁇ 1 adrenergic receptor subtypes using isolated rat tissues.
  • FIG. 8 is a graph showing concentration-response curves of the compound of the present invention described in Example 4 via four ⁇ 1 adrenergic receptor subtypes using rat isolated tissues.
  • FIG. 9 is a graph showing the concentration-response curves of Comparative Compound A mediated by four types of ⁇ 1 adrenergic receptor subtypes using isolated rat tissues.
  • FIG. 10 is a graph showing the concentration-response curves of Comparative Compound B via four types of ⁇ 1 adrenergic receptor subtypes using rat isolated tissues.
  • FIG. 9 is a graph showing concentration-response curves of Comparative Compound A mediated by four types of ⁇ 1 adrenergic receptor subtypes using isolated rat tissues.
  • FIG. 10 is a graph showing the concentration-response curves of Comparative Compound B via four types of ⁇ 1 adrenergic receptor subtypes using rat isolated tissues.
  • FIG. 11 is a graph showing the influence of the compound of the present invention described in Example 2, Comparative Compound B and phenylephrine on diastolic blood pressure (DBP) in urethane anesthetized rabbits.
  • FIG. 12 is a graph showing the effects of the compound of the present invention described in Example 2, Comparative Compound B, and phenylephrine on intraurethral pressure (IUP) in urethane anesthetized rabbits.
  • IUP intraurethral pressure
  • Examples of the imidazoline derivative of the present invention or a pharmacologically acceptable salt thereof include the following compounds.
  • Examples of the pharmacologically acceptable salt of the compound of the present invention include acid addition salts such as hydrochloric acid, hydrobromic acid, and methanesulfonic acid.
  • the compound of the present invention can be produced, for example, by the method described in the following synthesis scheme.
  • the starting material (a) can be synthesized by a known method (G. Dessigne, Compt. Rend., 200, 466-468 (1935)) or a method described later. 2) First Step The compound of the general formula (b) can be obtained by reacting the starting material (a) with N-iodosuccinimide at ⁇ 10 ° C. to room temperature in concentrated sulfuric acid or trifluoromethanesulfonic acid.
  • Second step The reaction of compound (b) with cyanoacetic acid ester is carried out in a solvent not involved in the reaction such as dimethyl sulfoxide, 1,4-dioxane or hexamethylphosphoric triamide, potassium carbonate, sodium carbonate, cesium carbonate or The reaction is performed at a temperature of 70 ° C. to 170 ° C. in the presence of a base such as sodium hydride and a catalyst such as copper iodide. 4) Third step Conversion of compound (c) to compound (d) is carried out by a normal hydrolysis / decarboxylation reaction under acidic conditions or basic conditions.
  • a solvent not involved in the reaction such as dimethyl sulfoxide, 1,4-dioxane or hexamethylphosphoric triamide, potassium carbonate, sodium carbonate, cesium carbonate or The reaction is performed at a temperature of 70 ° C. to 170 ° C. in the presence of a base such as sodium hydride and a catalyst such as
  • This conversion can also be performed by heating the compound (c) in a mixed solvent of dimethyl sulfoxide and water in the presence of lithium chloride or sodium chloride. In the case of the latter reaction, the reaction temperature is 80 to 160 ° C. 5)
  • the imidazoline derivative represented by the general formula (e) can be synthesized by reacting compound (d) with ethylenediamine at a temperature of 60 to 120 ° C. in the presence of thioacetamide as a catalyst. In this case, ethylenediamine can also be used as a solvent.
  • the imidazoline derivative of the general formula (e) can also be synthesized by the following two-step reaction.
  • Step 5 The compound of the present invention represented by the general formula (f) can be synthesized by reducing the nitro group of the compound (e).
  • a reduction reaction with a metal such as iron powder or a catalytic hydrogenation reaction using palladium-carbon or the like as a catalyst is used.
  • Second Step The compound of the general formula (o) is prepared by reacting compound (n) with N-iodosuccinimide or N-bromosuccinimide in concentrated sulfuric acid, or N-iodosuccinic acid in trifluoromethanesulfonic acid. It can be synthesized by any of the methods in which an imide is allowed to act. The reaction temperature in both reactions is ⁇ 10 ° C. to room temperature.
