Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
• • 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
• • 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]
• • 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
• • 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
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

• the present invention relates to a 2-naphthamides which are useful as an active ingredient of pharmaceutical preparations.
• the 2-naphthamides of the present invention have an IP receptor antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with IP receptor activity.
• 2-naphthamide derivatives of the present invention are useful for treatment and prophylaxis of urological diseases or disorders.
• the compounds of the present invention are also useful for treatment of pain; hypotension; hemophilia and hemorrhage; inflammation; respiratory states from allergies or asthma, since the disease also is alleviated by treatment with an IP receptor antagonist.
• Prostaglandins are a group of bioactive lipid mediators generated from membrane phospholipids. They are formed from 20-carbon essential fatty acids containing 3, 4, or 5 double bonds, and carry a cyclopentane ring. They are divided into 6 main classes (D, E, F, G, H or I) by the cyclopentane ring structure. The main classes are further subdivided by subscripts 1, 2, or 3, reflecting their fatty acid precursors.
• PGI2 is a member of prostanoids, and it has a double ring structure and is derived from arachidonic acid. The receptor for PGI2 is a seven transmembrane G-protein coupled receptor, called IP receptor.
• IP receptor couples at least to Gs-type G-protein, and activates adenylate cyclase and phospholipase C.
• the expression of IP receptor is demonstrated in aorta, coronary/pulmonary/cerebral arteries, platelets, lung, and dorsal root ganglions in addition to several other tissues.
• IP receptor antagonists may prevent hypotension associated with septic shock.
• IP receptor antagonists may enhance the platelet activation and suppress excessive bleeding such as, but not limited to, hemophilia and hemorrhage.
• PGI2 also participate in the inflammation. In the inflamed tissue, various inflammatory mediators, including prostaglandins, are produced. PGI2 is also generated and induces vasodilation to increase blood flow. This enhances vascular permeability, edema formation and leukocyte inflammation in the inflamed region (T. Murata et al,
• IP receptor antagonists may be efficacious for the treatment of inflammation.
• PGI2 may be involved in the pathogenesis of respiratory allergy or asthma. It is spontaneously generated and the major prostaglandin in human lung, and the appropriate antigen challenge increases PGI2 production (E.S. Schulman et al, J Appl Physiol 1982, 53(3), 589-595.). Therefore, IP receptor antagonists may have a utility for the treatment of those respiratory diseases.
• IP receptor knockout mice T. Murata et al., Nature 1997, 388, --,_-,-ministered with IP receptor knockout mice
• PGI2 Injection of acetic acid into the peritoneal cavity induced production of PGI2.
• This PGI2 is considered to bind to IP receptor on sensory neurons.
• IP receptor couples to the activation of both adenylate cyclase and phospholipase C, cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) are activated.
• PKA and PKC are known to modulate ion channels on sensory neurons such as VR1,
• PGI2 sensitizes sensory neurons to enhance the release of neurotransmitters.
• acetic acid injection induces nociceptive response (writhing) in mice.
• This acetic acid-induced writhing was greatly reduced in PGI2 receptor-null mice as the same level as indomethacin-treated wild type mice.
• IP receptor antagonists may be useful for the treatment of pain.
• A-delta sensory fibers are considered to play a major role to sense the bladder distention.
• BOO bladder outlet obstruction caused by benign prostate hyperplasia
• IP receptor antagonists are expected to be useful in the treatment of overactive bladder and related urinary disorders.
• WO 00/31045 discloses anti-thrombotics agents represented by the general formula:
• WO 98/44797 discloses integrin antagonists and farnesyl protein transferase inhibitors represented by the general formula:
• EP-A-220 118 discloses pharmaceutical composition intended for the treatment of dermatological, respiratory and ophthalmological conditions represented by the general formula:
• IP receptor antagonistic activity The development of a compound, which has effective IP receptor antagonistic activity and can be used for the prophylaxis and treatment of diseases alleviated by treatment with an IP receptor antagonist, has been desired.
