JPS5948447A - Novel phenetanol amines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention relates to new phenetanolamines 1, processes for their preparation, new intermediates thereof and pharmaceutical preparations based on these compounds. [
7;
Di- or tri-substituted noenyl; X2id hydrogen, lower argyl, phenyl or /? l, /l'2 and R3 -, Nimakani represents trisubstituted phenyl; Y represents hydrogen, lower alkyl, hydroxymegyl, carboxy or lower alkoxycarbonyl; Z is the formula % formula % R1, R2 and R3 is hydrogen, halogen, hydroxy,
Pentyloxy, lower alkyl, lower alkoxy, hydroxymethyl, amine, acylamino, lower alkoxybenzuruamino, nitro, carbamoyl, trifluoromethyl still represents lower alkylsulfonylmethyl: R4, R5 and J (SI is hydrogen, lower alkyl 1 Lower alkoxy, lower alkanoyl, carboxy, cyano, hydroxy, hydroxy lower alkyl, acyloxy/or group -C(R6)=C(R))COOR8, -5O7
RΩ, -C(C))R9 or -C,H2R
10, provided that when 1-5 represents hydroxy, lower alkyl or lower alkoxy, R4 does not represent hydrogen; R6, R7 and/? 8 represents hydrogen or lower alkyl; represents a lower aliphatic, fatty group, or r;, f: an ether group of an aromatic or aliphatic group, and Ll: represents an ether group of a phenol; '
, R2 and l?゛1 Hydrogen, halokene, hydroxy,
1 ``j''
and its physiologically compatible The term "lower" as used herein refers to groups containing 1 to 6 carbon atoms, with groups containing 1 to 4 carbon atoms being preferred. Alkyl and alkoxy groups can be straight or branched, examples being methyl, ethyl, propyl, impropyl, n-butyl and isobutyl, or methoxy, ethoxy, propoxy, inopropoquine, butoxy and isobutoxy. be. Acyl groups are aliphatic, araliphatic or aromatic carboxylic acids such as lower alkane carboxylic acids such as formic acid, acetic acid, propionic acid and butyric acid; or phenyl-lower alkane carboxylic acids;
For example derived from phenylacetic acid; or benzoic acid. Examples of alcohol radicals R are lower alkoxy radicals; cyclohexyloxy and hiscyclope/thyloxy as well as benzyloxy and substituted penzyloxy radicals, such as p-methoxybennooxy. The halogen is preferably chlorine, C, or bromine. The compounds of formula I form salts with acids, and these salts are also very much part of the invention. Examples of such salts are raw'41
! Academically no 1 (co-produced mine 1 night, lj toe v) ゛Hawaka Konoha 1112, culture hydrogen acid, (+ifr: string and ring iri,
Or t+N force Jr+' (for example, methanesulfone l
'l'2, ii; l'pi, propionic acid, citric acid, succinic acid, maleic acid, fumaric acid, phenylacetic acid or salicylic acid. Carboxylic acids of formula (2) can also form salts. Examples of such salts are alkali metal salts, alkali salts, ammonium salts and alkyl ammonium salts, such as alkali metal salts, ammonium salts, and alkylammonium salts, such as alkali metal salts, ammonium salts, and alkyl ammonium salts, such as alkali metal salts, ammonium salts, and alkyl ammonium salts, such as alkali metal salts, ammonium salts,
X, calcium salt, trimethylammonium salt and ethanolammonium salt. Compounds of formula (1) contain one or more asymmetric carbon atoms and are therefore optically active enantiomers. Xl preferably represents phenyl or m-trifluoromethyl-phenyl, especially phenyl. X2 is preferably phenyl, m-trifluoromethyl-
Represents phenyl, lower alkyl or hydrogen, especially phenyl. Y is preferably hydrogen or lower alkyl, especially methyl. , /('4 preferably represents hydrogen. R5 and 1?51 preferably represent lower alkanoyl, carbamoyl, sulfamoyl, lower alkoxycarbonyl or lower alkylcarbamoyl, especially lower alkanoyl or carbamoyl. Compounds of formula I are , according to the present invention, an epoxide of the formula /\ ;One of X3 and
On the other hand, the group X2 is Ikuwa L; Zl represents Ha2,
R12 and R12 phosphohydrogen, IJk class alkyl, lower alkoxy, lower alkanoyl, carboxy, cyano, hydroxy, hydroxy-lower alkyl, acyloxygen & -C(R6) =C(R7) COOR
8, 5O2R'. -C(0)RQ or =C no 12R, only 1
~, when R12 represents hydroxy, lower alkyl or lower alkoxy, /? Assume that 11 does not represent hydrogen: [7te n, X'. , l(2, Y, R, R6, /<7 , R8 and R'' have the meanings given above, and the compound of formula Ut or II+ is converted into a compound of formula
When reacting with a compound of
prepared by reduction to yo be able to. The reaction of the compound 20 with the compound of the formula 2 or 2 can be carried out by a method known per se in which an epoxide and an amine are reacted to produce an amino alcohol. Advantageously, the reaction partner is placed in an appropriate solvent and then
Heat it up. l'? 〒1'JL and inactive 4-=a
Solvents such as somethylsulfoside, acetonitrile, ether, C2L tetrahydrofuran or d, sooxane, alcohols such as ethanol can be omitted. The reaction τ1ζJIJ- is critical and d,
The reaction is advantageously carried out at a temperature between 60'C and the boiling point of the two-needle reaction mixture. However, the reaction of a compound I of formula 111 with a compound of formula 1 to 1 or V can be carried out in a manner known per se to form a solution 91J1.
, preferred 1. < can be carried out in the presence of an aprotic solvent such as a halogenated hydrocarbon (e.g. chloroform) at a temperature of up to 20°C (1°C). ■ Keto group X+-(,'(0)-also t, X2-C(0
) - reduction to the secondary alcohol, of course in a manner known per se. This reduction can be carried out under the same conditions as described for the reduction of compounds 2~'1~X below,
Complex metal hydrides, particularly Suiseki Hina) IJum, are more preferred because of their selectivity. Reactive substituents in the reaction product thus obtained, in particular the groups -C(R6), =C□(1)C0OR'', C(
0) R91klri-50,, RQ, fall ChiZ
Compounds of formula I representing the df group z + can be functionally modified. Esterification of carboxyl groups can be carried out in a manner known per se, for example with alkyl halides such as methyl iodide and bases. Saponification of ester groups is carried out under alkaline conditions, e.g.