  • Second Step The compound represented by the general formula (p) can be synthesized by a cross-coupling reaction between the compound of the general formula (o) and isopropenyl boronic acid pinacol ester.
  • This reaction is carried out in a solvent such as N, N-dimethylformamide using a palladium catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct and cesium carbonate, sodium carbonate, hydrogen carbonate. It is carried out in the presence of a base such as sodium.
  • the reaction temperature is 50 to 120 ° C. 3
  • the conversion from the compound (p) to the compound (q) can be performed by a catalytic hydrogenation reaction using palladium-carbon or platinum (IV) oxide as a catalyst.
  • the reaction solvent methanol, ethanol or the like is used, and the reaction temperature is from room temperature to 60 ° C.
  • First Step The compound of the general formula (g) can be obtained by reducing the nitro group of the compound represented by the general formula (d) (described in the above production method (A)).
  • As the reduction method catalytic hydrogenation reaction using palladium-carbon or platinum (IV) oxide as a catalyst in a solvent such as methanol or ethanol, or a metal such as zinc powder or iron powder under acidic or neutral conditions.
  • the reduction reaction is used.
  • Second Step The compound represented by the compound (h) can be synthesized by a reductive amination reaction of the compound (g) with formaldehyde.
  • Ns-Cl represents 2-nitrobenzenesulfonyl chloride, and Z is as defined above
  • the compound of the general formula (j) can be synthesized by allowing 2-nitrobenzenesulfonyl chloride to act on the compound of the general formula (g) (described in the production method of (B) above).
  • the solvent pyridine, dichloromethane or the like is used. In the latter case, triethylamine or the like is used as the base. In either case, the reaction temperature is 0 ° C. to room temperature.
  • Second Step The compound of the general formula (k) can be synthesized by reacting the compound of the general formula (j) with methyl iodide in the presence of a base such as anhydrous potassium carbonate. This reaction is performed at a temperature of 0 to 50 ° C. in a solvent that does not participate in the reaction such as N, N-dimethylformamide.
  • Second Step The compound of the present invention represented by the general formula (m) can be synthesized by reacting compound (k) with ethylenediamine in the presence of thioacetamide. The reaction temperature is 60 to 120 ° C., and the 2-nitrobenzenesulfonyl group, which is a protecting group for the amino group, is removed in this reaction.
  • the compound of the present invention can be synthesized by converting the starting hydroxyl group to a cyano group and then applying the reaction described in the fourth step of production method A to the resulting product.
  • Other compounds included in the general formula (I) can also be produced by the same methods as those described above, the examples described later, and the synthesis methods described in Patent Documents 2 to 9.
  • FIGS. 1 to 5 Table 1
  • IUP intraurethral pressure
  • DBP diastolic blood pressure
  • Example 7 The results described in Example 2 above compared to the increase in DBP and IUP by intravenous administration of phenylephrine 30 ⁇ g / kg.
  • the response when intravenously administering 1 ⁇ g / kg of the inventive compound was somewhat persistent with IUP and was almost the same, and was clearly small with DBP (data loss due to poor contact at the beginning of administration).
  • Comparative Compound B when 1 ⁇ g / kg of Comparative Compound B was intravenously administered, the IUP increased very continuously, but the maximum response did not reach that of phenylephrine, and DBP showed the same increase as phenylephrine.
  • the compound of the present invention since the compound of the present invention has high ⁇ 1L selectivity, it is useful as an active ingredient of a remedy for dysuria, preferably urinary incontinence, more preferably stress urinary incontinence that can be expected to reduce side effects such as an increase in blood pressure. is there.
  • the compound of the present invention is useful as an ⁇ 1L adrenergic receptor agonist.
  • the compound of the present invention is useful as an active ingredient of a therapeutic agent for a disease in which ⁇ 1L adrenergic receptor is more involved than ⁇ 1B adrenergic receptor.
  • the compound of the present invention is useful as an active ingredient of a therapeutic agent for a disease in which ⁇ 1L adrenergic receptor is more involved than ⁇ 1A adrenergic receptor.
  • the compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
  • an appropriate administration method such as general oral administration or parenteral administration.
  • it can be produced into a dosage form such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by conventional methods in the technical field of formulation.
  • usual excipients, disintegrants, binders, lubricants, dyes, diluents and the like are used.