• This invention is to provide a novel 2-naphthamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:
• n and n independently represent an integer from 0 to 2;
• -R 1 represents -O-R 10 -OR ⁇ , -OR 11 , -SR 11 , -S(O)R ⁇ , -S(O) 2 R ⁇ , -NR 12 R 13 , or -CHR 14 R 15 ,
• R 11 represents aryl, (C 2 . 6 )alkenyl optionally substituted by aryl or heteroaryl, (C 2 . 6 )alkynyl optionally substituted by aryl or heteroaryl, or ( - ⁇ ) alkyl optionally substituted by (C 3 - 8 )- cycloalkyl, aryl or heterocycle comprising 4-9 carbons and at least one N, O, or S as a heteroatom,
• said (C 3 . 8 )cycloalkyl, aryl and heterocycle optionally have one or two substituents selected from the group consisting of halogen, hydroxy, nitro, (Ci- 6 ) alkyl optionally substituted by mono-, di-, or tri halogen, and (C 1-6 ) alkoxy optionally substituted by (C 3-8 )cycloalkyl, or mono-, di-, or tri halogen;
• R 12 and R 13 independently represent hydrogen, (C 2-6 )alkenyl optionally substituted by aryl or heteroaryl, (C 2 - 6 )alkynyl optionally substituted by aryl or heteroaryl, or (C 1-6 ) alkyl optionally substituted by aryl or heteroaryl, or R 12 and R 13 form, together with the nitrogen atom, a 5-7 membered saturated hetero ring optionally interrupted by O or NH;
• R 14 and R 15 independently represent hydrogen, (C 2 - 6 )alkenyl optionally substituted by aryl or heteroaryl, (C 2 -6)alkynyl optionally substituted by aryl or heteroaryl, (C ⁇ - 6 ) alkyl optionally substituted by aryl or heteroaryl, or alkoxy optionally substituted by aryl or heteroaryl, or
• R 14 and R 15 form, together with the CH, a (C - 8 )cycloalkyl optionally interrupted by NH, or O, or a phenyl optionally substituted by hydroxy, halogen or alkyl;
• R >2 represents hydrogen, hydroxy, cyano, (C 1-6 ) alkoxy, (C 2-6 )alkenyl,
• said aryl and heteroaryl optionally have one or two substituents selected from the group consisting of halogen, hydroxy, nitro, amino, N((C 1-6 ) alkyl sulfonyl)amino, morpholino, phenyl, pyridyl, alkoxy optionally substituted by mono-, di-, or tri halogen, and (C 1-6 ) alkyl optionally substituted by mono-, di-, or tri halogen; and
• R represents hydrogen, or ( - ⁇ ) alkyl.
• the compounds of the present invention show excellent IP receptor antagonistic activity. They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat IP receptor related diseases.
• the 2-naphthamide derivatives of the present invention antagonize IP receptor, they are useful for treatment and prophylaxis of urological diseases or disorder.
• Such diseases or disorders include bladder outlet obstruction, overactive bladder, urinary incontinence, detrusor hyper-reflexia, detrusor instability, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benighn prostatic hypertrophy (BPH), prostatitis, urinary frequency, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity.
• BPH benighn prostatic hypertrophy
• the compounds of the present invention are also useful for treatment of pain including, but not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, dental pain, premenstrual pain, visceral pain, headaches, and the like; hypotension; hemophilia and hemorrhage; inflammation; respiratory states from allegies or asthma, since the disease is also alleviated by treatment with an IP receptor antagonist.