This is preferably carried out with alcoholic alkali hydroxides (eg water-methanolic potassium hydroxide). Carbamoyl groups can be converted to aminomethyl groups by reduction with lead metal hydrides such as lithium aluminum hydride. In a similar manner, the mono-lower alkylated carbamoyl group 2° corresponding to A-mono-lower alkylated amine methyl group V can be prepared. The formula V consists of: t +
-'rj and 0 times 'I' 6735 /71-ryJ(
1 yo 1] 2 is publicly known. Formula V preparation! 1gC [a) Formula () in which "in" - does not have the above meaning a) The compound + of is reacted with a compound of formula 1v; or b) 011 Y 1 X'-C1i- C'112-N=c-(c'112),
L-7'%=IX4-c-C112-N,,=t
'-(C//2) -Z' W0
It can be produced by reducing one of the compounds of Y O〃 OY 1 OY where X4, ZIXY and n have the above meanings. The reaction between compound 2〇-1 and compound 2■ is carried out using an inert solvent, preferably a lower alkanol (for example, ethanol).
This can be done in a protic solvent such as. The reaction temperature is not critical; it can be between room temperature and the cooling temperature of the reaction mixture. The lending source of compounds 2~1 is contact 1'1'C water, J: addition (
So (e.g. 1, yo, Pundumu or platinum 11pj)
(in the presence of a catalyst to gold such as a medium), or
, water can also be treated with a lead metal hydride such as sodium. The reaction conditions used can be those for such 1.:L j+'', contacting water addition t, L favor L-?: &J5, in an inert organic solvent, such as a lower alkanol (e.g. ethanol). - Raise the temperature slightly (e.g. 20 to 8
0°C). (By 11 gold 114 hydride:
The lu addition is advantageously carried out in lower alkanols (eg methanol) at temperatures of 20 to 30'. Compounds of formulas 11 to ILE< and For the reduction of the compounds NiMl and XTsukuda,
Sodium borohydride is a suitable complex metal hydride. The compound of formula (1) is preferably converted to Kffi by lithium aluminum hydride. The compounds of formula 1 and their salts can be used as active substances in pharmaceutical preparations for obesity and/or diabetes, especially for diabetic adults who are obese. jjb
In physical experiments, an increase in mainly fat catabolism was observed after administration of the compound of formula (1). Additionally, compounds of formula 1 have been shown to be effective in rats and obese-ILyp.
erglycaemic) was found to stimulate the formation of brown adipose tissue in mice. It is known that brown adipose tissue defects play a substantial role in the development of obesity. In obese-hyperglycemic mice, the compound of formula (1) has a significant anti-diabetic effect, which is because the compound has hypoglycemic activity (hypoglycemic activity).
ity) and to reduce glycosuria. The compound of formula (II) exhibits a slight active effect on the functioning of the heart and circulatory system. The dosage ranges from 0.5 to 1 per 111 in tJL for adults, depending on the strength of activity of the individual compound and the requirements of the individual patient.
0001′・U, preferably V”, 2 to 200 ih-!
and this dosage %i) 1 ld
It can be crotched in one go or in several 11" increments. In addition, in IIIJ qQ experiments with compound VC of formula I, there was an increase in body fat
Therefore, the compound of formula ■ brings about the addition of j″1q of the fat-free A′1(formation) by eliminating the Jlif rib. .Catch me and prepare for the ceremony! 1./Ii, I especially, Tan myself
) with the addition of 1'+1 can be used as a medicine in humans in the late post-operative period. this",
In case 5:J, the dosage to be administered: 1a' is the same as in case of fertilization and/or diabetes mellitus #'t. The compounds of formula (1) and their salts can be used for feeding fattening animals such as meat cattle, pigs, sheep and 'J-F'. In this case, the dosage administered and the drug form administered can be similar to that for vitamins. Additionally, the compounds of formula I can also be used as feed additives at dosages of 01 to 100 my/Ky, depending on the compound, type and age of the animal. Pharmaceutical preparations may be prepared in combination with compatible pharmaceutical preparations and inorganic carrier substances such as water, gelatin, acacia, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, yellow petrolatum, etc. Contains active substances. It is preferred to administer the pharmaceutical preparation orally, for example in the form of tablets, capsules, pills, powders, granules, solutions, syrups, suspensions, elixirs and the like. However, the crotch cloth can also be administered parenterally, for example in the form of a sterile solution, suspension or emulsion. Pharmaceutical preparations must be sterile and /map
j preservative, adhesive ↓ agent, wet A+'j ha'L emulsification/+1,
Make friends with osmotic pressure/Rice salt and %! It may contain components such as ij Qi'J quality. Activity of the new compound of formula I 6i following N''vI:l'jE
A: l'+ 41! It is clear from: Body Ql 6 (1-1.80 f Jll: albino rat 2''';+'fiilk
: After eating Ir, put it in the metabolic basket. The cage was ventilated with -21 6 room air/'min, equilibrated at t.times., point zT:. Samples of the air used, after equilibration, were collected for 14 minutes in each case and analyzed for elemental content and carbon dioxide content. After 1, the animals were divided into groups of 6! 9' Lurei (5-row gum arabic) straddle test* quality (5% gum arabic mixed with P) was orally given to the 11th proboscis. Thereafter, foot measurements were carried out for 12 hours. In Table 1, the average oxygen consumption after mulling during the first 3 hours, taking into account the corresponding correction for the variation in the false 'j1% li1'. and the percentage of the entire test period (12 hours) of oxygen consumption during the application period. Oxygen consumption and carbon dioxide production were measured over a period of 1211.'1. After 4 hours, the animals were given a placebo (5 sticks of gum arabic) or the test substance (gum arabic clouded with ifW) orally. .tr: u In the table, we show the mean decrease in respiratory volume (c0210t) during the 8 hours after administration of the test substance compared to the last 3 hours before administration of the test substance. Placebo iff
The fluctuations appearing in the equation were taken into account in the calculation. Table 11 Female hyperglycemic fatty mice were fed iF4 on a diet of 32/day/animal. Test compound (Suspended gum arabic (5) or 1./b-1G (5・Must ajibiagono,) IcI Ll 2 times, 15 441/. Urine was extracted for 6 days per week, and urine glucose was determined by dill.
