Method of producing amide derivatives or their pharmaceutically acceptable acid-additive salts

专利摘要:
The invention concerns novel phenoxyacetic acid amide derivative of the formula I <CHEM> (and pharmaceutically acceptable salts thereof) in which R<1> is hydrogen or fluoro, R<2> is phenyl, cyclo-alkyl, alkyl or alkenyl as defined herin, and R<3> is hydrogen, methyl or ethyl, or R<2> and R<3> together form polymethylene as defined herein. The invention also includes pharmaceutical compositions containing the amide derivatives, means for the manufacture of the said derivatives and for their use in the treatment of obesity and related conditions and/or in the manufacture of novel medicaments.
公开号:SU1549476A3
申请号:SU874202958
申请日:1987-07-22
公开日:1990-03-07
发明作者:Рой Холлоувей Бриан；Хауе Ральф；Синг Рао Балбир；Стриблинг Дональд
申请人:Империал Кемикал Индастриз Плс (Фирма)；
IPC主号:

专利说明:

one
(21) 4202958 / 23-04
(22) 07.22.87
(31) 8617986; 8701832
(32) 07.23.86; 28.01,87
(33) GB
(46) 07.03.90. Bul f, 9
(71) Imperial Chemical Industries PLC (GB)
(72) Brian Roy Holloway, Ralph Haue, Balbir Sing Rao and Donald Stribling (GB)
(53) 547.298.1 .07 (088.8)
(56) EP (G 171760, class C 07 C 103/34, published on Feb. 19, 1986.
(54) METHOD FOR OBTAINING AMIDA DERIVATIVES OR THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITIVE SALTS
(57) The invention relates to the preparation of amide derivatives of f-ly I
O-OCH2CH (OH) CH2NHCH7CH70- @ OCH7COM
where M is R - H or F; R2 is a cycloalkyl group, C.-alkenyl or -alkyl, which
may be replaced by one hydroxyl, carbamoyl, C-C-alkoxy, phenyl or chlorophenyl group; , methyl or ethyl or R and R5 together with N form a piperidino, pyrrolidino, morsbolino or 1,2,3,4-tetrahydroisoquinol 2-yl group, or their pharmaceutically acceptable acid addition salts, which have the property to stimulate thermogenesis warm-blooded animals and can be used in medicine or veterinary medicine. The goal is to develop a method for populating more active compounds. Getting lead by the reaction of the ether f-ly I, where R ,, is the above; M is a C-C4-alkoxy group, or its optically active Lorma with an amine in the form of HNR2R3, where R2 and R are indicated, followed by assignment of the product obtained in the form of an enantiomer or optically active form as a free base, or with its translation into a pharmaceutically acceptable acid addition salt by reaction with an appropriate acid. 3 tab.
with SS
(L
ate
С С Ј j
05
The invention relates to organic chemistry, namely to a process for obtaining Ri OH @ -OCH2CHCH2NHCH2CH20-grOCH2CONR2R:
where R, is hydrogen or fluorine;
R- - cycloalkyl group C-j-Cg-, C5-C (. - alkenyl or C, -C4-alni new derivatives of amide of the general formupa
(I)

LM
kil, which prays to be substituted by one hydroxyl, carbamoyl, C (-C-alcock
a strong phenyl or chlorophenyl group; R is hydrogen, methyl or ethyl, or R and R together form a piperidine, pyrrolidino, morpholino or 1,2,3,4-tetrahydroisoquinol 2-yl group, or their pharmaceutically acceptable acid addition salts, which have the ability to stimulate thermal - Genesis of warm-blooded animals and can be used in medicine or veterinary medicine.
The aim of the invention is to develop an accessible process for the preparation of compounds of formula (I) which possess high thermogenic activity.
In the examples given, as in other cases, all operations are performed at room temperature, i.e. 18-26 ° C; evaporation under reduced pressure on a rotary evaporator; kieselguhr chromatography (Merck, grade 7734) obtained from E-Mer, Darmstadt, HGF; Nuclear Magnetic Resonance (NMR) spectra are recorded on a 200 MHz instrument in dg-DMSO in as a solvent using tetramethylsilane (TMS) as an internal standard; for protons, data are given in the delta scale (in ppm) relative to TMS; all crystalline final products have satisfactory microanalysis and NMR spectra.