• the present invention provides 2-naphthamide derivatives of the formula (I'), its tautomeric or stereoisomeric form, or a salt thereof:
• R n represents aryl, (C 2 -6)alkenyl optionally substituted by aryl or heteroaryl, (C 2 - 6 )alkynyl optionally substituted by aryl or heteroaryl, or alkyl optionally substituted by (C 3 - 8 )- cycloalkyl, aryl or heterocycle comprising 4-9 carbons and at least one N, O, or S as a heteroatom
• said (C 3-8 )cycloalkyl, aryl and heterocycle optionally have one or two substituents selected from the group consisting of halogen, hydroxy, nitro, ( - ⁇ ) alkyl optionally substituted by mono-, di-, or tri halogen, and alkoxy optionally substituted by (C 3 . 8 )cycloalkyl, or mono-, di-, or tri halogen;
• R 12 and R 13 independently represent hydrogen, (C 2 . 6 )alkenyl optionally substituted by aryl or heteroaryl, (C 2 - 6 )alkynyl optionally substituted by aryl or heteroaryl, or (C ⁇ 6 ) alkyl optionally substituted by aryl or heteroaryl, or
• R 12 and R 13 form, together with the nitrogen atom, a 5-7 membered saturated hetero ring optionally interrupted by O or NH;
• R 14 and R 15 independently represent hydrogen, (C 2 . 6 )alkenyl optionally substituted by aryl or heteroaryl, (C 2-6 )alkynyl optionally substituted by aryl or heteroaryl, (Ci- 6 ) alkyl optionally substituted by aryl or heteroaryl, or (C ⁇ ) alkoxy optionally substituted by aryl or heteroaryl, or
• R 14 and R 15 form, together with the CH, a (C 3 - 8 )cycloalkyl optionally interrupted by NH, or O, or a phenyl optionally substituted by hydroxy, halogen or (C 1-6 ) alkyl;
• R represents hydroxy, cyano, amino, (d- ⁇ alkylamino, thienyl, pyridyl, naphthyl, lH-pyrrolo[2,3-b]pyridin-3-yl, indolyl optionally substituted by halogen or hydroxy, or phenyl,
• phenyl and naphthyl optionally have one or two substituents selected from the group consisting of halogen, hydroxy, nitro, amino, ((C ⁇ -6) alkyl)amino, di(C 1-6 ) alkylamino, N((C ⁇ ) alkyl sulfonyl)amino, morpholino, phenyl, pyridyl, (C 1-6 ) alkoxy optionally substituted by mono-, di-, or tri halogen, and (Ci- 6 ) alkyl optionally substituted by mono-, di-, or tri halogen; and
• R ,22 represents hydrogen or hydroxy.
• R 1 represents phenoxy, (C 1-6 ) alkoxy optionally substituted by cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, imidazolyl, pyridyl, pyrrolyl, phenyl, or thiazolyl optionally substituted by (C 1-6 )alkyl,
• phenyl has optionally one or two substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, (C 1-6 )alkyl optionally substituted by mono-, di, or tri halogen, and (C ⁇ -6 ) alkoxy optionally substituted by mono-, di, or tri halogen, cyclopropyl, or cyclohexyl.
• R 1 represents phenoxy ⁇ - ⁇ alkyl, phenoxy(C 1 - 6 )alkenyl, phenoxy(C 1-6 )- alkynyl, or phenyl(C 1 - 6 )alkoxy.
• R 2 represents phenyl ( - ⁇ alkyl
• phenyl has optionally one or two substituents selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxy, nitro, amino, N(methanesulfonyl)amino, morpholino, phenyl, pyridyl, methoxy, ethoxy, and trifluoromethyl.
• R 1 represents phenoxy, (d- 6 ) alkoxy optionally substituted by cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, imidazolyl, pyridyl, pyrrolyl, phenyl, or thiazolyl optionally substituted by (d- ⁇ alkyl,
• phenyl has optionally one or two substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, (C ⁇ )alkyl optionally substituted by mono-, di, or tri halogen, and (C ⁇ ) alkoxy optionally substituted by mono-, di, or tri halogen, cyclopropyl, or cyclohexyl;
• R ,21 represents cyano, thienyl, pyridyl, phenyl, naphthyl, lH-pyrrolo[2,3- b]pvridin-3-yl, or indolyl optionally substituted by halogen or hydroxy,
• phenyl and naphthyl have one or two substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, nitro, amino,
• R 22 represents hydrogen or hydroxy.
• said 2-naphthamide derivatives of the formula (I) or (F) are selected-from the group consisting of:
• the present invention provides a medicament which include one of the compounds described above and optionally pharmaceutically acceptable excipient.
• Alkyl per se and "alk” and “alkyl” in alkoxy, alkylene, alkanoyl, alkylamino, alkylaminocarbonyl, alkylaminosulphonyl, alkylsulphonylamino, alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino represent a linear or branched alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
• Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
• Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n- hexyl-arnino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N- methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
• Aryl per se represents a mono- to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms, illustratively and preferably representing phenyl, naphthyl and phenanthrenyl.
• Heterocyclic ring per se and hetero ring in heteroaryl refers to a 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclic ring radical may be optionally oxidized and the heterocyclic ring system may be partially or fully saturated or aromatic.
