WO2011068288A1 - Agent de prévention ou de traitement d'hyperplasie prostatique bénigne, comprenant un dérivé de quinazoline - Google Patents

Agent de prévention ou de traitement d'hyperplasie prostatique bénigne, comprenant un dérivé de quinazoline Download PDF

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WO2011068288A1
WO2011068288A1 PCT/KR2010/002240 KR2010002240W WO2011068288A1 WO 2011068288 A1 WO2011068288 A1 WO 2011068288A1 KR 2010002240 W KR2010002240 W KR 2010002240W WO 2011068288 A1 WO2011068288 A1 WO 2011068288A1
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Prior art keywords
acid
benign prostatic
prostatic hyperplasia
agent
formula
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PCT/KR2010/002240
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English (en)
Inventor
Sungsook Lee
Jeakwang Lee
Hojin Choi
Younghoon Kim
Kyung Joo Lee
Seungkee Moon
Soojin Kim
Nina Ha
Semi Kim
Inchang Hwang
Dalhyun Kim
Sungkwon Kang
Hongwoo Lee
Daisig Im
Seonwoo Lee
Youngmin Kim
Intaek Lim
Hosung Yu
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Chong Kun Dang Pharmaceutical Corp.
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Publication of WO2011068288A1 publication Critical patent/WO2011068288A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate

Definitions

  • the present invention relates to an agent for preventing or treating benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the present invention relates to a composition for preventing or treating benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the present invention relates to a method for preventing and treating benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • BPH benign prostatic hyperplasia
  • BPH has become defined as a condition showing lower urinary tract symptoms (LUTS) generically referring to bladder storage failure symptoms such as frequent urination involving more than eight times urination/day in males over the age of 50, nocturia, urination urgency with an accompanying intense, sudden and impatient desire to void, urgency incontinence, and urination pain; and bladder emptying failure symptoms such as hesitancy, interrupted micturition, voiding with abdominal straining, weak urine flow, feeling of post-void residual urine, and urinary retention.
  • LUTS lower urinary tract symptoms
  • a main pathogenic cause of BPH is the imbalance between contraction and relaxation of prostatic smooth muscle or urethral smooth muscle, the most significant factors of which are an increasing age and the presence of male hormones.
  • the onset of BPH may also be affected by race and environment, dietary habits, and hereditary factors.
  • BPH generally occurs in thirties and forties and manifests symptoms thereof usually after the age of 60. More than 50% of microscopic hypertrophied prostate progresses with age to palpable hypertrophied prostate (Prostate 1996 (suppl. 6) 67-73).
  • Diagnosis of BPH is made by severity of symptoms and promotion of the prostate in the rectum.
  • the extent of bladder outlet obstruction and bladder irritative symptoms is referred by urodynamic or ultrasonic-based minute examination.
  • An appropriate treatment method is selected based on such examination,
  • an alpha blocker and a 5-alpha-reductase inhibitor are largely used as a BPH therapeutic agent.
  • alpha blocker examples include alfuzosin, terazosin, doxazosin, prazosin, and tamsulosin, which reduce the tonicity of smooth muscle in prostate tissues, thus decreasing obstruction symptoms.
  • the target disease returns to an initial state before the treatment is applied when medication is stopped, because the alpha blocker directly dilates the urethra to solve the urinary disturbance.
  • the alpha blocker is not an appropriate therapeutic agent for BPH patients with accompanying erectile dysfunction, due to side effects such as postural hypotension and retrograde ejaculation. Further, careful administration should be taken for patients with severe liver and kidney function disorders.
  • finasteride i.e., 5-alpha-reductase inhibitor decreases the differentiation of prostate tissues through blockade of dihydrotestosterone (DHT) leading to enlargement of the prostate, and reduces a size of the prostate, thus increasing a urinary flow rate and alleviating voiding disturbance symptoms in the long term.
  • DHT dihydrotestosterone
  • finasteride exhibits its medicinal efficacy only after it has been used for a long period of time, at least 6 months, and also disadvantageously causes side effects such as erectile dysfunction, decreased libido, ejaculation disorder and gynecomast ia .