Example 1. A mixture of methyl 2-I- (2-hydroxy-3-phenoxypropyl) -amino ethoxy phenoxyacetate (0.38 g) in methanol (20 ml) and 33% (May / vol) solution of methylamine in ethanol (10 ml) incubated at rooms
NMR: 3.08 (d. D., 1H, CHCH22SH) 3.26 (dd, 1H,); 3.36 (2HS NHCH2CHa); 3.7 (s., ZN, SOGSN 4.0 (d., 2H, OCH-CH); 4.25 (m, OCH2, CHON-); 4.74 (s., 2H, OCH 6.8-7 , 05 (m., 7 aromatic prins); 7.31 (m., 2 aromatic
within 3 hours. The solution is evaporated, and the recrystallized precipitate is 45 tones)
called from ethyl acetate to give N-hydrochloride (1.9 g); transfer-α-methyl 2-p-2- ((2-hydroxy-3-phenoxy-propyl) amino ethoxy-phenoxy-acetamide
(0.24 g), m.p. 115 ° C.
Found,%: C 63.9; H 70.0; N 7.3
C,
Calculated,%: C 64.2; H 7.0; N 7.5.
NMR: 1.84 (broad s., 1H, NH); 2.68 (m, 5H, CH (OH) CHZNH + NHCH3); 2.86 (t, 2H, MHCNHCH20); 3.90 (m., 5H, OCH2-CH3OH, + OCH2CH2); 4.38 (s, 2H, OCH2CO); 4.80 (broad s., 1H, OH); 6.80-7.00 (MO, 7 Aromatic 50
55
a mixture of 5% (w / v) solution of sodium bicarbonate (50 ml) and g of chloromethane (50 ml). Organic dried (MgSO4) and solvent UPA
yut. The remaining solid residue n crystallizes from methanol, pp pa 2-P- | 2- (2-hydroxy-3-phenoxy
Ipyl) amino ethoxy1phenoxyacetate (1.67 g), m.p. 116-118 ° C.
The original derivative propyl receive the following way.
A. A stirred mixture of 2- (proxyphenoxy) ethylamine (4.0 g) and
0
five
kih N); 7.25 (m, 2 aromatic H); 7.80 (broad s., 1H, CONH).
Starting materials are prepared as follows.
A mixture of N-benzyl-N- (2-G-hydroxyphenoxyethyl) -2-hydroxy-3-phenoxypropylamine (4.0 g), methyl bromoacetate (1.56 g), anhydrous potassium carbonate (1.7 g) and potassium iodide (0.05 g) are stirred at reflux in dry acetone (50 ml) for 24 hours. The reaction mixture is cooled, the precipitate is filtered, the solvent is evaporated. The residue methyl 2-p-{2- (H-benzyl-2-hy-roxy-3-phenoxypropyl) amino ethoxy-β-phenoxy acetate is dissolved in methanol (90 ml) and acetic acid (30 ml). The resulting solution is hydrogenated in the presence of 10% (May / May.) Palladium on carbon (0.4 g) at 20 bar and 60 ° C for 48 hours. The mixture is cooled, the solid residue is removed by filtration, and the solvent is evaporated. The residual oil is dissolved in methanol and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid is recrystallized twice from methanol to give methyl--2-P-2-C (2-hydroxy-3-phenoxypropyl) amino ethoxy-phenoxyacetate acetate hydrochloride (0.22 g), m.p. 170 ° C.
Found,%: C 58.2; H 6.3; N 3,6; C1 8.8.
0
CWHWNC106
Calculated,%: C 58.3; H 6.3; N 3.4; C1 8.6.
NMR: 3.08 (dd, 1H, CHCH22SH); 3.26 (dd, 1H,); 3.36 (t, 2HS NHCH2CHa); 3.7 (s., ZN, COGCH3); 4.0 (d, 2H, OCHACH); 4.25 (m., 3N, OCH2, SNON-); 4.74 (s., 2H, OCHACO); 6.8-7.05 (m, 7 aromatic protons); 7.31 (m, 2 aromatic protons)
Hydrochloride (1.9 g) transferred
0
five
a mixture of 5% (w / v) sodium bicarbonate solution (50 ml) and dichloromethane (50 ml). The organic layer was dried (MgSO4) and the solvent was evaporated. The remaining solid residue is recrystallized from methanol to give 2-P- | 2- (2-hydroxy-3-phenoxypropyl) amino ethoxy-phenoxyacetate (1.67 g), m.p. 116-118 ° C.
