Patent Application
20050085476
The present invention relates to fused pyridazine derivative compounds.
More particularly, the present invention relates to
Poly(ADP-ribose)polymerase (abbreviated as PARP hereinafter), which is a nuclear enzyme activated by DNA strand breaks, plays a role in the transfer reaction of ADP-ribose moiety from nicotinamide adenine dinucleotide (abbreviated as NAD+ hereinafter) to various proteins such as histones, DNA-polymerases and DNA-topoisomerases, etc.
DNA strand breaks caused by Peroxynitrite (ONOO−) and oxygen radicals lead to overactivation of PARP (PARP is activated up to 100 times when Zn finger domain of PARP binds to DNA with nicks.). It is thought that overactivation of PARP causes depletion of NAD+, which is essential for electron transport system, and consequently depletion of ATP, leading to energy failure, ultimately resulting in cell death. (The suicide hypothesis of PARP activation: Free Radic. Biol. Med., 21, 855 (1996); TIPS., 19, 287 (1998)). Therefore, it is considered that PARP inhibitor is useful as inhibitor of cell death.
Since caspase-3, which is one of interleukin-1β-converting enzyme family, specifically cleaves PARP as the substrate (Cell., 81, 801 (1995)), it is suggested PARP is associated with apoptosis.
It is reported that 3-aminobenzamide and nicotinamide generally known as inhibitors of PARP are useful for inhibition of cell death and improvement of diseases on various models of ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (arthritis, inflammatory bowel disease or multiple sclerosis etc.), diabetes, shock, extrapyramidal disease (TIPS., 19, 287 (1998); Eur. J. Pharmacol, 350, 1 (1998)) and hyperalgesia (Pain, 72, 355 (1997)) in vitro, in vivo and in PARP knockout mouse. And it is reported that PARP inhibitor is useful as an antiretroviral drug such as an anti HIV drug (Biochem. Biophys. Res. Commum., 180, 504 (1991)), a sensitizer of anticancer therapy (Radiat. Res., 126, 367 (1991); Br. J. Cancer., 72, 849 (1995)) or an immunosuppressant (Int. J. Immunopharmac., 17, 265 (1995)).
PARP inhibitor is useful for prevention and/or treatment of various diseases, for example, ischemic diseases (cerebral infarction, myocardial infarction, reperfusion injury or postoperative injury etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis, arthritis or lung injury etc.), neurodegenerative disorders (extrapyramidal disease, Parkinson's disease, Alzheimer's disease, muscular dystrophy or lumbar spinal canal stenosis etc.), glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure, hyperalgesia or blood flow obstruction etc. And it is useful as an antiretroviral drug such as an anti HIV drug, a sensitizer of anticancer therapy or an immunosuppressant.
As PARP inhibitor, for example, in the specification of WO00/44726, it is described that 2H-phthalazin-1-one derivatives represented by formula (A)
(wherein R1A is
In the specification of DE3302021, it is described that compounds represented by formula (B)
(wherein R1B is hydrogen or C1-3 alkyl, R2B is hydrogen, R1B and R2B, taken together, are C1-4 alkylene, R3B is hydrogen or methyl, nB is 0-3, R4B is 1-pyrrolyl. Necessary parts were extracted from the description of groups.) have inhibitory activity of platelet aggregation.
In the specification of WO98/31674, it is described that compounds represented by formula (C)
(wherein R1C is C1-4 alkoxy etc., R2C is C1-8 alkoxy etc., R3C and R4C is hydrogen or R3C and R4C, taken together, are bond, R5C is hydrogen etc. Necessary parts were extracted from the description of groups.) have phosphodiesterase inhibitory activity.
In Journal of Medicinal Chemistry., 44(16), 2511-2522 and 2523-2535 (2001), it is described that 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 244077-36-9) and 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 358368-98-6) have phosphodiesterase inhibitory activity.
In Tetrahedron., 39(20), 3419-27 (1983), 4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (CAS Registry No. 89311-30-8) is described as synthetic intermediate.
In Synthesis., 240-242 (1995), 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-22-7), 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-23-8), 4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-24-9), 4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-25-0), and 4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-26-1) are described as synthetic intermediate.
In Bioorganic and Medicinal Chemistry., 6, 349-454 (1998), 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (CAS Registry No. 206126-90-1) and 4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one (CAS Registry No. 206126-96-7) are described as synthetic intermediate.
In Journal of Medicinal Chemistry., 43(12), 2310-2323 (2000), 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 212142-89-7) is described as synthetic intermediate.
In the specification of FR2647676, 4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 134972-12-6) and 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 134973-24-3) are described as synthetic intermediate.
In order to find a compound having poly(ADP-ribose)polymerase activity, the present inventors have conducted intensive studies and found, as a result, that the objects can be accomplished by the pyridazine derivative represented by formula (I), and thus the present invention has been accomplished.
The present invention relates to
In the specification, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or isomeric groups thereof.
In the specification, C2-8 alkenyl means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or isomeric groups thereof.
In the specification, C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl or isomeric groups thereof.
In the specification, C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or isomeric groups thereof.
In the specification, C2-8 alkenyloxy means ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy or isomeric groups thereof.
In the specification, C2-8 alkynyloxy means ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy or isomeric groups thereof.
In the specification, C1-8 alkylthio means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio or isomeric groups thereof.
In the specification, C1-4 alkylene means methylene, ethylene, trimethylene, tetramethylene or isomeric groups thereof.
In the specification, C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene or isomeric groups thereof.
In the specification, C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene or isomeric groups thereof.
In the specification, C1-8 alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl or isomeric groups thereof.
In the specification, trihalomethyl is methyl substituted by three halogen atoms.
In the specification, trihalomethoxyl is methoxyl substituted by three halogen atoms.
In the specification, C2-8 acyl means ethanoyl (acethyl), propanoyl (propionyl), butanoyl (butyryl), pentanoyl (valeryl), hexanoyl, heptanoyl, octanoyl or isomeric groups thereof.
In the specification, C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
In the specification, halogen means chlorine, bromine, fluorine or iodine.
In the specification, partially or fully saturated C3-10 mono-carbocyclic aryl represented by
is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclohexadiene, cycloheptadiene, cyclooctadiene etc.
In the specification, partially or fully saturated 3-10 membered mono-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms represented by
means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane etc.
In the specification, among partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur atom represented by Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 and Cyc8, 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur atom means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiaine, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole etc.
Also, partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1-4 hetero atoms selected from oxygen, nitrogen or sulfur atom, means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane etc.
The above hetero ring includes N-oxide which is the compound where nitrogen is oxidized.
In the specification, partially or fully saturated C3-10 mono- or bi-carbocyclic aryl represented by Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 and Cyc8 is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, azulene, perhydroazulene, perhydropentalene, indene, perhydroindene, indan, naphthalene, teterahydronaphthalene or perhydronaphthalene etc.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkylene and alkoxy group includes straight or branched ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer, diastereomer), optically active isomers (D-, L-, d-, l-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
According to the present invention, unless otherwise indicated and as is apparent for those skilled in the art, symbol
indicates that it is bound to the opposite side of the sheet (namely α-configuration), symbol
indicates that it is bound to the front side of the sheet (namely β-configuration), symbol
indicates that it is α-, β- or a mixture thereof, and symbol
indicates that it is a mixture of α-configuration and β-configuration.
The compound of the present invention can be converted into a pharmaceutically acceptable salt by known methods.
The pharmaceutically acceptable salt is preferably water-soluble.
The pharmaceutically acceptable salt means, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium, tetrabutylammonium, etc.), salts of organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine, etc.), acid-addition salts (inorganic acid salts (hydrochloride, hydrobromate, hydroiodate, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), etc.
Furthermore, solvates or solvates of the above alkai (earth) metals, ammonium, organic amines and acid-addition salts of the compound of the present invention are included in the pharmaceutically acceptable salt of the present invention.
The solvate is preferably nontoxic and water-soluble. Appropriate solvate means, for example, solvates such as water, an alcohol solvent (ethanol etc.), etc.
In the specification,
is preferably partially or fully saturated C3-7 mono-carbocyclic aryl, or partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atom. Moreover, partially or fully saturated C3-7 mono-carbocyclic aryl, or partially or fully saturated 3-7 membered mono-hetero aryl is preferably following compounds,
Partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms is preferably following compounds;
In the specification, A is preferably A1, A2 or A3.
In the specification, D1 is preferably —NR6C(O)—, —NR6C(S)—, —NR6SO2— or —CH2—NR6—, and more preferably —NR6C(O)—.
In the specification, D2 is preferably C1-8 alkylene, C2-8 alkenylene, —(C1-4 alkylene)-O—(C1-4 alkylene)-, —(C1-4 alkylene)-S—(C1-4 alkylene)-, —(C1-4 alkylene)-NR8—(C1-4 alkylene)- or —(C1-8 alkylene)-(Cyc2)-, and more preferably C1-8 alkylene.
In the specification, D3 is preferably —NR9R10 or Cyc3.
In the specification, E1 is preferably C1-4 alkylene.
In the specification, E2 is preferably —C(O)NR24, —NR24C(O)—, NR24 or —S—.
In the specification, E3 is preferably bond or C1-8 alkylene.
In the specification, E4 is preferably Cyc5 or NR25R26.
In the specification, Cyc1 is preferably partially or fully saturated 3-10 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atom.
In the specification, when A is A3 or A4, at least one of X and Y is preferably N.
In the specification, when A is A3 or A4,
is preferably
Among the compounds of the present invention represented by formula (I), preferred compounds are compounds represented by formula (I-A-1)
(wherein all symbols have the same meanings as described above.), compounds represented by formula (I-A-2)
(wherein all symbols have the same meanings as described above.), compounds represented by formula (I-B-1)
(wherein all symbols have the same meanings as described above.), compounds represented by formula (I-B-2)
(wherein all symbols have the same meanings as described above.), compounds represented by formula (I-C-1)
(wherein all symbols have the same meanings as described above.), and compounds represented by formula (I-C-2)
(wherein all symbols have the same meanings as described above.).
Concrete compounds of the present invention include compounds shown in Tables 1 to 90, compounds described in Examples, and pharmaceutically acceptable salts thereof.
In each Table, Me represents methyl group, Et represents ethyl group, Pr represents propyl group, i-Pr represents isopropyl group, Bu represents butyl group, c-Pr represents cyclopropyl group, c-Bu represents cyclobutyl group, c-Pen represents cyclopentyl group, c-Hex represents cyclohexyl group, Ph represents phenyl group, Bn represents benzyl group, and other symbols have the same meanings as described above.
Processes for the Preparation of the Compound of the Present Invention:
The compound represented by formula (I) can be prepared by the following method described in Example.
The compound represented by formula (IA-1) can be prepared by the amidation of the compounds of formula (II)
(wherein R31 is NHR6 or —CH2—NHR6, and R1-1, R4-1 and
are R1, R4 and
respectively. With proviso that, hydroxyl or amino in the group represented by R1-1, hydroxyl or amino represented by R4-1, and amino in the group represented by
may be protected, if necessary. Other symbols have the same meanings as defined above.) and a compound represented by formula (III)
HOOC-D2-1-D3-1 (III)
(wherein D2-1 and D3-1 are D2 and D3 respectively. With proviso that, amino in the group represented by D2-1, and carboxy, hydroxy, amino, amidino or guanidino in D3-1 may be protected, if necessary.), if necessary, followed by removal of the protective group from the resulting product.
The method of amidation is known. For example, it includes the method
These methods are explained as follows.
(1) The method via an acyl halide may be carried out, for example, by reacting carboxylic acid with an acyl halide (e.g., oxalyl chloride or thionyl chloride etc.) in an organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent at −20° C. to reflux temperature. And then the obtained acyl halide derivative may be reacted with amine in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0 to 40° C. As an alternative, the obtained acyl halide derivative may be reacted in an organic solvent (dioxane, tetrahydrofuran) using an alkaline aqueous solution (e.g., sodium bicarbonate, sodium hydroxide) at 0 to 40° C.
(2) The method via a mixed acid anhydride may be carried out, for example, by reacting carboxylic acid with an acyl halide (e.g., pivaloyl chloride, tosyl chloride or mesyl chloride) or an acid derivative (ethyl chloroformate or isobutyl chloroformate) in an organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran) or without a solvent, in the presence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at 0 to 40° C. And then the obtained mixed acid anhydride derivative may be reacted with amine in an organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran), at 0 to 40° C.
(3) The method using a condensing agent may be carried out, for example, by reacting carboxylic acid with amine in an organic solvent (e.g., chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence or absence of 1-hydroxybenzotiazole (HOBt), at 0 to 40° C.
The reaction described in (1), (2) and (3) may be carried out under an inert gas (e.g., argon, nitrogen) to avoid water in order to obtain a preferable result.
The removal of the protective group may be carried out by following method.
The reaction for removing the protective group for carboxyl, hydroxyl, amino, amidino or guanidino is well known, including, for example, the following:
These methods are explained as follows.
(1) The deprotection through alkali hydrolysis may be effected, for example, in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane) by the use of an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide) or a carbonate (e.g., sodium carbonate, potassium carbonate), or an aqueous solution thereof or their mixture, at 0 to 40° C.
(2) The deprotection under acidic condition may be effected, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, anisole) with an organic solvent (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid) or their mixture (hydrogen bromide/acetic acid), at 0 to 100° C.
(3) The deprotection through hydrogenolysis may be effected, for example, in a solvent (e.g., ether-type (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether), alcohol-type (e.g., methanol, ethanol), benzene-type (e.g., benzene, toluene), ketone-type (e.g., acetone, methyl ethyl ketone), nitrile-type (e.g., acetonitrile), amide-type (e.g., dimethylformamide), water, ethyl acetate, acetic acid, or mixed solvent of two or more of these), in the presence of a catalyst (e.g., palladium-carbon, palladium-black, palladium hydroxide, platinum oxide, Raney nickel), in a normal-pressure or increased-pressure hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200° C.
(4) The silyl deprotection may be effected, for example, in a water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile) by the use of tetrabutylammonium fluoride, at 0 to 40° C.
The carboxyl-protective group includes, for example, methyl, ethyl, t-butyl and benzyl.
The hydroxyl-protective group includes, for example, methoxymethyl, 2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl and benzyl.
The amino, amidino and guanidino-protective group includes, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl, 9-fluorenylmethoxycarbonyl and trimethylsilyl.
The carboxyl, hydroxyl, amino, amidino or guanidino-protective group may be any others than those mentioned above, capable of being readily and selectively removed, and are not specifically defined. For example, those described in T. W Greene, Protective Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999 may be used.
The intended compounds of the invention may be readily produced through selective use of the deprotecting reaction, which could be readily understood by anyone skilled in the art.
(2) Among the compounds of the present invention represented by formula (I), a compound in which A represents A1, and D1 represents —NR6SO2—, i.e., a compound represented by formula (IA-2)
(wherein all symbols have the same meanings as described above.) can be prepared by the following method.
The compound represented by formula (IA-2) can be prepared by the sulfonamidation of the compounds of formula (II-1)
(wherein all symbols have the same meanings as defined above.) and a compound represented by formula (IV)
(wherein R32 is halogen atom and other symbols have the same meanings as defined above.), if necessary, followed by removal of the protective group from the resulting product.
This sulfonamidation is known. For example, it is carried out at 0 to 40° C. in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine).
The removal of the protective group may be carried out by the above method.
The compound represented by formula (IA-3) can be prepared by esterifying the compounds of formula (V)
(wherein all symbols have the same meanings as defined above.) with the above compound represented by formula (III)
HOOC-D2-1-D3-1 (III)
(wherein all symbols have the same meanings as defined above.), if necessary, followed by removal of the protective group from the resulting product.
The method of esterification is known. For example, it includes the method
These methods are explained as follows.
(1) The method via an acyl halide may be carried out, for example, by reacting carboxylic acid with an acyl halide (e.g., oxalyl chloride or thionyl chloride etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent at −20° C. to reflux temperature. And then the obtained acyl halide derivative may be reacted with alcohol in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0 to 40° C.
(2) The method via a mixed acid anhydride may be carried out, for example, by reacting carboxylic acid with an acyl halide (e.g., pivaloyl chloride, tosyl chloride or mesyl chloride) or an acid derivative (ethyl chloroformate or isobutyl chloroformate) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran) or without a solvent, in the presence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at 0 to 40° C. And then the obtained mixed acid anhydride derivative may be reacted with alcohol in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran), at 0 to 40° C.
(3) The method using a condensing agent may be carried out, for example, by reacting carboxylic acid with alcohol in an organic solvent (e.g., chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of tertiary amine (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1′-carbodiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide), in the presence or absence of 1-hydroxybenzotiazole (HOBt), at 0 to 40° C.
The reaction described in (1), (2) and (3) may be carried out under an inert gas (e.g., argon, nitrogen) to avoid water in order to obtain a preferable result.
The removal of the protective group may be carried out by the above method.
The compound represented by formula (IA-4) can be prepared by the etherification of the compounds of formula (VI-1)
(wherein all symbols have the same meanings as described above.) and the compound of formula (VII-1)
R33-D2-1-D3-1 (VII-1)
(wherein R33 is a leaving group (halogen atom, mesyloxy or tosyloxy, etc.) and other symbols have the same meanings as described above.), if necessary, followed by removal of the protective group, by the etherification of the compounds of formula (VI-2)
(wherein all symbols have the same meanings as described above.) and the compound of formula (VII-2)
HO-D2-1-D3-1 (VII-2)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protective group, or by the etherification of the above compounds of formula (VI-1)
(wherein all symbols have the same meanings as described above.) and the compound of formula (VII-2)
HO-D2-1-D3-1 (VII-2)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protective group.
This etherification of the compound of formula (VI-1) and the compound of formula (VII-1), and the compound of formula (VI-2) and the compound of formula (VII-2) is known. For example, it is carried out at 0 to 100° C. in an inert organic solvent (e.g., dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide) or a carbonate (e.g., sodium carbonate, potassium carbonate), or an aqueous solution thereof or their mixture.
This etherification of the compound of formula (VI-1) and the compound of formula (VII-2) is known. For example, it is carried out at 0 to 60° C. by reacting with a corresponding alcohol compound in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.).
The deprotection reaction of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-5) can be prepared by reacting the above compound of formula (II-1)
(wherein all symbols have the same meanings as described above.) with the compound of formula (VIII-1)
R32-D2-1-D3-1 (VIII-1)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group, or by reacting the compound of formula (IX)
(wherein all symbols have the same meanings as described above.) with the compound of formula (VIII-2)
R6HN-D2-1-D3-1 (VIII-2)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
This reaction of the compound of formula (II) and the compound of formula (VIII-1), and the compound of formula (IX) and the compound of formula (VIII-2) is known. For example, it is carried out at 0 to 100° C. in an inert organic solvent (e.g., dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran or acetonitrile) in the presence or absence of a base (e.g., triethylamine, pyridine).
The deprotection reaction of the protective group may be carried out by the methods described above.
Among the compounds of the present invention represented by formula (IA-5), a compound in which D2 is C1-8 alkylene, C2-8 alkenylene, —(C1-4 alkylene)-O—(C1-4 alkylene)-, —(C1-4 alkylene)-S—(C1-4 alkylene)-, —(C1-4 alkylene)-NR8—(C1-4 alkylene)-, —(C1-8 alkylene)-(Cyc2)- or —(C1-4 alkylene)-(Cyc2)—(C1-4 alkylene)-, i.e., a compound represented by formula (IA-5-1)
(wherein D2′ is C1-8 alkylene, C2-8 alkenylene, —(C1-4 alkylene)-O—(C1-4 alkylene)-, —(C1-4 alkylene)-S—(C1-4 alkylene)-, —(C1-4 alkylene)-NR8—(C1-4 alkylene)-, —(C1-8 alkylene)-(Cyc2)- or —(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)- and other symbols have the same meanings as described above.) can be prepared by reductive amination of the above compound of formula (II-1)
(wherein all symbols have the same meanings as described above.) and the compound of formula (VIII-3)
OHC-D2″-D3-1 (VIII-3)
(wherein D2″ is C1-7 alkylene, C2-7 alkenylene, —(C1-3 alkylene)-O—(C1-4 alkylene)-, —(C1-3 alkylene)-S—(C1-4 alkylene)-, —(C1-3 alkylene)-NR8—(C1-4 alkylene)-, —(C1-7 alkylene)-(Cyc2)- or —(C1-3 alkylene)-(Cyc2)—(C1-4 alkylene)- and other symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reductive amination is well known. For example, it may be carried out in an organic solvent (e.g., methanol, ethanol) in the presence of reducing agent (e.g., sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride) and, if necessary, in the presence of an acid (e.g., acetic acid, hydrogen chloride) at −20 to 60° C.
The removal of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-6) can be prepared by reacting the compound of formula (X)
(wherein all symbols have the same meanings as described above.) with the above compound of formula (VIII-1)
R32-D2-1-D3-1 (VIII-1)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group, or by reductive amination of the compound of formula (XI)
(wherein all symbols have the same meanings as described above.) with the above compound of formula (VIII-2)
R6HN-D2-1-D3-1 (VIII-2)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction of the compound of formula (X) and the compound of formula (VIII-1) may be carried out by the same method as the above reaction of the compound of formula (IX) and the compound of formula (VIII-2).
The reaction of the compound of formula (XI) and the compound of formula (VIII-2) may be carried out by the same method as the above reaction of the compound of formula (II-1) and the compound of formula (VIII-3).
The removal of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-7) can be prepared by reacting the above compound of formula (II-1)
(wherein all symbols have the same meanings as described above.) with the compound of formula (XII)
O═C═N-D2-1-D3-1 (XII)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction is known. It may be carried out in organic solvent (e.g., tetrahydrofuran, methylene chloride, diethyl ether) at 0 to 100° C.
The removal of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-8) can be prepared by reacting the above compound of formula (II-1)
(wherein all symbols have the same meanings as described above.) with the compound of formula (XIII)
S═C═N-D2-1-D3-1 (XIII)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction is known. It may be carried out in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether) at 0 to 100° C.
The removal of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-9) can be prepared by reacting the above compound of formula (II-1)
(wherein all symbols have the same meanings as described above.) with the compound of formula (XIV)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction is known. It may be carried out in an organic solvent (e.g., tetrahydrofuran, methylene chloride, diethyl ether) at −78 to 40° C.
The removal of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-10) can be prepared by thiocarbonylation of the compound of formula (XV)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction is known. It may be carried out in an organic solvent (e.g., dioxane, benzene, toluene, xylene, tetrahydrofuran), using Lawesson reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) at 20 to 150° C.
The removal of the protective group may be carried out by the methods described above.
The compound of formula (IA-11) can be prepared by reacting the above compound of formula (II-1)
(wherein all symbols have the same meanings as described above.) with the compound of formula (XVI)
(wherein R34 is C1-4 alkyl and other symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction is known. For example, it may be carried out in an organic solvent (e.g., methanol, ethanol) at 0 to 50° C.
The removal of the protective group may be carried out by the methods described above.
The compound represented by formula (IA-12) cam be prepared by reacting a compound of formula (XVII)
(wherein all symbols have the same meanings as described above.) with a compound of formula (XVIII)
H—NR9R10 (XVIII)
(wherein all symbols have the same meanings as described above.) or a compound of formula (XIX)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction of the compound of formula (XVII) and the compound of formula (XVIII) or (XIX) may be carried out by the same method as the above reaction of the compound of formula (IX) and the compound of formula (VIII-2).
The removal of the protective group may be carried out by the methods described above.
The compound of formula (IB-1) can be prepared by amidation of a compound of formula (XX)
(wherein all symbols have the same meanings as described above.) and the compound of formula (XXI)
(wherein E4-1 is E4. With proviso that, hydroxyl, amino or carboxyl in the group represented by E4-1 may be protected, if necessary. Other symbols have the same meanings as defined above.), if necessary, followed by removal of the protecting group.
The amidation and the removal of the protective group may be carried out by the methods described above.
The compound of formula (IB-2) can be prepared by amidation of a compound of formula (XXII)
(wherein all symbols have the same meanings as described above.) and a compound of formula (XXIII)
HOOC-E3-E4-1 (XXIII)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The amidation and the removal of the protective group may be carried out by the methods described above.
The compound of formula (IB-3) can be prepared by reacting a compound of formula (XXIV)
(wherein all symbols have the same meanings as described above.) with the above compound of formula (XXI)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction of the compound of formula (XXIV) and the compound of formula (XXI) may be carried out by the same method as the above reaction of the compound of formula (IX) and the compound formula (VIII-2).
The removal of the protective group may be carried out by the methods described above.
The compound of formula (IB-4) can be prepared by esterifying the compound of formula (XX)
(wherein all symbols have the same meanings as described above.) with a compound of formula (XXV)
HO-E3-E4-1 (XXV)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The esterifying and the removal of the protective group may be carried out by the methods described above.
The compound of formula (IB-5) can be prepared by reacting a compound of formula (XXVI)
(wherein all symbols have the same meanings as described above.) with a compound of formula (XXVII)
R32-E3-E4-1 (XXVII)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction is known. For example, it may be carried out in an inert organic solvent (e.g., dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile) in the presence or absence of a base (e.g., triethylamine, pyridine) at 0 to 100° C.
The removal of the protective group may be carried out by the methods described above.
The compound of formula (IB-6) can be prepared by reacting a compound of formula (XXVIII)
(wherein all symbols have the same meanings as described above.) with a compound of formula (XXIX)
H—NR25R26 (XXIX)
(wherein all symbols have the same meanings as described above.) or a compound of formula (XXX)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The reaction of the compound of formula (XXVIII) and the compound of formula (XXIX) or (XXX) may be carried out by the same method as the above reaction of the compound of formula (IX) and the compound of formula (VIII-2).
The removal of the protective group may be carried out by the methods described above.
The compound of formula (IC-1) can be prepared by reacting a compound of formula (XXXI)
(wherein G1-1 is bond or C1-7 alkylene, Cyc1′ and G2-1 are Cyc1 and G2 respectively. With proviso that amino in the group represented by Cyc1, and hydroxy and amino in the group represented by G2-1 may be protected, if necessary. Other symbols have the same meanings as described above.) with hydrazine or a salt thereof (e.g., hydride, chloride), if necessary, followed by removal the protecting group.
The reaction is known. For example, it may be carried out in an organic solvent (e.g., methanol, ethanol, propanol, isopropanol, butanol, acetic acid, tetrahydrofuran) at 50° C. to reflux temperature.
The removal of the protective group may be carried out by the methods described above.
Moreover, among the compounds of the present invention represented by formula (IC-1), a compound in which Cyc1 is hetero ring represented by
(The hetero ring is a hetero ring having at least one nitrogen atom (The nitrogen atom binds to G1.) in Cyc1.), i.e., a compound of formula (IC-1-1)
(wherein
is a hetero ring having at least one nitrogen atom (The nitrogen atom binds to G1.) in Cyc1 and other symbols have the same meanings as described above.) can be prepared by following method.
The compound of formula (IC-1-1) can be prepared by reacting a compound of formula (XXXII)
(wherein all symbols have the same meanings as described above.) with a compound of formula (XXXIII)
(wherein all symbols have the same meanings as described above.), if necessary, followed by removal the protecting group.
The reaction of the compound of formula (XXXII) and the compound of formula (XXXII) may be carried out by the same method as the above reaction of the compound of formula (IX) and the compound of formula (VIII-2).
The removal of the protective group may be carried out by the methods described above.
The reaction is known. For example, it may be carried out in an organic solvent (e.g., methanol, ethanol, propanol, isopropanol, butanol, acetic acid, tetrahydrofuran) at 50° C. to reflux temperature.
The removal of the protective group may be carried out by the methods described above.
The reaction is known. For example, it may be carried out in an organic solvent (e.g., methanol, ethanol, propanol, isopropanol, butanol, acetic acid, tetrahydrofuran) at 50° C. to reflux temperature.
The removal of the protective group may be carried out by the methods described above.
Moreover, among the compound of formula (ID-1), a compound in which X is N,
is single bond, i.e., a compound of formula (ID-1-1)
(wherein all symbols have the same meanings as described above.) can be prepared by the following method.
The compound of formula (ID-1-1) can be prepared by reacting a compound of formula (XXXVI)
(wherein all symbols have the same meanings as described above.) with a compound of formula (XXXVII)
(wherein R35 has the same meaning as described above.), if necessary, followed by removal of the protecting group.
The reaction may be carried out, for example, in an organic solvent (e.g., toluene, tetrahydrofuran, chloroform, methylene chloride) in the presence or absence of catalyst (e.g., p-toluenesulfonic acid, pyridine) at 50° C. to reflux temperature.
The removal of the protective group may be carried out by the methods described above.
The compounds represented by formulae (II), (II-1), (III), (IV), (V), (VI-1), (VI-2), (VII-1), (VII-2), (VIII-1), (VIII-2), (VIII-3), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV-1), (XXXIV-2), (XXXV), (XXXVI) and (XXXVII) are known compounds or can be prepared by known methods or methods as described in Examples.
For example the compounds of formulae (II), (II-1), (V), (VI-1), (VI-2), (IX), (X), (XI), (XX), (XXII), (XXIV), (XXVI), (XXXI), (XXXIV-1), (XXXIV-2), (XXXV) and (XXXVI) can be prepared by the method described in reaction scheme 1, 2, 3 and 4.
In each reaction scheme, R36 is —NHR6, —CH2—NHR6, —OH, —CH2—OH, —CH2—R33 or halogen atom. With proviso that hydroxy and amino in the group represented by R36 may be protected, if necessary. R37 is the protecting group of amino, R38 is —NHR6, —CH2—NHR6, —OH, —CH2—OH, —CH2—R33 or halogen atom, BOP is benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, Me is methyl, Et is ethyl, E1-1 is bond or C1-3 alkylene, Ph is phenyl, TBAF is tetrabutylammonium fluoride, TMSN3 is trimethylsilylazide, and R39 is COOH, —NHR24, halogen atom or —SCOCH3. With proviso that amino or carboxy in the group represented by R39 may be protected, if necessary. R40 is COOH, —NHR24, halogen atom or —SCOCH3, and other symbols have the same meanings as described above. The compound represented by formulae (XXXIX) and (XXXXXV) with bromo instead of chloro may be used, which could be readily understood by anyone skilled in the art.
In Reaction Schemes 1, 2, 3 and 4, the compounds used as the starting materials are known compounds or can be prepared easily by known methods.
In each reaction described herein, the reaction product can be purified by general purification techniques such as distillation under ordinary pressure or a reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing and recrystallization. Purification may be carried out in each reaction or after completion of several reactions.
Pharmacological Activities:
It has been confirmed that the compounds of the present invention of formula (I) have PARP inhibitory activity by the following experimental results.
1) Enzyme Assay In Vitro
Methods
The below procedure was carried out with 96 well plate at room temperature. In a final volume of 80 μL, the reaction mixture contained each 10 μL of 500 mM Tris/HCl (pH 8.0, WAKO), 100 mM MgCl2, 50 mM dithiothreitol (sigma), 1 mg/mL activated DNA and 1 mM NAD (containing 3H-NAD). The 10 μL of test compound was added to the reaction mixture and the reaction was started by addition of 10 μL of 0.1 U/μL PARP (TREVIGEN). The reaction was terminated at 10 minutes by addition of 100 μL of 20% trichloroacetic acid. Poly(ADP-ribose), which is the reaction product, was collected on a glass fiber filter (GF/C, PACKARD). The radioactivity was measured by topcount (PACKARD). Inhibitory activity of the compound was represented by 50% inhibitory concentration calculated as 100% of control (distilled water). The results were shown in Table 91.
