JPS6340420B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a group of secondary amine derivatives having anti-obesity and anti-hyperglycemic properties, a process for their preparation and their use as anti-obesity and/or anti-hyperglycemic agents when formulated in pharmaceutical compositions. Regarding use. Formula (A) (In the formula, R ₁ is hydrogen, fluorine, or chlorine atom, or hydroxyl, hydroxymethyl, methoxy, amino, formamide, acetamide, methylsulfonylamide, nitro, benzyloxy,
methylsulfonylmethyl, ureido, trifluoromethyl or p-methoxybenzylamino group, R ₂ is hydrogen, fluorine or chlorine atom or hydroxyl group, R ₃ is hydrogen or chlorine atom or hydroxyl group, and Q is an isopropyl or t-butyl group). Some compounds have β-adrenoceptor agonist activity.
activity). (e.g. DTCollins et al, J.Med.Chem., 1970,
13, 674). Certain compounds encompassed by formula (A), where Q is a group such as phenylaminoethyl, are disclosed in Belgian Patent No. 851,232 as having β-adrenergic receptor excitatory activity. Belgian Patent No. 809831 is included in formula (A),
It describes that certain compounds, where Q is specifically a substituted phenylthyl group, are useful as agents for the treatment of skin diseases. US Pat. No. 3,818,101 discloses certain compounds encompassed by formula (A) that can be used to induce polyphagia in meat-producing animals, where Q can specifically be an aralkyl group.
Certain compounds encompassed by formula (A), where Q may be a hydroxybenzyl or alkoxybenzyl group, have been shown to have β-adrenergic excitatory and blocking properties in South African Patent No. 6715591. These prior documents do not describe compounds of formula (A) as having anti-obesity activity combined with anti-hyperglycemic activity;
The compound represented by is not described as having anti-obesity activity alone. The inventors expressed the formula (A)
We have discovered a group of compounds that are somewhat related to the compounds represented by and have anti-obesity and/or anti-hyperglycemic properties. Such compounds could therefore be used in the treatment of obesity or hyperglycemia, and are expected to be of particular interest in conditions such as mature-onset diabetes, where obesity is, in turn, combined with hyperglycemia. sell. The present invention is based on the formula (): [In the formula, R ₁ , R ₂ and R ₃ are the same or different and are each a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group, R ₅ is a hydrogen atom or a lower alkyl group, and R ₆ is a hydrogen atom or a lower alkyl group, R ₇ is a hydrogen atom or a lower alkyl group, R ₈ is a hydrogen atom or a lower alkyl group, Y is an alkylene group having 2 or less carbon atoms,
and R ₉ is a carboxyl group, a lower alkyl ester thereof, or a group -CONHR ₁₀ (R ₁₀ is a hydrogen atom or a lower alkyl group), or a pharmaceutically acceptable salt thereof. Preferred compounds according to the invention are of the formula () (wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ and Y have the same meanings as in formula (), and
R ₁₀ is a C _1-4 alkyl group, preferably methyl, or a hydrogen atom) or a pharmaceutically acceptable salt thereof. Most preferably the group -CR ₇ = is attached in the para position to the Y moiety. Suitable variables for R ₁ include hydrogen, fluorine, chlorine and bromine atoms and trifluoromethyl groups. The portion Y may be 1 or 2 if desired, for example
It may also be branched in such a way that it has several methyl groups. A preferred group Y has the formula -( _CH2 )n-, where
n is an integer of 1 or 2). A particularly preferred value for R ₂ is a hydrogen atom. Suitably R ₂ is a hydrogen atom. Particularly preferred groups R ₁ R ₂ R ₃ C ₆ H ₂ include phenyl, 3-
Included are chlorphenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl and 3-bromphenyl groups. A preferred group R ₁ R ₂ R ₃ C ₆ H ₂ is a phenyl group.
Another preferred group R ₁ R ₂ R ₃ C ₆ H ₂ is the 3-chlorophenyl group, and another is the 3-trifluoromethyl group. A preferred group for R ₅ is a hydrogen atom. even more advantageous
The group R ₅ is a methyl group. A preferred group for R ₆ is a hydrogen atom. A further preferred radical for R ₆ is the methyl radical. Most preferably C(R ₅ )R ₆ is a CH ₂ , CHCH ₃ or C(CH ₃ ) ₂ group. In the compound of the present invention, C
Those in which (R ₅ ) R ₆ is CH ₂ or C(CH ₃ ) ₂ are less effective as anti-obesity agents than those in which C(R ₅ )R ₆ is CH (CH ₃ ); Since it has one less chiral center, it offers the advantage of being somewhat easier to synthesize. Compounds in which C(R ₅ )R ₆ is a CH(CH ₃ ) group offer the distinct advantage of having higher potency as anti-obesity agents. In the compound of the present invention in which Y is a -( _CH2 )n- group, n is 1 or 2. The group R ₇ is a hydrogen atom or a methyl group. The group R ₈ is a hydrogen atom or a methyl group. One group of preferred compounds of the invention has the formula (): (In the formula, R ₁₃ is a hydrogen atom or a methyl group,
R ₁₄ is a hydrogen atom or a methyl group, m is 1 or 2, and R ₁ ¹ is a hydrogen, chlorine, fluorine or bromine atom or a trifluoromethyl group, and R ₇ is a hydrogen atom or a methyl group; , R ₈ is a hydrogen atom or a methyl group, and R ₉ is a carboxyl group or a lower alkyl ester thereof,
or a group -CONHR ₁₀ (R ₁₀ is a hydrogen atom or a lower alkyl group)] or a pharmaceutically acceptable salt thereof. Another group of preferred compounds of the invention is of the formula () (wherein R ₁ ¹ , R ₁₃ , R ₁₄ and m have the same meanings as in formula () and R ₁₀ has the same meaning as in formula ()) or pharmaceutically That salt is acceptable. Preferably the R ₁ ¹ C ₆ H ₅ group is 3-chlorophenyl,
3-fluorophenyl, 2-fluorophenyl,
3-trifluoromethylphenyl, 3-bromphenyl or phenyl. Most preferably R ₁₃ is a hydrogen atom. Most preferably R ₁₄ is a methyl group. Advantageously m is 1. Advantageously m is 2. Compounds of the invention may also be provided as acid addition salts. Such salts may be of organic or inorganic acids, but are usually salts of pharmaceutically suitable acids.
Suitable acid addition salts include hydrochloric acid, hydrobromic acid, orthophosphoric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, acetylsalicylic acid. It is formed with an acid such as The compound represented by the formula () is the following formula (
a) It has an asymmetric center on one of the carbon atoms marked with an asterisk. (wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and Y have the same meanings as in formula ()).