The initial propylamine derivative was prepared as follows.
A. A stirred mixture of 2- (phydroxyphenoxy) ethylamine (4.0 g) and benzaldehyde (5.0 g) in methanol (50 ml) is cooled with ice and sodium borohydride (2.0 g) is added in portions over 1 After stirring for 18 hours, the solvent is evaporated. The residue was partitioned between 2 M hydrochloric acid (200 ml) and ethyl acetate (100 ml). The acid layer is separated, made alkaline with potassium carbonate and then extracted with ethyl acetate. The extracts are dried (MgSO4) and evaporated. The residual oil is dissolved in ethyl acetate and passed through dry
ten
and vnapuBaiOT solvent. The residual oil is dissolved in ethyl acetate. Dry hydrochloride is then passed through the solution until the precipitate t precipitates out. The solid precipitate is separated by filtration and recrystallized from a mixture of methanol and ethyl acetate to obtain N-benzyl-2 (p-hydroxyphenoxy) ethylamine hydrochloride (0S9 g), m.p. 182 - 184 ° C.
PRI mme R 2. The procedure described in Example 1 is repeated using the (-) - enantiomeric form.
hydrogen chloride until then, until you- 15 methyl-2-C-2- (2-hydroxy-3-phenoxy
propyl) amino ethoxy Loxoacetate (Z) in the amount of 0.66 g to obtain the corresponding optically active form of N-methyl-2-I- | 2- (2-hydroxy-3-20-phenoxypropyl) amino-ethoxyjphenoxyacetamide (.0 , 50 g), so pl. 114-1 O -8.1 ° (C 0.97, ethanol).
The starting material (Z) was prepared as follows.
25 A mixture of methyl 2-p- {2- (2-hydroxy- -3-phenoxypropyl) amino ethoxyTphenoxyacetate (0.92 g), (-) - di-p-tolyl tartaric acid monohydrate (0.99 g) in methanol (15 ml), evaporated under reflux, obtaining a final volume of 5 ml. Methyl acetate (0 ml) is added and the mixture is again evaporated to a volume of 5 ml. This treatment is repeated once more. The mixture is left at room temperature for 18 hours. The resulting solid is collected and recrystallized from methanol and ethyl acetate to form (-) - di-ft-tolyl solvent () -methyl-2-m-4 (2- hydroxy-3-phenoxypropyl) amino ethoxy phenoxy-isetate (0.337 g), m.p. 46-148 ° C; M -80.3 ° (C 0.97S methanol).
(-) - Di-p-tolyl tartrate (()) methyl 2- 45 - {2- (2-hydroxy-3-phenoxypropyl) amino ethoxy-phenoxyacetate (0S33 g) is distributed between 5% (May / vol. ) a solution of sodium bicarbonate (10 ml) and dichloromethane (10 ml). Op - 5Q Ganic layer is evaporated, dried
(MgSO4), the solvent is evaporated. The remaining solid (0.148 g), so pl. 114-1 16 ° C, -7.8 y (C 0.97, dichloromethane). dissolved in α-g methyl acetate. Gaseous dry hydrogen chloride is passed through the solution until precipitation stops. The precipitate is separated and recrystallized from methanol and the methyl acetophode is precipitated. The precipitated precipitate is collected and recrystallized from methanol and ethyl acetate to give M-benzyl-2- (P-hydroxyphenoxy) ethylamine hydrochloride (2.3 g), m.p. 182 - 184 ° C.
B. N-Benzyl 2- (I-hydroxyroxyphenoxy) ethylamine hydrochloride (3.5 g) is shaken with 1M sodium hydroxide solution (20 ml) and dichloromethane {20 ml). The organic layer was separated and washed with water (10 ml), dried (MgSO4) and the solvent was evaporated to yield K-benzyl-2- (p-hydroxyphenoxy) -ethylamine as an oil.
B. A mixture of M-benzyl-2- (c-hydroxyphenoxy) ethylamine (2.5 g) and 1,2-epoxy-3-phenoxypropane (1.54 g) in procac-2-ol (50 ml) is heated at boiling for 72 hours. The solvent is removed by evaporation to give M-benzyl-K - (2-l-hydroxyphenoxyethyl) -2-hydroxy-3-phenoxypropylamine in the form of an oil that is sufficiently pure, as shown by thin layer chromatography (TLC) method (using silica gel granules and 5% methanol in dichloromethane as eluent), and which is used further without purification
The starting N-benzyl 2-- (M-hydroxyphenyl) ethylamine hydrochloride can also be prepared by the following method.
