Aminoalkylphenol Derivatives and Related Compounds

专利摘要:
The present invention relates to novel aminoalkylphenols, intermediates for their preparation and methods for preparing these compounds, and methods for alleviating memory impairment using aminoalkylphenols or compositions thereof.
公开号:KR20010040254A
申请号:KR1020007003296
申请日:1998-09-04
公开日:2001-05-15
发明作者:레이몬드 더블유. 쥬니어 코슬리；마크 지. 팰레모；스티븐 제이. 쉼쇽；베로니카 울프
申请人:스티븐 엘. 네스빗；아벤티스 파마슈티칼스 인크；
IPC主号:

专利说明:

Aminoalkylphenol Derivatives and Related Compounds
The present invention relates to aminoalkylphenols. More specifically, the present invention is useful for alleviating memory impairment, and thus is used in the treatment of Alzheimer's disease, wherein the aminoalkylphenol derivative of formula (1) or optical isomer or pharmaceutically acceptable thereof, alone or in combination with an adjuvant It relates to possible salts.
In the formula,
R ₁ is hydrogen, lower alkyl, CONR ₆ R ₇ group, CH ₂ COOR ₈ group, CH ₂ CH ₂ OH group, CH ₂ CN group, group, Group or Si (R ₁₁ ) ₃ group,
R ₂ is hydrogen, lower alkyl, CONR ₆ R ₇ groups, SO ₂ R ₁₀ groups, Group or Si (R ₁₁ ) ₃ group,
R ₃ is hydrogen or lower alkyl,
R ₄ is hydrogen or lower alkyl,
R ₅ is hydrogen, lower alkyl, Flag or Or
R ₄ and R ₅ together with the nitrogen atom to which they are attached group, group, group, Form a flag,
R ₆ is hydrogen or lower alkyl,
R ₇ is alkyl having 1 to 10 carbon atoms, group, Flag or Or
R ₆ and R ₇ together with the nitrogen atom to which they are attached Form a flag,
R ₈ is lower alkyl,
R ₉ is hydrogen, a C (R ₁₄ R _{14 ′} ) OH group, group, Gigi,
R ₁₀ is lower alkyl,
R ₁₁ is lower alkyl,
R ₁₂ is lower alkyl, hydroxy lower alkyl, a COR ₁₅ group, group, group, group, Flag or Gigi,
R ₁₃ is hydrogen or lower alkyl,
R ₁₄ is hydrogen or lower alkyl,
R _{14 '} is hydrogen or lower alkyl,
R ₁₅ is Group or lower alkyl,
R ₂₀ is lower alkyl,
X is hydrogen or halogen,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano, or a R ₂₀ CO or OCONR ₆ R ₇ group,
m is 1 or 2,
n is 0 or 1,
p is 1 or 2,
q is 0, 1 or 2,
r is 0, 1 or 2.
Typical compounds for this compound
(a) R ₁ is a CONR ₆ R ₇ group, or
(b) R ₂ is lower alkyl, or
(c) R ₂ is CONR ₆ R ₇ or
(d) R ₂ is lower alkyl, or
(e) R ₄ and R ₅ together with the nitrogen atom to which they are attached form a group of fig. 4
(f) R ₁ is a CONR ₆ R ₇ group and R ₄ and R ₅ together with the nitrogen atom to which they are attached form a group of Figure 4, n is 0, or
(g) R ₂ is a CONR ₆ R ₇ group, R ₄ and R ₅ together with the nitrogen atom to which they are attached form a group of Figure 4, where n is 0.
The present invention also relates to a compound of formula (2), or an optical isomer or pharmaceutically acceptable salt thereof, useful as an intermediate for the preparation of the aminoalkylphenols of the invention, which is useful in reducing memory impairment.
In the formula,
R ₁₆ and R ₁₇ are independently hydrogen or alkyl having 1 to 10 carbon atoms,
R ₁₈ is Gigi,
W is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl,
s is 1 or 2,
X is hydrogen or halogen,
m is 1 or 2.
The present invention also relates to a compound of formula (3), or an optical isomer or pharmaceutically acceptable salt thereof, useful as an intermediate for the preparation of the aminoalkylphenols of the invention, which is useful in alleviating memory impairment.
In the formula,
R ₁ is lower alkyl, benzyl, Group or CONR ₆ R ₇ group wherein R ₆ is hydrogen and R ₇ is lower alkyl
R ₂ is hydrogen, lower alkyl, or a Si (R ₁₁ ) ₃ group, where R ₁₁ is lower alkyl, or
R ₂ is a COR ₆ R ₇ group wherein R ₆ is hydrogen and R ₇ is lower alkyl
X is hydrogen or halogen,
m is 1 or 2.
The present invention also relates to a compound of formula (4), or an optical isomer or a pharmaceutically acceptable salt thereof, as an intermediate for the preparation of the aminoalkylphenols of the invention, which is useful for alleviating memory impairment.
In the formula,
R ₁ is lower alkyl, Group, CH ₂ COOR ₈ group, Groups, CONR ₆ R ₇ groups or Si (R ₁₁ ) ₃ groups,
R ₂ is a SO ₂ R ₁₀ group, Groups, Si (R ₁₁ ) ₃ groups or CONR ₆ R ₇ groups,
R ₈ is lower alkyl,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano,
p is 1 or 2,
R ₆ is hydrogen,
R ₇ is Where R ₁₃ is lower alkyl, Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano and p is 1 or 2,
X is hydrogen or halogen,
m is 1 or 2.
The present invention also relates to a compound of formula (5), or an optical isomer or a pharmaceutically acceptable salt thereof, useful as an intermediate for the preparation of the aminoalkylphenols of the invention, which is useful in alleviating memory impairment.
In the formula,
R ₂ is hydrogen, lower alkyl or a CONR ₆ R ₇ group wherein R ₆ and R ₇ are lower alkyl,
R ₃ is hydrogen or lower alkyl,
R ₄ and R ₅ together with the nitrogen atom to which they are attached Where R ₁₂ is Term)
n is 0,
X is hydrogen or halogen,
m is 1 or 2.
The invention also relates to a compound of formula 43, its optical isomers or pharmaceutically acceptable salts.
R ₂ is hydrogen, lower alkyl or a CONR ₆ R ₇ group,
R ₃ is hydrogen or lower alkyl,
R ₄ and R ₅ together with the nitrogen atom to which they are attached Form a flag,
R ₁₂ is Gigi,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro, cyano or COCH ₃ ,
m is 1 or 2,
n is 0 or 1,
p is 1 or 2.
As used herein and in the claims, "alkyl" refers to a saturated straight or branched chain hydrocarbon radical having 1 to 12 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl, 3-nonyl, 4-decyl, undecyl, dodecyl, and the like. to be. "Alkanol" refers to a compound formed by the combination of an alkyl group and a hydroxy radical. Examples of alcohols are methanol, ethanol, 1- and 2-propanol, 2,2-dimethylethanol, hexanol, octanol and decanol and the like. "Alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or an alkyl group. Examples of alkanoic acid are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid and decanoic acid and the like. "Halogen" refers to a member of the fluorine, chlorine, bromine or iodine family. "Alkanoyl" refers to a radical formed by removing hydroxyl functionality from an alkanoic acid. Examples of alkannoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl and decanoyl and the like. "Alkoxy" refers to a monovalent substituent that is linked through ethereal oxygen and that is free of atoms from etheric oxygen. Examples of alkoxy groups are methoxy, ethoxy, propoxy, 2,2-dimethylethoxy, hexoxy, octoxy and decoxyl and the like. As used in any of the above groups, "lower" refers to a group having a carbon skeleton containing up to 10 carbon atoms.
Compounds of the present invention without symmetric elements exist in optical symmetry and racemic forms thereof. The optical symmetry is for example a compound of the invention characterized by the presence of a basic amino group and an optically active acid, the separation of a diastereomer of a compound of the invention characterized by the presence of a carboxylic acid group and an optically active base, or It can be prepared from the corresponding racemic form by standard optical resolution techniques, including synthesis from optically active precursors.
The present invention includes all optical isomers and racemic forms of the compounds described and claimed herein. The structural formulas of the compounds depicted herein are intended to include all expressed possible optical isomers of the compounds of the invention.
The novel aminoalkylphenols of the compounds of the present invention are prepared by the methods illustrated in the schemes. To prepare aminoalkylphenol 1, wherein R ₃ is hydrogen or lower alkyl and n is 0, benzaldehyde 6 or phenylalkylketone 10 is condensed with amine 7 in the presence of a reducing agent to produce compounds of 8 or 11, respectively. do. Reductive amination is generally carried out in the presence of a mild selective reducing agent in a suitable solvent, for example alkali metal trialkanoyloxyborohydride or alkali metal cyanoborohydride. Among the alkali metal trialkanoyloxyborohydrides which may be mentioned are lithium-, sodium- and potassium triacetoxyborohydride. Among the alkali metal cyanoborohydrides, mention may be made of lithium-, sodium- and potassium cyanoborohydride. Among the suitable solvents which may be mentioned are halocarbons such as dichloromethane, trichloromethane, 1, 2-dichloromethane and 1,1-dichloromethane, or optionally trialkanoyloxyborohydrides. Altanol (eg, methanol or ethanol) in the presence of an etheric solvent (eg, tetrahydrofuran) containing an alkanic acid (eg, acetic acid), or an inorganic acid such as hydrochloric acid, or hydrogenation. If anoboron is used, it is a lacanoic acid (for example acetic acid). Sodium triacetoxyborohydride is a preferred reducing agent. 1,2-dichloroethane is a preferred halocarbon. The reaction with benzaldehyde 6 and secondary amine 7 is preferably carried out in the absence of alkanoic acid such as acetic acid. If the temperature at which the reaction is carried out is not narrow, it is convenient that the reaction is carried out at ambient temperature.
In contrast, aminoalkylphenol 1 (where R ₃ is hydrogen and n is 0) is prepared by condensing benzyl halide 9 with amine 7 to produce 13. Although condensation is not carried out at reduced or elevated temperatures, halocarbons such as chloromethane, dichloromethane, or alkali metal hydrides in 1,1- or 1,2-dichloroethane or dimethylformamide at ambient temperature, For example, it can be achieved using sodium hydride. Preferred condensation medium is sodium hydride as a suspension in oil in dichloromethane.
To prepare aminoalkylphenol 1, wherein R ₃ is hydrogen or lower alkyl and n is 1, haloethylphenol 12 is condensed with amine 7 to produce 13 by the process described herein.
To prepare aminoalkylphenol 1, wherein R ₃ is hydrogen or lower alkyl, n is 0, phenylalkylacetone 10 is condensed with amine 7 to yield 11. The reaction can be carried out in a suitable solvent such as acetonitrile or dichloromethane near ambient temperature, followed by a reducing agent such as titanium (IV) alkoxide followed by alkanol or alkalic acid (eg acetic acid) or inorganic acid (eg hydrochloric acid), Optionally at ambient temperature and in the presence of alkali metal cyanoborohydride in alkanoic acid. Among the titanium (IV) alkoxides that may be mentioned are titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) 2-propoxide and titanium (IV) 1-propoxide. Among the alkali metal cyanoborohydrides that may be mentioned are lithium cyanoborohydride, sodium cyanoborohydride and potassium cyanoborohydride. Among the alkanols which may be mentioned are methanol, ethanol, 1-propanol and 2-propanol. Preferred reagents for performing reductive condensation are titanium (IV) 2-propoxide, sodium cyanoborohydride and dichloromethane.
The aminoalkylphenol derivatives of the general formula (I) having the above functional groups in the benzene ring and the side chains and related compounds thereof, ie, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, m and n are as described above. Compounds of the same formula (1) can be prepared from benzaldehyde 6, phenylalkyl ketone 10, benzyl halide 9 or phenylethyl halide 12 with unsubstituted functional groups, or from aminoalkylphenyl derivatives 8, 11 or 13 by treating the functional groups. have.
The aromatic hydroxyl group (-OH) is a carbamoyl residue ( Aminoalkylphenol in the presence of an acid acceptor such as a suitable alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or dichloromethane or combinations thereof near ambient temperature 1, wherein R ₁ or R ₂ is hydrogen, for example, R ₆ R ₇ NCOHal wherein R ₆ and R ₇ are as defined herein and Hal is bromo or chloro Treat with barmoyl halides. Cesium carbonate is the preferred acid acceptor.
In addition, in the reaction of phenol 1 with carbamoyl halide 14, tertiary amines are used as the acid acceptor, for example 1,8-diazabicyclo [5.4.0] undec-7-ene, and acetonitrile is used as the solvent. Can be.
Carbamoyl moiety of an aromatic hydroxyl group (-OH) Conversion to Aminoalkylphenol 1 (wherein R ₁ or R ₂ is hydrogen) in the presence of copper (I) halide, wherein halide is chloro or bromo) in ethyl acetate, acetonitrile or dichloromethane or combinations thereof Can be carried out by treatment with isocyanate 15.
R ₆ or R ₇ -N = C = O
Wherein R ₆ or R ₇ are as defined herein. Carbamoyl group using isocyanate 15 ( ) Can be achieved in an ethereal solvent such as tetrahydrofuran in the presence of an alkali metal carbonate of sodium carbonate. In addition, the conversion of the hydroxyl group (-OH), that is, carbamoyloxy functional group ( Conversion to 1,1 in tetrahydrofuran It can be carried out using amine 16 HNR ₆ R ₇ in which R ₆ and R ₇ are as defined herein in the presence of carbonyldiimidazole.
Formula 1 wherein R ₁ is as defined by R ₉ herein Group), ie an ethynylalkyl moiety To be introduced into the phenoxy clock, following the sulfonylation of the alkanesulfonyl benzaldehyde of benzaldehyde 17 from benzaldehyde 17, wherein R ₁ is lower alkyl and X and m are as defined herein, followed by 20 in 19 compound. Ethynylmethoxybenzaldehyde 20 prepared by ethynylalkylation of ethenylalkoxy benzaldehyde to a compound is substituted with aminoalkylbenzene 21, wherein R ₁ and R ₁₅ are lower alkyl and R ₃ , R ₄ , R ₅ and n As defined herein), which is also hydrolyzed to aminoalkylphenol 22 and carbamoylated to carbamate 23, wherein R ₆ and R ₇ are as defined herein. . The conversion of ethynylalkoxybenzaldehyde 20 to aminoalkylbenzene 21 is accomplished by the method defined herein. Hydrolysis of sulfonyloxybenzene 21 to phenol 22 is carried out in aqueous alkanols containing alkali metal hydroxides, for example aqueous methanol, at temperatures ranging from about 25 ° C. to 75 ° C., where the hydrolysis temperature is about 50 ° C. desirable. Carbamoylation from the compound of formula 22 to the compound of formula 23 is performed as defined herein. Phenol 22 is also converted to carbamate 23 after conversion to carbamate 23 by treatment with alkali metal carbonates such as potassium carbonate in an ethereal solvent such as tetrahydrofuran at ambient temperature as defined herein.
Substituted ethynylmethoxybenzenecarbamate 26, wherein R ₉ is a group defined herein other than hydrogen, protects its phenolic group starting from the compound of formula 22 and introduces the R ₉ residue Prepared by the production of nialmethoxybenzene 25, removal of the protecting group of the compound of formula 25 and treatment of carbamoyloxy benzene 26, wherein R ₆ and R ₇ are as defined herein.
The protective reaction of the phenolic groups of ethynylmethoxyhydroxybenzene 22 is carried out at ambient temperature, for example, by dipolar aprotic solvents such as dimethylacetamide, dimethylformamide, hexamethylphosphoramide or dimethylsulfoxide (of which Dimethylformamide is preferred) by treating phenol 22 with tri- (2-propyl) silyl chloride of formula 27a in the presence of an acid acceptor such as a tertiary amine, for example di- (2-propyl) ethylamine. do.
((CH ₃ ) ₂ CH) ₃ SiCl
A substituent (R ₉ ), i.e., a formula (R ₁₄ R _{14 '} ) CHOH group, wherein R ₁₄ is as defined herein, or Flag or The group is a carbonyl compound of formula 28a after treatment of ethynylmethoxybenzene 24 with alkyllithium, such as n-butyllithium, in an ethereal solvent such as tetrahydrofuran at a temperature in the range of about -30 to about -50 ° C. Flag or The compound of the group is treated and introduced.
(R ₁₄ R _{14 '} ) C = O
Conversion of substituted ethynylmethoxybenzene 25 to carbamoyloxy derivative 26 was carried out by treating the compound of formula 25 with tetra-n-butylammonium fluoride at an ambient temperature in an ethereal solvent such as tetrahydrofuran to remove the protecting group. , Prepared in situ by treating the compound of formula 15 in the presence of lithium halide, preferably lithium chloride.
Similarly, to prepare an aminoalkylphenol of Formula 1, i.e., a compound of Formula 30 (wherein R ₉ is as defined herein), ethynylalkoxyaldehyde 28 is prepared by ethynylalkylating hydroxybenzaldehyde 27. The resulting solution is reductively aminoated with aminoalkylethynylalkoxybenzene 30 and then alkylated with ethynylalkoxy carbinol 30. The sequence of reactions is carried out as described herein.
To prepare an aminoalkylphenol derivative of formula 1, wherein R ₁ is -OCH ₂ CH ₂ OH, ie hydroxyaminoalkylbenzene, hydroxybenzaldehyde 27 is converted to ester 32, which is reduced to aminoalkylbenzene 32 And then reduced to hydroxyalkoxybenzene 33. The conversion of phenol 27 to ester 31 is carried out by treating the compound of formula 27 with an alkyl haloacetate of formula 34 in the presence of an acid acceptor such as an alkali metal carbonate in a suitable solvent such as acetone at an elevated temperature near the reflux temperature of the reaction mixture.
HalCH ₂ CO ₂ R ₈
Wherein R ₈ is as defined herein,
Hal is bromo or chloro.
The conversion of benzaldehyde 31 to aminoalkylbenzene 32 is accomplished by the method described herein. Reduction of ester 32 is carried out by treating alkoxycarbonylalkoxybenzene 32 with an alkali metal hydride such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at a reaction temperature near ambient temperature.
Hydroxy to alkoxy compounds by the process in the present specification for the preparation of hydroxyethoxyaminophenol 33 where R ₂ is hydrogen, by conversion to carbamate 1, wherein R ₂ is carbamoyl. Aldehyde 27 where R ₂ is benzyl is converted to hydroxyethoxyaminoalkylbenzyloxybenzene 33 where R ₂ is benzyl. The benzyl group of alkylbenzyloxybenzene 33 is removed at ambient temperature using hydrogen under atmospheric pressure in the presence of a metal catalyst, preferably on a support such as carbon, under a palladium catalyst on an alkaline acid (eg acetic acid). Introduction of the carbamoyl group can be accomplished by the methods described herein.
The removal of functional groups bound to the potential phenolic oxygen atoms of the aminoalkoxybenzenes of the present invention, ie the formation of aminoalkylphenols of formulas 36 and 37, is carried out by hydrolysis, debenzylation and / or demethylation. For example, the aminocarbonyl group of a compound of formula 35, wherein R ₁ is a CONR ₆ R ₇ group, R ₂ is hydrogen, lower alkyl or benzyl, and R ₆ and R ₇ are as defined herein To remove, carbamate 35 is treated with alkali metal hydroxide in alcohol at ambient temperature. Among the alkali metal hydroxides that may be mentioned are lithium hydroxide, sodium hydroxide or potassium hydroxide. Among the alkanols that may be mentioned are methanol, ethanol or 1-propanol. Sodium hydroxide in methanol is the preferred alkali metal hydroxide and methanol is the preferred alkanol.
Similarly, the removal of alkanoyl groups from aminoalkylbenzene 35, wherein R ₂ is a RCO group, R is lower alkyl and R ₁ is hydrogen, lower alkyl or benzyl, is also carried out by hydrolysis. In this case, the hydrolysis is carried out at a slightly higher temperature of about 50 ° C., although the hydrolysis temperature range near the reflux temperature of the reaction mixture near ambient temperature is reduced to ester 35 with alkali metal hydroxides such as sodium hydroxide and alkanes such as aqueous ethanol. Achieve this by treating it with ol.
Debenzylation with aminoalkylbenzene 35 by removing the benzyl group from the compound of formula 35 wherein R ₂ is benzyl and R ₁ is lower alkyl is carried out at the reflux temperature of the reaction mixture, such as dichloromethane, in a halocarbon. Treatment with ferric iron or with a metal catalyst in a solvent such as acetic acid or methanol.
To remove the alkoxy group from the compound of formula 35, i.e., to dealkylate aminoalkylbenzene 35, wherein R ₂ is lower alkyl, hydroalkyl acid such as hydrobromic acid, such as hydrobromic acid, To be processed.
To prepare aminoalkylphenol 40, ie R ₁ , R ₂ , R ₃ , X and m, characterized by the presence of heterocyclic moieties, as defined herein, near the reflux temperature of the reaction medium. Benzylamine 38 is condensed with 2-methylthio-2-imidazoline 39 in halocarbons such as trichloromethane.
To prepare hydrazone 42, benzaldehyde 6 is combined with hydrazine 41. Condensation is carried out in halocarbons such as dichloromethane, preferably in sodium triacetoxyborohydride.
Compounds of formula (43) of the present invention wherein the 3-position of the benzene ring is unsubstituted are prepared in a manner substantially similar to that described for preparing 3-substituted phenyls of the compounds of the present invention.
<Formula 43>
R ₂ is hydrogen, lower alkyl or a CONR ₆ R ₇ group,
R ₃ is hydrogen or lower alkyl,
R ₄ and R ₅ together with the nitrogen atom to which they are attached Form a flag,
R ₁₂ is Gigi,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro, cyano or COCH ₃ ,
m is 1 or 2,
n is 0 or 1,
p is 1 or 2.
To prepare aminoalkylbenzene 46, wherein R ₂ , R ₄ and R ₅ are as defined above and Y is halo or alcoyl, phenyl acetic acid 44 is converted to amine 46 by the method described herein and Reduced to amine 46.
To prepare aquinoalkylcarbamate 48 and 50, aminoalkylphenol 47 is converted to carbamate 48 and aminoalkylphenol 49 followed by carbamate 50 by the method described herein.
The aminoalkylphenol derivatives and related compounds of the present invention are useful as functional disorder drugs associated with mechanical impairment, in particular with reduced choline activity, such as in Alzheimer's disease. Reduction of memory impairment activity is an assay for measuring the ability of a drug to inhibit memory impairment and inactivation of acetylcholine, a neurotransmitter implicated in the etiology of Alzheimer's dementia, in vitro inhibition of acetylcholinesterase assays. Is proven. G.L. Ellman, et al., Biochemical Pharmacology, 7, 88 (1961), the following reagents were prepared and used in this assay, a modification of the test described in Ellman, et al.
0.05 M Phosphate Buffer (pH 7.2)
A solution of monobasic sodium phosphate monohydrate (6.85 g) in distilled water (100 mL) was added to a solution of sodium dibasic sodium phosphate heptahydrate (13.4 g) and water (100 mL) until pH 7.2. The solution was diluted 1 to 10 times with distilled water.
2. Substrate in Buffer
Sufficient 0.05 M phosphate buffer (pH 7.2) was added to acetylthiocholine (198 mg) so that the total volume was 100 ml.
3. 5,5-Dithiobisnitrobenzoic acid in buffer
Sufficient 0.05 M phosphate buffer (pH 7.2) was added to 5,5-dithiobisnitrobenzoic acid so that the total volume was 100 ml.
4. Stock Solution of Drugs
Two millimoles of the test drug were prepared in sufficient amount of acetic acid or dimethyl sulfoxide using 5,5-dithiobisnitrobenzoic acid in complete solution. The stock solution of drug was serially diluted so that the final cuvette concentration was 10 ^-4 moles.
19-volume 0.05 M phosphate buffer (approximately) using a Potter-Elvejhem homogenizer by chopping male Wistar rats, removing brain rapidly, dissecting striatum, weighing, and using a Potter-Elvejhem homogenizer 7 mg protein / ml). 25 μl aliquots of this suspension were added to 1 ml of excipient or various concentrations of test drug and preincubated at 37 ° C. for 10 minutes. Enzyme activity was measured using a Beckman DU-50 spectrophotometer equipped with the following software and equipment.
1. Kinetic Soft-Pac (tradename) module # 598273;
2. Program # 6 Kindata;
3. Source-Vis;
4. Wavelength -412 nm
5. Sipper-None;
6. Cuvette-2 ml cuvette with autoghk 6-sampler;
7. blank-1 hour at each substrate concentration;
8. Time interval-15 seconds (15 or 30 seconds depending on kinematics);
9. Total time-5 minutes (5 to 10 minutes depending on kinetics);
10. plot-presence;
11. full width-automation;
12. slope-increase;
13. Result-present (gradient form);
14. Factor-1
Reagents were added to the blank and sample cuvettes as follows.
1.Blank: 0.8 ml of 5,5-dithiobisnitrobenzoic acid
0.8 ml substrate in buffer
2. Control: 0.8 ml of 5,5-dithiobisnitrobenzoic acid / enzyme
0.8 ml substrate in buffer
3. Drugs: 0.8 ml of 5,5-dithiobisnitrobenzoic acid / drug / enzyme
0.8 ml substrate in buffer
Blank values are determined for the control for nonenzymatic hydrolysis of the substrate at each cycle, which values are automatically excluded by the Kindata program available in the Dynamics Soft-Pack module. The program also calculates the rate of change of absorbance in each cuvette.
For IC ₅₀ measurements, the substrate concentration was diluted 10 mmol 1: 2 in the assay to a final concentration of 5 mmol. The 5,5-dithiobisnitrobenzoic acid concentration ranged from 0.5 mmol to 0.25 mmol in final concentration.
% Suppression = [(Control Slope-Drug Slope) ÷ Control Slope] × 100
IC ₅₀ values were calculated from log probit analysis.
compoundInhibition of Acetylcholinesterase Activity IC ₅₀ (μM) 4- (methylaminocarbonyloxy) -3- (propargyloxy) pyrrolidinomethylbenzene0.0036 4-methoxy-3- (propargyl) -1-[[4-pyridin-2-yl) piperazin-1-yl] methyl] benzene26.9 4-[[3-methoxy-4- (methylaminocarbonyloxy) phenylmethyl] -1- (pyridin-2-yl) piperazine0.536 4-[[4-methoxy-3- (methylamicarbonyloxy)] phenylmethyl-1- (pyridin-2-yl) piperazine2.39 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (methylphenyl) piperazine0.148 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4-pyridin-2-ylpiperazine0.358 N- (2-bromo-4- [dimethylcarbamoyloxy] -5-methoxy) -N '-(pyridin-2-yl) piperazine0.018 Dimethylcarbamic acid-2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenyl ester0.515 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-fluorophenyl) piperazine5.06 1- [1- (4-N, N-dimethylcarbamoyloxy-3-fluorophenyl) ethyl] -4-pyridin-2-yl-piperazine14.0 Tacrine (for reference)0.31
Reduction of memory impairment is achieved when an effective oral, parenteral or intravenous dose of 0.01-50 mg / kg body weight is administered to a patient in need thereof for treating an alkylaminophenol derivative and related compounds of the present invention. . A particularly effective amount is about 10 mg / kg body weight per day. However, it will be appreciated that for any particular patient, the particular dosage regimen may be adjusted according to personal requirements and the judgment of the person administering or administering the compound. It is also to be understood that the dosages described herein are for illustrative purposes only and do not limit the scope or practice of the present invention.
The alkylaminophenol derivatives and related compounds of the invention are also useful as drugs for the treatment of depression. Depression treatment has been demonstrated in the in vivo clonidine binding: α ₂ -receptor assay, which is described by DC U'Prichard, et al, Molecular Pharmacology, 16, 47 (1979) and DC U'Prichard, et al, Molecular Pharmacology , 13, 454 (1976) to determine the ability of a drug to bind to clonidine: α ₂ -receptor, which is performed by modifying the assay described in the following.
The following reagents were prepared.
Tris buffer, pH 7.7
a. Tris hydrochloride 57.2 g
16.2 g tris base to 1 liter (0.5 M Tris buffer, pH 7.7)
b. Dilute 1: 1 in distilled H ₂ O (0.05 M Tris buffer, pH 7.7)
2. Tris buffer containing physiological ions
a. Stock Buffer
7.014 g sodium chloride
0.372 g of potassium chloride
Calcium chloride 0.222 g-until 100 ml in 0.5 M Tris buffer
0.204 g magnesium chloride
b. Dilute to 1:10 in distilled water H ₂ O. This produces 0.05 M Tris hydrochloride at pH 7.7 containing sodium chloride (120 mM), potassium chloride (5 mM), calcium chloride (2 mM) and magnesium chloride (1 mM).
3. [4- ³ H] -clonidine hydrochloride (20-30 Ci / mmol) was obtained from New England Nuclear.
IC ₅₀ Measurement: ³ H-clonidine was prepared at a concentration of 120 nM and 50 μl was added to each tube (final concentration 3 nM in 2 mL volume analysis).
4. Clonidine hydrochloride was obtained from Boehring Ingelheim. To measure nonspecific binding, stock solutions of 0.1 mM clonidine were prepared to specify nonspecific binding. This resulted in a final concentration of 1 μm in the assay (20 μl to 2 mL).
5. Test Compound. In most assays, 1 mM stocks were prepared by continuous dilution in a suitable solvent, resulting in a range of final concentrations of 10 ⁻⁵ to 10 ⁻⁸ upon analysis. Seven concentrations were used for each assay, and higher or lower concentrations may be used depending on the efficacy of the drug.
B. Tissue Formulation
Male Wistar rats were sacrificed and their cortical tissues dissected quickly. This tissue was homogenized in a 50-fold volume of 0.05 M Tris buffer (pH 7.7) using Brinkman Polytron and then centrifuged at 40,000 g for 15 minutes. The supernatant was discarded and the pellet was homogenized again in the original volume of 0.05 M Tris buffer (pH 7.7) and centrifuged again as above. The supernatant was discarded and the final pellet was homogenized again in a 50-fold volume of buffer 2b. This tissue suspension was stored again on ice. The final tissue concentration was 10 mg / ml. Specific binding was 1% of total ligand added and 80% of total bound ligand.
C. Analysis
100 μl 0.05 M Tris-physiological salt, pH 7.7 (buffer 2a)
830 μl of water
20 μl of excipient (for total binding) or 0.1 mM clonidine (non-specific binding) or suitable drug concentrate
50 μl of ³ H-clonidine stock solution
1000 μl tissue suspension
Tissue homogenates were incubated with 3 nM ³ H-clonidine for 20 minutes at 25 ° C., and the drug concentrations varied, then immediately filtered on Whatman GF / B filters under reduced pressure. The filter was washed three times with 5 ml of ice cold 0.05 M Tris buffer (pH 7.7) and then transferred to the scintillation vial. 10 ml of liquefaction counting solution was added to each sample and counted with a liquid scintillation spectrometer. Specific clonidine was defined as the difference between total binding and performed using logarithmic profit analysis. The percentage inhibition in each drug is the average of three trials.