2) Ischemia-Reperfusion Injury Model (Brain and Heart)
Model of cerebral or coronary ischemia-reperfusion was prepared according to procedures described previously (Jpn. J. Stroke, 8, 1 (1986), Stroke, 27, 1624-1628 (1996) and Eur. J. Pharmacol., 270, 45 (1994)). The compounds of the present invention were improvement effective of these diseases.
Toxicity:
The toxicity of the compounds of the present invention represented by formula (I) is very low (For example, as a result of administering the compounds of the present invention to rats, they did not affect circulatory parameters, such as blood pressure, an electrocardiogram, and heart rate.) and therefore the compounds may be considered safe for pharmaceutical use.
Application to Pharmaceutical:
Since the compound of the present invention represented by formula (I) has PARP inhibitory activity, it is useful for prevention and/or treatment of various diseases, for example, ischemic diseases (cerebral infarction, myocardial infarction, reperfusion injury or postoperative injury etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis, arthritis or lung injury etc.), neurodegenerative disorders (extrapyramidal disease, Parkinson's disease, Alzheimer's disease, muscular dystrophy or lumbar spinal canal stenosis etc.), glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure or hyperalgesia etc. Moreover, it is useful as an antiretroviral drug such as an anti HIV drug, a sensitizer of anticancer therapy or an immunosuppressant.
The compound represented by formula (I) or pharmaceutically acceptable salt thereof may be administered in combination with other pharmaceutical preparations to accomplish the following purposes:
The compound represented by formula (I) and other pharmaceutical preparations may be administered in the form of formulation having these components incorporated in one preparation or may be administered in separate preparations. In the case where these pharmaceutical preparations are administered in separate preparations, they may be administered simultaneously or at different times. In the latter case, the compound represented by formula (I) may be administered before the other pharmaceutical preparations. Alternatively, the other pharmaceutical preparations may be administered before the compound represented by formula (I). The method for the administration of these pharmaceutical preparations may be the same or different.
The diseases on which the preventive and/or treatment effect of the aforementioned combined preparations works are not specifically limited but may be those for which the preventive and/or treatment effect of the compound represented by formula (I) is complemented and/or enhanced.
Examples of the other pharmaceutical preparations for complementing and/or enhancing the preventive and/or treatment effect of the compound represented by formula (I) on ischemic diseases include radical scavenger, astrocyto modulator, N-methyl-D-aspartate (NMDA) antagonist, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) antagonist, antithrombotic agent, thrombolytic agent, immunosuppressive agent, cell adhesion molecules inhibitor, nitrogen oxide synthase (NOS) inhibitor, neurotrophic factor and interleukin-8 inhibitor etc.
Examples of the other pharmaceutical preparations for complementing and/or enhancing the preventive and/or treatment effect of the compound represented by formula (I) on lumbar spinal canal stenosis include nitrogen oxide synthase (NOS) inhibitor, aldose reductase (AR) inhibitor, radical scavenger, N-methyl-D-aspartate (NMDA) antagonist, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) antagonist, neurotrophic factor and interleukin-8 inhibitor etc.
Examples of the radical scavenger include, for example, edaravone and ebselen (DR-3305) etc.
Examples of the astrocyto modulator include, for example, ONO-2506 etc.
Examples of the antithrombotic agent include, for example, sodium ozagrel, argatroban and aspirin etc.
Examples of the thrombolytic agent include, for example, tissue plasminogen activator (t-PA), urokinase and heparin etc.
Examples of the immunosuppressive agent include, for example, cyclosporin A, cyclophosphamide and tacrolimus etc.
Examples of the NOS inhibitor include, for example, L-NMMA and ONO-1714 etc.
Examples of the AR inhibitor include, for example, epalrestat, zenarestat, fidarestat, zopolrestat and AS-3201 etc.
The weight proportion of the compound represented by formula (I) and the other pharmaceutical preparations is not specifically limited.
Arbitrary two or more of the other pharmaceutical preparations may be administered in combination.
Examples of the other pharmaceutical preparations for complementing and/or enhancing the preventive and/or treatment effect of the compound represented by formula (I) include not only those which have so far been found but also those which will be found on the basis of the aforementioned mechanism.
In order to use the compound of the present invention represented by formula (I) or the pharmaceutically acceptable salt thereof, or the compound represented by formula (I) in combination with the other pharmaceutical preparations, these compounds are normally administered to the entire or local part of human body orally or parenterally.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, and from 1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compound represented by formula (I) or the pharmaceutically acceptable salt thereof, or the concomitant drug combined the compound represented by formula (I) with pharmaceutical preparations may be administered in the form of, for example, solid compositions, liquid compositions or other compositions each for oral administration, or injections, preparations for external use or suppositories, each for parenteral administration.
Solid compositions for oral administration include compressed tablets, pills, capsules, powders, and granules.
Capsules include hard capsules and soft capsules.
In such solid compositions, one or more of the active substance(s) may be admixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium aluminometasilicate. The compositions may comprise, in accordance with the conventional process, additives other than the inert diluent, for example, lubricants such as magnesium stearate, disintegrants such as cellulose calcium glycolate, stabilizer such as lactose, and solubilizing agent such as glutamic acid or aspartic acid. Tablets or pills may be coated with a film of a gastric soluble or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropyl methylcellulose phthalate, or with two or more layers, if necessary. Furthermore, capsules made of a substance which can be absorbed in the body, for example, gelatin, are included.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups and elixirs etc. Such liquid compositions comprise one or more of the active substance(s) and an ordinarily employed inert diluent(s) (for example, purified water or ethanol) dissolving the substance(s) therein. The compositions may comprise, in addition to the inert diluent, an adjuvant such as humectants or suspending agents, sweetening agents, flavoring agents, aromatic agents and antiseptics.
The other compositions for oral administration include sprays which comprise one or more active substance(s) and are formulated in a manner known per se in the art. The compositions may comprise, in addition to an inert diluent, a stabilizer such as sodium bisulfite and an isotonization buffer such as sodium chloride, sodium citrate or citric acid. The preparation process of sprays is described in detail in, for example, U.S. Pat. Nos. 2,868,691 and 3,095,355.
In the present invention, injections for parenteral administration include sterile aqueous and/or non-aqueous solutions, suspensions and emulsions. The aqueous solutions or suspensions include, for example, distilled water for injection and saline. The non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohol such as ethanol and Polysorbate 80 (trade mark). Furthermore, sterile aqueous and non-aqueous solutions, suspensions, and emulsions may be used in combination. Such compositions may additionally comprise adjuvants such as antisaptic, humectant, emulsfier, dispersant, stabilizer (such as lactose) and solubilizing agent (such as glutamic acid and aspartic acid). They are sterilized by filtration through a bacteria retaining filter, the addition of a sterilizer, or irradiation. Also, a sterile solid composition is prepared and then, for example, a freeze-dried product may be dissolved in sterilized or sterile distilled water for injection or another sterile solvent before use.
The other compositions for parenteral administration include liquids for external use, ointments, endermic liniments, suppositories for intrarectal administration and pessaries for vaginal administration which comprise one or more of the active substance(s) and may be prepared by methods known per se.
The present invention is explained below in detail based on Reference Examples and Examples, however, the present invention is not limited thereto.
The solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations or TLC. The solvents in the parentheses in NMR show the solvents for measurement.
To a solution of 3,4,5,6-tetrahydrophthalic acid anhydride (3.04 g) in tetrahydrofuran (40.0 mL) was added a solution of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride in tetrahydrofuran (1M, 20.0 mL) at −78° C. The mixture was stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction mixture, which was filtrated. The filtrate was concentrated to give an oily product. Thionyl chloride (5.20 mL) was added dropwise to methanol (20.0 mL) at −10° C. and then the solution was stirred at 0° C. for 15 minutes. To the solution was added the oily product obtained previously and the solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The obtained residue was dissolved in methylene chloride (20 mL) and thereto was added triethylamine (2.79 mL) at 0° C. Water was added to the reaction solution, which was extracted with methylene chloride. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:7) to give the title compound (2.56 g) having the following physical data.
NMR (DMSO-d6): δ 7.03 (t, J=7.8 Hz, 1H), 6.60-6.47 (m, 3H), 5.21 (brs, 2H), 3.20 (s, 3H), 2.17-1.60 (m, 8H).
A solution of the compound prepared in Reference example 1 (2.56 g) and hydrazine monohydrate (503 mg) in ethanol (30.0 mL) was refluxed for 18 hours. After cooling the reaction mixture to room temperature, the deposited crystal was collected by filtration. It was washed with hexane and dried under reduced pressure. 4N hydrogen chloride in dioxane (0.10 mL) was added dropwise to a suspension of the obtained solid (32.0 mg) in methanol (1.00 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The obtained crystal was dried under reduced pressure to give the compound of the present invention (36.2 mg) having the following physical data. Moreover, the compound was converted to methanesulfonate thereof by conventional method.
Hydrochloride:
TLC: Rf 0.27 (ethyl acetate:hexane=2:1);
NMR (DMSO-d6): δ 12.95 (s, 1H), 9.40 (brs, 3H), 7.47 (t, J=8.1 Hz, 1H), 7.32-7.26 (m, 3H), 2.43-1.59 (m, 8H).
Methanesulfonate:
TLC: Rf 0.55 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.94 (s, 1H), 8.31 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.18 (s, 1H), 2.48-2.34 (m, 4H), 2.31 (s, 3H), 1.71-1.60 (m, 4H).
By the same procedure as described in Reference Example 1→Example 1, if necessary, by converting to corresponding salts by conventional method, using 3,4,5,6-tetrahydrophthalic acid anhydride in tetrahydrofuran or a corresponding derivative, and 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride or a corresponding derivative, the following compounds of the present invention were obtained.
TLC: Rf 0.50 (methanol:methylene chloride=1:9);
NMR (CD3OD): δ 7.66-7.58 (m, 2H), 7.51-7.44 (m, 2H), 5.82 (m, 1H), 5.73 (m, 1H), 3.21 (m, 1H), 2.74 (s, 3H), 2.72-2.47 (m, 3H), 2.27 (m, 1H), 1.92 (m, 1H).
Methanesulfonate
TLC: Rf 0.47 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 13.01 (br-s, 1H), 7.45 (m, 1H), 7.20-7.09 (m, 3H), 2.86-2.80 (m, 2H), 2.58-2.52 (m, 2H), 2.31 (s, 3H), 1.86-1.76 (m, 2H), 1.58-1.46 (m, 4H).
TLC: Rf 0.24 (ethyl acetate:hexane=1:1);
NMR (DMSO-d6): δ 13.07 (s, 1H), 8.17 (d, J=1.5 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (dd, J=8.4, 1.5 Hz, 1H), 2.48-2.38 (m, 4H), 1.71-1.58 (m, 4H).
To a solution of thiomorpholin-3-ylcarboxylic acid ethyl ester (5.05 g) in methylene chloride (120 mL) were added dimethylaminopyridine (352 mg), triethylamine (4.9 mL) and 3-nitrobenzoyl chloride (5.62 g) in ice bath and then the mixture was stirred at room temperature overnight. 2N hydrochloric acid was added to the reaction mixture, which was extracted with methylene chloride. The extract was wash with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (5.91 g) having the following physical data.
TLC: Rf 0.23 (hexane:ethyl acetate=2:1);
NMR (CDCl3): δ 8.32-8.30 (m, 2H), 7.79-7.62 (m, 2H), 5.78 and 4.57 (m, 1H), 4.98-4.93 and 3.84-3.79 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.71-3.63 and 3.28-3.02 and 2.91-2.70 (m, 4H), 2.61-2.57 and 2.43-2.39 (m, 1H), 1.36 (t, J=7.2 Hz, 3H).
To a solution of the compound prepared in Reference example 2 (5.88 g) in toluene (90 mL) was added Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) (8.62 g) and the mixture was refluxed for 2 hours. After cooling to room temperature, the raction mixture was filtrated and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (6.16 g) having the following physical data.
TLC: Rf 0.27 (hexane:ethyl acetate=4:1);
NMR (CDCl3): δ 8.24-8.17 (m, 2H), 7.66-7.55 (m, 2H), 6.96-6.93 and 4.88-4.86 (m, 1H), 5.96-5.90 and 4.13-4.06 (m, 1H), 4.39-4.32 (m, 2H), 3.83-3.73 and 3.59-3.50 (m, 1H), 3.37-3.30 and 3.12-3.07 (m, 1H), 3.20-3.14 and 3.02-2.94 (m, 1H), 2.94-2.88 and 2.80-2.71 (m, 1H), 2.72-2.64 and 2.49-2.41 (m, 1H), 1.40-1.28 (m, 3H).
To a solution of the compound prepared in Reference example 3 (4.78 g) in ethanol (50 mL) was added hydrazine monohydrate (2.0 mL) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration to give the compound of the present invention (2.30 g) having the following physical data.
TLC: Rf 0.45 (chloroform:methanol=19:1);
NMR (DMSO-d6): δ 10.65 (s, 1H), 8.30-8.27 (m, 2H), 7.89-7.86 (m, 1H), 7.76-7.70 (m, 1H), 4.24 (dd, J=10.8, 2.7 Hz, 1H), 3.49 (dt, J=13.8, 2.7 Hz, 1H), 3.17-3.08 (m, 1H), 2.97 (dd, J=13.2, 10.8 Hz, 1H), 2.88-2.82 (m, 1H), 2.71 (dt, J=12.6, 2.7 Hz, 1H), 2.32-2.27 (m, 1H).
By the same procedure as described in Reference example 2→Reference example 3→Example 3, using thiomorpholin-3-ylcarboxylic acid ethyl ester or a corresponding derivative, and 3-nitrobenzoyl chloride or a corresponding derivative, the following compounds of the present invention were obtained.
TLC: Rf 0.50 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.48 (s, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.22 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 3.91 (m, 1H), 3.17 (m, 1H), 2.87 (m, 1H), 2.10 (m, 1H), 1.86 (m, 1H), 1.43 (m, 4H).
TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
NMR (DMSO-d6): δ 10.53 (s, 1H), 7.50-7.38 (m, 5H), 4.23 (dd, J=9.6, 3.6 Hz, 1H), 3.52 (m, 1H), 3.08 (m, 1H), 2.94-2.80 (m, 2H), 2.68 (m, 1H), 2.30 (d, J=10.5 Hz, 1H).
TLC: Rf 0.18 (hexane:ethyl acetate=1:1);
NMR (CDCl3): δ8.32 (dd, J=8.1, 1.5 Hz, 1H), 8.27 (s, 1H), 8.14 (br, H), 7.72 (d, J=8.1 Hz, 1H), 7.66 (t, J=8.1 Hz, 1H), 4.39 (dd, J=10.8, 2.7 Hz, 1H), 3.72 (dt, J=14.1, 2.7 Hz, 1H), 3.24 (m, 1H), 3.13 (m, 1H), 2.99 (dd, J=14.1, 10.8 Hz, 1H), 2.77 (m, 1H), 2.32 (m, 1H);
[α]D=−71.9 (c, 0.16, MeOH).
TLC: Rf 0.28 (ethyl acetate:hexane=1:1);
NMR (DMSO-d6): δ 10.69 (s, 1H), 8.28 (d, J=8.4 Hz, 2H), 7;73 (d, J=8.4 Hz, 2H), 4.26 (dd, J=10.2, 3.0 Hz, 1H), 3.48 (d, J=14.4 Hz, 1H), 3.17-2.29 (m, 5H).
TLC: Rf 0.17 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.50 (s, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.00-6.93 (m, 3H), 4.20 (dd, J=10.5, 3.0 Hz, 1H), 3.76 (s, 3H), 3.53 (dt, J=13.8, 3.0 Hz, 1H), 3.10-3.01 (m, 1H), 2.93-2.78 (m, 2H) 2.73-2.63 (m, 1H), 2.32-2.27 (m, 1H).
TLC: Rf 0.50 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 7.40-7.26 (m, 2H), 7.04-6.92 (m, 2H), 4.20 (dd, J=9.3, 4.2 Hz, 1H), 3.77 (s, 3H), 3.57 (dt, J=14.1, 2.7 Hz, 1H), 3.06 (m, 1H), 2.94-2.78 (m, 2H), 2.68 (m, 1H), 2.30 (m, 1H).
TLC: Rf 0.50 (methylene chloride:methanol=10:1);
NMR (CDCl3):δ8.14 (br, 1H), 7.21 (ddd, J=8.4, 7.5, 2.1 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.80 (td, J=7.5, 1.2 Hz, 1H), 6.74 (dd, J=8.4, 1.2 Hz, 1H), 4.35 (dd, J=10.5, 3.0 Hz, 1H), 3.72 (dt, J=13.8, 3.0 Hz, 1H), 3.14 (m, 1H), 3.08-2.90 (m, 2H), 2.79 (m, 1H), 2.21 (dd, J=13.8, 1.2 Hz, 1H).
TLC: Rf 0.27 (methylene chloride:methanol=20:1);
NMR (DMSO-d6): δ 11.02 (brs, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.28 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.76 (t, J=8.1 Hz, 1H), 6.28 (s, 1H), 3.61 (m, 2H), 3.16 (m, 2H).
TLC: Rf 0.51 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.89 (s, 1H), 7.45 (m, 5H), 6.24 (s, 1H), 3.60 (m, 2H), 3.14 (m, 2H).
TLC: Rf 0.53 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.57 (br-s, 1H), 7.50-7.40 (m, 5H), 4.29 (dd, J=6.9, 4.5 Hz, 1H), 3.44-3.36 (m, 1H), 3.16-3.00 (m, 3H), 2.78-2.70 (m, 2H), 1.80-1.64 (m, 1H), 1.55-1.40 (m, 1H).
TLC: Rf 0.60 (chloroform:methanol=9:1).
TLC: Rf 0.50 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 7.21 (dd, J=8.1, 7.2 Hz, 1H), 6.75 (m, 1H), 6.72-6.58 (m, 2H), 4.20 (dd, J=10.5, 3.0 Hz, 1H), 3.58 (dt, J=13.8, 2.7 Hz, 1H), 3.04 (m, 1H), 2.98-2.76 (m, 2H), 2.90 (s, 6H), 2.68 (m, 1H), 2.30 (m, 1H).
TLC: Rf 0.39 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 11.07 (s, 1H), 8.33 (m, 2H), 8.02 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 4.53 (m, 2H), 4.28 (m, 1H), 3.46 (m, 2H).
TLC: Rf 0.44 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 7.41 (dd, J=2.1, 2.1 Hz, 1H), 7.32 (dd, J=2.1, 1.2 Hz, 1H), 6.94 (dd, J=2.1, 1.2 Hz, 1H), 6.52 (brs, 1H), 6.01 (brs, 2H), 4.23 (dd, J=7.5, 3.0 Hz, 1H), 3.57 (m, 1H), 3.10 (m, 1H), 3.00-2.76 (m, 2H), 2.68 (m, 1H), 2.33 (m, 1H).
TLC: Rf 0.51 (methylene chloride:methanol=10:1).
TLC: Rf 0.26 (hexane:ethyl acetate 1:1);
NMR (DMSO-d6): δ 10.55 (s, 1H), 7.50-7.24 (m, 10H), 4.53 (d, J=12.3 Hz, 1H), 4.48 (d, J=12.3 Hz, 1H), 4.16 (dd, J=8.7, 7.2 Hz, 1H), 4.09-4.03 (m, 1H), 3.54 (dd, J=10.8, 3.0 Hz, 1H), 3.44 (dd, J=10.8, 4.8 Hz, 1H), 2.39-2.31 (m, 1H), 2.24-2.15 (m, 1H).
TLC: Rf 0.10 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.73 (s, 1H), 8.31-8.27 (m, 2H), 7.95 (dt, J=7.5, 1.5 Hz, 1H), 7.75-7.69 (m, 1H), 7.34-7.24 (m, 5H), 4.53 (d, J=12.0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.24-4.19 (m, 1H), 4.11-4.04 (m, 1H), 3.57 (dd, J=10.5, 3.0 Hz, 1H), 3.50 (dd, J=10.5, 5.1 Hz, 1H), 2.41-2.33 (m, 1H), 2.28-2.19 (m, 1H).
TLC: Rf 0.51 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.45 (s, 1H), 7.34-7.24 (m, 5H), 7.03 (t, J=7.8 Hz, 1H), 6.72 (t, J=1.8 Hz, 1H), 6.60 (dd, J=7.8, 1.8 Hz, 1H), 5.19 (s, 2H), 4.53 (d, J=12.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.14-4.01 (m, 2H), 3.54 (dd, J=10.8, 2.4 Hz, 1H), 3.46 (dd, J=10.8, 4.8 Hz, 1H), 2.38-2.30 (m, 1H), 2.22-2.13 (m, 1H).
TLC: Rf 0.55 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.55 (br-s, 1H), 7.53-7.43 (m, 5H), 4.43 (d, J=13.8 Hz, 1H), 4.20 (dd, J=12.0, 2.4 Hz, 1H), 4.06 (dd, J=13.8, 2.4 Hz, 1H), 3.21 (m, 1H), 2.88 (m, 1H), 2.07 (m, 1H), 1.80 (m, 1H).
TLC: Rf 0.55 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.70 (br-s, 1H), 8.40 (m, 1H), 8.33 (m, 1H), 7.96 (m, 1H), 7.75 (m, 1H), 4.48 (d, J=14.1 Hz, 1H), 4.24 (dd, J=12.0, 2.1 Hz, 1H), 4.14 (dd, J=14.1, 2.1 Hz, 1H), 3.23 (m, 1H), 2.91 (m, 1H), 2.08 (m, 1H), 1.86 (m, 1H).
TLC: Rf 0.33 (methylene chloride:methanol=20:1);
NMR (DMSO-d6): δ 10.97 (brs, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.70 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 6.27 (s, 1H), 3.61 (m, 2H), 3.14 (m, 2H), 2.55 (s, 3H).
TLC: Rf 0.20 (hexane:ethyl acetate=1:1);
NMR (CDCl3): δ 8.10 (br, 1H), 7.75 (dt, J=6.9, 1.8 Hz, 1H), 7.68 (m, 1H), 7.62-7.55 (m, 2H), 4.36 (dd, J=11.1, 2.7 Hz, 1H), 3.69 (dt, J=11.1, 2.7 Hz, 1H), 3.21 (ddd, J=14.1, 12.0, 2.7 Hz, 1H), 3.12 (dt, J=10.8, 2.4 Hz, 1H), 2.96 (dd, J=14.1, 11.1 Hz, 1H), 2.74 (m, 1H), 2.32 (ddd, J=11.1, 4.5, 2.4 Hz, 1H).
TLC: Rf 0.59 (chloroform:methanol=9:1).
TLC: Rf 0.63 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 7.56-7.46 (m, 1H), 7.36-7.24 (m, 3H), 4.20 (dd, J=10.2, 3.6 Hz, 1H), 3.54-3.44 (m, 1H), 3.16-3.02 (m, 1H), 2.96-2.78 (m, 2H), 2.76-2.64 (m, 1H), 2.36-2.24 (m, 1H).
TLC: Rf 0.66 (chloroform:methanol=9:1).
TLC: Rf 0.59 (chloroform:methanol=9:1).
TLC: Rf 0.54 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 11.03 (brs, 1H), 8.32-8.25 (m, 2H), 7.77-7.70 (m, 2H), 6.29 (s, 1H), 3.64-3.54 (m, 2H), 3.20-3.12 (m, 2H).
TLC: Rf 0.49 (chloroform:methanol=9:1);
NMR (CDCl3): δ 8.64 (s, 1H), 7.93 (dd, J=7.8, 1.5 Hz, 1H), 7.50-7.40 (m, 2H), 4.34 (dd, J=11.1, 2.4 Hz, 1H), 3.41 (dt, J=11.1, 2.7 Hz, 1H), 3.24-3.00 (m, 2H), 2.91 (dd, J=13.5, 11.1 Hz, 1H), 2.70-2.40 (m, 4H), 2.30-2.26 (m, 1H).
TLC: Rf 0.46 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.85 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.08-6.96 (m, 3H), 6.23 (s, 1H), 3.77 (s, 3H), 3.64-3.56 (m, 2H), 3.16-3.08 (m, 2H).
TLC: Rf 0.30 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.92 (s, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.73 (dd, J=8.7, 2.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.25 (s, 1H), 3.96 (s, 3H), 3.65-3.60 (m, 2H), 3.20-3.15 (m, 2H).
TLC: Rf 0.37 (methylene chloride:methanol=10:1);
NMR (CDCl3): δ 8.03 (br, 1H), 7.39-7.24 (m, 5H), 4.17 (dd, J=10.8, 2.7 Hz, 1H), 3.93 (dt, J=14.4, 2.7 Hz, M1), 3.06 (ddd, J=14.4, 12.0, 2.7 Hz, 1H), 2.89 (dt, J=13.5, 2.7 Hz, 1H), 2.78 (dd, J=13.5, 10.8 Hz, 1H), 2.21 (ddd, J=14.4, 12.0, 2.7 Hz, 1H), 2.06 (dq, J=14.4, 2.7 Hz, 1H).
TLC: Rf 0.60 (chloroform:methanol=9:1);
NMR (CDCl3): δ 8.61 (s, 1H), 8.20-8.10 (m, 2H), 7.64-7.54 (m, 2H), 6.39 (s, 1H), 3.82 (s, 2H), 3.80-3.74 (m, 2H), 2.76-2.72 (m, 2H).
TLC: Rf 0.67 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.34 (s, 1H), 7.44-7.34 (m, 5H), 3.86 (dd, J=11.1, 3.0 Hz, 1H), 3.20 (dt, J=13.2, 2.1 Hz, 1H), 2.77 (td, J=13.2, 2.1 Hz, 1H), 2.06 (m, 1H), 1.85 (m, 1H), 1.49-1.26 (m, 4H).
TLC: Rf 0.30 (ethyl acetate:hexane=1:1);
NMR (DMSO-d6): δ 10.99 (s, 1H), 7.48 (m, 5H), 5.39 (s, 1H), 3.97 (ddd, J=12.0, 6.3, 1.2 Hz, 1H), 3.35-3.25 (m, 1H), 2.92 (ddd, J=10.0, 6.3, 1.2 Hz, 1H), 2.59-2.48 (m, 1H).
The compound prepared in Example 4(28) (150 mg) and lithium chloride (59 mg) were dissolved in dimethylformamide (2.0 mL) and the mixture was refluxed for 16 hours. After cooling to room temperature, to the reaction mixture was added 1N hydrochloric acid. The precipitate was collected by filtration. It was dried to give the compound of the present invention (126 mg) having the following physical data.
TLC: Rf 0.19 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 11.45 (brs, 1H), 10.89 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.58 (dd, J=9.0, 2.4 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.24 (s, 1H), 3.65-3.60 (m, 2H), 3.20-3.15 (m, 2H).
To a solution of the compound prepared in Example 3 (537 mg) in ethanol (4 mL) was added tin chloride dihydrate (2.07 g) and the mixture was refluxed for 30 minutes. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. To methanol (2 mL) was added the obtained solid (137 mg) and then 4N hydrogen chloride in dioxane (0.26 mL) was added to the mixture, which was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was recrystallized from a mixture solvent (isopropanol:ethanol=4:1) to give the compound of the present invention (144 mg) having the following physical data. Moreover, the compound was converted to methanesulfonate thereof by conventional method.
Hydrochloride:
TLC: Rf 0.42 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.90-10.70 (br, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.40-7.36 (m, 3H), 4.25 (dd, J=10.2, 3.0 Hz, 1H), 3.58-3.49 (m, 1H), 3.14-3.06 (m, 1H), 2.96-2.82 (m, 2H), 2.77-2.67 (m, 1H), 2.34-2.30 (m, 1H).
Methanesulfonate:
TLC: Rf 0.36 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.84-10.48 (br, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.25-7.18 (m, 3H), 4.24 (dd, J=9.9, 3.3 Hz, 1H), 3.56-3.49 (m, 1H), 3.15-3.05 (m, 1H), 2.95-2.81 (m, 2H), 2.75-2.65 (m, 1H), 2.33-2.30 (m, 4H).
By the same procedure as described in Example 6, if necessary, by converting to corresponding salts by conventional method, using the compounds prepared in Example 4, 4(2), 4(3), 4(6), 4(7), 4(10), 4(12), 4(14), 4(13), 4(18), 4(19), 4(21), 4(23)-4(26), 4(28), 4(30) or 5 instead of the compound prepared in Example 3, the following compounds of the present invention were obtained.
TLC: Rf 0.44 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 10.65 (brs, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13-7.04 (m, 3H), 3.93 (m, 1H), 3.26 (d, J=13.2 Hz, 1H), 2.82 (m, 1H), 2.31 (s, 3H), 2.07 (m, 1H), 1.86 (m, 1H), 1.46 (m, 4H).
TLC: Rf 0.27 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 10.44 (s, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.57 (d, J=7.5 Hz, 1H), 6.53 (s, 1H), 6.47 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.19 (t, J=6.6 Hz, 1H), 3.62 (m, 1H), 3.03 (m, 1H), 2.84-2.80 (m, 2H), 2.66 (m, 1H), 2.31 (d, J=13.2 Hz, 1H).
TLC: Rf 0.39 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.87 (brs, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.26 (dd, J=10.6, 3.0 Hz, 1H), 3.66 (brd, J=14.1 Hz, 1H), 3.16-2.35 (m, 5H), 2.30 (s, 3H).
TLC: Rf 0.22 (methylene chloride:methanol=10:1);
NMR (CDCl3): δ 8.24 (brs, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 4.34 (dd, J=11.7, 2.7 Hz, 1H), 3.95 (brs, 2H), 3.72 (m, 1H), 3.13 (m, 1H), 3.08-2.92 (m, 2H), 2.80 (m, 1H), 2.21 (m, 1H).
Free Form:
TLC: Rf 0.31 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.81 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 6.56 (s, 1H), 6.50 (d, J=7.8 Hz, 1H), 6.21 (s, 1H), 5.28 (s, 2H), 3.62 (m, 2H), 3.14 (m, 2H).
Methanesulfonate:
TLC: Rf 0.48 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 10.93 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.19 (m, 3H), 6.26 (s, 1H), 3.60 (m, 2H), 3.15 (m, 2H), 2.33 (s, 3H).
TLC: Rf 0.44 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.47 (br-s, 1H), 7.04 (m, 1H), 6.62-6.52 (m, 3H), 5.21 (br-s, 2H), 4.25 (dd, J=6.9, 4.5 Hz, 1H), 3.52-3.42 (m, 1H), 3.14-2.96 (m, 3H), 2.76-2.60 (m, 2H), 1.82-1.56 (m, 2H).
TLC: Rf 0.56 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 10.81 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.72 (s, 1H), 6.63 (m, 2H), 5.25 (s, 2H), 4.50 (d, J=9.3 Hz, 1H), 4.41 (d, J=9.3 Hz, H), 4.16 (t, J=7.2 Hz, 1H), 3.36 (m, 2H).
TLC: Rf 0.44 (methylene chloride:methanol=10:1);
NMR (CDCl3): δ 8.01 (br, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.76-6.69 (m, 2H), 6.64 (t, J=1.8 Hz, 1H), 4.33 (dd, J=10.8, 3.0 Hz, 1H), 3.85 (dt, J=10.8, 3.0 Hz, 1H), 3.78 (br, 2H), 3.11 (m, 1H), 3.05 (m, 1H), 2.94 (dd, J=13.5, 10.8 Hz, 1H), 2.74 (m, 1H), 2.25 (m, 1H).
TLC: Rf 0.25 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 5.82 (t, J=1.8 Hz, 1H), 5.75 (d, J=1.8 Hz, 2H), 4.86 (brs, 4H), 4.15 (dd, J=9.3, 4.2 Hz, 1H), 3.72 (m, 1H), 3.00 (m, 1H), 2.84-2.50 (m, 3H), 2.32 (m, 1H).