  • ⁇ ii> The above drugs are effective to some extent for obstruction symptoms, but exhibit substantially no improving effects on storage failure symptoms such as frequent urination, and urination urgency,
  • an anticholinergic agent has recently been used to improve bladder functions which are weakened due to benign prostatic hyperplasia, but there is always a risk of side effects in conjunction with limited effects thereof. To this end, there is an urgent need for the development of a drug to solve the above-mentioned problems.
  • cyclic nucleotides cAMP and cGMP can decrease the tonicity of smooth muscles, and they are degraded by cyclic nucleotide phosphodiesterases (PDEs) which effectively control an intracellular concentration of cAMP and cGMP.
  • PDEs cyclic nucleotide phosphodiesterases
  • a PDE5 inhibitor suppresses the degradation of c-GMP (cyclic guanosine monophosphate) to result in relaxation of prostatic smooth muscles and bladder smooth muscles, which not only enables the treatment of lower urinary tract symptoms (LUTS) arising from benign prostatic hyperplasia (Curr Opin Urol 2009 19:7-12, Eur J Pharmacol 1994 266:269-275), but also inhibits the proliferation of human prostate stromal cells (BJU Int 2006 98; 1259-1263), thus suppressing abnormal enlargement of the prostate.
  • LUTS lower urinary tract symptoms
  • tadalafil (Cialis, Lilly ICOS) and vardenafil (Levitra, GSK), which are currently used as an erectile dysfunction therapeutic agent, also find their applications for the use of a medicine, as a BPH therapeutic agent and an overactive bladder therapeutic agent.
  • vardenafil When it is administered to 220 BPH patients with the age of 45 to 65 twice a day for 8 weeks, vardenafil exhibited significant improvements in IPSS (International Prostatic Symptom Score) and QoL (Quality of Life) (Euro Urol 2008; 1236-44).
  • tadalafil As a test result of clinical stage 2, when 5 mg of tadalafil as a BPH therapeutic agent is administered to 281 BPH patients once a day for 6 weeks, followed by an increased dose of 20 mg, tadalafil exhibited significant improvements in IPSS at both 6 weeks and 12 weeks, as compared to a placebo group, and also improvements in LUTS due to BPH (J Uro 2007; 1401-7). Further, udenafil is also under development as a BPH therapeutic agent since it is known as a PDE5 inhibitor (Korean Patent No. 10-0792126).
  • a quinazoline derivative of Formula (1) of the present invention exhibits superior effects on BPH and accompanying LUTS, than vardenafil having the most excellent PDE5 inhibitory capacity, among the conventional developed agents. Further, it was confirmed that the compound of the present invention gives no risk of side effects, due to outstanding selectivity to isozymes as compared to conventional agents, and has a moderate in vivo half-life as compared to other PDE5 inhibitors, whereby the compound can exert sufficient medicinal efficacy even with a single administration/day without a risk of drug accumulation, thus increasing drug compliance.
  • the present invention has been completed based on these findings.
  • the present invention is intended to provide an agent for preventing or treating benign prostatic hyperplasia, comprising a quinazoline derivative represented by Formula (1) or a pharmaceutically acceptable salt thereof as an act i ve ingredient .
  • the present invention is intended to provide a composition comprising a quinazoline derivative represented by Formula (1) or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of benign prostatic hyperplasia.
  • the present invention is intended to provide a method for preventing or treating benign prostatic hyperplasia, including administering a composition or an agent comprising a quinazoline derivative represented by Formula (1) or a pharmaceutically acceptable salt thereof to a mammal including a human.
  • the present invention provides an agent for preventing or treating benign prostatic hyperplasia, comprising a quinazoline derivative represented by Formula (1) below ⁇ methyl 4-(3-chloro-4-methoxybenzylamino)-8-(2- hydroxyethyl )-7-methoxyquinazol in-6-yl (methyl )carbamate ⁇ or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a quinazoline derivative represented by Formula (1) below ⁇ methyl 4-(3-chloro-4-methoxybenzylamino)-8-(2- hydroxyethyl )-7-methoxyquinazol in-6-yl (methyl )carbamate ⁇ or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof for use in treatment or prevention of benign prostatic hyperplasia.
