Method for producing n-heterocyclic-4-piperidineamines or pharmaceutically acceptable salts thereof

专利摘要:
Novel N-(bicyclic heterocyclyl)-4-piperidinamines of the formula the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, which compounds are useful as anti-allergic agents; pharmaceutical compositions containing such compounds as an active ingredient; methods of preparing said compounds and pharmaceutical compositions; new intermediates, used in the preparation of said compounds, which are themselves useful as anti-allergic agents and pharmaceutical compositions containing the latter as active ingredients.
公开号:SU1297728A3
申请号:SU833608869
申请日:1983-06-27
公开日:1987-03-15
发明作者:Эдвард Жанссенс Франс；Лео Гисланус Торреманс Юзеф；Францис Хенс Юзеф；Тересиа Йоанес Мария Ван Оффенверт Теофилус
申请人:Жанссен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

R. ,, - 1., Y and n decree; above, combining Gob1 |; her dioi) i-- yjii-i -C „H ,, where the winters M and m are indicated above, W is halogen, and with VJ it is the lowest alkoxy group, in the environment of a reactive, oppoinert solvent. The invention relates to organic chemistry, in particular to a method for producing HO3i: .X Hg heteronyl-L; -C; U p1 G {ln-; 11pg ..) 1 .; obp s-- yurmu.py I
Compounds 1 are administered in free or in the form of a pharmaceutically acceptable salt. Studies of compounds 1 show that they exhibit antihistamine activity in d, oz 0.1-1-100, better 1-50 mg / day d. 8 tabl,
2
where or 1;
, 1, 2.3 or A;
Y is a bond, an ohm oxygen, yes, sepa, a group-COO-, -SCILT--,
H-1
HI N.
 one
rm
R is hydrogen, g; .- C, -alkyl, neza-MemeHHLiii iian for; -; e of the most common (non-, or odyuzamscheyn) halogen, C; With -alkyl or With, -C. cox11 group), iiridilone, 2-giirazi saw, tienshyum, furanyl (unsubstituted or monosubstituted alkl), thiazolyl or 3 (tilimidazolshum);
K „is hydrogen, or - benzyl;
L - glad, ikal-N (2 niridinyl) peridinyl, nesme, ssn: th or mono-- in the ring the irgschina chloro - or nitro rune,
or L is a radical

(N
or L is a radical of the formula
 f..V. V
 -,, ---, (
a. iKiiJi, islsl, an;; g-i.15 Oepzsn; ;
Gett is a sixth member; hegerotion - chesky Ko. ibjp with o / ijiiiM or D1; with nitrogen atoms in 1 c: c, 1I2. associated with n, e- and e, C) 1. according to aTONpy of carbon, n substituted, single or double halogen, oxy-, am1L1O- or pitroprivoy, C-C, -alkyl, C -C - alkoxy,
a ip okarbonI, rI, benzyl, halo: 1dza. benzyl 11LI. (halo dzamepenny benzyl) amine ogruipo1 1, or condensed with a benzene ring, or their pharmaceutically acceptable salts, which can be used as hygistagcip X drugs and drugs possessing their serotonin a.tagonist - with; and. for the treatment of allergic diseases.
Preparation of intermediate compounds.
Preparation: trichlorohydra.ta (2 aminoethyl) -4-Sh1peridinyl -1 - - C (4-fluorofensh1) methylJ-IN-benzimidazole-2-amine; trichlorohydrate-N 1 monohydrate - (3 aminopropyl) -4-niperidi-- (4-fluorophenyl) methyl-P1-benzyl shdazol-2-amine; - (4-fluorophenyl) me- - (phenylmethyl) amino-ethyl-4-piperidinyl -1P-benzimidazole 2-α-amine; (2-xnop-ethyl) -4-piperidiyl -1- (4-fluorophenyl) methyl -1H-benzimidazol-2-amine dihydrochloride.