The compound represented by formula () has R ₁ to R ₃ and R ₅ to
Formula (a) when R ₉ and Y have the same meaning as in formula () and when R ₅ is different from R ₆
has another asymmetric center on the carbon atom marked with two asterisks. The invention extends to the individual stereoisomeric forms of the compounds of formula () as well as to mixtures thereof. These compounds containing two asymmetric centers, suitably of the formula (), are provided in the form of separated diastereomers. Such separated diastereomers, of course, contain a pair of compounds that are mirror images of each other. X-ray analysis can be used to determine absolute stereochemistry and to understand correlations. In a ¹³ CNMR spectrum of a compound containing a methyl group on the carbon atom in the alpha position to the nitrogen atom (i.e. existing in diastereomeric form), R ^* , R ^** ; S ^* , S ^{* *} Diastereomers are those in which the methyl groups appear more upfield (lower numbers in ppm, typically <20 ppm downfield from tetramethylsilane) in the d ₆ DMSO solution, whereas they appear more downfield ( Resonances with higher numbers (typically >20 ppm downfield from TMS) are R ^* ,
S ^** ; S ^* , R ^** belongs to the species. The amount of each diastereomer can be calculated from the relative intensity of the absorption line and is shown in the examples as a ratio (R ^* R ^** , S ^* S ^** : R ^* S ^** , S ^* R ^** ) . Other paired resonances can occur at carbons in the β position relative to the nitrogen atom, with the carbon atom and hydroxyl group directly bonded to the nitrogen atom. Diastereomers of the compounds can also be determined by gas chromatography techniques as described below. t-Butyldimethylsilyl chloride (0.083g)
and imidazole (0.038g) in pyridine (1ml)
The compound (~0.001g) was added to 250μ of the solution dissolved in the solution and the solution was heated at 135°C for 1 hour. Trifluoroacetylimidazole (25 μ) was added to the silylated mixture and the whole was further heated at 135°C.
Heated for 0.5 hour. 0.2μ of this solution was added to Carlo under the following conditions.
Retained in Erba4160Gas Chromatograph
Injected into a 25mSP-1000W.COT capillary column. Injection block temperature 250℃ Furnace temperature 240℃ Carrier gas - Hydrogen (column velocity 2ml/min)
Split ratio 10:1 The diastereomer elutes after about 25 minutes and the ratio is determined by area integration using a spectrophysics SP-4000 data system. -CR ₇ =C(R ₈ )R ₉ or - of the aforementioned compound
CR ₇ =CR ₈ CONHR ₁₀ The moiety may be cis, but is more suitably trans. The invention also provides pharmaceutical compositions containing a compound of the invention and a pharmaceutically suitable carrier. Although the compositions of the present invention can also be formulated for oral administration, parenteral dosage forms, such as compositions formulated for injection, are also possible. Particularly suitable dosage forms are unit dosage forms, such as tablets or capsules. Other fixed unit dosage forms can also be used, eg, powders provided in drug containers. In accordance with normal pharmaceutical practice, the carrier is a diluent,
It may be composed of a binder, a filler, a disintegrant, a wetting agent, a coloring agent, a flavoring agent, etc. Thus, typical carriers may consist of agents such as microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulfate, sucrose, and the like. Most suitably, the composition may be provided in the form of a dosage form. The dosage for such dosage forms is usually
It contains from 0.01 to 100 mg, more usually from 0.2 to 50 mg, and advantageously from 0.5 to 20 mg. Such dosages are administered 1 to 6 times per day, with a total daily dose for a 70 kg adult, usually about 0.1 to 100 mg, and more usually about 2
~80mg, given in such a way. Preferred, more potent compounds are usually presented in unit doses containing 0.1 to 10 mg, more usually 0.25 to 5 mg. The dosage for these days is usually about 0.5-20mg,
More commonly it will be 1-10 mg, such as 2-5 mg. In addition to use as human medicine, the compositions of the invention can be used to treat obesity in domestic mammals such as dogs. Administration to domestic mammals is generally by the oral route, and usually about
0.025-2.5mg/Kg, e.g. 0.1-2mg/Kg once daily
Or twice. The invention also provides methods for making the compounds of the invention. This method uses the formula (): (In the formula, -N=CR ₅ - or -NH-CH
(OH) _R5- group, and _R1 , _R2 , _R3 , _R7 ,
R ₈ , R ₉ and Y have the same meanings as in formula ()) and then, if desired, forming an addition salt of the initially formed compound of formula (). Become. Reduction of the compound represented by formula () is carried out using sodium borohydride or sodium cyanoborohydride.
This can be achieved using complex hydrides such as cyanoborohydride. This reduction is usually carried out in a lower alkanol solvent, such as methanol. An appropriate room temperature can be used, for example 20 to 30°C. The desired compound can be obtained from the reaction mixture by evaporation, extraction into a suitable solvent such as ethyl acetate, and evaporation. The initially obtained product can be conveniently purified, for example by chromatography or crystallization. The compound represented by the formula () is the formula (): (wherein R ₁ , R ₂ and R ₃ have the same meanings as in formula ()) and formula (XI): (wherein R ₅ , R ₇ , R ₈ , R ₉ and Y have the same meanings as in formula ()). The condensation reaction can be carried out in a convenient solvent such as a lower alkanol, for example ethanol, or by azeotropic removal of water in benzene. Generally, the reaction is carried out at an elevated temperature, such as reflux temperature. In some cases, it is convenient to produce and use the compound represented by the general formula () in situ without isolation. In this case, the reaction is performed in the formula: R ₁ , R ₂ , R ₃ , R ₅ ,
It consists of the reduction of a mixture of a compound represented by formula () and a compound represented by formula (XI), in which R ₇ , R ₈ , R ₉ and Y have the same meanings as above. Such reduction may be carried out under conditions as described for the reduction of compounds of formula (). Compounds represented by the formula () and having the same meaning as above are also represented by the formula (): (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as in the formula ()) and a compound represented by the formula (): (In the formula, R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and Y are the formula ()
It can also be produced by reacting a compound represented by (having the same meaning as in). This reaction can be carried out in a lower alkane solvent such as methanol or ethanol. Yet another method for producing a compound represented by formula () is formula (): (In the formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and Y have the same meaning as in formula ())
It consists of the reduction of a compound represented by The reduction of the compound represented by the formula () is the formula ()
This can be carried out using borohydride as described in the reduction of the compound represented by. The compound represented by formula () is formula (XII) (wherein R ₁ , R ₂ and R ₃ have the same meanings as in formula ()) or a hydrate thereof or a hemiacetal of a lower alkanol, a compound represented by formula () having the same meaning as above It can be produced by reacting with a compound represented by: The above reactions are generally carried out under conditions that result in the removal of water produced during the reaction. Thus, an expedient method is to transfer water to Deam
azeotropically from a refluxing benzene solution using a refluxing benzene solution. The compound of formula () can be obtained from the reaction mixture by evaporation of the solvent. Compounds of the formula () having only one asymmetric center can be resolved by known methods, for example using an optically active acid using a resolving agent. It is expressed by the formula (), and the asymmetric center is 2
Individual compounds can be separated into their diastereomers by fractional crystallization from a suitable solvent, for example ethyl acetate. After such separation, the individual components of the diastereomers are obtained by known methods, for example by resolution using optically active acids as resolving agents. Suitable optically active acids that can be used in the resolution method are listed in Topics In Stereochemistry, Vol. 6, Wiley
Interscience1971, Allinger NLand Eliel W.