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, including administering an agent or a composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof to a mammal including a human.
  • the compound of Formula (1) may be a compound prepared by a method described in Example 79 compound of International Publication No. WO 08/020711 or Korean Patent Application Publication No. 10- 2008-0015594 Al, or is commercially available.
  • the term “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt conventionally known to a pharmaceutical manufacturer, and examples thereof include salts prepared from benzenesul fonic acid, benzoic acid, camphoric acid, camphorsul foni c acid, cinnamic acid, citric acid, formic acid, fu aric acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, ma Ionic acid, methanesul fonic acid, oxalic acid, phosphoric acid, sulfuric acid, tartaric acid and p-toluenesul fonic acid. More preferred is a hydrochloride.
  • Benign prostatic hyperplasia of the present invention includes lower urinary tract symptoms (LUTS) selected from frequent urination, nocturia, urination urgency, urgency incontinence, urination pain, hesitancy, interrupted micturition, voiding with abdominal straining, weak urine flow, feeling of post-void residual urine, and urinary retention.
  • LUTS lower urinary tract symptoms
  • the treatment and prevention of benign prostatic hyperplasia in accordance with the present invention is by the relaxation of prostatic smooth muscles or urethral smooth muscles or by the PDE5 activity inhibitory act ion.
  • composition or the agent for preventing or treating benign prostatic hyperplasia comprising a quinazoline derivative of Formula (1) as an active ingredient in accordance with the present invention can be used as an agent for preventing or treating lower urinary tract symptoms (LUTS) which are symptoms of benign prostatic hyperplasia, and can be used as a prostatic smooth muscle or urethral smooth muscle relaxant.
  • LUTS lower urinary tract symptoms
  • composition or the agent for preventing or treating benign prostatic hyperplasia in accordance with the present invention provides a composition or an agent for preventing or treating benign prostatic hyperplasia, wherein an IC 50 ratio of phosphodiesterase 6 (PDE6) to phosphodiesterase 5 (PDE5) is in the range of 300 to 100:1, and preferably about 200:1.
  • PDE6 phosphodiesterase 6
  • PDE5 phosphodiesterase 5
  • composition or agent for preventing or treating benign prostatic hyperplasia in accordance with the present invention provides a composition or an agent for preventing or treating benign prostatic hyperplasia, wherein an IC50 ratio of phosphodiesterase 11 (PDEll) to phosphodiesterase 5 (PDE5) is in the range of 20,000 to 10,000:1, and preferably about 17,000:1.
  • PDEll phosphodiesterase 11
  • PDE5 phosphodiesterase 5
  • the present invention provides a composition or an agent for preventing or treating benign prostatic hyperplasia, wherein visual color disturbance due to PDE6 activity or testicular toxicity or myalgia due to PDEll activity are not exhibited at a dose exhibiting therapeutic or preventive effects on benign prostatic hyperplasia.
  • the present invention provides a composition or an agent for preventing or treating benign prostatic hyperplasia, by improving overactive bladder.
  • the present invention provides a composition or an agent for preventing or treating benign prostatic hyperplasia, wherein medicinal efficacy is sustained for 5 to 10 hours at a single dose frequency without drug accumiilat ion.
  • the present invention provides a composition or an agent for preventing or treating benign prostatic hyperplasia, wherein a time taken to reach the highest blood concentration is in the range of 15 to 35 minutes.
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, wherein the compound of Formula (1) or the pharmaceutically acceptable salt thereof has an IC50 ratio of phosphodiesterase 6 (PDE6) to phosphodiesterase 5 (PDE5) in the range of 300 to 100:1.
  • PDE6 phosphodiesterase 6
  • PDE5 phosphodiesterase 5
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, wherein the compound of Formula (1) or the pharmaceutically acceptable salt thereof has an IC50 ratio of phosphodiesterase 11 (PDE11) to phosphodiesterase 5 (PDE5) in the range of 20,000 to 10,000:1.
  • PDE11 phosphodiesterase 11
  • PDE5 phosphodiesterase 5
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, which does not exhibit visual color disturbance at a dose exhibiting therapeutic or preventive effects on benign prostatic hyperplasia.