compoundClonidine binding activity IC ₅₀ (μM) 4-methoxy-3- (propargyloxy) -1-[[4- (pyridin-2-yl) piperazin-1-yl] methyl] benzene0.0346 4-[[3-methoxy-4 (methylaminocarbonyloxy) phenylmethyl] -1- (pyridin-2-yl) piperazine4.47 6,7-dimethoxy-N-[(4-methoxy) -3- (propargyloxy) phenylmethyl] -1,2,3,4-tetrahydroisoquinoline0.369 4-[[4-methoxy-3- (methylaminocarbonyloxy)] phenylmethyl] -1- (pyridin-2-yl) piperazine0.800 4-[[[4-dimethylaminocarbonyloxy-3- (methoxyphenyl] methyl] -1- (pyridin-2yl) piperazine9.11 2- [3-methoxy-4- (methylaminocarbonyloxy) phenylmethyl] -1- (6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline3.37 4- [3-methoxy) -4-[(1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyloxy] phenylmethyl] -1-pyridin-2-yl) piperazine8.02 1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl] -4- (2-methoxyphenyl) piperazine1.54 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-methylphenyl) piperazine0.98 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine5.19 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-fluorophenyl) piperazine2.71 Amitriptyline (for reference)0.039
Depression treatment is achieved when an effective oral, parenteral or intravenous dose of 0.01-50 mg / kg body weight is administered to a patient in need thereof with an alkylaminophenol derivative and related compounds. A particularly effective amount is about 10 mg / kg body weight per day. However, it will be appreciated that for any particular patient, the particular dosage regimen may be adjusted according to personal requirements and the judgment of the person administering or administering the compound. It is also to be understood that the dosages described herein are for illustrative purposes only and do not limit the scope or practice of the present invention.
Acetylcholinesterase inhibitors and clonidine binding inhibitors are known to be useful as relievers of memory impairment and as antidepressants, respectively (V. Kumar in Alzheimer's Disease: Therapeutic Strategies, E. Giacobini and R. Becker Eds .: Birkhauser, Boston 1994 for memory dysfunction utility and KF Tipton in Biochemical and Pharmacological Aspects of Depression, KF Tipton and UBH Youdin, Eds., Taylor and Francis, London 1989, for antidepressant utility.
Depression often involves memory impairment associated with Alzheimer's disease and responds to antidepressive coordination. Thus, the pharmacological properties of the antidepressive components of the compounds of the present invention have a desirable effect on the chemical construct and are provided as therapeutic agents when administered to where indicated to be used (see, eg, WW Pendlebury and PRSolomon, Neurobiology of Aging, 15, 287 (1994) to 287).
An effective amount of a compound of the present invention may be administered to a patient by any of a variety of methods, orally, e.g. in capsules or tablets, parenterally in the form of a sterile solution or suspension, and in some cases, intravenously in the form of sterile solution. Can be. The final free base product is effective on its own but can be formulated and administered in the form of its pharmaceutically acceptable addition salts for the purpose of increasing stability, ease of crystallization and solubility.
Preferred pharmaceutically acceptable addition salts of inorganic acids include, for example, salts of hydrochloric acid, sulfuric acid and nitric acid, salts of monobasic carboxylic acids (e.g. acetic acid and propionic acid, etc.), dibasic carboxylic acids ( For example, there are salts of maleic acid, fumaric acid and oxalic acid, and salts of tribasic carboxylic acids (eg, carboxysuccinic acid and citric acid, etc.).
The active compounds of the present invention can be administered orally, for example in combination with an inert carrier or an edible carrier. They can be included in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets and oral tablets, capsules, elixirs, suspensions, syrups, cachets and chewing gums and the like. Such formulations should contain 0.5% of active ingredient, but may vary depending on the particular form and may conveniently be from 4% to about 75% of the unit weight. The amount of the compound of the present invention in such a composition is such that a suitable dosage will be achieved. Preferred compositions and formulations according to the present invention are prepared to contain 1.0 to 300 mg of active compound in unit oral dosages. Tablets, pills, capsules and oral tablets may also contain the following ingredients: binders, for example Microcrystalline cellulose, gum tragaganth or gelatin; Excipients such as starch or lactose, disintegrants such as alginic acid, primogel, corn starch and the like; Yunhorase, for example magnesium stearate or Sterotes; Glidants such as colloidal silicon dioxide; And sweetening agents such as sucrose or saccharin, or flavoring agents such as peppermint, methyl, salicylate or orange flavor. If the dosage unit is a capsule, it may contain a liquid carrier, for example fat or oil, in addition to the substances of this kind. Other dosage unit may contain various other materials, such as coatings, which can change the physical form of the dosage unit. Thus, tablets or pills may be coated with a sugar, shellac or other enteric coating. Syrups may contain sucrose and optional preservatives, dyes and colorings and flavors as sweeteners in addition to the active compound. The materials used to prepare these various compositions must be pharmaceutically pure and nontoxic in the amounts used.
For parenteral therapeutic administration, the active compounds of the present invention may be incorporated into solutions or suspensions. Such formulations should contain at least 0.1% of the compound, but may vary from 0.5 to about 50% by weight. The amount of active compound in such a composition is such that a suitable dosage can be obtained. Preferred compositions and preparations according to the invention are prepared such that the oral dosage unit contains from 0.5 mg to 100 mg of the active compound.
The solution or suspension may also contain the following components: sterile diluents, for example water for injection, saline solution, nonvolatile oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol or til parabens; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediaminetetraacetic acid; Buffers such as acetates, citrates or phosphates, and osmotic agents such as sodium chloride or dextrose. Parenteral preparations may be included in ampoules, disposable syringes or composite vials made of glass or plastic.
The following examples are for illustrative purposes only and do not limit the invention in any way.
Example 1
4-methoxy-3-propargyloxydimethylaminomethylbenzene hydrochloride
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (2.05 a) in anhydrous dichloromethane (20 mL) in dimethylamine (1.26 a) in anhydrous dichloromethane (20 mL) was added with stirring followed by triacetoxyboro Hydride (3.44 g) was added. After 0.5 h, the reaction was poured into cold 10% sodium hydroxide (30 mL) and extracted with chloroform (50 mL). The organic extract was extracted with water (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in a minimum amount of chloroform and purified by flash chromatography (silica gel and 5% methanol: chloroform) and eluted with the same solvent system followed by 10% and 2% methanol: chloroform, respectively. The appropriate fractions were combined and concentrated to give 2.20 g (93%) of free base product. To the hydrochloride prepared by dissolving the free base in chloroform and diethyl ether, ethereal hydrogen chloride was added and the precipitate was collected. Melting point was 176-180 degreeC.
Example 2
4- [3- (2-methoxy-5- (dimethylamino-1-ylmethyl) phenoxy) propyn-1-yl] tetrahydrothiopyran-4-ol hydrochloride
At 0 ° C., a solution of 4-methoxy-3-propargyloxydimethylaminomethylbenzene (14.2), azeotropically dried with toluene in anhydrous tetrahydrofuran (85 mL) was kept at or below 5 ° C. A solution of 25 M n-butyllithium (25.2 mL) in acid was added dropwise with stirring. The reaction mixture was stirred for 10 min at 5-5 ° C and cooled to -30 ° C-35 ° C. To the reaction mixture was added dropwise a solution of tetrahydrothiopyran-4-one (7.13 g) in tetrahydrofuran (85 mL) over 0.5 h at a rate such that the internal temperature was kept below -30 ° C. The reaction mixture was poured into ice / water (600 mL) and extracted with chlorolol (600 mL). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to high performance liquid chromatography, eluting successively with 2%, 3%, 5% and 10% of methanol: chloroform. Appropriate fractions were collected and concentrated. Toluene was added to the residue and the solution was concentrated to give 15.0 g (69%) of free base product. One part of this was dissolved in chloroform and diethyl ether and etheric hydrogen chloride was added to give the product. Melting point was 208-210 degreeC.
Example 3
4-methoxy-3-[(propargyloxy) morpholino-4-yl-methyl] benzene hydrochloride
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (20 mL) in 1,2-dichloroethane (400 mL) was added morpholine (9.17 g) followed by sodium triacetoxyborohydride (29.2 g). It was added with stirring. The reaction mixture was stirred at ambient temperature for 1 hour and then poured into ice / 10% sodium hydroxide solution and extracted with chloroform. The extract was extracted with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash chromatography (silica gel) eluting with chloroform followed by 5% methanol / mechloroform. The appropriate fractions were combined and concentrated to give 27.5 g (100%) of free base product. Some of the free base (3.00 g) was dissolved in ether and ethereal hydrogen chloride was added. Melting point was 176-178 degreeC.
Example 4
4- (methoxy) -3- (propargyloxy) -1-pyrrolidinomethylbenzene hydrochloride
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (20 g) in 1,2-dichloroethane (400 mL) pyrrolidin (7.47 g) followed by sodium triacetoxyborohydride (29.2 g) Was added with stirring. The reaction mixture was stirred at ambient temperature for 1 hour, poured into ice / 10% sodium hydroxide solution and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with chloroform, 1%, 2% and 5% methanol / chloroform. The appropriate fractions were combined and concentrated to give 21 g (85.6%) of free base product. 3 g as part of the free base was dissolved in ether and ethereal hydrogen chloride was added. Melting point was 163-166 degreeC.
Example 5
4- [3- (2-methoxy-5- (morpholinylmethyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol hydrochloride
2.5 M in a solution of 4-methoxy-3- (propargyloxy) -1- (morpholino-4-yl-methyl) benzene (3.88 g) in anhydrous tetrahydrofuran (20 mL) in ice / salt n-butyllithium (5.79 mL) was added dropwise with stirring. The solution was stirred for 25 minutes, cooled to −40 to −50 ° C., and a solution of tetrahydrothiopyran-4-one (1.66 g) was added dropwise at −45 to −35 ° C. over 45 minutes. The reaction mixture was poured into ice / water, extracted with chlorolol, the extract washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and chromatographed using high performance liquid chromatography eluting with chloroform, 1%, 2%, 3% and 4% methanol / chloroform, respectively. The appropriate fractions were combined and concentrated to give 3.51 g (65.6%) of free base product. This free base was dissolved in ether and ethereal hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 187-189 degreeC.
Example 6
4-methoxy-3-propargyloxy-1-[(piperidin-1-yl) methyl] benzene hydrochloride
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (12 ml) in 1,2-dichloroethane (125 ml) piperidine (6.25 ml) followed by 1,2-dichloroethane (125 ml) and Sodium triacetoxyborohydride (20 g) was added. The reaction mixture was stirred at ambient temperature for 1 hour and poured into 10% sodium hydroxide solution / ice (200 mL). The layers were separated and the aqueous phase was extracted with chloroform (400 mL). The organic extract was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was subjected to flash chromatography (silica gel) eluting with chloroform, 3% and 5% methanol: chloroform. The appropriate fractions were combined and concentrated to give 13.1 g (80%) of free base as product. Some of this residue (3.59) was dissolved in chloroform and subjected to flash chromatography (silike gel) eluting with chloroform, 3% and 4% methanol: chloroform. The appropriate fractions were combined and concentrated to give 2.67 g of additional free base. The organic base was dissolved in diethyl ether, filtered and etheric hydrogen bromide was added. The precipitates were collected to give the product. Melting point was 135-137 degreeC.
Example 7
3-[[(2- (hydroxy) -2-methylpent-3-yn-5-yl] oxy] -4- (methoxy) -1-pyrrolidinomethylbenzene
Butyllithium in hexane (19.7) in a solution of 4- (methoxy) -3- (propargyloxy) -1-pyrrolidinomethylbenzene (18.2 g) in anhydrous tetrahydrofran (50 mL) in an ice / salt bath. Ml) was added. The solution was stirred for about 20 minutes at bin temperature and cooled to -40 to -45 ° C. To the solution was added dropwise a solution of acetone (3.176 mL) (dried in molecular sieve) in anhydrous tetrahydrofuran (5 mL). The reaction mixture was stirred at −50 to −35 ° C. for 35 minutes, poured into ice / water, and the layers separated. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. High performance liquid chromatography (silica gel) was eluted with chloroform, 1%, 2% and 5% methanol / chloroform. The appropriate fractions were combined and concentrated to give 11.9 g (80%) of free base as product. 2 g of some of the free base was dissolved in ether and ethereal hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 102-104 degreeC.
Example 8
4- [3- [3-methoxy-5-[(piperidin-1-yl) methyl] phenoxy] propyl-1-yl] tetrahydrothiopyran-4-ol hydrochloride
2.2 M in a solution of 4-methoxy-3-propargyloxy-1-[(piperidin-1-yl) methyl] benzene (2.83 g) in anhydrous tetrahydrofuran (14 mL) at 0-5 ° C. n-butyllithium (5.0 mL) was added dropwise over 20 minutes with stirring. The temperature was cooled to −35 to −30 ° C. and stirred at this temperature for 20 minutes. At -35 to -30 ° C, a solution of tetrahydrothiopyran-4-one (1.22 g) in anhydrous tetrahydrofuran (14 mL) was added dropwise. At this temperature the reaction mixture was stirred for 0.5 h, poured into water / ice (200 mL) and the mixture was extracted with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance liquid chromatography eluting with dichloromethane (trace amount of ammonium hydroxide) followed by 2%, 3%, 4% and 8% methanol: dichloromethane (trace amount of ammonium hydroxide). The appropriate fractions were combined and concentrated to give 2.46 g (60%) of free base as product. This free base was dissolved in diethyl ether and filtered to concentrate the filtrate. The residue was dissolved in chloroform and diethyl ether and ethereal hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 185-187 degreeC.
Example 9
4-methoxy-3-propargyloxy-1-[(4-methylpiperazin-1-yl) methyl] benzene dihydrochloride
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (19.9 g) in 1,2-dichloroethane (210 mL) followed by 1-methylpiperazine (11.7 mL) followed by 1,2-dichloroethane (210 mL) ) And sodium triacetoxyborohydride (32.5 g) were added. The reaction mixture was stirred at ambient temperature for 2 hours, poured into 10% sodium hydroxide / ice (1000 mL) and extracted with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to high performance liquid chromatography eluting with 2%, 4%, 5% and 10% methanol: chloroform. The appropriate fractions were combined and concentrated to give 15.8 g (52.3%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 220-223 degreeC (decomposition).
Example 10
4-methoxy-3-propargyloxy-1-[[(methyl) (phenethyl) amino] methyl] benzoic acid
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (19.9 g) in 1,2-dichloroethane (210 mL) N-methylphenethylamine (15.3 mL), sodium triacetoxyborohydride (33.3 g) and 1,2-dichloroethane (210 mL) were added with stirring. The reaction mixture was stirred for 1 h at ambient temperature under nitrogen, poured into 10% sodium hydroxide / ice (1000 mL) and extracted with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to high performance liquid chromatography eluting with chloroform followed by 2.5% methanol: chloroform. The appropriate fractions were combined and concentrated to give 15.3 g (52.3%) of free base as product. The free base was dissolved in diethyl ether and etheric citric acid was added. The precipitates were collected to give the product. Melting point was 45-65 degreeC.
Example 11
4-methanesulfonyloxy-3- (propargyloxy) benzaldehyde
In a stirred suspension of sodium hydride (2.52 g) in anhydrous dimethylformamide (56 mL) in a 20 ° C. water bath of 3-hydroxy-4-methanesulfonyloxybenzaldehyde (14.08 g) in dimethylformamide (56 mL) The solution was added dropwise at a rate where the internal temperature was kept below 25 ° C. The reaction mixture was stirred for 5 minutes, cooled to 0-5 ° C. in an ice / salt, and a solution of propargyl bromide (7 mL) in dimethyl formamide (56 mL) was added dropwise. The reaction mixture was stirred at 0-5 ° C. for 0.5 h, poured into ice / water and extracted with chloroform. The layers were separated, sodium carbonate was added to the aqueous phase and the aqueous acid was extracted with chloroform. The combined chloroform extracts were dried over anhydrous sodium sulfate and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with cold 10% sodium hydroxide solution, filtered and concentrated. The residue was dried under high vacuum at 80 ° C. to give 7.0 g (43.8%) of product. Recrystallization from ethanol gave an analytical sample. Melting point was 81-83 degreeC.
Example 12
4- [3- [2-methoxy-5- (4-methylpiperazin-1-ylmethyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol dihydrochloride dihydrate
To a solution of 4-methoxy-3-propargyloxy-1-[(4-methylpiperazin-1-yl) methyl] benzene (5.69 g) in anhydrous tetrahydrofuran (25 mL) at 0-5 ° C. 2.2 M n-butyllithium (9.50 mL) was added dropwise with stirring over 20 minutes at a rate such that the internal temperature was maintained at 0 ° C. or lower. The reaction mixture is stirred at 0 ° C. over 20 minutes, cooled to −30 to −35 ° C., and stirred at this temperature for 20 minutes, followed by tetrahydrothiopyran-4-one in anhydrous tetrahydrofuran (25 mL). (2.29 g) of solution was added over 15 minutes. The reaction mixture was stirred at −30 to −35 ° C. for 30 minutes, poured into ice / water (250 mL) and the mixture was extracted with chloroform. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride and subjected to high performance liquid chromatography eluting with methylene chloride (trace amount of ammonium hydroxide) followed by 2.5% methanol: methylene chloride (trace amount of ammonium hydroxide). The appropriate fractions were combined and concentrated to give 4.37 g (52%) of free base as product. The free base was dissolved in ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 230-232 degreeC (decomposition).
Example 13
4- [3- [2-methoxy-5-[[(methyl) -2-phenethyl] aminomethyl] phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol hydrochloride hydrate
A solution of 4-methoxy-3-propargyloxy-1- (N- (methyl-N- (phenethylamino) methyl] benzene (5.81 g) in anhydrous tetrahydrofuran (21 mL) at 0-5 ° C. 2.2 M n-butyllithium (7.0 mL) was added dropwise with stirring over 30 minutes at a rate such that the internal temperature was kept below 0 ° C. The reaction mixture was stirred at 0 ° C. over 20 minutes and was -30 to -37 After cooling to 20 ° C. and stirring at this temperature for 20 minutes, tetrahydrothiopyran-4-one (1.70 g) in anhydrous tetrahydrofuran (20 mL) was added over 10 minutes. Stir for 30 minutes at 35 ° C., pour into ice / water and extract the mixture with chloroform The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated The residue is methylene chloride (traces of ammonium hydroxide) 2.5% methanol: methylene chloride (a trace amount of ammonium hydroxide) High performance liquid chromatography was eluted with and the appropriate fractions were combined and concentrated to give 4.73 g (72%) of free base as product The free base was dissolved in ether and ethereal hydrogen chloride was added. The melting point was from 70 to 75 ° C.
Example 14
4- [3- [2-methoxy-5 (pyrrolidin-1-yl-methyl) phenoxy] prop-1-ynyl] cyclohexan-4-ol citrate
2.25 M in a solution of 4-methoxy-3-propargyloxy-1-[(pyrrolidin-4-yl) methyl] benzene (8.96 g) in anhydrous tetrahydrofuran (50 mL) at 0-5 ° C. n-butyllithium (16 mL) was added dropwise with stirring over 0.5 hour. The mixture was stirred at this temperature for 0.5 h, cooled to -45 ° C and a solution of cyclohexanone (3.50 mL) in anhydrous tetrahydrofuran (50 mL) was added dropwise. The reaction mixture was stirred for 1 h at -45 to -40 ° C, poured into ice / water (250 mL) and extracted with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride and high performance liquid chromatography was eluted with methylene chloride (trace amount of ammonium hydroxide) followed by 1%, 3%, 5%, 10% methanol: methylene chloride (trace amount of ammonium hydroxide). The appropriate fractions were combined and concentrated to give 5.55 g (44%) of free base as product. The free base was dissolved in diethyl ether and etheric citric acid was added. The precipitates were collected to give the product. Melting point was 55-80 degreeC.
Example 15
4- (Methanesulfonyloxy) -3- (propargyloxy) -1- (pyrrolidin-1-yl) methylbenzene citrate
To a solution of 4- (methanesulfonyloxy) -3- (propargyloxy) benzaldehyde (6.7 g) in 1,2-dichloroethane (135 mL) followed by pyrrolidine (1.88 g) followed by sodium triacetoxyboro Hydride (7.37 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 1.5 hours and poured into ice / water / dichloromethane. The layers were separated and the organic phase was washed with water and concentrated to give 6.37 g (94.9%) of free base as product. 500 g of the sample in the free base product was dissolved in chloroform and subjected to flash column chromatography (silica gel) eluting with chloroform, 1%, 2% and 5% methanol / chloroform. Appropriate fractions were collected and evaporated. The residue was dissolved in ether and etheric citric acid was added. The precipitates were collected to give the product. Melting point was 33-59 degreeC.
Example 16
3-methoxy-4- (triisopropylsiloxy) benzaldehyde, (pyridyl-2-yl) hydrazone hydrochloride
To a solution of 3-methoxy-4-triisopropylbenzaldehyde (4.97 g) in 1,2-dichloroethane (34 mL) followed by 2-hydrazinopyridine (1.77 g) followed by 1,2-dichloroethane (8.0 mL) And sodium triacetoxyborohydride (5.13 g) and 1,2-dichloroethane (13 mL) were added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / water (200 mL) and extracted with chloroform. The organic extract was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 5.79 g (90.0%) of free base as product. The free base product was dissolved in chloroform / diethyl ether. Etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 200-223 degreeC (decomposition).
Example 17
4- (methylaminocarbonyloxy) -3- (propargyloxy) -1- (pyrrolidinomethyl) benzene citrate
In an ice bath, methyl isocyanate (0.31 mL) in a suspension of 4-hydroxy-3 (propargyloxy) (pyrrolidinomethyl) benzene (0.35 g) and pure sodium carbonate (0.42 g) in tetrahydrofuran (6 mL). Was added by syringe. The suspension was stirred at 0-5 ° C. for 0.5 h, warmed to ambient temperature and stirred for 0.5 h further. The suspension was filtered over a silica gel column packed in chloroform and eluted with chloroform followed by 1% methanol: chloroform, 2%, 5% and 10% methanol: chloroform. The appropriate fractions were combined and concentrated to give 0.146 g (34%) of free base as product. The free base was dissolved in chloroform and etheric citric acid was added. The precipitates were collected to give the product. Melting point was 52-66 degreeC.
Example 18
4- (Methanesulfonyloxy) -3-methoxy- (pyrrolidin-1-yl) -methyl] benzene citrate
Pyrrolidine (1.65 mL) followed by sodium triacetoxyborohydride (5.5 g) in a solution of 4-methanesulfonyloxy-3-methoxybenzaldehyde (5.0 g) in 1,2-dichloroethane (100 mL) Was added with stirring. The reaction mixture was stirred at ambient temperature for 1.5 hours and poured into ice / water / 10% sodium hydroxide solution. The layers were separated and the organic phase was washed with water and concentrated. The residue was dissolved in ether and extracted with 10% hydrochloric acid. The extract was neutralized with 10% sodium hydroxide solution and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 4.9 g (79%) of free base as product. Free base (300 mg) was dissolved in ether and etheric citric acid was added. The precipitates were collected and dried at ambient temperature to yield the product. Melting point was 43-62 degreeC.
Example 19
3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde, (pyridyl-2-yl) hydrazone
To a solution of 4-hydroxy-3-methoxybenzaldehyde, (pyridin-2-yl) hydrazone (0.99 g) in tetrahydrofuran (10 mL), 1,1'-carbo in tetrahydrofuran (10 mL) A solution of nildiimidazole (0.99 g) was added with stirring. The mixture was stirred at ambient temperature for 2.5 hours, glacial acetic acid (4.0 mL) was added followed by methylamine (0.40 mL) and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was poured into ice / water (300 mL) and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and methanol, followed by flash chromatography (silica gel) eluting with dichloromethanol followed by 1% methanol: dichloromethane (trace amount of ammonium hydroxide). Appropriate fractions were collected and concentrated. The residue was recrystallized from ethanol to give 0.23 g (98%) of product. Melting point was 202-204 degreeC.
Example 20
4-hydroxy-3-methoxybenzaldehyde, (pyridyl-2-yl) hydrazone
Tetrabutylammonium fluoride (3.70) with stirring in a solution of 3-methoxy-4- (triisopropylsiloxy) benzaldehyde, (pyridin-2-yl) hydrazone (3.94 g) in anhydrous tetrahydrofuran (150 mL) Ml) was added by syringe. The reaction mixture was stirred at ambient temperature for 45 minutes, tetrabutylammonium fluoride (3.70 mL) was added and the solution stirred at ambient temperature for 1 hour and poured into ice / water. The mixture was extracted with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash column chromatography (silica gel, 3% methanol: dichloromethane) (trace amount of ammonium hydroxide). The appropriate fractions were combined and concentrated to give 2.19 g (90%) of product. Recrystallization from ethyl acetate gave an analytical sample. Melting point was 126-130 degreeC.
Example 21
3-propargyloxy-1- (pyrrolidin-1-yl) methyl-3- (triisopropylsiloxy) benzene
A solution of 3-hydroxy-1- (pyrrolidin-1-yl) methyl-3-hydroxybenzene (0.95 g) in anhydrous dimethylformamide (5 mL) was followed by diisopropylbutylamine (1.1 mL). Triisopropylsilyl chloride (0.97 mL) was added by syringe with stirring. The reaction mixture was stirred at ambient temperature for 1 hour, 910 g) of ice was added and after stirring for 10 minutes, the mixture was poured into ice / water and extracted with ethyl acetate. The extract was washed with water, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was subjected to flash column chromatography (silica gel) eluting with dichloromethane, 1%, 2% and 5% methanol / dichloroform. The appropriate fractions were combined and concentrated to give 0.65 g of product. Additional fractions were combined, concentrated and dried over silica gel. The appropriate fractions were concentrated to give 0.15 g of product. Total yield was 0.80 g (50%).
Example 22
4-methoxy-3-propargyloxy-1-[[N- (methyl)-(3,4-dimethoxyphenyl) amino] methyl] benzene citrate monohydrate
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (5.0 7 g) in 1,2-dichloroethane (50 mL) followed by N-methylveratrilamine (4.9 mL) followed by sodium triacetoxyborohydride ( 8.48 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 1 hour, 1,2-dichloroethane (50 mL) was added and the reaction mixture was stirred at ambient temperature for 0.5 hours. The reaction mixture was poured into ice / 10% sodium hydroxide solution (250 mL) and extracted with chloroform. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance liquid chromatography eluting with 2% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 8.27 g (84%) of free base as product. The free base was dissolved in diethyl ether and etheric citric acid was added. The precipitates were collected to give the product. Melting point was 40-80 degreeC.
Example 23
4-methoxy-3 (propargyloxy) benzaldehyde, (pyridyl-4-yl) hydrazone hydrochloride
To a solution of 4-methoxy-3-propargyloxybenzaldehyde (1.34 g) in 1,2-dichloroethane (20 mL) 4-hydrazinopyridine (0.77 g), 1,2-dichloroethane (8 mL) And sodium triacetoxyborohydride (2.25 g) were added with stirring. The reaction mixture was stirred at ambient temperature for 2 hours, poured into 10% sodium hydroxide / water (200 mL) and extracted with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in methanol: dichloromethane and flash chromatography (silica gel, dichloromethane) eluting with dichloromethane followed by 3%, 5%, 10% and 20% methanol: dichloromethane. The appropriate fractions were combined and combined to yield 1.43 g (71.9%) of free base as product. The free base was dissolved in diethyl ether / chloroform and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 200-210 degreeC.