7. Surface fluid glucose and) Ij intraoral i:・l, 11!
'! The weight of the IC was measured at the end of the study. Trial cutting results? +9・'Darkness value percentage and L7 'l'S
Shown in III 'I<. Table 111 (3) As mentioned above, female hyperblooded ax 1
: Human fat mice were tested for 15 days at 1/2 m. After the end of the treatment, the composition of the carcasses was measured. The following examples further illustrate the invention. Example 1 Preparation of 5-[3-[(S
)-β-hydroxynoenedyl]amine]propyl]-
2-thiophenecarboxamide 2682 and (R)-
Phenylethylene oxide 1,4'intZ' 95
The cells were incubated at 11°C for 24 hours. Water was poured into the mixture and extracted three times with dichloromethane. The methylene chloride solution was washed twice with water/<5.'1 and evaporated under vacuum. The residue was chromatographed with ether/methanol on a silica shell and chromatographed with 5-(3-[11
R)-β-Hydroxyphenethyl]-[(S)-β-hydroxyphenethyl]aminoJ7'oel]-2-thiophenecarboxamide 1,489 was obtained. UV:
6277=10780° 5-[: used as starting material
3-[(S)-β-Hydroxyphenethyl]amine]globil]-2-thiophenecarboxamide could be prepared as follows: 2-(p-toluenesulfonyloxy)propyl foff-r- 7(/, Org, Ch, ern, 36.1
971°2236) with acetyl chloride and aluminum trichloride in methylene chloride to give 5-acetyl-2-
(p-)Luenesulfonyloxy)propylthiophene was obtained. From this, 5-(3-asodoprobyl)-2
-Chenyl methyl ketone was obtained. Oxidation with hydrobromide gives 5-(3-azidopropyl)- with a melting point of 71-72°C.
2-thiophenecarboxylic acid was obtained. Reaction of this acid with thionyl chloride followed by treatment with concentrated ammonia produces 5-(3-azidoprogyl)-2- with a melting point of 85-87°C.
Thiophenecal was obtained from xyamide. From this, triphenylphosphine (.
After 0.1975.1659), t1 unique point 1435~l
44"C, 5-(3-azidopropyl)-52-thiophenecarboxamide (crystallized from water) was obtained. S)-phenylbutylene oxide (heated to 95° C.). This mixture was diluted with water and chloride, and the aqueous phase was extracted twice with methylene chloride. The methylene phase was washed with water, dried over hβ sodium-L and evaporated under vacuum. The residue was chromatographed on a silica gel with methanol to give a 5-43-
[[GS)-β-hydroxyphenegul]amine]propyl]-2-thiophenecarboxamide 14+; [α]6. . = +19° (c = o, 1%, in dumexane); ε256""8490: ε275"
'l 0780° Example 2 5-(3-aminopropyl)-2-thiophenecarboxamide 5W and (S) in 68 ml of somethyl oxide
- 3.4 ml of phenylethylene oxide for 26 hours9
The mixture was stirred at 5°Gvc. Add this mixture to 200 al. of water! and extracted three times with 150 mc of methylene chloride. The methylene chloride solution was washed with water, dried and evaporated. The residue was chromatographed with ether/methanol on a chromatogram and purified with 5-[3-[bis-[(S)-β-]
Hydroxyphenethyl[amino]glopyr)-2-F-
Ofuf)) /l/boki7 amide 285y was obtained:
[α”J D = +76° (c = 0.18φ, in dioxane): UJ': ε7.a = 10390 Example 3 5-(a-aminopropyl)-2-thiophenecarboxy in 4.7 ml of ethanol Amide 75 Q m・ノ andhi(±)-Phenylethylene oxide 0.47 m+
The mixture was boiled for 4 hours. f#j! A! : After evaporation under a phosphor vacuum, ether/ on a silica cell.
5-[:,3
-Cbis-(β-bitroxyphenethyl)amine)propyl]-2-thiophenecarboxamide 400π2 was obtained; UV: ε2tt”=112.50゜Example 4 In trimethylsulfoxide 400a/ 5-(aminopropyl)-2-thiophenecarboxamide: +oy and 0:(R)-phenylethylene oxide 2 (1,2m
1 was stirred at 95°C for 24 hours. After cooling, the mixture was diluted with 1.3 t of water and extracted three times with 600 me of methylene chloride. The methylene chloride solution was washed twice with water, dried on silica gel and evaporated under vacuum. The residue was chromatographed on silica gel with ether/methanol to give 5-(3-[bis[(]<)-]β-hydroxyphenethyl]amine]propyl]2-thio7enecarpoxyamide 212; UV −,ε,,e=990
0: [α': 1D=-69° (C=0.18% in dioxane). Example 5 According to Example 3, methyl 4-(3-aminopropyl)benzoate and h(±)-phenylethylene oxide were prepared from amorphous material and
-hydroquinphenethyl)amine]propyl]benzoate: 623s = 17520° Example 6 According to Example 3, from 4-(3-aminopropyl)-benzamide and (±)-phenylethylene oxide, p
-C3-Cbis-(β-hydroxyphenethyl)amino]probylcopenzamide was obtained; amorphous; ε23
6=14270゜Example 7 According to Example 3, 4'-(3-amitubl]pil)-
p-[3-bis[[I(1-β-hydroxyphenethyl]amino]propyl]benzamide was found from benzamide 1″ and (R)-phenylethyl V 7 oxide: ε234″’14240° Example 8 Actual performance 1 According to Ugly Example 3, (S)-1-methyl-3-(4-
aminocarbonylphenyl)zo[1-bylamine and (R
) - styrene oxide?