A mixture of c - (2-bromoethoxy) phenol (2.2 g), benzylamine (1.07 g) and triethylamine (1.01 g) in ethanol (30 ml) is heated at boiling for 18 h. The solvent is evaporated, and the residue is taken up in a mixture of 2M hydrochloric acid (100 ml) and ethyl acetate (50 ml). The acid layer is separated, made alkaline with potassium carbonate and then extracted with ethyl acetate. The extracts are dried (MgSO4)
35
40
0
and vnapuBaiOT solvent. The residual oil is dissolved in ethyl acetate. Dry hydrochloride is then passed through the solution until the precipitate t precipitates out. The solid precipitate is separated by filtration and recrystallized from a mixture of methanol and ethyl acetate to obtain N-benzyl-2 (p-hydroxyphenoxy) ethylamine hydrochloride (0S9 g), m.p. 182 - 184 ° C.
PRI mme R 2. The procedure described in Example 1 is repeated using the (-) - enantiomeric form.
methyl 2-C-2- (2-hydroxy-3-phenoxy
tata to obtain (-) - methyl--2-p- (2-hydroxy-3-phenoxypropyl) amino ethoxy-phenoxyacetate hydrochloride (0.092 g), mp. 156-15 7 ° C, -12.1 ° (C 1, O, methanol),
Examples 3-16 Use the procedure described in example 1, but using a suitable amine of the formula NMIgDz and conducting the reaction to its completion according to silica gel TLC, the following compounds of formula (I) are obtained with a yield of 60-90%, isolated either as a free base or as hydrochloride or oxalate salts by reacting the free base with an ethereal solution of hydrochloric or oxalic acid and recrystallization from the indicated solvents (see, Table 1) „
The initial esters for Example 4 were prepared as follows.
A mixture of resorcinol (88 g) s 1,2-dibromo ethane (180 g) and potassium hydroxide (44.8 g) is stirred at reflux in methanol (600 ml) for 24 hours. The reaction mixture is cooled.
The precipitated solid was removed by filtration, and the filtrate was evaporated, yielding 3 f2-bromoethoxy) phenol in the form of an oil, which was sufficiently pure by TLC (using granulated silica gel and 10% (v / v) methanol in dichloromethane as eluant) and is used further without purification,
A mixture of 3- (2-bromoethoxy) phenol 40 g and benzylamine (39.2 g) is stirred at boiling in ethanol (800 ml) for 18 hours. The reaction mixture is cooled and the solvent is evaporated. The residual oil was dissolved in ethyl acetate (200 ml). The solution is washed with 2M hydrochloric acid (100 ml). The aqueous layer is made alkaline with solid potassium carbonate and extracted with ether of 2 x 100 ml. The extracts are washed effectively with water (50 ml) and saturated sodium chloride solution (50 ml) and then dried (MgSO4). The dry ether solution is treated with a solution of ether saturated with hydrogen chloride. The precipitated solid is recrystallized twice from methanol / ethyl acetate to give H benzyl 2- (m-hydroxy-phenoxy) ethylamine hydrochloride (19.2 g), m.p. 148-149 ° C.
NMR; 3.2 (t, 2H,); 4.2 (p. + T., 4H, CH2O, NCH2P); 6.4 (m,
0
five
five
0
five
50
55
3 aromatic H); 7.1 (t, 1 aromatic H); 7.3-7.8 (m, 5 aromatic H).
A mixture of hydrochloride N-benzyl-2- (m-hydroxyphenoxy) ethylamine (2.79 g), 1,2-epoxy-3-phenoxypropane (1.5 g), anhydrous potassium carbonate (2.0 g) is heated at boiling in propan-2-ole for 18 hours. The reaction mixture is cooled and the solvent is evaporated to give I-benzyl-I- (2-M-hydroxyphenoxyethyl) -2-hydroxy-3-phenoxypropylamine in the form of m turns out to be sufficiently pure according to TLC (granulated silica gel and 5% methanol in dichloromethane as eluent) and is used without purification.