Example 24
4- [3- [2- (methylaminocarbonyloxy) -5- (pyrrolidine-1-methyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol-citrate
4- [3- [5- (Pyrrolidin-1-yl-methyl) -2- (triisopropylsiloxy) phenoxy [rop-1-butylammoniumthiopyran- in tetrahydrofuran (5 mL) To a solution of 4-ol (0.54 g) was added 1 M tetra-n-butylammonium fluoride (0.41 mL) with stirring. The mixture was stirred at ambient temperature for 15 minutes, lithium chloride (250 mg) was added, the suspension was stirred for 15 minutes and methyl acetate (73.4 mg) was added by syringe. The reaction mixture was stirred at ambient temperature for 1 hour, poured into ice / water, extracted with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash column chromatography (silica gel) eluting with chloroform, 1%, 2%, 5% and 10% methanol / dichloroform. Appropriate fractions were collected and concentrated. The residue was dissolved in chloroform / ethane and etheric citric acid was added. The precipitates were collected to give 0.215 g (33.6%) of product. Melting point was 68-99 degreeC.
Example 25
To a solution of 3-methoxy-4-triisopropylsilylbenzaldehyde (3.55 g) in 1,2-dichloroethane (46 mL) was added with stirring 4-hydrazinopyridine (1.26 g). The reaction mixture was stirred at ambient temperature for 10 minutes, sodium triacetoxyborohydride (3.6 g) was added and the reaction mixture was stirred at ambient temperature for 3.6 hours. The reaction mixture was poured into 10% sodium hydroxide / ice (500 mL) and extracted with dichloromethane. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloroform and subjected to flash chromatography (silica gel, 3% methanol: dichloromethane) eluting with 3% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 1.93 g (42%) of free base as product. The free base was dissolved in methanol / diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 256-262 degreeC.
Example 26
4-hydroxy-3-methoxybenzaldehyde, (pyridyl-4-yl) hydrazone
To a solution of 3-methoxy-4- (triisopropylsiloxy) benzaldehyde, (pyridin-2-yl) hydrazone (1.01 g) in tetrahydrofuran (38 mL) 1 M in tetrahydrofuran (1.89 mL) Tetra-n-butylammonium fluoride was added with stirring. Tetrahydrofuran (30 mL) was added to the reaction mixture and the suspension was stirred at ambient temperature for 1.5 h, added to ice / water (100 mL) and extracted with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was recrystallized from ethyl alcohol to give 0.33 g (54%) of product. Melting point was 126-130 degreeC.
Example 27
4-methoxy-3- (propargyloxy) -1-[[4- (pyridin-2-yl) piperazin-1-yl] methylbenzene hydrochloride, monohydrate
To a solution of 4-methoxy-3- (propargyloxy) benzaldehyde in anhydrous 1,2-dichloroethane (22 mL) was added with stirring 1- (2-pyridyl) piperazine (0.80 mL) and the solution was added. Stir at ambient temperature for 10 minutes. Sodium triacetoxyborohydride (1.73 g) was added and the reaction mixture was stirred at ambient temperature for 3 hours, poured into 10% sodium hydroxide / ice and extracted with dichloromethane. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography (silica gel) eluting with 3% methanol: dichloromethane followed by 4% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 1.41 g (78%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 175-181 degreeC.
Example 28
1- (aminomethyl) -3-methoxy-4- (triisopropylsiloxy) benzene maleate
A solution of 3-methoxy-4- (triisopropylsiloxy) banzonitrile (5.08 g) in methanol (100 mL) was added to cobalt (II) chloride (4.03 g) with stirring while the temperature was rising 5 ° C. . The reaction mixture was cooled to 5 ° C. in an ice bath. After 10 minutes, sodium borohydride (6.03 g) was added very slowly over 40 minutes so that the internal temperature rose between 10 and 15 ° C. After the addition was complete, the reaction mixture was stirred at 5-10 ° C. for 30 minutes, warmed to ambient temperature and stirred for 2.5 hours. Pour the mixture into ice / water (400 mL) and add cold hydrochloric acid (50 mL) (pH = 2) followed by ethyl acetate (1000 mL), 10% sodium hydroxide solution (70 mL) and sodium bicarbonate (pH = 7). Was added. The suspension was filtered through celite and the filtrate was separated. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with 1% methanol: dichloromethane (containing traces of ammonium hydroxide) followed by 3% and 5% methanol: dichloromethane (containing traces of ammonium hydroxide). It was. The appropriate fractions were combined and concentrated to give 2.19 g (43%) of free base as product. The free base was dissolved in diethyl ether and etheric maleic acid was added. The precipitates were collected to give the product. Melting point was 1325-134 degreeC.
Example 29
3-cyanomethoxy-4-methoxy-10-[(pyrrolidin-1-yl) methyl] benzene
Pyrrolidine (6.6 mL) followed by sodium triacetoxyborohydride (22.2 g) in a solution of 3-cyanomethoxy-4-methoxybenzenealdehyde (10.0 g) in 1,2-dichloroethane (400 mL) Was added with stirring. The reaction mixture was stirred at ambient temperature for 1 hour and poured into 10% sodium hydroxide solution. The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance liquid chromatography eluting with dichloromethane, 1%, 2% and 5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 8.7 g (63.5%) of oil as product.
Example 30
3- [2-methoxy-5-[[4- (pyridin-2-yl) piperazin-1-yl] methyl] phenoxy (prop-1-ynyl) tetrahydrothiopyran-4-ol hydrochloride Monohydrate
4-methoxy-3- (propargyloxy) -1-[[4-pyridin-2-yl) -piperazin-1-yl] dissolved in tetrahydrofuran (7.0 mL) at 0-5 ° C. To a solution of methyl] benzene (1.81 g) was added 2.2 M n-butyllithium (2.4 mL) with stirring. The reaction mixture was stirred at this temperature for 1 hour, cooled to -30 to -40 ° C and stirred at -30 to -40 ° C for 30 minutes. Tetrahydrofuran-4-one (0.58 g) dissolved in tetrahydrofuran (7.0 mL) was added by syringe and the mixture was stirred at -30 to -35 ° C for 1.5 h. The reaction mixture was poured into ice / water (50 mL) and extracted with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography eluting with dichloromethane followed by 1, 2, 3 and 5% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.65 g (28%) of free base as product. The free base was dissolved in dichloromethane / diethyl ether and ethereal hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 190 to 201 ° C.
Example 31
3-ethoxycarbonylmethoxy-4-methoxy-1-pyrrolidinomethylbenzene hydrochloride
To a solution of 3-ethoxycarbonylmethoxy-4-methoxybenzaldehyde (10 g) in 1,2-dichloroethane (200 mL) followed by pyrrolidine (3.51 mL) followed by sodium triacetoxyborohydride (13.3 g) was added with stirring. The reaction mixture was stirred at ambient temperature for about 50 minutes, poured into ice / 10% sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance liquid chromatography. The appropriate fractions were combined and concentrated to yield 7.98 g (79.8%) of free base as product. The free base was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol to give the product. Melting point was 152-154 degreeC.
Example 32
3- (2-hydroxyethoxy) -3- (methoxy) pyrrolidinomethylbenzene
To a solution of 1 M lithium aluminum hydride (12.6 mL) in tetrahydrofuran (65 mL) in 3-ethoxycarbonylmethoxy-4-methoxy-1pyrrolidinomethylbenzene in anhydrous tetrahydrofuran (65 mL) ( 1.15 g) was added dropwise with stirring. The reaction mixture was stirred at ambient temperature for about 50 minutes and then cooled in an ice bath. Water (12.6 mL) was slowly added dropwise and the mixture was poured into degassed ice / water, shaken with ammonium chloride filtrate, treated with sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 0.43 g (44%) of product. Recrystallization from cyclohexane gave an analytical sample. Melting point was 55-57 degreeC.
Example 33
2- (3,4-dimethoxyphenylmethylamino) imidazoline hydrochloride
Veratrylamine (1.3 mL) was added to a stirred suspension of 2-methylthio-2-imidazoline hydrochloride in chloroform (9.0 mL) in chloroform (9.0 mL). The reaction mixture was heated at reflux for 2 h and stirred at ambient temperature overnight. The precipitates were collected and dried to yield 1.86 g (97%) of product. Recrystallization from ethanol gave an analytical sample. Melting point was 178-180 degreeC.
Example 34
3- [2-methoxy-5-[[N- (3,4-dimethoxyphenylethyl) [-N- (methyl) aminomethyl] phenoxy] (prop-1-ynyl) tetrahydropyran-4 -Ol hydrachloride
Solution of 4-methoxy-3-propargyloxy-1-[[N- (methyl) -N- (3,4-dimethoxyphenylethyl) amino] methyl] benzene in anhydrous tetrahydrofuran (4.5 mL) Was cooled to 0-5 [deg.] C. in an ice bath. 2.2 M n-butyllithium (1.1 mL) was added very slowly by syringe. The mixture was stirred for 45 minutes, cooled to -30 to -50 ° C and tetrahydropyran-4-one (0.276 g) in anhydrous tetrahydrofuran (2.0 mL) was added. After the addition was complete, the reaction mixture was stirred at -30 to -50 ° C for 1 hour, poured into ice / water (50 mL) and extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in a minimum amount of 2% methanol: dichloromethane (traces of ammonium hydroxide) and flash chromatography (silica gel) eluting with 2% and 5% methanol: dichloromethane / traces of ammonium hydroxide. The appropriate fractions were combined and concentrated to give 0.670 g (55%) of free base as product. The free base was dissolved in chloroform / diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 55-80 degreeC.
Example 35
4-[[3-methoxy-4- (methylaminocarbonyloxy) phenylmethyl] -1- (pyridin-2-yl) piperazine hydrochloride monohydrate
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.98 g) in 1,2-dichloroethane (40 mL) followed by 1- (2-pyridyl) piperazine (1.5 mL) followed by sodium Triacetoxyborohydride (3.04 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / saturated sodium carbonate solution (100 mL) and extracted with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with 1% methanol: dichloromethane (containing traces of ammonium hydroxide) followed by 2% and 5% methanol: dichloromethane (containing traces of ammonium hydroxide). It was. The appropriate fractions were combined and concentrated to give 1.67 g (50%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 120-140 degreeC.
Example 36
6,7-dimethoxy-N-[(4-methoxy) -3- (propargyloxy) phenylmethyl] -1,2,3,4-tetrahydroquinoline hydrochloride
To a solution of 4-methoxy-3- (propargyloxy) benzaldehyde (2.37 g) in 1,2-dichloroethane (25 mL) 6,7-dimethoxy- in 1,2-dichloroethane (5.0 mL) A solution of 1,2,3,4-tetrahydroisoquinoline (2.40 g) was added followed by sodium triacetoxyborohydride (3.94 g) with stirring. The reaction mixture was stirred at ambient temperature for 5 hours, poured into ice / saturated sodium carbonate solution (100 mL) and extracted with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with 1% methanol: dichloromethane (containing traces of ammonium hydroxide) followed by 2% and 3% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 1.51 g (33%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 220-222 degreeC.
Example 37
4-benzyloxy-3-[(ethoxycarbonyl) methoxy] benzaldehyde
To a solution of 4-benzyloxy-3-hydroxybenzaldehyde in acetone (12.5 mL) was added potassium carbonate (1.20 g) and ethyl bromoacetate (0.48 mL) with stirring. The reaction mixture was heated for 1 h with stirring under reflux, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography (silica gel) eluting with dichloromethane followed by 1% methanol: dichloromethane. The appropriate fractions were combined and combined to give 0.63 g (98%) of product. Melting point was 36-43 degreeC.
Example 38
4-[[4-methoxy-3- (methylaminocarbonyloxy)] phenylmethyl] -1- (pyridin-2-yl) piperazine dihydrochloride
To a solution of 4-methoxy-3- (methylaminocarbonyloxy) benzaldehyde (2.00 g) in 1,2-dichloroethane (40 mL) followed by 1- (2-pyridyl) piperazine (1.50 mL) followed by sodium Triacetoxyborohydride (3.04 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / saturated sodium carbonate solution (100 mL) and extracted with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with 1% followed by 3% and 5% methanol: dichloromethane (containing traces of ammonium hydroxide). The appropriate fractions were combined and combined to give 2.73 g (80%) of free base as product. The free base was dissolved in chloroform / diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 235-237 degreeC (decomposition).
Example 39
4-[[4-benzyloxy-3 (ethoxycarbonylmethoxy) phenyl] methyl] -1- (pyridin-2-yl) piperazine dihydrochloride
To a solution of 4-benzyloxy-3- (ethoxycarbonylmethoxy) benzaldehyde (0.2 g) in dichloromethane (4 mL) (pyridin-2-yl) piperazine (0.12 mL) and sodium triacetoxyborohydride Ride (0.25 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 1.5 hours, poured into ice / saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 1% and 2% methanol: dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ether and ethereal hydrogen chloride was added. The suspension was filtered and the filter cake was dried at ambient temperature for 2 hours. Recrystallization from ethanol gave 0.143 g of product. The precipitates were collected to give the product. Melting point was 151-191 degreeC.
Example 40
4-[[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl] -1- (pyridin-2-yl) piperazine
To a solution of 4- (dimethylaminocarbonyloxy) -3-methoxybenzaldehyde (0.5 g) in dichloromethane (20 mL) (pyridin-2-yl) piperazine (0.62 mL) followed by sodium triacetoxyborohydride Ride (1.28 g) was added with stirring. The mixture was stirred at ambient temperature for 1 hour, poured into ice / saturated sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was crystallized from ether. The crystals were collected by filtration and dried overnight at ambient temperature to yield the product. Melting point was 140-145 degreeC.
Example 41
3-methoxy-4- [2- (phenyl) ethylaminocarbonyloxy] benzaldehyde
To a solution of vanillin (2.01 g), potassium carbonate (3.63 g) and tetrahydrofuran (60 mL) in an ice bath at 0 to -5 ° C., alpha-2-methylbenzeneisocyanate (2.37 mL) was added with a syringe while stirring. . The reaction mixture was stirred at 0-5 [deg.] C. for 15-20 minutes and at ambient temperature for 2 hours and then filtered. The residue was dissolved in a minimum amount of chloroform and subjected to flash chromatography eluting with 5% methanol: chloroform. The appropriate fractions were combined and evaporated to give 3.65 g (92%) of product. Recrystallization from 2-propanol gave an analytical sample. Melting point was 133-138 degreeC.
Example 42
2- [3-methoxy-4- (methylaminocarbonyloxy) phenylmethyl] -1- (6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline hydrochloride
6,7-dimethoxy-1,2,3,4-tetrahydro into a suspension of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (3.50 g) in 1,2-dichloroethane (67 mL) Isoquinoline (3.23 g) and sodium triacetoxyborohydride (5.32 g) were added with stirring. The reaction mixture was stirred at ambient temperature for 22 hours, poured into ice / saturated sodium carbonate solution (100 mL) and extracted with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with 1% methanol: dichloromethane. The appropriate fractions were combined and combined to give 3.52 g (54%) of free base as product. The free base was dissolved in chloroform / diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 205-208 degreeC (decomposition).
Example 43
4-[[4- (benzyloxy) -3- (2-hydroxyethoxy)] phenylmethyl] -1- (pyridin-2-yl) piperazine
To a solution of 1 M lithium aluminum hydride (2.47 mL) in tetrahydrofuran, 4-[[4-benzyloxy) -3- (ethoxycarbonylmethoxy)] phenylmethyl]-in anhydrous tetrahydrfuran (20 mL)- 1- (pyridin-2-yl) piperazine (1.14 g) was added dropwise with stirring. The reaction mixture was stirred at ambient temperature for 3 hours and then cooled in an ice bath and water (1 mL) and 10% sodium hydroxide solution (1 mL) and water (3 mL) were slowly added dropwise. The mixture was stirred several times, filtered and the filtrate was poured into ice / water and extracted with ethyl acetate. The extract was washed with water, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography on silica gel eluting with dichloromethane followed by 1%, 2% and 5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.87 g (85%) product. Melting point was 90-95 degreeC.
Example 44
N- (2-bromo-5-hydroxy-4-methyl) benzyl-N '-(pyridin-2-yl) piperazine
At 0 ° C., sodium hydride (80%) (1.38 g) was added 4-bromo-5-bromomethyl-2-methoxyphenol (2.61 g) and N- (2-pyridinyl in dichloromethane (150 mL). ) Was added to a solution of piperazine (1.61 mL). The reaction mixture was warmed overnight with stirring to ambient temperature, quenched with water and the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was separated, extracted with ethyl acetate and washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered and the filtrate was concentrated. Flash column chromatography eluting the residue with 0-5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.88 g (56%) of product. Recrystallization from ethyl acetate / heptane gave an analytical sample. Melting point was 122-124 degreeC.
Example 45
2- [4- (dimethylaminocarbonyloxy) -3- (methoxy) phenylmethyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
To a solution of 4- (dimethylaminocarbonyloxy) -3- (methoxy) benzaldehyde (1.02 g) in 1,2-dichloroethane (16 mL) and 6,7-dimethoxytetrahydroisoquinoline (0.97 g) and Sodium triacetoxyborohydride (1.35 g) was added with stirring. The mixture was stirred at ambient temperature for 1 hour, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash column chromatography (silica gel) eluting with 1% and 2% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.92 g (50.3%) of product. Recrystallization from ethyl acetate gave an analytical sample. Melting point was 126-128 degreeC.
Example 46
4- [3- (methoxy)-[(1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyloxy] phenylmethyl] -1- (pyridin-2-yl) piperazine
[3-methoxy-4- (1,2,3,4-tetrahydrocarbonyloxy] phenylmethyl-1- (pyridin-2-yl) piperazin (0.76 in 1,2-dichloroethane (10 mL) To the solution of g) was added 1- (2-pyridine) piperazine (0.37 mL) followed by sodium triacetoxyborohydride (0.78 g) with stirring The suspension was stirred at ambient temperature for 3.5 hours and ice / Poured into saturated sodium carbonate solution (50 mL) and extracted with dichloroform The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated The residue was dissolved in dichloromethane and Flash column chromatography (silica gel) eluting with dichloromethane (containing traces of ammonium hydroxide) followed by 1% methanol: dichloromethane (containing traces of ammonium hydroxide) collected the appropriate fractions, concentrated to 0.72 g ( 64%) (C) to give a sample for analysis was recrystallized from ethyl acetate.
Example 47
4-[[4-hydroxy-3- (methoxy) phenylmethyl] -1- (pyridin-2-yl) piperazine dihydrochloride
To a solution of 20% sodium hydroxide (50 mL) 4-[[3-methoxy-4- (methylaminocarbonyloxy] phenylmethyl] -1- (pyridin-2-yl) piperazine in methanol (50 mL) (2.43 g) was added with stirring The reaction mixture was stirred at ambient temperature for 25 hours and ice / saturated sodium bicarbonate solution (100 mL) was added The mixture was extracted with chloroform The combined organic extracts were water and brine. Washed with, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product (62%) The free base was recrystallized from ethyl acetate and treated with etheric hydrogen chloride to give a sample for analysis. 120 to 190 ° C.
Example 48
2- [3-hydroxy-4- (methoxy) phenylmethyl] -1- (6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline hydrochloride
To a solution of 20% sodium hydroxide (40 mL) in 2- [4-methoxy-3- (methylaminocarbonyloxy) phenylmethyl] -1- (6,7-dimethoxy) -1 in methanol (40 mL) , 2,3,4-tetrahydroisoquinoline (2.23 g) was added. The reaction mixture was stirred at ambient temperature for 17 hours and ice / saturated sodium carbonate solution (100 mL) was added. The mixture was extracted with chloroform. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 1.23 g (60%) of product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol to give an analytical sample. Melting point was 160-163 degreeC (decomposition).
Example 49
1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl] -4- (2-methoxyphenyl) piperazine dihydrochloride
To a solution of 4- (dimethylaminocarbonyloxy) -3- (methoxy) benzaldehyde (0.5 g) in 1,2-dichloroethane (9 mL) 2-methylphenylpiperazine (0.47 g) and sodium triacetoxyboro Hydride (0.66 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / sodium carbonate solution and the layers separated. The organic layer was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash column chromatography (silica gel) eluting with dichloromethane followed by 1%, 2% and 5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.53 g (59.4%) of free base as product. The free base was dissolved in chloroform / ethyl and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 196-206 degreeC.
Example 50
1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl-4- (4-methoxyphenyl) piperazine dihydrochloride
To a solution of 4- (dimethylaminocarbonyloxy) -3- (methoxy) benzaldehyde (0.5 g) in 1,2-dichloroethane (9 mL) 4-methoxyphenylpiperazine (0.5 g) and sodium triacetox Ciborohydride (0.66 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 13 hours, poured into ice / saturated sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 1% and 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.57 g (63%) of free base as product. The free base was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 193-199 degreeC.
Example 51
1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl-4- (3-methoxyphenyl) piperazine hydrochloride hydrate
1- (3-methoxyphenyl) piperazine (4.8 g) in a solution of 4- (dimethylaminocarbonyloxy) -3- (methoxy) benzaldehyde (0.5 g) in 1,2-dichloroethane (9 mL) And sodium triacetoxyborohydride (0.66 g) were added with stirring. The reaction mixture was stirred at ambient temperature for 16 hours, poured into ice / saturated sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with chloroform, 1% and 2% methanol / chloroform. Appropriate fractions were collected and concentrated. The residue was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 144-153 degreeC.
Example 52
2-[[4-hydroxy-3 (methoxy) phenyl] methyl] -6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline hydrochloride
To a solution of 20% sodium hydroxide (34 mL) in 2-[[3-methoxy-3-4- (methylaminocarbonyloxy) phenyl] methyl- (6,7-dimethoxy)-in methanol (34 mL) 1,2,3,4-tetrahydroisoquinoline (1.18 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 23 hours and ice / saturated sodium carbonate solution (50 mL) was added. The combined organic mixture was extracted with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 0.52 g (32%) of free base as product. The free base was dissolved in ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from acetonitrile to give a sample for analysis. Melting point was 210-218 degreeC (decomposition).
Example 53
4-[[4- (hydroxy) -3- (2-hydroxyethyl) phenylmethyl] -1- (pyridin-2-yl) piperazine dihydrochloride
10% palladium on carbon (35 mg) in glacial acetic acid (1 ml) to 4-[[4- (benzyloxy) -3- (2-hydroxyethyl)] phenylmethyl] -1- (in glacial acetic acid (1 ml) A solution of pyridin-2-yl) piperazine (176 mg) was added. The mixture was stirred under 1 atmosphere of hydrogen for 6 hours. The suspension was filtered and concentrated. The residue was dissolved in chloroform and subjected to flash chromatography (silica gel) eluting with chloroform, 1% methanol, 2% methanol and 5% methanol / chloroform. The appropriate fractions were combined and concentrated to give 119 mg (86%) of free base as product. The free base was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected and dried at ambient temperature for 2 hours to afford the product by recrystallization from isopropyl alcohol. Melting point was 120-167 degreeC.
Example 54
4-[[[4- (methylaminocarbonyloxy) -3- (methoxy)] phenyl] methyl-1- (pyrimidin-2-yl) piperazine hydrochloride
Pyrazin-2-yl-pyrazine 1 in 1,2-dichloroethane in a solution of 4- (methylaminocarbonyloxy) -3- (methoxy) benzaldehyde (0.94 g) in 1,2-dichloroethane (16 mL) (0.85 g) of solution was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / saturated sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash chromatography (silica gel) eluting with chloroform followed by 1%, 2% and 5% methanol: chloroform. The appropriate fractions were combined and concentrated to give 0.87 g (54%) of free base as product. The free base was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from ethanol to obtain analytical samples. Melting point was 231-235 degreeC.
Example 55
Dimethylcarbamic acid 2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenyl ester hydrochloride
A solution of 2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) ethyl) phenol (1.0 g) in 25% acetonitrile / dichloromethane was dimetalcarbamoyl chloride (0.7 g) was added and the reaction mixture was stirred under nitrogen for 18 hours. The reaction mixture was diluted with ethyl acetate and concentrated. Flash chromatography (silica gel) eluting the residue with 2% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and etheric hydrogen chloride was added. The precipitates were collected to yield 0.9 g (73%) of product. Melting point was 192-193 degreeC.
Example 56
N- (4-benzyloxy-2-bromo-5-methoxy) benzyl-N '-(pyridin-2-yl) piperazine
Sodium hydride-80% dispersion in oil (0.35 g) was added to (4-benzyloxy-2-bromo-5-methoxy) benzyl and N- (pyridin-2-yl) piperazine in dichloromethane (150 mL). 1.4 ml) was added to a 0 ° C. solution. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water and the layers separated. The organic layer was washed with brine and the aqueous layer was extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash column chromatography (silica gel) eluting the residue with 0-10% ethyl acetate / chloroform. The appropriate fractions were combined to give 2.2 g (61%) of product. Recrystallization from dichloromethane gave an analytical sample. Melting point was 130-132 degreeC.
Example 57
1-[[(3,4-dimethoxy) phenyl] methyl] -4- (2-dimethylaminocarbonyloxyphenyl) piperazine hydrochloride
In an ice bath, 1-[[(3,4-dimethoxy) phenyl] methyl] -4- (2-hydroxyphenyl) piperazine (0.4 g), 1,8-diazabicyclo [5.4.0.] Ound To a suspension of -7-ene (0.206 g) and acetonitrile (3.5 mL) was added dimethylcarbamyl chloride (0.14 g) with stirring. The reaction mixture was stirred for 2.5 hours at ice bath temperature, warmed to ambient temperature for 2.5 hours, cooled again in ice bath and poured into ice / sodium bicarbonate solution. The layers were separated and separated with ethyl acetate. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash column chromatography (silica gel) eluting with 1%, 2%, 3% and 4% methanol / chloroform. The appropriate fractions were combined to give 0.26 g (49%) of product. The free base was collected and recrystallized from 2-propanol to give a sample for analysis. Melting point was 213-215 degreeC.
Example 58
N- (2,6-dibromo--3hydroxy-4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine
Sodium hydride-80% dispersion in oil (4.0 g) was dissolved in (2,6-dibromo-3-hydroxy-4-methoxy) benzylbromide and N- (pyridin-2-yl) in dichloromethane (150 mL). ) Piperazine was added to a solution of 95.40 g) at 0 ° C. The reaction mixture was stirred at ambient temperature for 72 hours, quenched with water, the layers separated and washed with brine. The aqueous layer was extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated. Flash column chromatography (silica gel, 0-20%) eluting the residue with 0-20% ethyl acetate / dichloromethane. The appropriate fractions were combined to give 5.32 g (56%) of product. Recrystallization from dichloromethane / heptane yielded an analytical sample. Melting point was 158-160 degreeC.
Example 59
Morpholin-4-carboxylic acid 2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenyl ester hydrochloride
Under nitrogen, a solution of 2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) methyl) phenol (1.5 g) and cesium carbonate in 25% acetonitrile / dichloromethane 4-Morpholincarbonyl chloride (1.4 g) was added with stirring. The reaction mixture was stirred under nitrogen for 18 hours, diluted with ethyl acetate and the layers separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated, and the flash chromatography (silica gel) eluting with 2% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The precipitates were collected to give the product and recrystallized from ethyl ethanol / ether to give 0.9 g (75%) of the product. Melting point was 185-186 degreeC.
Example 60
4-[[(3-methoxy) -4- (methylaminocarbonyloxy) [henyl [methyl] -1- (4-fluorophenyl) piperazine hydrochloride monohydrate
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.01 g) in 1,2-dichloroethane (19 mL) 1- (4-fluorophenyl) piperazine and sodium triacetoxyboro Hydride (0.73 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance flash chromatography (silica gel) eluting with dichloromethane and 1% methanol: dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in chloroform and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol to give 0.51 g (30%) of product. Melting point was 200-202 degreeC.
Example 61
1- (hydroxyethyl) -4-[[4- (methylaminocarbonyloxy) -3- (methoxy) phenyl)] methyl] piperazine dihydrochloride