Described in L.eds. Stereospecific synthesis can also be used to obtain specific enantiomers. Therefore, for example, the expression ()
One enantiomer of the compound can be used to react with a compound of formula (XI) prior to reduction with boron hydride. Similarly expression ()
One enantiomer of a compound of formula (wherein R ₅ is not the same as R ₆ ) can be used with a compound of formula ( ). Similarly, the expression ()
One enantiomer of a compound of formula (wherein R ₅ is not the same as R ₆ ) can be used with a compound of formula (XII) or before reduction with borohydride. The specific enantiomers produced by these methods can then be separated by conventional means, such as fractional distillation from a suitable solvent, such as ethyl acetate. Yet another method for producing the compound represented by the formula () is the formula () (wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ and Y have the same meanings as in formula (), and
R ₁₅ represents a C _1-4 alkyl group) is reacted with an amine represented by the formula () R ₁₀ NH ₂ () (wherein R ₁₀ has the same meaning as in formula ()) It consists of things. The reaction is suitably carried out at room temperature in the presence of an aqueous lower alkanol solution, preferably an aqueous methanol solution. Preferably R ₁₅ is methyl and R ₁₀ is methyl. The following examples illustrate the invention, and the examples illustrate the preparation of useful intermediates. Example 1 N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2
-Hydroxy-2-phenylethanamine 4-(E)-(2-carbomethoxyethenyl)phenylpropan-2-one (2.18g) and 2-hydroxy-2-phenylethanamine (1.37g) The mixture was refluxed in benzene in a Dean and Stark apparatus until the theoretical amount of water was collected. The solvent was evaporated and methanol was added followed by sodium borohydride (1.0 g) portionwise at room temperature.
The solution was left stirring for 0.5 h, then the solvent was removed. Water was added, the mixture was extracted with ether and the combined extract layers were dried (MgSO ₄ ).
Removal of the solvent gave the title compound as a 1:1 mixture of diastereomers and mp 99-100.5.
The title compound was obtained as the hemifumarate hemihydrate at 0.degree. C. (ethyl acetate). τ (DMSO) 8.95 (3H, d, J = 6Hz), 6.4−
7.5 (5H, m), 6.31 (3H, s), 5.2−4.9 (1H,
m), 3.45 (1H, d, J = 16Hz + 2H, s), 2.15−
2.9 (10H, m), 1.6 (4H, s, disappeared with _D2O ). Example 2 N-{2-(4-{(E)-2-carboxamidoethenyl}phenyl)-1-methylethyl}-2
-Hydroxy-2-(3-chlorophenyl)ethanamine 4-(E)-(2-carboxamidoethenyl)phenylpropan-2-one (1.16g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (0.98 g) mixture in benzene in a Dean and Stark apparatus until the theoretical amount of water has been collected (~4
time) refluxed. The solvent was evaporated, methanol was added, and sodium borohydride (2.0 g) was added portionwise. The solvent was evaporated, the residue was partitioned between water and chloroform, and the chloroform layer was dried (MgSO ₄ ). Removal of the solvent gave an oil which was chromatographed on Kieselgel60. The title compound was purified by elution with 10-15% methanol-chloroform, mp 98-125°C.
Obtained as a 22:78 mixture of diastereomers of (CHCH ₃ ). τ (CDCl ₃ ) 9.05 (3H, d, J = 6Hz), 6.4-7.5
(9H, m), 5.5 (1H, m), 3.58 (1H, d, J=16
Hz), 2.24−3.0 (9H, m). Example 3 N-{2-(4-{(E)-N'-methylcarboxamidoethenyl}phenyl)-1-methylethyl}-2-hydroxy-2-(3-chlorophenyl)ethanamine This is an example 4-(E)-(2-carboxamide ethenyl) in the same manner as for the compound described in 2.
Phenylpropan-2-one is converted into 4-(E)-(2-
N'-methylcarboxamidoethenyl) phenylpropan-2-one was used instead. The title compound was purified by chromatography of the resulting oil on Kieselgel 60, eluting with 5% methanol-chloroform, mp 98-125°C.
Obtained as a 25:75 mixture of diastereomers (EtOAc). τ (CDCl ₃ ) 8.9 (3H, d, J = 6Hz),
7.48 (3H, d, J = 4Hz, collapses into a single line with D ₂ O),
6.35−7.8 (6H, m; disappeared in 1HD ₂ O), 5.45 (1H, t.
J=5Hz), 4-5 (1H, wide, disappears with D ₂ O),
3.45 (1H, d, J = 16Hz), 2.45−2.9 (9H, m),
2.01 (1H, q, J = 4Hz, gradually disappears with D ₂ O). Example 4 N-{2-(4-(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2-
Hydroxy-2-(4-chlorophenyl)ethanamine This was prepared using the same method as the compound described in Example 1 to prepare -2-hydroxy-2-(4-chlorophenyl)ethanamine (1.97 g) and 4-{(E)- 2
―Carbomethoxyethenyl}phenylpropane―
2-one (2.55g). The title compound was obtained as an oil (4.0 g) with a melting point of 76
Crystallized from hexane as a ˜1:1 mixture of diastereomers (0.86 g) at ˜102° C. τ (CDCl ₃ ) 8.85 (3H, d, J = 6Hz), 6.9−7.6
(7H, m, 2H, disappears with D ₂ O), 6.25 (3H, s),
5.45 (1H, m), 3.65 (1H, d, J=16Hz), 2.9
(2H, d, J=8Hz), 2.8 (4H, s), 2.6 (2H,
d, J = 8Hz), 2.35 (1H, d, J = 16Hz). Example 5 N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2
-Hydroxy-2-(3-chlorophenyl)ethanamine This was prepared by preparing 2-hydroxy-2-(3-chlorophenyl)ethanamine (5.45 g) and 4-{(E) in the same manner as the compound described in Example 1. -2
―Carbomethoxyethenyl}phenylpropane―
2-one (7.11g). The resulting oil was chromatographed on Kieselgel 60. Elution with 5% methanol-chloroform gave the title compound (9.8 g). τ (CDCl ₃ ) 8.9 (3H, d, J = 6Hz), 6.8−7.5
(7H, m, 2H, disappears with D ₂ O), 6.25 (3H, s),
5.4 (1H, m), 3.6 (1H, d, J=16Hz), 2.5−2.9
(8H, m), 2.35 (1H, d, J = 16Hz). Example 6 N-{2-(4-{2-carboethoxy-2-
methylethenyl}phenyl)-1-methylethyl}-2-hydroxy-2-phenylethanamine 2-hydroxy-2-phenylethanamine (0.51 g) was prepared in the same manner as the compound described in Example 1. and 4-{2-carboethoxy-2
-Methylethenyl}phenylpropan-2-one (1.0g). The title compound was isolated as an oil. The oil was dissolved in methanol and treated with fumaric acid (0.43g) in methanol. Evaporation of the solvent gave an oil which was triturated with ethyl acetate and recrystallized from ethyl acetate to give the title compound hemifumarate salt (0.38 g).
