Method of obtaining pentasaccharide

专利摘要:
Bicyclic heterocyclyl containing N-(bicyclic heterocyclyl)-4-piperidinamines having antihistaminic and serotonin-antagonistic properties which compounds are useful agents in the treatment of allergic diseases.
公开号:SU1694064A3
申请号:SU874203318
申请日:1987-09-17
公开日:1991-11-23
发明作者:Эдуард Жанссенс Франс；Лео Гисланус Торреманс Йозеф；Терезия Йоаннес Мария Ван Оффенверт Теофилс
申请人:Жансен Фармасетика Н.В.(Фирма)；
IPC主号:

专利说明:

obtain thermochemical isomeric forms. .New compounds more active-1
than the known analogues but activity. 14 tab.
This invention relates to the field of organic synthesis and relates to a process for the preparation of new N- (bicyclic steroids) - 4-piperidinamine / pharmaceutically acceptable acid addition salt or stereochemically possible isomeric form thereof.
9nH2n R p
Het-Y-AlK-NON-Dg
% rz
R
where —A (, is a bivalent radical having the formula: —CH CH — CH CH — —N OH — CH CH—, R j is hydrogen, halogen or hydroxyl; Rg. is hydrogen or halogen; R is thienyl, furanyl , unsubstituted or substituted with 0. -alkyl, pyridinyl, pyrazinyl, thiazolyl, phenyl or halophenyl; Alk - C, - (- alkanediyl; Y is the group NH or is a simple bond; Het is a bidicles system of the general formula
where in (Ta) X is 0 or S; R.J is hydrogen or C, -Cl-alkyl; B (- —CH CH — CH CH or —N CH — NR4-,
where - With-C4 lk,
and in (1b) - (-C-Alksht,
B.CH CK6-CH CRg, -CH CH-CR7-Cn- 0
—CHrCHRg — CH —CHRg, —CH —UHi — CHRg — CHg,
-S-CCK), s- (mon)
where R is each independently hydrogen
or (1 -C4 is alkyl;
R7 is C (-Sf-alkyl or halogen, -c which are histamine or serotonin antagonists.
JN-g with t о о i pi Cl o-4-liperra diac-amines of formula
R
i
 (0)
which have the same heh activity, but less effective.
The purpose of the invention is to develop a method for producing new compounds with higher activity.
Compounds of general formula (I) are prepared by alkylation of a piperidine of formula
n gt-tg
9iAn to li
- (
Htf
5 5
0
0
with
where n, R, R -A -A -Aj-A. - have the indicated meanings when interacting with an alkylation agent of the formula
Het - Y - Alk-W (IV)
where Het, Y and Alk have the indicated meanings, and W is a split group
The reaction is carried out in an inert solvent such as N, N-dimethylformamide, NjN-dimethylacetamide in the presence of an alkali metal carbonate, such as potassium or sodium carbonate, optionally in the presence of an alkali metal iodide, for example potassium iodide or sodium. Preferably, the reaction occurs at elevated temperatures. Then, the compounds of formula (I), where Het is a radical (la), where X is S, are optionally converted into the corresponding compounds of formula (I), where X is 0, by reacting the starting compound with hydrogen peroxide in a mixture of Cj -C.-alkanol / water, and, if desired, convert compounds of formula (I) into therapeutically active non-toxic acid addition salts by treating with an appropriate acid or vice versa, convert the acid addition salt to the free base with
using alkali and / or receive its stereochemically isomeric forms.
The compounds of formula (I) possess basic properties and, therefore, they can be converted into their therapeutically active non-toxic acid addition salts when treated with appropriate acids, such as, for example, inorganic acids, hydrohalic acids, such as hydrochloric, hydrobromic, etc. , nitric, phosphoric acid and the like. Salts can be converted by alkali treatment into a free base.
Preparation of intermediate compounds.
1 p and me r 1. A mixture of 90 parts of 4-chloro-3- (itropyridine, 71 parts of 4-fluorobenzene-methanamine, 63 parts of sodium carbonate and 900 hours M, n-dimethylacetamide is stirred for 1 hour at 50 ° C. Water is added and the product is extracted with 4-methyl-2-pentanone.The extract is dried, filtered and evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried, yielded 160 h, (75%) N- (4-fluorophenyl) -methyl - 3-nitro-4-pyridine-amine, TopPl ,, 136.8 ° C (intermediate 1).
Similarly, receive the intermediate products shown in table 1.
PRI mme R 2. To a stirred and cooled to OS, a solution of 8.7 h, N-Ј (4-fluorophenyl) methyl-4-nitro-3-pyridinamine, 1 h of oxide and 150 h, trichloromethane added 10.2 parts of phosphorus trichloride are dropped in drops in 75 parts of trichloromethane. Upon completion of addition, the mixture is allowed to warm to room temperature and stirring is continued for 1 hour at reflux. The reaction mixture is cooled and the solvent is distilled off. The residue is stirred in trichloromethane. The product is filtered off and dried, 9 parts are obtained. N-Ј (4-fluorophenyl) -methyl-4-nitro-3-pyridine-amine monohydrochloride (intermediate 9).
PRI me R 3. A mixture of 56 parts of N- (3-nitro-2-pyridinyl) -2-pyridinemethanamine, 2 h. A 4% solution of thiophene in ethanol and 400 parts of methanol saturated with ammonia are hydrogenated under normal pressure at room temperature for 4 hours of 5% palladium on carbon as a catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is crystallized from acetonitrile, 43.5 parts are obtained. M- (2-pyridinylmethyl) -2,3-pyridinamine, m.p. 134.9 ° C (intermediate 10).
Similarly, receive intermediate products listed in table 2.