To a suspension of 3- (methoxy) -4- (methylaminocarbonyloxy) benzaldehyde (1.0 g) in dichloroethane (16 mL) 2-hydroxyethylpiperazine (0.72 g in 2-dichloroethane (2 mL) ) And sodium triacetoxyborohydride (5.32 g) were added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash chromatography (silica gel) eluting with chloroform and 1%, 2%, 5%, 10% and 20% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.37 g (24%) of free base as product. The free base was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 211-214 degreeC (decomposition).
Example 62
1 [[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (4-trifluoromethylphenyl) piperazine hydrochloride
To a suspension of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.0 g) in 1,2-dichloroethane (19 mL) 1- (trifluoromethylphenylpiperazine) (0.89 mL) and sodium tria Cetoxyborohydride (1.52 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3.5 hours, poured into ice / saturated sodium carbonate solution (50 mL) and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance flash chromatography (silica gel) eluting with dichloromeform and 1% methanol: chloroform. Appropriate fractions were combined and concentrated. The residue was chromatographed again as above. The appropriate fractions were combined and concentrated to give 0.708 g (32%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol to give the product. Melting point was 215-220 degreeC.
Example 63
1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-chlorophenyl) piperazine hydrochloride
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.08 g) in 1,2-dichloroethane (10 mL) 1- (2-chlorophenyl) in 1.2-dichloroethane (10 mL) Piperazine (1.01 g) and sodium triacetoxyborohydride (10 mL) were added with stirring. The reaction mixture was stirred at ambient temperature for 3.5 hours, poured into ice / saturated sodium carbonate solution (50 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography (silica gel) eluting with dichloromethane followed by 1% and 2% methanol: chloromethane. Appropriate fractions were collected and concentrated. The residue was chromatographed again as above but chloroform was used instead of dichloromethane. The residue was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give 0.66 g (30%) of product. Melting point was 210-213 degreeC.
Example 64
N- (2-bromo-4-hydroxy-5-methoxy) benzyl-N '-(pyridin-2-yl) piperazine
At ambient temperature, anhydrous ferric chloride (10.5 g) was added N- (4-benzyloxy-2-bromo5-methoxy) benzyl-N '-(pyridin-2-yl) in dichloromethane (100 mL). To a solution of piperazine (4.0 g) was added. The reaction mixture was heated at reflux for 24 h, cooled and filtered. The filter cake was washed with dichloromethane. The filter cake was suspended in 5% potassium hydroxide solution and filtered again. The filter was neutralized with hydrochloric acid and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 0-5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.95 g (60%) of product. Recrystallization from ethyl acetate / heptane gave an analytical sample. Melting point was 167-168 degreeC.
Example 65
N- (2,6-dibromo-3- [dimethylcarbamoyloxy] -4- (methoxy) benzyl-N '-(pyridin-2-yl) piperazine
At ambient temperature, cesium carbonate (0.75 g) was added N- (2-bromo-5-hydroxy-methoxy) benzyl-N '-(pyridin-2-yl) piperazine (0.58) in dichloromethane (15 mL). to solution of g). The mixture was stirred at ambient temperature for 30 minutes and dimethylcarbamoyl chloride (50 mL) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched free, diluted with brine and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 0-5% methanol / ethyl acetate. The appropriate fractions were combined and concentrated to yield 0.64 g (93%) of product. Recrystallization from dichloromethane / heptane yielded an analytical sample. Melting point was 167-168 degreeC.
Example 66
N- (2-bromo-5- [dimethylcarbamoyloxy] -4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine
At ambient temperature, cesium carbonate (0.75 g) was added N- (2-bromo-5-hydroxy-4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine in dichloromethane (15 mL). (0.58 g) to the solution. The reaction mixture was stirred at ambient temperature for 30 minutes and dimethylcarbamoyl chloride (0.50 mL) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, brine and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting with 0-5% methanol / ethyl acetate. The appropriate fractions were combined and concentrated to yield 0.64 g (93%) of product. Recrystallization from dichloromethane / petroleum ether yielded an analytical sample. Melting point was 167-168 degreeC.
Example 67
N- (2-bromo-4- [dimethylcarbamoyloxy] -5- (methoxy) benzyl-N '-(pyridin-2-yl) piperazine
At ambient temperature, cesium carbonate (0.66 g) was added N- (2-bromo-4-hydroxy-5-methoxy) benzyl-N '-(pyridin-2-yl) piperazine in dichloromethane (15 mL). (0.50 g) was added to the solution. The reaction mixture was stirred at ambient temperature for 30 minutes and dimethylcarbamoyl chloride (0.60 mL) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, brine and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting with 0-2% methanol / ethyl acetate. The appropriate fractions were combined and concentrated to yield 0.53 g (90%) of product. Recrystallization from dichloromethane / petroleum ether yielded an analytical sample. Melting point was 145-147 degreeC.
Example 68
N- (4-benzyloxy-2-chloro-5-methoxy) benzyl-N '-(pyridin-2-yl) piperazine
At ambient temperature, the suspension in sodium hydride-80% oil was added with 4-benzyloxy-2-chloro-5-methoxybenzyl chloride (3.85 g) and N- (2-pyridin-2-yl in dichloromethane (125 mL). A solution of piperazine (2.60 g) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine and diluted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 0-1% methanol / ethyl acetate. The appropriate fractions were combined and concentrated to give 3.26 g (59%) of product. Melting point was 120-122 degreeC.
Example 69
1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl-4- (2-methoxyphenyl) -piperazine hydrochloride monohydrate
To a suspension of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.08 g) in 1,2-dichloroethane (95 mL) 1- (2-methoxyphenyl in 1.2-dichloroethane (8.0 mL) Piperazine (5.03 g) and sodium triacetoxyborohydride (8.0 mL) were added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / saturated sodium carbonate solution (200 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance liquid chromatography eluting with dichloromethane followed by 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 6.62 g (66%) of free base as product. The precipitates were collected to give a sample for analysis. Melting point was 138-155 degreeC.
Example 70
1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-hydroxyphenyl) -piperazine dihydrochloride
Sodium triacetoxyboro in a suspension of 3- (methoxy) -4- (methylaminocarbonyloxy) benzaldehyde (1.0 g), 2- (hydroxyphenyl) piperazine (0.98 g) and dichloroethane (16 mL) Hydride (0.32 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 2 hours, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and flash chromatography eluting with chloroform, 1%, 2% and 5% methanol / chloroform. The residue was dissolved in chloroform and subjected to high performance liquid chromatography, eluting with chloroform, 1% methanol and 2% methanol / chloroform / trace amount of ammonium hydroxide, to give 1.44 g (81.2%) of free base as product. Appropriate fractions were collected and concentrated. The free base was dissolved in chloroform and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 152-154 degreeC.
Example 71
1-[[3- (methoxy)-4 (methylaminocarbonyloxy) phenyl] methyl] -4- (2-fluorophenyl) -piperazine hydrochloride monohydrate
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.00 g) in 1,2-dichloroethane (19 mL) 1- (2-fluorophenyl) piperazine (0.55 mL) and sodium Triacetoxyborohydride (1.53 g) was added with stirring. The reaction mixture was stirred at ambient temperature overnight, poured into ice / saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.44 g (24%) of free base as product. The free base was dissolved in ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 204-208 degreeC.
Example 72
1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-methylphenyl) -pipefenml hydrochloride monohydrate
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.00 g) in 1,2-dichloroethane (19 mL) 1- (2-fluorophenyl) piperazine (0.55 mL) and sodium Triacetoxyborohydride (1.54 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into ice / saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.64 g (36%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 185-190 degreeC.
Example 73
1- [1- (3-fluoro-4-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine hydrochloride
Under nitrogen, titanium (IV) was added to a stirred solution of 2-fluoro-4-methoxyacetophenone (4.0 g) and 1- (2-pyridyl) piperazine (3.6 mL) in acetonitrile (50 mL). Isopropoxide (11 mL) was added with stirring. The reaction mixture was stirred for 1 hour. Sodium cyanoborohydride (1.0 g) was added along with anhydrous ethanol (50 mL). After 24 hours, the reaction mixture was diluted with ethyl acetate, quenched with a saturated solution of sodium sulfate, filtered, dried over anhydrous sodium sulfate, and concentrated, the flash chromatography eluting with 2% acetone / 2% methanol / dichloromethane. Photography (silica gel) was performed. Appropriate fractions were collected and concentrated. The residue was dissolved in ether and ethereal hydrogen chloride was added. The precipitates were collected to give the product and recrystallized from acetonitrile / propanol to give the product. Melting point was 231-232 degreeC.
Example 74
1- [1- (4-N, N-dimethylcarbamoyloxy-3-fluorophenyl) ethyl] -4-pyridin-2-yl-piperazine
Under nitrogen, 1- [1- (3-fluoro-4-hydroxyphenyl) ethyl] -4-pyridin-2-yl-piperazine (0.4 g) and cesium carbonate (0.4 in 25% acetonitrile / dichloromethane To the solution of g) was added dimethylcarbamyl chloride (0.4 g) with stirring. The reaction mixture was stirred for 28 h, diluted with ethyl acetate, washed with melon, dried over anhydrous sodium sulfate and concentrated, and the flash chromatography (silica gel) eluting with 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to yield 0.3 g (85%) of product. Melting point was 116-117 degreeC.
Example 75
2-fluoro-4- [1- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenol hydrochloride hemihydrate
Under nitrogen, a solution of 1- [1- (3-fluoro-4-methoxyphenyl) ethyl] -4-pyridinyl-2-yl-piperazine (1.1 g) in 48% hydrobromic acid (15 mL) was removed. It was taken up to 100 g for 4 hours. The reaction mixture was diluted with ethyl acetate, neutralized with saturated sodium carbonate solution, dried over anhydrous sodium carbonate and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 4% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.10 g (25%) of free base as product. The free base was dissolved in ether and acidified with ethereal hydrogen chloride to give the product. Melting point was 182-183 degreeC.
Example 76
1-[[3- (methoxy) -4 (methylaminocarbonyloxy) phenyl] methyl] -4- (2,4-difluorophenyl) piperazine hydrochloride
Of 3- (methoxy) -4- (methylaminocarbonyloxy) benzaldehyde (1.26 g), (2,4-difluorophenyl) piperazine (1.42 g) and 1,2-dichloroethane (22 mL) To the suspension was added sodium triacetoxyborohydride (1.67 g) with stirring. The reaction mixture was stirred at ambient temperature for 2 hours, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane, 1%, 2% and 5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.96 g (83%) of free base as product. The free base was dissolved in chloroform and flash chromatography (on silica gel) eluting with chloroform, 1%, 2% and 5% methanol / chloroform. Appropriate fractions were collected and concentrated. The residue was dissolved in chloroform / ether. Etheric hydrogen chloride was added. The precipitates were collected and recrystallized from ethanol to give the product. Melting point was 192-195 degreeC.
Example 77
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine Hemihydrate
1- [1-4-acetoxy-3-methoxyphenyl) ethyl] 4-pyridinyl-2-yl-piperazine (2.0 g) in 50% sodium hydroxide solution (5 mL) and 50% ethanol (40 mL) ) Solution was heated under nitrogen to 50 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 4% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.5 g (40%) of product. Melting point was 45-46 degreeC.
Example 78
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine dihydrochloride
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine (0.6 g) in 25% acetonitrile / dichloromethane (50 mL) and To a solution of cesium carbonate (0.6 g) was added dimethylcarbamyl chloride (0.4 g) with stirring. The reaction mixture was stirred for 18 h, diluted with ethyl acetate, washed with melon, dried over anhydrous sodium sulfate and concentrated, and the flash chromatography (silica gel) eluting with 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.2 g (15%) of product. Melting point was 155-156 degreeC.
Example 79
1-[[3-methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-cyanophenyl) piperazine hydrochloride
Sodium triacetoxyborohydride in a suspension of 3- (methoxy) -4- (methylaminocarbonyloxy) benzaldehyde (0.93 g), (cyanophenyl) piperazine (0.98 g) and dichloroethane (16 mL) (1.32 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 2 hours, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloroform and subjected to flash chromatography (silica gel) eluting with dichloroform in 1% and 2% methanol / chloroform. Appropriate fractions were collected and concentrated. The residue was chromatographed again on chloroform and silica gel eluting with 1%, 2% methanol / chloroform. The appropriate fractions were combined and concentrated to give 0.98 g (58%) of free base as product. The free base was dissolved in chloroform / ether. Etheric hydrogen chloride was added. The precipitates were collected and recrystallized from ethanol to give the product. Melting point was 218-222 degreeC.
Example 80
1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (phenyl) piperazine hydrochloride
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.0 g) in 1,2-dichloroethane (20 mL) 1-phenylpiperazine (0.73 mL) and sodium triacetoxyborohydride (1.52 g) was added with stirring. The reaction mixture was stirred at ambient temperature overnight, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane and 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.24 g (73%) of free base as product. Etheric hydrogen chloride was added. The solids were combined to give the product. Melting point was 210-214 degreeC.
Example 81
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine dihydro hemihydrate
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine in 50% sodium hydroxide solution (5 ml) and 50% ethanol (40 ml) 2.7 g) of the solution was heated under nitrogen to 50 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 2% acetone, 2% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate (150 mL) and ethereal hydrogen chloride was added. The precipitates were collected to yield 0.5 g (25%) of product. Melting point was 130-131 degreeC.
Example 82
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine Hemihydrate
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenylpiperazine (0.3 g) in 25% acetonitrile / dichloromethane (15 mL) and To the solution of cesium carbonate (0.3 g) was added with stirring dimethylcarbamyl chloride (0.2 g) The reaction mixture was stirred for 18 hours, diluted with ethyl acetate (150 mL), washed with water and dried over anhydrous sodium sulfate. Flash chromatography (silica gel) eluting with 2% methanol / dichloromethane The appropriate fractions were combined and concentrated to give 70 mg (20%) of the product. It was.
Example 83
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine dihydrochloride hemihydrate
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine in 50% sodium hydroxide solution (5 ml) and 50% ethanol (40 ml) 2.5 g) solution was heated under nitrogen to 50 ° C. for 4 h. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 2% acetone / 2% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and etheric hydrogen chloride was added. The precipitates were collected to give 0.5 g (45%) of product. Melting point was 121-122 degreeC.
Example 84
N-2-chloro-4-hydroxy-5-methoxybenzyl-N'-pyridin-2-yl-piperazine
At ambient temperature, a solution of N- (4-benzyloxy-2-chloro-5-methoxy) benzyl-N'-pyridin-2-yl piperazine (3.11 g) in dichloromethane (25 mL) was diluted with dichloromethane ( 75 ml) was added to a solution of ferric chloride (6.40 g). The reaction mixture was heated under reflux for 3 hours, cooled to ambient temperature and filtered. The filter cake was washed with ethyl acetate, suspended in 10% sodium hydroxide solution (500 mL) and filtered again. The filtrate was neutralized with hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1% methanol / ethyl acetate. The appropriate fractions were combined and concentrated to yield 0.58 g (24%) of product. Recrystallization from ethyl acetate / heptane gave an analytical sample. Melting point was 170-172 degreeC.
Example 85
N-2,6-dibromo-3-hydroxy-4-methoxybenzyl-N'-2-methoxyphenyl piperazine
At ambient temperature, 80% dispersion (1.0 g) in sodium hydride-oil (3.05 g) in (2,6-dibromo-3-hydroxy-4-methoxy) benzylbromide in dichloromethane (75 mL) and To a solution of N-2-methoxyphenyl piperazine (1.85 g) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to 5.22 g of product. Flash column chromatography (silica gel) eluting the residue with 10-80% ethyl acetate / heptane. The appropriate fractions were combined to give 3.71 g (94%) of product. Recrystallization from dichloromethane / heptane yielded an analytical sample. Melting point was 178-180 degreeC.
Example 86
N-2-bromo-5-hydroxy-4-methoxybenzyl-N'-2-methoxyphenyl piperazine
At ambient temperature, 80% dispersion (0.40 g) in sodium hydride-oil was removed with 2-bromo-5-hydroxy-4-methoxybenzyl bromide (1.0 g) and 2-methoxyphenyl in dichloromethane (30 mL). To a solution of piperazine (0.87 g) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash column chromatography (silica gel) eluting the residue with 20-50% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to yield 1.01 g (73%) of product. Recrystallization from dichloromethane / heptane yielded an analytical sample. Melting point was 177-179 degreeC.
Example 87
1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-furoyl) -piperazine hydrochloride
Sodium triacetoxybo in a suspension of 3- (methoxy) -4- (methylaminocarbonyloxy) benzaldehyde (1.5 g), 1- (2-furoyl) piperazine (1.54 g) and dichloroethane (26 mL) Low hydride (2.0 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3.5 hours, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash chromatography on silica gel eluting with chloroform in 1%, 2% and 3% methanol / chloroform. Appropriate fractions were collected and concentrated. The residue was dissolved in chloroform and chromatographed again on silica gel eluting with the same solvent system. The appropriate fractions were combined and concentrated to give 2.03 g (76%) of free base as product. The free base was dissolved in chloroform / ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from ethanol to give an analytical sample. Melting point was 224-229 degreeC.
Example 88
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine hydrochloride hydrate
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine (0.5 g) in 25% acetonitrile / dichloromethane (30 mL) And dimethylcarbamyl chloride (0.3 g) was added to the solution of cesium carbonate (0.5 g) with stirring. The reaction mixture was stirred for 18 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated. Flash chromatography (silica gel) eluting the residue with 2% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and etheric hydrogen chloride was added. The precipitates were collected to give 0.3 g (55%) of product. Melting point was 142-143 degreeC.
Example 89
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-ethoxyphenyl) piperazine hemihydrate
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine in 50% sodium hydroxide solution (5 ml) and 50% ethanol (40 ml) 2.5 g) solution was heated under nitrogen to 50 ° C. for 4 h. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 2% acetone / 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to yield 1.0 g (45%) of product. Melting point was 58-59 degreeC.
Example 90
1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine tetrahydrate
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine (0.5 g) and copper chloride in 25% acetonitrile / dichloromethane (30 mL) 25% acetonitrile / dichloromethane (30 mL) was added to the solution of (II) (catalyst contact amount) with stirring. The reaction mixture was stirred for 4 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.25 g (40%) of product. Melting point was 61-62 degreeC.
Example 91
1-[[3- (methoxy) -4- (methylcarbonyloxy) phenyl] methyl] -4- (4-nitrophenyl) piperazine
1- (4-nitrophenyl) piperazine (1.0 g) and sodium tria in a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.01 g) in 1,2-dichloroethane (19.0 mL) Cetoxyborohydride (1.54 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 3 hours, poured into saturated sodium carbonate solution (100 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was subjected to flash chromatography (silica gel) eluting with dichloromethane followed by 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.66 g (86%) of free base as product. Recrystallization from ethyl acetate gave an analytical sample. Melting point was 155-157 degreeC.
Example 92
1- [3,4-dimethoxyphenyl] methyl] -4- (2-hydroxyphenyl) -piperazine hydrochloride
Sodium triacetoxyborohydride (2.67 g) was stirred in a suspension of 3,4-dimethoxybenzaldehyde (2.0 g) and 1- (2-hydroxyphenyl) piperazine (2.03 g) in dichloroethane (35 mL). Was added. The reaction mixture was stirred at ambient temperature for 2.5 hours, poured into ice / sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to liquid chromatography eluting with dichloromethane, 1% and 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.03 g (32.8%) of free base as product. The free base was dissolved in chloroform / ether. The precipitates were collected and recrystallized from ethanol to give the product. Melting point was 245-249 degreeC.
Example 93
1-[[3- (methoxy) -4- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-chlorophenyl) piperazine hydrochloride
1- (2) dissolved in 1,2-dichloroethane (9.0 mL) in a solution of 3-methoxy-4- (dimethylaminocarbonyloxy) benzaldehyde (1.0 g) in 1,2-dichloroethane (9.0 mL) -Chlorophenyl) piperazine (0.88 g) and sodium triacetoxyborohydride (1.42 mL) were added with stirring. The reaction mixture was stirred at ambient temperature for 4 hours, poured into ice / saturated sodium carbonate solution (50 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography eluting with dichloromethane / 0.1%, 0.5% and 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.37 g (75%) of free base as product. Recrystallization from 2-propanol gave an analytical sample. Melting point was 190-193 degreeC.
Example 94
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-ethoxyphenyl) piperazine dihydrochloride hemihydrate
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine (0.42 g) and cesium carbonate in 25% acetonitrile / dichloromethane (30 mL) To a solution of 25% acetonitrile / dichloromethane (30 mL) was added with stirring. The reaction mixture was stirred for 18 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% acetone / 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and etheric hydrogen chloride was added. The precipitates were collected to give 0.2 g (60%) of product. Melting point was 118-119 degreeC.
Example 95
1- [1- (3-methoxy-4-N-methylcarbamoyloxy phenyl) ethyl] -4- (2-ethoxyphenyl) piperazine
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-ethoxyphenyl) piperazine (0.6 g) and copper chloride (I) in ethyl acetate (20 mL) To the solution of was added methyl isocyanate (0.1 g) with stirring. The reaction mixture was stirred for 3 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.2 g (30%) of product. Melting point was 64-65 degreeC.
Example 96
1-[[3,4-dimethoxy) phenyl] methyl] -4- (2-methylaminocarbonyloxyphenyl) piperazine dihydrochloride
To a suspension of 1-[[3,4- (dimethoxy) phenyl] methyl] -4- (2-hydroxyphenyl) piperazine (0.3 g) and pure potassium carbonate (0.18 g) under nitrogen, anhydrous tetrahydrofuran ( 7 ml) was added with stirring. The mixture was cooled in an ice bath and methyl isocyanate (59.8 g) was added. The reaction mixture was stirred at ice bath temperature for 1.5 hours, concentrated to ambient temperature and stirred for 1 hour. The reaction mixture was cooled in an ice bath, poured into ice / water and extracted with ethyl acetate. The extract was washed with cold 2% sodium hydroxide solution and cold brine, dried over anhydrous sodium sulfite, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% and 2% methanol / chloroform. The appropriate fractions were combined and concentrated to yield 0.25 g (72%) of free base as product. The free base was dissolved in chloroform / ether. Etheric chloride was added. The precipitates were collected and recrystallized from ethanol to give the product. Melting point was 163-192 degreeC.
Example 97
4- [3- [2-methoxy-5- (pyrrolidin-1-yl-methyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol hydrochloride
2.5 M n-butyllithium (7.3 mL) was added to a solution of 4-methoxy-3-propargyloxypyrrolidinomethylbenzel (4.58 g) in anhydrous tetrahydrofuran (25 mL) cooled in an ice bath. It was added dropwise at a rate maintained at 5 ° C or less. The reaction mixture is stirred at -5 ° C to 5 ° C for 20 minutes, cooled to -30 to -35 ° C, and a solution of tetrahydrothiopyran-4-one (2.07 g) in tetrahydrofuran (23 mL)- It was added dropwise at a rate maintained at 30 ° C or less. The reaction mixture was stirred for 30 min at -35 to -30 ° C, poured into ice / water, extracted with chloroform, the combined chloroform extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and chromatographed on silica gel (high performance liquid chromatography) eluting with 5% methanol / chloroform followed by 10% methanol / chloroform. The appropriate fractions were combined and concentrated to give 4.50 g (66.3%) of free base as product. The free base was dissolved in ether and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 178-180 degreeC.
Example 98
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine Hemihydrate
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine in 50% sodium hydroxide solution (8 ml) and 50% aqueous ethanol (50 ml) 8.0 g) was heated under nitrogen to 50 ° C. for 24 h. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1% acetone / 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 4.5 g (90%) of product. Melting point was 62-63 degreeC.
Example 99
N- (2-Chloro-4- [N, N-dimethylcarbamoyloxy] -5-methoxy) benzyl-N'-pyridin-2-yl-piperazine
Cesium carbonate (0.51 g) was added N- (2-chloro-4-hydroxy-5-methoxy) benzyl-N'-pyridin-2-ylpiperazine (0.53 g) and N in dichloromethane (20 mL). To the solution of N-dimethylcarbamoyl chloride was added and the reaction mixture was stirred at ambient temperature for 48 hours. Water and brine (250 mL) were added and the mixture was extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 25-100% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to yield 0.40 g (95%) of product. Recrystallization from ethyl acetate gave an analytical sample. Melting point was 120-127 degreeC.
Example 100
N- (2-chloro-4-benzyloxy-5-methoxy-N '-(2-chlorophenyl) piperazine
At ambient temperature, sodium hydride (50% suspension in oil, 0.85 g) was added 4-benzyloxy-2-chloro-5-methoxybenzyl chloride (2.0 g) and 2-chlorophenylpiperazine in dichloromethane (70 mL). To a solution of monohydrochloride (1.9 g) was added and the reaction mixture was stirred at ambient temperature for 24 hours. Water and brine (250 mL) were added and the mixture was extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 20-60% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 1.94 g (62%) of product. Melting point was 95-97 degreeC.
Example 101
N- (2-chloro-4-hydroxy) benzyl-N '-(2-methoxyphenyl) piperazine
Sodium triacetoxyborohydride (3.80 g) was added to a solution of 2-chloro-4-hydroxybenzaldehyde (2.15 g) and 2-methoxyphenyl piperazine (2.93 g) in dichloromethane (75 mL) at ambient temperature. Was added. The reaction mixture was stirred at ambient temperature for 72 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 20-60% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 2.34 g (51%) of product. Recrystallization from ethyl acetate / heptane gave an analytical sample. Melting point was 186-187 degreeC.
Example 102
N- (2-bromo-5- [N, N-dimethoxycarbamoyloxy] -4-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine
At ambient temperature, cesium carbonate (0.50 g) was added N- (2-bromo-5-hydroxy-4-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine in dichloromethane (20 mL). (0.42 g) and N, N-dimethylcarbamoyl chloride (0.25 mL). The reaction mixture was stirred at ambient temperature for 72 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane / heptane to give 0.31 g (73%). Melting point was 139-140 degreeC.
Example 103
N- (3-fluoro-4-hydroxy) benzyl-N '-(2-methoxyphenyl) piperazine
At ambient temperature, sodium triacetoxyborohydride (2.68 g) was added to 3-fluoro-4-methoxybenzaldehyde (1.50 g) and N- (2-methoxyphenyl) piperazine in dichloromethane (40 mL). 2.28 g) was added to the solution. The reaction mixture was stirred at ambient temperature for 48 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 20-60% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 3.06 g (95%) of product. Melting point was 55-57 degreeC.