A 50:50 mixture of diastereomers with a melting point of 135-138 °C was obtained. τ (CDCl ₃ ) 8.8 (3H, d, J = 6Hz), 8.7 (3H,
t, J=7Hz) 8.0 (3H, s), 6.35−7.5 (7H,
m, 2H, disappears with D ₂ O), 5.8 (2H, q, J = 7Hz)
4.85 (1H, m) 3.15 (1H, s), 2.8 (9H, m),
2.47 (1H, s), 1.8 (2H, wide, disappears in _D2O ). Example 7 N-{2-(4-{(E)-2-carboxyethenyl}phenyl)-1-methylethyl}-2-hydroxy-2-phenylethanamine sodium salt Sodium hydroxide (0.31 g) Aqueous solution (10ml) of
N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl-1-methylethyl}-2-hydroxy-2-phenylethanamine (2.6 g)
was added to a methanol (20 ml) solution and the solution was refluxed for 3 hours. The title compound (0.6 g) containing 0.5 mol of sodium hydroxide by evaporating the solvent and recrystallizing the resulting mass from ethanol,
A melting point >270°C was obtained. τ( _DMSOd6 + _MeOHd4 )9.1(3H,d,J=6
Hz), 7.0−7.5 (5H, m), 5.4 (1H, m), 3.6 (1H,
d, J = 16Hz), 2.5−3.0 (10H, m). Example 8 N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2
-Hydroxy-2-(3-trifluoromethylphenyl)ethanamine 2-Hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.05g) was prepared in the same manner as the compound described in Example 1. and 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g). 1.48 g (hexane) of the title compound with a melting point of 80-83°C was separated into diastereomers by elution with 2% methanol-chloroform on Kieselgel 60.
Obtained as a 45:55 mixture. τ( _CDCl3 ) 8.95 (3H, d, J=6Hz), 6.9−7.7
(7H, m, 2H, disappears with D ₂ O), 6.25 (3H, s),
5.4 (1H, m), 3.6 (1H, d, J=16Hz), 2.5−2.9
(8H, m), 2.45 (1H, d, J = 16Hz). Example 9 N-{3-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylpropyl}-
2-hydroxy-2-(3-chlorophenyl)
Ethanamine 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.71 g) and 4-{(E)-2-
Carbomethoxyethenyl}phenylbutane-2-
(2.32g). Kieselgel60
Elution with 1% methanol-chloroform gave the title compound as a 50:50 mixture of diastereomers, mp 87-89°C (hexane). τ (CDCl ₃ ), 8.9 (3H, d, J = 6Hz), 8.15−
8.55 (2H, m), 6.9−7.7 (7H, m, 2H, disappeared with D ₂ O), 6.3 (3H, s), 5.45 (1H, m), 3.65 (1H,
d, J = 16Hz), 2.55-2.9 (8H, m), 2.4 (1H,
d, J = 16Hz). Example 10 N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2
-Hydroxy-2-(2-fluorophenyl)
Ethanamine 2-hydroxy-2-(2-fluorophenyl)ethanamine (1.55 g) and 4-{(E)-2 were prepared in the same manner as the compound described in Example 1.
―Carbomethoxyethenyl}phenylpropane―
2-one (2.18g).
Melting point 111-116℃ (benzene-chloroform) was eluted with 1% methanol-chloroform on Kieselgel60.
The title compound (1.2 g) of heptane) was obtained as a ~40:60 mixture of diastereomers. τ (CDCl ₃ ) 8.95 (3H, d, J = 6Hz), 6.85−
7.7 (disappeared with 7H, m, 2H, D ₂ O), 6.25 (3H, s),
5.1 (1H, m), 3.6 (1H, d, J=16Hz), 2.5−3.2
(8H, m), 2.35 (1H, d, J = 16Hz). Example 11 N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2
-Hydroxy-2-(3-fluorophenyl)
Ethanamine 2-hydroxy-2-(3-fluorophenyl)ethanamine (1.55 g) and 4-{(E) were prepared in the same manner as the compound described in Example 1.
-2-Carbotomethoxyethenyl}phenylpropan-2-one (2.18 g).
Elution with 1% methanol-chloroform in Kieselgel gave the title compound (1.4 g) as a ˜45:55 mixture of diastereomers, mp 75-110° C. (benzene-heptane). τ (CDCl ₃ ) 8.9 (3H, d, J = 6Hz), 6.9−7.8
(7H, m, 2H, disappears with D ₂ O), 6.25 (3H, s),
5.45 (1H, m), 3.6 (1H, d, J=16Hz), 2.55−
3.2 (8H, m), 2.35 (1H, d, J = 16Hz). Example 12 N-{(2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-
2-hydroxy-2-(3-bromphenyl)
Ethanamine 2-hydroxy-2-(3-bromphenyl)ethanamine (2.16 g) and 4-{(E)-
Produced using 2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g).
The title compound was purified by elution with 1% methanol-chloroform on Kieselgel 60, mp 105-111 °C.
was obtained as a 42:58 mixture of diastereomers as 1.6 g of a solid (benzene-petroleum 80-100). τ( _CDCl3 ) 8.95 (3H, d, J=6Hz), 6.9−7.7
(7H, m, 2H, disappears with D ₂ O), 6.2 (3H, s), 5.5
(1H, m), 3.6 (1H, d, J=16Hz), 2.55 (8H,
m), 2.35 (1H, d, J = 16Hz). Example 13 N-{2-(4-{2-carbomethoxy-1-
methylethenyl}phenyl)-1-methylethyl}-2-hydroxy-2-phenylethanamine phenylglyoxal hydrate (0.86g) and 2-{4-(2-carbomethoxy-1-methylethenyl)phenyl A mixture of }-1-methylethanamine (1.4 g) was refluxed in benzene (100 ml) in a Dean and Stark head until water removal was complete (4 hours). The solvent was evaporated and methanol (50ml) was added followed by sodium borohydride (0.5g) and the solution was left for 10 minutes. The methanol was evaporated and the residue was shaken with water and extracted with ethyl acetate. The organic layers were combined, dried (MgSO ₄ ) and evaporated to give an oil, which was
Chromatographed on Kieselgel60.
Elution with 2% methanol-chloroform gave the title compound as a mixture of diastereomers, mp 75-85°C (hexane). τ (CDCl ₃ ) 8.94 (3H, d, J = 6Hz), 7.45
(3H, d, J = 1.5Hz) 6.9-7.6 (5H, m), 6.25
(3H, s), 4.3 (1H, m), 3.87 (1H, q, J=1.5
Hz), 2.5−3.0 (9H, m). Example 14 N-{3-(4-{2-carbomethoxy-1-
Methylethenyl}phenyl)-1,1-dimethylpropyl}-2-hydroxy-2-phenylethanamine This product was prepared by preparing phenylglyoxal hydrate (1.34 g) in the same manner as the compound described in Example 13. )
and 3-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1,1-dimethylpropanamine (2.61 g).