TLC: Rf 0.40 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.61 (br-s, 1H), 7.42 (m, 1H), 7.29-7.16 (m, 3H), 4.45 (d, J=13.8 Hz, 1H), 4.21 (dd, J=12.0, 2.4 Hz, 1H), 4.11 (dd, J=13.8, 2.4 Hz, 1H), 3.21 (m, 1H), 2.88 (m, 1H), 2.32 (s, 3H), 2.08 (m, 1H), 1.78 (m, 1H).
TLC: Rf 0.38 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.88 (s, 1H), 8.30 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.09 (s, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.25 (s, 1H), 3.61 (m, 2H), 3.16 (m, 2H), 2.32 (s, 3H), 2.24 (s, 3H).
TLC: Rf 0.42 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 7.40-7.35 (m, 1H), 7.30-7.25 (m, 2H), 4.25 (dd, J=10.2, 3.6 Hz, 1H), 3.60-3.50 (m, 1H), 3.20-3.05 (m, 1H), 2.95-2.80 (m, 2H), 2.80-2.65 (m, 1H), 2.40-2.25 (m, 7H).
TLC: Rf 0.37 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.65 (brs, 1H), 6.55-6.40 (m, 3H), 4.21 (dd, J=10.2, 3.3 Hz, 1H), 3.64-3.54 (m, 1H), 3.14-3.02 (m, 1H), 2.94-2.78 (m, 2H), 2.76-2.64 (m, 1H), 2.40-2.30 (m, 4H).
TLC: Rf 0.40 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.43 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.51 (dd, J=8.1, 2.4 Hz, 1H), 6.45 (brs, 1H), 4.20-4.12 (m, 1H), 3.40-3.26 (m, 1H), 3.06-2.94 (m, 1H), 2.90-2.70 (m, 2H), 2.58-2.46 (m, 1H), 2.34-2.22 (m, 1H), 2.02 (s, 3H).
TLC: Rf 0.39 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.85 (brs, 1H), 7.40-7.32 (d, J=8.4 Hz, 2H), 7.12-7.05 (d, J=8.4 Hz, 2H), 6.24 (s, 1H), 3.64-3.58 (m, 2H), 3.20-3.12 (m, 2H), 2.34 (s, 3H).
TLC: Rf 0.41 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 7.35-7.27 (m, 2H), 7.20 (brs, 1H), 4.34-4.21 (m, 1H), 3.26-3.16 (m, 1H), 3.10-2.98 (m, 1H), 2.96-2.78 (m, 2H), 2.58-2.48 (m, 1H), 2.34 (s, 3H), 2.32-2.22 (m, 1H), 2.17 (s, 3H).
TLC: Rf 0.53 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.86 (s, 1H), 7.24-7.10 (m, 3H), 6.25 (s, 1H), 3.90 (s, 3H), 3.65-3.58 (m, 2H), 3.20-3.13 (m, 2H), 2.32 (s, 3H).
TLC: Rf 0.14 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.72 (s, 1H), 9.45 (brs, 1H), 6.66 (d, J=7.5 Hz, 1H), 6.60 (d, J=2.1 Hz, 1H), 6.42 (dd, J=7.5, 2.1 Hz, 1H), 6.19 (s, 1H), 4.70 (brs, 2H), 3.70-3.60 (m, 2H), 3.20-3.10 (m, 2H).
TLC: Rf 0.29 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.69 (s, 1H), 6.95 (dt, J=1.2, 7.2 Hz, 1H), 6.44-6.32 (m, 3H), 6.06 (s, 1H), 5.08 (s, 2H), 3.72-3.64 (m, 2H), 3.58 (s, 2H), 2.76-2.66 (m, 2H).
To a solution of the compound prepared in Example 4(16a) (76 mg) in methylene chloride (0.5 mL) was added boron tribromide (2 mL; 1.0 M in methylene chloride) at −40° C. and the mixture was stirred for 1.5 hours. To the reaction mixture was added sodium hydrogen carbonate (ca 1 g). The reaction mixture was allowed to return to room temperature slowly and then brine was added to the reaction mixture, which was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=19:1→9:1) to give the compound of the present invention (57 mg) having the following physical data.
TLC: Rf 0.37 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.69 (s, 1H), 8.30-8.27 (m, 2H), 7.99-7.96 (m, 1H), 7.76-7.71 (m, 1H), 5.21 (d, J=3.6 Hz, 1H), 4.22-4.13 (m, 2H), 3.40 (d, J=3.6 Hz, 2H), 2.17-2.12 (m, 2H).
To a solution of the compound prepared in Example 4(16b) (188 mg) in methylene chloride (2 mL) was added aluminum trichloride (153 mg) and the mixture was stirred at room temperature overnight. Moreover, aluminum trichloride (151 mg) was added to the reaction mixture, which was stirred at room temperature for 7 hours. Sodium hydrogen carbonate (ca 1 g), small amount of water and methanol were added, sequentially, to the reaction mixture, which was stirred for 30 minutes. The reaction mixture was filtrated through Celite. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=19:1→9:1→4:1). To methanol (1 mL) was added the obtained solid and thereto was added a solution of methanesulfonic acid (42 mg) in methanol (1 mL). The mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give the compound of the present invention (147 mg) having the following physical data.
TLC: Rf 0.17 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.90-10.62 (br, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.34-7.21 (m, 3H), 4.24-4.16 (m, 2H), 3.44 (dd, J=10.5, 2.4 Hz, 1H), 3.39 (dd, J=10.5, 4.8 Hz, 1H), 2.32 (s, 3H), 2.16-2.12 (m, 2H).
To a solution of 4-((3-chloromethylphenyl)carbonothioyl)thiomorpholine-3-carboxylic acid ethyl ester (131 mg, It was prepared by the same procedure as described in Reference example 2→Reference example 3, using 3-chloromethylbenzoyl chloride instead of 3-nitrobenzoyl chloride) in dimethylformamide (1.5 mL) was added phthalimide potassium salt (70 mg) and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with a mixed solvent (hexane:ethyl acetate=1:1). The extract was washed with water and brine sequentially, dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained solid in ethanol (2 mL) was added hydrazine monohydrate (92 μL) and the mixture was refluxed for 1 hour. After cooling the reaction mixture to room temperature, the precipitate was separated by filtration and the filtrate was concentrated. The precipitate and the residue were purified by column chromatography on silica gel (chloroform:methanol:water=8:2:0.2), respectively. To the obtained solid was added a solution of methanesulfonic acid in methanol (1M, 0.11 mL) and the mixture was concentrated. To the obtained residue was added ethyl acetate and the precipitate was separated by filtration. The precipitate was dried under reduced pressure to give the compound of the present invention (40 mg) having the following physical data.
TLC: Rf 0.11 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 10.59 (s, 1H), 8.14 (br, 3H), 7.60-7.40 (m, 41), 4.25 (t, J=6.6 Hz, 1H), 4.12-4.02 (m, 2H), 3.52 (m, 1H), 3.12 (m, 1H), 2.88-2.83 (m, 2H), 2.72 (m, 1H), 2.30 (m, 1H), 2.28 (s, 3H).
By the same procedure as described in Reference example 2→Example 6→Reference example 3→Example 3 using 3,4-dihydro-2H-1,4-thiazine-5-carboxylic acid ethyl ester instead of thiomorpholin-3-ylcarboxylic acid ethyl ester, and 3-nitro-4-fluorobenzoyl chloride instead of 3-nitrobenzoyl chloride, the compound of the present invention having the following physical data.
TLC: Rf 0.41 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.81 (s, 1H), 7.04 (dd, J=11.4, 7.8 Hz, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.55 (m, 1H), 6.22 (s, 1H), 5.34 (s, 2H), 3.61 (m, 2H), 3.12 (m, 2H).
Under an atmosphere of hydrogen, a mixture of 8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (100 mg; It was prepared by the same procedure as described in Reference example 1→Example 1 using furo[3,4-b]pyridine-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and phenylmagnesium chloride instead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride), platinum(IV)oxide (10 mg), 1N hydrochloric acid (0.5 mL) and dimethylformamide (5 mL) was stirred at room temperature for 6 hours. The reaction mixture was filtrated through Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to give the compound of the present invention (42 mg) having the following physical data. Moreover, the compound was converted to a corresponding salt thereof by conventional method.
Free Form:
TLC: Rf 0.43 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.11 (br-s, 1H), 7.52-7.40 (m, 5H), 5.72 (br-s, 1H), 3.13 (m, 2H), 2.39 (t, J=6.6 Hz, 2H), 1.72 (m, 2H).
Hydrochloride:
TLC: Rf 0.40 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.41 (brs, 1H), 7.52-7.40 (m, 5H), 5.88 (brs, 2H), 3.16 (t, J=5.4 Hz, 2H), 2.43 (t, J=6.3 Hz, 2H), 1.73 (tt, J=6.3, 5.4 Hz, 2H).
Methanesulfonate:
TLC: Rf 0.39 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.37 (s, 1H), 7.54-7.40 (m, 5H), 4.53 (brs, 2H), 3.22-3.08 (m, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.35 (s, 3H), 1.82-1.64 (m, 2H).
By the same procedure as described in Example 11, if necessary, by converting to corresponding salts by conventional method, using a corresponding derivative instead of 8-phenylpyrido[2,3-d]pyridazin-5(6H)-one, the following compounds of the present invention were obtained.
TLC: Rf 0.30 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 13.30 (s, 1H), 8.94 (br-s, 2H), 7.55-7.43 (m, 5H), 4.00 (s, 2H), 3.37 (t, J=6.0 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.30 (s, 3H).
TLC: Rf 0.29 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.93 (br-s, 1H), 7.52-7.40 (m, 5H), 3.61 (br-s, 2H), 2.79 (t, J=5.7 Hz, 2H), 2.32 (m, 2H).
TLC: Rf 0.49 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.51 (br-s, 1H), 7.50-7.36 (m, 5H), 6.69 (br-s, 1H), 3.27 (m, 2H), 2.39 (t, J=5.7 Hz, 2H), 1.67 (m, 2H).
Hydrochloride:
TLC: Rf 0.40 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 1.73 (m, 2H) 2.41 (t, J=6.04 Hz, 2H) 3.14 (m, 2H) 5.92 (br. s., 1H) 7.37 (m, 3H) 7.52 (m, 1H) 12.23 (br. s., 1H).
Dihydrochloride:
TLC: Rf 0.33 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.60 (brs, 1H), 7.64-7.42 (m, 4H), 6.07 (br, 4H), 3.24-3.08 (m, 2H), 2.44 (t, J=6.0 Hz, 2H), 1.84-1.64 (m, 2H).
After washing sodium hydride (103 mg; 62.6% in oil) with hexane, the mixture was suspended in dimethylformamide (1.5 mL). A solution of 8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (200 mg; It was prepared by the same procedure as described in Reference example 1→Example 1 using furo[3,4-b]pyridine-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and phenylmagnesium chloride instead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride) in dimethylformamide (5.7 mL) was added dropwise to the suspension at 0° C. The mixture was stirred at room temperature for 40 minutes. Methoxymethyl chloride (0.27 mL) was added dropwise to the reaction mixture, which was stirred at room temperature overnight. The reaction mixture was concentrated. The obtained residue was diluted in a mixed solvent of water and ethyl acetate. The mixture was poured in a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (269 mg) having the following physical data. The obtained compound was used in next reaction without purification.
TLC: Rf 0.78 (chloroform:methanol=8:1).
Under an atmosphere of argon, to platinum oxide (70 mg) was added dimethylformamide (1.0 mL). A solution of the compound prepared in Reference example 4 (269 mg) in dimethylformamide (8.0 mL) was added dropwise to the reaction mixture and 1N hydrochloric acid (0.9 mL) was added thereto. Under an atmosphere of hydrogen, the mixture was stirred at room temperature for 4 hours. Under an atmosphere of argon, the reaction mixture was filtrated through Celite. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=40:1→30:1) to give the title compound (224 mg) having the following physical data.
TLC: Rf 0.16 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 7.56-7.40 (m, 5H), 5.92 (brs, 1H), 5.23 (s, 2H), 3.29 (s, 3H), 3.20-3.06 (m, 2H), 2.43 (t, J=6.0 Hz, 2H), 1.84-1.64 (m, 2H).
After washing sodium hydride (141 mg; 62.6% in oil) with hexane, the mixture was suspended in dimethylformamide (1.0 mL). A solution of the compound prepared in Reference example 5 (200 mg) in dimethylformamide (6.4 mL) was added dropwise thereto at 0° C. and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.37 mL) was added dropwise to the reaction mixture, which was stirred at room temperature overnight. After adding water to the reaction mixture, it was poured in ice water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=100:1→50:1) to give the title compound (116 mg) having the following physical data.
TLC: Rf 0.23 (hexane:ethyl acetate=1:1).
6N hydrochloric acid (2.4 mL) was added dropwise to a solution of the compound prepared in Reference example 6 (110 mg) in methanol (1.2 mL), which was stirred at room temperature overnight. 6N hydrochloric acid (2.4 mL) was added dropwise to the reaction mixture, which was stirred at 110° C. overnight. After cooling the reaction mixture to room temperature, it was poured in cold water. After neutralizing with 5N sodium hydroxide solution, the solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate to give the compound of the present invention (39 mg) having the following physical data.
TLC: Rf 0.44 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.50 (s, 1H), 7.58-7.34 (m, 5H), 3.12-3.00 (m, 2H), 2.41 (t, J=6.0 Hz, 2H), 2.27 (s, 3H), 1.84-1.66 (m, 2H).
To a solution of 1-t-butoxycarbonylpiperidine-2-carboxylic acid (2.29 g) in methylene chloride (30 mL) were added N,O-dimethylhydroxyamine hydrochloride (1.17 g), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (4.87 g, BOP reagent) and triethylamine (4.88 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with ethyl acetate. The diluted solution was washed water, 1N hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous sodium sulfate and concentrated to give the title compound (2.59 g) having the following physical data.
TLC: Rf 0.54 (hexane:ethyl acetate=3:1);
NMR (CDCl3): δ 5.30-4.86 (m, 1H), 4.06-3.84 (m, 1H), 3.77 (br-s, 3H), 3.56-3.36 (m, 1H), 3.19 (s, 3H), 2.04-1.96 (m, 1H), 1.76-1.32 (m, 14H).
A solution of phenyllithium in cyclohexane-ether (1.06 M, 6.23 mL) was added dropwise to a solution of the compound prepared in Reference example 7 (1.63 g) in tetrahydrofuran (30 mL) at −25° C. and the mixture was stirred at −25° C. for 3 hours. The reaction mixture was poured in 1M sodium dihydrogen phosphate solution and extracted with ethyl acetate. The extract was washed with water and brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1) to give the title compound (850 mg) having the following physical data.
TLC: Rf 0.56 (hexane:ethyl acetate=4:1);
NMR (CDCl3): δ 7.96-7.84 (m, 2H), 7.66-7.40 (m, 3H), 5.70-5.44 (m, 1H), 4.04-3.86 (m, 1H), 3.30-3.08 (m, 1H), 2.20-1.98 (m, 1H), 1.92-1.76 (m, 1H), 1.74-1.20 (m, 13H).
To the compound prepared in Reference example 8 (270 mg) was added 4N hydrogen chloride-ethyl acetate solution (4 mL) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated to give the title compound (211 mg) having the following physical data.
TLC: Rf 0.48 (chloroform:methanol:acetic acid=40:10:1);
NMR (DMSO-d6): δ 9.02 (br-s, 2H), 8.05 (m, 2H), 7.75 (m, 1H), 7.61 (m, 2H), 5.09 (dd, J=12.0, 3.0 Hz, 1H), 2.97 (m, 1H), 2.09 (m, 1H), 1.82-1.58 (m, 4H), 1.44 (m, 1H).
The compound prepared in Reference example (199 mg) was separated with ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution and the water layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained powder was dissolved in toluene (10 mL). Thereto were added hydrazine carboxylic acid ethyl ester (184 mg) and p-toluenesulfonic acid monohydrate (8.4 mg) and the mixture was refluxed overnight. After cooling the reaction mixture to room temperature, it was diluted in ethyl acetate. The diluted solution was washed with 1N hydrochloric acid, water and brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→1:1). The more polar fraction was recrystallized from ethyl acetate to give the compound a (16.3 mg) having the following physical data. The less polar fraction was recrystallized from a mixed solution of ethyl acetate and hexane (1:1) to give the compound b (13.6 mg) having the following physical data.
Compound a:
TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.14 (s, 1H), 7.76-7.66 (m, 2H), 7.46-7.34 (m, 3H), 4.77 (dd, J=11.7, 2.7 Hz, 1H), 4.18 (m, 1H), 2.72 (m, 1H), 1.88-1.34 (m, 6H).
Compound b:
TLC: Rf 0.46 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.74 (s, 1H), 7.56-7.34 (m, 5H), 4.82 (t, J=4.5 Hz, 1H), 3.64 (m, 2H), 2.10 (m, 2H), 1.71 (m, 2H).
By the same procedure as described in Reference example 7→Reference example 8→Reference example 9→Example 13 using 3-t-butoxycarbonyl-1,3-thiazinane-4-carboxylic acid instead of 1-t-butoxycarbonylpiperidine-2-carboxylic acid, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.42 (s, 1H), 7.75-7.70 (m, 2H), 7.46-7.38 (m, 3H), 5.10 (dd, J=11.4, 2.7 Hz, 1H), 4.90 (dd, J=13.2, 2.7 Hz, 1H), 4.34 (d, J=13.2 Hz, 1H), 3.36 (m, 1H), 2.75 (m, 1H), 1.88-1.62 (m, 2H).
A solution of 3,4,5,6-tetrahydrophthalic acid anhydride (3.04 g) and (triphenylphosphoranylidene)acetic acid methyl ester (6.69 g) in chloroform (50.0 mL) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, it was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9→3:7) to give the title compound (1.93 g) having the following physical data.
TLC: Rf 0.71 (ethyl acetate:hexane=1:1);
NMR (CDCl3): δ 5.92 (s, 1H), 3.76 (s, 3H), 2.81 (m, 2H), 2.38 (m, 2H), 1.76 (m, 4H).
A solution of the compound prepared in Reference example 10 (1.04 g) and hydrazine monohydrate (250 mg) in ethanol (10.0 mL) was refluxed for 18 hours. After cooling the reaction mixture to room temperature, it was concentrated. The obtained crystal was washed with ethanol and ethyl acetate, and dried under reduced pressure to give the compound of the present invention (672 mg) having the following physical data.
TLC: Rf 0.45 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.66 (brs, 1H), 3.65 (s, 2H), 3.63 (s, 3H), 2.38 (m, 4H), 1.64 (m, 4H).
By the same procedure as described in Reference example 10→Example 15 using 2-(triphenylphosphoranylidene)propanoic acid ethyl ester instead of (triphenylphosphoranylidene)acetic acid methyl ester, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.56 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.67 (brs, 1H), 4.07 (q, J=6.9 Hz, 2H), 3.91 (q, J=6.9 Hz, 1H), 2.48-2:33 (m, 4H), 1.65 (m, 4H), 1.33 (d, J=6.9 Hz, 3H), 1.13 (t, J=6.9 Hz, 3H).
5N sodium hydroxide solution (1.72 mL) was added dropwise to a suspension of the compound prepared in Example 15 (635 mg) in methanol (10.0 mL) in ice bath and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrate. 2N hydrochloric acid was added to the residue, which was adjusted to pH 2. The deposited crystal was collected by filtration. It was washed with hexane and dried under reduced pressure to give the title compound (478 mg) having the following physical data.
TLC: Rf 0.62 (methanol:methylene chloride:acetic acid=2:8:0.1);
NMR (DMSO-d6): δ 12.62 (brs, 2H), 3.54 (s, 2H), 2.39 (m, 4H), 1.64 (m, 4H).
By the same procedure as described in Reference example 11 using the compound prepared in Example 16 instead of the compound prepared in Example 15, the title compound having the following physical data was obtained.
TLC: Rf 0.28 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.64 (s, 1H), 12.48 (brs, 1H), 3.81 (q, J=7.5 Hz, 1H), 2.48-2.37 (m, 4H), 1.65 (brs, 4H), 1.32 (d, J=7.5 Hz, 3H).
By the same procedure as described in Reference example 10→Example 15→Example 11, if necessary, by converting to corresponding salts by conventional method, using a corresponding derivative instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and (triphenylphosphoranylidene)acetic acid ethyl ester instead of (triphenylphosphoranylidene)acetic acid methyl ester, the following compounds of the present invention were obtained.
TLC: Rf 0.46 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 11.88 (br-s, 1H), 6.32 (br-s, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 3.15 (m, 2H), 2.33 (t, J=6.3 Hz, 2H), 1.69 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).
TLC: Rf 0.48 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.60 (br-s, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.75 (br-s, 2H), 3.28 (m, 2H), 2.45 (m, 2H), 1.77 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).
The compound prepared in Example 15 (350 mg) was dissolved in tetrahydrofuran (8.0 mL). Under an atmosphere of argon, sodium borohydride (239 mg) was added thereto at 0° C. and the mixture was refluxed for 13 hours. After cooling to 0° C., 1N hydrochloric acid was added to the reaction mixture, which was adjusted to pH 5. The deposited solid was collected by filtration. The filtrate was concentrated and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated to give the title compound having the following physical data.
TLC: Rf 0.32 (chloroform:methanol=9:1);
NMR (CD3OD): δ 3.87 (t, J=6.6 Hz, 2H), 2.80 (t, J=6.6 Hz, 2H), 2.64-2.58 (m, 2H), 2.54-2.48 (m, 2H), 1.88-1.70 (m, 4H).
To a solution of the compound prepared in Reference example 12 g (2.47 g) and pyridine (201 mg) in methylene chloride (60 mL) was added thionyl chloride (2.25 g) and the mixture was stirred at room temperature for 20 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, which was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to give the title compound (2.58 g) having the following physical data.
TLC: Rf 0.52 (chloroform:methanol=9:1);
NMR (CD3OD): δ 3.88 (t, J=7.2 Hz, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.60-2.50 (m, 4H), 1.85-1.70 (m, 4H).
A solution of the compound prepared in Reference example 13 (106 mg), trimethylsilylazide (86.4 mg) and tetrabutylammonium fluoride (237 mg) in tetrahydrofuran (2.00 mL) was refluxed for 24 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give the title compound (85.0 mg) having the following physical data.
TLC: Rf 0.52 (ethyl acetate:hexane=4:1);
NMR (DMSO-d6): δ 12.62 (brs, 1H), 3.63 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H), 2.48-2.37 (m, 4H), 1.67 (m, 4H).
Under an atmosphere of hydrogen, a suspension of the compound prepared in Reference example 14 (50.0 mg) and 5% palladium on calcium carbonate (20.0 mg) in ethanol (3.0 mL) was stirred at room temperature for 6 hours. The reaction mixture was filtrated through Celite. The filtrate was concentrated. 4N hydrogen chloride-ethyl acetate solution (0.5 mL) was added dropwise to a solution of the obtained solid (44.0 mg) in methanol (3.0 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from a mixed solvent of methanol and ethyl acetate to give the title compound (45.9 mg) having the following physical data.
TLC: Rf 0.39 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.1);
NMR (DMSO-d6): δ 12.65 (s, 1H), 8.07 (brs, 3H), 3.07 (m, 2H), 2.83 (t, J=7.2 Hz, 2H), 2.44 (m, 2H), 2.38 (m, 2H), 1.66 (m, 4H).
To a suspension of the compound prepared in Reference example 13 (500 mg) in tetrahydrofuran (12 mL) were added trimethylsilyl cyanide (0.94 mL) and tetrabutylammonium fluoride (1.84 g) and the mixture was stirred at 80° C. overnight. After cooling to room temperature, the reaction mixture was poured in a cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=20:1). The obtained solid was washed with t-butyl methyl ether to give the title compound (249 mg) having the following physical data.
TLC: Rf 0.52 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.66 (s, 1H), 2.94-2.72 (m, 4H), 2.60-2.26 (m, 4H), 1.78-1.54 (m, 4H).
To a suspension of the compound prepared in Reference example 16 (130 mg) in ethanol (3.2 mL) was added 5N sodium hydroxide solution (0.64 mL) and the mixture was stirred at 90° C. for 1 day. After cooling to 0° C., the reaction mixture was poured in cold water and washed with ethyl acetate. The water layer was neutralized with 2N hydrochloric acid and concentrated. The residue was washed with water. The solid was washed water and ether to give the title compound (131 mg) having the following physical data.
TLC: Rf 0.36 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.51 (s, 1H), 12.08 (brs, 1H), 2.71 (t, J=6.9 Hz, 2H), 2.56 (t, J=6.9 Hz, 2H), 2.54-2.26 (m, 4H), 1.78-1.54 (m, 4H).
To a suspension of the compound prepared in Example 1 (100 mg) in methylene chloride (1.5 mL) and dimethylformamide (1.5 mL) was added sulfur trioxide pyridine complex (144 mg) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was washed with ethyl acetate to give the compound of the present invention (160 mg) having the following physical data.
TLC: Rf 0.17 (chloroform:methanol=4:1);
NMR (CD3OD): δ 8.90-8.78 (m, 2H), 8.59 (dddd, J=7.8, 7.8, 1.5, 1.5 Hz, 1H), 8.12-7.98 (m, 2H), 7.48-7.14 (m, 3H), 6.89 (m, 1H), 2.66-2.52 (m, 2H), 2.52-2.38 (m, 2H), 1.90-1.60 (m, 4H).
To a solution of the compound prepared in Example 4(20) (127 mg) in dimethylformamide (3 mL) were added sodium hydrosulfide (215 mg) and magnesium chloride hexahydrate (474 mg) and the mixture was stirred at room temperature for 3 hours under an atmosphere of argon. To the reaction mixture was added ethyl acetate and the precipitate was separated by filtration. The filtrate was wash with water and brine sequentially, dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained solid (277 mg) in acetone (2 mL) was added methyl iodide (0.15 mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. To the residue were added methanol (2 mL) and ammonium acetate (43 mg) and the mixture was refluxed for 2 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol:water=9:1:0.1→8:2:0.2). The obtained solid was washed with a mixed solvent of methanol, ethyl acetate and hexane and converted to methanesulfonate thereof by conventional method to give the compound of the present invention (149 mg) having the following physical data.
TLC: Rf 0.22 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 10.68 (s, 1H), 9.36 (s, 2H), 9.02 (s, 2H), 7.86 (d, J=7.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.69 (t, J=7.8 Hz, 1H), 4.26 (dd, J=8.7, 4.8 Hz, 1H), 3.50 (m, 1H), 3.16 (m, 1H), 2.95-2.84 (m, 2H), 2.71 (m, 1H), 2.366 and 2.362 (s, 3H), 2.30 (d, J=13.8 Hz, 1H).
To a solution of the compound prepared in Example 4(4) (175 mg) in methylene chloride (1.3 mL) was added boron tribromide (1.3 mL; 1.0 M in methylene chloride) in ice bath and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added boron tribromide (1.3 mL; 1.0 M in methylene chloride) and the mixture was stirred at room temperature overnight. Methanol was added to the reaction mixture, which was concentrated. The residue was washed with methylene chloride. Water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile to give the compound of the present invention (73 mg) having the following physical data.
TLC: Rf 0.43 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.47 (s, 1H), 9.67 (bs, 1H), 7.20 (t, J=7.8 Hz, 1H), 6.81-6.73 (m, 3H), 4.19 (dd, J=9.3, 3.9 Hz, 1H), 3.56 (dt, J=14.1, 3.0 Hz, 1H), 3.09-2.99 (m, 1H), 2.90-2.79 (m, 2H) 2.69-2.60 (m, 1H), 2.33-2.28 (m, 1H).
By the same procedure as described in Example 20 using the compound prepared in Example 4(5) or 4(27) instead of the compound prepared in Example 4(4), the following compounds of the present invention were obtained.
TLC: Rf 0.32 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 9.74 (brs, 1H), 7.24-7.14 (m, 2H), 6.84-6.74 (m, 2H), 4.18 (dd, J=8.1, 5.1 Hz, 1H), 3.60 (dt, J=14.1, 2.7 Hz, 1H), 3.05 (m, 1H), 2.92-2.78 (m, 2H), 2.68 (m, 1H), 2.31 (m, 1H).
TLC: Rf 0.40 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.83 (s, 1H), 9.70 (s, 1H), 7.24 (t, J=7.8 Hz, 1H), 6.88-6.75 (m, 3H), 6.22 (s, 1H), 3.66-3.56 (m, 2H), 3.16-3.06 (m, 2H).
To a suspension of the compound prepared in Example 1 (60 mg) in ethanol (2.5 mL) was added 2-naphthylmethylethanimidothioate (74 mg) and the mixture was stirred at room temperature for 4 hours. Methanol (1.5 mL) and 2-naphthylmethylethanimidothioate (222 mg) were added to the reaction mixture, which was stirred at 75° C. overnight. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=20:1→6:1) to give the compound of the present invention (84 mg) having the following physical data.
TLC: Rf 0.24 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.97 (s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.50 (m, 1H), 7.44-7.34 (m, 2H), 2.54-2.32 (m, 4H), 2.34 (s, 3H), 1.80-1.50 (m, 4H).
By the same procedure as described in Example 21 using the compound prepared in Example 6, 6(5) or 11(4) instead of the compound prepared in Example 1, the following compounds of the present invention were obtained.
TLC: Rf 0.25 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 11.13 (br, 1H), 10.60 (s, 1H), 9.43 (br, 1H), 8.56 (br, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, if), 7.38 (d, J=7.8 Hz, 1H), 7.36 (s, 1H), 4.24 (dd, J=9.6, 3.9 Hz, 1H), 3.63 (d, J=13.8 Hz, 1H), 3.10 (d, J=12.0 Hz, 1H), 2.96-2.82 (m, 2H), 2.72 (m, 1H), 2.32 (s, 3H), 2.29 (m, 1H).
TLC: Rf 0.24 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 10.95 (s, 1H), 9.30 (br, 1H), 8.87 (br, 1H), 8.35 (br, 1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.42-7.36 (m, 2H), 6.28 (s, 1H), 3.72-3.64 (m, 2H), 3.20-3.12 (m, 2H), 2.30(brs, 3H).
TLC: Rf 0.14 (chloroform:methanol=4:1).
To a suspension of the compound prepared in Example 6(5) (100 mg) in methanol (1.1 mL) were added a solution of sodium methylate in methanol (0.5 mL; 28% solution) and paraformaldehyde (32 mg) and the mixture was stirred at room temperature for 3 hours. Methanol (1.1 mL) and sodium borohydride (22 mg) were added to the reaction mixture, which was stirred at 75° C. for 1 hour. After cooling to room temperature, water was added to the reaction mixture, which was poured in cold water. The solution was concentrated. The residue was washed with a mixed solvent of methanol and methylene chloride and filtrated through Celite. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=15:1) to give the compound of the present invention (15 mg) having the following physical data.
TLC: Rf 0.44 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 10.80 (s, 1H), 7.15 (dd, J=7.5, 7.5 Hz, 1H), 6.66-6.46 (m, 3H), 6.21 (s, 1H), 5.86 (q, J=4.8 Hz, 1H), 3.68-3.56 (m, 2H), 3.20-3.06 (m, 2H), 2.67 (d, J=4.8 Hz, 3H).
The mixture of the compound prepared in Reference example 11 (183 mg), triethylamine (178 mg), N-(2-aminoethyl)carbamic acid t-butyl ester (160 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (338 mg), 1-hydroxybenzotriazol (238 mg) and dimethylformamide (3.00 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. To the residue was added water and the deposited crystal was collected by filtration. It was washed with ethyl acetate and dried under reduced pressure to give the compound of the present invention (189 mg) having the following physical data.