N-Benzyl-N- (2-M-hydroxyphenoxy-ethyl) -2-hydroxy-3-phenoxypropylamine (1.6 g) is reacted with methyl bromo acetate (0.5 g), anhydrous potassium carbonate (0, 6 g) and potassium iodide (0.05 g) in acetone (80 ml) using the same procedure as described for the starting ester in Example 1 and with intermediate recovery of methyl 2-M-2-y-benzyl (2 β-hydroxy-3-phenoxypropyl) amino ethoxy 1-phenoxyacetate (1.1 g). Methyl-2-M- 2- Ј (2-hydroxy-3-phenoxypropyl) amino ethoxy phenoxyacetate hydrochloride (0.35 g) is obtained, m.p. 164-167 ° C.
Found,%: C 58.0; H 6.5; N 3.3; C1 8.7.
C2H26NC10e
Calculated,%: C 58.3; H 6.4; N 3.4; C1 8.6.
NMR: 3.1 (dd, 1H, CH 2 H 2 H); 3.25 (dd, 1H,); 3.4 (t., 2HS NHCH4CH4)} 3.7 (s., 3N, C02CH3); 3.9-4.1 (m., 2H, OCHNGCH); 4.2-4.4 (m., 3N, OCH2SNOH-); 4.78 (s, 2H,); 5.98 (d, 1H, CHOH); 6.5-6.7 (m, 3 aromatic H); 6.9-7.0 (s 9 3 aromatic H); 7.1-7.4 (m, 3 aromatic H); 9.1 (s., 2H, №f.
Examples 17, and 18. Using the procedure described for examples 3-16, but starting from methyl 2- (3-o-fluorophenoxy-2-hydroxypropyl) amino ethoxyphenoxyacetate, compounds are obtained in a yield of approximately 80-90%:
K-methyl 2-I-2-Ј (3-o-fluoro-phenoxy--2-hydroxypropyl) amino ethoxy-phenoxy-acetamide as hydrochloride, m.p.
168-169CC (recrystallization from a mixture of methanol and ethyl acetate) - Example 1
I-piperidino-2-c-2- (3-0-fluorophenoxy-2-hydroxypropyl) amino ethoxy-phenoxy-acetamide as hydrochloride, m.p. 144-146 ° C (recrystallization from a mixture of ether and methanol) - Example 18.
Essential Methyl Needs
esters are prepared as follows.
A mixture of N-benzyl-2- (hydroxy-ester) ethylamine hydrochloride (see Example 1) (5.6 g), 1,2-epoxy-3-9-fluorophenoxy-propane (3.6 g) and anhydrous potassium carbonate ( 2.7 g) is heated at boiling in propan-2-ol (100 ml) for 24 hours. The reaction mixture is cooled, the solid precipitate is removed by filtration, the solvent is evaporated from the filtrate. The residual oil is purified by chromatography on silica gel, 1% - (May / May.) methanol in dichloroethane to give N-6eH3Kn-N- (2-n-raflpOK siphenoxyethyl) -3-0-fluorophenoxy-2-hydroxypropylamine as a colorless oil.
NMR: 2.27-3.15 (m, 4H, CHINCHg); 3.8 (dd, 2H, NCH4P) j 3.9-4.2 (m, 5H, .o -F-PhOCHz); 6.7 (s, 4 aromatic protons); 6.8-7s (m, 4 aromatic protons H) j 7S3 (m, 5H,).
A mixture of 1-benzyl-M- (2-P-hydroxyphenoxyethyl) -3-O-fluorophenoxy-2-hydroxypropylamine (5.4 g), methyl bromo acetate (2.0 g), anhydrous potassium carbonate (1 , 79 g) potassium iodide (0.05 g) is stirred at boiling in dry acetone (80 ml) for 24 hours. The reaction mixture is cooled, the solid precipitate is removed by filtration and the solvent is evaporated. The residue was dissolved in dichloromethane (40 ml) and washed effectively with a 10% (May / vol) solution of sodium bicarbonate (20 ml) and water (20 ml), then dried (MgSO4) and the solvent was removed by evaporation. The oil (6.18 g) is purified by chromatography on silica gel, eluting with 1%
(v / v) methanol in dichloromethane to give methyl 2-P- {2- (K-benzyl-3-0-α-fluorophenoxy-2-hydroxypropyl) amino ethoxyphenoxyacetate as a colorless oil. This oil is dissolved in methanol (100 ml) and stirred with bleaching activated carbon (1 g) for 1 hour. The coal is removed by filtration and the filtrate is subjected
hydrogenation in the presence of benzyl chloride (0.71 g) and 10% (May / May) palladium on coal for 2 hours at atmospheric pressure. The catalyst was removed by filtration and the solvent was evaporated from the filtrate. The remaining solid was recrystallized twice from a mixture of methanol and anhydrous ether, to obtain methyl-2-P- {2-C 3 -O-fluoro-enoxy-2-hydroxypropyl) amino ethoxy-phenoxyacetate hydrochloride (0.55 g), t. square 120-122 ° C.