[:), as an amorphous substance °cz
p-((S)-3-Lbis-[(R)-β-hydroxyne enegur]amino]-butyl]benzamide was obtained; ε235""14130; [α]2°knee28°(C Section 205, in methanol). l) Practical Example 9 According to Example 3, from 4-(3-aminopropyl)-benzenesulfonamide and U (R) -, 7)-[3-[bis-[
(R)-β-Hydroxyphenethyl[amine]propyl]-benzenesulfonamide was obtained; ε23=16
820; [α]20=-60°(c=1.o
in timethanol). The 4-(3-aminopropyl)benzenesulfonamide used as the starting material could be prepared as follows: p-7 minosulfonylpenzaldehyde with diethylcyanomethyl-phosphonate/sodium hydride in tetrahydrofuran. The reaction yielded 1-Schiff/-2-(4-aminosulfonylphenyl)-ethane, which was hydrogenated in methanol using Raney cobalt as a catalyst to give 4-(3-aminopropyl)benzenesulfone. Amide Strength 1 Example 10 According to Example 3, ('')''-1-methyl-3-(4-aminecarbonylphniL)furobylamine Ilt,U
(S) - p-[(10-3-4bis[(S)-β
-Hydroxyphenethyl]amino J-butyl]benzamide was a4); ε2s, ""14230; [α)
'/J = + 45° (c = 1. oq et al. in methanol). Example 11 According to Example 3, from [R)-1-menal-to(4-aminosulfonylphenyl)furobylamine and R-styrene oxide, p-[(R)
-3-Cbis-(/< )-β-hydroxyphenethyl]amine]butyl]benzenesulfonamide was obtained; ε224""l 7410: [α) 2; = -ta
so (c = o, spar, in methanol). Example 12 According to Example 3, (j?)-styrene oxide and (R
)-1-methyl-3-(4-aminocarbonylphenyl)propylamine to p-[(nose)-3-[bis-
[(]?)-β-Hydroxyphenethyl]amine]-butyl]benzamide was obtained; ε234=144"0
; (α]2°=-99° horn (C=O,S%, in methanol). Example 13 According to Example 3, (R)-styrene oxide and (,5
)-t-methyl-3-(4-aminosulfonylphenyl)propylamine, p-((S)
-3-(bis-[(R)-β-hydroxyphenethyl]
Amine [butyl]benzenesulfonamide is obtained;
ε232”'14820: [α) 20 == −13
° (C=O, S% in methanol). (S)-1-methyl-3-(4-
7minosulfonylphenyl)-solobylamine could be prepared as follows: 4-(4-aminosulfonylphenyl)phthanone-2, aqueous) rl in toluene (,5° )-(-)-α-phenylethylamine and I female/7.1,1. ' and 7)-toluenesulfonic acid and Schiff (Schiff).
f's) base, (S)-#-(rl-methylbennol)-1-methyl-3-(4-aminosulfonylphenyl)propylimine 4(!j). This imine was dissolved in methanol in the presence of Raney nickel. Hydrogenated with N-
(α-methylbennol)-1-J-1-ru 3- (
A mixture of optical isomers of 4-aminosulfonylphenyl)propylamine was obtained. This amine was converted to the oxalate form with oxalic acid, and this was crystallized twice to obtain t, .k14123. Pure (5)-1- at ~127°C
Methyl-3-(4-aminosulfonylphenyl) 780
Obtain bilamin oxalate; [α] should be −68° (
c = 1.0 yen in methanol). This material was hydrogenolyzed in alcohol under 4 par hydrogen pressure at 60°C for 24 hours to obtain pure (S)-1-methyl-3-(4-aminosulfonylphenyl)probylamine. Example 14 Ethylene oxide 5 me in 90% ethanol 20ml
1.01 of p-[a-4[(R)-β-hydroxyphenethyl]amine]propyl]benzamide in the solution was added to a suspension cooled to 0° C. with stirring. After incubating at +5°C for 30 minutes, everything dissolved,
The solution was held at +5 pac for an additional 20 hours. For working up, the solvent and excess ethylene oxide are removed by evaporation under vacuum and the residue is poured into a solica shell with 10 ml of ethylene oxide.
Chromatographed on 02. Pure amorphous p-(a-((2-hydroquinethyl)-((,1?)) with ethyl acetate/methanol (95:5)
-β-Hydroxyphay, thyl[amine]globil]benzamide'oy":?'l'tr#ill can/this; (tx nib; 慝-,s 4° (c"
(1.5% in methanol); e2311=1370
Example 15 According to Example 3, an amorphous substance and j〜
14t of p-[(S)-3-[bis-((10-α-hydroxyphenethyl]amine]butyl]-N-methylbenzamide was obtained; [α]gar-22° (c =
1. o ・n, in methanol); ε2s5'= 1
2800° Example 16 According to Example 14, from pl:3-[L(/<)-β-nitroxyphenethyl]amine]norovir]benzamide and propylene oxide (1,2-epochynepropane), free As a regular substance p-[:3-L:[(R)-
β-Hydroxyphenethyl]-[(R,,5)-2-hydroxyglobyl]amine]propyl]benzamide was obtained; [α]■ = −40° (c = 0.4%,
in methanol). Example 17 According to Example 14, p-[:(S)-3-[[(S)-
β-Hydroxyphenethyl[amine]butyl]benzamide and ethylene oxide, p-C(S) as oil
-3-((2-hydroquinethyl)-[(/?)-β-
Hydroxyphenethyl]amino]butyl]benzamide was obtained: [α]:=-ts° (c = 0.5
%, Jri/-#medium). Example 18 According to Example 14, p-C(R)-3-([(R)-
From β-hydroxyphenethyl[amine]butyl]benzamide and ethylene oxide as a colorless oil, 7)-
[(1-:u-[2-hydroquinethyl]-C()7)
-β-Hydroxy7noei, thyl]amine]glutyl]benzamide was obtained [C1] '73 "" -7
6° (c = 0.3 q6, in l l / -l)
. Example 19 Tetrahy) Ronran 60 rat, Medium (' 5- [
3-(bis-((R)-β-hydroxyphenotyl Jamino)zolopyl]-2-thiophenecal HS-7amide 35 Q m... and lithium aluminum hydride Uno...