Example 104
N- (2,6-dibromo-3- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso Quinoline
At ambient temperature, cesium carbonate (0.75 g) was added N- (2,6-dibromo-3-hydroxy-4-methoxy) benzyl-6,7-dimethoxy-1, in dichloromethane (20 mL), To a solution of 2,3,4-tetrahydroisoquinoline (0.75 g) and dimethylcarbamoyl chloride (0.35 mL) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography, eluting the residue with 20-60% ethyl acetate / heptane, gave 0.47 g (55%). Melting point was 162-163 degreeC.
Example 105
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-trifluoromethoxyphenyl) piperazine hydrochloride
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-trifluoromethine) pipepe in 50% sodium hydroxide solution (5 mL) and 50% aqueous ethanol (50 mL) A solution of lazine (2.8 g) was heated under nitrogen to 50 ° C. for 24 h. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1% acetone / 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate (150 mL) and etheric hydrogen chloride was added. The precipitates were collected and dried to give 0.4 g (16%). Melting point was 180-181 degreeC.
Example 106
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-trifluoromethylphenyl) piperazine hydrochloride
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine (0.5 g) and cesium carbonate in 25% acetonitrile / dichloromethane (15 mL) To a solution of (0.4 g) was added dimethylcarbamyl chloride (0.3 g) with stirring. The reaction mixture was stirred for 18 hours and diluted with ethyl acetate (150 mL). The solution was washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined, concentrated and treated with ethereal hydrogen chloride to yield 0.20 g (33%) of the product. Melting point was 123-124 degreeC.
Example 107
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2 = chlorophenyl) -piperazine
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine (0.75 g) and cesium carbonate in 25% acetonitrile / dichloromethane (35 mL) To a solution of (0.70 g) was added dimethylcarbamyl chloride (0.47 g) with stirring. The reaction mixture was stirred for 18 hours and diluted with ethyl acetate. The solution was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined, concentrated and treated with ethereal hydrogen chloride to give 0.2 g (22%) of product. Melting point was 55-56 degreeC.
Example 108
1- [1- (3-methoxy-4-N-methylcarbamoylphenyl) ethyl] -4- (2-trifluoromethylphenyl) -piperazine hemihydrate
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-trifluoromethylphenyl) piperazine (0.65 g) and copper chloride in ethyl acetate (20 mL) To the solution of I) (catalyst contact amount), methyl isocyanate (0.1 g) was added while stirring. The reaction mixture was stirred for 3 hours and diluted with ethyl acetate. The solution was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.22 g (30%) of product. Melting point was 61-62 degreeC.
Example 109
1- [1- (4-hydroxy-3-methoxyoxyphenyl) ethyl] -4- (2-methylphenyl) piperazine hydrochloride hemihydrate
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine in 50% sodium hydroxide solution (8 mL) and 50% aqueous ethanol (50 mL) (3.2 g) of the solution was heated under nitrogen to 50 ° C. for 24 h. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1% acetone / 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate (100 mL) and etheric hydrogen chloride was added. The precipitates were collected and dried to give 2.5 g (78%). Melting point was 135-136 degreeC.
Example 110
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-methylphenyl) -piperazine sesquichloride hemihydrate
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methylphenyl) piperazine (1.0 g) and cesium carbonate (1.0 in 25% acetonitrile / dichloromethane (35 mL) To the solution of g) was added dimethylcarbamyl chloride (0.8 g) with stirring. The reaction mixture was stirred for 18 hours and diluted with ethyl acetate. The solution was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was treated with ethereal hydrogen chloride to give 0.2 g (16%) of product. Melting point was 128-129 degreeC.
Example 111
1-[[4-methoxy-3- (dimethylaminocarbonyloxy) phenyl] methyl-4- (2-chlorophenyl) piperazine hydrochloride
1- (2) dissolved in 1,2-dichloroethane (17 mL) in a solution of 4-methoxy- (3-dimethylaminocarbonyloxy) benzaldehyde (2.0 g) in 1,2-dichloroethane (17 mL) -Chlorophenyl) piperazine (2.85 g) followed by sodium triacetoxyborohydride (2.85 mL) was added with stirring. The reaction mixture was stirred at ambient temperature for 2 hours, poured into saturated sodium carbonate solution (100 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography eluting with dichloromethane followed by 0.1, 0.2, 0.3, 0.4, 0.5% methanol / dichloromethane, respectively. The appropriate fractions were combined and concentrated to give 2.86 g (79%) of free base as product. The precipitates were collected, dried at ambient temperature under high vacuum and recrystallized from 2-propanol to give the product. Melting point was 214-216 degreeC.
Example 112
1-[[3- (methoxy) -4- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-methylphenyl) piperazine hydrochloride
To a solution of 3- (methoxy) -4-dimylaminocarbonyloxybenzaldehyde (1.0 g) in 1,2-dichloroethane (18 mL) 1- (2-tolyl) piperazine (0.80 g) and sodium triacetox Ciborohydride (1.44 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 2 hours, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography eluting with dichloromethane followed by 0.1, 0.2, 0.3, 0.5, 1% methanol / dichloromethane, respectively. Appropriate fractions were collected and concentrated. The residue was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected, dried at ambient temperature under high vacuum and recrystallized from 2-propanol to give the product. Melting point was 230-250 degreeC.
Example 113
N- (2,6-dibromo-3-hydroxy-4-methoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
At ambient temperature, sodium hydride (80%, suspension in oil, 0.96 g) was added (2,6-dibromo-3-hydroxy-4-methoxy) benzyl bromide (3.0 g) in dichloromethane (100 mL). And 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 25-75% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 2.9 g (74%) of product as free base. Some of the free base was dissolved in ethyl acetate, cooled to 0 ° C., and etheric hydrogen chloride followed by diethyl acetate. The precipitate was collected and recrystallized from methanol / diethyl ether to give the product. Melting point was 159-162 degreeC.
Example 114
N- (2,6-dibromo-3-hydroxy-4-methoxy) benzyl-N '-(2-chlorophenyl) piperazine
At ambient temperature, sodium hydride (80%, suspension in oil, 0.40 g) was dissolved in dichloromethane (30 mL) (2,6-dibromo-3-hydroxy-4-methoxy) benzyl bromide (1.0 g) And a solution of N- (2-chlorophenyl) piperazine (0.88 g). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 10-25% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 1.2 g (85%) as product free base. Melting point was 159-162 degreeC.
Example 115
N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(2-chlorophenyl) piperazine
At ambient temperature, sodium hydride (80%, suspension in oil, 0.60 g) was dissolved in dichloromethane (40 mL) (2-chloro-5-hydroxy-4-methoxy) benzyl bromide (1.0 g) and N- ( To a solution of 2-chlorophenyl) piperazine (1.3 g). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 10-25% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.50 g (28%) of product. Melting point was 155-157 degreeC.
Example 116
N- (4-benzyloxy-2chloro-5-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine
At ambient temperature, sodium hydride (80%, suspension in oil, 0.60 g) was added (4-benzyloxy-2-chloro-5-methoxy) benzyl chloride (2.0 g) and N- (in dichloromethane (5 mL). To a solution of 2-chlorophenyl) piperazine (1.6 g). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 20-40% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 2.0 g (64%) of product. Trituration from dichloromethane gave an analytical sample. Melting point was 86-88 degreeC.
Example 117
N- (3-fluoro-4-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine
At ambient temperature, sodium triacetoxyborohydride (3.58 g) was added to 3-fluoro-4-methoxybenzaldehyde (2.04 g) and N- (2-chlorophenyl) piperazine (3.05 in dichloromethane (50 mL). to solution of g). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 10-35% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 3.92 g (87%) of free base as product. Some of the free base was dissolved in ytel acetate, cooled to 0 ° C., ethereal hydrogen chloride was added, the precipitate was collected and concentrated in vacuo. Recrystallization from methanol / diethyl ether gave an analytical sample. Melting point was 242-245 degreeC.
Example 118
N- (3-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine
At ambient temperature, a solution of N- (4-benzyloxy-2-chloro-5-methoxy) benzyl-N'-pyridin-2-yl piperazine (1.70 g) in dichloromethane (25 mL) was diluted with dichloromethane ( 50 ml) was added to a solution of ferric chloride (3.70 g). The reaction mixture was heated under reflux for 24 h, cooled to ambient temperature, filtered and the filter cake washed with dichloromethane. The filter cake was suspended in 5% potassium hydroxide solution (250 mL) and stirred at ambient temperature for 2 hours. The suspension was neutralized with hydrochloric acid and filtered. The filtrate was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 20-50% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.80 g (58%) of product. Recrystallization from ethyl acetate / heptane gave an analytical sample. Melting point was 143-1452 degreeC.
Example 119
1-[[4-methylaminocarbonyloxy-3-) methoxy) phenyl] methyl-4- (3-fluoropyridin-3-yl) piperazine hydrochloride hydrate
A solution of 4- (methylaminocarbonyloxy) -3-methoxybenzaldehyde (0.49 g), 3- (fluoropyridin--2 yl) piperazine (0.506 g) and 1,2-dichloroethane (7 mL) Was added with stirring sodium triacetoxyborohydride (0.65 g). The reaction mixture was stirred at ambient temperature for 2.5 hours, poured into ice / sodium carbonate and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in chloroform and subjected to flash chromatography (silica gel) eluting with chloroform, 1% and 2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.79 g (90%) of free base as product. The free base was dissolved in diethyl ether and etheric hydrogen chloride was added. The precipitates were collected, dried at ambient temperature and re-cured from acetonitrile to give 0.321 g of product. Melting point was 172-174 degreeC.
Example 120
1-[[3-methoxy-4- [1- (phenyl) ethylaminocarbonyloxy] phenyl] methyl] -4- (2-fluorophenyl) piperazine hydrochloride
To a solution of 3-methoxy-4 [1- (phenyl) ethylaminocarbonyloxy] benzaldehyde (0.69 g) in 1,2-dichloroethane (120 mL) 1- (2-fluorophenyl) piperazine (0.42 g) was then added with stirring sodium triacetoxyborohydride (0.73 g). The reaction mixture was stirred at ambient temperature for 5 hours, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to high performance liquid chromatography (silica gel) eluting with dichloromethane followed by 0.2, 0.4, 0.6, 1.0% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.61 g (57%) of free base as product. The free base was dissolved in base ethyl ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol (78 ° C., dried under high vacuum for 2 hours) to afford the product. Melting point was 204-207 degreeC (decomposition).
Example 121
N- (2-chloro-4- [N, N-dimethylcarbamoyloxy] benzyl-N- (2-methoxyphenyl) piperazine hydrochloride hydrate
At ambient temperature, cesium carbonate (0.85 g) was added N- (2-chloro-4-hydroxy) benzyl-N '-(2-methoxyphenyl) piperazine (0.75 g) and N in dichloromethane (20 mL). To a solution of, N-dimethylcarbamoyl chloride (0.40 mL). The reaction mixture was stirred at ambient temperature for 72 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting the residue with 10-40% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.58 g (64%) of free base as product. The free base was dissolved in ethyl acetate, cooled to 0 ° C. and ethereal hydrogen chloride was added. Diethyl ether was added and the precipitate collected. Recrystallization from methanol / diethyl ether gave an analytical sample. Melting point was 208-210 degreeC.
Example 122
N- (2-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine hydrochloride hydrate
At ambient temperature, a solution of N- (4-hydroxy-2-chloro-5-methoxy) benzyl-N- (2-methoxyphenyl (piperazine (1.30 g) in dichloromethane (20 mL) was added to dichloromethane. (40 mL) was added to a suspension of ferric chloride (2.35 g) The reaction mixture was heated under reflux for 25 h, filtered and the filter cake washed with dichloromethane The filter cake was washed with 5% potassium hydroxide solution. (250 mL) and stirred at ambient temperature for 2 hours The suspension was neutralized with hydrochloric acid and filtered The aqueous filtrate was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated Flash chromatography (silica gel) eluting with 20-100% ethyl acetate / heptane The appropriate fractions were combined and concentrated to give 0.60 g (58%) of free base as product. Was dissolved in methanol, acidified with ethereal hydrogen chloride, concentrated to about 5 mL, triturated with diethyl ether and recrystallized from methanol / diethyl ether to give an analytical sample, melting point was 173-175 ° C. .
Example 123
N- (3-fluoro-4-hydroxy) benzyl-N '-(2-chlorophenyl) piperazine hydrochloride hemihydrate
N- (3-fluoro-4-hydroxy) benzyl-N'-2-chlorophenyl) piperazine (3.0 g) was added to 48% hydrobromic acid (45 mL) at ambient temperature. The reaction mixture was heated at 100 ° C. for 24 h, cooled to ambient temperature, diluted with water (200 mL), neutralized with potassium hydroxide and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1-5% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 2.27 g (79%) of free base as product. Some of the free base was dissolved in methanol and etheric hydrogen chloride was added. The precipitate was collected and recrystallized from methanol / diethyl ether to give a sample for analysis. Melting point was 130-132 degreeC.
Example 124
1- [1- (3-methoxy-4-N-methylcarbamoyloxy phenyl) ethyl] -4- (2-chlorophenyl) piperazine hydrochloride hemihydrate
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine (0.75 g) and copper chloride (I) in ethyl acetate (20 mL) To the solution of was added methyl isocyanate (0.12 g) with stirring. The reaction mixture was stirred for 3 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate (100 mL) and acidified with ethereal hydrogen chloride. The precipitates were collected to give 0.20 g (23%) of product. Melting point was 141-142 degreeC.
Example 125
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-quinolinyl) piperazine Hemihydrate
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine in 50% sodium hydroxide solution (8 mL) and 50% aqueous ethanol (50 mL) (4.7 g) of the solution was heated under nitrogen to 50 ° C. for 24 h. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1% acetone / 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 1.8 g (43%) of product. Melting point was 53-54 degreeC.
Example 126
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-quinolinyl) piperazine Hemihydrate
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methylphenyl) piperazine (0.6 g) and carbonic acid in 25% acetonitrile / dichloromethane (15 mL) To a solution of cesium (0.5 g) was added dimethylcarbamyl chloride (9.4 g) with stirring. The reaction mixture was stirred for 18 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to yield 0.3 g (46%) of product. Melting point was 58-59 degreeC.
Example 127
1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-quinolinyl) piperazine dihydrochloride
Under nitrogen, of 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-quinoline) piperazine (0.90 g) and copper chloride (I) in ethyl acetate (15 mL) To the solution was added methyl isocyanate (0.14 g) with stirring. The reaction mixture was stirred for 3 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and acidified with ethereal hydrogen chloride. The precipitates were collected to give 0.20 g (23%) of product. Melting point was 182-183 degreeC.
Example 128
1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-methylphenyl) piperazine hydrochloride hydrate
Under nitrogen, of 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methylphenyl) piperazine (0.50 g) and copper (I) chloride in ethyl acetate (15 mL) To the solution was added methyl isocyanate (0.09 g) with stirring. The reaction mixture was stirred for 3 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. Appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate (100 mL) and acidified with ethereal hydrogen chloride. The precipitates were collected to give 0.20 g (23%) of product. Melting point was 178-179 degreeC.
Example 129
1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- [2- (4-methylquinolinyl)] piperazine Hemihydrate
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methylquinolinyl) piperazine (1.0 g) and copper chloride in ethyl acetate (20 mL) To the solution of I) was added methyl isocyanate (0.15 g) with stirring. The reaction mixture was stirred for 3 hours, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Flash chromatography (silica gel) eluting the residue with 1% methanol / dichloromethane. The appropriate fractions were combined and concentrated to yield 0.3 g (27%) of product. Melting point was 65 to 66 ℃
Example 130
1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- [2- (4-methylquinolinyl)] piperazine dihydrochloride
1- [1- (4-acetoxy-3-methoxyphenyl) ethyl] -4-[(2-methoxyquinolinyl) in 50% sodium hydroxide solution (8 mL) and 50% aqueous ethanol (50 mL) )] A solution of piperazine (35 g) was heated under nitrogen to 50 ° C. for 24 hours. The reaction mixture was diluted with ethyl acetate (150 mL), neutralized with 10% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1% acetone / 1% methanol / dichloromethane. Appropriate fractions were combined and concentrated. The residue was dissolved in ethyl acetate (100 mL) and etheric hydrogen chloride was added. The precipitates were collected to yield 2.2 g (71%) of product. Melting point was 155-156 degreeC.
Example 131
1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4-[(2- (4-methylquinolinyl)] piperazine
Under nitrogen, 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4-[(2- (4-methylquinolinyl)] in 25% acetonitrile / dichloromethane (20 mL) To a solution of piperazine (1.0 g) and cesium carbonate (0.8 g) was added with stirring dimethylcarbamyl chloride (0.6 g) The reaction mixture was stirred for 18 hours, diluted with ethyl acetate, washed with brine, Dry over anhydrous sodium sulfate, filter and concentrate the filtrate The flash chromatography (silica gel) eluting with 1% methanol / dichloromethane The appropriate fractions were collected and concentrated to give 0.4 g (36%) of product. Melting point was 68 to 69 ° C.
Example 132
N- (3-fluoro-4-hydroxy) benzyl-N '-(2-hydroxy) phenylpiperazine hydrochloride
N- (3-fluoro-4-methoxy) benzyl-N'-2- (hydroxy) piperazine (2.37 g) was added to 48% hydrobromic acid (35 mL) at ambient temperature. The reaction mixture was heated at 100 ° C. for 24 h, cooled to ambient temperature, diluted with water (200 mL), neutralized with potassium hydroxide and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 1-2% methanol / dichloromethane. The appropriate fractions were combined and concentrated to give 0.50 g (23%) of free base as product. The free base was dissolved in methanol, cooled to 0 ° C. and ethereal hydrogen chloride was added. The mixture was concentrated to about 5 mL and triturated with diethyl ether. The precipitate was collected and recrystallized from methanol / diethyl ether to give the product. Melting point was 153-155 degreeC.
Example 133
N- (2-chloro-5- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine
At ambient temperature, cesium carbonate (1.1 g) was dissolved in N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine in dichloromethane (15 mL). 0.40 g) and N, N-dimethylcarbamoyl chloride (0.35 mL). The reaction mixture was stirred at ambient temperature for 72 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting the residue with 25-100% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.43 g (88%) of free base as product. Recrystallization from dichloromethane / heptane yielded an analytical sample. Melting point was 203-205 degreeC.
Example 134
N- (2-chloro-5- [N, N-dimethylcarbamoyloxy] -5-methoxy) benzyl-N '-(2-chloro) phenylpiperazine hydrochloride
At ambient temperature, cesium carbonate (0.40 g) was added N- (2-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-chloro) phenylpiperazine (0.35) in dichloromethane (15 mL). g) and N, N-dimethylcarbamoyl chloride (0.20 mL). The reaction mixture was stirred at ambient temperature for 72 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting the residue with 25-100% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.32 g (84%) of free base as product. The free base was dissolved in ethyl acetate, cooled to 0 ° C. and ethereal hydrogen chloride was added. The precipitate was collected and recrystallized from methanol / ethyl acetate to give the product. Melting point was 172-174 degreeC.
Example 135
N- (2-chloro-5- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-N '-(2-chloro) phenylpiperazine
At ambient temperature, cesium carbonate (0.12 g) was added N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(2-chloro) piperazine (0.10 g in dichloromethane (5 mL). ) And N, N-dimethylcarbamoyl chloride (0.10 mL). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and recrystallized from dichloromethane / heptane to give an analytical sample. Melting point was 139-141 degreeC.
Example 136
N- (2-chloro-4-benzyloxy-5-methoxy-N '-(2-methyl) phenylpiperazine hydrochloride
At ambient temperature, sodium hydride (80%, suspension in oil, 0.64 g) was added 4-benzyloxy-2-chloro-5-methoxybenzyl chloride (2.0 g) and 2- (methyl) in dichloromethane (50 mL). To a solution of phenylpiperazine (1.5 g) was added. The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 10-30% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 1.9 g (63%) of product. Trituration from dichloromethane / heptane yielded an analytical sample. Melting point was 91-93 degreeC.
Example 137
N- (2-chloro-4- [N, N-dimethylcarbamoyloxy] -5-methoxy) benzyl-N '-(2-methoxy) phenylpiperazine hydrochloride hydrate
At ambient temperature, cesium carbonate (0.35 g) was added N- (2-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-methoxyphenyl) pipet in dichloromethane (3 x 250 mL). To a solution of lazine (0.30 g) and N, N-dimethylcarbamoyl chloride (0.30 mL) was added. The reaction mixture was stirred at ambient temperature for 48 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting the residue with 25-100% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.31 g (86%) of free base as product. The free base was dissolved in ethyl acetate, cooled to 0 ° C. and ethereal hydrogen chloride was added. The precipitate was collected and recrystallized from methanol / diethyl ether to give the product. Melting point was 189-191 degreeC.
Example 138
1-[[3-methoxy-4- (methylaminocarbonyloxy) phenyl] methyl] -4- (4-acetylphenyl) piperazine
To a solution of 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde (1.0 g) in 1,2-dichloroethane (20 mL) followed by 4'-piperazinoacetophenone (0.98 g) followed by sodium triaceto Ciborohydride (1.53 g) was added with stirring. The reaction mixture was stirred at ambient temperature overnight, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and subjected to flash chromatography (silica gel) eluting with 1% methanol: dichloromethane in the same solvent system. Appropriate fractions were combined and concentrated. The residue was recrystallized from ethyl acetate to give the product. Melting point was 120-123 degreeC.
Example 139
1-[[3-methoxy-4- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-fluorophenyl) piperazine
Sodium triacetoxyborohydride in 1,2-dichloroethane (13 mL) in a solution of 3-methoxy-4- (dimethylaminocarbonyloxy) benzaldehyde (1.50 g) in 1,2-dichloroethane (14 mL) Ride (2.14 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 4 hours, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 0.1, 0.2, 0.4, 0.5, 1 and 2% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 2.03 g (78%) of product. Recrystallization from ethyl acetate gave an analytical sample. Melting point was 130-133 degreeC.
Example 140
1-[[3-methoxy-4-[(1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyloxy] phenyl] methyl] -4- (2-fluorophenyl) -pipe Lazine Hydrochloride
To a solution of [3-methoxy-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyloxy] benzaldehyde (0.52 g) in 1,2-dichloroethane (6.6 mL) -(2-fluorophenyl) piperazine (0.30 g) followed by sodium triacetoxyborohydride (0.53 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 5 hours, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 0.2, 0.5 and 0.8% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.68 g (87%) as product free base. The free base was dissolved in diethyl acetate and etheric hydrogen chloride was added. The precipitates were collected to give the product. Melting point was 200-207 degreeC.
Example 141
1-[[3-methoxy-4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-nitrophenyl) piperazine hydrochloride
To a solution of 3-methoxy-4- (dimethylaminocarbonyloxy) benzaldehyde (0.60 g) in 1,2-dichloroethane (6 mL) 1- (2-nitro in 1,2-dichloroethane (5.5 mL) Phenyl) piperazine (0.60 g) followed by sodium triacetoxyborohydride (0.92 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 6 hours, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 0.2, 0.5, 1.0 and 2.0% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.78 g (68%) of free base as product. The free base was dissolved in dichloromethane, diluted with diethyl ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol to give the product. Melting point was 214-218 degreeC.
Example 142
1-[[3-methoxy-4- (dimethoxycarbonyloxy) phenyl] methyl] -4- (2-nitrophenyl) piperazine
To a solution of 3-methoxy-4- (dimethylaminocarbonyloxy) benzaldehyde (0.60 g) in 1,2-dichloroethane (5 mL) 1- (2-nitro in 1,2-dichloroethane (6 mL) Phenyl) piperazine (0.56 g) followed by sodium triacetoxyborohydride (0.85 g) was added with stirring. The reaction mixture was stirred at ambient temperature for 6 hours, poured into saturated sodium carbonate solution (75 mL) and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatography (silica gel) eluting with dichloromethane followed by 0.2, 0.5, 0.8, 1.0 and 2.0% methanol: dichloromethane. The appropriate fractions were combined and concentrated to give 0.75 g (67%) of free base as product. The free base was dissolved in dichloromethane, diluted with diethyl ether and etheric hydrogen chloride was added. The precipitates were collected and recrystallized from 2-propanol to give the product. Melting point was 185-188 degreeC.
Example 143
N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine hydrochloride
At ambient temperature, sodium hydride (80%, 0.90 g) was added N- (2-chloro-5-hydroxy-4-methoxy) benzyl chloride (2.0 g) and N- (pyridine-) in dichloromethane (40 mL). To a solution of 2-yl) piperazine (1.9 g). The reaction mixture was stirred at ambient temperature for 24 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 10-25% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.85 g (26%) as product free base. The free base was dissolved in ethyl acetate, cooled to 0 ° C., ethereal hydrogen chloride was added and diethyl ether was added. The precipitate was collected. Recrystallization from ethanol / diethyl ether gave the product. Melting point was 220-22 degreeC.
Example 144
N- [4- (dimethylcarbamoyl) -3-fluoro] benzyl-N '-(2-chlorophenyl) piperazine hydrochloride
At ambient temperature, cesium carbonate (1.22 g) was added N- (2-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-chlorophenyl) piperazine (1.00 in dichloromethane (15 mL). g) and N, N-dimethylcarbamoyl chloride (0.60 mL). The reaction mixture was stirred at ambient temperature for 48 hours, quenched with water, diluted with brine (250 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo and flash chromatography (silica gel) eluting the residue with 25-100% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.90 g (74%) of free base as product. The free base was dissolved in ethyl acetate, cooled to 0 ° C., acidified with ethereal hydrogen chloride and diluted with diethyl ether. The precipitate was collected. Recrystallization from methanol / diethyl ether gave an analytical sample. Melting point was 235-237 degreeC.
Example 145
N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine
At ambient temperature, sodium hydride (80%, suspension in oil) was added 2-chloro-4-hydroxybenzyl chloride (1.02 g) and 1- (2-methoxyphenyl) piperazine (1.05) in dichloromethane (40 mL). to solution of g). The reaction mixture was stirred at ambient temperature for 48 hours, quenched with water, diluted with brine (250 mL) and diluted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Flash chromatography (silica gel) eluting the residue with 20-40% ethyl acetate / heptane. The appropriate fractions were combined and concentrated to give 0.590 g (33%) of product. Recrystallization from dichloromethane / petroleum ether yielded an analytical sample. Melting point was 72-75 degreeC.