Melting point 98 after chromatography on Kieselgel 60 eluting with 1% methanol-chloroform
The title compound (2.17 g) was obtained at ~102°C (benzene-hexane). τ (CDCl ₃ ) 8.85 (6H, s), 8.1−8.7 (2H, m),
6.8−7.8 (9H, m), 6.2 (3H, s), 5.3 (1H, dd),
3.82 (1H, wide), 2.65 (9H, m). Example 15 N-{2-(4-{2-carbomethoxy-1-
Methylethenyl}phenyl)ethyl}-2-hydroxy-2-phenylethanamine This product was prepared from phenylglyoxal hydrate (1.50
g) and 2-{4-(2-carbomethoxy-1-
methylethenyl) phenyl} ethanamine (2.19
g). After chromatography on Kieselgel 60 eluting with 1% methanol-chloroform, the melting point was 120-125°C (benzene-chloroform).
The title compound (1.18 g) of hexane) was obtained. τ (CDCl ₃ ) 7.5 (3H, d, J = 1.5Hz), 7.5 (2H,
m), 7.2 (6H, m), 6.3 (3H, s), 5.29 (1H,
dd), 3.87 (1H, q, J=1.5Hz), 2.85 (2H, d,
J = 9Hz), 2.7 (5H, s), 2.6 (2H, d, J = 9
Hz). Example 16 N-{2-(4-{2-carbomethoxy-1-
Phenylglyoxal hydrate (1.5
g) and 2-{4-(2-carbomethoxy-1-
Produced using methylethenyl)phenyl}-1,1-dimethylethanamine (2.47g).
Melting point 98 after chromatography on Kieselgel 60 with 1% methanol-chloroform elution.
The title compound (2.02 g) was obtained at ~103°C (benzene-hexane). τ (CDCl ₃ ) 8.9 (6H, s), 7.55 (3H, d, J=
1.5Hz), 7.35 (2H, s), 6.8-7.6 (4H, m), 6.3
(3H, s), 5.4 (1H, dd), 3.85 (1H, q, J=
1.5Hz), 3.0−2.2 (9H, m). Example 17 N-{2-(4{2-carbomethoxy-1-methylethenyl}phenyl)-1-(R)-1-methylethyl}-2-hydroxy-2-(3-trifluoromethylphenyl) Ethanamine 3-trifluoromethylphenylglyoxal (1.06 g) and 2-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1 were prepared in the same manner as the compound described in Example 13.
Prepared using -(R)-1-methylethanamine (1.3g) as a 39:61 mixture of diastereomers. τ (CDCl ₃ ) 8.9 (3H, d, J = 6Hz), 7.4 (3H,
s), 6.8−7.6 (7H, m), 6.29 (3H, s), 5.3
(1H, m), 3.9 (1H, bs), 2.3−3.05 (8H, m). Example 18 Separation of diastereomers of the compound of Example 5 N-{2-(4-{(E)-2-carbomethoxyethyl}phenyl)-1-methylethyl}-2-hydroxy-2-(3 -Chlorphenyl)ethanamine (9.8 g) with a diastereomeric ratio of 35:65 by recrystallization from methanol, melting point
2.06 g of sample at 106-120°C was obtained. By recrystallizing this sample again from methanol, <5:>95
Melting point of diastereomer ratio (RS, SR) of 120 ~
1.0 g of sample at 123°C was obtained. ¹³ Cnmr ( _DMSOd6 )
20.06ppm. A sample with a melting point of 96-100 °C consisting of a 63:37 mixture of diastereomers by evaporating the initial mother liquor and recrystallizing the resulting solid from methanol.
0.71g was obtained. By concentrating this mother liquor, which consists of an 80:20 mixture of diastereomers, a melting point of 101
A second crop (1.52g) of ~106°C was obtained.
^13Cnmr ( _DMSOd6 ) 19.77 and 20.02ppm. Example 19 Separation of diastereomers of the compound of Example 8 N-{2-(4-{(E)-2-carbomethoxyethenyl}phenyl)-1-methylethyl}-2-
Recrystallizing hydroxy-2-(3-trifluoromethylphenyl)ethanamine (5.4 g) from benzene yields 0.25 g of a sample with a melting point of 97-105°C.
I got it. After concentrating the mother liquor, a second crop (0.66 g) was obtained with a melting point of 95-105°C. By combining these two yields and recrystallizing from hexane, 15:
Melting point 105-108℃ with diastereomeric ratio of 85
A trial amount of 0.61 g was obtained. A sample with a melting point of 107-109°C with a 3:97 diastereomer ratio (RS, SR) by further recrystallization from benzene-hexane
0.61g was obtained. ^13Cnmr ( _DMSOd6 ) 20.16ppm. By adding hexane to the initial mother liquor
Melting point 65-102 with 38:62 diastereomeric ratio
An additional yield of 1.22 g of °C was obtained. The liquid was evaporated and the residue (2.0g) was dissolved in benzene-hexane.
By recrystallizing twice, 0.6 g of a sample having a diastereomer ratio of 90:10 and a melting point of 89-91°C was obtained.
^13Cnmr ( _DMSOd6 ) 19.94ppm and 20.16ppm. Description example 1 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one 1-(4-{(E)-2-carbomethoxyethenyl}-2-nitroprop-1-ene ( Concentrated hydrochloric acid (309 ml) was added dropwise under reflux to a suspension of iron powder (49.4 g) and iron powder (49.4 g) in methanol (500 ml). After the addition was complete, the solution was refluxed for 1 hour.
Add water (500ml), evaporate methanol,
The aqueous phase was extracted with chloroform (3x300ml).
The chloroform layers were combined, washed with water and sodium bicarbonate solution, and dried (MgSO ₄ ). Removal of the solvent gave the title compound (40.3g). τ (CDCl ₃ ) 7.85 (3H, s), 6.3 (2H, s) 6.2
(3H, s), 3.6 (1H, d, J=16Hz), 2.75 (2H,
d, J=8Hz), 2.5 (2H, d, J=8Hz), 2.32
(1H, d, J = 16Hz). Description example 2 1-(4-{(E)-2-carbomethoxyethenyl}phenyl)-2-nitroprop-1-ene butylamine (36.5ml) and 4-{(E)-2-carbomethoxyethenyl} Benzaldehyde (50.7
The mixture of g) was refluxed in benzene for 2 hours under Dean and Stark apparatus conditions. The solvent was removed under reduced pressure and replaced with glacial acetic acid and nitroethane (49ml) was added. Heat the solution to 110 °C and add 0.75 to this temperature
Holds time. Upon cooling, the title compound (49.5
g) was precipitated. τ (CDCl ₃ ) 7.6 (3H, s), 6.2 (3H, s), 3.3
(1H, d, J=16Hz), 2.0−2.5 (5H, m), 1.9
(1H, s). Description example 3 4-{2-carboethoxy-2-methylethenyl}phenylpropan-2-one 4-formylphenylpropan-2-one-2
A mixture of -ethylene acetal (3.11 g) and 1-carboethoxyethylidene triphenylphosphorane (5.47 g) was refluxed in tetrahydrofuran for 1 hour under a nitrogen atmosphere. The solvent was evaporated and the residue was chromatographed on alumina (200g). Elution with dichloromethane gave the title compound as ethylene acetal (1.7g).