300...l was boiled under reflux for 1.5 hours. This (11° mixture is carefully combined with 2N water 1-+) I
Treated with Jum treatment, extracted 3 times with ether/Co ether bath, washed with water, neutralized, and dried [2,
The residue was chromatographed on a silica gel with methanol and 5-[3-[bis-[(/<)-β-
Hydroxyphenethyl [amine] propyl]-2-aminomethyl-thiophene 650I. Example 20 Practical HFU Example t4 to prepare p-[3-[:(2-hydroxy ethyl)-[(R)-
β-Hydroxyphenethyl[amine]propyl]benzenesulfonamide was obtained; [α]21) = -39°
(c = 0.3 coefficient, in methanol); ε224 =
14720°p-[a-[(R
)-β-hydroxy/phenethyl[amino]propyl]benzenesulfonamide could be prepared as follows: 4-(3-aminopropyl)benzenesulfonamide 2
A mixture of 16.82 ml of (R)-styrene/oxide and 500 rhe of acetonitrile was heated under reflux for 40 hours. The solvent was then removed by evaporation under vacuum and the residue was chromatographed on a silica gel. Chlo 1 coform/? ? -Clopanol/25・
μs ammonia (16 (10: t o . : 4) causes points 165 to l fi 6° (
Pure p-[3-El
: (/<m!-Hydroxyphenethyl]amino]prohyl]Hensensulfonamide 83 Gundt 1:1
You can/this. [α)”=-13,4° (c
= 1.0φ, metasol); ε224 = 14710
Example 21 According to Example 3, p-[-Cbis-[(R)-β-hydroxyphenethyl]amino was prepared from 4-(3-aminopropyl)benzenenitrile and (R)-styrene oxide as a colorless oil. ] globil] benzonitrile is obtained; [α] 20−− s 7° (c = 0.48 t,
ε232 = 17570° Actual MIj Example 22 According to Example 3, from methyl p-[(R)-2-aminopropyl-β-methyl-cinnamate and 3-trifluoromethyl-sylene oxide, methyl p-[ (/<
)-2-bis-[(R5)-β-hydroxy-m-()
Lifluoromethyl)phenethyl]propyl]-β-methylunnamate was obtained; [α':l 20--5
3° (c = 0.2ch in methanol): 6276
= 18500° Example 23 According to Example 3, from 71-[(S)-2-amino-propyl]benzoic acid and (/?)-styrene oxide, p
-[(S)-2,2-bis-[[(R)-β-hydroxyphenethyl]amine]propyl]benzoin imitation was obtained; [α) 20 == -ao (c-0, 5%, in methanol); ε13 = 11700° Example 24 According to Example 3, p-[(S)-2-aminopropyl]
From benzamide and styrene oxide, p-[(S)
-2+2-bis-[:i/l')-β-hydroxyphenethyl]amine]propyl]benzamide was obtained; ;ε22. :11700゜Example 25 Same as Example 4, (lIS)-! 1-(
From 3-aminobutyl)-2-thiophenecarboxamide and h(j<)-phenylethyleneo A.cyto, 5-
((R5)-3-(bis-[(/i)-β-hydroxyphenethyl]amine]butyl]-2-thiophenecarphokidiamide was obtained; [α]D=−90° (c=
0.1 section, in dioxin); UV: ε277 ""1
1100: ε2. =4700° (/l'5)-5-(3-aminobutyl)-2-thiophenecarboxamide used as a starting material could be produced as follows. 4-(5-acetyl-2-chenyl)-2-butane (T etraheclron 35.1979.32
9) React with ethylene glycol, triethyl orthoformate and p-toluenesulfonic acid in total methylene chloride to produce methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2 -Chenyl ketone was obtained. oxidized with sodium hypobromite, then hydrolyzed,
5-(:(-oxobutyl)-2-thiophenecarboxylic acid was prepared. 5-(3
-Hydroxybutyl)-2-thiophenecarboxylic acid was obtained which was diconverted into the methyl ester with methyl iodide and sodium carbonate in trimethylacetamide. Treatment with p-toluenesulfochloride in birinone and reaction with sodium and in trimethylsulfoxide yields methyl 5-(3-andethyl)-2-thiophenecarboxylate. 1, and the corresponding acid was obtained by saponification. This C1 is converted into 5-(3-andethyl)-2- with thionyl chloride to give 5-(3-andethyl)-2- with thionyl chloride. Diofenylpoxyamide was obtained. Azudo is (i-) Riphenylposphine, then dihydrolyzed, ,(,;y
H ((R5)-5-(3-amitubudel)-2-thiofe/Cal71?quinoamitoy@-+ at points 65-75°
:t;C2,. = 7780: ε27* ””99
0 Q. Actual MIj Example 26 Same as in Example 25, with t=1, from p-(2-aminoethyl)-benzamide and H(/< )-phenylethylene oxide, p-C2-Cbis-C(/l')- β-Hydroxyphenethyl[amine]ethyl]benzamide was obtained; [α]IJ--59° (c = 0.1%,
(in dioxane): UV: C7,4-13500° The p-(2-aminoethyl)benzamide used as starting material can be prepared as follows: p-(2-bromoethyl)acetophenone (J. Δ, C, S, 62.1940.1-13 s) was reacted with sodium and in dimethyl sulfoxide and p
-(2-andethyl)acetophenone was produced. Oxidation with sodium hypobromite gives p-(2-andethyl)benzoic acid (mp 130-131°C, crystallized from acetone/hexane), which is converted to the corresponding acid chloride with thionyl chloride. did. This acid chloride was treated with ammonia to obtain p-(2-7sodoethyl)benzamide. treated with triphenylphosphine and hydrolyzed,
p-(
2-Aminoethyl)benzamide was obtained. Performance 91 Example 27 In the same manner as in Example 4, 5-[2-[bis-[(
R)-β-human L1 xysoenethyl"amino]ethyl]
-2-thiophenecarphok-7amide was obtained; [α]
5;=-610 (c=olφ, in dioxane);ε2
77 ””l 05600 starting material and [7] 5-
(2-Aminoethyl)-2-thiophenecarboxyamidine 11 as follows jJ! ! could be prepared by: 2-(2-chenyl)ethyl p-toluenesulfonate (J, Δ, (,', 5.9s, 1973.1247) by reacting acedel chloride and aluminum chloride in methylene chloride, 2 -((5-acetyl-2-chenyl)ethyl p-toluenesulfonate (F point 111-112°C,
crystals) were obtained from ethanol. This was converted to 5-(2-andethyl)-2-thenylmethylketone with sodium chloride in dimethylsulfoxide. Hypobromite r1 oxidized with sodium, melting point 53-55°0
-(2-andethyl)-2-thiophenecarz? I got some acid. Treatment of this acid with thionyl chloride gave the corresponding acid chloride, which was treated with ammonia L,5-(
2-andethyl)-2-thiophenecarxamide (melting point 104-105°C, crystallized from ethanol) was obtained. By reaction and hydrolysis of this amide with triphenylphosphine (J. Org, Chem, 40.1975.1659),
5 with a melting point of 134-136°C (crystals from acetonitrile)
-(2-amineethyl)-2-thiophenecarboxamide was obtained. Example 28 Similar to Example 4, R7 is (R)-phenylethylene oxide and 5-((/l')-2-aminofurovir)
-2-thiophenecarboxamide to 5-((#5
)-2-[BisJ-[:'(R) -β-Hydroxyphenethyl]amine]Procyl]-2-thiophenecarboxyamide is added to the secondary / [α] man =-58°
(c=o1φ, in sooxane); ε2□. =8450
゜5-[:(#5)-2 used as 7 as Idemitsu 11 course no f
-Aminozolopyl]-2-thiophenecal7'-'quinamide can be prepared with j- as follows: α-
Methyl-2-thiopheneethanol (J. A, C1S, 64.1942.477), acedel chloride and aluminum chloride are reacted in methylene chloride, (
/? 5) -2-(s-acetyl-2-chenyl)-1-
Obtain methyl ethyl acetate. This material was saponified with sodium hydroxide in methanol, and 5-[(R5)-
2-Hydroxyzolobyl-2-thenylmethylketone is obtained, which is subsequently reacted with p-toluenesulfochloride to give (R,5) with a melting point of 101-103°C.
