DESCRIPTION
CYCLIC ETHERAMINE DERIVATIVES AS MEDICAMENTS FOR MALIGNANT TUMORS
Technical Field
This invention relates to cyclic etheramine derivatives useful as remedies for malignant tumors , the prognoses of which are not promising, such as neuroblastomas .
Background Art
Among infantile malignant tumors, progressive neuroblastoma (NB) is still not promising in prognosis in spite of multidisciplinary treatment . From a study conducted using 13-cis-retinoic acid, it is known that a down regulation takes place in the expression of the N-i-iyc gene to exhibit differentiation-inducing effect . This acid is, however, not considered to bring about sufficient clinical effects for neuroblastomas . An object of the present invention is, therefore, to provide a medicament effective for malignant tumors, the prognoses of which are not promising, such as neuroblastomas.
Disclosure of the Invention By stimulating cultured cell strains of human
neuroblastoma origin with nerve growth factor (NGF) , the present inventors conducted an investigation as to whether or not the expression of c-fos, which is one of the initial expression gene groups located downstream of the intracellular signal transduction system, would take place. As a result, cultured cell strains - in each of which upon NGF stimulation, the signal was transducted to c-fos - were found to be those recognized to express NGF high affinity receptor ( trk-A) and NGF low affinity receptor (LNGFR) . It was also suggested that each cultured cell strain, on which the expression of c-fos was not confirmed despite the possession of both of the receptors, developed a certain abnormality in the course of the transduction of the signal.
Therefore, the present inventors synthesized a variety of compounds, and conducted an investigation as to whether or not they would repair the signal transduction system in the case of the above-described abnormality in the expression of c-fos and would act to induce differentiation. As a result, it has been found that cyclic etheramine derivatives represented by the below-described formula have effect to repair the expression of c-fos, leading to the completion of the present invention.
Described specifically, the present invention provides a cyclic etheramine derivative represented by the following formula (1) :
wherein Y
1 and Y
2 maybe the same or different and each represents an oxygen atom or two hydrogen atoms, and R
1 and R
2 may be the same or different and each represents a hydrogen atom or a substituted or unsubstituted alkyl group; or a salt thereof. The present invention also provides a medicament which comprises as an active ingredient the cyclic etheramine derivative represented by the formula (1) or the salt thereof . The present invention further provides a medicament composition which comprises the cyclic etheramine derivative represented by the formula (1) or the salt thereof and a pharmaceutically acceptable carrier.
The present invention further provides use of the cyclic etheramine derivative represented by the formula (1) or the salt thereof for the production of the medicament.
The present invention still further provides a method for treating a malignant tumor, which comprises administering an effective amount of the cyclic etheramine derivative represented by the formula (1) or the salt thereof.
Best Modes for Carrying Out the Invention
In the formula (1) , Y1 and Y2 may be the same or different and each represents an oxygen atom or two hydrogen atoms. In this definition, the representation of two hydrogen atoms by each of Y1 and Y2 is more preferred.
R1 and R2 may be the same or different and each represents a hydrogen atom or a substituted or unsubstituted alkyl group . In this definition, the alkyl group may preferably be a Ci-Cβ alkyl group, with a Ci-Cβ alkyl group being more preferred. The alkyl group can be linear or branched. Examples of the alkyl group can include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and n-hexyl .
Illustrative of substituents which can substitute the alkyl group are carboxyl groups, alkoxycarbonyl groups, hydroxyl groups, halogen atoms, substituted or unsubstituted aryl groups, and substituted or unsubstituted heterocyclic groups. Examples of the alkoxycarbonyl groups can include Ci-Cδ alkoxycarbonyl groups, more specifically methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl. Examples of the halogen atoms can include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms .
Examples of the aryl groups can include C6-C10 aryl groups, more specifically phenyl and naphthyl . Examples of the heterocyclic group can include 5- or β-membered,
nitrogen-containing heterocyclic groups, more specifically pyrrolyl, imidazolyl, ' yrazolyl, pyridyl, pyrimidinyl and pyrazinyl. Of these, pyridyl is particularly preferred. It is to be noted that this pyridyl group can include such a case that the nitrogen atom in the pyridine ring is bonded with an alkyl group to form a pyridinium salt.
Illustrative of groups which can substitute on these aryl and heterocyclic groups are an amino group, C-Cβ alkylamino groups and di (Ci-Cg alkyl) amino groups. More specific substituents can include amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and diisopropylamino. Of these, di (Ci-Cε alkyl) amino groups are more preferred, with a dimethylamino group being particularly preferred. Preferred examples of the salt of the cyclic etheramine derivative represented by the formula (1) are mineral salts such as the hydrochloride, sulfate and nitrate . When R1 and/or R2 contain a group with a pyridinium salt formed therein, its counter ion may preferably be a halogen ion such as a chlorine ion or a bromine ion.
In the present invention, solvates represented by hydrates are also included. The compound according to the present invention can have one or more asymmetric carbon atoms depending on the substituents. In such a case, optically active isomers are also included in the present invention.
The cyclic etheramine derivative represented by the formula (1) or the salt thereof, which may hereinafter be referred to as "the compound (1) of the present invention", can be produced, for example, in accordance with the following reaction scheme:
(1 a) (l b)
(l e) (I f) wherein X1 and X2 each independently represents a halogen atom,
R3 represents a hydrogen atom, an alkyl group, a phenyl group or a substituted or unsubstituted phenyl group, R4 represents an alkyl group, R5 represents an alkyl group, and R6 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group.
Specifically described, a halogenoacetic acid ester (3) is reacted with 4, 4' -dihydroxydiphenylmethane (2) to afford a compound (4). Ester residual groups of the compound (4) may be converted into active ester moieties as needed, followed by the reaction with ammonia to yield a compound (5) . The compound (5) is then reduced to obtain the compound (6) . The compound (6) and the compound (4) are reacted to afford a cyclic etheramine (la) . Reduction of this compound (la) provides a compound ( lb) , with which an α, β-unsaturated fatty acid ester or halogenofatty acid ester is reacted to obtain a compound (lc) . Reduction of this compound (lc) provides a compound (Id) , halogenation of which results in a compound (le) . Reaction of desired one of various aryl compounds and heterocyclic compounds with the compound (le) provides a compound (If) .
A description will hereinafter be made reaction step by reaction step. Step (a)
In the step (a) , the halogenoacetic acid ester is reacted with 4, 4' dihydroxydiphenylmethane (2) to obtain the compound
(4) .
Illustrative of the halogenoacetic acid ester are methyl bromoacetate and ethyl bromoacetate. This reaction can be conductedpreferably in the presence of a base such as potassium carbonate, sodium hydroxide or sodium carbonate. It is also preferred to conduct this reaction at 0 to 100°C in a polar solvent such as dimethylformamide.
The ester residual groups of the compound (4) may be converted into active estermoieties, for example, substituted aryl ester moieties typified, for example, by pentafluorophenyl ester moieties to make the reaction with ammonia more efficient. To convert into such active ester moieties, the compound (4) may be hydrolyzed, followed by the reaction with a substituted phenol such as pentafluorophenol . This esterification reaction can be conducted preferably in the presence of a condensing agent such as N^N'-dichlorohexylcarbodiimide. Step (b)
In the step (b) , ammonia is reacted with the compound (4) to afford the compound (5) .
The reaction is conducted by reacting aqueous ammonia with the compound (4) in a solvent such as tetrahydrofuran. As a reaction temperature, 0 to 80°C or so is sufficient. Step (c) In the step (c) , the compound (5) is reduced to yield
the compound (6).
This reducing reaction can be conducted preferably by using a boron hydride compound such as a boran-dimethyl sulfide complex. It is preferred to conduct the reaction in a solvent such as tetrahydrofuran at 0°C to the reflux temperature of the solvent.