权利要求:
Claims (180)
[1" claim-type="Currently amended] Compounds of formula (1), optical isomers or pharmaceutically acceptable salts thereof.
<Formula 1>

In the formula,
R ₁ is hydrogen, lower alkyl, CONR ₆ R ₇ group, CH ₂ COOR ₈ group, CH ₂ CH ₂ OH group, CH ₂ CN group, group, Group or Si (R ₁₁ ) ₃ group,
R ₂ is hydrogen, lower alkyl, CONR ₆ R ₇ groups, SO ₂ R ₁₀ groups, Group or Si (R ₁₁ ) ₃ group,
R ₃ is hydrogen or lower alkyl,
R ₄ is hydrogen or lower alkyl,
R ₅ is hydrogen, lower alkyl, Flag or Or
R ₄ and R ₅ together with the nitrogen atom to which they are attached group, group, group, Form a flag,
R ₆ is hydrogen or lower alkyl,
R ₇ is alkyl having 1 to 10 carbon atoms, group, Flag or Or
R ₆ and R ₇ together with the nitrogen atom to which they are attached Form a flag,
R ₈ is lower alkyl,
R ₉ is hydrogen, a C (R ₁₄ R _{14 ′} ) OH group, group, Gigi,
R ₁₀ is lower alkyl,
R ₁₁ is lower alkyl,
R ₁₂ is lower alkyl, hydroxy lower alkyl, a COR ₁₅ group, group, group, group, Flag or Gigi,
R ₁₃ is hydrogen or lower alkyl,
R ₁₄ is hydrogen or lower alkyl,
R _{14 '} is hydrogen or lower alkyl,
R ₁₅ is Group or lower alkyl,
R ₂₀ is lower alkyl,
X is hydrogen or halogen,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano, or a R ₂₀ CO or OCONR ₆ R ₇ group,
m is 1 or 2,
n is 0 or 1,
p is 1 or 2,
q is 0, 1 or 2,
r is 0, 1 or 2.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ₁ is a CONR ₆ R ₇ group.
[3" claim-type="Currently amended] The compound of claim 1, wherein R ₂ is lower alkyl.
[4" claim-type="Currently amended] The compound of claim 1, wherein R ₂ is a CONR ₆ R ₇ group.
[5" claim-type="Currently amended] The compound of claim 1, wherein R ₁ is lower alkyl.
[6" claim-type="Currently amended] The compound of claim 1, wherein R ₄ and R ₅ together with the nitrogen to which they are attached Compounds that form groups.
[7" claim-type="Currently amended] The compound of claim 2, wherein R ₁ is a CONR ₆ R ₇ group and R ₄ and R ₅ together with the nitrogen to which they are attached Forming a group, wherein n is zero.
[8" claim-type="Currently amended] 5. A compound according to claim 4, wherein R ₂ is a CONR ₆ R ₇ group and R ₄ and R ₅ together with the nitrogen to which they are attached Forming a group, wherein n is zero.
[9" claim-type="Currently amended] The compound of claim 1, which is 4- [3- [2-methoxy-5 (pyrrolidin-1-yl-methyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol.
[10" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3-propargyloxydimethylaminomethylbenzene.
[11" claim-type="Currently amended] The compound of claim 1, which is 4- [3- (2-methoxy-5- (dimethylamino-1-yl-methyl) phenoxy) propyn-1-yl] tetrahydrothiopyran-4-ol.
[12" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3- (propargyloxy) morpholino-4-yl-methylbenzene.
[13" claim-type="Currently amended] The compound of claim 1, which is 4- [3- [2-methoxy-5- (morpholin-4-yl-methyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol.
[14" claim-type="Currently amended] The compound of claim 1, which is 4- (methoxy) -3- (propargyloxy) -1-pyrrolidinomethylbenzene.
[15" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3-propargyloxy-1-[(piperidin-1-yl) methyl] benzene.
[16" claim-type="Currently amended] 4. The compound of claim 3, which is 1-[[2- (hydroxy) -2-methyl-pent-3-yn-5-yl] oxy] -4-methoxy-1-pyrrolidinomethylbenzene.
[17" claim-type="Currently amended] The compound of claim 1, which is 4- [3- [2-methoxy-5-[(piperidin-1-yl) methyl] phenoxy] propin-1-yl] tetrahydrothiopyran-4-ol .
[18" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3-propargyloxy-1-[(4-methylpiperazin-1-yl) methyl] benzene.
[19" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3-propargyloxy-1-[[(methyl) (phenethyl) amino] methyl] benzene.
[20" claim-type="Currently amended] The compound according to claim 1, which is 4- [3- [2-methoxy-5- (4-methylpiperazin-1-yl-methyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran-4-ol compound.
[21" claim-type="Currently amended] The compound according to claim 1, wherein 4- [3- [2-methoxy-5-[[(methyl) -2-phenethyl] aminomethyl] phenoxy] prop-1-ynyl] tetrahydrothiopyran-4- All-in compound.
[22" claim-type="Currently amended] The compound of claim 1, which is 4- [3- [2-methoxy-5- (pyrrolidin-1-yl-methyl) phenoxy] prop-1-ynyl] cyclohexan-4-ol.
[23" claim-type="Currently amended] The compound of claim 1, which is 4- (methanesulfonyloxy) -3- (propargyloxy) (pyrrolidin-1-yl) methylbenzene.
[24" claim-type="Currently amended] The compound of claim 4, which is 4- (methylaminocarbonyloxy) -3- (propargyloxy) pyrrolidinomethylbenzene.
[25" claim-type="Currently amended] The compound of claim 1, which is 4- (methanesulfonyloxy) -3-methoxy-[(pyrrolidin-1-yl) methyl] benzene.
[26" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3-propargyloxy-1-[[N- (methyl) -N- (3,4-dimethoxyphenethyl) amino] methyl] benzene.
[27" claim-type="Currently amended] The compound of claim 4, wherein the 4- [3- [2- (methylaminocarbonyloxy) -5- (pyrrolidin-1-yl-methyl) phenoxy] prop-1-ynyl] tetrahydrothiopyran- 4-ol compound.
[28" claim-type="Currently amended] The compound of claim 1, which is 4-methoxy-3- (propargyloxy) -1-[[4- (pyridin-2-yl) piperazin-1-yl] methyl] benzene.
[29" claim-type="Currently amended] The compound of claim 1, which is 1- (aminomethyl) -3-methoxy-4- (triisopropylsiloxy) benzene.
[30" claim-type="Currently amended] The compound of claim 1, which is 3-cyanomethoxy-4-methoxy-1-[(pyrrolidin-1-yl) methyl] benzene.
[31" claim-type="Currently amended] The compound of claim 1, wherein 3- [2-methoxy-5-[[4- (pyridin-2-yl) piperazin-1-yl] methyl] phenoxy (prop-1-ynyl) tetrahydrothiopyran Compound that is -4-ol.
[32" claim-type="Currently amended] The compound of claim 1, which is 3-ethoxycarbonylmethoxy-4-methoxy-1-pyrrolidinomethylbenzene.
[33" claim-type="Currently amended] The compound of claim 1, which is 3- (2-hydroxyethoxy) -3- (methoxy) pyrrolidinomethylbenzene.
[34" claim-type="Currently amended] The compound of claim 1, which is 2- (3,4-dimethoxyphenylmethylamino) imidazoline.
[35" claim-type="Currently amended] The compound of claim 1, wherein 3- [2-methoxy-5-[[N- (3,4-dimethoxyphenethyl)]-[N- (methyl) aminomethyl] phenoxy]-(prop-1 -Ynyl) tetrahydrothiopyran-4-ol.
[36" claim-type="Currently amended] The compound of claim 8, which is 4-[[3-methoxy-4- (methylaminocarbonyloxy) phenylmethyl] -1- (pyridin-2-yl) piperazine.
[37" claim-type="Currently amended] The compound of claim 1, which is 6,7-dimethoxy-N-[(4-methoxy) -3- (propargyloxy) phenylmethyl] -1,2,3,4-tetrahydroisoquinoline.
[38" claim-type="Currently amended] 8. A compound according to claim 7, which is 4-[[4-methoxy-3- (methylaminocarbonyloxy)] phenylmethyl] -1- (pyridin-2-yl) piperazine.
[39" claim-type="Currently amended] The compound of claim 6, which is 4-[[4-benzyloxy-3- (ethoxycarbonylmethoxy) fetyl] methyl] -1- (pyridin-2-yl) piperazine.
[40" claim-type="Currently amended] The compound of claim 8, which is 4-[[[4- (dimethylaminocarbonyloxy) -3- (methoxy)] phenyl] methyl] -1- (pyridin-2-yl) piperazine.
[41" claim-type="Currently amended] The compound of claim 4, wherein 2- [3-methoxy-4- (methylaminocarbonyloxy) phenylmethyl] -1- (6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline Phosphorus compounds.
[42" claim-type="Currently amended] The compound of claim 6, which is 4-[[4- (benzyloxy) -3- (2-hydroxyethyl) phenylmethyl] -1- (pyridin-2-yl) piperazine.
[43" claim-type="Currently amended] 7. N- (2-bromo-5-hydroxy-4-methoxy) benzyl-N according to claim 6 -(Pyridin-2-yl) piperazine.
[44" claim-type="Currently amended] The compound of claim 4, which is 2- [4-dimethylaminocarbonyloxy) -3- (menoxy) phenylmethyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
[45" claim-type="Currently amended] The compound of claim 8, wherein 4- [3- (methoxy) -4- [1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyloxy] phenylmethyl] -1- (pyridine-2 -Yl) piperazine.
[46" claim-type="Currently amended] 7. A compound according to claim 6, which is 4-[[4-hydroxy-3- (methoxy)] phenylmethyl] -1- (pyridin-2-yl) piperazine.
[47" claim-type="Currently amended] The compound of claim 1, which is 2- [3-hydroxy-4- (methoxy) phenylmethyl] -1- (6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline.
[48" claim-type="Currently amended] The compound of claim 8, which is 1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl] -4- (2-methoxyphenyl) piperazine.
[49" claim-type="Currently amended] The compound of claim 8, which is 1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl-4- (4-methoxyphenyl) piperazine.
[50" claim-type="Currently amended] The compound of claim 8, which is 1-[[4- (dimethylaminocarbonyloxy) -3- (methoxy) phenyl] methyl-4- (3-methoxyphenyl) piperazine.
[51" claim-type="Currently amended] The compound of claim 1, which is 2-[[4-hydroxy-3- (methoxy) phenyl] methyl]-(6,7-dimethoxy) -1,2,3,4-tetrahydroisoquinoline.
[52" claim-type="Currently amended] The compound of claim 6, which is 4-[[4- (hydroxy) -3- (2-hydroxyethyl)] phenylmethyl] -1- (pyridin-2-yl) piperazine.
[53" claim-type="Currently amended] The compound of claim 8, which is 4-[[[4- (methylaminocarbonyloxy) -3- (methoxy)] phenyl] methyl] -1- (pyrimidin-2-yl) piperazine.
[54" claim-type="Currently amended] The compound of claim 8, which is dimethylcarbamic acid 2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenyl ester.
[55" claim-type="Currently amended] A compound according to claim 6, wherein N- (4-benzyloxy-2-bromo-5-methoxy) benzyl-N -(Pyridin-2-yl) piperazine.
[56" claim-type="Currently amended] The N- (2,6-dibromo-3-hydroxy-4-methoxy) benzyl-N according to claim 6 -(Pyridin-2-yl) piperazine.
[57" claim-type="Currently amended] The compound of claim 8, which is morpholine-4-carboxylic acid 2-methoxy-4- [2- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenyl ester.
[58" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (4-fluorophenyl) piperazine.
[59" claim-type="Currently amended] The compound of claim 8, which is 1- (hydroxyethyl) -4-[[4- (methylaminocarbonyloxy) -3- (methoxy) phenyl] methyl] piperazine.
[60" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (4-trifluoromethylphenyl) piperazine.
[61" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-chlorophenyl) piperazine.
[62" claim-type="Currently amended] 7. N- (2-bromo-4-hydroxy-5-methoxy) benzyl-N according to claim 6 -(Pyridin-2-yl) piperazine.
[63" claim-type="Currently amended] 8. A compound according to claim 7, wherein N- (2,6-dibromo-3- [dimethylcarbamoyloxy] -4-methoxy) benzyl-N -(Pyridin-2-yl) piperazine.
[64" claim-type="Currently amended] 8. A compound according to claim 7, wherein N- (2-bromo-5- [dimethylcarbamoyloxy] -4-methoxy) -N -(Pyridin-2-yl) piperazine.
[65" claim-type="Currently amended] The compound of claim 8, wherein N- (2-bromo-4- [dimethylcarbamoyloxy] -5-methoxy) benzyl-N -(Pyridin-2-yl) piperazine.
[66" claim-type="Currently amended] The compound of claim 6, wherein N- (4-benzyloxy-2-chloro-5-methoxy) benzyl-N -(Pyridin-2-yl) piperazine.
[67" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-methoxyphenyl) piperazine.
[68" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-hydroxyphenyl) piperazine.
[69" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-fluorophenyl) piperazine.
[70" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-methylphenyl) piperazine.
[71" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2,4-difluorophenyl) piperazine.
[72" claim-type="Currently amended] The compound of claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine.
[73" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine.
[74" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-cyanophenyl) piperazine.
[75" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (phenyl) piperazine.
[76" claim-type="Currently amended] The compound of claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine.
[77" claim-type="Currently amended] The compound of claim 8, which is 1- [1,4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-methoxyphenyl) piperazine.
[78" claim-type="Currently amended] The compound of claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine.
[79" claim-type="Currently amended] 7. N-2-chloro-4-hydroxy-5-methoxybenzyl-N according to claim 6 A compound that is -pyridin-2-ylpiperazine.
[80" claim-type="Currently amended] The N-2,6-dibromo-3-hydroxy-4-methoxybenzyl-N according to claim 6 2-methoxyphenylpiperazine.
[81" claim-type="Currently amended] 7. N-2-bromo-5-hydroxy-4-methoxybenzyl-N according to claim 6 Methoxyphenyl piperazine.
[82" claim-type="Currently amended] The compound of claim 8, which is 1-[[(3-methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-furoyl) piperazine.
[83" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine.
[84" claim-type="Currently amended] 7. A compound according to claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-ethoxyphenyl) piperazine.
[85" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-fluorophenyl) piperazine.
[86" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (4-nitrophenyl) piperazine.
[87" claim-type="Currently amended] The compound of claim 6, which is 1-[[3- (methoxy) -4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-hydroxyphenyl) piperazine.
[88" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-ethoxyphenyl) piperazine.
[89" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-ethoxyphenyl) piperazine.
[90" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-chlorophenyl) piperazine.
[91" claim-type="Currently amended] The compound of claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine.
[92" claim-type="Currently amended] The compound of claim 8, which is 1- [2- (chloro) -4- (dimethylaminocarbonyl) -5-methoxyphenyl] methyl-4-pyridin-2-ylpiperazine.
[93" claim-type="Currently amended] The compound of claim 6, which is 1-[[1- (chloro) -4- (benzyloxy) -5-methoxyphenyl] methyl] -4- (2-chlorophenyl) piperazine.
[94" claim-type="Currently amended] 7. The compound of claim 6, which is 1-[[2- (chloro) -3- (hydroxy) phenyl] methyl] -4- (2-methoxyphenyl) piperazine.
[95" claim-type="Currently amended] 8. A compound according to claim 7, which is 1-[[2- (bromo) -4- (methoxy) -5- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-methoxyphenyl) piperazine compound.
[96" claim-type="Currently amended] Compounds of formula (2), optical isomers or pharmaceutically acceptable salts thereof.
<Formula 2>