Example 1. a. A mixture of 15.7 parts. 1 - chlorine - 2-nitrobenzene, 9.7 hours, 2-furanmethanamine, 8.4 parts of acid sodium carbonate, and 45 parts. first night from
0
five
120 C. The reaction mixture is cooled,
water is introduced, the resulting product is extracted with 1,1-oxybisethane. Dry extract1,1t, filtered. And evaporated. The residue after evaporation shchip; ayut in
a chromatographic column filled with ammonia is hydrogenated under normal pressure and at room temperature using 4 parts of catalyst palladium on charcoal (10%). After absorbing the calculated amount of hydrogen, the catalyst is filtered and the filtrate is evaporated, resulting in half a half, 50 5 h, (95%) N - -H (5-methyl-2-furanyl) methylJ-1,2-benzenediamine as a residual product
NOx silica gel using trichloromethane as eluent. Pure fractions are collected and the eluent is evaporated. The residual oil is mixed with petroleum zfir. The product fo is filtered and dried, resulting in 15 hours obtained. N- (2-nitrophenyl) -2 -2-furanmethanamine with mp, 85.6 C
(intermediate 1).
6. A mixture of 40 parts of 5-methyl-2-furanme-J5 evaporation (intermediate tetanamine, 46 parts of 1-chloro-2 nitrobenzene 8). la and 210 hours K, M-diethylethanamine is stirred and heated under reflux for 2 days. The reaction mixture is evaporated, water is added and 20% extracigated dichloromethane.
The extract is dried, filtered and evaporated. The evaporation residue is purified by filtration.
Osu1death process in the same way get
N - (4-fluorophenyl) methyl-3,4-pyridinediamine with m.p. 163.7 ° C (intermediate 9);
monohydrochloride N - (4fluorophenyl) - -methyl-3,4 pyridine sc with m.p. 208.9 ° C (intermediate 10), passed through silica gel, using 25 - (2-pyridinyl ietyl) -2,3-pyr-trichloromethane as eluent. Fildinediamine, m.p. 134, (the residue is evaporated, resulting in a precise compound 11); 62 parts (89%) of 5-methyl-M- (2-nit-K- (3-furanylmethyl) -1,2-benzenediprophenyl) -2-furanmethane are obtained as ostamine as residual product (evaporation (intermediate compound 12); num 2) .N - (2-thienylmethyl) -1,2-benzoldi. A mixture of 50 parts of 2-chloro-3-nitropyridine, 32.5 parts of 2-cyridinemethanamine, 53 parts of sodium carbonate and 675 parts of N, N-dimethylacetamide is stirred to form diamine as a residual product (run 1 h at 100 ° C. The reaction mixture is cooled and filtered by passing it through Hyflo.
amine as a residue (intermediate 13);
N - (2-furanylmethyl) -2,3-pyridine intermediate compound 14);
L- (2-furanylmethyl) -1,2-benzenediamine amine as a residue (intermediate 15); 40 - (4-fluorophenyl) methyl-4-methoxy-1,2-benzenediamine as residual
The filtrate is poured into 1000 parts of water and the whole mixture is stirred overnight at room temperature. The resulting product is filtered and dried. As a result, 56.4 h are obtained.
tanamine with a melting point of 13.6 ° C (intermediate 3),
Carrying out the process in the same way as described in p. In, receive:
H- (3-nitro-2-pyridinyl) -2-pyridine - 45 8.7 parts of N- (4-fluorophenyl) methyl-4-nitro-3-pyridinamine, -oxide, and 150 h, trichloromethane added 10.2 parts of phosphorus trichloride in 75 parts of trichloromethane are dripped. After stopping the N- (4-fluorophenyl) methyl-4-nitro-3-50 of this addition, the mixture is brought to -pyridinamine, 2-oxide (intermediate to KOhfflaTHoA temperature and stirred compound 4); for I. h
2-nitro-H- (2-thienylmethyl) benzene at reflux temperature, amine (intermediate 5); The reaction mixture is cooled and the plant is N- (2-nitrophenyl) -3-furanmethanamine 55. The solvent is evaporated. The residue is stirred in trichloromethane. The resulting product is filtered and dried (intermediate 6);
4-fluoro-N- (5-methoxy-2-nitrophenyl) benzenemethanamine (intermediate compound 7).