This was dissolved in ethanol-2N hydrochloric acid and stirred at ambient temperature until tic showed no acetal present. The aqueous solution was extracted with ether (3x50ml) and the ethereal layers were combined, washed with water (x2) and sodium bicarbonate solution and dried ( _MgSO4 ). Removal of the solvent gave the title compound (1.05g). τ (CDCl ₃ ) 8.7 (3H, t, 3=7Hz), 7.92
(3H, S), 7.9 (3H, S), 6.35 (2H, S), 5.8
(2H, q, J=7Hz), 2.8 (2H, d, J=8Hz),
2.6 (2H, d, J=8Hz), 2.35 (1H, S). Description example 4 4-formylphenylpropane-2-one-2
-Ethylene acetal 4-hydroxymethylphenylpropane-2-
A mixture of ethylene acetal (5.0 g) and manganese dioxide (45 g) was stirred in chloroform at ambient temperature for 2 days. Filtration and solvent removal gave the title compound (4.83g). τ (CDCl ₃ ) 8.7 (3H, s), 7.05 (2H, s), 6.05
-6.45 (4H, m), 2.6 (2H, d, J=8Hz), 2.3
(2H, d, J=8Hz), 0.1 (1H, s). Description example 5 4-{(E)-2-carbomethoxyethenyl}phenylbutan-2-one 4-{(E)-2-carbomethoxyethenyl}toluene (17.6g), N-bromsuccinimide (17.8g) and traces of dibenzoyl peroxide were refluxed in carbon tetrachloride under illumination until the brown-red color disappeared. 4- by filtration and solvent evaporation
{(E)-2-carbomethoxyethenyl}benzyl bromide (25.3 g) was obtained. This was dissolved in dry tetrahydrofuran and heated with the sodium salt of ethyl acetoacetate (15.2 g) and traces of potassium iodide and refluxed for 1.5 days. remove the solvent,
The residue was partitioned between ether and water and the ether layer was dried. Removal of the solvent produces an oily substance (26.6
g) was obtained. This was stirred with sodium hydroxide (10g) in water (400ml) for 2 days. The solution was extracted with ether and the aqueous phase was acidified with hydrochloric acid, which was heated in a steam bath for 1 hour. The solution was extracted with chloroform and the organic layer was dried (MgSO ₄ ). Removal of the solvent gave the title compound acid (11.0 g). The title compound was obtained by esterifying this with methanol-sulfuric acid. τ (CDCl ₃ ) 7.9 (3H, s), 7.0−7.5 (4H, m),
6.25 (3H, s), 3.65 (1H, d, J=16Hz), 2.85
(2H, d, J=8Hz), 2.6 (2H, d, J=8Hz),
2.4 (1H, d, J = 16Hz). Production example 6 2-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1-methylethylamine An aqueous solution (30 ml) of sodium hydroxide (6 g) was mixed with N-acetyl-2-{4-(2-carbomethoxy Ethoxy-1-methylethenyl)phenyl}-1-methylethanamine (8.5g) was added and the mixture was stirred and heated to reflux for 8 hours. The solution was cooled and evaporated to dryness. The residue was dissolved in methanol (30ml) and acidified by addition of concentrated hydrochloric acid. The precipitated sodium chloride was removed by filtration and the methanol solution was dried over molecular sieves overnight. This solution was then heated to -70 with dry ice/acetone.
It was added to a solution of thionyl chloride (8 ml) in dry methanol (10 ml) kept at 0.degree. After heating to ambient temperature, the solution was stirred and heated to reflux for 1 hour.
The solution was cooled, filtered and evaporated, the residue was shaken with aqueous potassium carbonate and extracted with chloroform. The chloroform extract was dried (MgSO ₄ ) and evaporated to form an oil (2.8
g) was obtained. τ (CDCl ₃ ) 8.9 (3H, d, J = 8Hz), 8.5 (2H,
bs, replaceable with _D2O ). 7.45 (3H, d, J=1.5
Hz), 7.2-7.4 (2H, m), 6.6-7.0 (1H, m), 6.3
(3H, s), 3.92 (1H, q, J=1.5Hz), 2.5−3.0
(4H, m). Example 7 N-acetyl-2-{4-(2-carboethoxy-1-methylethenyl)phenyl}-1-methylethanamine A solution of triethylphosphonoacetate (10.81 g) in dry THF was added with sodium hydride ( 1.17 g) was added and the mixture was stirred for 0.5 h.
N-acetyl-2-(4-acetylphenyl)-
A THF solution of 1-methylethanamine (10.57 g) was then added and the mixture was heated to reflux (monitoring t, l, c.) until the reaction was complete. After cooling to ambient temperature, the solution was passed through Celite to evaporate the THF. The residue was dissolved in ethyl acetate and chromatographed on silica gel, eluting with ethyl acetate to give the title compound (8.5g). τ (CDCl ₃ ) 8.9 (3H, d, J = 7Hz), 8.7 (3H,
t, J=7Hz), 8.1 (3H, s), 7.48 (3H, s),
7.15−7.35 (2H, m), 6.0 (1H, m), 5.83 (2H,
q, J=7Hz), 4.6 (1H, b), 3.9, 4.15 (1H,
s, s) 2.5-3.0 (4H, m). Description example 8 3-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1,1-dimethylpropanamine This product was prepared by the same method as the compound described in description example 6, N-formyl-3-{ 4-(2-carboethoxy-1-methylethenyl)phenyl}-
1,1-dimethylpropanamine was produced. τ( _CDCl3 / _D2O (8.8(6H, s)8.5−8.1(2H,
m), 7.48 (3H, d, J=1.5Hz), 7.5−7.1 (2H,
m), 6.3 (3H, s), {4.1 (wide) + 3.88 (q, J =
1.5Hz), total 1H}, 2.8 (2H, d, J=7Hz), 2.55
(2H, d, J = 7Hz). Description example 9 N-formyl-3-{4-(2-carboethoxy-1-methylethenyl)phenyl}-1,1
-Dimethylpropanamine This product was prepared using the same method as the compound described in Description Example 7 to obtain N-formyl-3-(4-acetylphenyl)-1,1-dimethylpropanamine (17.25g) and triethylphosphonic acetate (16.6g). g) and sodium hydride (1.78g) to obtain the title compound (12.7g). τ (CDCl ₃ ) 8.65 (3H, t, J = 6Hz), 8.6
(6H, s), 8.4-7.9 (2H, m), 7.45 (3H, d, J
= 1.5Hz), 7.5-7.0 (2H, m), 5.8 (2H, q, J =
6Hz), {4.2 (wide) + 3.9 (q, J = 1.5Hz), total
1H}, 3.4 (1H, wide), 2.6 (4H, m), 2.1 (1H,
d, J=5Hz). Description example 10 N-formyl-3-(4-acetylphenyl)