In the formula,
R ₁₆ and R ₁₇ are independently hydrogen or alkyl having 1 to 10 carbon atoms,
R ₁₈ is Gigi,
W is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl,
s is 1 or 2,
X is hydrogen or halogen,
m is 1 or 2.
[97" claim-type="Currently amended] 97. The compound of claim 96, which is 1-[[3,4- (dimethoxy) phenyl] methyl] -4- [2- (methylaminocarbonyloxy) phenyl] piperazine.
[98" claim-type="Currently amended] 97. The compound of claim 96, which is 1-[[3,4- (dimethoxy) phenyl] methyl] -4 [2- (dimethylaminocarbonyloxy) phenyl] piperazine.
[99" claim-type="Currently amended] Compounds of formula (3), optical isomers or pharmaceutically acceptable salts thereof.
<Formula 3>

In the formula,
R ₁ is lower alkyl, benzyl, Group or CONR ₆ R ₇ group wherein R ₆ is hydrogen and R ₇ is lower alkyl
R ₂ is hydrogen, lower alkyl, or a Si (R ₁₁ ) ₃ group, where R ₁₁ is lower alkyl, or
R ₂ is a COR ₆ R ₇ group wherein R ₆ is hydrogen and R ₇ is lower alkyl
X is hydrogen or halogen,
m is 1 or 2.
[100" claim-type="Currently amended] 103. The compound of claim 99, which is 3-methoxy-4- (triisopropylsiloxy) benzaldehyde, (pyridyl-2-yl) hydrazone.
[101" claim-type="Currently amended] 105. The compound of claim 99, which is 3-methoxy-4- (methylaminocarbonyloxy) benzaldehyde, (pyridyl-2-yl) hydrazone.
[102" claim-type="Currently amended] 103. The compound of claim 99, which is 4-hydroxy-3-methoxybenzaldehyde, (pyridyl-2-yl) hydrazone.
[103" claim-type="Currently amended] 105. The compound of claim 99, which is 4-methoxy-3- (propargyloxy) benzaldehyde, (pyridin-4-yl) hydrazone.
[104" claim-type="Currently amended] 103. The compound of claim 99, which is 3-methoxy-4- (triisopropylsiloxy) benzaldehyde, (pyridyl-4-yl) hydrazone.
[105" claim-type="Currently amended] 103. The compound of claim 99, which is 4-hydroxy-3-methoxybenzaldehyde, (pyridyl-4-yl) hydrazone.
[106" claim-type="Currently amended] A compound of formula 4 or an optical isomer thereof.
<Formula 4>