• rings include, but are not limited to thienyl, furyl, benzothienyl, furanyl, benzofuranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrirnidinyl, pyrrolyl, isothiazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, thiadiazoyl, benzothiadiazolyl, oxadiazolyl, benzothiazolyl, indolyl, indazolyl, carbazolyl, quinolyl, isoqinolyl, benzodioxolyl, indazolyl, indazolinolyl, pyrrolidinyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, morpholinyl, thiothi
• the compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods.
• one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3rd
• the compound of the formula (I) of the present invention can be, but not limited to be, prepared by the method [A] below. Method [A]
• the compound of the formula (I) (wherein R 1 , R 2 , R 3 , m, and n are the same as defined above) can be prepared by deprotection of the compound of formula (H) (wherein R 1 , R 2 , R 3 , m, and n are the same as defined above and X represents d- 6 alkyl, benzyl, 4-methoxybenzyl or 3, 4-dimethoxybenzyl).
• the deprotection of carboxyl group can be conducted by using a base including, for instance, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide, lithium hydroxide and potassium hydroxide, or an acid including, for instance, HCl, HBr, trifluoroacetic acid and BBr 3 .
• a base including, for instance, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide
• alkali metal hydroxide such as sodium hydroxide, lithium hydroxide and potassium hydroxide
• an acid including, for instance, HCl, HBr, trifluoroacetic acid and BBr 3 .
• the removal of protective group Z ⁇ can be conducted by using a base including, for instance, sodium hydroxide, lithium hydroxide and potassium hydroxide, or an acid including, for instance, HCl, HBr, trifluoroacetic acid and BBr 3 .
• a base including, for instance, sodium hydroxide, lithium hydroxide and potassium hydroxide
• an acid including, for instance, HCl, HBr, trifluoroacetic acid and BBr 3 .
• the deprotection can also be done by hydrogenation using a catalyst including, for instance, palladium on carbon and palladium hydroxide, when Z ⁇ is benzyl, 4- methoxybenzyl or 3, 4-dimethoxybenzyl.
• a catalyst including, for instance, palladium on carbon and palladium hydroxide, when Z ⁇ is benzyl, 4- methoxybenzyl or 3, 4-dimethoxybenzyl.
• the deprotection can be done by using a reagent such as eerie ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), when Z ⁇ is 4- methoxybenzyl or 3, 4-dimethoxybenzyl.
• a reagent such as eerie ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), when Z ⁇ is 4- methoxybenzyl or 3, 4-dimethoxybenzyl.
• the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N- methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); alcohols such as methanol, ethanol, 1 -propanol, isopropanol and tert-butanol; water, and others.
• halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
• ethers such as diethyl ether
• the reaction temperature can be optionally set depending on the compounds to be reacted.
• the reaction temperature is usually, but not limited to, about 20°C to 100°C.
• the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
• the compound of formula (TI) (wherein R 1 , R 2 , R 3 , X, and n are the same as defined above) can be prepared by the reaction of compound (III) (wherein R 1 is the same as defined above) or (III') (wherein R 1 is the same as defined above and ⁇ L is leaving group, for instance, halogen atom such as chlorine, bromine, or iodine atom and azole such as 1,3-imidazole and 1,2,4-triazole) with the compound of formula (IV) (wherein R 2 , R 3 , X, m and n are the same as defined above).
• the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tefrahydrofuran (THF)and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N- methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); and others.
• a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tefrahydrofuran (THF
• the reaction temperature can be optionally set depending on the compounds to be reacted.
• the reaction temperature is usually, but not limited to, about 0°C to 100°C.
• the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
• reaction of compound of (III) and (IV) may be carried out using coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotiazole, and others.
• coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotiazole, and others.
• reaction of compound of (III) and (IV) can also be advantageously conducted in the presence of a base, including, for instance, such as pyridine, triethylamine and N,N-diiso ⁇ ro ⁇ ylethylamine, dimethylaniline, diethylaniline, and others.
• a base including, for instance, such as pyridine, triethylamine and N,N-diiso ⁇ ro ⁇ ylethylamine, dimethylaniline, diethylaniline, and others.
• Step 1 the compound of formula (Ha) (wherein R , R , R , X, m and n are the same as defined above and A represents O or S) can be prepared by the reaction of compound (Va) (wherein R , R , X, m and n are the same as defined above and A represents O or S) with the compound of formula (Via) (wherein R 11 is the same as defined above and Y represents a leaving group, e.g., halogen, and alkylsulfonyloxy).