-1,1-dimethylpropanamine N-formyl-3-phenyl-1,1-dimethylpropanamine (115 g) was dissolved in 1,2-dichloroethane (850 ml) at 0°C. Acetyl bromide (116ml) was added followed by aluminum chloride (263g) portionwise over 0.5 hours. After the addition was complete, the mixture was allowed to warm to room temperature and then refluxed for 1 hour. The hot solution was poured onto crushed water (3Kg) and the mixture was extracted with chloroform. The chloroform extract was washed with water and sodium bicarbonate and dried (MgSO ₄ ). Evaporation of the solvent gave an oil, 25 g of which was chromatographed on Kieselgel 60 (1 Kg). Elution with 1% methanol-chloroform gave the title compound as an oil (18g). τ (CDCl ₃ ) 8.6 (6H, s) 8.4−7.75 (2H, m),
7.45 (3H, s), 7.5-7.05 (2H, m), 3.0-4.0
(1H, wide), 2.7 (2H, d, J=8Hz), 2.15
(2H, d, J = 8Hz), 1.2 (1H, d, J = 5Hz). Description example 11 2-{4-(2-carbomethoxy-1-methylethenyl)phenyl}ethanamine This product was prepared using the same method as the compound described in description example 6 to prepare N-formyl-2-{4-(2-carboethoxy -1-methylethenyl)phenyl}ethanamine. τ (CDCl ₃ ) 8.2 (2H, wide), 7.35 (3H, d, J
= 1.5Hz), 7.3-6.7 (4H, m), 6.2 (3H, s), 3.8
(1H, wide), 2.8 (2H, d, J=8Hz), 2.5 (2H,
d, J=8Hz). Description example 12 N-formyl-2-{4-(2-carboethoxy-1-methylethenyl)phenyl}ethanamine This product was prepared using the same method as the compound described in description example 7 to prepare N-formyl-2-(4-acetyl The title compound (13.2
g) was obtained. τ (CDCl ₃ ), 8.7 (3H, t, J = 7Hz), 7.5+
7.45 (3H, s+s), 7.2 (2H, t, J=7Hz),
6.45 (2H, m), 5.75 (2H, q, J=7Hz), 4.1+
3.85 (1H, s+s), 4.1 (1H, wide), 2.8 (2H,
d, J=8Hz), 2.55 (2H, d, J=8Hz), 1.85
(1H, wide). Production example 13 N-formyl-2-(4-acetylphenyl)
Ethanamine This product was prepared using N-formyl-2-phenylethanamine (95
g), acetyl bromide (128 ml), aluminum chloride (288 g) in 1,2-dichloroethane (900 ml). 25g of the crude product was added to Kieselgel60 (1
Kg). Elution with 1% methanol-chloroform gave the title compound as an oil (18 g). τ (CDCl ₃ ) 7.42 (3H, s), 7.1 (2H, t, J=
7Hz), 6.5 (2H, m), 3.45 (1H, wide), 2.7 (2H,
d, J=8Hz), 2.1 (2H, d, J=8Hz), 1.9
(1H, s). Example 14 2-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1,1-dimethylethanamine N-formyl-2-{4 -(2-carboethoxy-1-methylethenyl)phenyl}-1,1-dimethylethanamine. τ (CDCl ₃ ) 8.8 (6H, s), 8.55 (2H, wide),
{7.75(d)+7.3(dJ=1.5Hz), total 3H}, 7.25(2H,
s), 6.15 (3H, s), {4.0 + 3.75 (q, J = 1.5Hz)
,
Total 1H}, 2.75 (2H, d, J=8Hz), 2.5 (2H, d,
J=8Hz). Description example 15 N-formyl-2-{4-(2-carboethoxy-1-methylethenyl)phenyl-1,1-
Dimethylethanamine N-formyl-2-{4-acetylphenyl}-1,1-dimethylethanamine (11.4 g),
Produced using triethylphosphonoacetate (11.7g) and sodium hydride (1.25g) to give the title compound (10.2g). τ (CDCl ₃ ) 8.7 (3H, t, J = 7.Hz), 8.69 (6H,
s), {7.85(s)+7.45d, J=1.5Hz, total 3H}, 7.2+
6.9 (2H, s+s), 5.75 (2H, q, J=7Hz),
4.7 (1H, wide), {4.1(s)+3.85 (wide) 1H}, 2.7
(4H, m), 1.9 (1H, s). Description example 16 N-formyl-2-(4-acetylphenyl)
-1,1-dimethylethanamine This product was prepared using the same method as the compound described in Description Example 10, including aluminum chloride (26 g), acetyl bromide (115 ml) and N-formyl-2-phenyl-1,
1-dimethylethanamine (101.5g) in 1,2
-obtained in dichloroethane (850ml). τ (CDCl ₃ ) 8.62 (6H, s), 7.45 (3H, s), 7.1
+6.85 (2H, s+s), 3.85 (1H, wide), 2.7 (2H,
d, J=8Hz), 2.1 (2H, d, J=8Hz), 1.9
(1H, s). Example 17 2-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1-(R)-1-methylethanamine This product was prepared using the same method as the compound described in Description Example 6 to convert N-acetyl -2-{4-(2-carboethoxy-1-methylethenyl)phenyl}-
It was produced using 1-(R)-1-methylethanamine (7 g). The title compound (1.3g) was isolated as an oil. τ (CDCl ₃ ) 8.88 (3H, d, J = 6Hz), 8.5
(Can be replaced with 2H, bs, D ₂ O), 7.8 + 7.4 (3H, d),
7.3 (2H, m), 6.5-7.1 (1H, m), 6.2 (3H, s),
3.9 + 4.5 (1H, q), 2.5 - 2.95 (4H, m). Production example 18 N-acetyl-2-{4-(2-carboethoxy-1-methylethenyl)phenyl}-1-
(R)-Methylethanamine This product was prepared using the same method as the compound described in Description Example 7 to obtain N-acetyl-2-(4-acetylphenyl)-1-(R)-1-methylethanamine (10.57Kg ) ({d} ²⁰ _D +20.28 (MeOH), sodium hydride (1.3 g) and triethylphosphonoacetate (10.81 g) in dry THF. Elute with 1% methanol-chloroform on Kieselgel 60. The title compound was isolated as an oil (7 g) after chromatography. τ( _CDCl3 ) 8.85 (3H, d, J=6Hz), 8.65
(3H, t, J=75Hz), 8.05 (3H, s), 7.8+7.40
(3H, d, J=1.5Hz), 7.20 (2H, m), 5.8 (2H,
q, J=7Hz), (1H, m), 4.0 (1H, b, d),
4.15+3.85 (1H, q), 2.5−2.95 (4H, m). Demonstration of Compound Efficacy (i) Antiobesity Activity Compounds were added to water or carboxymethyl cellulose suspension and administered daily as oral gavage to genetically obese mice for 28 days.
After this period, cadaver composition was determined. The results obtained are as follows.

[Table] (ii) Effect on energy expenditure The effect of the compound on energy expenditure in mice was demonstrated by the following method. Female CFLP mice, each weighing approximately 24 g, were given their desired amount of food and water before and during the experiment. The compounds were dissolved in water by adding the same number of moles of hydrochloric acid, and these solutions were orally administered to each of 12 animals. Another 12 mice were given water orally. The mice were placed in a box, air was blown into the box, and the oxygen content of the air coming out of the box was measured. Energy expenditure in mice was measured for 21 hours after administration by JBde V. Weir (J.Physiol.