PRI me R A. To a stirred and cooled mixture, 4 parts of sodium hydroxide, LO parts of water are added successively 7.9 parts of carbon disulfide and 17.2 parts of ethyl 4-amino-1-piperidinecarboxylate at temperature below 10 ° C. Stirring is continued for 30 minutes at this temperature. Then 10.9 parts of ethyl carbonic chloride are added dropwise (exothermic reaction, the temperature rises to 35 ° C). But the termination of the addition continues stirring for 2 hours at S) ° C. The reaction mixture is cooled and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated, yielding 22 parts (100%) of ethyl 4-isothiocyanato-1-piperidinecarboxylate as a residue (intermediate 19).
A mixture of 54 parts of ethyl 4-isothiocyanato-1 1-piperidinecarboxylate, 48 parts of 2 - (.-Furanylmethyl) -2,3-pyridinediamine and 450 parts of tetrahydrofuran are stirred and the whole night is heated under reflux. The reaction mixture is evaporated and the residue is crystallized from a mixture of 2-propanone and 2,2-hydroxypropane. The product is filtered off and dried, yielding 7b parts (75%) of ethyl 4- (2-furanylmethyl) -amino-3-pyridinyl-amino-nematoxy-amino-1-piperidinecarboxylate, m.p. 132.7 C (intermediate 20).
Similarly, receive intermediate products listed in table 3.
PRI me R 5. A mixture of 42.5 hours. ethyl 4- {Cphenylmethyl) -amino -1-piperidinecarboxylate, 30 ps 1-isothiocyanato-2-nitrobenzene and 270 h of tetrahydrofuran are stirred for 3 hours at room temperature, 2.2-oxo biopropane is added and stirred overnight. The precipitated product is filtered off and dried, 48.5 parts (68.5%) of ethyl 4- | X (2-nitrophenyl) amino-amino thioxomethyl (phenylmethyl) amino.-1-piperidinecarboxylate, t are obtained. square 140 ° C (Intermediate 30).
7
sixteen
A mixture of 48.5 parts of ethyl 4-GЈH2-nitrophenyl) amino-amino thioxomethyl (phenylmethyl) amino -1-piperidinecarboxylate and 600 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at 30 C for 15 hours. 10% palladium on carbon as a catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off on the Hyflo filter and the filtrate was evaporated, 47 parts (100% ethylH 2 C2 aminophenyl) -amino-amyoG thioxomethyl- (phenylmethyl) amino3 -1-piperidinecarboxylate were obtained, mp. 140 ° C (intermediate 30).
A mixture of 48.5 parts of ethyl 4-GG (2-nitrophenyl) amino-amino thioxomethyl (phenylmethyl) amino -1-piperidinecarboxylate and 600 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at 30 ° C for 15 hours. 10% palladium on carbon as a catalyst. After absorption of the calculated amount of hydrogen, the catalyst is filtered off on the filter Hyflo and filter. The evaporate is obtained; 47 hours (100%) of ethyl QЈ (2-aminophenyl) amino-amino thioxomethyl (phenylmethyl) amino -1-piperidinecarboxylate are obtained as residue (intermediate 31) :.
II p and me R 6. A mixture of 74 hours ethyl-4
2- G (2-furanylmethyl) -amino -3-piUU- J -,
Ridinyl α-aminothioxomes aMHHOj -j-piperidinecarboxylate, 96 parts of bivalent mercury oxide, 0.1 parts of sulfur and 800 parts of ethanol are stirred and boiled for 3 hours under reflux. The reaction mixture was filtered through a Hyflo filter and the filtrate was evaporated. The residue is crystallized from acetonitrile, 52.5 parts (79%) of ethyl-4 3- (2-furanylmethyl) -3H-imidazo | G4,5-a | -pyridine-amino--1-piperidinecarboxylate are obtained. tspl. 149.2 C (intermediate 32).
Similarly, receive intermediate products listed in tabl.
Example 7. A mixture of 57.5 parts ethyl 4- (H-benzimidazole) 1-piperidine carboxylate, 33 parts 2- (chloromethyl) pyridine hydrochloride, 43 parts sodium carbonate 0.1 parts iodide potassium and 630 hours M, .dimethylformamide is stirred and heated overnight at 70 ° C. The reaction mixture is cooled and poured into water. Extracted product:


Ruta 4-methyl 2-pentanone. The extract is dried, filtered and evaporated. Remains
0
five
the current is purified by chromatography on a column of silica gel using a mixture of tri-1 chloromethane and methanol (96: 4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-mityl-2-pentanone, 30 parts (40%) of ethyl 4- {Ј1-Ј (2-pyridinyl) methyl -1H-benzimidazol-2-yl amino -1-piperidinecarb oxate) are obtained. m.p. 161.5 ° C (intermediate 42).
 Similarly, receive intermediate products listed in table 5.
Example 8. A mixture of 50 h0 ethyl- (2-furanylmethyl) -311-imidazo-4,5-in-pyridin-2-yl-amino-1-lepiperidinecarboxylate, 50 h, potassium hydroxide, 400 parts of propanol 2 and 20 drops of water are stirred and boiled under reflux for 5 hours. The reaction mixture is evaporated and water is added to the residue. The product is extracted twice with 4-methyl-2-pentanonomo. The combined extracts are dried, filtered and evaporated. The solid residue is stirred into 1,1-oxybisethane; The product is filtered and dried, yield 34 hours "(85%) 3-Ј.- wagon nilmethyl -N- (4-peep epidinyl) -ZN0 imidase about -4,5-bj-pyridin-2-amine, so pl. 159.0 ° C (intermediate 48).