  • lactose lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca) and the like, as the lubricant, magnesium stearate,
  • binders include talc and the like, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
  • the dose is usually about 0.01 mg to 100 mg of the compound of the present invention, which is an active ingredient in injections, and 0.1 mg to 500 mg per day for oral administration in adults.
  • the dose may be increased or decreased depending on age, symptoms, etc. Can do.
  • reaction mixture was poured into 5% aqueous hydrochloric acid (800 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate, 90:10) to give the title compound (25 .6 g) was obtained as a yellow oil.
  • Non-patent Document 1 Choinese hamster oocytes (CHO cells) in which ⁇ 1 adrenergic receptor is forcibly expressed was used, and ⁇ 1 agonist activity was subtyped using an increase in intracellular Ca 2+ concentration as an index.
  • the ⁇ 1 subtype selectivity of the compound of the present invention and noradrenaline, comparative compound A and comparative compound B was examined according to the method described below.
  • ⁇ -1A gene (ADRA1A), ⁇ -1B gene (ADRA1B) and ⁇ -1D gene (ADRA1D) of human adrenergic receptor were introduced into CHO cells by FuGen 6 reagent (Roche), and puromycin (10 ⁇ g / The cell lines that stably express the h ⁇ 1A , h ⁇ 1B, and h ⁇ 1D subtypes were established, respectively.
  • a human system-rich epidermal growth factor-like domain 1 ⁇ (CRELD1 ⁇ ) gene was introduced into cells stably expressing the h ⁇ 1A subtype, and selection with G-418 (1.5 mg / mL) was performed, and the h ⁇ 1L subtype was expressed.
  • CELD1 ⁇ human system-rich epidermal growth factor-like domain 1 ⁇
  • Patent Document 1 A stable expression cell line with a high abundance ratio was established (Patent Document 1). Each cell was washed with 5 ⁇ mol / L Fura-2 AM (DOJIN) containing 0.02% (w / v) Pluronic F-125 and 1.4 mmol / L probenecid for 45 minutes. Thereafter, the cells were resuspended in Ca 2+ assay buffer containing 1.4 mmol / L probenecid and 3% (v / v) FBS, and the fluorescence spectrophotometer CAF-110 (with Fura-2 fluorescence intensity ratio as an index).
  • Intracellular Ca 2+ concentration was measured by JASCO Corporation (excitation wavelengths 340 and 380 nm, fluorescence wavelength 510 nm, 250 ms interval).
  • the h ⁇ 1A subtype co-expressed in stably expressing cells having a high abundance ratio of the h ⁇ 1L subtype is blocked by treatment with prazosin (5 nmol / L). did.
  • Noradrenaline the compounds of the present invention (compounds described in Examples 2 and 4), comparative compound A and comparative compound B are intracellular dose-dependent cells in each of the h ⁇ 1 adrenergic receptor subtype forced expression cell lines. An increase in Ca 2+ concentration was shown. The results are shown in FIGS. 1 to 5 as concentration-response curves. As is apparent from FIGS. 1, 2, 4 and 5, the compound of the present invention (compound described in Example 2) and the comparative compounds A and B are compared with noradrenaline in cells that are forced to express h ⁇ 1B and h ⁇ 1D subtypes.
  • Comparative compound A 2- (6-Bromo-3-dimethylamino-2-methylphenylimino) imidazolidine hydrochloride (ESR1150CL)
  • Comparative compound B 2-[(5-chloro-3-isopropyl-2-methylphenyl) methyl] imidazoline hydrochloride (compound of the above formula (B) described in Patent Document 6
  • Compound of the present invention 2- (5-dimethylamino) -3-Isopropyl-2-methylbenzyl) imidazoline hydrochloride (Example 2)
  • Compound of the present invention 2- (6-dimethylamino-3-isopropyl-2-methylbenzyl) imidazoline hydrochloride (Example 4)
  • PEC50 value in h [alpha 1L subtype expressing cells of the present invention compound (compound described in Example 2 and 4) is greater than noradrenaline, the difference was 1.3 and 0.8.
  • the comparative compound A showed somewhat greater pEC50 values h [alpha 1L subtype expressing cells compared to noradrenaline showed greater pEC50 values h [alpha 1A subtype expressing cells.