(London) (1949) 109.1-9) from the volume of air leaving the box and its oxygen content. The mice's food intake was measured over this same 21 hour period.
Results were expressed as a percentage of the average food intake or energy expenditure of mice receiving water.

[Table] (iii) Cardiac activity Rat hearts were perfused using Langendorff's method. The heart is incised 30 seconds after death,
Krebs insufflated with 95% O ₂ :5% CO ₂
Ringer bicarbonate solution (PH 7.4, 37°C) was retroperfused through the aorta and coronary artery. The flow rate is 8~
It was 12ml/min. Responses were obtained after injecting the drug dissolved in isotonic saline into the perfusion medium.
The core frequency and tension were displayed on an OrmedM×2p recorder using a tension transducer and a core frequency meter. Results were expressed as percentage of salbutamol-based response.

[Table] (iv) Hypoglycemic activity Female CFLP mice weighing approximately 25 g were fasted for 24 hours prior to the study. The test compound was orally administered to each of 8 mice. Thirty minutes later, a blood sample (20 ml) was taken from the tail for blood glucose analysis. Immediately after ingestion of this blood sample, each mouse was given glucose (1 g/kg body weight, subcutaneous injection).
Blood samples were then obtained from each mouse at 30 minute intervals over a 120 minute period. Significant increase in blood glucose (p
Compounds that produced a decrease of <0.05) were considered active.
The area under the blood glucose curve was calculated for each compound over a 2-hour period after glucose administration;
The values were compared with those for control animals.

【table】

【table】

Claims (1)

[Claims] 1 Formula () [In the formula, R ₁ , R ₂ and R ₃ are the same or different and are each a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group, R ₅ is a hydrogen atom or a lower alkyl group, and R ₆ is a hydrogen atom or a lower alkyl group, R ₇ is a hydrogen atom or a lower alkyl group, R ₈ is a hydrogen atom or a lower alkyl group, Y is an alkylene group having 2 or less carbon atoms,
and R ₉ is a carboxyl group or a lower alkyl ester thereof, or a group -CONHR ₁₀ (R ₁₀ is a hydrogen atom or a lower alkyl group), or a pharmaceutically acceptable salt thereof. 2 The compound has the formula () (wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ and Y have the same meanings as in formula (), and
2. The compound according to claim 1, which is an amide represented by (R ₁₀ is a C _1-4 alkyl group or a hydrogen atom) or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, wherein the group --CR ₇ = is bonded to Y at the para position. 4 The group R ₁ R ₂ R ₃ C ₆ H ₂ is phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl or 3-bromphenyl A compound according to any one of claims 1 to 3, which represents a group. 5 The compound has the formula () [In the formula, R ₁ ¹ is a hydrogen, chlorine, fluorine or bromine atom or a trifluoromethyl group, R ₁₃ is a hydrogen atom or a methyl group, R ₁₄ is a hydrogen atom or a methyl group, and m is 1 or 2,
R ₇ is a hydrogen atom or a methyl group, R ₈ is a hydrogen atom or a methyl group, and R ₉ is a carboxyl group or a lower alkyl ester thereof, or a group -CONHR ₁₀ (R ₁₀ is a hydrogen atom or a lower alkyl group). 1) or a pharmaceutically acceptable salt thereof. 6 The compound has the formula () (wherein R ₁ ¹ , R ₁₃ , R ₁₄ and m have the same meanings as in formula () and R ₁₀ has the same meaning as in formula ()) or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 5 or 6, wherein the group R ₁ ¹ C ₆ H ₅ is 3-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3-trifluoromethylphenyl. 8. The compound according to any one of claims 1 to 7, wherein m is 1. 9. The compound according to any one of claims 1 to 8, wherein the compound is in the form of one type of stereoisomer. 10. The compound according to any one of claims 1 to 8, wherein the compound is in the form of a mixture of two or more stereoisomers. 11 The compound according to any one of claims 1 to 8, which is obtained as a diastereomer having two asymmetric centers and containing no other diastereomers. 12 formula () [In the formula, R ₁ , R ₂ and R ₃ are the same or different and are each a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group, R ₅ is a hydrogen atom or a lower alkyl group, and R ₆ is a hydrogen atom or a lower alkyl group, R ₇ is a hydrogen atom or a lower alkyl group, R ₈ is a hydrogen atom or a lower alkyl group, Y is an alkylene group having 2 or less carbon atoms,
and R ₉ is a carboxyl group or a lower alkyl ester thereof, or a group -CONHR ₁₀ (R ₁₀ is a hydrogen atom or a lower alkyl group) or a pharmaceutically acceptable salt thereof. , (a) Formula (): (In the formula, -N=CR ₅ - or -NH-C
(OH) _R5- group, and _R1 , _R2 , _R3 ,
R ₇ , R ₈ , R ₉ and Y have the same meanings as in formula ()) and then if desired form an addition salt of the resulting compound, or (b) reduce the compound of formula ( ) (wherein R ₁ , R ₂ and R ₃ have the same meanings as in formula ());
formula(): (wherein R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and Y have the same meanings as in formula ()), or (c) formula (): (In the formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉
and Y have the same meanings as in formula (). 13 Formula () [In the formula, R ₁ , R ₂ and R ₃ are the same or different and are each a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group, R ₅ is a hydrogen atom or a lower alkyl group, and R ₆ is a hydrogen atom or a lower alkyl group, R ₇ is a hydrogen atom or a lower alkyl group, R ₈ is a hydrogen atom or a lower alkyl group, Y is an alkylene group having 2 or less carbon atoms,
and R ₁₀ is a hydrogen atom or a lower alkyl group)
In a method for producing a compound represented by formula () or a pharmaceutically acceptable salt thereof, (wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ and Y have the same meanings as in formula (), and
R ₁₅ represents a C _1-4 alkyl group) is reacted with an amine represented by the formula () R ₁₀ NH ₂ () (wherein R ₁₀ has the same meaning as in formula ()) A method for producing a compound of formula () or a pharmaceutically acceptable salt thereof, characterized in that: 14 formula () [In the formula, R ₁ , R ₂ and R ₃ are the same or different and are each a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group, R ₅ is a hydrogen atom or a lower alkyl group, and R ₆ is a hydrogen atom or a lower alkyl group, R ₇ is a hydrogen atom or a lower alkyl group, R ₈ is a hydrogen atom or a lower alkyl group, Y is an alkylene group having 2 or less carbon atoms,
and R ₉ is a carboxyl group or a lower alkyl ester thereof, or a group -CONHR ₁₀ (R ₁₀ is a hydrogen atom or a lower alkyl group) or a pharmaceutically acceptable salt thereof; A pharmaceutical composition for use in the treatment or prevention of obesity or hyperglycemia, comprising a carrier that can be used. 15. The composition of claim 14 in the form of a dosage form. 16. The composition of claim 15, wherein each dose contains from 0.01 to 100 mg of active compound.