WO2011136308A1 - 泌尿器疼痛を伴う疾患の予防又は治療剤 - Google Patents
泌尿器疼痛を伴う疾患の予防又は治療剤 Download PDFInfo
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- WO2011136308A1 WO2011136308A1 PCT/JP2011/060332 JP2011060332W WO2011136308A1 WO 2011136308 A1 WO2011136308 A1 WO 2011136308A1 JP 2011060332 W JP2011060332 W JP 2011060332W WO 2011136308 A1 WO2011136308 A1 WO 2011136308A1
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- carboxylate
- piperidine
- pyridin
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- 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
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- 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
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- 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
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to a preventive or therapeutic agent for diseases associated with urological pain such as interstitial cystitis / bladder pain syndrome and chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- Interstitial cystitis / bladder pain syndrome and chronic non-bacterial prostatitis / chronic pelvic pain syndrome are both diseases with frequent urination and bladder pain as one of the main symptoms (Neurourology and Urodynamics, Vol. 21, 167-178, 2002; The Journal of Urology, 168, 593-598, 2002).
- Interstitial cystitis is a non-infectious cystitis that is common in women in their 20s and 60s, and is primarily a disease of upper pubic pain, frequent urination, and urgency. However, there are still no common diagnostic criteria or definitive treatments.
- NIDDK National Institute of Diabetic, Digestive and Kidney Disease
- Chronic nonbacterial prostatitis / chronic pelvic pain syndrome is one of the typical urinary pain disorders, and the prostate was proposed by the National Institutes of Health (NIH) in 1999. It is classified as a group of diseases whose main symptoms are pain / discomfort and urinary sensation of the pelvis such as the perineum, testis, and penis, and urination symptoms such as frequent urination as Category III of the four categories of inflammation syndrome Yes. However, unlike Category I acute bacterial prostatitis and Category II chronic bacterial prostatitis, no definitive treatment has been found because the etiology is unknown.
- NIH-CPSI NIH Chronic Prostate Inflammation Index
- Fatty acid amide hydrolase (FAAH) is known to lose its activity by hydrolyzing endocannabinoids (Prostaglandins Leukotrienes and Essential Fatty Acids, Vol. 66, 143- 160, 2002; British Journal of Pharmacology, 141, 253-262, 2004; Nature, 384, 83-87, 1996; Biochemical Pharmacology, 62, 517-526 Page, 2001).
- Endocannabinoid endocannabinoid
- Endocannabinoid is a general term for in vivo substances that act on cannabinoid receptors and exert physiological actions.
- Typical endocannabinoids include anandamide, palmitoylethanolamide, oleamide, and glycerol 2-arachidonic acid, which are known to be hydrolyzed by FAAH and lose their activity.
- ⁇ 9-tetrahydrocannabinol which is considered to be an active component of cannabis (marijuana), is known to activate cannabinoid receptors (Current Medicinal Chemistry, Vol. 6, pp. 635-664). 1999).
- CB1 and CB2 cannabinoid receptors
- CB1 is expressed in the central and peripheral nervous systems, and its activation causes psychiatric and analgesic effects.
- CB2 is expressed in immune system tissues, and its activation induces anti-inflammatory and analgesic (inflammatory) effects.
- cannabinoid receptor agonists increase bladder capacity and micturition threshold (The Journal of Neuroscience, Vol. 22, 7147-7153, 2002; Pain, Vol. 76, 189 -199, 1998), and side effects such as hallucinations, delusions, tachycardia, and orthostatic hypotension observed when cannabinoid receptor agonists are administered to animals are observed when FAAH inhibitors are administered (Nature Medicine, Vol. 9, pp. 76-81, 2003), FAAH inhibitors are less susceptible to side effects and addictive, interstitial cystitis / bladder pain syndrome, and / or chronic non-bacteria Expected to be a therapeutic agent for systemic prostatitis / chronic pelvic pain syndrome.
- Patent Document 1 discloses a pyridyl non-aromatic nitrogen-containing hetero-1-carboxylate compound as a compound useful for the treatment of frequent urination, urinary incontinence, overactive bladder, pain and the like. However, there is no specific disclosure of efficacy for the treatment of interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- Patent Document 2 discloses a pyridyl non-aromatic nitrogen-containing hetero-1-carboxylate compound as a compound useful for the treatment of neuropathic pain. However, there is no specific disclosure of efficacy for the treatment of interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- Patent Document 3 discloses that aryl and heteroaryl piperidinecarboxylic acid derivatives are useful for the treatment of urinary incontinence and cystitis as one aspect of many diseases listed. However, there is no disclosure of data specifically showing the effectiveness for treatment of urinary incontinence or cystitis.
- Patent Document 4 discloses that an amide compound is useful for the treatment of interstitial cystitis as an aspect of many listed diseases. However, no data specifically showing the effectiveness for the treatment of interstitial cystitis is disclosed.