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, which does not exhibit testicular toxicity or myalgia at a dose exhibiting therapeutic or preventive effects on benign prostatic hyperplasia.
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, which improves overactive bladder.
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, which exhibits sustained medicinal efficacy for 5 to 10 hours at a single dose frequency without drug accumulation.
  • the present invention provides a method for preventing or treating benign prostatic hyperplasia, wherein the compound of Formula (1) or the pharmaceutically acceptable salt thereof has a time taken to reach the highest blood concentration in the range of 15 to 35 minutes.
  • the term "benign prostatic hyperplasia” is defined as a condition of a decreased urinary flow caused by the urethral obstruction due to blockade of a urinary passage at the lower part of the bladder resulting from enlargement of the prostate, and histologically the proliferation of prostate stromal or epithelial cells, in conjunction with lower urinary tract symptoms (LUTS) generically referring to bladder storage failure symptoms such as frequent urination, nocturia, urination urgency, urgency incontinence, and urination pain; and bladder emptying failure symptoms such as hesitancy, interrupted micturition, voiding with abdominal straining, weak urine flow, feeling of post-void residual urine, and urinary retention.
  • LUTS lower urinary tract symptoms
  • composition or the agent for preventing or treating benign prostatic hyperplasia or the pharmaceutical preparation for preventing or treating benign prostatic hyperplasia in accordance with the present invention may further contain one or more active ingredients having the same or similar function in addition to a compound of Formula (1) or a pharmaceutically acceptable salt thereof .
  • composition or the method for preventing or treating benign prostatic hyperplasia in accordance with the present invention may include administering a compound of Formula (1) or a pharmaceutically acceptable salt thereof , in admixture with one or more active ingredients having the same or simi lar funct ion.
  • composition or the agent for preventing or treating benign prostatic hyperplasia or the pharmaceutical preparation for preventing or treating benign prostatic hyperplasia in accordance with the present invention may further contain one or more pharmaceutically acceptable carriers besides the aforesaid components, to be formulated into a variety of dosage forms for desired applications.
  • the pharmaceutically acceptable carrier may include saline, sterile water, Ringer's solution, buffered physiological saline, dextrose solution, maltodextrin solution, glycerol, and ethanol . These materials may be used alone or in any combination thereof . If necessary, other conventional additives may be added such as antioxidants, buffers, bacteriostatic agents, and the like.
  • compositions or the agent may be preferably formulated into a desired dosage form, depending upon diseases to be treated and ingredients, using any appropriate method known in the art, or the method as disclosed in "Remington's Pharmaceutical Sciences (late edition),” Mack Publ i shing Co. , Easton, PA.
  • composition or the agent for preventing or treating benign prostatic hyperplasia in accordance with the present invention may be administered via oral routes or parenteral routes (for example, intravenously, subcutaneous ly, intraperitoneally, or locally), depending on desired applications. Further, the method for preventing or treating benign prostatic hyperplasia in accordance with the present invention may be carried out via oral routes or parenteral routes.
  • a dose of the compound of Formula (1) or the pharmaceutically acceptable salt thereof in accordance with the present invention may vary depending on weight, age, sex, health status, and dietary habits of patients, administration times and routes, excretion rates, and severity of disease.
  • the compound of Formula (1) of the present invention may be preferably administered at a dose of about 0.1 to 300 mg/day, and preferably 1 to 30 uig/day once or several times a day.
  • the agent for preventing or treating benign prostatic hyperplasia in accordance with the present invention may be used alone or in combination with methods employing surgical operation, hormone therapy, medication therapy and biological response modifiers.
  • the method for preventing or treating benign prostatic hyperplasia in accordance with the present invention may be used alone or in combination with methods employing surgical operation, hormone therapy, medication therapy and biological response modi f iers .
  • Sildenafil, vardenafil , and udenafil have side effects of visual color disturbance resulting from inhibition of PDE6, and tadalafi l gives a risk of side effects such as myalgia and decreased spermatogenesis, resulting from inhibition of PDEll, whereas a composition or an agent comprising the compound of Formula (1) of the present invention exhibits no such side effects due to very high selectivity to PDE5 rather than to PDE6 and PDEll.