Similarly, receive intermediate products listed in table 6 „
five
0
ethyl
PRI me R-9. A mixture of 30 Ј1- (2-pyridinyl) methyl -1H-benzimy-dazol-2-yl-amino-1-piperidinecarboxyllate and 300 parts of a 40% aqueous solution of hydrobromic acid in water is stirred and heated for 3 hours at 80 ° WITH. The reaction mixture is evaporated and the residue is crystallized from methanol; o- (93.2%) trihydrobromide 5 N- (4-piperidinyl) -1- f (2-pyridinyl) - methyl -1H-benzimidazol-2-amine is obtained in 41 hours, t .pl. 295.9 CC (intermediate 54).
Similarly, receive intermediate products listed in Table 7 „
B. Obtaining target compounds.
Example Y. A mixture of 5.52 parts of 6- (2-bromoethyl) -3,7-dimetgote-5H-triazolo-p, 2-a pyrimidin-5-one monohydrobromide, 7.3 hours 1 - (4 fluorophenyl) - methyl} - N- (4-piperidinyl) - 1H-benzimidazol-2-amine dihydrobromide, b, b h sodium carbonate and 135 h M, gy-dime. tilformamide is stirred and heated
0
they are kept overnight at 70 ° C. The reaction mixture is poured into water. “The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a column of silica gel. using a mixture of trichloromethane and methanol (94: 6 by volume) saturated with ammonia as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile to give 5 hours (62.8%) b 2-V-flJ- (4-fluorophenyl) methyl -1H-benzimidazol-2-yl amino - 1-pipridine ethyl -3,7-dimethyl-5H-thiazo, 2-adlirimidin-5-one, t „pl. 141 / s (connection 1) „
Using the same procedure and using equivalent amounts of the corresponding raw materials, the compounds are listed in Table 80.
“PRI mme R 11. A mixture of 3.34 h. 3- (2 chloroethyl) -2-methyl-4H-pyrido Ј1, pyrimidin-4-one, 6 h. 3- (4-fluorophenide-methyl) ( 4-piperidinyl) -ZH-imidazole Ј4,5-in pyridin-2-amine dihydrochloride 4.8 parts of sodium carbonate, 0.1 parts of iodide and 135 hours K, M-dimethylformamide is stirred and heated all the new. at 70 C. The reaction mixture is poured
in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using a mixture of trichloromethane and methanol saturated with ammonia (96: 4 by
 volume) as eluent. Collect the pure fractions and evaporate the eluent. The residue is crystallized from acetonitrile; 4 parts (60%) of (4-fluorophenyl) methyl-3H-imidazo 4, 5-BJ pyridine-2-pcs amino -1-piperidine-ethyl} 2-methyl-4H-pyrido 1 are obtained. , 2-a pyrimidine-4-one-dihydrochloride, tt.t. 195.7 ° C (compound 18).
The compounds shown in Table 9 are prepared analogously.
Example 12. A mixture of 3.15 h „3- (2-chloroethyl) -2-methyl-4H-pyrido Јl, 2-a pyrimidin-4-one, 8.26 h. N- (4 piperidinyl) -1- (2 pyrazinylmethyl) -1I-benzimidazol-2-amine trihydrobromide, 6.4 parts of sodium carbonate, 0.1 h of potassium iodide and 90 parts of N, N-dimethylformamide are stirred and heated overnight at 80 ° C. The reaction mixture is poured into water. The product is extracted with grichloromethane. The extract is dried, filtered and evaporated. Residue clean chromium--
0
five
five
0
0
five
0
five
0
five
silica gel column chromatography using a mixture of trichloromethane and methanol saturated with ammonia (96: 4) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried, get 5 hours (67.4%) 2-methyl-3-p-4- | Tl- (2-pyraznilmetil-1H-benzimidazole-2 ip-amino-1-piperidinyl - this is J-4H-pyrido J, 2-aj pyrimidin-4-one, mp 204.4 ° C (compound 48) 0
The compounds shown in Table 10 are prepared analogously.
In a similar way also receive:
3-, 4- 1- (2-furanylmethyl) -1H-benzimidazol-2 wnj adano-1-daperidine-n ethyl ethyl 2,4 (1H, 3N) quinazolinedione, m.p. 194.3 ° C (compound 72);
3 2- 4- $ (2-furakilmetil) -1H-benzimidazole-2-units amino -1-piperidinyl e {ylZ-2,3-dihydro-1-methyl-2-thioxo-4 (1H) -quinazolinone m.p. 188.4 ° C (compound 73);
 1- (2-furanylmethyl) -1H-benzimidazole-2-HiiJaMHHoJ-1-piperidinyl, 3-dihydro-2-thioxo-4 (1H) quinazolinone, mp. 146.0 C (compound 74);
 (4-Fluorophenyl) methyl | -1 h-b Enzimidazol-2-ylD-amine-1 1-lipidinyl ethyl 3-methyl-zi-imidazo 4,5-b1 pyridin-2-amino, m.p. 202.0 ° C (compound 75).
Protection of rats against mortality caused by the connection 48/80.
Compound 48/80, a mixture of oligomers obtained by condensation of 4-methyroxy-N-methylbenzeneethanamine and formaldehyde, has been described as a potent agent for the release of histamine. Protection against the lethal circulatory collapse caused by 48/80 is a simple way to quantify the antihistamine activity of the tested compounds. In the experiment, male rats of the Wistar inbred line weighing 240-2S) were used. After fasting overnight, the rats were transferred to laboratory conditions (temperature 21 f 1 ° CV relative humidity 65 ± 5%).
Rats were injected subcutaneously or orally with the test compound or solvent (0.9% sodium chloride solution). After 1 h after treatment, the compound 48/80 was injected by intravenous injection. freshly dissolved in water
one
1116
at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight). In control experiments in which 250 solvent-treated animals injected a standard dose of 48/80, no more than 2.8% of the animals survived after 4 hours. Consequently, the number of survivors after 4 hours was considered as a criterion for the reliability of the protective effect of drug administration.