- An object of the present invention is to provide a preventive or therapeutic agent for diseases associated with urological pain such as interstitial cystitis / bladder pain syndrome and chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- compound of formula (I) a pyridyl non-aromatic nitrogen-containing hetero-1-carboxylate compound of formula (I) (hereinafter referred to as “compound of formula (I)”) Or a salt thereof, based on FAAH inhibitory action, has not only an effective bladder capacity increasing action, but also an analgesic action against bladder pain and testicular pain, interstitial cystitis / bladder pain syndrome, and The present invention has been completed by finding that it is useful for the prevention or treatment of chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- the present invention provides a compound of formula (I) (Where A is a benzene ring, a 5- to 7-membered cycloalkane ring or a 5- to 7-membered nitrogen-containing heterocycle; L is a single bond, lower alkylene, lower alkenylene, -N (R 8 ) -CO-, -CO-N (R 8 )-, -lower alkenylene-CO-, -O- or -CO-; R 8 is H or lower alkyl; X is CH or N; R 1 , R 2 and R 3 are the same or different and may be substituted with H, halogen, —CN, —CF 3 , lower alkyl, —O-lower alkyl, or a group selected from the following group G: Aryl, nitrogen-containing heteroaryl optionally substituted with a group selected from Group G below, R 9 -lower alkylene-O—, R 9 -lower alkylene-N (R 8
- an interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome ie, interstitial cystitis / bladder
- the present invention relates to a pharmaceutical composition for preventing or treating pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- the present invention also provides interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain comprising administering to a mammal an effective amount of a compound of formula (I) or a salt thereof.
- the present invention relates to a method for preventing or treating a syndrome.
- the present invention provides a compound of formula (I) or a salt thereof for the manufacture of an agent for the prevention or treatment of interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome
- a compound of formula (I) or a salt thereof for the prevention or treatment of interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome
- interstitial also relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- the active ingredient of the present invention is a pyridyl ⁇ non-aromatic nitrogen-containing heterocycle-1-carboxylate compound of the formula (I) or a salt thereof, interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostate It can be used as a preventive or therapeutic agent for flame / chronic pelvic pain syndrome.
- lower alkyl means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In another embodiment, it is C 1-4 alkyl, and in another embodiment, it is methyl or ethyl.
- “Lower alkylene” means linear or branched C 1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethyl. Ethylene, 1,1,2,2-tetramethylethylene and the like. Another embodiment is methylene, ethylene, trimethylene or pentamethylene.
- the “lower alkenylene” is linear or branched C 2-6 alkenylene such as vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, 1,3-pentadienylene and the like.
- Another embodiment is C 2-4 alkenylene, and yet another embodiment is vinylene.
- the “5- to 7-membered cycloalkyl” is a C 5-7 saturated hydrocarbon ring group, specifically, cyclopentyl, cyclohexyl or cycloheptyl. Another embodiment is cyclohexyl.
- the “5- to 7-membered cycloalkane ring” means a ring constituting “5- to 7-membered cycloalkyl”, specifically, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
- Halogen means F, Cl, Br, I.
- Aryl is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and examples thereof include phenyl, naphthyl and the like. In another embodiment, it is phenyl.
- “5- to 7-membered nitrogen-containing heterocycle” means a 5- to 7-membered monocycle containing 1 to 4 heteroatoms selected from O, S and N, and always containing at least one N Means a saturated or unsaturated ring of the formula. Unsaturated rings include aromatic heterocycles. In addition, ring atoms S or O may be oxidized to form an oxide or a dioxide.
- pyrrolidine imidazolidine, pyrazolidine, oxazolidine, thiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, diazepan, pyrroline, dihydropyridine, tetrahydropyridine, azepine, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, Isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine and the like.
- Nonrogen-containing heteroaryl means a 5- to 10-membered monocyclic or dicyclic compound containing 1 to 4 heteroatoms selected from O, S and N, and always containing at least one or more N atoms. It means a cyclic aromatic ring group.
- optionally substituted means unsubstituted or having 1 to 5 substituents.
- those substituents may be the same or may mutually differ.
- “urinary pain” means pain / compression / discomfort in the upper pubic region including the bladder, and pain / discomfort in the pelvic region such as the perineum, testis, and penis. To do.
- tautomers and geometric isomers may exist depending on the type of substituent.
- the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
- the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist.
- the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
- the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and
- the active ingredient of the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances.
- the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
- a pharmaceutical composition containing one or more of the compounds of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier.
- Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
- a solid composition for oral administration tablets, powders, granules and the like are used.
- one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
- the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. .
- tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
- Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. In addition to the inert diluent, the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
- the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
- aqueous solvent include distilled water for injection or physiological saline.
- non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name).
- Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
- External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
- ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
- ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
- a transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid or semi-solid form, and can be produced according to a conventionally known method.
- known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
- an appropriate device for inhalation or insufflation can be used.
- a known device such as a metered dose inhalation device or a nebulizer
- the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
- the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
- a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
- the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
- the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
- a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
- the compound of the formula (I) can be used in combination with various preventive or therapeutic agents for interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- the combination may be administered simultaneously, separately separately, or at desired time intervals.
- the simultaneous administration preparation may be a compounding agent or may be separately formulated.