  • the respective differences are 0.5 and 0.8, and the comparative compound A has an increase in intracellular Ca 2+ concentration of 50% of the maximum response in each cell at a concentration of about 1/3 and 1/6 times that of noradrenaline. Shows that cause.
  • the comparison compound B compared to noradrenaline showed great pEC50 values h [alpha 1L subtype expressing cells and h [alpha 1A subtype expressing cells, each of the difference was 1.8 and 2.0.
  • Comparative Compound B causes 50% of the maximum response in each cell at a concentration of about 1/63 and 1/100 times that of noradrenaline.
  • the compounds of the present invention (compounds described in Examples 2 and 4) in the h ⁇ 1L subtype expressing cells A are close to 1, indicating that the maximum response via the h ⁇ 1L subtype obtained by the compounds of the present invention (compounds described in Examples 2 and 4) is close to the maximum response obtained by noradrenaline.
  • Agonist potency is affected by a variety of factors, including binding affinity and potency for the receptor, and receptor expression density.
  • Cultured cells are systems that expressed artificially alpha 1 subtype. Therefore, the subtype selectivity of the compounds of the present invention in the native tissue was set using test conditions that can selectively detect contraction responses via each subtype, and examined using a rat-extracted specimen. .
  • Rat prostate specimen This tissue was used as a specimen to examine the response via the ⁇ 1L subtype. The prostate gland was separated for each lobe, and each was used for experiments.
  • Rat tail artery specimen This tissue was used as a specimen for examining the response via the ⁇ 1A subtype. A 2 mm long ring specimen was prepared from the central part of the tail artery.
  • Rat femoral artery specimen This tissue was used as a specimen for examining the response via the ⁇ 1B subtype. A ring specimen having a length of 2 mm from the origin of the femoral artery was prepared, and the reaction of the annular muscle was recorded.
  • L-NAME (100 ⁇ mol / L) was excluded in order to exclude involvement of vascular endothelial cell-derived NO
  • silodosin (3 nmol / L) and BMY 7378 were excluded in order to exclude the reaction of coexisting ⁇ 1A receptor and ⁇ 1D receptor. (20 nmol / L) was treated respectively.
  • Rat Thoracic Aorta Specimen This tissue was used as a specimen for examining the response via ⁇ 1D subtype. A ring specimen with a length of 2 mm was prepared and the reaction of the ring-shaped muscle was recorded. In order to exclude the involvement of vascular endothelial cell-derived NO, L-NAME (100 ⁇ mol / L) was treated.
  • noradrenaline showed high affinity for the ⁇ 1D subtype (rat thoracic aorta), and no clear difference was observed among the remaining three subtypes. Therefore, the potency of noradrenaline was in the order of ⁇ 1D > ⁇ 1L , ⁇ 1B , ⁇ 1A .
  • the compounds of the present invention show the highest affinity for the ⁇ 1L subtype (rat prostate) as shown in FIGS. 7 and 8, and the potency is ⁇ 1L > ⁇ 1A > ⁇ 1B and ⁇ 1D in this order.
  • Comparative Compound A shows almost equal high affinity for ⁇ 1L subtype (rat prostate) and ⁇ 1A subtype (rat tail artery), and the potency is ⁇ 1L ⁇ ⁇ 1A > ⁇ 1D > ⁇ 1B in this order.
  • Comparative Compound B as shown in FIG. 10, the difference between ⁇ 1L , ⁇ 1A and ⁇ 1D is small, and the potencies are ⁇ 1L , ⁇ 1A , ⁇ 1D > ⁇ 1B. It was.
  • Table 2 shows the pEC50 values and the Ratio value in rats resected specimen (the ratio of 50% reaction concentration of each subtype for 50% reaction concentration of at alpha 1L subtype) of each test compound.
  • the compound of the present invention (compounds described in Examples 2 and 4) is different from Comparative Compound A and Comparative Compound B in rat native tissues, and ⁇ 1L subtype compared to ⁇ 1A subtype. It was shown to have a high selectivity for the type.
  • Comparative compound A compound of the above formula (A) (ESR1150CL)
  • Comparative compound B Compound of the above formula (B) described in Patent Document 6
  • Compound of the present invention 2- (5-dimethylamino-3-isopropyl-2-methylbenzyl) imidazoline hydrochloride (Example 2)
  • Compound of the present invention 2- (6-dimethylamino-3-isopropyl-2-methylbenzyl) imidazoline hydrochloride (Example 4)
  • the neck was incised (about 5 cm) with an electric knife, and a cannula for blood pressure measurement was inserted into the carotid artery.