Step (d)
In the step (d) , the compound (4) is reacted with the compound (6) to obtain the cyclic etheramine (la). The reaction can be conducted preferably in an inert solvent, such as methylene chloride, in the presence of a base, such as triethylamine or pyridine, at 0°C to the reflux temperature of the solvent.
Step (e) In the step (e) , the compound (la) is reduced to afford the compound (lb) .
This reducing reaction can be conducted under similar conditions as in the above-described step (c) .
Step (f) In the step (f) , alkoxycarbonylalkyl groups (-R4-COOR5) are introduced onto the amino groups of the compound (lb) , respectively, to obtain the compound (lc) .
Illustrative of a rawmaterial for introducing the groups
(-R-COOR5) are α, β-unsaturated fatty acid esters such as acrylic acid esters and β-halogenofatty acid esters such as
β-bromopropionic acid esters.
When a β-halogenofatty acid ester is used, the introduction can be effected as in the step (a) . When an α, β-unsaturated fatty acid ester is used, on the other hand, the introduction can be conducted preferably in the presence of a metal catalyst, such as cupric nitrate or cupric acetate, in a solvent, such as methanol, at a temperature of from 0 to 150°C.
Step (g) In the step (g) , the compound (lc) is reduced to yield the compound (Id) .
This reducing reaction can be conducted preferably by using a reducing agent such as lithium borohydride. It is preferred to conduct the reaction in a solvent, such asmethanol or tetrahydrofuran, at room temperature to the reflux temperature of the solvent.
Step (h)
In the step (h) , the compound (Id) is halogenated to provide the compound (le) . As a halogenating agent, thionyl chloride or the like is used. The reaction canbe conductedpreferably in a solvent, such as methylene chloride, at 0 to 100°C.
Step (i)
In the step (i) , desired ones of various aryl groups and heterocyclic groups are introduced into the compound (le)
to obtain the compound (If) .
The reaction can be conducted preferably in the presence of a base such as dimethylaminopyridine.
As a method for isolating the target compound from the reactionmixture, it is preferred to use two or more of washing, recrystallization, various chromatographic techniques and the like in combination as needed. Further, the conversion into a salt can be conducted by a process known per se in the art. The compound (1) of the present invention obtained as described above has effect to repair an abnormality in the expression of c- os in cells ofneuroblastoma origin stimulated by NGF, and is useful as a remedy for malignant tumors represented neuroblastomas in mammals including human beings . The medicament according to the present invention can be obtained by adding to the compound (1) of the present invention one or more of pharmaceutically acceptable carriers such as excipients, binders, lubricants, disintegrators, coating agents, emulsifiers, suspending agents, solvents, stabilizers, absorption aids and ointment bases as needed and formulating the thus-obtained mixture into a preparation form for oral administration, injection administration or rectal administration or for external use by a method known per se in the art. Preferred preparations for oral administration can
include granules, tablets, sugar-coated tablets, capsules, pills, liquids, emulsions and suspensions; preferred preparations for administration by injections can include intravenous injections, intramuscular injections, subcutaneous injections and instillations; and preferred preparations for rectal administration can include soft capsular suppositories.
The medicament according to the present invention can be administered to mammals, including human beings, as such preparations as described above.
The medicament according to the present invention can be administered preferably in a daily dose of from about 1 to 500 mg/kg one to four times a day.
Examples
The present invention will next be described in further detail based on Examples. It should however be borne in mind that the present invention is by no means limited to or by these Examples. Referential Example 1 Synthesis of Compound A (in the formula
(4), R3 = CH3) A mixture of 4, 4' -dihydroxydiphenylmethane (1.0 g, 5 mmol), methyl bromoacetate (1.53 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) in N/ N-dimethylformamide (20 mL) was stirred at room temperature for 24 hours. The reaction
mixture was filtered, and the filtrate was extracted with ethyl acetate (50 mL x 3) . The extract was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reducedpressure, andthe residue waspurified by column chromatography on silica gel (ethyl acetate: chloroform = 1:9) to afford colorless needles (1.6 g, 93%) .
p 64-65°C.