- Example 1 Screening for substances that inhibit FAAH activity using human bladder epithelial cancer-derived cells (1) Screening of substances that inhibit FAAH activity Human bladder epithelial cancer-derived cell line 5637 cells (HTB-9; ATCC) in a 48-well cell culture plate, 1x10 5 cells per well, 10% fetal bovine serum (HyClone) ) Containing RPMI1640 medium (Invitrogen). After culturing at 37 ° C. for 12 hours or more, the cells were washed with 400 ⁇ l of a buffer (Hank's Balanced Salt Solution, 20 mM Hepes-NaOH (pH 7.4)) per well.
- a buffer Hank's Balanced Salt Solution, 20 mM Hepes-NaOH (pH 7.4)
- a test substance dissolved in DMSO was added to a substrate solution (3 ⁇ Ci / ml radiolabeled anandamide (Anandamide [ethanolamine 1-3 H]) and 10 ⁇ M anandamide) in a volume of 0.003 nM to 30 nM. Only DMSO was added as a control. 100 ⁇ l of substrate solution per well was added to the cells, and incubated at 37 ° C. for 30 minutes in a CO 2 incubator.
- the cell culture plate is transferred onto ice, the substrate solution is removed by suction, and 75 ⁇ l per well of ice-cold cell lysis solution (0.5% TritonX-100, 10 ⁇ M compound cyclohexylcarbamic acid 3 having FAAH inhibitory activity 3 '-carbamoylbiphenyl-3-yl ester (URB597; Cayman Chemical Co .; Kathuria et al., Nature Med., Vol. 9, pp. 76-81, 2003)) was added and stirred. The resulting cell lysate was transferred per well to a 1.5 ml sample tube, and 150 ⁇ l of a 1: 1 (volume ratio) solution of chloroform and methanol was added and stirred.
- TritonX-100 10 ⁇ M compound cyclohexylcarbamic acid 3 having FAAH inhibitory activity 3 '-carbamoylbiphenyl-3-yl ester
- Centrifugation (15000 revolutions / minute, 2 minutes) separates ethanolamine (ethanolamine 1-3 H), the degradation product, into the upper layer (water / methanol layer) and unreacted radiolabeled anandamide in the lower layer (chloroform layer).
- a substance that decreases the measured value compared with the control was selected as a substance that inhibits FAAH activity.
- Example 2 Effect of Compound on Cyclophosphamide (CPA) -Induced Frequent Urination Rat
- CPA Cyclophosphamide
- acrolein a metabolite
- CPA administration induces bladder pain or frequent urination associated with hemorrhagic cystitis, so that the efficacy of these symptoms can be evaluated.
- 9-week-old female Wistar rats (Nippon Charles River Co., Ltd.) were used in the experiment. CPA (100 mg / kg) was intraperitoneally administered, and the experiment was conducted 2 days later.
- test compound was orally administered using 0.5% methylcellulose as a solvent, and distilled water (30 ml / kg) was forcibly orally administered 15 minutes later. Rats were placed in metabolic cages and urine weights were measured continuously for 1 hour. Effective bladder capacity was calculated by dividing total urination volume by total urination frequency. As a result, in the solvent administration group, the effective bladder capacity decreased and a frequent urination was observed.
- the effective oral dose of Compound A and Compound B is 3 mg / kg
- Example 3 Effect of Compound on Bladder Pain Model Rat
- the analgesic effect of the compound on bladder pain was examined using a pathological model.
- Cyclophosphamide 150 mg / kg was intraperitoneally treated, and 2 days later, under non-restraining conditions, physiological saline was flowed through a cannula inserted transurethrally into the bladder at a flow rate of 45 ml / h.
- the bladder was rapidly stretched by injecting with. By rapidly extending the bladder, amplification of the external oblique muscle EMG spike with pain-related behavior is observed. Since the injection amount at that time can be regarded as the bladder pain threshold, it is possible to evaluate the efficacy of the bladder pain threshold.
- Example 4 Effect of Compound on Testicular Pain Model Rat
- the analgesic effect of the compound on testicular pain was examined using a pathological model.
- the rat right and left testis are treated with 1% acetic acid at a rate of 1 ml / kg using an injection needle, pain behavior associated with testicular pain is observed, and thus the efficacy of the pain behavior can be evaluated.
- the compound of formula (I) or a salt thereof can be used for the prevention or treatment of interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostatitis / chronic pelvic pain syndrome.
- the active ingredient of the present invention is a pyridyl ⁇ non-aromatic nitrogen-containing heterocycle-1-carboxylate compound of the formula (I) or a salt thereof, interstitial cystitis / bladder pain syndrome and / or chronic non-bacterial prostate It can be used as a preventive or therapeutic agent for flame / chronic pelvic pain syndrome.