In the formula,
R ₁ is lower alkyl, , CH ₂ COOR ₈ groups, Groups, CONR ₆ R ₇ groups or Si (R ₁₁ ) ₃ groups,
R ₂ is a SO ₂ R ₁₀ group, Groups, Si (R ₁₁ ) ₃ groups or CONR ₆ R ₇ groups,
R ₈ is lower alkyl,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano,
p is 1 or 2,
R ₆ is hydrogen,
R ₇ is Where R ₁₃ is lower alkyl, Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano and p is 1 or 2,
X is hydrogen or halogen,
m is 1 or 2.
[107" claim-type="Currently amended] 107. The compound of claim 106, which is 4-methanesulfonyloxy-3- (propargyloxy) benzaldehyde.
[108" claim-type="Currently amended] 107. The compound of claim 106, which is 4-benzyloxy-3-[(ethoxycarbonyl) methoxy] benzaldehyde.
[109" claim-type="Currently amended] 107. The compound of claim 106, which is 3-methoxy-4- [2- (phenyl) ethylaminocarbonyloxy] benzaldehyde.
[110" claim-type="Currently amended] Compounds of formula 5, optical isomers or pharmaceutically acceptable salts thereof.
<Formula 5>

In the formula,
R ₂ is hydrogen, lower alkyl or a CONR ₆ R ₇ group wherein R ₆ and R ₇ are lower alkyl,
R ₃ is hydrogen or lower alkyl,
R ₄ and R ₅ together with the nitrogen atom to which they are attached Where R ₁₂ is Term)
n is 0,
X is hydrogen or halogen,
m is 1 or 2.
[111" claim-type="Currently amended] 111. The compound of claim 110, which is 1- [1- (3-fluoro-4-methoxyphenyl) ethyl] -4-pyridin-2-yl-piperazine.
[112" claim-type="Currently amended] 112. The compound of claim 110, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-fluorophenyl) ethyl] -4-pyridin-2-yl-piperazine.
[113" claim-type="Currently amended] 111. The compound of claim 110, which is 2-fluoro-4- [1- (4-pyridin-2-yl) -piperazin-1-yl) ethyl] phenol.
[114" claim-type="Currently amended] A method for alleviating the disorder in a mammal, comprising administering an effective amount of the compound of claim 1 to a mammal in need of alleviating the memory disorder.
[115" claim-type="Currently amended] A composition for reducing memory function disorder, comprising an effective amount of the compound of claim 1 and an adjuvant as an active ingredient.
[116" claim-type="Currently amended] A method of alleviating said disorder in a mammal comprising administering an effective amount of the compound of claim 96 to a mammal in need thereof.
[117" claim-type="Currently amended] A composition for reducing memory function disorder, comprising an effective amount of the compound of claim 96 and an adjuvant as an active ingredient.
[118" claim-type="Currently amended] A method for alleviating said disorder in a mammal comprising administering an effective amount of the compound of claim 110 to a mammal in need thereof.
[119" claim-type="Currently amended] A memory functional disorder reducing composition comprising an effective amount of the compound of claim 110 and an adjuvant as an active ingredient.
[120" claim-type="Currently amended] Preparation of a compound of formula 1, an optical isomer or a pharmaceutically acceptable salt thereof, comprising treating a compound of formula 1 wherein one of R ₁ or R ₂ is hydrogen or lower alkyl with a compound of formula 14 in the presence of an acid acceptor Way.
<Formula 1>

<Formula 4>
R ₆ R ₇ NCOHal
In the formula,
R ₁ is hydrogen, lower alkyl or a CONR ₆ R ₇ group,
R ₂ is hydrogen, lower alkyl or a CONR ₆ R ₇ group,
R ₃ is hydrogen or lower alkyl,
R ₄ is hydrogen or lower alkyl,
R ₅ is hydrogen, lower alkyl or Or
R ₄ and R ₅ together with the nitrogen atom to which they are attached group, group, group, Form a flag,
R ₆ is hydrogen or lower alkyl,
R ₇ is alkyl having 1 to 10 carbon atoms, group, Flag or Or
R ₆ and R ₇ together with the nitrogen atom to which they are attached Form a flag,
R ₈ is lower alkyl,
R ₉ is hydrogen, a C (R ₁₄ R _{14 ′} ) OH group, group, Gigi,
R ₁₀ is lower alkyl,
R ₁₁ is lower alkyl,
R ₁₂ is lower alkyl, hydroxy lower alkyl, a COR ₁₅ group, group, group, group, Flag or Gigi,
R ₁₃ is hydrogen or lower alkyl,
R ₁₄ is hydrogen or lower alkyl,
R _{14 '} is hydrogen or lower alkyl,
R ₁₅ is Group or lower alkyl,
X is hydrogen or halogen,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro or cyano, R ₂₀ CO or OCONR ₆ R ₇ group,
m is 1 or 2,
n is 0 or 1,
p is 1 or 2.
q is 0, 1 or 2,
r is 0, 1 or 2,
Hal is bromo or chloro.
[121" claim-type="Currently amended] 121. The method of claim 120, wherein the acid acceptor is an alkali metal carbonate.
[122" claim-type="Currently amended] 124. The method of claim 121, wherein the alkali metal carbonate is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.
[123" claim-type="Currently amended] 123. The method of claim 122, wherein the alkali metal carbonate is cesium carbonate.
[124" claim-type="Currently amended] 121. The method of claim 120, wherein a solvent is used.
[125" claim-type="Currently amended] 124. The method of claim 124, wherein the solvent is acetonitrile.
[126" claim-type="Currently amended] 124. The method of claim 124, wherein the solvent is halocarbon.
[127" claim-type="Currently amended] 126. The method of claim 126, wherein the halocarbon is dichloromethane.
[128" claim-type="Currently amended] The compound of claim 6, which is N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine.
[129" claim-type="Currently amended] The compound of claim 6, which is N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine.
[130" claim-type="Currently amended] The compound of claim 4, which is 1-[[3-methoxy-4- (dimethoxycarbonyloxy) phenyl] methyl] -4- (2-nitrophenyl) piperazine.
[131" claim-type="Currently amended] The compound of claim 4, which is 1-[[3-methoxy-4- (methylaminocarbonyloxy) phenyl] methyl] -4- (2-nitrophenyl) piperazine.
[132" claim-type="Currently amended] 5. The compound of claim 4 wherein 1-[[3-methoxy-4-[(1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyloxy] phenyl] methyl] -4- (2- Fluorophenyl) -piperazine.
[133" claim-type="Currently amended] The compound of claim 4, which is 1-[[3-methoxy-4- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-fluorophenyl) piperazine.
[134" claim-type="Currently amended] The compound of claim 4, which is 1-[[3-methoxy-4- (methylaminocarbonyloxy) phenyl] methyl] -4- (4-acetylphenyl) piperazine.
[135" claim-type="Currently amended] The compound of claim 4, which is N- (2-chloro-4- [N, N-dimethylcarbamoyloxy] -5-methoxy) benzyl-N '-(2-methoxy) phenylpiperazine.
[136" claim-type="Currently amended] The compound of claim 1, which is N- (2-chloro-4-benzyloxy-5-methoxy-N '-(2-methyl) phenylpiperazine.
[137" claim-type="Currently amended] 8. A compound according to claim 7, which is N- (2-chloro-5- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-N '-(2-chloro) phenylpiperazine.
[138" claim-type="Currently amended] The compound of claim 8, which is N- (2-chloro-4- [N, N-dimethylcarbamoyloxy] -5-methoxy) benzyl-N '-(2-chloro) phenylpiperazine.
[139" claim-type="Currently amended] 8. A compound according to claim 7, which is N- (2-chloro-5- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-N '-(pyridin-2-yl) piperazine.
[140" claim-type="Currently amended] 8. A compound according to claim 7, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-repidinyl) piperazine.
[141" claim-type="Currently amended] 7. The compound of claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-repidinyl) piperazine.
[142" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- [2- (4-methylquinolinyl)] piperazine.
[143" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-methylphenyl) piperazine.
[144" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-quinolinyl) piperazine.
[145" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-quinolinyl) piperazine.
[146" claim-type="Currently amended] A compound according to claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-quinolinyl) piperazine.
[147" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine.
[148" claim-type="Currently amended] The compound of claim 6, which is N- (2-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine.
[149" claim-type="Currently amended] The compound of claim 1, which is N- (2-chloro-4- [N, N-dimethylcarbamoyloxy] benzyl-N '-(2-methoxyphenyl) piperazine.
[150" claim-type="Currently amended] The compound of claim 1, which is 1-[[3-methoxy-4- [1- (phenyl) ethylaminocarbonyloxy] phenyl] methyl] -4- (2-fluorophenyl) piperazine.
[151" claim-type="Currently amended] 8. A compound according to claim 7, which is 1-[[4- (methylaminocarbonyloxy-3-methoxy) phenyl] methyl] -4- (3-fluoropyridin-2-yl) piperazine.
[152" claim-type="Currently amended] The compound of claim 6, which is N- (3-chloro-4-hydroxy-5-methoxy) benzyl-N '-(2-chlorophenyl) piperazine.
[153" claim-type="Currently amended] The compound of claim 6, which is N- (4-benzyloxy-2-chloro-5-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine.
[154" claim-type="Currently amended] The compound of claim 6, which is N- (2-chloro-5-hydroxy-4-methoxy) benzyl-N '-(2-chlorophenyl) piperazine.
[155" claim-type="Currently amended] The compound of claim 6, which is N- (2,6-dibromo-3-hydroxy-4-methoxy) benzyl-N '-(2-chlorophenyl) piperazine.
[156" claim-type="Currently amended] A compound according to claim 1 which is N- (2,6-dibromo-3-hydroxy-4-methoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline .
[157" claim-type="Currently amended] The compound of claim 8, which is 1-[[3- (methoxy) -4- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-methylphenyl) piperazine.
[158" claim-type="Currently amended] 8. A compound according to claim 7, which is 1-[[4-methoxy-3- (dimethylaminocarbonyloxy) phenyl] methyl] -4- (2-chlorophenyl) piperazine.
[159" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-methylphenyl) piperazine.
[160" claim-type="Currently amended] A compound according to claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-methylphenyl) piperazine.
[161" claim-type="Currently amended] The compound according to claim 8, which is 1- [1- (3-methoxy-4-N-methylcarbamoyloxyphenyl) ethyl] -4- (2-trifluoromethylphenyl) piperazine.
[162" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine.
[163" claim-type="Currently amended] The compound of claim 8, which is 1- [1- (4-N, N-dimethylcarbamoyloxy-3-methoxyphenyl) ethyl] -4- (2-trifluoromethylphenyl) piperazine.
[164" claim-type="Currently amended] A compound according to claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-trifluoromethylphenyl) piperazine.
[165" claim-type="Currently amended] 8. A compound according to claim 7, wherein N- (2,6-dibromo-3- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-6,7-dimethoxy-1,2,3 , 4-tetrahydroisoquinoline.
[166" claim-type="Currently amended] 8. A compound according to claim 7, which is N- (2-bromo-5- [N, N-dimethylcarbamoyloxy] -4-methoxy) benzyl-N '-(2-methoxyphenyl) piperazine.
[167" claim-type="Currently amended] The compound of claim 6, which is N- (2-chloro-4-benzyloxy-5-methoxy-N '-(2-chlorophenyl) piperazine.
[168" claim-type="Currently amended] The compound of claim 8, which is N- (2-chloro-4- [N, N-dimethylcarbamoyloxy] -5-methoxy) benzyl-N'-pyridin-2-ylpiperazin.
[169" claim-type="Currently amended] The compound of claim 6, which is 1- [1- (4-hydroxy-3-methoxyphenyl) ethyl] -4- (2-chlorophenyl) piperazine.
[170" claim-type="Currently amended] Reduction of memory impairment and treatment of depression in a mammal in need of treatment of depression and memory impairment Simultaneous treatment method.
[171" claim-type="Currently amended] A composition for simultaneous treatment of depression treatment and memory disorder reduction comprising an effective amount of the compound of claim 1 and an adjuvant as an active ingredient.
[172" claim-type="Currently amended] A compound of formula 43, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
<Formula 43>

R ₂ is hydrogen, lower alkyl or a CONR ₆ R ₇ group,
R ₃ is hydrogen or lower alkyl,
R ₄ and R ₅ together with the nitrogen atom to which they are attached Form a flag,
R ₁₂ is Gigi,
Z is hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy, trifluoromethyl, nitro, cyano or COCH ₃ ,
m is 1 or 2,
n is 0 or 1,
p is 1 or 2.
[173" claim-type="Currently amended] 172. The compound of claim 172, wherein R ₂ is a CONR ₆ R ₇ group.
[174" claim-type="Currently amended] 172. The compound of claim 172, wherein n is zero.
[175" claim-type="Currently amended] 172. The N- (2-chloro-4-hydroxy) benzyl-N according to claim 172. A compound that is-(2-methoxyphenyl) piperazine.
[176" claim-type="Currently amended] 172. The N- (3-fluoro-4-hydroxy) benzyl-N according to claim 172. A compound that is-(2-methoxyphenyl) piperazine.
[177" claim-type="Currently amended] 172. The N- (3-fluoro-4-methoxy) benzyl-N according to claim 172. A compound that is-(2-chlorophenyl) piperazine.
[178" claim-type="Currently amended] 172. The N- (3-fluoro-4-hydroxy) benzyl-N according to claim 172. A compound that is-(2-chlorophenyl) piperazine.
[179" claim-type="Currently amended] 172. The N- (3-fluoro-4-methoxy) benzyl-N according to claim 172. A compound that is-(2-hydroxyphenyl) piperazine.
[180" claim-type="Currently amended] 172. The composition of claim 172, wherein N- [4- (N, N-dimethylcarbamoyloxy) -3-fluoro] benzyl-N A compound that is-(2-chlorophenyl) piperazine.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-09-29|Priority to US93946697A

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1997-09-29|Priority to US08/939,466

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1998-09-04|Application filed by 스티븐 엘. 네스빗, 아벤티스 파마슈티칼스 인크

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1998-09-04|Priority to PCT/US1998/018587

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2001-05-15|Publication of KR20010040254A

优先权:

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申请号 | 申请日 | 专利标题

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US93946697A| true| 1997-09-29|1997-09-29|

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US08/939,466|1997-09-29|

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PCT/US1998/018587|WO1999016746A1|1997-09-29|1998-09-04|Aminoalkylphenol derivatives and related compounds|