1H-NMR(CDC13) δ :3.80(s,6H), 3.85(s,2H), 4.60(s,4H), 6.82 (d,4H, J=8.8Hz) , 7.08 (d, 4H, J=8.8Hz) .
MS (El) (m/z) : 344 [M]+. HRMS(EI)Calcd for Cι9H2o06 : 344.1259. Found 344.1256. Referential Example 2 Synthesis of Compound B (in the formula (4) , R3 = H)
Amixture of CompoundA (1.0 g, 5mmol) and5 KOH-methanol solution (4 mL) in methanol (40 mL) was refluxed for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in water (100 mL) , and the resultant solution was extracted with ethyl acetate (100 mL) . The aqueous layer was acidified with 10% hydrochloric acid, followed by the extraction with ethyl acetate (300mL) . The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford colorless powder (1.09 g, 100%).
mp 199-200°C.
1H-NMR(DMSO-d6) δ :3.79(s,2H), 4.59(s,4H), 6.80 (d, 4H, J=8.
8Hz), 7.10 (d,4H, J=8.8Hz) , 12.90(s,2H). MS(EI) (m/z) : 316[M] + . HRMS(EI) (m/z) : Calcd for Cι7Hι606 : 316.0946. Found 316.0944. Referential Example 3 Synthesis of Compound C (in the formula
(4), R3 = pentafluorophenyl) A mixture of Compound B (2.95 g, 9.3 mmol), pentafluorophenol (3.46 g, 18.8 mmol) and
N,N' -dicyclohexylcarbodiimide (3.88 g, 18.8 mmol) in tetrahydrofuran (100 mL) was stirred for 24 hours at room temperature. After the reaction mixture was filtered, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel
(dichloromethane) to afford colorless crystals (5.56 g, 92%) .
mp 135-136°C.
1H-NMR(CDC13) δ :3.90(s,2H), 4.97(s,4H), 6.89 (d, 4H, J=8.4H z) , 7.13(d,4H, J=8.4Hz) . MS (FAB) (m/z) :648[M]+.
HRMS(EI) (m/z) : Calcd for C29Hι4Fιo06 : 648.0630. Found 648.0628. Referential Example 4 Synthesis of Compound D (Formula (5) ) A mixture of Compound C (4.0 g, 6.17 mmol) and 25% aqueous ammonia (12 mL) in tetrahydrofuran (30 mL) was stirred at room temperature for 12 hours. A saturated aqueous solution of
sodium hydrogencarbonate (200 mL) was added to the reaction mixture. The precipitate was collected by filtration, washed with water, ethanol and diethyl ether, and dried under vacuum to afford colorless crystals (1.9 g, 98%).
mp 233-234°C.
1H-NMR(DMSO-d6) δ :3.80(s,2H), 4.36(s,4H), 6.85 (d, 4H, J=8.
8Hz), 7.11 (d,4H, J=8.8Hz) , 7.32(s,2H), 7.43 (s,2H) . MS (FAB) (m/z) : 315[M+1]+. HRMS(FAB) (m/z) : Calcd for Cι7H19N204 : 315.1344. Found 315.1346. Referential Example 5 Synthesis of Compound E (Formula (6) )
A mixture of Compound D (314 mg, 1 mmol) and boran-dimethyl sulfide complex (1.16 mL, 12 mmol) in tetrahydrofuran (12 mL) was refluxed for 24 hours. A 0.7 M HCl-methanol solution (6 mL) was added, and the mixture was refluxed for 30 minutes. After the solvent was evaporated under reduced pressure, the residue was basified with 25% aqueous ammonia and then extracted with dichloromethane (300 L) . The extract was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a pale yellow oil. The oil was purified by column chromatography on silica gel (chloroform: methanol: 25% aqueous ammonia = 100: 40:4) to afford a colorless amorphous solid (243 mg, 85%) .