Abstract
Description
間質性膀胱炎(interstitial cystitis)は、20~60代の女性に多く見られる非感染性の膀胱炎で、恥骨上部の痛みや頻尿、尿意切迫感を主症状とする疾患である。しかし未だ共通の診断基準や決定的な治療法はない。1987年にNational Institute of Diabetic, Digestive and Kidney Disease(NIDDK)によって研究用の厳格なエントリー基準が示されたが、これが現在では臨床診断基準として捉えられ、診断に用いられている場合が多い。しかしながら、この基準を適用すると厳格になりすぎるという批判もある。そこで、有痛性膀胱症候群(painful bladder syndrome)あるいは膀胱痛症候群(bladder pain syndrome)と名を変えて、症状でこの疾患を把握しようとする試みがなされ、2002年に国際禁制学会(International Continence Society)で「尿路感染症や他の明らかな病的状態が認められない、昼間頻尿又は夜間頻尿等の他の症状を伴う、膀胱充満に関連する恥骨上部痛の愁訴(“The complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology”)」という有痛性膀胱症候群の疾患定義が初めて提唱された。現在では、2008年に米国ウロダイナミクス・女性泌尿器科学会(Society for Urodynamics and Female Urology)で「感染症や他の鑑別可能な原因が認められない、6週間以上の下部尿路症状を伴う、膀胱に関連すると考えられる違和感(痛み、圧迫感、不快感)(“An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes”)」という間質性膀胱炎/膀胱痛症候群の疾患定義が提唱されている。
上述のように、間質性膀胱炎/膀胱痛症候群、慢性非細菌性前立腺炎/慢性骨盤痛症候群のように泌尿器疼痛を伴う疾患に対する決定的な治療法は未だ見出されておらず、有効性、安全性に優れる治療薬の開発が切望されている。
即ち、本発明は、式(I)
Aは、ベンゼン環、5~7員シクロアルカン環又は5~7員含窒素ヘテロ環であり;
Lは、単結合、低級アルキレン、低級アルケニレン、-N(R8)-CO-、-CO-N(R8)-、-低級アルケニレン-CO-、-O-又は-CO-であり;
R8は、H又は低級アルキルであり;
Xは、CH又はNであり;
R1、R2及びR3は、同一又は異なって、H、ハロゲン、-CN、-CF3、低級アルキル、-O-低級アルキル、下記G群から選択される基で置換されていてもよいアリール、下記G群から選択される基で置換されていてもよい含窒素ヘテロアリール、R9-低級アルキレン-O-、R9-低級アルキレン-N(R8)-又はR10R11N-CO-であり;
R9は、下記G群から選択される基で置換されていてもよいアリール、下記G群から選択される基で置換されていてもよい含窒素ヘテロアリール又は5~7員シクロアルキルであり;
R10及びR11は、同一又は異なって、H又は低級アルキルであるか、或いは、結合しているN原子と一体となって、5~7員含窒素ヘテロ環を形成し;
G群は、ハロゲン、-CN、-CF3、低級アルキル及び-O-低級アルキルからなり;
R4は、H又は低級アルキルであり;
R5、R6及びR7は、同一又は異なって、H、低級アルキル、-CO-O-低級アルキル、-CO2H又は-CONH2である。)の化合物又はその塩を有効成分とする間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療剤、即ち、間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療用医薬組成物に関する。
本発明の間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療剤の有効成分である式(I)の化合物又はその塩は、前述の特許文献1及び2に開示の化合物であり、当該特許文献の記載に基づいて製造することができる。
ピリジン-3-イル 4-{4-[(3-フルオロベンジル)オキシ]フェノキシ}ピペリジン-1-カルボキシラート(以下、「化合物A」)、
5-{[(4-{4-[(3-フルオロベンジル)オキシ]フェノキシ}ピペリジン-1-イル)カルボニル]オキシ}ニコチン酸(以下、「化合物B」)、
5-({[4-(2-フェニルエチル)ピペリジン-1-イル]カルボニル}オキシ)ニコチン酸(以下、「化合物C」)、
5-[({4-[4-(2-シクロヘキシルエトキシ)フェノキシ]ピペリジン-1-イル}カルボニル)オキシ]ニコチン酸(以下、「化合物D」)、
5-[({4-[(E)-2-フェニルビニル]ピペリジン-1-イル}カルボニル)オキシ]ニコチン酸(以下、「化合物E」)、
5-{[(4-{3-[1-(6-メチルピリジン-2-イル)ピペリジン-4-イル]プロピル}ピペリジン-1-イル)カルボニル]オキシ}ニコチン酸(以下、「化合物F」)、
5-(アミノカルボニル)ピリジン-3-イル 4-{2-[3-(アミノカルボニル)フェニル]エチル}ピペリジン-1-カルボキシラート(以下、「化合物G」)、
5-(アミノカルボニル)ピリジン-3-イル 4-(2-{3-[(ジメチルアミノ)カルボニル]フェニル}エチル)ピペリジン-1-カルボキシラート(以下、「化合物H」)、
5-(アミノカルボニル)ピリジン-3-イル 4-{2-[3-(ピペリジン-1-イルカルボニル)フェニル]エチル}ピペリジン-1-カルボキシラート(以下、「化合物I」)、
5-(アミノカルボニル)ピリジン-3-イル 4-{2-[3-(ピロリジン-1-イルカルボニル)フェニル]エチル}ピペリジン-1-カルボキシラート(以下、「化合物J」)、
ピリジン-3-イル 4-[(2E)-3-フェニルプロパ-2-エノイル]ピペラジン-1-カルボキシラート(以下、「化合物K」)、
ピリジン-3-イル 4-(アニリノカルボニル)ピペリジン-1-カルボキシラート(以下、「化合物L」)、
5-(アミノカルボニル)ピリジン-3-イル 4-(2-フェニルエチル)ピペリジン-1-カルボキシラート(以下、「化合物M」)、
ピリジン-3-イル 4-(2-フェニルエチル)ピペラジン-1-カルボキシラート(以下、「化合物N」)、