TLC: Rf 0.50 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 8.01 (brs, 1H), 6.77 (brs, 1H), 3.39 (s, 2H), 3.08-2.95 (m, 4H), 2.38 (m, 4H), 2.25 (m, 4H), 1.37 (s, 9H).
By the same procedure as described in Example 23, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 11 or a corresponding carboxylic acid derivative, and N-(2-aminoethyl)carbamic acid t-butyl ester or a corresponding derivative, the following compounds of the present invention were obtained.
TLC: Rf 0.37 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.60 (brs, 1H), 11.06 (brs, 1H), 8.45 (t, J=5.7 Hz, 1H), 3.95-3.77 (m, 4H), 3.47 (s, 2H), 3.43 (m, 4H), 3.18-3.02 (m, 4H), 2.37 (m, 4H), 1.64 (brs, 4H).
Free Form:
TLC: Rf 0.60 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.1);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 7.94 (brt, J=6.2 Hz, 1H), 3.40 (s, 2H), 3.13 (td, J=6.2, 6.2 Hz, 2H), 2.43 (brs, 2H), 2.36 (brs, 2H), 2.26 (t, J=6.2 Hz, 2H), 2.12 (s, 6H), 1.63 (brs, 4H).
Hydrochloride:
TLC: Rf 0.69 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 10.22 (brs, 1H), 8.39 (t, J=5.7 Hz, 1H), 3.41-2.98 (m, 4H), 2.24 (m, 8H), 2.48-2.36 (m, 4H), 1.64 (brs, 4H).
NMR (DMSO-d6): δ 12.56 (s, 1H), 7.97 (t, J=5.1 Hz, 1H), 6.75 (m, 1H), 3.39 (s, 2H), 3.02 (q, J=6, 6 Hz, 2H), 2.90 (q, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H), 1.68-1.58 (m, 4H), 1.55-1.44 (m, 2H), 1.36 (s, 9H).
TLC: Rf 0.59 (chloroform:methanol:water=8:2:0.2);
NMR (CDCl3): δ 10.69 (br, 1H), 6.88 (br, 1H), 3.49 (s, 2H), 3.45-3.32 (m, 4H), 2.86 (s, 3H), 2.60-2.48 (m, 4H), 1.90-1.80 (m, 4H), 1.45 (s, 9H).
TLC: Rf 0.24 (ethyl acetate:acetic acid:water=3:3:1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 10.46 (br, 1H), 8.39 (m, 1H), 3.61-3.50 (m, 2H), 3.47 (s, 2H), 3.40 (q, J=6.0 Hz, 2H), 3.17 (q, J=6.0 Hz, 2H), 3.04-2.90 (m, 2H), 2.50-2.34 (m, 4H), 2.04-1.90 (m, 2H), 1.90-1.80 (m, 2H), 1.70-1.60 (m, 4H).
TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.66 (s, 1H), 4.80 (t, J=5.1 Hz, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.66 (s, 2H), 3.55 (q, J=5.1 Hz, 2H), 2.45-2.34 (m, 4H), 1.70-1.60 (m, 4H).
TLC: Rf 0.12 (chloroform:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.60 (s, 1H), 10.43 (br, 1H), 8.28 (m, 1H), 3.42 (s, 2H), 3.11 (q, J=6.0 Hz, 2H), 3.04-2.96 (m, 2H), 2.71 (s, 3H), 2.69 (s, 3H), 2.46-2.34 (m, 4H), 1.84-1.74 (m, 2H), 1.68-1.48 (m, 4H).
TLC: Rf 0.82 (chloroform:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 14.64 (br, 1H), 12.60 (s, 1H), 9.17 (m, 1H), 8.39 (m, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 4.22 (t, J=6.6 Hz, 2H), 3.44 (s, 2H), 3.03 (q, J=6.6 Hz, 2H), 2.46-2.32 (m, 4H), 1.93(quin, J=6.6 Hz, 2H), 1.68-1.46 (m, 4H).
TLC: Rf 0.44 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.60 (s, 1H), 7.93 (t, J=5.1 Hz, 1H), 6.74 (brs, 1H), 3.66 (q, J=7.2 Hz, 1H), 3.05 (m, 2H), 2.96 (m, 2H), 2.48-2.30 (m, 4H), 1.63 (m, 4H), 1.36 (s, 9H), 1.30 (d, J=7.2 Hz, 3H).
TLC: Rf 0.59 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.61 (s, 1H), 10.42 (brs, 1H), 8.56 (m, 1H), 3.58-2.96 (m, 9H), 2.42-2.36 (m, 4H), 2.08-1.64 (m, 8H), 1.24 (t, J=6.9 Hz, 3H).
TLC: Rf 0.48 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.00 (brt, 1H), 3.64-3.48 (m, 4H), 3.46-3.18 (m, 6H), 3.14-2.96 (m, 2H), 2.50-2.14 (m, 6H), 1.74-1.44 (m, 6H).
TLC: Rf 0.25 (chloroform:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.59 (s, 1H), 10.59 (br, 1H), 8.25 (br, 1H), 3.52-3.38 (m, 4H), 3.17-3.00 (m, 4H), 2.98-2.84 (m, 2H), 2.46-2.32 (m, 4H), 2.00-1.75 (m, 6H), 1.69-1.58 (m, 4H).
TLC: Rf 0.47 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.67 (s, 1H), 11.31 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.43 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.7, 4.8 Hz, 1H), 3.78 (s, 2H), 2.48-2.39 (m, 4H), 1.65 (brs, 4H).
TLC: Rf 0.53 (chloroform:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.60 (s, 1H), 10.30 (br, 1H), 8.44 (br, 1H), 3.50-3.34 (m, 2H), 3.31 (s, 2H), 3.10-2.96 (br, 2H), 2.90-2.72 (br, 2H), 2.48-2.32 (m, 4H), 1.80-1.68 (br, 4H), 1.68-1.56 (br, 6H), 1.50-1.40 (br, 2H).
TLC: Rf 0.26 (chloroform:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.60 (s, 1H), 10.40 (br, 1H), 8.32 (br, 1H), 3.48 (s, 2H), 3.42-3.12 (m, 3H), 2.58 (s, 6H), 2.46-2.32 (m, 4H), 1.68-1.58 (m, 4H), 1.12 (d, J=6.0 Hz, 3H).
NMR (CD3OD): δ 8.12 (br, 1H), 6.59 (br, 1H), 3.54 (s, 2H), 3.23-3.15 (m, 2H), 3.08-2.98 (m, 2H), 2.56-2.47 (m, 4H), 1.82-1.74 (m, 4H), 1.56-1.46 (m, 4H), 1.42 (s, 9H).
TLC: Rf 0.51 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.64 (s, 1H), 11.08 (s, 1H), 8.33 (m, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.87 (m, 1H), 7.18 (m, 1H), 3.77 (s, 2H), 2.45-2.38 (m, 4H), 1.65 (brs, 4H).
Free Form:
TLC: Rf 0.51 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.66 (s, 1H), 4.13 (t, J=5.7 Hz, 2H), 3.64 (s, 2H), 2.44 (t, J=5.7 Hz, 2H), 2.44-2.35 (m, 4H), 2.12(s, 6H), 1.72-1.58 (m, 4H).
Hydrochloride:
TLC: Rf 0.51 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.70 (s, 1H), 10.72 (br, 1H), 4.44-4.36 (m, 2H), 3.74 (s, 2H), 3.40-3.32 (m, 2H), 2.75 (s, 6H), 2.46-2.32 (m, 4H), 1.72-1.60 (m, 4H).
TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.11 (m, 1H), 6.69 (d, J=1.2 Hz, 2H), 5.96 (d, J=1,2 Hz, 2H), 3.92 (t, J=6.0 Hz, 2H), 3.38 (s, 2H), 3.35 (t, J=6.0 Hz, 2H), 2.40-2.24 (m, 4H), 1.68-1.58 (m, 4H).
TLC: Rf 0.56 (chloroform:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.56 (s, 1H), 8.10 (m, 1H), 7.73 (br, 1H), 6.86 (s, 1H), 3.39 (s, 2H), 3.34-3.23 (m, 2H), 2.74-2.62 (m, 2H), 2.40-2.30 (m, 4H), 1.66-1.56 (m, 4H).
TLC: Rf 0.38 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.59 (s, 1H), 7.93 (t, J=5.7 Hz, 1H), 6.77 (m, 1H), 3.66 (q, J=7.0 Hz, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.48-2.26 (m, 4H), 1.63 (brs, 4H), 1.42-1.28 (m, 16H).
TLC: Rf 0.85 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.60 (s, 1H), 8.62 (t, J=6.0 Hz, 1H), 8.49 (m, 1H), 7.75 (dt, J=7.5, 1.8 Hz, 1H), 7.29 (m, 1H), 7.25 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.51 (s, 2H), 2.48-2.34 (m, 4H), 1.70-1.58 (m, 4H).
TLC: Rf 0.64 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.32 (m, 1H) 3.52-3.44 (m, 2H), 3.43 (s, 2H), 3.42-3.33 (m, 2H), 2.48-2.33 (m, 4H), 2.70-1.60 (m, 4H).
TLC: Rf 0.60 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 8.10 (t, J=6.0 Hz, 1H), 3.51 (t, J=6.0 Hz, 2H), 3.40 (s, 2H), 3.15 (q, J=6.0 Hz, 2H), 2.45-2.33 (m, 4H), 1.93(quin, J=6.0 Hz, 2H), 1.68-1.59 (m, 4H).
NMR (DMSO-d6): δ 12.56 (s, 1H), 7.99 (t, J=6.0 Hz, 1H), 6.75 (t, J=6.0 Hz, 1H), 3.38 (s, 2H), 3.10 (q, J=6.0 Hz, 2H), 2.86 (q, J=6.0 Hz, 2H), 2.45-2.33 (m, 4H), 1.69-1.62 (m, 4H), 1.44-1.29 (m, 4H), 1.36 (s, 9H), 1.28-1.18 (m, 2H).
TLC: Rf 0.57 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.65 (brs, 1H), 12.12 (brs, 1H), 7.12 (s, 1H), 3.73 (s, 2H), 2.39 (m, 4H), 2.32 (s, 3H), 1.65 (brs, 4H).
TLC: Rf 0.11 (methylene chloride:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.59 (s, 1H), 10.92 and 10.51 (br, 1H), 3.68 and 3.66 (s, 2H), 3.43 and 3.36 (t, J=6.6 Hz, 2H), 3.80-2.90 (m, 2H), 3.01 and 2.82 (s, 3H), 2.73 and 2.71 and 2.69 (s, 6H), 2.42-2.32 (m, 4H), 2.02-1.82 (m, 2H), 1.67-1.58 (m, 4H).
TLC: Rf 0.21 (methylene chloride:methanol:water=7:3:0.3);
NMR (DMSO-d6): δ 12.59 (s, 1H), 10.69 and 9.93 (br, 1H), 3.75 and 3.68 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20 (q, J=6.0 Hz, 2H), 3.04 and 2.84 (s, 3H), 2.79 and 2.77 and 2.76 (s, 6H), 2.42-2.33 (m, 4H), 1.68-1.60 (m, 4H).
TLC: Rf 0.65 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 8.02 (t, J=6.3 Hz, 1H), 3.52 (t, J=6.3 Hz, 2H), 3.39 (s, 2H), 3.06 (q, J=6.3 Hz, 2H), 2.45-2.33 (m, 4H), 1.82-1.73 (m, 2H), 1.67-1.58 (m, 4H), 1.58-1.48 (m, 2H).
NMR (CD3OD): δ 4.15 (t, J=5.7 Hz, 1H), 3.71 (m, 2H), 3.54 (t, J=5.7 Hz, 2H), 3.29 (t, J=5.7 Hz, 1H), 3.14 (t, J=5.7 Hz, 1H), 2.56-2.47 (m, 4H), 1.91-1.84 (m, 4H), 1.43 (s, 9H).
NMR (DMSO-d6): δ 12.73 (brs, 1H), 12.67 (s, 1H), 3.88 (s, 2H), 3.80 (s, 2H), 2.38 (brs, 4H), 1.65 (brs, 4H).
TLC: Rf 0.49 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.52 (brs, 1H), 11.03 (brs, 1H), 4.00 (s, 2H), 3.58 (s, 2H), 2.90 (s, 3H), 2.41 (m, 4H), 1.63 (brs, 4H).
TLC: Rf 0.66 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.50 (s, 1H), 7.87 (brt, 1H), 6.78 (brt, 1H), 3.12-2.84 (m, 4H), 2.78-2.62 (m, 2H), 2.56-2.26 (m, 6H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).
TLC: Rf 0.79 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.39 (t, J=5.7 Hz, 1H), 3.43 (s, 2H), 3.32-3.23 (m, 2H), 2.64 (t, J=6.3 Hz, 2H), 2.45-2.33 (m, 4H), 1.68-1.60 (m, 4H).
TLC: Rf 0.75 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.57(s 1H), 8.03 (m, 1H), 7.60 (s, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 3.94 (t, J=6.6 Hz, 2H), 3.38 (s, 2H), 3.05 (q, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H), 1.74-1.60 (m, 6H), 1.31(quin, J=6.6 Hz, 2H).
TLC: Rf 0.83 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57(s 1H), 8.13 (m, 1H), 3.58 (s, 3H), 3.38 (s, 2H), 3.32-3.24 (m, 2H), 2.50-2.43 (m, 2H), 2.42-2.32 (m, 4H), 1.68-1.60 (m, 4H).
TLC: Rf 0.81 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.56 (s, 1H), 3.68 and 3.60 (m, 2H), 3.63 and 3.31 (s, 2H), 3.45 and 3.41 (t, J=6.3 Hz, 2H), 3.02 and 2.81 (s, 3H), 2.41-2.33 (m, 4H), 2.01 and 1.90 (m, 2H), 1.70-1.60 (m, 4H).
A mixture of the compound prepared in Example 15 (222 mg) and 2-aminoethanol (305 mg) was stirred at 100° C. for 1 hour. After cooling the reaction mixture to room temperature, the deposited crystal was washed with ethyl acetate. The obtained crystal was recrystallized from a mixed solvent methanol and ethyl acetate to give the compound of the present invention (190 mg) having the following physical data.
TLC: Rf 0.23 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.55 (brs, 1H), 8.03 (t, J=5.4 Hz, 1H), 4.66 (t, J=5.4 Hz, 1H), 3.41 (s, 2H), 3.38 (m, 2H), 3.11 (m, 2H), 2.42 (brs, 2H), 2.36 (brs, 2H), 1.63 (brs, 4H).
By the same procedure as described in Example 24, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 15 or a corresponding ester derivative, and a corresponding derivative instead of 2-aminoethanol, the following compounds of the present invention were obtained.
TLC: Rf 0.36 (chloroform:methanol:28% ammonia water=15:5:1);
NMR (DMSO-d6): δ 12.32 (br-s, 1H), 8.41 (t, J=5.4 Hz, 1H), 8.06 (br-s, 3H), 3.49 (s, 2H), 3.30 (m, 2H), 3.20 (m, 2H), 2.86 (m, 2H), 2.38 (t, J=6.0 Hz, 2H), 1.70 (m, 2H).
TLC: Rf 0.53 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.11 (t, J=5.4 Hz, 1H), 3.41 (s, 2H), 3.32 (m, 2H), 3.23 (s, 3H), 3.19 (m, 2H), 2.41-2.36 (m, 4H), 1.63 (brs, 4H).
TLC: Rf 0.35 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 7.85 (t, J=5.4 Hz, 1H), 3.39 (s, 2H), 3.09 (q, J=6.6 Hz, 2H), 2.48-2.32 (m, 10H), 1.67-1.58 (m, 4H), 0.91 (t, J=7.2 Hz, 6H).
TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.56 (s, 1H), 8.00 (t, J=6.9 Hz, 1H), 3.39 (s, 2H), 2.99 (q, J=6.9 Hz, 2H), 2.46-2.32 (m, 4H), 1.68-1.58 (m, 4H), 1.39(sextet, J=6.9 Hz, 2H), 0.83 (t, J=6.9 Hz, 3H).
TLC: Rf 0.68 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.54 (brs, 1H), 8.00 (t, J=5.6 Hz, 1H), 4.37 (t, J=5.1 Hz, 1H), 3.38 (s, 2H), 3.36 (m, 2H), 3.02 (m, 2H), 2.42-2.36 (m, 4H), 1.63 (brs, 4H), 1.38 (m, 4H).
TLC: Rf 0.37 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.51 (t, J=5.4 Hz, 1H), 7.56 (m, 1H), 6.38 (m, 1H), 6.22 (m, 1H), 4.25 (d, J=5.4 Hz, 2H), 3.44 (s, 2H), 2.37 (m, 4H), 1.62 (brs, 4H).
TLC: Rf 0.21 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.2);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.92 (m, 1H), 8.63 (m, 1H), 8.19 (t, J=5.4 Hz, 1H), 3.42 (s, 2H), 3.21 (m, 2H), 2.97-2.72 (m, 4H), 2.38 (m, 4H), 1.76-1.26 (m, 9H).
TLC: Rf 0.45 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.10 (t, J=5.7 Hz, 1H), 3.85-3.56 (m, 3H), 3.42 (s, 2H), 3.18-3.04 (m, 2H), 2.41-2.36 (m, 4H), 1.90-1.42 (m, 8H).
TLC: Rf 0.20 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.60 (brs, 1H), 7.80 (t, J=5.7 Hz, 1H), 3.69 (q, J=6.9 Hz, 1H), 3.20-3.05 (m, 2H), 2.48-2.25 (m, 10H), 1.65-1.34 (m, 10H), 1.30 (d, J=6.9 Hz, 3H).
TLC: Rf 0.37 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.53 (brs, 1H), 8.44 (d, J=6.3 Hz, 2H), 8.10 (t, J=5.7 Hz, 1H), 7.22 (d, J=6.3 Hz, 2H), 3.35 (m, 4H), 2.84-2.63 (m, 2H), 2.34-2.27 (m, 4H), 1.59 (brs, 4H).
TLC: Rf 0.36 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.48 (d, J=3.9 Hz, 1H), 8.09 (t, J=5.4 Hz, 1H), 7.70 (m, 1H), 7.23 (m, 2H), 3.42 (td, J=6.9, 5.4 Hz, 2H), 3.36 (s, 2H), 2.87 (t, J=6.9 Hz, 2H), 2.33 (m, 4H), 1.60 (brs, 4H).
TLC: Rf 0.24 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.61 (s, 1H), 7.89 (t, J=6.0 Hz, 1H), 3.44 (s, 2H), 2.95 (d, J=6.0 Hz, 2H), 2.43 (m, 2H), 2.36 (m, 2H), 2.15 (s, 6H), 2.05 (s, 2H), 1.63 (brs, 4H), 0.78 (s, 6H).
TLC: Rf 0.27 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.57 (br, 1H), 7.96 (m, 1H), 3.40 (s, 2H), 3.09 (q, J=6.0 Hz, 2H), 2.66 (m, 1H), 2.58-2.48 (m, 2H), 2.45-2.32 (m, 4H), 1.68-1.59 (m, 4H), 0.93 (d, J=6.0 Hz, 6H).
TLC: Rf 0.22 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.53 (br, 1H), 7.96 (m, 1H), 3.40 (s, 2H), 3.10 (q, J=6.0 Hz, 2H), 2.57-2.45 (m, 4H), 2.45-2.34 (m, 4H), 1.68-1.58 (m, 4H), 0.97 (t, J=6.9 Hz, 3H).
TLC: Rf 0.20 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 8.01 (t, J=6.9 Hz, 1H), 3.38 (s, 2H), 3.07 (q, J=6.9 Hz, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.45-2.33 (m, 4H), 2.21 (s, 3H), 1.70-1.60 (m, 4H), 1.52 (quin, J=6.9 Hz, 2H).
TLC: Rf 0.47 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.40 (m, 2H), 8.10 (t, J=5.7 Hz, 1H), 7.61 (m, 1H), 7.30 (m, 1H), 3.36 (s, 2H), 3.31 (m, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.31 (m, 4H), 1.60 (brs, 4H).
Free Form:
TLC: Rf 0.38 (methanol:methylene chloride=1:10);
NMR (CD3OD): δ 7.36 (m, 5H), 3.76 (m, 1H), 3.69 (s, 2H), 3.59 (s, 2H), 3.01 (m, 2H), 2.56 (brs, 4H), 2.33 (m, 2H), 1.97-1.61 (m, 8H).
Hydrochloride:
TLC: Rf 0.49 (methanol:methylene chloride:saturated aqueous ammonia=1:9:0.1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 10.63 (brs, 1H), 8.33 (d, J=7.2 Hz, 1H), 7.58 (m, 2H), 7.44 (m, 3H), 4.29-2.92 (m, 9H), 2.38 (m, 4H), 1.94-1.70 (m, 4H), 1.62 (brs, 4H).
Free Form:
TLC: Rf 0.47 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.12 (t, J=5.7 Hz, 1H), 7.05 (dd, J=8.4, 7.2 Hz, 2H), 6.52 (m, 3H), 5.55 (t, J=5.7 Hz, 1H), 3.42 (s, 2H), 3.22 (m, 2H), 3.06 (m, 2H), 2.38 (m, 4H), 1.60 (brs, 4H).
Hydrochloride:
TLC: Rf 0.57 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.60 (s, 1H), 8.31 (m, 1H), 7.35-7.04 (m, 5H), 3.44 (s, 2H), 3.33-3.23 (m, 4H), 2.38 (m, 4H), 1.62 (brs, 4H).
TLC: Rf 0.47 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.13 (t, J=5.7 Hz, 1H), 6.58 (t, J=2.4 Hz, 1H), 5.84 (t, J=2.4 Hz, 11), 5.76 (brs, 1H), 3.49 (s, 3H), 3.39 (s, 2H), 3.24 (m, 2H), 2.64 (t, J=7.2 Hz, 2H), 2.37 (m, 4H), 1.63 (brs, 4H).
TLC: Rf 0.29 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 7.99 (t, J=5.4 Hz, 1H), 4.33 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.35 (m, 2H), 3.02 (td, J=6.3, 5.4 Hz, 2H), 2.39 (m, 4H), 1.63 (brs, 4H), 1.41-1.22 (m, 6H).
TLC: Rf 0.15 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.55 (brs, 1H), 7.97 (t, J=6.0 Hz, 1H), 7.30-7.17 (m, 5H), 3.67 (s, 2H), 3.40 (s, 2H), 3.15 (q, J=6.0 Hz, 2H), 2.56-2.35 (m, 6H), 1.61 (brs, 4H).
TLC: Rf 0.38 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.16 (t, J=5.7 Hz, 1H), 7.56 (t, J=1.5 Hz, 1H), 6.37 (dd, J=3.0, 1.5 Hz, 1H), 6.26 (d, J=3.0 Hz, 1H), 3.77 (s, 2H), 3.40 (s, 2H), 3.22 (m, 2H), 2.53-2.36 (m, 6H), 1.63 (brs, 4H).
TLC: Rf 0.43 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.00 (t, J=5.7 Hz, 1H), 3.38 (s, 2H), 3.03 (m, 2H), 2.73-1.96 (m, 11H), 1.63-1.13 (m, 10H), 0.94 (d, J=6.3 Hz, 3H).
TLC: Rf 0.41 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.01 (t, J=5.1 Hz, 11), 3.38 (s, 2H), 3.08 (m, 2H), 2.51-2.25 (m, 7H), 1.77-0.92 (m, 16H).
TLC: Rf 0.66 (methanol:methylene chloride: saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 7.95 (t, J=5.4 Hz, 1H), 3.40 (s, 2H), 3.11 (m, 2H), 2.55-2.36 (m, 8H), 1.63 (brs, 4H), 1.31 (m, 4H), 0.85 (t, J=6.9 Hz, 3H).
TLC: Rf 0.51 (methanol:methylene chloride:saturated aqueous ammonia=1:10:0.1);
NMR (DMSO-d6): δ 7.99 (t, J=5.1 Hz, 1H), 4.44 (brs, 1H), 3.62 (m, 1H), 3.40 (s, 2H), 3.11 (m, 2H), 2.57-2.37 (m, 8H), 1.63 (brs, 4H), 1.01 (d, J=6.3 Hz, 3H).
TLC: Rf 0.58 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.07 (t, J=5.4 Hz, 1H), 7.14 (t, J=7.5 Hz, 2H), 6.61 (m, 3H), 3.41 (s, 2H), 3.29 (m, 2H), 3.08 (m, 2H), 2.83 (s, 3H), 2.39 (m, 4H), 1.62 (m, 6H).
TLC: Rf 0.26 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.54 (brs, 1H), 7.99 (t, J=5.4 Hz, 1H), 4.41 (t, J=5.4 Hz, 1H), 3.40 (m, 2H), 3.39 (s, 2H), 3.09 (m, 2H), 2.39 (m, 4H), 1.63 (brs, 4H), 1.58-1.49 (m, 2H).
TLC: Rf 0.48 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.16 (t, J=5.7 Hz, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.94 (dd, J=5.1, 3.3 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H), 3.39 (s, 2H), 3.30 (m, 2H), 2.92 (t, J=6.9 Hz, 2H), 2.35 (brs, 4H), 1.62 (brs, 4H).
TLC: Rf 0.30 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.01 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.07 (m, 2H), 2.88 (m, 1H), 2.38 (m, 4H), 2.15 (s, 3H), 2.03-1.24 (m, 12H).
Free Form:
TLC: Rf 0.44 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 7.96 (t, J=5.4 Hz, 1H), 7.32-7.19 (m, 5H), 3.40 (s, 2H), 3.37 (s, 2H), 3.06 (m, 2H), 2.75 (m, 2H), 2.31 (m, 4H), 1.87-1.03 (m, 13H).
Hydrochloride:
TLC: Rf 0.48 (methanol:methylene chloride:saturated aqueous ammonia=1:9:0.1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 10.21 (brs, 1H), 8.05 (t, J=5.4 Hz, 1H), 7.56 (m, 2H), 7.45 (m, 3H), 4.24 (m, 2H), 3.38-2.78 (m, 8H), 2.37 (m, 4H), 1.83-1.31 (m, 11H).
TLC: Rf 0.18 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.55 (br, 1H), 7.99 (t, J=6.0 Hz, 1H), 4.43 (m, 1H), 3.44-3.37 (m, 2H), 3.40 (s, 2H), 3.11 (q, J=6.0 Hz, 2H), 2.59-2.52 (m, 4H), 2.45-2.33 (m, 4H), 1.68-1.60 (m, 4H).
TLC: Rf 0.60 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.05 (t, J=5.4 Hz, 1H), 3.39 (s, 2H), 3.11 (m, 2H), 2.44-2.36 (m, 6H), 2.02 (s, 3H), 1.66 (m, 6H).
TLC: Rf 0.63 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.59 (brs, 1H), 8.12 (t, J=5.4 Hz, 1H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.50 (m, 2H), 6.37 (d, J=7.2 Hz, 1H), 3.40 (s, 2H), 3.33-3.18 (m, 6H), 2.38 (m, 4H), 2.20 (s, 3H), 1.62 (brs, 4H), 1.04 (t, J=6.9 Hz, 3H).
TLC: Rf 0.34 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.01 (t, J=5.4 Hz, 1H), 4.31 (t, J=5.4 Hz, 1H), 3.39 (s, 2H), 3.19 (s, 6H), 3.01 (m, 2H), 2.39 (m, 4H), 1.63 (brs, 4H), 1.52-1.34 (m, 4H).
TLC: Rf 0.34 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 3.38 (s, 2H), 3.05 (q, J=5.7 Hz, 2H), 2.44-2.29 (m, 10H), 1.66-1.59 (m, 4H), 1.49(quin, J=5.7 Hz, 2H), 0.91 (t, J=6.9 Hz, 6H).
TLC: Rf 0.18 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.52 (br, 1H), 8.00 (m, 1H), 3.38 (s, 2H), 3.08 (q, J=6.0 Hz, 2H), 2.62(sep, J=6.0 Hz, 1H), 2.48-2.32 (m, 6H), 1.68-1.60 (m, 4H), 1.49(quin, J=6.0 Hz, 2H), 0.92 (d, J=6.0 Hz, 6H).
TLC: Rf 0.41 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.01 (t, J=5.7 Hz, 1H), 4.79 (t, J=4.8 Hz, 1H), 3.89-3.71 (m, 4H), 3.38 (s, 2H), 3.13 (m, 2H), 2.38 (m, 4H), 1.70 (m, 2H), 1.63 (brs, 4H).
TLC: Rf 0.14 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.60 (br, 1H), 8.00 (m, 1H), 3.38 (s, 2H), 3.08 (q, J=6.6 Hz, 2H), 2.47-2.34 (m, 8H), 1.70-1.60 (m, 4H), 1.50(quin, J=6.6 Hz, 2H), 1.38(sex, J=6.6 Hz, 2H), 0.83 (t, J=6.6 Hz, 3H).
TLC: Rf 0.31 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.59 (br, 1H), 7.96 (m, 1H), 3.40 (s, 2H), 3.11 (q, J=6.3 Hz, 2H), 2.57-2.47 (m, 2H), 2.45-2.33 (m, 6H), 1.70-1.60 (m, 4H), 1.37(sex, J=7.2 Hz, 2H), 0.84 (t, J=7.2 Hz, 3H).
TLC: Rf 0.47 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.04 (t, J=5.7 Hz, 1H), 7.10 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 3.70 (s, 3H), 3.36 (s, 2H), 3.24 (m, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.33 (m, 4H), 1.60 (brs, 4H).
TLC: Rf 0.39 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 10.38 (brs, 3H), 8.19 (t, J=5.4 Hz, 1H), 7.31 (m, 4H), 3.37 (s, 2H), 3.29 (q, J=6.9 Hz, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.35 (brs, 4H), 1.61 (brs, 4H).
TLC: Rf 0.40 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.27 (brs, 1H), 8.36 (m, 1H), 7.31 (t, J=7.8 Hz, 2H), 7.10-6.00 (m, 7H), 3.46 (s, 2H), 3.24 (m, 6H), 2.38 (t, J=6.3 Hz, 2H), 1.70 (m, 2H).
TLC: Rf 0.36 (methanol:methylene chloride:saturated aqueous ammonia=1:10:0.1);
NMR (DMSO-d6): δ 11.87 (s, 1H), 9.20 (brs, 1H), 8.05 (t, J=5.1 Hz, 1H), 7.48 (m, 5H), 6.38 (brs, 1H), 4.27 (m, 2H), 3.33-3.06 (m, 8H), 2.83 (m, 2H), 2.33 (m, 2H), 2.30 (s, 3H), 1.87-1.22 (m, 9H).
TLC: Rf 0.31 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 11.85 (s, 1H), 8.05 (t, J=5.4 Hz, 1H), 6.41 (s, 1H), 3.54 (m, 4H), 3.29 (m, 2H), 3.17 (brs, 2H), 3.06 (q, J=6.6 Hz, 2H), 2.28 (m, 8H), 1.69 (m, 2H), 1.53 (m, 2H).
TLC: Rf 0.14 (methanol:methylene chloride:acetic acid=1:4:0.2);
NMR (DMSO-d6): δ 11.91 (s, 1H), 8.94 (brs, 1H), 8.29 (t, J=5.4 Hz, 1H), 6.30 (brs, 1H), 3.50-3.38 (m, 6H), 3.12 (m, 4H), 2.90 (m, 2H), 2.35 (m, 2H), 2.32 (s, 3H), 1.98-1.33 (m, 8H).
TLC: Rf 0.29 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 11.85 (s, 1H), 7.99 (t, J=5.4 Hz, 1H), 6.40 (s, 1H), 3.53 (m, 4H), 3.34 (s, 2H), 3.16 (m, 4H), 2.30 (m, 8H), 1.70 (m, 2H).