The value of the ED of the compounds of formula (I) is given in column 1 of table 11. The indicated values of EDsp are the values at which the test compounds protect 50% of the test animals from mortality from 48/80.
The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are also mopdagm antagonists of serotonin. The potency of the proposed compounds as serotonin antagonists is clearly proved by the results obtained in the following tests, which investigate the antagonistic activity of the proposed compounds by the effect on serotonin.
Antagonistic activity on the action of serotonin in testing for gastric damage.
A. Damage caused by 48/80.
Compound 48/80 (a mixture of oligomers obtained by the condensation of 4-methoxy-U-methylbenzeneethanamine and formaldehyde) is a powerful stimulator of vasoactive amines from endogenous, such as histamine and serotonin. Rats given injections of compound 48/80 show significant changes in blood flow in various vascular beds: ear and limb cyanosis occurs 5 minutes after the injection of the compound, the roof dies from shock after 30 minutes of shock and subsequent death can be avoided if the rats enter pre-classic H 1 antagonist.
However, the stimulating effect on the secretion of the stomach is not suppressed, so rats that have been given compound 48/80 and protected from an H 1 shock by an antagonist can show all signs of an intense activity of the gastric gland: a large autopsy shows a distended stomach with abnormal contents and coarse bright red spots on the shape of the whole mucous
0
five
0
064
25
D5
thirty
35
40
50
55
12
one corresponding to the sites of destruction of the gland. A number of well-known serotonin antagonists, such as, for example, methylacetate, cyproheptadine, cyanserin, mianserin, pymperone, spiperone, pisotyphene and methergoline, completely prevent cyanosis of the ears and limbs, as well as damage to the glandular surface of the stomach and abnormal expansion of the stomach.
B. Method: Males of the Wister inbred rats weighing 220–250 g starve all Night, water is obtained at will. Test compounds are administered orally as solutions or as a suspension in an aqueous medium. A control rat and a pure rat receive the test compound. An hour later, all rats were administered subcutaneously at a dose of 2.5 mg / kg (diphenylmethyl-T-piperazinylmethyl-1-methyl-1H-b enz imide zol-2-methanol. 2 hours after oral or subcutaneous administration of the test compound Compound 48/80 (freshly dissolved in water at a concentration of 0.25 mg / ml) was administered by intravenous injection to all rats (dose 1 mg / kg), with the exception of a pure rat.
Four hours after the intravenous injection of the 48/80 compound, the rats are decapitated and the stomach is removed. Then the stomachs are examined for expansion and contents (blood, liquid and food) and washed thoroughly. Macroscopic damage is estimated from 0 to +++, 0 corresponds to the complete absence of visible damage, and the highest score corresponds to reddish coarse spots covering more than half of the glandular surface.
Column 2 of Table 11 shows a series of compounds of formula (I) in doses (in mg / kg body weight) in which the expansion of the stomach and damage to the glandular surface of the stomach is completely absent in 50% of the test rat animals (EJlfo values).
The values of AU 5 for known compounds are listed in Table 12.
Values for the proposed compounds are given in Table 13.
U, - 0 values for known compounds are given in Table 14
Thus, the proposed method allows to obtain new compounds with higher antihistamine properties in comparison with the known ones.
formula of invention
The method of obtaining No.- (bicyclic terocyclo) -piperidinamines of formula
t-Y-AlK A4
nor-A $.
G U D where R,
CHN2p K6
YVS- A "R,
ten
where rvg
R7 Pharmaceutical Compounds
peridia
()
YVS- A "R,
2
where - bivalent radical:, -N CH-CH CH-,,
Rt is hydrogen, halo or hydroxyl;
RЈ is hydrogen or halo; p 1-4;
R is thienyl, furanyl, unsubstituted or substituted, by alkyl, pyridinyl, pyrazinyl, thiazolyl, phenyl or halophenyl; Alk - (-Sf-alkanediyl ;,
Y is -NH or is a simple bond; Het is a bicyclic system of the general formula
R.
I
OS
: V
flK
about
where X is oxygen or. sulfur;
R, i is hydrogen or C, - (C.-alkyl;
B, - CH SI-SI CH- or -N CH-NR4, where R4 is -C-C-alkyl, or by the general formula
(is)
neither
Eskikh in about
$.
D where R,
2p K6
VS- "R,
ten
2
where R is C-C-alkyl;
Br - CH CRA-CH CR6, -CH CK-CH7 (G7
-CH2CHR6-CH-CHR6,.-CHRg-CHj, -, -S- (CH2) 2-,
-S- (CHZ),
each independently hydrogen
or (-Sf-alkyl, R7 is C-alkyl or halo, a pharmaceutically acceptable acid addition salt or the stereochemically possible isomeric form thereof,
differing peridia of the general formula:
the fact that pinH ct
 HN
9nHz R
 A, R.
where n, R, K (, R2, ..., A .- have the indicated meanings, are alkylated with the compound of the general formula
Ket-Y-Alk-W,
where Het, Y, Alk have the indicated meanings; .
W is a leaving group, in an inert solvent, and if necessary, convert compounds of the general formula (I), where .Het is a radical of the general formula (1a), where X is sulfur, with hydrogen peroxide in a mixture (, 4 alkanol / water to the corresponding compound of general formula (I), where Het is a radical of general formula (1a), where X is oxygen, and then, if necessary, the compound of general formula (l), into a therapeutically active non-toxic acid addition salt, by treating the corresponding acid or vice versa, the acid addition salt is converted into the free base alkali and / or prepared stereochemically isomeric forms.
15
1694064
Rb-CHfHliAA,
1-a
G - CH-Zh.2 H,
CH, -CH, -0-C-Nr N-C-N 4
0
Ift
Table 1
Table 2
four
(base)
CHj-CHj-O-cXIX O
Dihydrochloride monohydrate.