• the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tefrahydrofuran (THF)and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N- methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); ketones such as acetone; alcohols such as methanol, ethanol, 1 -propanol, isopropanol and tert- butanol; and others.
• halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
• ethers
• the reaction temperature can be optionally set depending on the compounds to be reacted.
• the reaction temperature is usually, but not limited to, about 0°C to 100°C.
• the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
• the reaction can be advantageously carried out in the presence of a base including, for instance, an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline earth metal alkoxides such as magnesium ethoxide; organic amines such as pyridine, triethylamine and N,N-diisopropylethyl- amine, dimethylaniline, diethylaniline and others.
• a base including, for instance, an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxid
• Step 1'; the compound of formula (JJa) (wherein R 2 , R 3 , X, m and n are the same as defined above, A represents O and R 11 represents aryl) can be prepared by the reaction of compound (Va) (wherein R 2 , R 3 , X, m and n are the same as defined above, A represents O and R 11 represents aryl) with the compound of formula (Via') (wherein R 11 represents aryl and M represents metal group including, for instance, organoborane group such as boronic acid and di-methoxy boryl; organostannyl group such as tributyl stannyl, and the like) in the presence of a copper catalyst such as copper(II) acetate and others.
• a copper catalyst such as copper(II) acetate and others.
• the reaction can be advantageously carried out in the presence of a base including, for instance, cesium carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine and others.
• a base including, for instance, cesium carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine and others.
• the reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimeth- oxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methyl- pyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); alcohols such as methanol, ethanol, 1 -propanol, isopropanol and tert-butanol; and others.
• ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimeth- oxyethane
• aromatic hydrocarbons such as benzene, toluene and
• two or more of the solvents selected from the listed above can be mixed and used.
• the reaction temperature can be optionally set depending on the compounds to be reacted.
• the reaction temperature is usually, but not limited to, about 0°C to 120°C.
• the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
• Step 2; the compound of formula (Villa) (wherein R 11 is the same as defined above, A represents O or S and Z ⁇ represents d- 6 alkyl, benzyl, 4-methoxybenzyl, 3, 4- dimethoxybenzyl and others) can be prepared by the reaction of compound (Vila) (wherein Z ⁇ is the same as defined above and A represents O or S) with the compound of formula (Via) (wherein R 11 is the same as defined above and Y represents a leaving group, e.g., halogen, and alkylsulfonyloxy) in the similar manner described in the step 1 of Procedure A-LI-a, for the preparation of the compound of formula (Lla).
• Step 3; the compound of formula (lla) (wherein R 2 , R 3 , R 11 , X, m and n are the same as defined above and A represents O or S) can be prepared by 1) the removal of protective group Z ⁇ of the compound of the formula (Villa) and then 2) the reaction with the compound of the formula (TV) (wherein R 2 , R 3 , X, m and n are the same as defined above).
• Step 1; the compound of formula (Vlllb) (wherein R 13 is the same as defined above and Z represents C 1-6 alkyl, benzyl, 4-methoxybenzyl, 3, 4-dimethoxybenzyl and others ) can be prepared by the reaction of compound (Vllb) (wherein Z 2 is the same as defined above) with the compound of formula (Vlb) (wherein R 13 is the same as defined above and Y represents a leaving group, e.g., halogen, and alkylsulfonyloxy).
• the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tefrahydrofuran (THF)and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N- methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); ketones such as acetone; alcohols such as methanol, ethanol, 1 -propanol, isopropanol and tert- butanol; and others.
• halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
• ethers
• the reaction temperature can be optionally set depending on the compounds to be reacted.
• the reaction temperature is usually, but not limited to, about 20°C to 180°C.
• the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 to 24 hours.
• the reaction can be advantageously carried out in the presence of a base including, for instance, cesium carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine and others.
• a base including, for instance, cesium carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine and others.
• Step 2; the compound of formula (Ilb-i) (wherein R 2 , R 3 , R 13 , X, m and n are the same as defined above) can be prepared by 1) the removal of protective group Z of the compound of the formula (Vlllb) and then 2) the reaction with the compound of the formula (IV) (wherein R 2 , R 3 , X, m and n are the same as defined above) in the similar manner described in Procedure A-I, for the preparation of the compound of formula (II).