TLC: Rf 0.35 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 11.84 (s, 1H), 8.02 (t, J=5.4 Hz, 1H), 6.76 (t, J=5.4 Hz, 1H), 6.38 (s, 1H), 3.31 (m, 2H), 3.18 (brs, 2H), 2.98 (td, J=6.6, 5.4 Hz, 2H), 2.90 (td, J=6.6, 5.4 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69 (m, 2H), 1.47 (m, 2H), 1.36 (s, 9H).
5-chloropentanoyl chloride (171 mg) was added dropwise to a mixed solution of the compound prepared in Example 1 (241 mg) and potassium carbonate (89.8 mg) in tetrahydrofuran (3.00 mL) and water (1.00 mL) in ice bath and the mixture was stirred for 30 minutes. Moreover, potassium carbonate (45.0 mg) and 5-chloropentanoyl chloride (85.5 mg) was added the reaction mixture, which was stirred for 30 minutes. 1N hydrochloric acid was added to the reaction mixture, which was adjusted to pH 2. Water was added thereto and the deposited crystal was collected by filtration. It was washed with water and hexane sequentially and dried under reduced pressure to give the compound of the present invention (347 mg) having the following physical data.
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.00 (s, 1H), 7.69 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 3.65 (t, J=6.0 Hz, 2H), 2.56-2.32 (m, 6H), 1.75-1.59 (m, 8H).
By the same procedure as described in Example 25 using a corresponding derivative instead of the compound prepared in Example 1, and a corresponding derivative instead of 5-chloropentanoyl chloride, the following compounds of the present invention were obtained.
TLC: Rf 0.28 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.00 (s, 1H), 7.69 (t, J=1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.2 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.2 Hz, 1H), 3.55 (t, J=6.6 Hz, 2H), 2.48-2.32 (m, 6H), 1.86-1.59 (m, 8H).
TLC: Rf 0.50 (chloroform:methanol=9:1);
NMR (CDCl3): δ 8.47-8.28 (br, 1H), 7.69 (bs, 1H), 7.62 (bs, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 4.35 (dd, J=10.5, 2.7 Hz, 1H), 3.85 (dt, J=13.5, 2.7 Hz, 1H), 3.67 (t, J=6.3 Hz, 2H), 3.21-3.11 (m, 1H), 3.08-3.02 (m, 1H), 2.94 (dd, J=13.5, 10.5 Hz, 1H), 2.86-2.76 (m, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.32-2.16 (m, 3H).
TLC: Rf 0.40 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 10.52 (s, 1H), 10.05 (s, 1H), 7.67 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.23 (dd, J=8.7, 4.8 Hz, 1H), 3.56 (m, 1H), 3.08 (m, 1H), 2.89-2.83 (m, 2H), 2.70 (m, 1H), 2.32 (m, 1H), 2.04 (s, 3H).
TLC: Rf 0.51 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.88 (s, 1H), 10.08 (s, 1H), 7.70 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.26 (s, 1H), 3.61 (m, 2H), 3.15 (m, 2H), 2.05 (s, 3H).
TLC: Rf 0.45 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.87 (s, 1H), 10.02 (s, 1H), 7.67 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 2.39 (m, 4H), 2.04 (s, 3H), 1.64 (m, 4H).
NMR (DMSO-d6): δ 10.89 (s, 1H), 10.12 (s, 1H), 7.71 (t, J=1.5 Hz, 1H), 7.62 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.10 (dt, J=7.8, 1.5 Hz, 1H), 6.26 (s, 1H), 3.70 (t, J=6.9 Hz, 2H), 3.64-3.58 (m, 2H), 3.18-3.13 (m, 2H), 2.35 (t, J=6.9 Hz, 2H), 2.03(quin, J=6.9 Hz, 2H).
TLC: Rf 0.27 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.90 (s, 1H), 10.40 (s, 1H), 7.68 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.25 (s, 2H), 2.39 (m, 4H), 1.68 (m, 2H), 1.59 (m, 2H).
TLC: Rf 0.20 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.15 (s, 1H), 7.70 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.72 (t, J=6.3 Hz, 2H), 2.95 (t, J=6.3 Hz, 2H), 2.48-2.34 (m, 4H), 1.70 (m, 2H), 1.60 (m, 2H).
Free Form:
TLC: Rf 0.31 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.11 (s, 1H), 10.06 (s, 1H), 7.70 (m, 1H), 7.61 (m, 1H), 7.37 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 5.37 (s, 1H), 3.20-3.06 (m, 2H), 2.39 (t, J=6.3 Hz, 2H), 2.04 (s, 3H), 1.82-1.60 (m, 2H).
Methanesulfonate:
TLC: Rf 0.31 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.31 (s, 1H), 10.06 (s, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.09 (m, 1H), 3.14 (m, 2H), 2.41 (t, J=6.2 Hz, 2H), 2.33 (s, 3H), 2.04 (s, 3H), 1.73 (m, 2H).
TLC: Rf 0.56 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.89 (s, 1H), 9.86 (brs, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 3.00 (s, 3H), 2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.59 (m, 2H).
TLC: Rf 0.41 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.11 (s, 1H), 10.09 (s, 1H), 7.72 (m, 1H), 7.63 (s, 1H), 7.38 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 5.74 (s, 1H), 3.69 (t, J=6.3 Hz, 2H), 3.22-3.04 (m, 2H), 2.60-2.32 (m, 4H), 2.12-1.94 (m, 2H), 1.82-1.64 (m, 2H).
TLC: Rf 0.68 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 8.33 (brt, J=5.1 Hz, 1H), 3.82 (s, 2H), 3.44-3.26 (m, 2H), 2.64 (t, J=6.9 Hz, 2H), 2.54-2.28 (m, 4H), 1.78-1.52 (m, 4H).
TLC: Rf 0.71 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.55 (brs, 1H), 8.07 (brt, J=6.0 Hz, 1H), 3.61 (t, J=6.0 Hz, 2H), 3.44-3.24 (m, 2H), 2.72-2.28 (m, 8H), 1.78-1.54 (m, 4H).
A mixture of the compound prepared in Example 1 (277 mg), triethylamine (223 mg), 5-(N-methyl-N-t-butoxycarbonylamino)pentanoic acid (277 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), 1-hydroxybenzotriazole (184 mg) and dimethylformamide (3.00 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the compound of the present invention (298 mg) having the following physical data.
TLC: Rf 0.49 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 9.97 (s, 1H), 7.69 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 3.15 (t, J=6.8 Hz, 2H), 2.74 (s, 3H), 2.48-2.30 (m, 6H), 1.70-1.50 (m, 8H), 1.36 (s, 9H).
By the same procedure as described in Example 26, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 1 or a corresponding derivative, and (N-methyl-N-t-butoxycarbonylamino)pentanoic acid or a corresponding derivative, the following compounds of the present invention were obtained.
TLC: Rf 0.29 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.88 (s, 1H), 9.98 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.32 (m, 6H), 7.08 (d, J=7.8 Hz, 1H), 5.04 (s, 2H), 3.28-2.33 (m, 11H), 1.69-1.51 (m, 8H).
TLC: Rf 0.48 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.07 (s, 1H), 7.69 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 3.69 (t, J=6.3 Hz, 2H), 2.46-1.59 (m, 12H).
TLC: Rf 0.30 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (CD3OD): δ 7.75 (t, J=1.8 Hz, 1H), 7.63 (brd, J=8.1 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.20 (brd, J=8.1 Hz, 1H), 3.16 (m, 2H), 2.89 (s, 6H), 2.74 (s, 3H), 2.66-2.50 (m, 6H), 1.81 (m, 8H).
TLC: Rf 0.79 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.88 (s, 1H), 9.97 (s, 1H), 7.69 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37-7.26 (m, 6H), 7.08 (d, J=7.8 Hz, 1H), 4.99 (s, 2H), 3.00 (m, 2H), 2.48-2.28 (m, 6H), 1.69-1.42 (m, 8H).
TLC: Rf 0.41 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.89 (s, 1H), 9.81 (s, 1H), 7.73 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 4.14 (s, 2H), 3.81 (s, 4H), 2.48-2.34 (m, 4H), 1.70-1.59 (m, 4H).
TLC: Rf 0.28 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 10.34 (s, 1H), 9.98 (s, 1H), 7.68 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.33 (m, 6H), 7.01 (d, J=7.8 Hz, 1H), 5.04 (s, 2H), 3.86 (m, 1H), 3.25-1.42 (m, 19H).
TLC: Rf 0.24 (methanol:chloroform=1:10);
NMR (DMSO-d6): δ 10.53 (s, 1H), 10.01 (s, 1H), 7.67 (t, J=1.5 Hz, 1H), 7.58 (m, 1H), 7.34 (m, 6H), 7.06 (m, 1H), 5.04 (s, 2H), 4.23 (dd, J=8.6, 4.8 Hz, 1H), 3.57 (brd, J=13.8 Hz, 1H), 3.28 (m, 3H), 3.07 (t, J=12.0 Hz, 1H), 2.88-2.65 (m, 5H), 2.33 (m, 3H), 1.52 (m, 4H).
TLC: Rf 0.54 (chloroform:methanol=9:1);
NMR (CDCl3): δ 10.58 (br-s, 1H), 8.21 (br-s, 11), 7.69 (br-s, 1H), 7.60 (m, 1H), 7.40-7.28 (m, 6H), 7.04 (m, 1H), 5.13 (s, 2H), 3.42-3.28 (m, 2H), 3.00-2.86 (m, 5H), 2.70-2.64 (m, 2H), 2.46-2.30 (m, 2H), 1.94-1.84 (m, 2H), 1.80-1.60 (m, 8H).
TLC: Rf 0.35 (methylene chloride:methanol=10:1).
TLC: Rf 0.35 (methylene chloride:methanol=10:1).
TLC: Rf 0.31 (hexane:ethyl acetate=1:3);
NMR (DMSO-d6): δ 12.87 (s, 1H), 9.95 (s, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.34 (dd, J=7.8, 7.8 Hz, 1H), 7.07 (m, 1H), 5.10 (m, 1H), 3.72 (d, J=6.6 Hz, 2H), 3.16-3.00 (m, 2H), 2.62-2.40 (m, 2H), 2.40-2.22 (m, 4H), 1.78-1.30 (m, 8H), 1.64 (s, 3H), 1.60 (s, 3H), 1.36 (s, 9H).
TLC: Rf 0.63 (chloroform:methanol:water=8:2:0.2);
NMR (CD3OD): δ 7.74 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.14 (d, J=7.8 Hz, 1H), 6.39 (s, 1H), 5.08 (s, 2H), 3.73-3.68 (m, 2H), 3.38-3.28 (m, 2H), 3.16-3.10 (m, 2H), 2.91(brs, 3H), 2.44-2.25 (m, 2H), 1.78-1.50 (m, 4H).
TLC: Rf 0.27 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.92 (s, 1H), 10.97 (s, 1H), 9.96 (brs, 1H), 7.72 (m, 1H), 7.65 (m, 1H), 7.43 (dd, J=7.8, 7.8 Hz, 11), 7.20 (m, 1H), 4.16 (s, 2H), 2.87 (s, 6H), 2.60-2.24 (m, 41), 1.80-1.50 (m, 4H).
TLC: Rf 0.27 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.13 (s, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.12 (m, 1H), 4.08-3.84 (m, 4H), 3.46 (m, 1H), 2.54-2.28 (m, 4H), 1.78-1.52 (m, 4H), 1.38 (s, 9H).
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.07 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.17 (m, 1H), 3.38-2.34 (m, 8H), 1.98-1.60 (m, 6H), 1.38 (s, 9H×⅓), 1.26 (s, 9H×⅔).
TLC: Rf 0.31 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.54 (s, 1H), 7.82 (brt, 1H), 6.91 (brt, 1H), 3.47 (d, J=6.3 Hz, 2H), 3.40-3.26 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.56-2.30 (m, 4H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).
TLC: Rf 0.44 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.54 (s, 1H), 7.92 (t, J=6.0 Hz, 1H), 6.72 (brt, 1H), 3.42-3.18 (m, 2H), 3.16-3.02 (m, 2H), 2.68-2.28 (m, 6H), 2.18 (t, J=7.2 Hz, 2H), 1.78-1.52 (m, 4H), 1.36 (s, 9H).
TLC: Rf 0.62 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.54 (brs, 1H), 7.80 (t, J=5.7 Hz, 1H), 3.44-3.24 (m, 2H), 2.80 (s, 2H), 2.64 (t, J=7.2 Hz, 2H), 2.54-2.26 (m, 4H), 2.16 (s, 6H), 1.76-1.52 (m, 4H).
TLC: Rf 0.67 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.53 (s, 1H), 7.85 (t, J=5.4 Hz, 1H), 6.78 (t, J=5.7 Hz, 1H), 3.40-3.20 (m, 2H), 2.94-2.80 (m, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.56-2.28 (m, 4H), 2.01 (t, J=7.2 Hz, 2H), 1.78-1.46 (m, 6H), 1.36 (s, 9H).
The compound prepared in Reference example 13 (40 mg), sodium iodide (8.4 mg) and benzylamine (0.21 mL) were stirred at room temperature for 10 hours. Methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, which was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to give the compound of the present invention (18 mg) having the following physical data.
TLC: Rf 0.29 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.46 (s, 1H), 7.40-7.15 (m, 5H), 3.69 (s, 2H), 2.80-2.60 (m, 4H), 2.50-2.30 (m, 4H), 1.63 (brs, 4H).
By the same procedure as described in Example 27, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Reference example 13 or a corresponding derivative, and a corresponding derivative instead of benzylamine, the following compounds of the present invention were obtained.
Free Form:
TLC: Rf 0.38 (chloroform:methanol:acetic acid=90:10:1);
NMR (CD3OD): δ 3.74-3.66 (m, 4H), 2.84-2.77 (m, 2H), 2.75-2.66 (m, 2H), 2.64-2.48 (m, 8H), 1.88-1.72 (m, 4H).
Hydrochloride:
TLC: Rf 0.24 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.68 (s, 1H), 10.85 (brs, 1H), 4.02-3.92 (m, 2H), 3.82-3.70 (m, 2H), 3.54-3.44 (m, 2H), 3.44-3.32 (m, 2H), 3.15-3.05 (m, 2H), 3.05-2.96 (m, 2H), 2.53-2.33 (m, 4H), 1.76-1.58 (m, 4H).
TLC: Rf 0.12 (chloroform:methanol=9:1);
NMR (CD3OD): δ 3.78-3.66 (m, 2H), 3.63 (t, J=8.1 Hz, 2H), 3.26-3.10 (m, 2H), 3.06 (t, J=8.1 Hz, 2H), 2.62-2.48 (m, 4H), 2.26-1.96 (m, 4H), 1.90-1.72 (m, 4H).
TLC: Rf 0.32 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.68 (s, 1H), 11.80 (brs, 2H), 4.00-3.20 (m, 10H), 3.10-2.95 (m, 2H), 2.80 (s, 3H), 2.50-2.30 (m, 4H), 1.75-1.55 (m, 4H).
TLC: Rf 0.34 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.66 (s, 1H), 10.45 (brs, 1H), 3.52-3.42 (m, 2H), 3.34-3.22 (m, 2H), 3.06-2.96 (m, 2H), 2.96-2.80 (m, 2H), 2.54-2.32 (m, 4H), 1.84-1.56 (m, 9H), 1.46-1.26 (m, 1H).
TLC: Rf 0.34 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.65 (s, 1H), 8.85 (brs, 2H), 3.26-3.10 (m, 2H), 3.10-2.96 (m, 1H), 2.90 (t, J=7.2 Hz, 2H), 2.50-2.36 (m, 4H), 2.06-1.98 (m, 2H), 1.80-1.54 (m, 7H), 1.40-1.00 (m, 5H).
TLC: Rf 0.28 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.66 (s, 1H), 10.55 (s, 1H), 3.46-3.28 (m, 4H), 3.20-3.06 (m, 2H), 3.06-2.98 (m, 2H), 2.56-2.46 (m, 2H), 2.44-2.34 (m, 2H), 1.90-1.50 (m, 12H).
TLC: Rf 0.29 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.51 (s, 1H), 3.32-3.24 (m, 6H), 2.70-2.60 (m, 2H), 2.60-2.50 (m, 2H), 2.40-2.30 (m, 6H), 1.72-1.56 (m, 4H), 1.37 (s, 9H).
TLC: Rf 0.40 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.67 (s, 1H), 10.90 (brs, 1H), 3.84-3.70 (m, 2H), 3.44-3.30 (m, 2H), 3.24-3.10 (m, 4H), 3.08-2.98 (m, 2H), 2.90-2.76 (m, 2H), 2.52-2.44 (m, 2H), 2.42-2.34 (m, 2H), 1.76-1.58 (m, 4H).
TLC: Rf 0.28 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 12.66 (s, 1H), 9.70-9.45 (m, 2H), 3.98-3.88 (m, 2H), 3.70 (t, J=2.4 Hz, 1H), 3.30-3.18 (m, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.48-2.32 (m, 4H), 1.76-1.58 (m, 4H).
TLC: Rf 0.19 (chloroform:methanol=5:1);
NMR (CD3OD): δ 2.84-2.76 (m, 2H), 2.75-2.67 (m, 2H), 2.67-2.47 (m, 12H), 2.44 (q, J=7.5H, 2H), 1.79 (m, 4H), 1.10 (t, J=7.5 Hz, 3H).
TLC: Rf 0.49 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.66 (s, 1H), 8.86 (brs, 2H), 3.26-3.08 (m, 2H), 3.02-2.88 (m, 2H), 2.86-2.70 (m, 2H), 2.58-2.30 (m, 4H), 1.88-1.50 (m, 10H), 1.32-0.82 (m, 5H).
TLC: Rf 0.41 (chloroform:methanol=5:1);
NMR (CD3OD): δ 3.61 (t, J=6.6 Hz, 2H), 3.58-3.30 (m, 4H), 3.08 (t, J=6.6 Hz, 2H), 2.62-2.50 (m, 4H), 2.12-1.60 (m, 14H).
TLC: Rf 0.29 (chloroform:methanol:saturated aqueous ammonia=5:1:0.1);
NMR (CD3OD): δ 3.26 (m, 4H), 3.08-3.01 (m, 4H), 2.96 (t, J=6.0 Hz, 2H), 2.84 (m, 2H), 2.81 (s, 3H), 2.60 (m, 2H), 2.52 (m, 2H), 2.03 (m, 2H), 1.80 (m, 4H).
TLC: Rf 0.47 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.52 (brs, 1H), 6.73 (brt, 1H), 3.34 (br, 1H), 3.06-2.94 (m, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.70-2.54 (m, 4H), 2.54-2.28 (m, 4H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).
TLC: Rf 0.50 (chloroform:methanol=9:1);
NMR (CD3OD): δ 7.23 (dd, J=7.5, 7.5 Hz, 2H), 6.97 (d, J=7.5 Hz, 2H), 6.83 (dd, J=7.5, 7.5 Hz, 1H), 3.20 (m, 4H), 2.90-2.70 (m, 8H), 2.62 (m, 2H), 2.52 (m, 2H), 1.80 (m, 4H).
TLC: Rf 0.44 (chloroform:methanol=9:1);
NMR (CDCl3): δ 10.61 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.8, 7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.98 (dd, J=7.8, 7.8 Hz, 1H), 3.11 (m, 4H), 2.78 (s, 4H), 2.74 (m, 4H), 2.59 (m, 2H), 2.53 (m, 2H), 1.78 (m, 4H).
TLC: Rf 0.43 (chloroform:methanol=9:1);
NMR (CD3OD): δ 7.36-7.22 (m, 5H), 3.54 (s, 2H), 2.84-2.64 (m, 4H), 2.64-2.45 (m, 12H), 1.86-1.72 (m, 4H).
TLC: Rf 0.33 (chloroform:methanol=9:1);
NMR (CD3OD): δ 7.63 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 3.90 (s, 2H), 2.96 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 2.52 (m, 4H), 1.77 (m, 4H).
Free Form:
TLC: Rf 0.32 (chloroform:methanol=9:1);
NMR (CD3OD): δ 7.28 (m, 5H), 3.56 (s, 2H), 2.83-2.65 (m, 4H), 2.49 (m, 4H), 2.31 (s, 3H), 1.73 (m, 4H).
Methanesulfonate:
TLC: Rf 0.44 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.69 (s, 1H), 9.42 (m, 1H), 7.49 (m, 5H), 4.48 (m, 1H), 4.31 (m, 1H), 3.50-3.25 (m, 2H), 2.98 (m, 2H), 2.75 (m, 3H), 2.38 (m, 4H), 2.29 (s, 3H), 1.68 (m, 4H).
TLC: Rf 0.41 (methanol:methylene chloride=1:10);
NMR (CD3OD): δ 7.37 (m, 5H), 3.52 (t, J=6.8 Hz, 2H), 3.38 (m, 2H), 3.07 (m, 4H), 2.60 (m, 4H), 1.85 (m, 4H).
TLC: Rf 0.37 (chloroform:methanol=0.9:1);
NMR (CD3OD): δ 7.44 (d, J=7.5 Hz, 2H), 7.23 (d, J=7.5 Hz, 2H), 3.82 (s, 2H), 2.93 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H), 2.59-2.49 (m, 4H), 1.77 (m, 4H).
TLC: Rf 0.55 (chloroform:methanol=9:1);
NMR (CD3OD): δ 8.08 (m, 1H), 7.56 (m, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.68 (dd, J=6.3, 4.8 Hz, 1H), 3.54 (t, J=5.1 Hz, 4H), 2.90-2.74 (m, 4H), 2.68 (t, J=5.1 Hz, 4H), 2.62 (m, 2H), 2.52 (m, 2H), 1.79 (m, 4H).
TLC: Rf 0.26 (chloroform:methanol=9:1);
NMR (CD3OD): δ 7.18-7.08 (m, 2H), 6.74-6.64 (m, 3H), 3.48-3.36 (m, 4H), 3.22 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.51 (m, 4H), 1.78 (m, 4H).
TLC: Rf 0.21 (chloroform:methanol=9:1);
NMR (CD3OD): δ 3.62-3.52 (m, 4H), 2.85-2.70 (m, 4H), 2.64-2.48 (m, 8H), 2.09 (s, 3H), 1.79 (m, 4H).
TLC: Rf 0.45 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.49 (brs, 1H), 8.15 (m, 1H), 7.89 (m, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.53-7.40 (m, 4H), 4.15 (s, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.35 (m, 4H), 1.62 (brs, 4H).
TLC: Rf 0.41 (chloroform:methanol=9:1);
NMR (CD3OD): δ 7.30-7.20 (m, 5H), 3.60 (s, 2H), 2.72 (s, 4H), 2.62 (q, J=7.2 Hz, 2H), 2.48 (m, 2H), 2.40 (m, 2H), 1.70 (m, 4H), 1.10 (t, J=7.2 Hz, 3H).
TLC: Rf 0.17 (methylene chloride:methanol:water=9:1:0.1);
NMR (CD3OD): δ 7.43-7.23 (m, 5H), 3.60 (s, 2H), 3.41 (t, J=6.6 Hz, 2H), 3.14 (m, 1H), 3.06-2.98 (m, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.60-2.50 (m, 4H), 2.22-2.06 (m, 4H), 1.86-1.60 (m, 6H).
TLC: Rf 0.44 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.19 (m, 5H), 3.65 (t, J=8.7 Hz, 2H), 3.61 (s, 2H), 2.78-2.67 (m, 6H), 2.43 (m, 2H), 2.30 (m, 2H), 1.64 (m, 4H).
TLC: Rf 0.55 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 3.30-2.70 (m, 13H), 2.59 (m, 2H), 2.51 (m, 2H), 2.05 (m, 2H), 1.91 (m, 2H), 1.86-1.65 (m, 6H), 1.44-1.20 (m, 4H).
Free Form:
TLC: Rf 0.50 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 7.41 (m, 2H), 7.10 (dd, J=8.7, 8.7 Hz, 2H), 3.94 (s, 2H), 3.10 (t, J=6.9 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.52 (m, 4H), 1.78 (m, 4H).
Hydrochloride:
TLC: Rf 0.43 (methylene chloride:methanol=4:1);
NMR (DMSO-d6): δ 12.68 (s, 1H), 9.00 (s, 2H), 7.57 (m, 2H), 7.29 (m, 2H), 4.20 (m, 2H), 3.21 (m, 2H), 2.90 (m, 2H), 2.58-2.38 (m, 4H), 1.67 (m, 4H).
TLC: Rf 0.39 (methylene chloride:methanol:saturated aqueous ammonia=4:1:0.3);
NMR (CD3OD): δ 7.40 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.15 (s, 2H), 3.81 (s, 3H), 3.37 (t, J=6.9 Hz, 2H), 2.95 (t, J=6.9 Hz, 2H), 2.53 (m, 4H), 1.78 (m, 4H).
TLC: Rf 0.38 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.50 (m, 5H), 4.48 (q, J=6.9 Hz, 1H), 3.29 (m, 2H), 2.92 (t, J=6.6 Hz, 2H), 2.51 (m, 4H), 1.78 (m, 4H), 1.70 (d, J=6.9 Hz, 3H).
TLC: Rf 0.39 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.48-7.06 (m, 4H), 4.06 (s, 2H), 3.20 (t, J=6.9 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.53 (m, 4H), 1.77 (m, 4H).
TLC: Rf 0.48 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.48-7.40 (m, 4H), 7.32-7.13 (m, 6H), 4.25 (s, 1H), 3.16 (t, J=5.1 Hz, 2H), 2.81-2.40 (m, 14H), 1.78 (m, 4H).
TLC: Rf 0.44 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.32 (dd, J=8.1, 8.1 Hz, 1H), 7.02-6.90 (m, 3H), 4.05 (s, 2H), 3.81 (s, 3H), 3.24 (t, J=6.9 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.51 (m, 4H), 1.77 (m, 4H).
TLC: Rf 0.26 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 11.94 (s, 1H), 9.31 (brs, 1H), 6.39 (brs, 1H), 3.60-3.10 (m, 6H), 3.06-2.74 (m, 4H), 2.34 (t, J=6.6 Hz, 2H), 1.94-1.50 (m, 7H), 1.38 (m, 1H).
TLC: Rf 0.62 (methylene chloride:methanol:water=4:1:0.2);
NMR (CD3OD): δ 7.26 (dd, J=8.1, 8.1 Hz, 2), 6.98-6.88 (m, 3H), 4.11 (t, J=5.1 Hz, 2H), 3.14-3.05 (m, 4H), 2.84 (t, J=6.6 Hz, 2H), 2.60-2.50 (m, 4H), 1.78 (m, 4H).
Free Form:
TLC: Rf 0.67 (methylene chloride:methanol:saturated aqueous ammonia=4:1:0.3);
NMR (CD3OD): δ 7.34 (m, 5H), 5.11 (s, 2H), 3.54 (m, 4H), 2.82-2.70 (m, 8H), 2.60 (m, 2H), 2.52 (m, 2H), 1.90-1.72 (m, 6H).
Methanesulfonate:
TLC: Rf 0.64 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.7 (s, M1), 9.35 (s, 1H), 7.40-7.30 (m, 5H), 5.11 (s, 2H), 3.89 (m, 1H), 3.72-3.40 (m, 7H), 3.35-3.16 (m, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.65-2.50 (m, 4H), 2.30 (s, 3H), 1.85 (m, 2H), 1.67 (m, 4H).
TLC: Rf 0.14 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 4.00-3.40 (m, 11H), 3.12 (t, J=7.5 Hz, 2H), 2.62-2.50 (m, 4H), 2.22-2.15 (m, 2H), 1.92-1.68 (m, 10H).
TLC: Rf 0.16 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 4.10-3.45 (m, 8H), 3.74 (t, J=7.2 Hz, 2H), 3.30 (m, 2H), 3.16 (t, J=7.2 Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 1.90-1.75 (m, 6H), 1.45 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).
TLC: Rf 0.36 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.17 (s, 1H), 11.85 (brs, 1H), 5.09 (br, 3H), 3.98-3.08 (m, 11H), 2.96 (m, 2H), 2.36 (t, J=6.0 Hz, 2H), 2.10 (m, 2H), 1.94-0.98 (m, 12H).
TLC: Rf 0.75 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.66 (s, 1H), 9.39 (brs, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 4.19 (m, 2H), 3.18 (m, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H).
TLC: Rf 0.68 (methylene chloride:methanol=4:1);
NMR (CD3OD) δ 4.04-3.45 (m, 8H), 3.71 (t, J=7.2 Hz, 2H), 3.26 (m, 2H), 3.15 (t, J=7.2 Hz, 2H), 2.59 (m, 2H), 2.53 (m, 2H), 1.80 (m, 6H), 1.39 (m, 6H), 0.93 (t, J=6.9 Hz, 3H).
TLC: Rf 0.25 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 4.12-3.58 (m, 11H), 3.18 (t, J=6.9 Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 1.80 (m, 4H), 1.44 (d, J=6.9 Hz, 6H).
TLC: Rf 0.65 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 7.61-7.50 (m, 2H), 7.32-7.20 (m, 2H), 4.39 (s, 2H), 3.51 (t, J=6.9 Hz, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.52 (m, 4H), 1.79 (m, 4H).
TLC: Rf 0.42 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 3.55 (t, J=6.6 Hz, 2H), 3.45 (t, J=6.9 Hz, 2H), 3.35 (s, 3H), 3.21 (t, J=6.9 Hz, 2H), 2.99 (t, J=6.6 Hz, 2H), 2.54 (m, 4H), 1.97 (m, 2H), 1.79 (m, 4H).
TLC: Rf 0.30 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.41 (brs, 1H), 9.60 (brs, 2H), 7.65 (dd, J=8.4, 5.7 Hz, 2H), 7.27 (dd, J=8.4, 8.4 Hz, 2H), 6.00 (brs, 2H), 4.16 (m, 2H), 3.34-3.06 (m, 4H), 2.95 (t, J=7.2 Hz, 2H), 2.39 (t, J=6.0 Hz, 2H), 1.71 (m, 2H).
TLC: Rf 0.32 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.66 (s, 1H), 9.33 (brs, 2H), 7.78 (d, J=1.5 Hz, 1H), 6.65 (d, J=3.3 Hz, 1H), 6.53 (dd, J=3.3, 1.5 Hz, 1H), 4.27 (m, 2H), 3.18 (m, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H).
TLC: Rf 0.16 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.66 (s, 1H), 9.23 (brs, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 4.13 (m, 2H), 3.16 (m, 2H), 2.92 (t, J=7.2 Hz, 2H), 2.40 (m, 4H), 2.31 (s, 3H), 1.66 (m, 4H).
TLC: Rf 0.34 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 7.50-7.42 (m, 2H), 7.15-7.00 (m, 2H), 4.29 (s, 2H), 3.92 (s, 3H), 3.48 (t, J=6.6 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.53 (m, 4H), 1.78 (m, 4H).
TLC: Rf 0.069 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 3.47 (t, J=6.6 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.63-2.50 (m, 4H), 2.12 (s, 3H), 2.01 (m, 2H), 1.90-1.75 (m, 4H).
TLC: Rf 0.39 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 8.53 (d, J=6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 4.06 (s, 2H), 3.15 (t, J=6.9 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.60-2.45 (m, 4H), 1.88-1.72 (m, 4H).
TLC: Rf 0.26 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.24 (s, 1H), 11.73 (brs, 1H), 5.59 (br, 3H), 4.00-3.06 (m, 14H), 2.97 (t, J=8.1 Hz, 2H), 2.37 (t, J=6.0 Hz, 2H, 1.73 (m, 2H), 1.26 (t, J=6.9 Hz, 3H).