-2-(5-7cetyl-2-chenyl)-1-methylethyl p-toluenesulfonate was obtained. From this, 5-
[(R8)-2-Azudoprobyl]-2-thenylmethylketone was obtained, which was oxidized with bromine in total sodium hydroxide to give 5-[(R5)-2-Azudoprobyl]-
2-thiophenecarboxylic acid was obtained. This acid was converted to the corresponding chloride with thionyl chloride.1-1 This was treated with ammonia to give 5-((R5)-2-asodopropylene) with a melting point of 79-80°C (crystallized from ether).
-2-thiophenecarboxamide was obtained. This amide was treated with triphenylphosphine and hydrolyzed to give 5-[(]
<5)-2-Aminozolopyl]-2-aonecarboxyaminocarboxyamyl 1°>rl). Example 29 In the same manner as in Example 4, (R5)-5-(3-aminobutyl)-2-thiophenecarphox/amide and m-(
) trifluoromethyl)f: r-nylethylene oxide, 5-[(/rS)-3-(bis, -((l?S)-
β-Hydroxy-? 7z-(trifluoromethyl)phenethylamine]-2-thiophenecarboxamide was found: ε271! =11840゜Example 30 Ethyl (E)-5-((J<S)-2-γminone. Lobil]-β-methyl-2-thiophene acrylate 5
V and '0: 3.71 m-(trifluoromethyl)phenylethylene oxide was stirred in 50 me of trimethyl sulfoxide at 90° for 22 hours. Furthermore, m-(trifluoromethyl)phenylethylene oxide 1.23
r was added and the kernel mixing tube was heated to 90° C. for an additional 19 hours. The treatment was carried out in the same manner as in Example 4. Chromatography on Briquette and ethyl (E)-5 ((
R5)-z-(bis-[(/?, 5)-β-hydroxy-tn-(trifluoromethyl)phenethyl]amine]
Furovir]-β-methyl-2-thiophene acrylate
I got a ticket. ε323=17310゜Ethyl (E)-51(R5)- used as “starting material”
2-7minoprovir]-β-methyl-2-thiophene acrylate could be prepared as follows: s-[(R5)-2-hydroxyglovir]-2-thenylmethylketo/and triethyl Phosphonoacetate is reacted in alcohol in the presence of sodium ethylate T to give ethyl (E)-5-((/<5)-2-hydroxypropyl"-β-methyl-2-thimepheneacryl-7-tro. From this, ethyl (A')-β-methyl-5-[(R
5)-2-[(p-)luenesulfonyl)oxy]fluoro
Robyl]-2-thiono-acrylate (melting point 12
This ester was reacted with sodium azide in methyl sulfoxide to give ethyl (E)-s-[(
R5)-2-azidonorol]-β-methyl-2-
I chose thiophene acrylate. The ester of the scoundrel is reduced with triphenylphosphine and hydrolyzed,
Ethyl(,1)-5-[(R,5)-2-aminopropylj-β-methyl-2-dionephene acrylate-1
-*: iAr ffj= did. Real M (+Example 31 In the same manner as in Example 30, ethyl (/4) -5-(
A mixture of (R8)-3-aminobutyl-β-methyl-2-thiophene acrylate and (R)-phenylethylene oxide was obtained: ethyl (E)-5-
C(1?)-3-Cbis-(1?)-β-hydroxyphenethyl[amine]butyl]-β-methyl-2-thiophene acrylate; [α]2=-126° (C , in dioxane); ε32. = 19030
: and ethyl 1)-s-((S)-3-[bis-(R)
-β-Hydroxyphenethyl[amine]butyl]-β-
Methyl-2-thiophene acrylate; [α)20=-
4o° (c = o, lchi, soogisan); εq
, 3-"18050° starting material and [7] Ethyl 1)-5-(:(R8)
-3-aminobutyl-β-methyl-2-thiophene acrylate could be trimmed as follows: (R5)-4-(2-chenyl)-2-butanol (
C'oll, (,'zeck, C'hem
, (,”o m1n,, 4 1.1976
．． (R,
5)-3-(5-acetyl-2-chenyl)-1-methylglobyl acetate was obtained. Look at this - Saponification of water c'15'' with sodium dioxide in methanol, (R
,5)-5-(3-hydroxybutyl)-2-chenylmethylketone was obtained. This was reacted with triethylphosphonoacetate in alcohol in the presence of sodium alcoholate, and ethyl(E)-5-((t(S)
) -3-Hydroxybutyl]-! -Methyl-2-thiophene acrylate'#: A47. Reaction with p-toluenesulfochloride, followed by sodium treatment, i! l! Then, ethyl(1)-5-[(R5)-
3-azidobutyl)]-]//-methyl-2-thionoene acrylate kJ4i. By reaction with triphenylphosphine followed by hydrolysis, ethyl (E)-s-[(R5)-3-aminobutylcy β-methyl-2-thiophene acrylate was obtained; ε320=
17465゜Example 32 In the same manner as in Example 4, ? x-()lifluoromethyl)
-Phenylethylene oxide &Up-(2-aminoethyl)-benzamide, p-'C2-[bis-[(R
8) -β-Hydroxy-m-(trifluoromethyl)phenethyl[amine]ethyl]benzamide;
ε232-142oo0 Example 33 Same as Example 4 [7, from (l?)-phenylethylene oxide and 2-acetyl-5-[(R5)-2-aminopropyl cothiophore, 5-C1,5] -2- [
Bis-[(R)-β-hydroxy/phenethyl]amine]
Propyl]-2-y-enylmethylketone was obtained;
[ ] 20 = -46° (c = 0.1%, in methanol): 62011''10400;
)-2-Amindi"]biru]thiophe/ is 5-(l<