5-(メトキシカルボニル)ピリジン-3-イル 4-(2-フェニルエチル)ピペラジン-1-カルボキシラート(以下、「化合物O」)、
5-(アミノカルボニル)ピリジン-3-イル 4-[2-(3-フルオロフェニル)エチル]ピペリジン-1-カルボキシラート(以下、「化合物P」)、
5-(アミノカルボニル)ピリジン-3-イル 4-[2-(3-シアノフェニル)エチル]ピペリジン-1-カルボキシラート(以下、「化合物Q」)、
5-(アミノカルボニル)ピリジン-3-イル 4-(5-フェニルペンチル)ピペラジン-1-カルボキシラート(以下、「化合物R」)、
ピリジン-3-イル 4-(3-フェニル-1H-1,2,4-トリアゾール-5-イル)ピペリジン-1-カルボキシラート(以下、「化合物S」)、
6-メチルピリジン-3-イル 4-[3-(4-フルオロフェニル)-1H-1,2,4-トリアゾール-5-イル]ピペリジン-1-カルボキシラート(以下、「化合物T」)、
6-メチルピリジン-3-イル 4-[5-(4-フルオロフェニル)-1,3-オキサゾール-2-イル]ピペリジン-1-カルボキシラート(以下、「化合物U」)、
2,6-ジメチルピリジン-3-イル 4-[5-(3,4-ジフルオロフェニル)-1,2,4-オキサジアゾール-3-イル]ピペリジン-1-カルボキシラート(以下、「化合物V」)、
2-メチルピリジン-3-イル 4-[3-(2-フルオロフェニル)-1H-1,2,4-トリアゾール-5-イル]ピペリジン-1-カルボキシラート(以下、「化合物W」)、及び
6-メチルピリジン-3-イル 4-(3-フェニル-1H-ピラゾール-1-イル)ピペリジン-1-カルボキシラート(以下、「化合物X」)からなる群から選択される化合物又はその塩である。
なお、化合物A~化合物Rは前述の特許文献1に記載の化合物であり、化合物S~化合物Xは前述の特許文献2に記載の化合物である。
また、式(I)の化合物には、不斉炭素原子や軸不斉を有する場合があり、これに基づく光学異性体が存在しうる。本発明は、式(I)の化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
ヒト膀胱上皮癌由来細胞を用いたFAAH活性を阻害する物質のスクリーニング
(1)FAAH活性を阻害する物質のスクリーニング
ヒト膀胱上皮癌由来細胞株5637細胞(HTB-9;ATCC)を48ウェルの細胞培養プレートに1ウェルあたり1x105個、10%ウシ胎児血清(HyClone社)を含有するRPMI1640培地(Invitrogen社)を用いて播種した。37℃で12時間以上培養した後、細胞を1ウェルあたり400 μlの緩衝液(Hank’s Balanced Salt Solution、20 mM Hepes-NaOH(pH 7.4))で洗浄した。基質液(3 μCi/ml放射標識アナンダミド(Anandamide [ethanolamine 1-3H])、10 μMアナンダミドを含む前記緩衝液)にDMSOに溶解した試験物質を0.003 nM~30 nMになるように添加した。コントロールとしてDMSOのみを添加した。上記細胞に1ウェルあたり100 μlの基質液を加え、CO2インキュベーター内で、37℃で30分間インキュベートした。その後、細胞培養プレートを氷上に移し、基質液を吸引除去し、1ウェルあたり75 μlの氷冷した細胞溶解用の溶液(0.5% TritonX-100、10 μMのFAAH阻害活性を有する化合物cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester(URB597;Cayman chemical社;Kathuriaら、Nature Med.、第9巻、第76-81頁、2003年)を含む前記緩衝液)を加え攪拌した。得られた細胞溶解液をウェルごとに1.5 ml容のサンプルチューブに移し、150 μlのクロロホルムとメタノールの1:1(容量比)溶液を加え攪拌した。遠心分離(15000回転/分、2分間)すると、上層(水/メタノール層)に分解産物のエタノールアミン(ethanolamine 1-3H)が、下層(クロロホルム層)に未反応の放射標識アナンダミドが分離される。上層の25 μlを96ウェルの有機溶媒耐性白色マイクロプレート(PicoPlate-96;PerkinElmer社)に移し、150 μlのマイクロシンチ20(PerkinElmer社)を加えマイクロプレートシンチレーションカウンター(TopCountTM;Beckman社)にて測定した。コントロールと比較して測定値を減少させる物質を、FAAH活性を阻害する物質として選択した。
(2)FAAH活性阻害物質のIC50値の測定
DMSOに10 mMになるように溶解した被験化合物を0.003 nM~30 nMになるように、基質液に加え、上記に記載の方法でFAAH活性に及ぼす影響を調べた。ネガティブコントロールとしてDMSOを、ポジティブコントロールとしてURB597を10 μMになるように基質液に添加し、ポジティブコントロールの測定値を0%、ネガティブコントロールの測定値を100%としてIC50値を求めた。結果を表1に示す。
シクロフォスファミド(CPA)誘発頻尿ラットに対する化合物の作用
化合物の膀胱刺激症状改善作用を病態モデルを用いて検討した。シクロフォスファミド(CPA)は全身投与により代謝物であるアクロレインに変換され、尿中から膀胱粘膜を傷害することが知られている。ラットにおいては、CPA投与により出血性膀胱炎に伴う膀胱痛あるいは頻尿状態が誘発されるため、これら症状に対する薬効評価が可能である。実験には9週齢のWistar系雌性ラット(日本チャールス・リバー株式会社)を用いた。CPA(100 mg/kg)を腹腔内投与し、その2日後に実験を行った。溶媒として0.5% メチルセルロースを用いて被験化合物を経口投与し15分後に、蒸留水(30 ml/kg)を強制的に経口投与した。ラットを代謝ケージに入れ、排尿重量を1時間連続的に測定した。総排尿量を総排尿回数で割ることにより、有効膀胱容量を算出した。その結果、溶媒投与群においては有効膀胱容量が減少し、頻尿状態が認められた。一方、化合物A及び化合物Bの有効経口投与量は3 mg/kgで、化合物C、化合物D、化合物E、化合物F、化合物G、化合物H、化合物J、化合物L及び化合物Xの有効経口投与量は1 mg/kgであり、これらの化合物は減少した有効膀胱容量を増加させ頻尿状態を改善した。
膀胱痛モデルラットに対する化合物の作用