  • composition or an agent comprising the compound of Formula (1) of the present invention provides significant relaxation of contracted prostatic smooth muscles of rats, and improvements even by a single administration in contraction interval and involuntary bladder contraction in a bladder outlet obstruction-induced BPH and LUTS rat model , with superior effects to those of conventional developed agents vardenafil and tadalafil .
  • composition or an agent comprising the compound of Formula (1) in accordance with the present invention has a half-life of 5 to 10 hours, can exert sufficient medicinal efficacy even with a single daily administration without a risk of drug accumulation due to no observation of drug accumulation even upon 7-day repeated administration, thus increasing drug compliance, and exhibits excellent stability also in the human liver mi crosome .
  • (1) in accordance with the present invention can be used effectively, safely and conveniently as an agent for preventing or treating benign prostatic hyperplasia and lower urinary tract symptoms (LUTS) associated therewith, or as a prostatic smooth muscle relaxant.
  • LUTS benign prostatic hyperplasia and lower urinary tract symptoms
  • FIG. 1 is a graph illustrating relaxation effects of a compound of Formula (1) on the prostate tissue section when the compound of Formula (1) is directly perfused into the rat-extracted prostate tissue section contract ion.
  • Fig. 2 is a graph illustrating changes in internal pressure of the bladder, as measured for a Sham group and a bladder outlet obstruction- induced overactive bladder group (BOO).
  • Fig. 3 is a graph illustrating improvement effects of Formula (1), vardenafil, and tadalafil on contraction intervals, in a bladder outlet obstruction-induced rat overactive bladder model.
  • Fig. 4 is a graph illustrating improvement effects of Formula (1), vardenafil, and tadalafil on non-voiding contraction, in a bladder outlet obstruction-induced rat overactive bladder model.
  • Phosphodiesterase 5 was extracted from bovine thrombocytes
  • Phosphodiesterase 6 was extracted from a bovine ocular retina
  • the extracted enzyme was diluted with an enzyme activity assay buffer solution (10 mM HEPES, pH 7.5, 77 mM KCI, 35 mM NaCl , 2 mM MgCl 2 , 1 mM CaCl 2 , 1.25 mM
  • EGTA([Ca ]free 240 nM), 1 mM DTT), and trypsin was added thereto at a final concentration of 50 ⁇ g /niL. After reaction in an ice bath for 30 minutes, 2.5 mg/mL of a trypsin inhibitor was added at a final concentration of 250 ⁇ g/mL, followed by reaction for another 5 minutes and dilution with a buffer solution to prepare an activated PDE6 solution. The enzyme activity assay was carried out in the same manner as in assay of PDE5 activity.
  • Phosphodiesterase 11 was prepared by constructing an expression vector containing a catalyt i cal ly active partial gene using a genetic engineering method (PNAS, 2000, 97, 3702-3707), followed by expression in an insect cell (Bac-To-Bac Baculovi rus) . The experiment was carried out in the same manner as the enzyme activity assay of PDE5.
  • Phosphodiesterase 1 was extracted from a bovine myocardial tissue
  • PDE2 phosphodiesterase 2
  • PDE3 phosphodiesterase 3
  • Each of the extracted enzymes was diluted with an enzyme activity assay buffer solution (40 mM MOPS, pH 7.5, 10 mM MgCl 2 , 1 mM DTT) and used in experiments.
  • the enzyme activity assay was carried out in the same manner as in assay of PDE5 activity.
  • Table 1 shows inhibitory effects of Formula (1) (CKD-533), and sildenafil, tadalafil, vardenafil and udenafil on PDE5 activity, and selective effects of PDE5 on PDEl, 2, 3, 6 and 11, as measured according to the above-mentioned method.
  • the compound of Formula (1) (CKD-533) exhibited a potent PDE5 inhibitory capacity on PDE5, i .e. , an IC 50 value of 0.7 nM, and also exhibited more potent PDE5 inhibitory activity particularly as compared to vardenaf il having the most excellent medicinal efficacy among the conventional developed agents.
  • a relaxation rate of the extracted prostate tissue section was measured to thereby assay relaxation effects.