, u CH-fR1 0 CHg-CHj-O-C-X v 2
about
Table4
Table3
 3 (base)
nineteen
YEN, -CH, - HOOK 1 2 H-fr
2-Furanyl- -N CH-CH CH- Same 202.4 methyl
20
Table
Table
2i169406422
Continued table. eight.
6, .1 SvA CH34-F Ctf 114-013.- —CH CH CH-CH CH — O — 241.1,
the knowledge
ABOUT
23
1694064
15
sixteen
4-Thiazolyl - CH CH-CH CH-OsH-167.1 Methane
2-Furanyl - N-CH-CH CH- Same 221.0
methyl
17
2-Furanyl-methyl
ъ-о ™ 1Ј
nineteen
2- burakyl-tCH SI-H: H CH-Osnovy metilivanie
20
4-h-С6114-СНЈ- -N CH-C1I CH-HЈ0
21
2-churanyl methyl
22
4-F-C H4-CII2-CH CH-CH CH-Base
J
Sh3 (CH2) g
2 Furanyl-methyl
24 Continued table. eight,
-N CH-CH CH- 219, 7
R,
Table9
238.4
251.6
-N CH-CH CH- Foundation
231.7.
115.1
-N CH-CH CH- To the same 186.4
(CH,) 2
32
33
34
(CH2) 2
2 Furanyl-3HC1
methyl
4-to-sbk4-sng-sn sn-sn snnyzs
2H20
2-Furanyl- -N CH-CH CH- Basically methyl

27
L940b4
28 Continuation of table. 9
2
n
I
ABOUT
.0
SNG) 2
2-Pyridinyl-N CH-CH CH
L
-O-in-lWS
-
A4
vC “3”
  -, 2-Furanyl - N CH-C1I CHG 2/2 methyl
ABOUT
32 Furanyl - N CH-CH CHr
CH2) 2
Y (CFch methyl
X mon
55
ABOUT
VPU, -H, (: H, - siici
2 2. 2N.O
I
IIZI
Base
240.2
AND
Table 10
218.3 140.6
251.6
: 0
ABOUT
Hsn.)
22
5-Methyl 2-Fur and Nilmethyl
Continued table. ten
-K CH-SI CH- -
Table 11
33
1694064Jb
Continued table.11
NEH-Ak-N
H (CH, X, 4F-CJLl ± y.
O - (CH -), - 4F-C.H, H g.
 - (СН2) 2- р-Sat ЧСЕГАг Table
0, 31 1.25 0.63
0.31
37
HN - (CH2) 2-4F-c6i: 40 (CK2) 2-4F-C6IJ4
 F
 -C1 SI-SI CH-Hay- 222,70,16
all
2- uranyl - SP C1 - SII C11 - M20 129., 10.08
methyl
CH,
12
A-V-C, lU-CHe- -CH CH-CH CH-3HC1 229,10,16
21IZ0
13
GT
.SN
Al-C -aV -K CH-CH CH-ZNS1 239,30,16
1694064
38 Continued table. one.
1.25 2.5
Table 13
nineteen
go
21
22
V
VKCH,),
R
1СН2) г
2-Furanil - SP JV-JV CH Osno-238,40,08
methylation
4-F-C6H4-CIIj- -N "CI1-CH CI1- HU0 251.60.16
HE
Y °
ZhSNG) g
2-Furanil - No. "SI CH" CH-Osno-231.7
methylation
ABOUT
, СН34-Е-С6Н, .- СНг the same 115.1
(SNg) 2
0.08 0.08
AX.CHj (CH7) 2
H
(SNg) 3
2- uranyl - K-CH-CH CH- -. 186.4
methyl
2-Furanyl- -CH CH-C11 CH-250.7 methyl

rW
T (HF
- 5 tCHib
H
(CH)
2 0 uranyl -CH SI-CH CH- 103.6
methyl
2-Furanyl - N CH-CII CH 234.0
methyl
about sn.
I 3

(CIS) 2
sn,
I l
.0
0. (CH,),
2 Furanyl-- € 11 CH-SI CH-Osno-217.4 methyl
2-Furanyl - N CH-CtI CH-same 195.0 methyl
29
sn,
I 3
IOG (sn, a)
 N CH-CH CH 2HC1 291,20,16
thirty
H
 . -N CH-CU CH-H20 236,10,16

0.08 0.08
0.04 0.16
0.04 0.04
0.08 0.02
41
31
No
Ln2) 2
4-К-С: еИ4-СН, - -М СН-СИ СН- 2ПС1 259.6
.SI,
(CH2) g
2-Furanyl - CI1 CH-CH CU- 3IIC1 211.2
methylZN O

xsn
kn
W0 "Well
Also
4-К-С6И4.-С11г- -CH CH-CH CI1-3IIC1 223.2
2-Furanyl-methyl
Also
-H (; n-cu ci Same
.
Basis 153.3
The same 153.8 153.8 1b3, 8
1694004
42 Continuation of table. 14,
0.04
0.16
0.08
3IIC1
Basis 153.3
The same 153.8 153.8 1b3, 8
0.08
0.16 0.16 0.16

权利要求:
Claims (4)
[1]
Claim
The method of obtaining Nr (bicyclic heterocyclo) -4 ^ -piperidinamines of the general formula
C _n H _2n R Het-Y-AlK-NON ^^ · '' (!) '* ⁴ R, I. _ * where -A <= A2-A ₃ = Af is a divalent radical: —CH = CH — SI = CH—, —N = CH — CH = CH—, —CH = N — CH = CH—, —CH = CH-N = CH-;
R _t is hydrogen, halogen or hydroxyl; .