化合物の膀胱痛に対する鎮痛作用を病態モデルを用いて検討した。シクロフォスファミド(150 mg/kg)を腹腔内処置し、その2日後に非拘束条件下にて、膀胱内へ経尿道的に挿入したカニューレを介して生理食塩液を45 ml/hの流速で注入することにより膀胱を急速伸展させた。膀胱を急速に伸展させることによって、疼痛関連行動を伴った外腹斜筋筋電図スパイクの増幅が認められる。その時点の注入量を膀胱痛閾値と捉えることができるため、膀胱痛閾値に対する薬効評価が可能である。実験には7週齢のSD系雌性ラット(日本チャールス・リバー株式会社)を用いた(n=3-6)。シクロフォスファミド前処置したラットにおいて、被験化合物投与前後における膀胱痛閾値を測定し、その変化量(Δml)を調べた。投与前値は、3回連続して安定した膀胱痛閾値が得られるまで膀胱伸展を行い、最後3回の膀胱痛閾値の平均を測定値とした。溶媒として0.5% メチルセルロースを用いて被験化合物(3 mg/5 ml/kg)を経口投与し、その60分又は120分後に膀胱痛閾値の測定を開始し、連続した3回の膀胱痛閾値の平均を投与後の測定値とした。結果を表2に示す。化合物投与群では溶媒投与群に比し有意に膀胱痛閾値が増加しており(全てp<0.05、検定法:Student's t-test)、化合物の膀胱痛に対する鎮痛作用が確認された。
精巣痛モデルラットに対する化合物の作用
化合物の精巣痛に対する鎮痛作用を病態モデルを用いて検討した。ラット左右精巣に1%酢酸を注射針を用いて1 ml/kgずつ処置すると、精巣痛に伴う疼痛行動(writhing)が観察されるため、この疼痛行動に対する薬効評価が可能である。実験には、3-4週齢のWistar系雄性ラット(日本チャールス・リバー株式会社)を用いた(n=9-13)。溶媒として0.5% メチルセルロースを用いて被験化合物(3 mg/5 ml/kg)を経口投与後55分又は115分に酢酸を精巣内処置して、直径30 cm、高さ50 cmのアクリル円筒状ケージにラットを移し、酢酸処置後5分から15分間の疼痛行動の回数を測定した。結果を表3に示す。化合物投与群では溶媒投与群に比し有意に疼痛行動の回数が減少しており(全てp<0.01、検定法:Student's t-test)、化合物の精巣痛に対する鎮痛作用が確認された。
Claims (6)
- 式(I)
Aは、ベンゼン環、5~7員シクロアルカン環又は5~7員含窒素ヘテロ環であり;
Lは、単結合、低級アルキレン、低級アルケニレン、-N(R8)-CO-、-CO-N(R8)-、-低級アルケニレン-CO-、-O-又は-CO-であり;
R8は、H又は低級アルキルであり;
Xは、CH又はNであり;
R1、R2及びR3は、同一又は異なって、H、ハロゲン、-CN、-CF3、低級アルキル、-O-低級アルキル、下記G群から選択される基で置換されていてもよいアリール、下記G群から選択される基で置換されていてもよい含窒素ヘテロアリール、R9-低級アルキレン-O-、R9-低級アルキレン-N(R8)-又はR10R11N-CO-であり;
R9は、下記G群から選択される基で置換されていてもよいアリール、下記G群から選択される基で置換されていてもよい含窒素ヘテロアリール又は5~7員シクロアルキルであり;
R10及びR11は、同一又は異なって、H又は低級アルキルであるか、或いは、結合しているN原子と一体となって、5~7員含窒素ヘテロ環を形成し;
G群は、ハロゲン、-CN、-CF3、低級アルキル及び-O-低級アルキルからなり;
R4は、H又は低級アルキルであり;
R5、R6及びR7は、同一又は異なって、H、低級アルキル、-CO-O-低級アルキル、-CO2H又は-CONH2である。)の化合物又はその塩を有効成分とする間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療剤。 - 式(I)の化合物又はその塩が、
ピリジン-3-イル 4-{4-[(3-フルオロベンジル)オキシ]フェノキシ}ピペリジン-1-カルボキシラート、
5-{[(4-{4-[(3-フルオロベンジル)オキシ]フェノキシ}ピペリジン-1-イル)カルボニル]オキシ}ニコチン酸、
5-({[4-(2-フェニルエチル)ピペリジン-1-イル]カルボニル}オキシ)ニコチン酸、
5-[({4-[4-(2-シクロヘキシルエトキシ)フェノキシ]ピペリジン-1-イル}カルボニル)オキシ]ニコチン酸、
5-[({4-[(E)-2-フェニルビニル]ピペリジン-1-イル}カルボニル)オキシ]ニコチン酸、
5-{[(4-{3-[1-(6-メチルピリジン-2-イル)ピペリジン-4-イル]プロピル}ピペリジン-1-イル)カルボニル]オキシ}ニコチン酸、
5-(アミノカルボニル)ピリジン-3-イル 4-{2-[3-(アミノカルボニル)フェニル]エチル}ピペリジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-(2-{3-[(ジメチルアミノ)カルボニル]フェニル}エチル)ピペリジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-{2-[3-(ピペリジン-1-イルカルボニル)フェニル]エチル}ピペリジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-{2-[3-(ピロリジン-1-イルカルボニル)フェニル]エチル}ピペリジン-1-カルボキシラート、
ピリジン-3-イル 4-[(2E)-3-フェニルプロパ-2-エノイル]ピペラジン-1-カルボキシラート、
ピリジン-3-イル 4-(アニリノカルボニル)ピペリジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-(2-フェニルエチル)ピペリジン-1-カルボキシラート、
ピリジン-3-イル 4-(2-フェニルエチル)ピペラジン-1-カルボキシラート、
5-(メトキシカルボニル)ピリジン-3-イル 4-(2-フェニルエチル)ピペラジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-[2-(3-フルオロフェニル)エチル]ピペリジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-[2-(3-シアノフェニル)エチル]ピペリジン-1-カルボキシラート、
5-(アミノカルボニル)ピリジン-3-イル 4-(5-フェニルペンチル)ピペラジン-1-カルボキシラート、