  • Wistar rats were anesthetized with intraperitoneal administration of pentobarbital sodium (50 mg/ml) at a dose of 0.3 ⁇ 0.05 ml/head, and the prostate was carefully extracted and placed in a Krebs- Henseleit solution. The extracted prostate tissue section was fixed in an organ bath, and the opposite side was connected to a K30 FORCE transducer.
  • bladder outlet obstruction leads to a variety of functional changes in the bladder such as changes in contractility and unstable bladder. This involves morphological, biochemical and physiological changes, consequently resulting in various functional changes.
  • the bladder outlet obstruction may clinically cause a variety of irritative symptoms. Even after remedy of bladder outlet obstruction, about 15 to 30% of patients complain of continuous irritative symptoms. Biological factors responsible for such symptoms may be due to that obstruct ion- induced changes in detrusor, changes in extracellular matrix, changes in micturition reflex pathways, and the like are not readily cured even after remedy of obstruction.
  • Conventional therapeutic agents are effective to some extent for obstruction symptoms, but have limitations associated with storage failure symptoms such as frequent urination and urination urgency.
  • mice 250 to 300g.
  • the control group employed animals which had undergone Sham surgery.
  • the experimental group was subjected to induction of partial obstruction in the bladder neck, followed by observation for 3 weeks.
  • cystometry was carried out in experimental animals of each group. After animals were anesthetized with ur ethane (12 mg/kg), the abdomen was incised longitudinally, a 25G needle was placed in the bladder through the upper part of bladder, and then physiological saline was infused at a rate of 0.04 ml/min into the bladder using a Harvard syringe pump. Pressure of the bladder was recorded by means of a transducer, and the contraction interval and non-voiding contraction were analyzed. Thereafter, 10 animals out of the experimental group were divided into 7 groups as follows, and the respective drugs were intravenously administered thereto, followed by observation and analysis of contraction interval and non-voiding contraction.
  • Formula (1) 1 mg/kg: observed after i .v. administration of Formula (1) at a dose of 1 mg/kg, 3 weeks later from partial obstruction of bladder neck.
  • Formula (1) 3 mg/kg: observed after i .v. administration of Formula (1) at a dose of 3 mg/kg, 3 weeks later from partial obstruction of bladder neck.
  • Vardenafil 3 mg/kg: observed after i .v. administration of vardenafil at a dose of 3 mg/kg, 3 weeks later from partial obstruction of bladder neck.
  • Fig. 2 is a view illustrating changes in internal pressure of the bladder, as measured for a Sham group and a BOO group.
  • the compound of Formula (1) exhibited an improvement of more than 60%, thus showing 3-fold or more medicinal efficacy than vardenafil having the most excellent PDE5 inhibitory capacity among the same class drugs, and also superior efficacy as compared to tadalafil having the most excellent efficacy in clinical trials (Table 3 and Fig. 3).
  • ⁇ I36> In order to evaluate metabolic stability of the compound of Formula (1) of the present invention in a liver microsome, the following experiment was carried out. Human, rat and rabbit liver microsomes were purchased from BD Sciences. The liver microsome and a test compound were dissolved in a phosphate buffer (pH 7.4), an NADPH regeneration factor (2.5 niM MgCl 2 , 2,5 mM glucose-6-phosphate, 1 mM NADP, 1 U/ml glucose-6-phosphate dehydrogenase) was added thereto, followed by reaction at 37 ° C for 1 hour. The sample was collected, and acetonitrile was added to stop the reaction, followed by extraction and LC/MS analysis.
  • an NADPH regeneration factor 2.5 niM MgCl 2 , 2,5 mM glucose-6-phosphate, 1 mM NADP, 1 U/ml glucose-6-phosphate dehydrogenase
  • Formula (1) of the present invention also exhibited a very excellent stability in the rat, rabbit and human liver microsomes.
  • T Bax was in the range of 18 to 33 minutes (0.31 to 0.56 hr), thus representing rapid absorption.
  • the compound of Formula (1) exhibits medicinal efficacy more rapidly than 1 mg/kg of sildenafil and 10 mg/kg of tadalafil.