TLC: Rf 0.60 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.10-7.00 (m, 4H), 3.82-3.72 (m, 4H), 3.67 (t, J=7.2 Hz, 2H), 3.42-3.30 (m, 4H), 3.15 (t, J=7.2 Hz, 2H), 2.65-2.50 (m, 4H), 1.82 (m, 4H).
TLC: Rf 0.14 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 8.28 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 4.50 (m, 2H), 3.95-3.30 (m, 6H), 3.71 (t, J=6.9 Hz, 2H), 3.18 (t, J=6.9 Hz, 2H), 2.62 (m, 2H), 2.53 (m, 2H), 1.81 (m, 4H).
TLC: Rf 0.45 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.23 (s, 1H), 12.22 (brs, 1H), 4.66 (br, 3H), 4.00-3.30 (m, 11H), 3.23 (m, 2H), 2.98 (m, 2H), 2.37 (t, J=6.0 Hz, 2H), 2.00 (m, 2H), 1.92-1.40 (m, 8H).
TLC: Rf 0.26 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.18 (s, 1H), 11.86 (brs, 1H), 4.55 (br, 3H), 3.98-3.30 (m, 11H), 3.22 (m, 2H), 2.97 (m, 2H), 2.37 (t, J=6.3 Hz, 2H), 1.72 (m, 2H), 1.30 (d, J=6.3 Hz, 6H).
TLC: Rf 0.32 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.65 (s, 1H), 9.59 (brs, 2H), 7.62 (d, J=5.1 Hz, 1H), 7.37 (d, J=2.7 Hz, 1H), 7.09 (dd, J=5.1, 2.7 Hz, 1H), 4.41 (s, 2H), 3.18 (m, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H).
TLC: Rf 0.72 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.15-6.90 (m, 4H), 3.87 (s, 3H), 3.82-3.05 (m, 8H), 3.67 (t, J=6.9 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.62-2.50 (m, 4H), 1.80 (m, 4H).
TLC: Rf 0.13 (methylene chloride:methanol:saturated aqueous ammonia=4:1:0.5);
NMR (CD3OD): δ 3.16 (t, J=6.3 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 2.94-2.83 (m, 4H), 2.78 (s, 6H) 2.61 (m, 2H), 2.52 (m, 2H), 2.48 (s, 3H), 1.80 (m, 4H).
TLC: Rf 0.54 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.20 (dd, J=8.4, 8.4 Hz, 1H), 6.66-6.52 (m, 3H), 3.90-3.08 (m, 8H), 3.77 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.61 (m, 2H), 2.54 (m, 2H), 1.81 (m, 4H).
TLC: Rf 0.53 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.52 (m, 2H), 7.42-7.32 (m, 3H), 6.96 (d, J=16.2 Hz, 1H), 6.36 (dt, J=16.2, 7.2 Hz, 1H), 4.04 (d, J=7.2 Hz, 2H), 3.90-3.45 (m, 10H), 3.13 (t, J=7.2 Hz, 2H), 2.59 (m, 2H), 2.53 (m, 2H), 1.79 (m, 4H).
TLC: Rf 0.13 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 4.15-3.40 (m, 11H), 3.15 (t, J=6.9 Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.02-1.58 (m, 6H), 1.41 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.5 Hz, 3H).
TLC: Rf 0.42 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.73 (dd, J=1.8, 0.9 Hz, 1H), 7.17 (dd, J=2.4, 0.9 Hz, 1H), 6.63 (dd, J=2.4, 1.8 Hz, 1H), 4.80-4.65 (m, 2H), 3.90-3.25 (m, 6H), 3.66 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 1.80 (m, 4H).
TLC: Rf 0.38 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.60 (s, 1H), 7.47 (s, 3H), 4.31 (s, 2H), 3.49 (t, J=6.9 Hz, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.72 (s, 3H), 2.54 (m, 4H), 1.79 (m, 4H).
TLC: Rf 0.42 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 7.58-7.45 (m, 5H), 4.28 (s, 2H), 3.47 (t, J=6.6 Hz, 2H), 3.34 (m, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.52 (t, J=6.6 Hz, 2H), 1.86 (m, 2H).
TLC: Rf 0.23 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 7.15 (m, 2H), 6.69 (m, 3H), 3.50 (m, 4H), 3.32 (m, 4H), 2.89 (t, J=6.6 Hz, 2H), 2.51 (t, J=6.6 Hz, 2H), 1.84 (m, 2H).
TLC: Rf 0.51 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 4.10-3.55 (m, 10H), 3.47 (t, J=5.7 Hz, 2H), 3.30 (m, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 1.92 (m, 2H), 1.81 (m, 2H), 1.39 (m, 6H), 0.93 (m, 3H).
TLC: Rf 0.15 (methanol:methylene chloride=1:10).
TLC: Rf 0.63 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 4.05-3.50 (m, 8H), 3.78 (t, J=7.2 Hz, 2H), 3.24-3.15 (m, 4H), 2.60 (m, 2H), 2.53 (m, 2H), 2.20 (m, 1H), 1.80 (m, 4H), 1.10 (d, J=6.6 Hz, 6H).
TLC: Rf 0.69 (methylene chloride:methanol=9:1);
NMR (CD3OD): δ 7.12-7.00 (m, 4H), 3.85-3.70 (m, 6H), 3.51 (t, J=5.7 Hz, 2H), 3.50-3.18 (m, 6H), 2.67 (t, J=6.3 Hz, 2H), 1.95 (m, 2H).
TLC: Rf 0.12 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 8.15 (d, J=7.8 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 3.90-3.75 (m, 4H), 3.35 (m, 2H), 3.05-2.78 (m, 8H), 2.69 (s, 3H), 2.52 (t, J=6.3 Hz, 2H), 1.86 (m, 2H).
TLC: Rf 0.65 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.0 (s, 1H), 9.53 (brs, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 6.42 (s, 1H), 3.80-3.60 (m, 4H), 3.69 (s, 3H), 3.50 (m, 2H), 3.30-3.18 (m, 4H), 2.98-2.80 (m, 4H), 2.35 (m, 2H), 2.32 (s, 3H), 1.73 (m, 2H).
TLC: Rf 0.10 (methylene chloride:methanol:saturated aqueous ammonia=4:1:0.5%);
NMR (CD3OD): δ 2.77 (m, 4H), 2.64-2.45 (m, 6H), 2.36 (m, 2H), 2.33 (s, 3H), 2.26 (s, 6H), 1.85-1.65 (m, 6H).
TLC: Rf 0.13 (methylene chloride:methanol:saturated aqueous ammonia=4:1:0.5%);
NMR (CD3OD): δ 3.38 (t, J=6.6H, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 3.05-2.92 (m, 6H), 2.62-2.48 (m, 4H), 1.80 (m, 4H), 1.21 (t, J=7.2H, 6H).
Free Form:
TLC: Rf 0.60 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 11.73 (s, 1H), 6.58 (s, 1H), 3.58-3.55 (m, 4H), 3.17 (m, 2H), 2.58 (m, 4H), 2.41 (m, 4H), 2.32 (t, J=6.0 Hz, 2H), 1.71-1.67 (m, 2H).
Methanesulfonate:
TLC: Rf 0.52 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 11.96 (s, 1H), 9.65 (brs, 1H), 6.36 (s, 1H), 4.01 (m, 2H), 3.65 (t, J=11.7 Hz, 2H), 3.45 (m, 4H), 3.16 (m, 4H), 2.83 (t, J=7.8 Hz, 2H), 2.35 (m, 2H), 2.31 (s, 3H), 1.72 (m, 2H).
TLC: Rf 0.41 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.1);
NMR (DMSO-d6): δ 11.85 (s, 1H), 10.28 (brs, 1H), 6.41 (s, 1H), 3.32-2.78 (m, 16H), 2.42-2.20 (m, 6H), 2.12 (m, 2H), 1.71 (m, 2H).
TLC: Rf 0.52 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 4.10-3.50 (m, 8H), 3.76 (t, J=6.9H, 2H), 3.20-3.12 (m, 4H), 2.65-2.48 (m, 4H), 1.98-1.65 (m, 12H), 1.48-1.00 (m, 3H).
TLC: Rf 0.28 (methylene chloride:methanol=4:1);
NMR (CD3OD): δ 4.15-3.60 (m, 8H), 3.80 (t, J=7.2 Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.28 (m, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.65 (t, J=6.6 Hz, 2H), 1.94 (m, 2H), 1.80 (m, 2H), 1.45 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).
TLC: Rf 0.43 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.48 (s, 1H), 3.54 (t, J=7.5 Hz, 4H), 2.54-2.43 (m, 4H), 2.40-2.28 (m, 6H), 2.22 (t, J=7.5 Hz, 2H), 1.74-1.60 (m, 4H), 1.64-1.48 (m, 2H), 1.50-1.37 (m, 2H), 1.40-1.26 (m, 2H).
A mixture of the compound prepared in Example 25(1) (115 mg) and morpholine (0.5 mL) was refluxed for 3 hours. The reaction mixture was concentrated. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from a mixed solvent of isopropanol and hexane. A solution of the obtained solid (56.2 mg) and methanesulfonic acid (13.2 mg) in methanol (3.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the compound of the present invention (67.9 mg) having the following physical data.
TLC: Rf 0.41 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.90 (s, 1H), 10.04 (s, 1H), 9.42 (brs, 1H), 7.70 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 3.96 (m, 2H), 3.61 (t, J=11.4 Hz, 2H), 3.43-2.30 (m, 12H), 2.29 (s, 3H), 1.63 (m, 8H).
By the same procedure as described in Example 28, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 25(1) or the compound prepared in Example 23(23), 23(24), 23(29), 23(37), 25, 25(2), 25(6) to 25(8), 25(11) to 25(13), 26(2) or 26(5), and morpholine or a corresponding derivative, the following compounds of the present invention were obtained.
TLC: Rf 0.22 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.90 (s, 1H), 10.12 (s, 1H), 9.54 (brs, 1H), 7.70 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 3.98 (m, 2H), 3.63 (t, J=11.6 Hz, 2H), 3.43-2.32 (m, 12H), 2.30 (s, 3H), 1.95 (m, 2H), 1.64 (m, 4H).
TLC: Rf 0.29 (methanol:methylene chloride=2:3);
NMR (DMSO-d6): δ 12.89 (s, 1H), 10.04 (s, 1H), 8.95 (brs, 1H), 7.70 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 3.52-2.33 (m, 13H), 3.24 (s, 3H), 2.29 (s, 3H), 2.15-1.46 (m, 12H).
TLC: Rf 0.50 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.91 (s, 1H), 10.00 (s, 1H), 9.78 (brs, 1H), 7.70 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.20 (s, 2H), 4.05-3.40 (m, 10H), 3.16 (m, 2H), 2.56-2.33 (m, 4H), 2.31 (s, 3H), 1.70-1.59 (m, 4H).
TLC: Rf 0.16 (chloroform:methanol=9:1);
NMR (DMSO-d6): δ 10.53 (s, 1H), 10.15 (s, 1H), 9.59 (bs, 1H), 7.70 (s, 1H), 7.58-7.55 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 4.28-4.18 (m, 1H), 3.99-3.94 (m, 2H), 3.68-3.42 (m, 5H), 3.17-3.00 (m, 5H), 2.90-2.80 (m, 2H), 2.74-2.64 (m, 1H), 2.43 (t, J=6.9 Hz, 2H), 2.33-2.26 (m, 4H), 2.00-1.90 (m, 2H).
TLC: Rf 0.30 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.03 (s, 1H), 8.93 (brs, 2H), 7.70 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, H), 7.09 (d, J=7.8 Hz, 1H), 3.92 (m, 2H), 3.72 (t, J=2.4 Hz, 1H), 2.96 (m, 2H), 2.48-2.32 (m, 6H), 2.31 (s, 3H), 1.65 (m, 8H).
TLC: Rf 0.36 (methanol:methylene chloride:saturated aqueous ammonia=1:9:0.1);
NMR (DMSO-d6): δ 12.88 (brs, 1H), 10.07 (s, 1H), 8.54 (brs, 2H), 7.71 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.08 (s, 1H), 5.07 (s, 1H), 3.51 (t, J=6.0 Hz, 2H), 2.89 (m, 2H), 2.48-2.34 (m, 9H), 1.77 (s, 3H), 1.69-1.59 (m, 8H).
TLC: Rf 0.48 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.05 (s, 1H), 9.43 (brs, 1H), 7.70 (s, 1H), 7.60 (m, 1H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.90 (m, 1H), 5.70 (m, 1H), 3.80 (m, 1H), 3.54 (m, 1H), 3.22-2.98 (m, 4H), 2.60-2.18 (m, 8H), 2.50 (s, 3H), 1.82-1.50 (m, 8H).
TLC: Rf 0.35 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.06 (s, 1H), 8.56 (brs, 2H), 7.70 (s, 1H), 7.60 (m, 1H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 3.08-2.90 (m, 2H), 2.69 (m, 1H), 2.56-2.20 (m, 6H), 2.34 (s, 3H), 1.80-1.46 (m, 8H), 0.84-0.64 (m, 4H).
TLC: Rf 0.69 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 10.89 (s, 1H), 10.16 (s, 1H), 9.52 (br, 1H), 7.74 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.27 (s, 1H), 4.02-3.94 (m, 2H), 3.69-3.58 (m, 4H), 3.50-3.42 (m, 2H), 3.20-3.01 (m, 6H), 2.48-2.42 (m, 2H), 2.02-1.92 (m, 2H).
TLC: Rf 0.30 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.89 (s, 1H), 10.19 (s, 2H), 7.83 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.38 (t, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.16 (s, 2H), 3.85 (t, J=5.1 Hz, 2H), 3.28 (m, 2H), 2.58 (m, 2H), 2.48-2.35 (m, 6H), 1.82-1.59 (m, 10H).
TLC: Rf 0.55 (methanol:methylene chloride:saturated aqueous ammonia=1:9:0.1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.66 (brs, 1H), 10.17 (s, 1H), 7.86 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.16 (s, 2H), 3.82-3.55 (m, 4H), 3.38 (m, 2H), 3.03 (m, 2H), 2.48-2.36 (m, 4H), 1.99-1.59 (m, 8H).
TLC: Rf 0.45 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.51 (brs, ½H), 10.24 (s, ½H), 10.20 (s, ½H), 9.11 (brs, ½H), 7.73 (s, 1H), 7.64 (m, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 3.74-3.20 (m, 8H), 3.14-2.94 (m, 2H), 2.80-2.24 (m, 8H), 2.16-1.10 (m, 10H).
TLC: Rf 0.44 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.92 (s, 1H), 10.92 (brs, 1H), 10.52 (brs, 1H), 7.71 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.20-2.27 (m, 14H), 1.69 (m, 2H), 1.60 (m, 2H).
TLC: Rf 0.43 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.92 (s, 1H), 10.88 (s, 1H), 9.64 (brs, 2H), 7.69 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.02 (s, 2H), 3.97 (s, 2H), 3.76 (t, J=2.1 Hz, 1H), 2.48-2.35 (m, 4H), 1.69 (m, 2H), 1.60 (m, 2H).
TLC: Rf 0.40 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.92 (s, 1H), 10.81 (s, 1H), 9.29 (m, 2H), 7.69 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 3.85-3.71 (m, 3H), 2.45-2.13 (m, 8H), 1.80-1.61 (m, 6H).
TLC: Rf 0.41 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.89 (s, 1H), 10.57 (brs, 1H), 10.42 (s, 1H), 7.70 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.96 (m, 2H), 3.74 (t, J=11.5 Hz, 2H), 3.42-3.33 (m, 4H), 3.09 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.60 (m, 2H).
TLC: Rf 0.40 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.89 (s, 1H), 10.43 (s, 1H), 9.37 (brs, 2H), 7.72 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.93-3.71 (m, 3H), 3.25 (m, 2H), 2.83 (t, J=6.9 Hz, 2H), 2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.59 (m, 2H).
TLC: Rf 0.25 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.89 (s, 1H), 10.24 (s, 1H), 9.35 (brs, 2H), 7.70 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 3.91 (d, J=2.7 Hz, 2H), 3.70 (t, J=2.7 Hz, 1H), 3.00 (m, 2H), 2.44 (m, 4H), 2.34 (m, 2H), 1.92 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H).
TLC: Rf 0.54 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.34 (brs, 1H), 11.04 (brs, 1H), 10.31 (s, 1H), 7.78-7.64 (m, 2H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.11 (m, 1H), 4.02-3.70 (m, 4H), 3.50-3.32 (m, 2H), 3.24-2.90 (m, 6H), 2.60-2.34 (m, 4H), 2.12-1.90 (m, 2H), 1.82-1.62 (m, 2H).
TLC: Rf 0.43 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 7.77 (t, J=5.7 Hz, 1H), 3.42-3.26 (m, 2H), 2.97 (s, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.54-2.28 (m, 8H), 1.76-1.52 (m, 8H).
TLC: Rf 0.21 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (br, 1H), 7.97 (t, J=6.0 Hz, 1H), 3.40 (s, 2H), 3.18-3.03 (m, 3H), 2.52-2.45 (m, 2H), 2.44-2.32 (m, 4H), 2.12-2.02 (m, 2H), 1.78-1.56 (m, 8H).
Free Form:
TLC: Rf 0.29 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.58 (br, 1H), 7.82 (t, J=6.0 Hz, 1H), 3.39 (s, 2H), 3.10 (q, J=6.0 Hz, 2H), 2.60-2.52 (m, 4H), 2.52-2.45 (m, 2H), 2.44-2.33 (m, 4H), 1.68-1.60 (m, 4H), 1.58-1.46 (m, 8H).
Hydrochloride:
TLC: Rf 0.34 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.61 (s, 1H), 10.44 (br, 1H), 8.49 (m, 1H), 3.51-3.42 (m, 2H), 3.47 (s, 2H), 3.42-3.31 (m, 2H), 3.18-3.03 (m, 4H), 2.46-2.34 (m, 4H), 1.88-1.76 (m, 4H), 1.72-1.50 (m, 8H).
TLC: Rf 0.17 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.55 (brs, 1H), 7.99 (t, J=5.4 Hz, 1H), 4.08 (br, 1H), 3.46-3.20 (m, 2H), 3.09 (m, 1H), 2.68-2.28 (m, 8H), 2.13 (t, J=6.9 Hz, 2H), 2.04 (m, 2H), 1.80-1.40 (m, 8H).
TLC: Rf 0.26 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.55 (s, 1H), 8.05 (t, J=5.4 Hz, 1H), 3.42-3.24 (m, 4H), 2.60 (t, J=7.2 Hz, 2H), 2.56-2.22 (m, 8H), 2.18 (t, J=7.2 Hz, 2H), 1.76-1.54 (m, 4H), 1.52-1.24 (m, 6H).
TLC: Rf 0.25 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 7.84 (m, 1H), 3.39 (s, 2H), 3.09 (q, J=6.0 Hz, 2H), 2.72 (m, 1H), 2.46-2.30 (m, 6H), 2.10 (s, 3H), 1.66-1.60 (m, 4H), 0.89 (d, J=6.6 Hz, 6H).
TLC: Rf 0.43 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.56 (s, 1H), 7.93 (m, 1H), 3.40 (s, 2H), 3.12 (q, J=6.0 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.44-2.32 (m, 2H), 2.04 (m, 1H), 1.68-1.60 (m, 4H), 0.37-0.30 (m, 2H), 0.20-0.14 (m, 2H).
TLC: Rf 0.20 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.70 (s, 1H), 8.00 (m, 1H), 3.38 (s, 2H), 3.04 (q, J=6.3 Hz, 2H), 2.46-2.33 (m, 4H), 2.32-2.16 (m, 6H), 1.68-1.60 (m, 4H), 1.59-1.42 (in, 6H), 1.41-1.30 (m, 2H).
TLC: Rf 0.35 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.62 (s, 1H), 8.44 (m, 2H), 8.21 (t, J=6.0 Hz, 1H), 3.46 (m, 1H), 3.46 (s, 2H), 3.38-3.26 (m, 2H), 300-2.92 (m, 2H), 2.45-2.34 (m, 4H), 2.00-1.86 (m, 2H), 1.74-1.60 (m, 6H), 1.60-1.48 (m, 41).
TLC: Rf 0.30 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.61 (s, 1H), 8.53 (m, 2H), 8.19 (t, J=6.0 Hz, 1H), 3.65 (quin, J=7.8 Hz, 1H), 3.42 (s, 2H), 3.12 (q, J=6.0 Hz, 2H), 2.80-2.70 (m, 2H), 2.45-2.36 (m, 4H), 2.20-2.00 (m, 4H), 1.84-1.60 (m, 8H).
TLC: Rf 0.26 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 8.53 (br, 2H), 8.09 (t, J=6.0 Hz, 1H), 3.64 (quin, J=6.0 Hz, 1H), 3.40 (s, 2H), 3.06, (q, J=6.0 Hz, 2H), 2.82-2.70 (m, 2H), 2.46-2.33 (m, 4H), 2.22-2.02 (m, 4H), 1.84-1.72 (m, 2H), 1.70-1.60 (m, 4H), 1.60-1.38 (m, 4H).
TLC: Rf 0.18 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.62 (br, 1H), 8.40-8.20 (m, 2H), 8.22 (m, 1H), 3.45 (s, 2H), 3.30 (m, 1H), 3.03-2.90 (m, 2H), 2.43-2.32 (m, 4H), 2.00-1.90 (m, 2H), 1.78-1.54 (m, 8H), 1.28-1.00 (m, 6H).
TLC: Rf 0.063 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.58(brs, 1H), 8.28-8.00 (br, 2H), 8.10 (m, 1H), 3.40 (s, 2H), 3.05 (q, J=6.0 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 2.52 (s, 3H), 2.48-2.32 (m, 4H), 1.70-1.60 (m, 4H), 1.60-1.36 (m, 4H).
TLC: Rf 0.28 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.58(s 1H), 8.37 (br, 2H), 8.11 (m, 1H), 3.43 (m, 1H), 3.41 (s, 2H), 3.07 (q, J=6.0 Hz, 2H), 2.92-2.83 (m, 2H), 2.46-2.33 (m, 4H), 2.00-1.88 (m, 2H), 1.74-1.40 (m, 14H).
TLC: Rf 0.56 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.61(s 1H), 8.30-8.00 (br, 2H), 8.22 (m, 1H), 3.43 (s, 2H), 3.43 (m, 1H), 3.14 (q, J=6.6 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.46-2.34 (m, 4H), 1.96-1.84 (m, 2H), 1.80-1.46 (m, 12H).
TLC: Rf 0.56 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.58(s 1H), 8.24 (br, 2H), 8.10 (m, 1H), 3.40 (s, 2H), 3.07 (q, J=6.3 Hz, 2H), 3.00-2.84 (m, 3H), 2.46-2.34 (m, 4H), 2.04-1.95 (m, 2H), 1.80-1.40 (m, 11H), 1.28-1.10 (m, 5H).
TLC: Rf 0.44 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.59(s 1H), 8.09 (t, J=6.0 Hz, 1H), 3.40 (s, 2H), 3.09 (q, J=6.0 Hz, 2H), 2.74 (t, J=5.2 Hz, 2H), 2.46-2.25 (m, 5H), 1.70-1.55 (m, 6H), 0.58-0.50 (m, 2H), 0.50-0.40 (m, 2H).
TLC: Rf 0.44 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.56(brs 1H), 8.01 (t, J=6.0 Hz, 1H), 3.38 (s, 2H), 3.18-2.98 (m, 2H), 2.60-2.52 (m, 2H), 2.46-2.32 (m, 4H), 2.06 (m, 1H), 1.70-1.60 (m, 4H), 1.44-1.35 (m, 4H), 0.40-0.34 (m, 2H), 0.26-0.18 (m, 2H).
TLC: Rf 0.20 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.60 (s, 1H), 8.62 and 8.42 (br, 2H), 3.68 (s, 2H), 3.43-3.34 (m, 2H), 3.02 and 2.82 (s, 3H), 3.00-2.78 (m, 3H), 2.42-2.32 (m, 4H), 2.02-1.54 (m, 12H), 1.32-1.17 (m, 4H).
TLC: Rf 0.20 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.60 (s, 1H), 8.73 and 8.49 (br, 2H), 3.68 and 3.67 (s, 2H), 3.46-3.36 (m, 3H), 3.01 and 2.82 (s, 3H), 2.98-2.78 (m, 2H), 2.42-2.34 (m, 4H), 1.98-1.76 (m, 4H), 1.70-1.44 (m, 10H).
TLC: Rf 0.24 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.63 (br, 2H), 3.67 and 3.65 (s, 2H), 3.62 (m, 1H), 3.44-3.30 (m, 2H), 3.00 and 2.81 (s, 3H), 2.82-2.67 (m, 2H), 2.41-2.32 (m, 4H), 2.20-2.04 (m, 4H), 1.90-1.70 (m, 4H), 1.70-1.60 (m, 4H).
TLC: Rf 0.24 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.59 and 12.57 (s, 1H), 8.57 (br, 2H), 3.67 (s, 2H), 3.46-3.30 (m, 2H), 3.01 and 2.81 (s, 3H), 2.95-2.82 (m, 2H), 2.57 (m, 1H), 2.41-2.33 (m, 4H), 1.95-1.75 (m, 2H), 1.70-1.58 (m, 4H), 0.81-0.72 (m, 2H), 0.72-0.64 (m, 2H).
Free Form:
TLC: Rf 0.38 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.00 (t, J=5.4 Hz, 1H), 3.55 (m, 4H), 3.39 (s, 21), 3.29-2.20 (m, 12H), 1.63 (brs, 4H), 1.40 (brs, 4H).
Hydrochloride:
TLC: Rf 0.37 (methanol:methylene chloride:saturated aqueous ammonia=1:9:0.1);
NMR (DMSO-d6): δ 12.59 (s, 1H), 10.34 (brs, 1H), 8.13 (t, J=5.4 Hz, 1H), 3.94 (m, 2H), 3.72 (t, J=11.4 Hz, 2H), 3.41 (s, 2H), 3.38 (m, 2H), 3.07 (m, 6H), 2.39 (m, 4H), 1.63-1.40 (m, 8H).
Methanesulfonate:
TLC: Rf 0.34 (methanol:methylene chloride:28% ammonia water=1:9:0.1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 9.54 (brs, 1H), 8.10 (t, J=5.4 Hz, 1H), 4.00-3.94 (m, 2H), 3.69-3.61 (m, 2H), 3.41 (s, 2H), 3.36 (m, 2H), 3.11-2.97 (m, 6H), 2.42-2.33 (m, 4H), 2.34 (s, 3H), 1.63 (m, 6H), 1.48-1.38 (m, 2H).
Under an atmosphere of hydrogen, a mixture of the compound prepared in Example 26(4) (430 mg) and 10% palladium on carbon (86.0 mg) in methanol (5.0 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtrated through Celite. The filtrate was concentrated. The obtained powder was recrystallized from ethyl acetate to give a free form of the title compound (268 mg). A suspension of the obtained free form (264 mg) and methanesulfonate (74.6 mg) in methanol (3.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the compound of the present invention (307 mg) having the following physical data.
TLC: Rf 0.28 (methanol:methylene chloride:saturated aqueous ammonia=4:8:0.1);
NMR (CD3OD): δ 7.80 (s, 1H), 7.66 (m, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.22 (m, 1H), 3.01 (brt, J=6.8 Hz, 2H), 2.75 (s, 3H), 2.68 (brt, J=6.0 Hz, 2H), 2.53 (m, 4H), 1.90-1.74 (m, 8H).
By the same procedure as described in Example 29, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 26(6) to 26(8), 26(12), 24(31) or 27(38) instead of the compound prepared in Example 26(4), the following compounds of the present invention were obtained.
TLC: Rf 0.34 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.2);
NMR (CD3OD): δ 10.02 (brs, 1H), 7.78 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.07 (m, 1H), 3.47 (m, 1H), 3.07 (t, J=6.9 Hz, 2H), 2.91 (m, 1H), 2.75 (s, 6H), 2.53 (t, J=6.6 Hz, 2H), 2.29-1.52 (m, 10H).
TLC: Rf 0.26 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.2);
NMR (CD3OD): δ 8.14 (t, J=1.8 Hz, 1H), 7.78 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.39 (m, 1H), 4.68 (dd, J=11.1, 2.4 Hz, 1H), 4.00 (dt, J=14.1, 3.0 Hz, 1H), 3.53-3.34 (m, 2H), 3.10 (m, 4H), 2.76 (s, 6H), 2.57 (m, 3H), 1.84 (m, 4H).
TLC: Rf 0.29 (chloroform:methanol:28% ammonia water=40:10:1);
NMR (DMSO-d6): δ 12.96 (br-s, 1H), 10.05 (s, 1H), 8.22 (br-s, 2H), 7.69 (m, 1H), 7.57 (m, 1H), 7.37 (m, 1H), 7.00 (m, 1H), 2.92-2.78 (m, 4H), 2.58-2.52 (m, 5H), 2.40-2.32 (m, 2H), 2.30 (s, 3H), 1.86-1.76 (m, 2H), 1.66-1.46 (m, 8H).
TLC: Rf 0.34 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 10.89 (s, 1H), 10.37 (br, 1H), 8.83 (br, 2H), 7.76 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.26 (s, 1H), 3.64-3.58 (m, 2H), 3.20-3.14 (m, 2H), 2.94-2.84 (m, 2H), 2.54-2.30 (m, 5H), 1.70-1.60 (m, 4H).
Free Form:
TLC: Rf 0.14 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.1);
NMR (DMSO-d6): δ 12.54 (brs, 1H), 8.44 (s, 1H), 8.01 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.08-2.26 (m, 12H), 1.63 (brs, 4H), 1.34-1.00 (m, 5H).
Methanesulfonate:
TLC: Rf 0.43 (methylene chloride:methanol:28% ammonia water=6:3:1);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.18 (brs, 2H), 8.02 (t, J=5.4 Hz, 1H), 3.38 (s, 2H), 3.22 (m, 2H), 3.08 (m, 2H), 2.76 (m, 2H), 2.46-2.34 (m, 4H), 2.30 (s, 3H), 1.77 (m, 2H), 1.63 (m, 4H), 1.50 (m, 1H), 1.40-1.24 (m, 4H).
TLC: Rf 0.083 (methylene chloride:methanol=4:1);
NMR (DMSO-d6): δ 12.5 (brs, 1H), 2.80-2.55 (m, 12H), 2.49 (m, 2H), 2.35 (m, 2H), 1.75-1.68 (m, 6H).
4N hydrogen chloride in dioxane (2.50 mL) was added dropwise to a solution of the compound prepared in Example 26 (290 mg) in methanol (3.0 mL) in ice bath, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (methanol:methylene chloride=1:9→methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1). 1N sodium hydroxide solution (0.34 mL) was added dropwise to a suspension of the obtained solid (134 mg) in methanol (1.0 mL) and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. A solution of the obtained solid (64.8 mg) and methanesulfonate (17.6 mg) in methanol (3.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the compound of the present invention (82.4 mg) having the following physical data.
TLC: Rf 0.27 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.5);
NMR (CD3OD): δ 10.00 (brs, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.63 (dd, J=8.1, 1.2 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 3.07 (brt, J=7.2 Hz, 2H), 2.74 (s, 6H), 2.65 (brt, J=6.3 Hz, 2H), 2.52 (m, 4H), 1.82 (m, 8H).
By the same procedure as described in Example 30, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 26(9), 26(10), 26(11), 23, 26(14), 26(15), 23(3), 23(4), 23(9), 23(16), 26(16), 27(7), 23(21), 26(17), 27(14), 26(19), 23(25), 23(33) or 24(48) instead of the compound prepared in Example 26, the following compounds of the present invention were obtained.