ピリジン-3-イル 4-(3-フェニル-1H-1,2,4-トリアゾール-5-イル)ピペリジン-1-カルボキシラート、
6-メチルピリジン-3-イル 4-[3-(4-フルオロフェニル)-1H-1,2,4-トリアゾール-5-イル]ピペリジン-1-カルボキシラート、
6-メチルピリジン-3-イル 4-[5-(4-フルオロフェニル)-1,3-オキサゾール-2-イル]ピペリジン-1-カルボキシラート、
2,6-ジメチルピリジン-3-イル 4-[5-(3,4-ジフルオロフェニル)-1,2,4-オキサジアゾール-3-イル]ピペリジン-1-カルボキシラート、
2-メチルピリジン-3-イル 4-[3-(2-フルオロフェニル)-1H-1,2,4-トリアゾール-5-イル]ピペリジン-1-カルボキシラート、及び
6-メチルピリジン-3-イル 4-(3-フェニル-1H-ピラゾール-1-イル)ピペリジン-1-カルボキシラートからなる群から選択される化合物又はその塩である請求項1記載の予防又は治療剤。 - 間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療剤の製造のための請求項1記載の式(I)の化合物又はその塩の使用。
- 間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療のための請求項1記載の式(I)の化合物又はその塩の使用。
- 間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療における使用のための請求項1記載の式(I)の化合物又はその塩。
- 請求項1記載の式(I)の化合物又はその塩の有効量を哺乳動物に投与することからなる間質性膀胱炎/膀胱痛症候群、及び/又は慢性非細菌性前立腺炎/慢性骨盤痛症候群の予防又は治療方法。
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2797420A CA2797420A1 (en) | 2010-04-28 | 2011-04-27 | Agent for preventing or treating diseases accompanied by urinary pain |
UAA201213609A UA106131C2 (uk) | 2010-04-28 | 2011-04-27 | Засіб для профілактики і лікування захворювань, які супроводжуються болем в органах сечовипускання |
CN2011800215031A CN102858340A (zh) | 2010-04-28 | 2011-04-27 | 伴有泌尿器官疼痛的疾病的预防剂或治疗剂 |
US13/640,824 US20130030006A1 (en) | 2010-04-28 | 2011-04-27 | Agent for preventing or treating diseases accompanied by urinary pain |
JP2012512901A JPWO2011136308A1 (ja) | 2010-04-28 | 2011-04-27 | 泌尿器疼痛を伴う疾患の予防又は治療剤 |
EP11775089.3A EP2564849A4 (en) | 2010-04-28 | 2011-04-27 | PROPHYLACTIC OR THERAPEUTIC FOR DISEASES RELATED TO PAIN IN THE HARNTRAKT |
AU2011246111A AU2011246111B2 (en) | 2010-04-28 | 2011-04-27 | Agent for preventing or treating diseases accompanied by urinary pain |
KR1020127031025A KR20130061684A (ko) | 2010-04-28 | 2011-04-27 | 비뇨기 동통을 수반하는 질환의 예방 또는 치료제 |
EA201291122A EA201291122A1 (ru) | 2010-04-28 | 2011-04-27 | Средство для профилактики и лечения заболеваний, которые сопровождаются болью в органах мочеиспускания |
BR112012026876A BR112012026876A2 (pt) | 2010-04-28 | 2011-04-27 | agente para prevenção ou tratamento de doenças acompanhadas por dor urinária |
MX2012012378A MX2012012378A (es) | 2010-04-28 | 2011-04-27 | Agente profilactico o terapeutico para enfermedades asociadas con dolores en los organos urinarios. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010-104262 | 2010-04-28 | ||
JP2010104262 | 2010-04-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011136308A1 true WO2011136308A1 (ja) | 2011-11-03 |
Family
ID=44861604
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2011/060332 WO2011136308A1 (ja) | 2010-04-28 | 2011-04-27 | 泌尿器疼痛を伴う疾患の予防又は治療剤 |
Country Status (13)
Country | Link |
---|---|
US (1) | US20130030006A1 (ja) |
EP (1) | EP2564849A4 (ja) |
JP (1) | JPWO2011136308A1 (ja) |
KR (1) | KR20130061684A (ja) |