R _z is hydrogen or halogen;
and
R
Aik y
Het i 1-4;
- thienyl, furanyl, unsubstituted or substituted by C _f —Of — alkyl, pyridinyl, pyrazinyl, thiazolyl, phenyl or halo phenyl;
- C (-C-alkanediyl ;, - - ^ 'H or a simple bond;
- a bicyclic system of the general formula o
- oxygen or 1 sulfur;
- hydrogen or C ₍ —Cф — alkyl;
- —CH = CH — CH = CH— or —N = C11-NR ₄ where X ^R 3 where R ₄ is C <—Cph-apkyl, or of the general formula
where R- is C ₄ -C ₄ -alkyl; .
- CH = CR ₆ -CH = CR ₆ , -CH = CH-CR ₇ = CH7 -CH ₉ CHR ₆ -CH -CHR _e , -CJU-CH _Z -Sr (CH _z ) where - each independently hydrogen or C, -C-alkyl,
R - C ₅ -C-alkyl or halogen, a pharmaceutically acceptable acid addition salt or a stereochemically possible isomeric form thereof, characterized in that piperidine of the general formula:
SNNGPN-O
- 'Ί. Where n, R, R (, R2, ~ A _f = A ₂ ~ A ^ = A f- have the indicated meanings, they are alkylated with a compound of the general formula
Het-Y-Alk-W, where Het, Y, Aik have the indicated meanings ;.
W is a leaving group in an inert solvent, and if necessary, compounds of the general formula (I) are converted, where .Het is a radical of the general formula (1a), where X is sulfur, with hydrogen peroxide in a C <-СФ alkanol / water mixture, into the corresponding a compound of general formula (I), where Het is a radical of general formula (1a), where X is oxygen, and then, if necessary, a compound of general formula (I) is added to a therapeutically active non-toxic acid addition salt, by treatment with an appropriate acid or vice versa, convert the acid addition salt to the free base with alkali and / or receive stereochemical iso— ₍ in measured forms.
Table 1
Intermediate product to ^{l' a}“ ^A 4 ~ ^a z- ^_a 3 ^_a 4 k Mp. ° C 2 2-furanyl -GH = CH-CH = CH- no ₂85.6 3 4-E-C ₆ Nf- CH = N / - 0 = / -CH = SI no ₂- 4 2-pyridine -N = CH-CH = CH- _Λno ₂ -113.6 . / nip 5 2-Thienyl -ns = sn-ss = sn- no ₂- 6 2-Thienyl -N = CH-CH = CH- no ₂- 7 3-furanyl -N = CH-CII = CH- no ₂- 8 5-Methyl — 2- furanyl -N = CH-CH = CH- no ₂
Table 2
V A ³
Intermediate product_R 1-a ~~ A A ^ A ^ A f Base T · pl · ° C eleven 2-furanyl -sn = sk-sn = sn- Base - 12 4-F-C ^ H ^ - -CH = CH-N = cn-163, 7 thirteen 4-F-C ^ - -CH = N-CH = CH- IIC1 208.5 14 2-Thienyl -sn = sn-sn = sn- Base - fifteen 2-furanyl -N = CH-CH = CH- - ⁿ - - 16 2-Thienyl -n = sn-sp = sn-- 17 3-furanyl -N = CH-CF = CF- - ⁿ ~. - 18 5 — Methyl — 2 — furanyl -N = CII-CH = CII--
Table 3
Intermediate product K < . ^{A _Α} ι r ^_A of 4 ^and° F ° C 1 e 3 4
² 1 2-Furanylmethyl -CH = CH-SI = SY-
22 4-FC ₆ H ₄ -CH ₂ - -CH = CH-N = CII-. 166.0
1 Ί
Continuation of Table J j
ί
23 4-FC ₆ H ₄ -CH ₂ . -UH = N-C11 = CH- - 24 2-pyridinylmethyl -N = CH-CH = CH- - 25 N -CH = CF-CE = CH- - 26 2-Thienylmethyl -CH = CH-CH = CH- - 27 2-Tie nylmethyl -N = CH-CH. = CH- - 28 Z-Furanylmethyl -N = Ch'-CH = CH- - 29th 5-Methyl-2-truck - nylmethyl -N = CH-CH = Cli-
33 2-Furanylmethyl N -sn = sn-cm = sn- 135.8 34 4-FC ₆ H _y -CH _zN -CH = Cn-N = Cll- - 35 * 4-FC ₆ H ₄ -CM _zN -CH = N-CH = CH- 168.6 36 2-Thienylmethyl N -sn = sn-sn = sn- 142.7 37 2-pyridinylmethyl ..and -N = CIi-CH = CII- 141.3 38 Η n -CH = CF-CF = CH-. 234.9 39 2-Thienylmethyl n -n = ch-cr = ch- -. 40 Z-Furanylmethyl n -N = CH-CH = CH- - 41 5-methyl-2-furanylmethyl n -N = CH-CH = CH-
Dihydrochloride Monohydrate
Table5
43 Z-pyridinyl H -CH = CH-CH = CII- 191.4 44 2-pyrazinyl li -CH = CH-CH = CH- 178.5- . I 179.3 45 4-FC _c H ₄H -CR = CE-CF = CR- 182.3 - 46 4-thiazolyl H -UP = CH-CH = SP- 156.2. 47 4-FC ₆ H ₊Chj. -CH = CH-CH = CII- -