TLC: Rf 0.20 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 10.56 (s, 1H), 10.17 (s, 1H), 8.45 (br, 2H), 7.71 (s, 1), 7.58 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 4.24 (dd, J=8.4, 4.5 Hz, 1H), 3.56 (m, 1H), 3.09 (m, 1H), 2.98-2.90 (m, 2H), 2.88-2.84 (m, 2H), 2.71 (m, 1H), 2.56 (t, J=6.0 Hz, 3H), 2.44 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 2.31 (m, 1H), 1.94-1.86 (m, 2H).
TLC: Rf 0.17 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 10.54 (s, 1H), 10.05 (s, 3H), 8.36 (br, 2H), 7.71 (s, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 4.24 (m, 1H), 3.59 (m, 1H), 3.08 (m, 1H), 2.92-2.82 (m, 2H), 2.71 (m, 1H), 2.60-2.40 (m, 3H), 2.31 (m, 1H), 2.293 (s, 3H), 2.289 (s, 3H), 1.68-1.55 (m, 4H), 1.40-1.30 (m, 2H).
TLC: Rf 0.34 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.88 (s, 1H), 10.24 (s, 1H), 8.84 (s, 2H), 7.73 (s, 1H), 7.64 (m, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.08 (m, 1H), 5.25 (t, J=7.2 Hz, 1H), 3.56-3.40 (m, 2H), 2.98-2.72 (m, 2H), 2.60-2.24 (m, 6H), 1.80-1.50 (m, 14H).
Free Form:
TLC: Rf 0.19 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 7.98 (m, 1H), 3.41 (s, 2H), 3.03 (q, J=6.6 Hz, 2H), 2.55 (t, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H), 1.70-1.60 (m, 4H).
Hydrochloride:
TLC: Rf 0.44 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.2);
NMR (DMSO-d6): δ 12.60 (brs, 1H), 8.42 (t, J=6.0 Hz, 1H), 8.11 (brs, 3H), 3.46 (s, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.84 (q, J=6.0 Hz, 2H), 2.39 (m, 4H), 1.63 (m, 4H).
TLC: Rf 0.18 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 10.43 (s, 1H), 9.10 (brs, 1H), 8.82 (brs, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.14 (m, 1H), 4.20-3.92 (m, 4H), 3.79 (m, 1H), 2.62-2.20 (m, 4H), 1.78-1.50 (m, 4H).
TLC: Rf 0.53 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 12.91 (s, 1H), 10.86 (s, 1H), 9.65 (brs, 1H), 8.67 (brs, 1H), 7.71 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, H), 4.37 (m, 1H), 3.27-2.26 (m, 6H), 1.94 (m, 4H), 1.70-1.59 (m, 4H).
TLC: Rf 0.41 (ethyl acetate:acetic acid:water=3:3:1);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.23 (br, 1H), 7.88 (br, 3H), 3.42 (s, 2H), 3.11 (q, J=6.6 Hz, 2H), 2.76 (q, J=6.6 Hz, 2H), 2.50-2.32 (m, 4H), 1.76-1.60 (m, 6H).
TLC: Rf 0.29 (ethyl acetate:acetic acid:water=3:3:1);
NMR (DMSO-d6): δ 12.60(brs, 1H), 8.86 (br, 2H), 8.38 (br, 1H), 3.47 (s, 2H), 3.35 (q, J=6.0 Hz, 2H), 2.94(quin, J=6.0 Hz, 2H), 2.53 (t, J=5.4 Hz, 3H), 2.50-2.34 (m, 4H), 1.70-1.60 (m, 4H).
TLC: Rf 0.62 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.2);
NMR (DMSO-d6): δ 12.62 (s, 1H), 8.25 (t, J=5.4 Hz, 1H), 8.00 (brs, 3H), 3.73 (q, J=6.9 Hz, 1H), 3.26 (m, 2H), 2.83 (m, 2H), 2.48-2.30 (m, 4H), 1.64 (m, 4H), 1.31 (d, J=6.9 Hz, 3H).
TLC: Rf 0.15 (ethyl acetate:acetic acid:water=3:1:1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 8.17 (t, J=6.3 Hz, 1H), 7.95 (br, 3H), 3.41 (s, 2H), 3.05 (q, J=6.3 Hz, 2H), 2.75 (m, 2H), 2.46-2.33 (m, 4H), 1.68-1.60 (m, 4H), 1.60-1.40 (m, 4H).
TLC: Rf 0.11 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.58 (brs, 1H), 8.59 (t, J=5.7 Hz, 1H), 8.19 (brs, 3H), 3.56-3.28 (m, 4H), 2.65 (t, J=7.2 Hz, 2H), 2.54-2.28 (m, 4H), 1.76-1.54 (m, 4H).
TLC: Rf 0.15 (chloroform:methanol=9:1);
NMR (CD3OD): δ 3.80-3.50 (m, 10H), 3.14 (t, J=7.5 Hz, 2H), 2.64-2.50 (m, 4H), 1.90-1.74 (m, 4H).
TLC: Rf 0.19 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 8.04 (t, J=5.4 Hz, 1H), 7.83 (brs, 3H), 3.69 (q, J=7.2 Hz, 1H), 3.09 (m, 2H), 2.74 (m, 2H), 2.48-2.25 (m, 4H), 1.64-1.42 (m, 8H), 1.31 (d, J=7.2 Hz, 3H).
TLC: Rf 0.11 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.24 (t, J=5.7 Hz, 1H), 7.94 (brs, 3H), 3.42-3.24 (m, 2H), 3.04-2.84 (m, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.56-2.28 (m, 6H), 1.76-1.52 (m, 4H).
TLC: Rf 0.10 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.1);
NMR (DMSO-d6): δ 12.69 (s, 1H), 9.63 (brs, 2H), 8.41 (brs, 3H), 3.78-3.06 (m, 6H), 2.94 (t, J=7.5 Hz, 2H), 2.58-2.30 (m, 4H), 1.78-1.54 (m, 4H).
TLC: Rf 0.10 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 8.09 (m, 4H), 3.36-3.20 (m, 2H), 2.82-2.66 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.54-2.28 (m, 4H), 2.15 (t, J=7.2 Hz, 2H), 1.84-1.52 (m, 6H).
TLC: Rf 0.34 (chloroform:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (br, 1H), 8.09 (m, 1H), 7.87 (br, 2H), 3.40 (s, 2H), 3.03 (q, J=6.0 Hz, 2H), 2.80-2.66 (m, 2H), 2.46-2.33 (m, 4H), 1.70-1.60 (m, 4H), 1.60-1.49 (m, 2H), 1.48-1.36 (m, 2H), 1.36-1.26 (m, 2H).
TLC: Rf 0.18 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.52 (s, 1H), 8.20 (t, J=5.4 Hz, 1H), 8.02 (brs, 3H), 3.36-3.20 (m, 2H), 2.92-2.76 (m, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.54-2.28 (m, 6H), 1.76-1.54 (m, 4H).
TLC: Rf 0.25 (methanol:acetic acid=5:1);
NMR (DMSO-d6): δ 12.24 (s, 1H), 8.41 (t, J=5.4 Hz, 1H), 7.94 (brs, 5H), 3.42 (s, 2H), 3.20 (t, J=5.4 Hz, 2H), 3.12 (m, 2H), 2.78 (m, 2H), 2.37 (t, J=6.0 Hz, 2H), 1.69 (m, 4H).
To a solution of the compound prepared in Reference example 13 (650 mg) in dimethylformamide (15 mL) were added potassium thioacetate (698 mg) and potassium carbonate (422 mg) and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured in cold water and extracted with ethyl acetate. The extract was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to give the compound of the present invention (688 mg) having the following physical data.
TLC: Rf 0.40 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 3.11 (t, J=7.2 Hz, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.56-2.28 (m, 4H), 2.31 (s, 3H), 1.76-1.54 (m, 4H).
By the same procedure as described in Example 31 using a corresponding derivative instead of the compound prepared in Reference example 13, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.43 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 11.82 (s, 1), 6.32 (s, 1H), 3.16 (m, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 2.31 (s, 3H), 1.69 (m, 2H).
To a suspension of the compound prepared in Example 31 (100 mg) in methanol (4.0 mL) were added benzyl bromide (0.06 mL) and potassium carbonate (82 mg) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured in cold 0.5N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=70:1→30:1) to give the compound of the present invention (47 mg) having the following physical data.
TLC: Rf 0.42 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.54 (s, 1H), 7.38-7.16 (m, 5H), 3.77 (s, 2H), 2.80-2.58 (m, 4H), 2.50-2.26 (m, 4H), 1.76-1.52 (m, 4H).
By the same procedure as described in Example 32, if necessary, by converting to corresponding salts by conventional method, using a corresponding derivative instead of benzyl bromide, the following compounds of the present invention were obtained.
TLC: Rf 0.57 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 2.78-2.70 (m, 4H), 2.58-2.20 (m, 12H), 1.76-1.56 (m, 6H), 1.54-1.26 (m, 6H).
Free Form:
TLC: Rf 0.28 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 2.82-2.70 (m, 4H), 2.68-2.56 (m, 2H), 2.54-2.22 (m, 10H), 1.76-1.55 (m, 4H), 1.54-1.26 (m, 6H).
Hydrochloride:
TLC: Rf 0.28 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.61 (s, 1H), 10.22 (brs, 1H), 3.44 (m, 2H), 3.19 (m, 2H), 3.04-2.68 (m, 8H), 2.62-2.28 (m, 4H), 1.90-1.54 (m, 9H), 1.35 (m, 1H).
To a solution of 4-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (300 mg; It was prepared by the same procedure as described in Example 32 using 1-t-butyldimethylsilyloxy-2-iodoethane instead of benzyl bromide.) in tetrahydrofuran (4.0 mL) was added tetrabutylammonium fluoride (638 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was poured in a cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated. The residue was washed with t-butyl methyl ether to give the compound of the present invention (191 mg) having the following physical data.
TLC: Rf 0.36 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 4.77 (t, J=5.4 Hz, 1H), 3.53 (dt, J=5.4, 6.6 Hz, 2H), 2.84-2.72 (m, 4H), 2.59 (t, J=6.6 Hz, 2H), 2.56-2.28 (m, 4H), 1.76-1.54 (m, 4H).
By the same procedure as described in Example 33 using 4-(2-(3-t-butyldimethylsilyloxypropylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 8-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one or 8-(2-(3-t-butyldimethylsilyloxypropylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one instead of 4-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, the following compounds of the present invention were obtained.
TLC: Rf 0.37 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.56 (s, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.44 (dt, J=5.1, 6.9 Hz, 2H), 2.80-2.68 (m, 4H), 2.56 (t, J=7.2 Hz, 2H), 2.54-2.30 (m, 4H), 1.76-1.54 (m, 6H).
TLC: Rf 0.31 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 11.78 (s, 1H), 6.33 (s, 1H), 4.78 (t, J=5.4 Hz, 1H), 3.53 (dt, J=5.4, 6.6 Hz, 2H), 3.17 (m, 2H), 2.84-2.60 (m, 4H), 2.59 (t, J=6.6 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69 (m, 2H).
TLC: Rf 0.32 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 11.77 (s, 1H), 6.33 (s, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.44 (dt, J=5.1, 5.7 Hz, 2H), 3.16 (m, 2H), 2.80-2.60 (m, 4H), 2.55 (t, J=7.2 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.78-1.50 (m, 4H).
To a solution of the compound prepared in Example 33 (160 mg) in chloroform (5.0 mL) were added triphenylphosphine (248 mg) and carbon tetrabromide (313 mg), and the mixture was stirred at room temperature for 2 hours. Methanol (1.0 mL) was added dropwise to the reaction mixture, which was stirred for 5 minutes and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=80:1→50:1) to give a crude compound of the present invention (598 mg) having the following physical data. The obtained compound was used in next reaction without purifying.
TLC: Rf 0.49 (chloroform:methanol=8:1);
NMR (CD3OD): δ 3.55 (t, J=6.3 Hz, 2H), 2.96-2.82 (m, 4H), 2.72 (t, J=6.3 Hz, 2H), 2.64-2.44 (m, 4H), 1.86-1.70 (m, 4H).
To a suspension of the compound prepared in Example 33(1) (110 mg) in methylene chloride (2.1 mL) were added thionyl chloride (0.08 mL) and pyridine (0.01 mL), and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured in cold water and extracted with methylene chloride. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to give the compound of the present invention (109 mg) having the following physical data.
TLC: Rf 0.49 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 12.57 (s, 1H), 3.70 (t, J=6.3 Hz, 2H), 2.82-2.72 (m, 4H), 2.64 (t, J=6.9 Hz, 2H), 2.54-2.30 (m, 4H), 1.95 (tt, J=6.9, 6.3 Hz, 2H), 1.76-1.54 (m, 4H).
By the same procedure as described in Example 28, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 34 or 35 instead of the compound prepared in Example 25(1) and cyclopentylamine instead of morpholine, the following compounds of the present invention were obtained.
TLC: Rf 0.36 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.56 (brs, 1H), 3.00 (quint, J=6.3 Hz, 1H), 2.82-2.72 (m, 4H), 2.71-2.28 (m, 8H), 1.80-1.16 (m, 12H).
TLC: Rf 0.38 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.99 (brs, 2H), 3.41 (m, 1H), 2.92 (m, 2H), 2.84-2.70 (m, 4H), 2.63 (t, J=7.2 Hz, 2H), 2.58-2.28 (m, 4H), 2.06-1.38 (m, 14H).
By the same procedure as described in Reference example 1→Example 1→Example 26→Example 29 using furo[3,4-d]pyrazine-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.17 (methanol:methylene chloride:saturated aqueous ammonia=1:4:0.2);
NMR (CD3OD): δ 7.81 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 3.50 (m, 2H), 3.39 (m, 2H), 3.08 (m, 2H), 2.75 (s, 3H), 2.74 (s, 3H), 2.53 (m, 2H), 1.81 (m, 4H).
A mixture of the compound prepared in Example 23(34) (180 mg), trimethyltin azide (285 mg) and toluene (1.5 mL) was refluxed overnight. The reaction mixture was concentrated. The residue was washed with ethyl acetate and hot methanol sequentially to give the compound of the present invention (113 mg) having the following physical data.
TLC: Rf 0.14 (methylene chloride:methanol:saturated aqueous ammonia=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.19 (t, J=6.0 Hz, 1H), 3.44 (q, J=6.0 Hz, 2H), 3.37 (s, 2H), 3.02 (t, J=6.0 Hz, 2H), 2.40-2.24 (m, 4H), 1.67-1.58 (m, 4H).
To a suspension of the compound prepared in Example 11(1) (150 mg) in tetrahydrofuran (2.9 mL) was added an aqueous solution (1.1 mL) of potassium carbonate (157 mg) and then thereto was added acetyl chloride (0.05 mL) at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and 1N hydrochloric acid was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ether to give the compound of the present invention (131 mg) having the following physical data.
TLC: Rf 0.36 (chloroform:methanol=8:1);
NMR (DMSO-d6): δ 13.08 (s, 1H), 7.60-7.40 (m, 5H), 4.28 (s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.04 (s, 3H).
By the same procedure as described in Example 39 and then by converting to a corresponding salt by conventional method, using 2-dimethylaminoacetyl chloride instead of acetyl chloride, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.57 (chloroform:methanol=4:1);
NMR (DMSO-d6): δ 13.17 (s, 1H), 9.75 (brs, 1H), 7.64-7.36 (m, 5H), 4.48-4.30 (m, 3H), 4.21 (m, 1H), 3.96-3.52 (m, 8H), 2.86-2.64 (m, 2H).
By the same procedure as described in Reference example 11 using the compound prepared in Example 23(36) instead of the compound prepared in Example 15, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.26 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.15 (m, 1H), 4.11 (m, 1H), 3.39 (s, 2H), 3.23 (q, J=6.0 Hz, 2H), 2.58-2.35 (m, 2H), 2.42-2.32 (m, 4H), 1.66-1.58 (m, 4H).
By the same procedure as described in Example 20 using the compound prepared in Example 24(41) instead of the compound prepared in Example 4(4), the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.35 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (s, 1H), 9.15 (s, 1H), 8.04 (t, J=5.7 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.36 (s, 2H), 3.22 (m, 2H), 2.58 (t, J=7.5 Hz, 2H), 2.33 (m, 4H), 1.61 (brs, 4H).
To a solution of 3,4,5,6-tetrahydrophthalic acid anhydride (10.0 g) in tetrahydrofuran (50.0 mL) was added sodium borohydride (600 mg) in ice bath. The mixture was stirred at room temperature for 30 minutes and refluxed for 5 hours. After cooling to room temperature, 1N hydrochloric acid (10.0 mL) was added to the reaction mixture, which was concentrated. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to give the title compound (5.40 g) having the following physical data.
TLC: Rf 0.64 (ethyl acetate:hexane=1:1);
NMR (CDCl3): δ 5.98 (brs, 1H), 4.90-4.50 (m, 1H), 2.52-2.40 (m, 1H), 2.32-2.16 (m, 3H), 1.86-1.60 (m, 4H).
A mixed solution of the compound prepared in Reference example 18 (1.54 g), tri-n-butylphosphine (2.02 g) and hydrogen bromide acetic acid solution (47%, 1.20 mL) in acetic acid (0.700 mL) was refluxed for 21 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=20:1) to give the title compound (3.56 g) having the following physical data.
TLC: Rf 0.51 (methanol:methylene chloride=1:10).
To a solution of the compound prepared in Reference example 19 (419 mg) and benzaldehyde (106 mg) in methylene chloride (4.00 mL) was added triethylamine (0.130 mL) and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to give the title compound (206 mg) having the following physical data.
TLC: Rf 0.83 (hexane:ethyl acetate=2:1).
A solution of the compound prepared in Reference example 20 (206 mg) and hydrazine monohydrate (49.0 μL) in ethanol (4.00 mL) was refluxed for 1 hour. Hydrazine monohydrate (49.0 μL) was added to the reaction mixture, which was refluxed for 1 hour. After cooling the reaction mixture to room temperature, the deposited crystal was collected by filtration. It was washed with ethanol and hexane, and dried under reduced pressure to give the compound of the present invention (152 mg) having the following physical data.
TLC: Rf 0.63 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.61 (s, 1H), 7.32-7.24 (m, 2H), 7.23-7.13 (m, 3H), 3.88 (s, 2H), 2.44-2.25 (m, 4H), 1.65-1.54 (m, 4H).
By the same procedure as described in Reference example 20→Example 42 using a corresponding derivative instead of benzaldehyde, the following compounds of the present invention were obtained.
TLC: Rf 0.51 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.54 (s, 1H), 7.35-7.15 (m, 5H), 2.90-2.82 (m, 2H), 2.81-2.72 (m, 2H), 2.52-2.42 (m, 2H), 2.41-2.32 (m, 2H), 1.70-1.58 (m, 4H).
TLC: Rf 0.42 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.59 (s, 1H), 8.45-8.39 (m, 2H), 7.56 (m, 1H), 7.31 (dd, J=7.5, 4.8 Hz, 1H), 3.92 (s, 2H), 2.46-2.33 (m, 4H), 1.72-1.56 (m, 4H).
TLC: Rf 0.59 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.58 (s, 1H), 8.45 (d, J=4.5 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.28-7.18 (m, 2H), 4.04 (s, 2H), 2.44-2.32 (m, 4H), 1.68-1.56 (m, 4H).
TLC: Rf 0.68 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 5.95 (m, 2H), 3.84 (s, 2H), 2.50-2.35 (m, 4H), 2.18 (s, 3H), 1.70-1.58 (m, 4H).
TLC: Rf 0.59 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.40 (s, 1H), 8.03 (dd, J=7.8, 1.2 Hz, 1H), 7.68 (dt, J=1.2, 7.8 Hz, 1H), 7.53 (m, 1H), 7.46 (d, J=7.8 Hz, 1H), 4.24 (s, 2H), 2.56-2.46 (m, 2H), 2.44-2.35 (m, 2H), 1.78-1.62 (m, 4H).
NMR (DMSO-d6): δ 12.61 (s, 1H), 8.15-8.06 (m, 2H), 7.68-7.57 (m, 2H), 4.06 (s, 2H), 2.47-2.34 (m, 4H), 1.70-1.56 (m, 4H).
TLC: Rf 0.60 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.65 (s, 1H), 8.16 (dt, J=6.9, 1.8 Hz, 2H), 7.46 (dt, J=6.9, 1.8 Hz, 2H), 4.05 (s, 2H), 2.42-2.33 (m, 4H), 1.70-1.55 (m, 4H).
Under an atmosphere of hydrogen, a mixed solution of the compound prepared in Example 43(4) (145 mg) and 10% palladium on carbon (30.0 mg) in methanol (15.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtrated through Celite. The filtrate was concentrated to give the compound of the present invention (129 mg) having the following physical data.
TLC: Rf 0.42 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.57 (s, 1H), 6.91 (dt, J=1.2, 7.8 Hz, 1H), 6.72 (dd, J=7.8, 1.2 Hz, 1H), 6.61 (dd, J=7.8, 1.2 Hz, 1H), 6.46 (dt, J=1.2, 7.8 Hz, 1H), 4.97 (s, 2H), 3.66 (s, 2H), 2.50-2.30 (m, 4H), 1.70-1.57 (m, 4H).
By the same procedure as described in Example 44 using the compound prepared in Example 43(5) or 43(6) instead of the compound prepared in Example 43(4), the following compounds of the present invention were obtained.
Free Form:
TLC: Rf 0.38 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 6.91 (t, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H), 6.31 (s, 1H), 6.29 (d, J=8.1 Hz, 1H), 5.00 (s, 2H), 3.71 (s, 2H), 2.45-2.30 (m, 4H), 1.70-1.50 (m, 4H).
Methanesulfonate:
TLC: Rf 0.53(methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.67 (s, 1H), 9.60 (br, 3H), 7.41 (t, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 3.93 (s, 2H), 2.43-2.28 (m, 4H), 2.33 (s, 3H), 1.67-1.54 (m, 4H).
TLC: Rf 0.44 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.55 (s, 1H), 6.78 (d, J=8.1 Hz, 2H), 6.47 (d, J=8.1 Hz, 2H), 4.90 (s, 2H), 3.68 (s, 2H), 2.42-2.25 (m, 4H), 1.70-1.50 (m, 4H).
A solution of (4aS,7aR)-4-phenyl-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[d]pyridazin-1-one (210 mg; It was prepared by the same procedure as described in Example 1 using (1R,2S)-2-benzoylcyclopentanecarboxylic acid instead of the compound prepared in Reference example 1.) and thionyl chloride (0.500 mL) in benzene (3.00 mL) was refluxed for 18 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was recrystallized from ethyl acetate to give the compound of the present invention (154 mg) having the following physical data.
TLC: Rf 0.21 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 13.02 (s, 1H), 7.62-7.58 (m, 2H), 7.50-7.42 (m, 3H), 2.99 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.06-1.96 (m, 2H).
To a solution of 2,3-pyridinedicarboxylic acid anhydride (19.4 g) in tetrahydrofuran (260 mL) was added aniline (11.8 mL) and the mixture was refluxed 2 hours. The reaction mixture was concentrated. Acetic anhydride (65 mL) was added to the reaction mixture, which was refluxed for 1.5 hours. After cooling in ice bath, the reaction mixture was poured in ice water (200 mL) and stirred for 1 hours. The precipitate was collected by filtration. It was washed with water and then washed with ethanol on heating to give the title compound (20.9 g) having the following physical data.
TLC: Rf 0.31 (hexane:ethyl acetate=1:1);
NMR (CDCl3): δ 7.48 (m, 5H) 7.70 (dd, J=7.69, 4.94 Hz, 1H) 8.28 (dd, J=7.69, 1.65 Hz, 1H) 9.06 (dd, J=4.94, 1.65 Hz, 1H).
A solution of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride in tetrahydrofuran (5.50 mL, 1.0M) was added dropwise to a suspension of the compound prepared in Reference example 21 (1.12 g) in tetrahydrofuran (20 mL) in ice bath and the mixture was stirred for 1 hour. 1N hydrochloric acid (10 mL) was added dropwise to the reaction mixture, which was stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate on heating to give the title compound (1.35 g) having the following physical data.
TLC: Rf 0.52 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 5.02 (s, 2H) 6.36 (m, 1H) 6.47 (m, 1H) 6.62 (t, J=1.92 Hz, 1H) 6.86 (t, J=7.83 Hz, 1H) 7.14 (m, 1H) 7.28 (m, 2H) 7.54 (m, 4H) 8.20 (dd, J=7.69, 1.65 Hz, 1H) 8.70 (dd, J=4.94, 1.65 Hz, 1H).
To the compound prepared in Reference example 22 (3.17 g) was added 6N hydrochloric acid (20 mL) and the mixture was refluxed overnight. The reaction mixture was cooled in ice bath, adjusted to pH 5 with 5N sodium hydroxide solution (24 mL) and concentrated. The residue was azeotroped with ethanol and suspended in ethanol (50 mL) with refluxing. Unnecessary sodium chloride was separated by filtration. The filtrate was concentrated. The residue was washed with isopropanol (15 mL) on heating to give the title compound (2.13 g) having the following physical data.
TLC: Rf 0.49 (methylene chloride:methanol:acetic acid=8:1:1);
NMR (DMSO-d6): δ 6.74 (m, 2H) 6.85 (t, J=2.00 Hz, 1H) 7.09 (t, J=7.87 Hz, 1H) 7.63 (dd, J=7.97, 4.76 Hz, 1H) 8.33 (dd, J=7.97, 1.55 Hz, 1H) 8.77 (dd, J=4.76, 1.55 Hz, 1H).
To a suspension of the compound prepared in Reference example 23 (1.94 g) in ethanol (40 mL) was added hydrazine monohydrate (400 mg) and the mixture was refluxed overnight. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration. It was washed with ethanol to give the title compound (1.70 g) having the following physical data.
TLC: Rf 0.54 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 5.14 (s, 2H) 6.64 (m, 1H) 6.94 (m, 1H) 6.99 (m, 1H) 7.09 (t, J=7.69 Hz, 1H) 7.84 (dd, J=8.06, 4.39 Hz, 1H) 8.63 (dd, J=8.06, 1.83 Hz, 1H) 9.12 (dd, J=4.39, 1.83 Hz, 1H) 13.00 (s, 1H).
To a suspension of the compound prepared in Reference example 24 (1.67 g) and platinum oxide (83 mg) in dimethylformamide (35 mL) was added 6N hydrochloric acid (2.5 mL) and the mixture was stirred 8 hours under an atmosphere of hydrogen. The reaction mixture was filtrated through Celite. The filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, which was extracted with tetrahydrofuran three times. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol (35 mL) on heating. Activated carbon (340 mg) was added to the mixture, which was stirred for 15 minutes. Activated carbon was filtrated through Celite. The filtrate was concentrated. The residue was washed with isopropanol on heating to give the compound of the present invention (1.25 g; free form) having the following physical data. The obtained compound (242 mg) was suspended in methanol (4 mL). A solution of methanesulfonic acid (96 mg) in methanol (1 mL) was added to the mixture, which was stirred. The deposited crystal was collected by filtration. It was washed with methanol to give the compound of the present invention (258 mg; methanesulfonate) having the following physical data.
Free Form:
TLC: Rf 0.40 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.00 (s, 1H), 7.07 (m, 1H), 6.64-6.60 (m, 2H), 6.53 (d, J=7.3 Hz, 1H), 5.60 (s, 1H), 5.21 (s, 2H), 3.15 (m, 2H), 2.38 (t, J=6.2 Hz, 2H), 1.71 (m, 2H).
Methanesulfonate:
TLC: Rf 0.40 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.28 (s, 1H), 7.53 (m, 1H), 7.40-7.30 (m, 3H) 3.13 (m, 2H), 2.40 (t, J=6.0 Hz, 2H), 2.35 (s, 3H), 1.73 (m, 2H).
By the same procedure as described in Reference example 21→Reference example 22→Reference example 23→Reference example 24→Example 46, if necessary, by converting to corresponding salts by conventional method, using furo[3,4-b]pyridine-5,7-dione or a corresponding derivative, and a corresponding derivative instead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride, the following compounds of the present invention were obtained.
TLC: Rf 0.56 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.29 (s, 1H), 7.39 (t, J=8.1 Hz, 1H), 7.22-6.78 (m, 3H), 3.15 (m, 2H), 3.01 (s, 6H), 2.41 (t, J=6.0 Hz, 2H), 2.33 (s, 3H), 1.73 (m, 2H).
TLC: Rf 0.51 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.13 (s, 1H), 7.31-7.16 (m, 5H), 6.22 (brs, 2H), 3.83 (s, 2H), 3.19 (t, J=6.0 Hz, 2H), 2.36 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 1.73-1.65 (m, 2H).
TLC: Rf 0.50 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.27 (s, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.03-6.96 (m, 3H), 6.21 (m, 2H), 3.78 (s, 3H), 3.16-3.13 (m, 2H), 2.41 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 1.76-1.71 (m, 2H).
TLC: Rf 0.25 (methylene chloride:methanol=19:1);
NMR (DMSO-d6): δ 12.2 (brs, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 3.14 (m, 2H), 2.40 (t, J=6.3 Hz, 2H), 2.33 (s, 3H), 1.73 (m, 2H).
TLC: Rf 0.49 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.21 (s, 1H), 9.79 (br-s, 1H), 7.80-7.37 (m, 4H), 5.83 (s, 1H), 4.40 (d, J=4.0 Hz, 2H), 3.96 (d, J=12.1 Hz, 2H), 3.62 (t, J=11.7 Hz, 2H), 3.30 (d, J=12.1 Hz, 2H), 3.20-3.06 (m, 4H), 2.40 (t, J=6.0 Hz, 2H), 2.30 (s, 3H), 1.73 (m, 2H).
TLC: Rf 0.50 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.38 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 6.95 (m, 2H), 3.15 (m, 2H), 2.99 (s, 6H), 2.42 (m, 2H), 2.34 (s, 3H), 1.73 (m, 2H).
TLC: Rf 0.51 (methylene chloride:methanol=10:1);
NMR (CD3OD): δ 7.72 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 4.46 (s, 2H), 4.11-4.02 (m, 2H), 3.80 (t, J=12.6 Hz, 2H), 3.42 (d, J=12.6 Hz, 2H), 3.40-3.18 (m, 4H), 2.69 (s, 6H), 2.72-2.64 (m, 2H), 2.00-1.89 (m, 2H).
TLC: Rf 0.54 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.32 (s, 1H), 9.45 (br, 1H), 7.76 (m, 1H), 7.64-7.53 (m, 2H), 7.43 (m, 1H), 5.64 (br, 1H), 4.25 (s, 2H), 3.87 (d, J=12.0 Hz, 2H), 3.67 (t, J=12.0 Hz, 2H), 3.25 (d, J=12.0 Hz, 2H), 3.16-3.00 (m, 4H), 2.42 (t, J=6.0 Hz, 2H), 2.33 (s, 3H), 1.79-1.66 (m, 2H).
TLC: Rf 0.42 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.40 (br, 1H), 11.99 (br, 1H), 7.77-7.69 (m, 2H), 7.62-7.48 (m, 2H), 6.30-5.30 (br, 3H), 4.45 (s, 2H), 3.80-3.50 (m, 4H), 3.70-3.40 (m, 4H), 3.30-3.00 (m, 4H), 2.42 (t, J=6.3 Hz, 2H), 1.80-1.66 (m, 2H), 1.24 (t, J=7.2 Hz, 3).
TLC: Rf 0.27 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.21 (s, 1H), 9.59 (br, 1H), 7.62-7.52 (m, 4H), 5.82 (s, 1H), 4.35-4.31 (m, 2H), 3.20-3.12 (m, 2H), 2.76 (s, 3H), 2.75 (s, 3H), 2.41 (t, J=6.3 Hz, 2H), 2.30 (s, 3H), 1.81-1.68 (m, 2H).