1H-NMR (CD3OD) δ : 2 . 99 (t, 4H, J=5 . 6Hz ) , 3 . 82 ( s , 2H) , 3. 98 (t, 4
H,J=5.6Hz), 6.84 (d,4H, J=8.4Hz) , 7.07(d,4 H, J=8.4Hz) . MS (FAB) (m/z) : 287[M+1]+. HRMS(FAB) (m/z) : Calcd for Cι7H23N202 : 287.1759. Found 287.1757. Example 1 Synthesis of Compound F (Formula (la) )
A mixture of Compound B (973 mg, 1.5 mmol), Compound E (430 mg, 1.5 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (300 mL) was refluxed for 24 hours. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate :methanol = 9 : 1) to afford colorless crystals (586 mg, 69%) .
mp 195-196°C.
1H-NMR(CDC13) δ :3.53(s,2H) , 3.70-3.73 ( , 4H) , 3.80(s,2H),
3.92 (t,4H, J=5.2Hz) , 6.63 (d, 4H, J=8.8Hz) , 6.71(d,4H, J=8.8Hz) , 6.87 (d, H, J=8.8Hz) , 6.94 (t,2H, J=5.2Hz) , 7.05 (d, 4H, J=8.8Hz) . MS (FAB) (m/z) :567[M+1] +.
HRMS(FAB) (m/z) : Calcd for C34H35 206 : 567.2495. Found 567.2496. Example 2 Synthesis of Compound G (Formula (lb) )
A mixture of Compound F (610 mg, 1.07 mmol) and boran-dimethyl sulfide complex (1.3 mL, 1.34 mmol) in THF (13 mL) was refluxed for 24 hours. A 0.7 M HCl-methanol solution
( 6.5 mL) was added, and the mixture was refluxed for 30 minutes . After the solvent was evaporated under reduced pressure, the residue was basified with 25% aqueous ammonia and then extracted with dichloromethane (100 mL) . The extract was washed with brine and then dried over anhydrous sodium sulfate . The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol: 25% aqueous ammonia = 100:10:1) to afford colorless powder (480 mg, 83%) .
mp 135-136°C.
1H-NMR(CDC13) δ : 3.00(t,8H, J=4.8Hz) , 3.80(s,4H), 4.06(t,8
H,J=4.8Hz), 6.75 (d,8H, J=8.4Hz) , 7.00(d,8 H, J=8.4Hz) . MS (FAB) (m/z) : 539[M+1]+. HRMS(FAB) (m/z) : Calcd for C34H39N2O4 : 539.2909. Found 539.2908. Example 3 Synthesis of Compound H (in the formula (lc) , R4 = (CH2)2, R5 = CH3) A mixture of Compound G (269 mg, 0.5 mmol), methyl acrylate (258 mg, 3 mmol) and cupric acetate monohydrate (10 mg, 0.05 mmol) in methanol (5 mL) was stirred at 100°C for 24 hours. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform: ethanol: 25% aqueous ammonia = 100:10:1) to
afford a colorless amorphous solid (305 mg, 86%) .
1H-NMR(CDC13) δ : 2.53(t,4H, J=7.2Hz) , 2.95 (t, 8H, J=6.0Hz) ,
2.99(t,4H, J=7.2Hz) , 3.65(s,6H), 3.81(s,4 H) , 3.94 (t,8H, J=6.0Hz) , 6.72 (d, 8H, J=8.4H z) , 7.00 (d,8H, J=8.4Hz) .
MS(FAB)(m/z) :711[M+1] +.