• Step 3 the compound of formula (Hb-ii) (wherein R 2 , R 3 , R 12 , R 13 , X, m and n are the same as defined above) can be prepared by the reaction of compound (Ilb-i) (wherein R 2 , R 3 , R 13 , X, m and n are the same as defined above) with the compound of formula (Vlb') (wherein R 12 is the same as defined above and Y represents a leaving group, e.g., halogen and alkylsulfonyloxy) in the similar manner described in step 1 of Procedure A-II-a, for the preparation of the compound of formula (Il-a).
• the compound (Va) can be commercially available or can be prepared by either the use of the similar procedure for the preparation of the compound of formula (IT) or known techniques.
• the compound (Via), (Via'), (VTIa), (Vlb), (Vib') and (VLTb) can be commercially available or can be prepared by the use of known techniques.
• the compound shown by the formula (I) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.
• Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, successively.
• Acids to form salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
• inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like
• organic acids such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
• Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
• inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
• the compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
• the compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
• the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
• the dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
• the compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.
• Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
• compositions of the present invention are pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients.
• the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.
• the carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
• a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
• the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate,
• the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
• the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
• Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.
• Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
• the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
• a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
• the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
• Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
• the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
• a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
• a "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
• the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
• Typical oral dosages of the present invention when used for the indicated effects, will range from about 0.01 mg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
• parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to 100 mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
• the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
• HEL 92.1.7 A human erythloleukemia cell line, HEL 92.1.7, was purchased from American Type
• HEL cells were collected with centrifugation and washed with cAMP assay buffer (CAB: Hank's balanced salt solution, 17 mM Hepes, 0.1% bovine serum albumin, 1 mM LBMX, 0.4% DMSO, and 1 mM L-ascorbic acid sodium salt (pH 7.4)).
• CAB Hank's balanced salt solution, 17 mM Hepes, 0.1% bovine serum albumin, 1 mM LBMX, 0.4% DMSO, and 1 mM L-ascorbic acid sodium salt (pH 7.4)).
• CAB Hank's balanced salt solution, 17 mM Hepes, 0.1% bovine serum albumin, 1 mM LBMX, 0.4% DMSO, and 1 mM L-ascorbic acid sodium salt (pH 7.4)
• Cells were suspended at the density of 2.5 x 10 5 cells/ml in CAB, and twenty thousand cells in 80 ⁇ l aliquot of cell suspension were put in a well of 96 well
• Rats were anesthetized by infraperitoneal administration of urethane (Sigma) at 1.25 g/kg.
• the trachea was cannulated with a polyethylene tube (HIBIKI, No. 8) to facilitate respiration; and a cannula (BECTON DICKINSON, PE-50) was placed in the left femoral vein for intravenous administration of testing compounds.
• the abdomen was opened through a midline incision, and after both ureters were cut, a water-filled baloon (about 1 ml capacity) was inserted through the apex of the bladder dome.
• the balloon was connected to a pressure transducer onto a polygraph.
• Rhythmic bladder contraction was elicited by raising up intravesical pressure to approximately 15 cm H 2 O. After the rhythmic bladder contraction was stable, a testing compound was administered intravenously. Activity was estimated by measuring disappearance time and amplitude of the rhythmic bladder contraction. The effect on amplitute of bladder contractions was expressed as a percent suppression of the amplitude of those after the disappearance was recovered. Experimental values were expressed as the mean ⁇ S.E.M. The testing compounds- mediated inhibition of the rhythmic bladder contraction was evaluated using Student's t-test. A probability level less than 5% was accepted as significant difference.
• Example 1-1 compounds in Example 1-2 to 1-94 as shown in Table 1 were synthesized.
• the methyl ester above was treated with lithium hydroxide monohydrate (0.036 g, 0.86 mmol) in tetrahydrofuran (1.0 mL), ethanol (0.5 mL) and water (1.0 mL) at 60°C for 2 hours.
• the mixture was neutralized with IN hydrochloric acid and extracted with ethyl acetate.
• the separated organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
• the residue was purified by recrystallization (ethyl acetate-hexane) to give N-(6- phenoxy-2-naphthoyl)phenylalanine (0.020 g, 9%) as a white powder.

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