5) -2-azidopropyl: -2-thenylmethylketone is reacted with triphenylphosphine, θ (with this product l sound ammonia water) 111 moisture 1'+'f
t. was able to be manufactured using Example 34 Ethyl ()<)-5-(
(l<5)-2-aminoso'lovir)-β-methyl-2
-thiophene acrylate and (R)-phenylethylene oxide, the lower one is: ethyl(L) -5-11(R) -2-(bis-C(/<)
-β-Hydroxyphenethyl] fmino J glovir” -β
-Methyl-2-thiophene acrylate; [α:) 2
, 0 = -76° (c = 0.1 section, in methanol); ε324 = 18690: and ethyl (1-5-((
S)-2-[bis-[:1R)-β-hydroxyphenethyl]amine]propyl]-β-methyl-2-thiophene acrylate; [α]20=-t18° (c=
o, 1% in methanol); ε325-18250° Example 35 In the same manner as in Example 30, methyl 5-[(R5)-3-
Aminobutyl]-2-thiophenecarboxylate and σ
The following was obtained from (R)-phenylethylene oxide: Methyl 5-C(R)-3-[bis-[(R)-β-hydroxyphenethyl]amine]butyl]-2-thiophenecarboxylate; α) 20=-103° (c
= 0.1% in methanol); ε27° = 13180
:ε255””9540 : and methyl 5-[:(,5
)-3-[bis-1/<1β-hydroxyphenethyl]
amine (butyl)-2-thiophenecar-? xylate = (tt) 20 = -18° (c = 0.1
% in methanol); 627g ”' 1215 +1
;ε25! l””8! l l 4゜Departure I+5
Meboul 5-((/<5)-3 used as i t<j
- Amitubdel J-2-thiophenecarboxylate is reacted with triphenylphosphine in methyl 5-(3-azidobdel)-2-thiophenecarboxylate τ bilison and the reaction product is subjected to threshold ammonia hydrolysis +
nI to produce methyl 5-[(R,5)-3-aminoptyl ni-2-thiophenecarboxylate; ε, , = l 1280
; C2,4-8760° Example 36 According to Example 2, methyl yy-[bis-((R) )-Hydroxyphenethyl]amino]globil]benzoate was obtained; [α] = -60° (c = 1.0 coefficient, in methanol): 6238 = 37700 Example 37 According to Example 2, p-[: (R)-2-aminoglobil]benzamide and (R)-styrene oxide cara, amorphous p-[(1-2-C bis-[(/?)-β-hydroxyphenethyl]amine]globil]benzamide obtained; [α]2°=-102° (c=0.71
%, in methanol); ε232=137800 Example 38 According to Example 2, from (R)-1-methyl-3-(4-aminocarbonylphenyl)furobylamine and m-)lifluoromethyl-styrene oxide, amorphous material and R
7, p-[(/+')-:(-(:(YUS)-β-hydroquino-rrL-(trifluoromethyl)phenethyl]amino]budel J benzamide is IL/this
; [α]', 5'--2o' (
c == 1. rl in methanol);
ε2g5=14! J90゜ real moga 11. Example 39 According to Example 2, methyl p-[2-[bis-C(,10-hydroxyphenethyl]aminocosi'lovir]benzoate ( Amorphous) was obtained; [α]2″=-9101ノ (C206, in methanol); ε7., ==1572
0° Example 40 13.67 4-amino-3,5-sochlorophenacyl bromide and (R), - in 100 mt chloroform
x-Methyl-3-(4-aminocarbonylphenyl)-
A 7M compound of propylamine 4.62 t was heated to 50° C. for 3 hours. This mixture was evaporated under vacuum, the residue was dissolved in 200 mt of methanol and 70 tnl of water, and a solution of 3.02 m of sodium borohydride in 20 m of water was added to it, making sure that the temperature did not rise above 20°C. The mixture was added dropwise while cooling with ice and stirring. After the addition is complete, add 5 to 1 liters of the mixture
The mixture was stirred for an additional 2 hours at 0°C, then poured into ice water and extracted with methylene chloride. The material isolated from the methylene chloride extracted Yik was chromatographed on a silica gel. Amorphous and pure p-
r: (R)-3-[bis-((R8)-4-amino-3
,5-sochloro-β-hydroxyphenethyl]amino]
Butyl]benzamide was obtained: [α] = -46°
(c=i, oji, in methanol); ε242=310
80; ε, o, = 72500 Example 41 S, &f4 According to Example 2, “, (from 1-styrene oxide and 2-(3,4-sometoquinphenyl)-L delamine, amorphous α, α′- ([(3,4-somethoxysoenyl)imino]someethylene]bis-[[(R)benzyl alcohol] is!) La JL * : [α] 2
0--52° (c = to6, in methanol)
;ε2. . =1]1120:ε2. . = 3 (+9
0゜Example 42 According to the ability Yamabushi 2, 4-Pentzuruoki 7 Styreneoki/
and 2-(3,4-nomethoxyenyl)ethylamine to form α,α′-(c3.4-nomethoxy7phenyl)imino]nomethylene]bis-
[(l?5)-p-pensoloxy-bennor alcohol] was obtained; ε226 = 379 :l O1ε2
, 4 = 6970, ε28° = 6610° Example 43 Tablets with the following composition were prepared in a conventional manner: Benzamide 25 On lactose.
200 rL! 9 Corn starch 300~corn starch base) 50111 Calcium distearate 5 #I6t Dicalcium phosphate 451112 Example 44 Methanol 2 p-[(]?)-3-[bis-
A solution of 216 ml of ((/<)-β-hydroxyphenethyl]amine[butyl]benzamide was added to 58 ml of 7-malic acid.