Found,%: C 55.7; H 5.9; N 3.2; C1 8.3.
CMH25NC1F06
Calculated,%: C 55.9; H 5.9; N 3.3; C1 18.2.
NMR: 3.1 (dd, 1H, CHCH2NH); 3.27 (m, under the signal from HO, 1H, CHCH NH) 3.41 (t, 2H, NHCH2CHa); 4.71 (s., H 2H, OCH200); 5.93 (d., W, CHON); 6.8-7.0 (m, 5 aromatic H); 7.1-7.3 (m, 3 aromatic H); 9.12 (broad s., 2H, NHp.
Example 19. Using the procedure described in example 2, (-) - enantiomeric phenoxyacetate (Z) (0.6 g) is converted to L- (2 hydroxyethyl) -2-n- | 2- (2 hydroxy 3- Phenoxy-propyl) amino ethoxy phenoxyacetamide (0.32 g), m.p. 111-113 ° C, 25 7.1 (C 0.99, ethanol), using ethanol-amine instead of methylamine,
Examples 20-27 Using a procedure similar to that described in Example 1, but using the appropriate amine of Formula and reaction wire until complete completion according to silica gel TLC, the following compounds of Formula I (the substituent is in position 4 of the ring) are obtained with an output 55 - 85%, isolated in the form of free bases and after recrystallization from the indicated solvents (see Table 2).
Example 28. Sodium hydride (0.132 g, 60% (May, May) suspension in mineral oil) is added to n -2-C (2-hydroxy-3-phenoxy-propyl) amino ethoxyT-phenol (1.0 d) s dissolved in dry dimethylformamide (DMF) (50 ml). The resulting suspension is stirred for approximately 30 minutes until a clear solution is obtained. A solution of N-α-phenyl-2-chloroacetamide (0.559 g) in dry DMF (20 ml) is added and the mixture is stirred for 18 hours. The mixture is then poured into water (150 ml). The resulting mixture was extracted with dichloromethane (2x100 ml). The extracts were washed with water (6x100 ml), then dried (MgS04J and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give N-phenyl-2-1 - | 2- (2-hydroxy-3-feioxypropyl) amino ethoxy phenoxy acetamide (0.365 g), mp 119-121 ° C. Found: C 68.7; H 6.5; N 6.3.
CWH4BN205
Calculated,%: C 68.8; N 6.4; H 6.4.
The latter has a satisfactory NMR spectrum.
Source phenols were prepared as follows.
A mixture of P- (2-aminoethoxy) phenol hydrochloride (1.89 g), triethylamine (1.01 g) and 1,2-epoxy-3-phenoxypropane (1.5 g) is heated at reflux for 24 h. The reaction mixture is cooled and the solvent evaporated. The residue is taken up in a mixture of dichloromethane (100 ml) and 10% (May / vol) solution of potassium carbonate. The organic layer was separated, sugaat (MgSO4), and the solvent was evaporated. The residual oil is dissolved in ethyl acetate and passed through dry hydrogen chloride until complete precipitation of the precipitate. The precipitate is separated and recrystallized from methanol and ethyl acetate to give p-2- (2-hydroxy-3-phenoxy-propyl) amino ethoxy phenol hydrochloride (0.53 g), m.p. 171-172 ° C.
Found,%: C 60.3; H 6.7; N 4.0; C1 10.6.
С „H NClO-v
Calculated,%: C 60.1; H 6.5; N 4.1; C1 10.5.
The corresponding hydrochloride (1.5 g obtained as described above was poured into a mixture of a 5% (May / vol) aqueous solution of sodium bicarbonate (15 ml) and dichloromethane (15 ml). The organic layer was dried (MgSO4 (j), the solvent is removed by evaporation to give h (2-hydroxy-3-phenoxypropylamino) ethoxy phenol as a thick syrup (1.1 g), which is used without further purification.
No.-Phenyl-2-chloroacetamide was prepared as follows.