Table!·
4 ^v . (base)
Intermediate productr ₂-A ₄ -A ₂ -A ₃ -Af- -] ------------I MpI ° C 49 2-Furanylmethyl AND -sn = sn-sn = sn- 211.0 fifty 2-Thienylmethyl. n -CH = CH-CII = CII-_ 51 2 — Thienylmethyl, n -N = CH-CH = CH- . - 52 3-fur anilmethyl n -n = 6h-ch = ch- * - 53 5-methyl-2-truck nylmethyl. n -N = CH-Cll = CH- -
Tables a7
CH -R ^1a
I ^L
Intermediate product R '* ^aAg — Hell A4 Base or salt T pl° C 55 Z-pyridinyl -sn = sn-sn = sn- ZNVg > 260 56 2-pyrazinyl. -sn = sn-sn = sn- ZNVg - 57 4-FC ₆ H <". -CH = CH-N = CH-. 2Nvg. '-279.4 58 2-iridinyl -N = CH-CH = CH- ZNVg. 265.5 59 4-F-CgH ^. -CH = N — CH = CH- 2Nvg ·· Hg.0 291.6 60 4-F-C5H4 —CH = CF — CF = CH- 2Nvg 210.6 61 4 — Thiazolyl -sn = sn-sn = sn- 2NVg-N _g 0 223.5
Connected Het A ₂ ~ Hell A ^ - Osno— Mp. singing waning ° C orsalt. 1 . 2. 34- 5 b
[2]
2-Furanyl- -SP = CH-CH = SI- Base 108.1 methylation
2-Furanyl- -N = CH — CH = CH- The same 202.4 methyl
Continuation of the table. 8. ~
Base 4-FC ₆ H ₄ -CH ₂ - -N = CU-CH “CH- 99.7
4Έ-Ο ₆ 1ί ₄ -ΟΗ _Ζ - -CH = CH-CH = CH- The same 222, 7 2-Furanylmethyl -SP = С11-С11 = СП- н ₂ о 129.1 2-Furanylmethyl -N = CII-CI1 = CH-waning 127.4 2-Furanylmethyl -SP = CH-SI "CH- The same 258.0
2-Furanylmethyl -C11 = CH-CH = CH-waning 107.4 2-Furanylmethyl -N = C11-C1I = CH- Also 161.2 4 — F-CgH ^ -CHg- CH = CH-SP = CH- ZNS1 2K _g 0 229.1 1 4-FC ₆ Hq-GU. - -N = CII-CH = CII- 3IIC1 239.3
4-B - С _£ 11 ₄ -СН _€ - -СИ = СН-СН = СН- Basis 241.1
Continuation of the table, 8,
44 Z
5 6
2-Furanyl- tСН = СП-СН = СН- Omni-methyl bath
4-1 <'- C ₆ AND ₄ -CH _g - -N = CH-C1I = CH- H _£ 0
238.4
251.6
2'-Furanyl-> methyl • No.СН-СН = СН0 with forging
4-FC _€ H ₄ -CII ₂ - -CH = CH-CH = CH- Base
2 ~ Furanyl — methyl — N = CH — CH = CH
231.7.
115.1
186.4
Continuation of the table. 9
I! 33
2-Furanyl— methyl
-sn = cn-cn = cn
2-Furanyl—methyl -CH = CH-CH = CH- The same
2-furanyl—.
—N = CH — CH = CII methyl
2-Furanyl— methyl
2-Furanyl—
Methyl —CH = CH — CH = CH—
-k = cn-cn = cn. -4-FC ₆ II ₄ -CII ₂ - —N = C11 — CH = CH— 21IC1
4-FC ₆ H ₄ -CH ₂ - -Y = CH-CH = CH- H ₂ ° 4-E-C _b N ₄ -SK ₂ - -N = CH-CH = CH- 2НС1
2-Furanyp— —CH = CH — C1! = CH— ZNS1 methyl sn O
4-rs _y n ₄ -0¾ - СН = СН-СП = СН-ЗНС1 ^2H Z °
2-Furanyl- —N = CI1-CH = CH-
250.7
103.6
234.0
217.4
195.00
291.2
236.1
259.6
211.2
223.2
153.8
A favor t abl. 9.
2 | E 4 5 6
2 — Thienyl— methyl -CH = CH-SI = CH- ^Base 2-Furanyl— -n = sn-sn = cn Also methyl
2 — Pyridinium — methyl
2 — Pyridinium — methyl
2-Furanyl— methyl
2 — Thienyl— methyl
4 - ^ - ^ 4- (¾
4 — F-CgH ^ —CHj
4-thiazolyl— methyl
-N = CH-CH = CH-CH = C11-CH = CH — N = CH — SP = CH— “
-cm = cn-si = cn-CH = CH-N = CH -N = CH-CH = CH-CH = СЯ-СН = СН219,4
175.6
207.3
193.8
208.4
214.0
230.5
166.0
158.8
2-Furanyl— —N = CH — CM = CH methyl
2 — Thiazolyl— —CH = CH — CH = CH— methyl. 2 — Pyridinium — —SP = CH — CH = CH— methyl
86.2
239.5
238.8
Continuation of the table
N CH
CM
2-Furanyl 'methyl
2-Furanylmethyl
2-Furanylmethyl
2-Furanylmethyl —N = CH — SP = CH— —N = GH-CII = CH
Foundation
Base • N = CH-CII = CH • N = CH-CH = CHr
218.3
140.6
4 — F — C ^ Hc, —CH ₂ -. —CH = N — SI = SP—
[3]
3IIC1
2H ₂ 0
251.6
Continuation of the table. 10
¢ 4! 3 4 5
2-Thienylmethyl
2 — Thienylmethyl
2-truck nylmethyl
5 — methyl — 3— furanyl
2-Thienyl— methyl
3-Furanylmethyl
5 — Methyl — 2 — furanylmethyl
2 — Thienylmethyl
2-Furanylmethyl
5-Methyl-2fur a nylmethyl
Base
243.4
-N = CH-CII = CH — N = 011-011 = 011— —N = CH — CH = OH