  • the lower abdomen about 10 cm above the pubic bone was carefully incised with an electric knife to expose the bladder.
  • a small incision (about 1 cm) was made in the bladder and the urine remaining in the bladder was drained.
  • a balloon catheter for measuring urethral pressure was inserted from a small incision in the bladder, and the tip of the balloon was once guided to the mouth of the outer urethra.
  • the balloon position was determined and fixed using the silk thread mark attached to the tip of the balloon as a guide, and water was poured into the balloon so that an internal pressure of 15 to 20 mmHg was generated.
  • a winged intravenous needle was inserted into the auricular vein, and the base was fixed with Aron Alpha.
  • the systemic blood pressure obtained from the carotid artery cannula and the intraurethral pressure obtained from the urethral balloon were recorded by a thermal recorder.
  • phenylephrine 30 ⁇ g / kg was intravenously administered over 5 minutes by an infusion pump to confirm the reactivity of the specimen.
  • the test compound dissolved in physiological saline was intravenously administered by the same method.
  • FIGS. 1 to 5 represent h ⁇ 1L- expressing cells.
  • Figure 1 ⁇ 5 ⁇ represents the h [alpha 1A-expressing cells.
  • Figure 1, 2, 4 and 5 of the ⁇ represent h [alpha 1B-expressing cells.
  • 1, 2, 4 and 5 represent h ⁇ 1D expressing cells.
  • 6, 7, 9, and 10 and ⁇ in FIG. 8 represent the prostate ( ⁇ 1L ).
  • the black circles in FIGS. 6 to 10 represent the tail artery ( ⁇ 1A ).
  • 6 to 10 represents the femoral artery ( ⁇ 1B ).
  • FIGS. 6, 7, 9 and 10 ⁇ and ⁇ in FIG. 8 represent the thoracic aorta ( ⁇ 1D ).
  • 11 and 12 represent the compound of the present invention described in Example 2.
  • the black circles in FIGS. 11 and 12 represent the comparative compound B.
  • the triangles in FIGS. 11 and 12 represent phenylephrine.

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Abstract

La présente invention concerne des dérivés imidazoline représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables de ceux-ci, présentant une sélectivité élevée pour le α1L et qui sont utiles comme médicaments destinés à traiter l'incontinence urinaire. Dans la formule générale (I), soit X soit Y représente un hydrogène, et l'autre représente NR1R2; R1 et R2 peuvent être identiques ou différents et représentent chacun un hydrogène ou un méthyle; et Z représente un chloro ou un méthyle.
PCT/JP2011/066188 2010-07-16 2011-07-15 Dérivés imidazoline WO2012008565A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2010-161431 2010-07-16
JP2010161431A JP2013199431A (ja) 2010-07-16 2010-07-16 イミダゾリン誘導体
JP2011034325A JP2013199432A (ja) 2011-02-21 2011-02-21 イミダゾリン誘導体
JP2011-034325 2011-02-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015152196A1 (fr) * 2014-03-31 2015-10-08 東レ株式会社 Dérivé d'imidazoline et utilisation pharmaceutique dudit dérivé

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JPH11503738A (ja) * 1995-04-20 1999-03-30 ベーリンガー インゲルハイム コマンディトゲゼルシャフト 尿失禁を治療するためのα▲下１Ｌ▼アゴニストの使用
JP4168086B1 (ja) * 2008-04-16 2008-10-22 国立大学法人福井大学 イミダゾリン誘導体

Patent Citations (2)

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JPH11503738A (ja) * 1995-04-20 1999-03-30 ベーリンガー インゲルハイム コマンディトゲゼルシャフト 尿失禁を治療するためのα▲下１Ｌ▼アゴニストの使用
JP4168086B1 (ja) * 2008-04-16 2008-10-22 国立大学法人福井大学 イミダゾリン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015152196A1 (fr) * 2014-03-31 2015-10-08 東レ株式会社 Dérivé d'imidazoline et utilisation pharmaceutique dudit dérivé

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