HRMS(FAB) (m/z) : Calcd for C42H51N208 : 711.3645. Found 711.3647. Example 4 Synthesis of Compound I (in the formula (Id) , R4 = (CH2)2)
A mixture of Compound H (300 mg, 0.42 mmol), lithium borohydride (84 mg, 3.8 mmol) and methanol (0.24 mL) in tetrahydrofuran (12 mL) was refluxed for 24 hours. Water and 1 N hydrochloric acid were added to quench the reaction, then the reaction mixture was basified with 25% aqueous ammonia. The resultant precipitate was collected by filtration, washed with water, and then dried under reduced pressure to afford colorless powder (260 mg, 95%) .
mp 182-183°C. xH-NMR(Pyridine-d5) δ : 1.91 (quint , 4H, J=6.3Hz) , 2.87(t,4H,
J=6.3Hz), 2.98 (t,8H, J=5.6Hz) , 3.84 (s,4H), 3.98 (t,4H, J=6.3Hz) , 4.07 (t,8H, J=5.6Hz) , 6.92 (d,8H, J=8.4H z) , 7.11(d,8H, J=8.4Hz) . MS(FAB) (m/z) : 655[M+1]+.
HRMS(FAB) (m/z) : Calcd for C40H5ιN2θ6 : 655.3746.
Found 655.3747. Example 5 Synthesis of Compound J (in the formula (le), R4 = (CH2)2, X2 = Cl) A mixture of Compound I (196 mg, 0.3 mmol) and thionyl chloride (2 L) in dichloromethane (10 mL) was stirred at room temperature for 24 hours and was then evaporated under reduced pressure. The residue was diluted with water, and basified with saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with dichloromethane (25 mL), washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (chloroform:methanol = 10:1) to afford colorless powder (207 mg, 100%) .
mp 103-104°C.
1H-NMR(CDC13) δ : 1.95 (quint, 4H, J=6.0Hz) , 2.78 (t, 4H, J=6. OH z), 2.92 (t,8H, J=6.0Hz) , 3.67 (t, 4H, J=6. OH z), 3.81(s,4H), 3.94 (t,8H, J=6.0Hz) , 6.72 (d,8H, J=8.4Hz) , 7.00 (d,8H, J=8.4Hz) . MS(FAB) (m/z) : 690[M+1]+, 692 [M+l] +37C1, 694 [M+l] +37C12.
HRMS(FAB) (m/z) : Calcd for C-30H48CI2N2O4 : 690.2990. Found 690.2988. Example 6 Synthesis of Compound K (in the formula (If) , R4 = (CH2)2. R6 = 4-dimethylaminopyridin-l-yl) A mixture of Compound J (48 mg, 0.07 mmol) and
4-dimethylaminopyridine (17 mg, 0.14 mmol) in methanol (2 mL) was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure. The resulting powder was washed with ethyl acetate, collected by filtration, and dried under reduced pressure to afford a colorless amorphous powder (65 mg, 100%) .
1H-NMR(D20) δ : 1.74 (brs,4H) , 2.13 (brs, 4H) , 2.41 (brs, 20H) , 3.26 (brs,4H) , 3.49 (brs, 8H) , 3.81 (brs, 4H) , 5.85 (d,4H, J=6.8Hz) , 6.34 (d, 8H, J=8.0Hz) , 6. 66(d,8H, J=8.0Hz) , 7.48 (d, 4H, J=6.8Hz) .
MS(FAB) (m/z) :899[M-C1]+, 432 [M-C12] 2+.
HRMS(FAB) (m/z) : Calcd for C54H68C1N604 : 899.4990.
Found 899.5074. Compound K
Example 7
As cultured strains of cultured neuroblastoma cells,
two strains (IMR-32, NB-39) were used. The compound of the present invention (the compound K) (1 μM/L) was caused to act on each strain for 60 minutes, and subsequently, NGF (100 ng/mL) was caused to act for 30 minutes. Total RNA was extracted, cDNA was produced, and RT-PCT was performed. As a result, it was clearly confirmed that for the NB-39 strain known to develop an abnormality in the expression of c-fos upon NGF stimulation, the cyclophane derivative according to the present invention was able to repair the expression of c-fos.
Industrial Applicability
The compounds (1) according to the present invention have reparative effect for an abnormality in the expression of c-fos, said abnormality being developed in neuroblastomas or the like, and are useful as remedies for various malignant tumors .