-N = CI1-CH = GH — N = CH-CH = CH — Ν = ΟΠ — SP = SP — N = CH — SP = CH—
-N = CH — CH = CH
-N = CH — CII = CH—
Same t
t
Table 11
Connected Column 1 Column 2 singing Mortality test from compound 48/80 in rats ED _I , mg / kg body weight Test for damage to the stomach ED _I , mg / kg body weight 1 0.08 0.63 2 0.16 - 2 0.16 0.04 18 0.16 - 21 0.08 - 3 0.08 0.63 4 0.04 0.31 1 0.31 0.63 5 0.16 0.63 6 0.08 0.17 7 0.08 0.16 22 0.08 - 8 0.08 0.04 9 0.16 0.31 23 0.04 0, 16 ' 24 0.16 - 25 0.04 0 26 0.04 - 75 0.04. 0.08 27 0.08 0.16 28 0.02 - 10 0.02 0.08 eleven 0.02 - eleven29th 0.16 - 12 0.16 0.31 thirty 0.16 - thirteen 0.16 - 31 0.04 - 32 0.16 - 33 0.08 - 74 0.16 - 14 0.31 0.63 73 0.08 0.31 34 0.08 - 72 0.08 - 69 0.08 0.04 68 0.16 - fifteen 0.08 0.01 49 0.16 - 70 • 0.16 - 67 0.16 • 0.63 fifty 0.31 0.63 71 0.08 - 48 0.08 -. 51 0,04 '  0.16 16 0.04 0.63 52, 0.01 -
Continuation of table 11
Connected Column 1 Column 2 nation Part Test— Pov test - i note from the connection birth is ¹48/80 on pipe ED _%rats ED _Img / kg weight mg / kg body weight body 53 0.08 • m 54 0.16 0.31 17 0.04 .. 0.63 55 0.16 ~ ' 35 0.31 . 1.25 36 0.31 - 37 0.08 0.16 38 0.16 39 0.04 0.63 40 0.08 0.31 42 0.04 0.31 43 0.04 0.63 44 0.08 0.63 56 0.16 0.63 45 0.08 0.31
CH <AG ’T a b l i c a 12
I 2
Het-X-AlK-NQ-NH- ^ J ^
Het X Aik  Ar Values of E ^, mg / kg, according to test 48/80 1 -2 34 . 5
- (snrg-0.31 -MU _r -. 4K-S ₆ And _D1.25 -4¾ - 4F-C ^ H ₄ - 0.63
n o
S
- (¾.
[4]
4E-C ₆ H40.31
Continuation of the table. 12
HN - (CH ₂ ) _Z - 4F-C ₆ I! ₄ ⁰ - < ^SK A- 4F-c ₆ ii ₄ 1.25
2,5
Table 13
Connected Het to, '-A, = L _r -L = A ₄ - Base or salt Mp.° C The value of ED _sa in the test 48/80, mg / kg
. 7
4-s- ₆ : 1 ₄ -sn _g - -CH = SP-SP = CH-waning 222.7 0.16 2-Furanylmethyl -C11 = SI-SP = C11- P ₂ 0 129., 1 0.08 2-Furanyl— methyl —N = Cl! —CII = CH—waning 127.4 0.08
2-Furanyl gCH = CH — CH = CH— Same 258.0 0.08 methyl
CH, ι ³
4-NC ₆ H ₄ -ClI ₂ - -K = CH-SP = SP-2! 1C1 n _z o 196.1 . 0.16 2 — Furanyl— -CH = CH-SP = CH- Osn- 107.4. 0.02 methyl waning
2-Furanyl— -M "CH-CH = CH- To’zhe 161.2 0.02 methyl
4-FC.II ₄ rCH _e - —CH = CH — Clf = CH— 3HC1 229.1
21I ₂ C
G 16
4-1 '' ~ C _in K, -SP _c - -N = CH-CH = CH- 3HC1 239.3 0.16
Table 14
Compound L^R < -A, = A _g -A _e = A ₄ - Base * bath or> salt Mp. ° C In the test, 48/80 IU $ ^ mg / kg 1 2 3 4 . 5 6 7
-sp "sn-sp" sn238.4
0.08
0.16
251.6
N = CI1 — CH = CP ′ ft = CH-Cll = CH2-31.7
0.08
0.08 —CH = CH — CH = CI1—
115.1
Same n ₂ 0
Base
Base
2-Furanylmethyl
2-Furanyl methyl ^ ί-ΟθΗψ-ΟΗ ^
-.27
2-Furanylmethyl —№CH — CH = CH— . 186.4 2-Furanyl -CH = CH-C11 = CH 250.7 methyl
2-Furanylmethyl -si-sy-sn-sn-  103.6 2-Furanylmethyl -№ CH-SI = CH 234.0
2-Furani-methyl -CH = CH-CH = CH- Basis - 217.4 bath 2-Furanyl -N = CH-Cll = CH- Same 195.0 methyl
4-E ^ C ^ H ₄ -CH _g - —N = CH — CH = CH— 2I1C1 291.2 4-FC ₆ H ₄ - ^: -CIl ₁ - . -N = CH — CH = CH— n ₂ about 236.1
0.04
0.16
0.04
0.04
0.08 '0.02
0.16
0.16
Continuation of the table. 14
31 SN sn, SGT * Lsn ₂ ) ₂32 qV ' ¹ 0 ²²2-Furanylmethyl
—N = CH — CH = CH— 2I1C1 259.6 0 04 —SP = CH — CH = SI— 3iid 211.2 0 16
sign ₂ about
334-U-C ₆ Ηψ-SI BL SN 34 sd 2-Furanyl Q ^ 2¼ methyl 70 Also' Also 5541
-sp = sn-si = sp- 3IIC1 2I _and 0 223.2 0.08 -H = C1! -CH = C11- Base 153.3 0.08 Also Also 153.8 0.16 - m ¹¹ ". 153.8 0.16153.8 0.16

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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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US55674283A| true| 1983-11-30|1983-11-30|

---