A mixture of aniline (9.3 g) and triethylamine (10.1 g) in dichloromethane (40 ml was added dropwise over 1 hour to an ice-cooled solution of chloroacetyl chloride (11.2 g) in dichloromethane (40 ml). Mixture further stirred for 18 hours. The organic phase is separated by filtration, washed with water (3 x 50 ml), dried (MgSO4), the solvent is removed by evaporation to obtain N-phenyl -2 -2 chloroacetamide (6.1 g) as a white solid. , mp 128-129 ° C, which is further used without further purification.
Example 29. Using the procedure described in Example 28, but using I-propyl-2-chloroacetamide (0.447 g) instead of N-phenyl-2-chloroacetamide, K-propyl-2 p- {2- 2- -hydroxy-3-phenoxypropyl) amino ethoxy} phenoxyacetamide (0.47 g), m.p. 105-107 ° C (recrystallization from ethyl acetate), virtually identical in all respects to the substance obtained in Example 16.
The starting 1 1-propyl-2-chloroacetamide is obtained as K-phenyl-2-chloroacetamide, i.e. by reaction of propylamine with chloroacetyl chloride, in the form of an oil, which is used without special purification.
The compounds of formula (I) have thermogenic properties and can be used in the treatment of obesity and / or related diseases of metabolic dysfunction, such as diabetes mellitus, especially in adulthood. In some cases, the compounds of formula (I) can be important in modifying body compositions by increasing the catabolism of animal fat, meat producers, such as cattle, pigs, sheep, goats, and / or rabbits.
The thermogenic effect of the compounds of Formula (I) can be demonstrated using one or more of the following standard tests.
A. Rats are adapted to cold by being in a cold environment (4 ° C) for 10 days in order to increase their ability to thermogenesis. They are then transferred to a thermoneutral medium (29 ° C). After 3 hours, the internal temperature was measured to establish the basic reference point of the thermometer readings, and the test substance was administered subcutaneously or orally as a solution or suspension in 0.45% n / m / v. Aqueous sodium chloride, 0.25% (May / vol.) polysorbate 80. After 1 h, the internal
medium temperature. In this test, a compound that causes a statistically noticeable increase in the internal temperature of 0.4 ° C or more with a subcutaneous dose of 15 mg / kg (or less) is considered to have significant activity. The test acts as a model of reduced thermogenesis occurring in the diet.
B. Rats are adapted to cold for 4 days in order to increase their ability to thermogenesis. They are then transferred to a warm environment (23 ° C) and incubated for 2 days. The next day, the test substance is administered subcutaneously or orally as described in step A.
After 1 h, the animals are sacrificed and the intra-scapular brown adipose tissue (BAT) is removed; a) as the magnitude of thermogenic activation. Each test includes a control in which only the diluent is administered as a solution or suspension, and a positive control in which isoprenaline (in the form of sulfate) is administered in an amount of 1 mg / kg. The test substance is dosed at 091; 0.3; 1.0; 3.0 and 10 mg / kg and the results are expressed in terms of the effect on GDP binding caused by isoprenaline. From these results, the dose () required to obtain a 50% isoprenaline effect is calculated by linear regression analysis. Compounds are considered active in this test if they cause a significant increase in binding compared to controls.
my experiences. This test establishes that the thermogenic eLFects observed in test A manifest themselves in an increase in the effect of BAT to a greater extent than through a non-specific mechanism or mechanism of toxicity.
B. Rats are adapted to thermoneutral medium (29 ° C) for 2 weeks to reduce their ability of BAT to induce non-shivering thermogenesis. During the last 3 days, animals are trained using an apparatus for calculating cardiac velocity using electrodes on foot pads connected to an ECG integration.
ten
15
.
25, Q 5. 35
45
50
55
a torus, we give a constant given heart rate. The test compound is administered subcutaneously at that indicated in test B, and the heart rate is determined 15-30 minutes after dosing. The procedure is then repeated in subsequent tests using the increasing multiple repeats of the ED50 indicated in test B} until the heart rate (HR) reaches or exceeds 500 beats per minute, which makes it possible to calculate the dose needed to obtain the heart rate 500 beats per minute (-toza).
The ratio of DSOO to EDbO in test B can be defined as the selectivity index (SI) and gives an estimate of the compounding selectivity for BAT as contraindicated to the cardiovascular system. Compounds having an SI greater than 1 are considered to have significant selectivity. Non-selective compounds have an SI less than 1 (e.g., isoprenaline 0.06).