I reacted. Add 10rnl of ether to this solution 6≦
After addition, p-((R)-3-(bis-[(R)-β-
Hydroxyphenethyl amine butyl penzamide fumarate, 210 mg. 4. After crystallization from acetonitrile, 92-95° l
, ij 1 point; [α'''! 11. 2 = -81゜l) (c = 1.o, in methanol); ε2+14'''
A person who completed 17400 4 times. Example 45 In the same manner as in Example 44,! "l'! /,',
1.127-12o' (methanol-needle 11+)
; [lχ”″.-1) -78° (c = O, s, in methanol); ε21
2-16900 p -[1' (R) -: (-(bis-[()ku)-]β-hydroquinephenemeth]amino]butyl]benzamide maleate. 'F'l' work application Person F.Hofmann U.R.O.Z./Company Akchenkaeselshaft C07C93/14 695
6-4101104 695
6-4103/29 737
5-4103/44 737
5-4121/78 773
1-4147106 666
7-4C07D 333/20
8214-4・333/24
8214-4333/38
8214-4 priority claim @May 2, 1983
7th ■Switzerland (CH)■2897783-〇0 Inventor Marcel Muller Switzerland 4402 Frenkendorbuk Ellenbeek 1〇=34:

Claims (1)

[Claims] 1. In the formula, n represents an integer of 1 to 5; Xl represents phenyl or phenyl substituted with R1, R2, and R3; X2 is hydrogen, lower alkyl , phenyl still 7? l, with 1<2 and R3-,
represents di- or tri-substituted phenyl; Y represents hydrogen, lower alkyl, hydroxymethyl, carboxy or lower alkoxycarbonyl; Z represents the formula %7? l, R2 and R3 are hydrogen, halokene, hydroxy, pennooxy, lower alkyl, lower alkoxy, hydroxymethyl, amine, acylamino, lower alkoxybenzylamide, nitro, carbamoyl, trifluoromethyl or lower alkylsulfonyl represents methyl; l?4, R'' and R1'1 are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, carboxy, cyano,
Hydroxy, hydroxy-lower alkyl, acyloxy or group -C(R')=C(R')COOR8, -502R'
, -c(o>r or -C1i2R", provided that when I?5 represents hydroxy, lower alkyl or lower alkoxy, R4 does not represent hydrogen; R6, R7 and R8 represent hydrogen or represents lower alkyl; R9 represents amino, mono-lower alkylamino or a group R; R represents no-lower alkylamino, piperidono, morpholino, thiamorpholino, piperidono or an ether group of a lower aliphatic, alicyclic or araliphatic alcohol; or represents an ether group of phenol; and R' represents a group R, and RI, R2 and R3 are hydrogen, halogen, hydroxy, pentyloxy, lower alkyl, lower alkoxy, hydroxymethyl, amine, lower alkoxypentuluamino group; Bamboo trifluoromethyl, and when Y also represents hydrogen, lower alkyl or hydroxymethyl, R' can also represent amino or mono-lower alkylamino; A salt that is scientifically acceptable. 2. J?' represents hydrogen; R2 and R3 are hydrogen;
Halogen, hydroxy, pentyloxy, lower alkyl, lower alkoxy, hydroxymethyl, amine, acylamino, lower alkylbenzulamino, nitro, trifluoromethyl or lower alkyl, acyloxy or group -C(R'),,=C (R7) C0
OR'', -5O2R', -C(0)lze9 or -C
112R"; and R5 and J (51 is a group -C
' (R6) = C(R)) C00R'', -5O2R
', -C(0)RQ or -C112RIG. 3. Compounds according to claim 1, wherein n represents 1 or 2, in particular 2. 4. Xl is phenylmata is m-trifluoromethyl-
Claim 1. which represents phenyl, in particular phenyl.
A compound according to item 2 or 3. 5. A compound according to claim 1, wherein X2 represents phenyl, m-trifluoromethyl-phenyl, lower alkyl or hydrogen, in particular phenyl. 6 Y is aqueous or lower alkyl, especially methyl! A compound according to any one of the ranges 1 to 5 of the clock 8 Seigyu. 7 R' represents hydrogen; and R1' and R51 represent lower alkanoyl, carbamoyl, sulfamoyl, lower alkoxycarbonyl or lower alkylcarbamoyl, especially lower alkanoyl or carbamoyl; Dimensions in box 1 or 3
The compound according to any one of items 1 to 6. B, n is 1'! f, or 2, especially 2♂2washi;
'caffeinyl' or rn-trinorolomedylphenyl, especially phenyl; X2 is phenyl, m-
trifluoromethyl-phenyl, lower alkyl or hydrogen, especially phenyl; Y represents hydrogen or lower alkyl, especially methyl; R4 represents hydrogen; and R5 and R51 are lower alkanoyl, carbamoyl, sulfamoyl, lower alkoxy Claims 1 or 3 representing carbonyl or lower alkylcarbamoyl, in particular ifM alkanoyl or yucarpamoyl.
The compound according to any one of items 1 to 7. 9. The compound according to claim 1, which is p-[(R)-3-[bis-[(R)-β-hydroxyphenethyl]amine]butyl]penzamide. 10. Compounds of formula I and their biologically acceptable salts as agents for the treatment of obesity, diabetes and conditions associated with increased body weight or as feed additives for fattening animals.11 , a pharmaceutical 1iIAI product containing a compound of formula I or a physiologically acceptable salt thereof.
The β-ketohalide ofゎl, ; Zl represents a group, /,
+11, l<12 and 7 (+121 is hydrogen, lower argyl, lower alkoxy, lower alkanoyl, carboxy,
Cyano, hydroxy, hydroxy-lower alkyl, acylox7 or group -C (/<6), =C (1<7)
C00//8, s() represents -C1/2R, provided that /(+12 represents hydroxy, lower alkyl or ↓lower alkoxy, RI' is hydrogen? l: not represented) and n, X', X2,
Y, R,,/? 6, l is R8 and R9 is + of patent claim
i'+j) having the meaning given in Box 2131, by reacting with the amine of
When reacting with a compound, X8 represents a group X1;
The group X1-C(0)- or X present in the resulting compound
2-C(0)- to group X'-CIIOII- or X2-
CIIOlf- and, if necessary, functionally modifying the reactive substituents contained in the groups X1, X2, Y or Zl of the reaction product. A process for preparing compounds of formula I and physiologically acceptable salts thereof.