CN (1) | CN102858340A (ja) |
AU (1) | AU2011246111B2 (ja) |
BR (1) | BR112012026876A2 (ja) |
CA (1) | CA2797420A1 (ja) |
EA (1) | EA201291122A1 (ja) |
MX (1) | MX2012012378A (ja) |
TW (1) | TW201206440A (ja) |
UA (1) | UA106131C2 (ja) |
WO (1) | WO2011136308A1 (ja) |
Cited By (1)
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JP2022141692A (ja) * | 2017-03-13 | 2022-09-29 | ルンドベック ラ ホヤ リサーチ センター,インク. | デュアルmagl及びfaahインヒビター |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JO3264B1 (ar) | 2013-03-13 | 2018-09-16 | Lilly Co Eli | مركبات ازيتيدينيل أوكسي فينيل بيروليدين |
WO2016033776A1 (en) * | 2014-09-04 | 2016-03-10 | Eli Lilly And Company | Crystalline (2s) -3- [ (3s, 4s) -3- [ (1r) -1-hydroxyethyl] -4- (4-methoxy-3- { [1- (5-methylpyridin-2-yl) azetidin-3-yl] oxy} phenyl) -3-methylpyrrolidin-1-yl] -3-oxopropane-1, 2-diol |
TW201625591A (zh) | 2014-09-12 | 2016-07-16 | 美國禮來大藥廠 | 吖丁啶基氧苯基吡咯啶化合物 |
PE20230164A1 (es) * | 2019-12-25 | 2023-02-01 | Nippon Shinyaku Co Ltd | Agente profilactico y/o terapeutico para la prostatitis cronica/sindrome de dolor pelvico cronico |
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-
2011
- 2011-04-26 TW TW100114442A patent/TW201206440A/zh unknown
- 2011-04-27 MX MX2012012378A patent/MX2012012378A/es active IP Right Grant
- 2011-04-27 CN CN2011800215031A patent/CN102858340A/zh active Pending
- 2011-04-27 AU AU2011246111A patent/AU2011246111B2/en not_active Ceased
- 2011-04-27 JP JP2012512901A patent/JPWO2011136308A1/ja active Pending
- 2011-04-27 KR KR1020127031025A patent/KR20130061684A/ko not_active Application Discontinuation
- 2011-04-27 US US13/640,824 patent/US20130030006A1/en not_active Abandoned
- 2011-04-27 BR BR112012026876A patent/BR112012026876A2/pt not_active IP Right Cessation
- 2011-04-27 UA UAA201213609A patent/UA106131C2/uk unknown
- 2011-04-27 EA EA201291122A patent/EA201291122A1/ru unknown
- 2011-04-27 WO PCT/JP2011/060332 patent/WO2011136308A1/ja active Application Filing
- 2011-04-27 EP EP11775089.3A patent/EP2564849A4/en not_active Withdrawn
- 2011-04-27 CA CA2797420A patent/CA2797420A1/en active Pending
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Also Published As
Publication number | Publication date |
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EP2564849A4 (en) | 2013-11-06 |
BR112012026876A2 (pt) | 2016-07-19 |
AU2011246111B2 (en) | 2014-07-17 |
UA106131C2 (uk) | 2014-07-25 |
EP2564849A1 (en) | 2013-03-06 |
AU2011246111A1 (en) | 2012-10-18 |
CA2797420A1 (en) | 2011-11-03 |
EA201291122A1 (ru) | 2013-04-30 |
MX2012012378A (es) | 2012-11-16 |
TW201206440A (en) | 2012-02-16 |
US20130030006A1 (en) | 2013-01-31 |
KR20130061684A (ko) | 2013-06-11 |
JPWO2011136308A1 (ja) | 2013-07-22 |
CN102858340A (zh) | 2013-01-02 |
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