G. Rats are adapted to cold at 4 ° C for 4 days to increase their ability to thermogenesis. Then they are kept in a warm environment at 23 ° C for 2 days. The next day, the rate of main metabolism is determined using an apparatus with oxygen circulating in a closed system (described by Arundel et al. Rats are then treated with doses (orally or subcutaneously) of the test compound in an amount of about 10 mg / kg as a solution or suspension at 0, 45% (May / vol) aqueous sodium chloride, 0.25% (.) Polysorbate 80. The metabolic rate is then determined at least 1 hour after the dose. The compounds are considered active according to this test if they cause a noticeable increase metabolic rates compared to control animals (Student s t-test, p 0.5), in which only the solution or suspension of the binder is administered.
In the tests described, compounds of formula (I) generally show the effects of the following order without apparent toxicity:
Test A, an increase in the internal temperature of about 0.5 ° C (or more) after subcutaneous administration of 15 mg / kg;
15
test B - subcutaneous EP50 for GDP-binding in BAT-mitochondria x 0.01-10 mg / kg;
test B - detects the SI 50.
To illustrate, the compound described in the accompanying example detects the following effect in the tests described:
A - 2.25 C at a subcutaneous dose of 10 mg / kg;
B - subcutaneous, 0.133 mg / kg, oral ED5o 1.18 mg / kg;
I am soo 3.3 mg / kg (subcutaneously), SI 10 (subcutaneously), SI 50 (orally).
In contrast, the known structurally related compound No.-methyl-2-p-2- (2-hydroxy-3-p-hydroxyphenoxypropyl) amino ethoxy phenoxy acetamide causes a temperature rise of 1.24 ° C in test A and does not show activity in test B, but causes a marked increase in heart rate (see Table 3).
154947616
When used to produce a thermogenic effect in warm-blooded animals, including humans,
, the dinene of formula (I) or a suitable pharmaceutically acceptable salt thereof must be administered so that a dose of 0.002-20 mg / kg is administered daily, as a single dose or as an individual
10 doses as needed. However, in this process, it is necessary to skillfully select the doses, since the dosage should vary accordingly, depending on the severity of the conditions in the treatment process and on the age and sex of the patient and should be consistent with the well-known principles of medicine.
The compounds of formula (I) may be used for medical (or veterinary) purposes.

权利要求:
Claims (1)
[1]
Invention Formula
25 Method for preparing amide derivatives of general formula
R, it is @ -osngsnngyunsn2sngo - @ - osn2sokrkkz
de r r
hydrogen or fluorine; a C-C-alkenyl or kil cycloalkyl group which may be substituted with one hydroxyl, carbamoyl, C-C4 alkoxy, phenyl or chlorophenyl group;
, 1 OH; O-OCH2CHCH7NHCH1CH20, where Rj has the indicated values
R, j-C-C-alkoxy, or its optically active form, is reacted with an amine of the formula HNRj, R3, where R has the indicated meanings, followed by isolation of the product obtained in the form of an enantiomer or optically active form, as a free base, or by converting it into pharmaceuticals, a suitable acid addition salt is reacted with an appropriate acid.
five
R-, - hydrogen, methyl or ethyl or R and R- together form. a piperidine, pyrrolidino, morpholino or 1,2,3,4-tetrahydroisoquinol-2-yl group, or their pharmaceutically acceptable acid addition salts, characterized in that the ester of the formula
-OCH2COR
0
five
Priority featured
07.23.86 when RJI is C-C-alkyl which can be mixed with a hydroxyl or C-C4 alkoxy group, RZH R3 together form a piperidino, pyrrolidino, morpholino group.
I
28.01.87 when Rg - C3-C5 - cycloalkyl, C3-C4-alkenyl, C C-alkyl, substituted by a carbamoyl, phenyl or chlorophenyl group, R2 and R3 together form 1,2,3,4-tetrahydroisoquinol- 2-yl.
2.25 1.75 1.76 2.35 1.25 2.08 1.79 1.68
0.13 0.23 1.32 0.27 0.16 0.29 0.13 NA
T a b l and c a
Table
Table 3
100 100
NA 100 100 100 100
NA
50
ten
74
100 100 100 10 100
nineteen
154947620
 Table 3
P
Note.– No data.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB868617986A|GB8617986D0|1986-07-23|1986-07-23|Amide derivatives|

---

GB878701832A|GB8701832D0|1987-01-28|1987-01-28|Carboxamides|

---