  • An oral absorption rate was more than 30%, thus showing a superior oral absorption rate as compared to sildenafil and vardenaf i 1.
  • T 1/2 was in the range of 5 to 10 hours, thus having a long half- life as compared to sildenafil and vardenafil. Further, the compound of Formula (1) was confirmed to have a half-life suitable for a single medication/day, as compared to tadalafil having ⁇ ⁇ 2 of more than 24 hours which is excessively long for a single medication/day. Further, when the compound of Formula (1) was repeatedly administered to rats once a day for 7 days, significant drug accumulation was not observed. Therefore, the compound of Formula (1) sustains medicinal efficacy for 5 to 10 hours in a single application without drug accumulation. Excellent medicinal efficacy can be obtained even by a single administration/day.
  • Example 6 Preparation of various salts of compound of Formula (1) ⁇ i58> The compound of Formula (1) (5 g) was dissolved in a solvent (50 ml) mentioned in the following table at room temperature, and an acid mentioned in the following Example at the same equivalent as that of the compound of Formula (1) was added thereto, followed by reaction for 1 to 2 hours to synthesize a salt of the compound of Formula (1).
  • the compound of Formula (1) was reacted with fumaric acid in the
  • the compound of Formula (1) was reacted with malic acid in the following solvent to synthesize a malate of the title compound.
  • H NMR value of the resulting product and a yield according to the solvent are as follows.
  • the compound of Formula (1) was reacted with phosphoric acid in the
  • the compound of Formula (1) was reacted with cinnamic acid in the
  • Example 6-0 Preparation of tartrate of compound of Formula (1) ⁇ 23i> The compound of Formula (1) was reacted with tartaric acid in the
  • the agent or composition comprising a compound of Formula (1) of the present invention can be used effectively, safely and conveniently as an agent for preventing or treating benign prostatic hyperplasia and lower urinary tract symptoms (LUTS) associated therewith, or as a prostatic smooth muscle relaxant .
  • LUTS benign prostatic hyperplasia and lower urinary tract symptoms

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Abstract

La présente invention porte sur un agent prophylactique ou thérapeutique pour hyperplasie prostatique bénigne (BPH) et accompagnée de symptômes de voie urinaire inférieure (LUTS), comprenant un dérivé de quinazoline en tant qu'ingrédient actif. En outre, la présente invention porte sur une composition comprenant un dérivé de quinazoline destiné à être utilisé dans le traitement ou la prévention d'une hyperplasie prostatique bénigne (BPH) et de symptômes de voie urinaire inférieure (LUTS) et sur un procédé de prévention ou de traitement d'une hyperplasie prostatique bénigne (BPH) et de symptômes de voie urinaire inférieure (LUTS), comprenant l'administration d'un agent ou d'une composition comprenant un dérivé de quinazoline à un mammifère, y compris à un être humain. L'agent prophylactique ou thérapeutique d'hyperplasie prostatique bénigne (BPH) ou la composition de la présente invention ont d'excellents effets inhibiteurs sur PDE5, présentent une faible activité inhibitrice sur PDE6 et PDE11 à une dose présentant une activité inhibitrice de PDE5, permettant ainsi d'entraîner moins d'effets secondaires, ont une demi-vie dans le sang modérée par rapport à l'inhibiteur de PDE5 et permettent ainsi de pouvoir exercer une efficacité médicinale suffisante, même avec une seule administration par jour sans risque d'accumulation de médicaments, permettant ainsi d'obtenir une conformité aux médicaments accrue et une excellente stabilité métabolique.
PCT/KR2010/002240 2009-12-04 2010-04-12 Agent de prévention ou de traitement d'hyperplasie prostatique bénigne, comprenant un dérivé de quinazoline WO2011068288A1 (fr)

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KR10-2009-0119829 2009-12-04
KR1020090119829A KR20110062943A (ko) 2009-12-04 2009-12-04 퀴나졸린 유도체를 유효성분으로 하는 전립선 비대증 예방 또는 치료제

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JP6367950B2 (ja) 2013-12-17 2018-08-01 ジェムバックス アンド カエル カンパニー，リミティド 前立腺癌治療用組成物
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