TLC: Rf 0.82 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.19 (s, 1H), 9.68 (br, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 5.76 (s, 1H), 4.34 (s, 2H), 3.18-3.10 (m, 2H), 2.76 (s, 6H), 2.40 (t, J=6.0 Hz, 2H), 2.31(s, 3H), 1.80-1.68 (m, 2H).
TLC: Rf 0.38 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.20 (s, 1H), 9.34 (br, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 5.77 (s, 1H), 4.36 (d, J=4.8 Hz, 2H), 3.12-3.02 (m, 6H), 2.40 (t, J=6.0 Hz, 2H), 2.30 (s, 3H), 1.80-1.68 (m, 2H), 1.24 (t, J=7.2 Hz, 6H).
TLC: Rf 0.49 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.95 (s, 1H), 9.64 (br, 1H), 7.60-7.52 (m, 4H), 4.33 (s, 2H), 2.76 (s, 6H), 2.50-2.40 (m, 2H), 2.40-2.32 (m, 2H), 2.30 (s, 3H), 1.76-1.66 (m, 2H), 1.66-1.55 (m, 2H).
TLC: Rf 0.50 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.12 (s, 1H), 9.41 (br, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 5.70 (s, 1H), 3.35-3.25 (m, 2H), 3.18-3.09 (m, 2H), 3.05-2.96 (m, 2H), 2.83 (s, 6H), 2.39 (t, J=6.3 Hz, 2H), 2.30 (s, 3H), 1.80-1.68 (m, 2H).
After cooling methanol (5 mL) to −15° C., thionyl chloride (1.3 mL) was added dropwise thereto and the solution was stirred for 15 minutes. To the solution was added the compound prepared in Reference example 23 (1.21 g). The solution was allowed to return to room temperature and then refluxed overnight. The reaction mixture was concentrated. To the residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from isopropanol (5 mL) to give the title compound (815 mg) having the following physical data.
TLC: Rf 0.37 (hexane:ethyl acetate=1:3);
NMR (DMSO-d6): 63.69 (s, 3H) 5.36 (s, 2H) 6.79 (m, 2H) 6.89 (m, 1H) 7.12 (t, J=7.83 Hz, 1H) 7.70 (dd, J=8.04, 4.81 Hz, 1H) 8.39 (dd, J=8.04, 1.65 Hz, 1H) 8.83 (dd, J=4.74, 1.65 Hz, 1H).
To a solution of the compound prepared in Reference example 25 (800 mg) in methylene chloride (15 mL) were added pyridine (505 μL) and trifluoroacetic acid anhydride (529 μL) sequentially in ice bath, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with methylene chloride and washed with 1N hydrochloric acid and water sequentially. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound (1.10 g) having the following physical data.
TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
NMR (CDCl3): δ 3.79 (s, 3H) 7.49 (t, J=7.97 Hz, 1H) 7.56 (dd, J=8.11, 4.81 Hz, 1H) 7.63 (m, 1H) 7.99 (m, 2H) 8.28 (s, 1H) 8.39 (dd, J=8.11, 1.65 Hz, 1H) 8.82 (dd, J=4.81, 1.65 Hz, 1H).
To a solution of the compound prepared in Reference example 26 (1.06 g) in dimethylformamide (12 mL) was added sodium hydride (127 mg) in ice bath and the mixture was stirred for 30 minutes. Methyl iodide (224 mL) was added to the reaction mixture, which was stirred at 0° C. for 1 hour and subsequently at room temperature for 6 hours. The reaction mixture was poured in ice water and extracted with a mixed solvent (ethyl acetate:hexane=1:1) twice. The combined organic layer was washed with water and brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a mixed solvent (isopropanol:hexane=1:1) to give the title compound (892 mg) having the following physical data.
TLC: Rf 0.31 (hexane:ethyl acetate=1:1);
NMR (CDCl3): δ 3.37 (s, 3H) 3.76 (s, 3H) 7.55 (m, 3H) 7.71 (s, 1H) 7.87 (d, J=7.69 Hz, 1H) 8.40 (dd, J=7.97, 1.65 Hz, 1H) 8.83 (dd, J=4.94, 1.65 Hz, 1H).
To a solution of the compound prepared in Reference example 27 (880 mg) in ethanol (12 mL) was added a solution of hydrazine monohydrate (240 mg) in ethanol (3 mL) and the mixture was refluxed overnight. 1N sodium hydroxide solution (5 mL) was added to the reaction mixture, which was refluxed for 1 hour. The reaction mixture was cooled in ice bath and 1N hydrochloric acid (5 mL) was added thereto. The precipitate was collected by filtration. It was washed with water and then washed with ethanol on heating to give the title compound (581 mg) having the following physical data.
TLC: Rf 0.39 (methylene chloride:methanol=19:1);
NMR (DMSO-d6): δ 2.69 (d, J=5.13 Hz, 3H) 5.73 (q, J=5.13 Hz, 1H) 6.62 (m, 1H) 6.97 (m, 2H) 7.18 (t, J=7.69 Hz, 1H) 7.85 (dd, J=8.06, 4.39 Hz, 1H) 8.64 (dd, J=8.06, 1.83 Hz, 1H) 9.13 (dd, J=4.39, 1.83 Hz, 1H) 13.02 (s, 1H).
By the same procedure as described in Example 46 using the compound prepared in Reference example 28 instead of the compound prepared in Reference example 24, the compounds of the present invention having the following physical data was obtained.
TLC: Rf 0.49 (methylene chloride:methanol=9:1);
NMR (DMSO-d6): δ 12.31 (s, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.18-6.85 (m, 3H), 3.16 (m, 2H), 2.83 (s, 3H), 2.41 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 1.73 (m, 2H).
By the same procedure as described in Reference example 25→Reference example 26→Reference example 27→Reference example 28→Example 46 using a corresponding derivative instead of the compound prepared in Reference example 23, the compounds of the present invention having the following physical data was obtained.
TLC: Rf 0.39 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.26 (brs, 1H), 7.27 (d, J=7.8 Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 5.96 (brs, 3H), 3.16 (m, 2H), 2.76 (s, 3H), 2.41 (m, 2H), 2.32 (s, 3H), 1.72 (m, 2H).
By the same procedure as described in Reference example 20→Example 42 using a corresponding derivative instead of benzaldehyde, the compounds of the present invention having the following physical data was obtained.
TLC: Rf 0.41 (methylene chloride:methanol=19:1);
NMR (DMSO-d6): δ 12.6 (s, 1H), 7.30-7.22 (m, 2H), 6.95-6.90 (m, 3H), 4.26 (t, J=6.9 Hz, 2H), 2.97 (t, J=6.9 Hz, 2H), 2.60-2.35 (m, 4H), 1.66 (m, 4H).
TLC: Rf 0.40 (methylene chloride:methanol=19:1);
NMR (DMSO-d6): δ 12.52 (s, 1H), 7.26 (m, 2H), 6.90 (m, 3H), 4.01 (t, J=6.3 Hz, 2H), 2.65 (t, J=7.5 Hz, 2H), 2.55-2.30 (m, 4H), 2.01 (m, 2H), 1.64 (m, 4H).
TLC: Rf 0.37 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.60 (s, 1H), 9.32(brs, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 3.81 (s, 21), 3.24-3.16 (m, 2H), 2.79 (s, 6H), 2.40-2.28 (m, 4H), 2.14-2.02 (m, 2H), 1.64-1.54 (m, 4H).
TLC: Rf 0.54 (methylene chloride:methanol=19:1);
NMR (DMSO-d6): δ 12.5 (s, 1H), 7.35-7.22 (m, 5H), 4.47 (s, 2H), 3.69 (t, J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.50-2.36 (m, 4H), 1.63 (m, 4H).
TLC: Rf 0.53(methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.60 (s, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.92 (dd, J=8.1, 1.5 Hz, 1H), 7.70 (ddd, J=8.1, 6.9, 1.5 Hz, 1H), 7.57 (ddd, J=8.1, 6.9, 1.5 Hz, 1H), 4.12 (s, 2H), 2.54-2.40 (m, 2H), 2.46-2.30 (m, 2H), 1.70-1.55 (m, 4H).
By the same procedure as described in Example 27, if necessary, by converting to corresponding salts by conventional method, using a corresponding derivative instead of the compound prepared in Reference example 13 and a corresponding derivative instead of benzylamine, the following compounds of the present invention were obtained.
TLC: Rf 0.83(methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.51 (s, 1H), 9.96 (br, 1H), 3.46-3.28 (m, 2H), 3.02-2.84 (m, 2H), 2.95-2.65 (m, 2H), 2.54-2.44 (m, 2H), 2.42-2.32 (m, 2H), 1.84-1.54 (m, 14H), 1.44-1.26 (m, 4H).
TLC: Rf 0.15 (methylene chloride:methanol:saturated aqueous ammonia=4:1:0.5%);
NMR (CD3OD): δ 3.69 (m, 4H), 3.33 (m, 2H), 2.78-2.42 (m, 22H), 1.85 (m, 2H).
TLC: Rf 0.19 (methylene chloride:methanol=19:1);
NMR (DMSO-d6): δ 11.97 (s, 1H), 9.39 (s, 1H), 7.41-7.30 (m, 5H), 6.38 (brs, 1H), 5.11 (s, 2H), 4.32 (brs, 2H), 3.87 (m, 1H), 3.70-3.40 (m, 7H), 3.30-3.15 (m, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.35 (t, J=6.3 Hz, 2H), 2.31 (s, 3H), 2.07 (m, 2H), 1.72 (m, 2H).
Hydrochloride:
TLC: Rf 0.29 (methylene chloride:methanol=10:1);
NMR (300 MHz, CD3OD) 3.10-3.00 (m, 4H), 2.37-2.26 (m, 4H), 2.25-2.16 (m, 2H), 1.85 (t, J=6.9 Hz, 2H), 1.83-1.75 (m, 2H), 1.75-1.67 (m, 2H), 1.08-0.88 (m, 8H).
Methanesulfonate:
TLC: Rf 0.25 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.55 (s, 1H), 9.52 (br, 1H), 4.01-3.92 (m, 2H), 3.64 (t, J=11.4 Hz, 2H), 3.45-3.36 (m, 2H), 3.17-2.95 (m, 4H), 2.58-2.43 (m, 4H), 2.43-2.34 (m, 2H), 2.31 (s, 3H), 1.77-1.54 (m, 8H).
By the same procedure as described in Example 24, if necessary, by converting to corresponding salts by conventional method, using a corresponding ester derivative instead of the compound prepared in Example 15 and a corresponding derivative instead of 2-aminoethanol, the following compounds of the present invention were obtained.
TLC: Rf 0.54 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 11.84 (s, 1H), 8.06 (t, J=5.7 Hz, 1H), 6.42 (s, 1H), 4.37 (t, J=4.8 Hz, 1H), 3.35 (m, 4H), 3.18 (m, 2H), 3.03 (td, J=6.6, 5.7 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69 (m, 2H), 1.41 (m, 4H).
TLC: Rf 0.22 (methanol:methylene chloride=1:4);
NMR (DMSO-d6): δ 11.84 (s, 1H), 8.06 (t, J=5.4 Hz, 1H), 6.43 (s, 1H), 3.55-3.52 (m, 4H), 3.32-3.31 (m, 2H), 3.18 (brs, 2H), 3.04 (m, 2H), 2.34-2.19 (m, 8H), 1.71-1.68 (m, 2H), 1.40-1.36 (m, 4H).
TLC: Rf 0.39 (methanol:methylene chloride:saturated aqueous ammonia=2:8:0.1);
NMR (DMSO-d6): δ 11.90 (s, 1H), 9.13 (brs, 1H), 8.30 (t, J=5.4 Hz, 1H), 6.30 (brs, 1H), 3.45-3.35 (m, 6H), 3.19-3.08 (m, 6H), 2.40-2.29 (m, 2H), 2.33 (s, 3H), 1.80-1.52 (m, 10H).
TLC: Rf 0.23 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.56 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 4.32 (t, J=5.1 Hz, 1H), 3.38 (s, 2H), 3.37-3.33 (m, 2H), 3.05-2.99 (m, 2H), 2.41-2.36 (m, 4H), 1.63 (m, 4H), 1.40-1.23 (m, 8H).
By the same procedure as described in Example 34 using a corresponding derivative instead of the compound prepared in Example 33, the following compounds of the present invention were obtained.
TLC: Rf 0.53(methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.57 (s, 1H), 8.02 (t, J=5.1 Hz, 1H), 3.51 (t, J=6.3 Hz, 2H), 3.39 (s, 2H), 3.04 (q, J=6.3 Hz, 2H), 2.46-2.33 (m, 4H), 1.78(quin, J=6.3 Hz, 2H), 1.70-1.58 (m, 4H), 1.48-1.30 (m, 4H).
TLC: Rf 0.37 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.57 (s, 1H), 7.99 (t, J=5.4 Hz, 1H), 3.51 (t, J=6.6 Hz, 2H), 3.38 (s, 2H), 3.06-3.00 (m, 2H), 2.41-2.36 (m, 4H), 1.82-1.75 (m, 2H), 1.64 (m, 4H), 1.41-1.16 (m, 6H).
By the same procedure as described in Example 28, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 53, 23(23) or 53(1) instead of the compound prepared in Example 25(1), the following compounds of the present invention were obtained.
TLC: Rf 0.57 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.57 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 3.54 (t, J=4.8 Hz, 4H), 3.38 (s, 2H), 3.02 (q, J=6.9 Hz, 2H), 2.46-2.33 (m, 4H), 2.33-2.25 (m, 4H), 2.21 (t, J=6.9 Hz, 2H), 1.68-1.58 (m, 4H), 1.39(quin, J=6.9 Hz, 4H), 1.31-1.19 (m, 2H).
TLC: Rf 0.67 (methanol:methylene chloride:28% ammonia water=2:8:0.1);
NMR (DMSO-d6): δ 12.63 (s, 1H), 9.37 (brs, 11H), 8.36 (t, J=5.7 Hz, 1H), 3.46 (s, 2H), 3.43-3.34 (m, 4H), 3.16-3.12 (m, 4H), 2.42-2.37 (m, 4H), 2.29 (s, 3H), 1.84-1.49 (m, 14H).
TLC: Rf 0.22 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 12.58 (s, 1H), 9.48 (brs, 1H), 8.03 (t, J=5.4 Hz, 1H), 3.98-3.94 (m, 2H), 3.67-3.39 (m, 6H), 3.07-3.01 (m, 6H), 2.48-2.36 (m, 7H), 1.63-1.27 (m, 12H).
By the same procedure as described in Reference example 22→Reference example 24→Example 20→Example 46, if necessary, by converting to corresponding salts by conventional method, using a corresponding derivative instead of 4-(bis(trimethylsilyl)amino)phenylmagnesium bromide, the following compounds of the present invention were obtained.
TLC: Rf 0.59 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 11.94 (s, 1H), 9.14 (br, 2H), 6.80 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.68 (m, 1H), 5.65 (s, 1H), 3.16-3.08 (m, 2H), 2.37 (t, J=6.0 Hz, 2H), 1.77-1.65 (m, 2H).
TLC: Rf 0.29 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 12.40 (brs, 1H), 9.20 (brs, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.16 (t, J=5.1 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 1.71 (m, 2H).
TLC: Rf 0.4 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.58 (br, 1H), 9.58 (br, 1H), 7.29 (t, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.88 (t, J=7.5 Hz, 1H), 5.96 (br, 1H), 3.23-3.12 (m, 2H), 2.54-2.4 (m, 2H), 1.82-1.64 (m, 2H).
By the same procedure as described in Example 46, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 43(1), Example 43(2), 23(17), 23(22), 24(11) or 24(16), or 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one instead of the compound prepared in Reference example 24 and, the following compounds of the present invention were obtained.
TLC: Rf 0.21 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.49 (br, 1H), 2.97-2.84 (m, 2H), 2.53-2.42 (m, 5H), 2.41-2.31 (m, 4H), 2.26 (m, 1H), 1.84 (m, 1H), 1.82 (s, 3H), 1.77-1.53 (m, 6H), 1.40 (m, 1H), 1.09 (m, 1H).
TLC: Rf 0.16 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.51 (br, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.58-2.40 (m, 7H), 2.40-2.32 (m, 2H), 1.86 (s, 3H), 1.74-1.45 (m, 7H), 1.38-1.20 (m, 2H), 1.10 (m, 1H).
TLC: Rf 0.58 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 12.47 (br, 1H), 3.01-2.91 (m, 2H), 2.56-2.42 (m, 6H), 2.41-2.32 (m, 4H), 1.81 (s, 3H), 1.80 (m, 1H), 1.70-1.55 (m, 6H), 1.22-1.07 (m, 2H).
TLC: Rf 0.27 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.64 (s, 1H), 9.22 (d, J=7.5 Hz, 1H), 8.77 (br, 21), 4.83 (m, 1H), 3.55 (s, 2H), 3.10 (m, 1H), 2.97 (m, 1H), 2.55-2.35 (m, 4H), 2.34 (s, 3H), 1.94-1.50 (m, 10H).
TLC: Rf 0.55 (methylene chloride:methanol:28% ammonia water=15:5:1);
NMR (DMSO-d6): δ 12.62 (s, 1H), 8.50 (m, 1H), 8.30-8.10 (m, 2H), 3.48 (s, 2H), 3.40-3.00 (m, 4H), 2.84 (m, 1H), 2.46-2.34 (m, 4H), 2.32 (s, 3H), 1.82-1.20 (m, 10H).
TLC: Rf 0.40 (methylene chloride:methanol:28% ammonia water=15:5:1);
NMR (DMSO-d6): δ 12.61 (s, 1H), 8.41 (m, 1H), 8.30-8.16 (m, 2H), 3.42 (s, 2H), 3.30-2.70 (m, 5H), 2.46-2.32 (m, 4H), 2.31 (s, 3H), 1.92-1.20 (m, 12H).
TLC: Rf 0.28 (methylene chloride:methanol:28% ammonia water=15:5:1);
NMR (DMSO-d6): δ 12.57 (brs, 1H), 8.26 (brs, 2H), 8.06 (t, J=5.5 Hz, 1H), 3.39 (s, 2H), 3.24-3.02 (m, 4H), 2.73 (m, 1H), 2.46-2.32 (m, 4H), 2.30 (s, 3H), 1.80-1.04 (m, 12H).
By the same procedure as described in Example 20, if necessary, by converting to corresponding salts by conventional method, using the compound prepared in Example 47(2) instead of the compound prepared in Example 4(4), the compounds of the present invention having the following data were obtained.
Free Form:
TLC: Rf 0.33 (methanol:methylene chloride=1:20);
NMR (DMSO-d6): δ 12.06 (s, 1H), 9.60 (s, 1H), 7.25 (t, J=8.1 Hz, 1H), 6.81 (m, 3H), 5.71 (s, 1H), 3.13 (m, 2H), 2.36 (m, 2H), 1.71 (m, 2H).
Sodium Salt:
TLC: Rf 0.43 (methanol:methylene chloride=1:9);
NMR (DMSO-d6): δ 11.85 (brs, 1H), 6.92 (t, J=7.8 Hz, 1H), 6.36 (brs, 2H), 6.17 (brs, 1H), 5.40 (s, 1H), 3.13 (m, 2H), 2.36 (m, 2H), 1.68 (m, 2H).
A mixed solution of the compound prepared in Example 24(44) (307 mg), 10% palladium on carbon (307 mg) and ammonium formate (236 mg) in methanol (3.00 mL) was refluxed for 30 minutes. After cooling to room temperature, the reaction mixture was filtrated through Celite. The filtrate was concentrated. The residue was washed with a mixed solution of methanol and ethyl acetate and dried under reduced pressure to give the compound of the present invention (187 mg) having the following physical data.
TLC: Rf 0.13 (methanol:methylene chloride:acetic acid=1:4:1);
NMR (DMSO-d6): δ 11.83 (brs, 1H), 8.06 (t, J=5.1 Hz, 1H), 6.44 (s, 1H), 3.18-2.09 (m, 13H), 1.69 (m, 2H), 1.52 (m, 2H), 1.29 (m, 3H), 0.94 (m, 2H).
Under an atmosphere of argon, to 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one (118 mg; It was prepared by the same procedure as described in Reference example 22→Reference example 23→Reference example 24 using pyridin-2-ylmagnesium bromide instead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride.) were added methanol (6 mL), methanesulfonate (51 mg) and platinum oxide (12 mg) sequentially. Under an atmosphere of hydrogen, the reaction mixture was stirred at room temperature for 5.5 hours. The reaction mixture was filtrated through Celite. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=20:1>methylene chloride:methanol:water=8:2:0.2) to give free form of the compound A (14 mg) and methanesulfonate of the compound B (77 mg) having the following physical data. The obtained compound A and B were converted to corresponding salts or free form by conventional method to give the compound of the present invention having the following physical data.
Free Form of the Compound A:
TLC: Rf 0.51 (methylene chloride:methanol=10:1).
NMR (DMSO-d6): δ 12.39 (br, 1H), 8.88 (br, 1H), 8.59 (m, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.93 (m, 1H), 7.44 (m, 1H), 3.40-3.25 (m, 2H), 2.43 (t, J=6.3 Hz, 2H), 1.85-1.74 (m, 2H).
Methanesulfonate of the Compound B:
TLC: Rf 0.15 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 12.36 (s, 1H), 8.76 (br, 2H), 6.63 (s, 1H), 4.21 (d, J=9.9 Hz, 1H), 3.30 (m, 1H), 3.28-3.16 (m, 2H), 2.89 (m, 1H), 2.36 (t, J=6.0 Hz, 2H), 2.29 (s, 3H), 2.03 (d, J=12.3 Hz, 1H), 1.84-1.60 (m, 6H), 1.43 (m, 1H).
Free Form of the Compound B:
TLC: Rf 0.14 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 11.74 (s, 1H), 7.36 (s, 1H), 3.54 (dd, J=9.6, 3.9 Hz, 1H), 3.26-3.16 (m, 2H), 2.94 (d, J=12.0 Hz, 1H), 2.65-2.50 (m, 1H), 2.32 (t, J=6.3 Hz, 2H), 1.79 (m, 1H), 1.76-1.26 (m, 7H).
Methanesulfonate of the Compound A:
TLC: Rf 0.50 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.63 (br, 1H), 9.45 (br, 2H), 8.60 (d, J=4.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.97 (t, J=8.4 Hz, 1H), 7.48 (m, 1H), 3.40-3.33 (m, 2H), 2.52-2.42 (m, 2H), 2.36 (s, 3H), 1.84-1.73 (m, 2H).
Dimethanesulfonate of the Compound B:
TLC: Rf 0.66 (methylene chloride:methanol:ammonia water=8:2:0.2);
NMR (DMSO-d6): δ 1.45 (m, 1H) 1.72 (m, 6H) 2.04 (d, J=12.82 Hz, 1H) 2.37 (m, 8H) 2.94 (s, 1H) 3.25 (m, 3H) 4.26 (t, J=10.44 Hz, 1H) 7.21 (m, 1H) 8.71 (m, 1H) 8.89 (m, 1H) 12.48 (s, 1H).
By the same procedure as described in Example 59, if necessary, by converting to corresponding salts by conventional method, using 8-(pyridin-3-yl)pyrido[2,3-d]pyridazin-5(6H)-one, 8-(pyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-one or 8-(1-benzylpyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-one instead of 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one, the following compounds of the present invention were obtained.
Compound A:
TLC: Rf 0.66 (methylene chloride:methanol=4:1);
NMR (DMSO-d6): δ 12.46 (s, 1H), 8.92 (s, 1H), 8.86 (d, J=5.1 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 7.91 (dd, J=7.5, 5.1 Hz, 1H), 6.20 (brs, 1H), 3.13 (m, 2H), 2.41 (m, 2H), 2.31 (s, 3H), 1.75 (m, 2H).
Compound B:
TLC: Rf 0.12 (methylene chloride:methanol:acetic acid=4:1:2%);
NMR (DMSO-d6): δ 11.75 (s, 1H), 6.48 (s, 1H), 3.18 (m, 2H), 2.98 (m, 2H), 2.71 (m, 1H), 2.44 (m, 2H), 2.32 (m, 2H), 1.86 (s, 3H), 1.83 (m, 1H), 1.74-1.43 (m, 5H).
Compound A:
TLC: Rf 0.28(methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 12.63 (br, 1H), 8.90 (d, J=6.0 Hz, 2H), 8.00 (d, J=6.0 Hz, 2H), 6.23 (br, 1H), 3.18-3.10 (m, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 1.82-1.70 (m, 2H).
Free Form of Compound B:
TLC: Rf 0.053 (methylene chloride:methanol:acetic acid=4:1:2%);
NMR (DMSO-d6): δ 11.71 (s, 1H), 6.33 (s, 1H), 3.16 (m, 2H), 2.94 (m, 2H), 2.74-2.38 (m, 3H), 2.32 (m, 2H), 1.75-1.32 (m, 6H).
Dimethanesulfonate of Compound B:
TLC: Rf 0.86 (methylene chloride:methanol:water=8:2:0.2);
NMR (DMSO-d6): δ 11.79 (br, 1H), 8.13 (br, 3H), 6.40 (s, 1H), 3.23-3.15 (m, 2H), 3.15-3.04 (m, 2H), 2.81-2.64 (m, 3H), 2.33 (t, J=6.3 Hz, 2H), 1.82 (s, 6H), 1.80-1.65 (m, 4H), 1.64-1.46 (m, 2H).
TLC: Rf 0.41 (methylene chloride:methanol:acetic acid=4:1:2%).
By the same procedure as described in Reference example 2→Reference example 3→Example 3 using thiomorpholin-3-ylcarboxylic acid ethyl ester or a corresponding derivative, and a corresponding derivative instead of 3-nitrobenzoyl chloride, the following compounds of the present invention were obtained.
TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
NMR (DMSO-d6): δ 10.27 (s, 1H), 5.79 (m, 1H), 4.03 (dd, J=10.3, 3.0 Hz, 1H), 3.82 (dt, J=13.8, 3.0 Hz, 1H), 3.06 (ddd, J=13.8, 11.7, 2.1 Hz, 1H), 2.77 (m, 1H), 2.74-2.58 (m, 2H), 2.42 (m, 1H), 2.10-2.00 (m, 4H), 1.68-1.50 (m, 4H).
TLC: Rf 0.37 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.66 (s, 1H) 7.80 (m, 1H), 6.72 (d, J=3.3 Hz, 1H), 6.58 (m, 1H), 4.22 (dd, J=10.2, 3.0 Hz, 1H), 3.73 (dt, J=14.1, 3.0 Hz, 1H), 3.22 (m, 1H), 2.94-2.72 (m, 3H), 2.49 (m, 1H).
TLC: Rf 0.37 (hexane:ethyl acetate=1:1);
NMR (DMSO-d6): δ 10.62 (s, 1H), 7.65 (dd, J=5.1, 1.2 Hz, 1H), 7.30 (dd, J=3.6, 1.2 Hz, 1H), 7.11 (dd, J=5.1, 3.6 Hz, 1H), 4.24 (dd, J=8.1, 3.3 Hz, 1H), 3.96 (dt, J=13.8, 3.3 z, 1H), 3.20 (m, 1H), 2.92-2.76 (m, 3H), 2.49 (m, 1H).
TLC: Rf 0.53 (hexane:ethyl acetate=1:1);
NMR (CDCl3): δ 8.24 (br, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 5.15 (m, 1H), 4.20 (dd, J=11.1, 3.0 Hz, 1H), 3.36-3.20 (m, 2H), 3.03-2.83 (m, 2H), 2.41 (m, 1H).
TLC: Rf 0.32 (methylene chloride:methanol=10:1);
NMR (CDCl3): δ 8.70 (dd, J=4.8, 1.8 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H), 8.13 (br, 1H), 7.71 (dt, J=8.1, 1.8 Hz, 1H), 7.39 (dd, J=8.1, 4.8 Hz, 1H), 4.38 (dd, J=11.1, 2.7 Hz, 1H), 3.75 (dt, J=14.1, 2.7 Hz, 1H), 3.21 (ddd, J=14.1, 12.0, 2.7 Hz, 1H), 3.11 (m, 1H), 2.98 (dd, J=14.1, 10.8 Hz, 1H), 2.76 (m, 1H), 2.31 (m, 1H).
TLC: Rf 0.30 (chloroform:methanol=9:1);
NMR (CD3OD): δ 8.10-8.00 (brs, 1H), 6.85-6.83 (in, 2H), 6.82-6.80 (m, 1H), 6.01 (s, 2H), 4.33 (dd, J=10.8, 2.4 Hz, 1H), 3.83 (dt, J=13.5, 2.7 Hz, 1H), 3.20-3.02 (m, 2H), 3.00-2.88 (m, 1H), 2.80-2.68 (m, 1H), 2.32-2.22 (m, 1H).
TLC: Rf 0.36 (methanol:methylene chloride=1:10);
NMR (DMSO-d6): δ 10.99 (s, 1H), 8.66 (m, 2H), 7.90 (dt, J=7.8, 2.1 Hz, 1H), 7.50 (dd, J=7.8, 4.8 Hz, 1H), 6.27 (s, 1H), 3.62 (m, 2H), 3.16 (m, 2H).
TLC: Rf 0.54 (methylene chloride:methanol=10:1);
NMR (DMSO-d6): δ 10.96 (s, 1H), 8.04-7.95 (m, 4H), 7.62-7.53 (m, 3H), 6.28 (s, 1H), 3.69-3.64 (m, 2H), 3.24-3.16 (m, 2H).
To a suspension of 4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one (150 mg; CAS Registry No. 89981-21-5; the compound described in Yakugaku Zassi., 82, 302-303 (1962)) in ethylene glycol (1.6 mL) was added piperazine (420 mg) and the mixture was stirred at 200° C. for 7 hours. After cooling to room temperature, the reaction mixture was poured in a cold saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=20:1→10:1) to give free form of the title compound (64 mg). To a solution of the obtained free form in methanol (2.0 mL) was added 4N hydrogen chloride-ethyl acetate solution (1 mL). The mixture was stirred at room temperature and concentrated. The residue was recrystallized from a mixed solution of methanol and ethyl acetate to give the compound of the present invention (21 mg) having the following physical data.
TLC: Rf 0.46 (methylene chloride:methanol:acetic acid=20:5:2);
NMR (DMSO-d6): δ 12.31 (s, 1H), 8.98 (brs, 2H), 3.24-3.02 (m, 8H), 2.58-2.30 (m, 4H), 1.78-1.50 (m, 4H).
By the same procedure as described in Example 60→Example 59 using 8-chloropyrido[2,3-d]pyridazin-5(6H)-one (the compound described in Chem. Pharm. Bull, 13(5), 586-593 (1965)) instead of 4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one, the compound of the present invention having the following physical data was obtained.
TLC: Rf 0.18 (methylene chloride:methanol:acetic acid=20:5:2);
NMR (DMSO-d6): δ 11.51 (s, 1H), 6.12 (s, 1H), 3.26-3.04 (m, 8H), 3.02-2.88 (m, 3H), 2.31 (t, J=6.0 Hz, 2H), 1.71 (m, 2H).
The following components were admixed in conventional method and punched out to obtain 100 tablets each containing 50 mg of active ingredient.
After mixing the following components by a conventional method, the resulting solution was sterilized by a conventional method and 5 ml portions thereof were filled in amples, respectively, and freeze-dried by a conventional method to obtain 100 amples of injection containing each 20 mg of the active ingredient.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2002-42259 | Feb 2002 | JP | national |
| 2002-199673 | Jul 2002 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP03/01694 | 2/18/2003 | WO |