sew, resulting in a gain of 9 hours of monohydrochloride N- (4-fluorophenyl)
EXAMPLE 2 A mixture of 62 parts of 5-methyl-N- (2-nitrophenyl) -2-fluoromethanamine, 2 parts of a solution of thiophene in methanol (4%), 400 parts of methanol, saturated monohydrochloride N - (4 fluorophenyl) - -methyl -3,4 pyridine sc with so pl. 208.9 ° C (intermediate compound 10 - (2-pyridinyl, ie, methyl) -2,3-pyridine diamine, with mp 134, (intermediate compound 11); K- (3-furanylmethyl) -1, 2-benzenediamine as residual product (intermediate compound 12); N - (2-thienylmethyl) -1,2-benzenediamine as residual product (intermediate compound 13);
N - (2-furanylmethyl) -2,3-pyridinediamine as residual product (pro-
interconnect 14);
L- (2-furanylmethyl) -1,2-benzenediamine amine as a residue (intermediate 15); - (4-fluorophenyl) methyl-4-methoxy-1,2-benzenediamine as residual
product (intermediate 16), I
Example 3. To the stirred and cooled (to 0 ° C) solution
sew, resulting in a gain of 9 hours of monohydrochloride N- (4-fluorophenyl)
5 1297728 6
methyl-4-nitro-3-pyridinamine (promethyl-4; 2- (2-pyridine)
comical connection P P
-17).
and measure 4. A mixture of 3 parts of 2,3-pyridinediamine and 4 parts of 1- (chloromethyl) -4-fluorobenzene is stirred overnight at. Trichloromethane and a dilute solution of hydroxide EMNiOHHH are introduced and the product is extracted. The organic phase is washed with water, dried, filtered and evaporated. The evaporation residue is purified by passing through a chromatographic column filled with silica gel using a mixture of trichloromethane and methanol (e.g. o6beMiOM ratio 90:10) as eluent. The second fraction is collected, the eluent is evaporated, resulting in 1.8 h N - (4-fluorophenyl) methyl -2,3-pyridine diamine as a residue (intermediate 18).
EXAMPLE 5 A mixture of 54 hours, ethyl-4-isothiocyanate-1-piperidinecarboxylate, 48 hours, N- (2-furanylmethyl) -2,3-β-pyridinediamine and 450 parts of tetrahydrofuran are mixed. and heated to reflux. The reaction mixture is evaporated and the evaporation residue is crystallized from a mixture of 2-propanone with 2,2-oxibibopropane. The product is filtered and dried, resulting in 76 parts (75%) of ethyl 4- 2- (2-furanylmethyl) amino-3-pyridinyl-amino-6-methyl 6-amino-1-piperidinecarboxyl with t, mp, 132,7 ° C (intermediate compound 19),
Carrying out the process in a similar way, also receive:
ethyl 4- 2- (2-furanylmethyl) amino-phenyl aminomethoxomethyl amino -1 -1 -1-piperidenecarboxylate as a residue (intermediate 20);
ethyl 4- 3- (4-fluorophenyl) methyl amino -2-pyridinyl aminothioxomethyl amino-piperidinecarboxylate as a residue (intermediate 21);
ethyl 4-4- (4-fluorophenyl) methyl amino2 3-pyridinyl aminothioxomethylt amino -1-piperidinecarboxylate, t, mp, (intermediate compound 22);
amino-3-pyridinyl aminothioxoeth amino 1-piperidinecarboxylate as a final product (intermediate c
5 dining 24);
ethyl 4- 2- (2-thienkmethyl) amphenyl-aminothioxomethyl} amino -1 peridinecarboxylate as a residue (intermediate compound
10 ethyl 4- 2- (3-furansh1methyl) a but} phenyl aminothioxomethylamino-piperidinecarboxylate as a residue (intermediate 26);
f5 ethyl 4-G 2- (5-methyl-2-furan methyl amino;) phenyl aminothioxomethylamino-β-piperidinecarboxylate as a residual product (intermediate dilation 27);
20 ethyl 4- 2- (4-methoxyphenyl) methyl amino (hetinn amino acid to amino acid; amino - piperidinecarboxylate as a residue (intermediate 28);
25 methyl-4-1- (4-fluorophen-1-sh) methi-6-methoxy-H-benzimidazol-2-yl a but - - -piperidinecarboxylate (intermediate compound 29), I
PRI me R 6. A mixture of 42.5 hours, e 4- (phenylmethyl) amino - -piperidine carboxylate, 30 hours, β-isothiocyan-2-nitrobenzene and 270 hours, tetragofuran was stirred for 3 at KONfflaTHOu tet- terature, B mixture
35, 2,2-oxybiopropane is added and the stirring is continued for a time. The precipitated product is filtered and dried, resulting in 48.5 h, (68.5%) of methyl 4-2-nitro-nemino-thioxomethyl (phenylmethyl-amino - -piperidinecarboxylate with mp. 40 ° С (intermediate 30),
thirty
40
45 Example7, Mix 48.5 h,
ethyl 4-gg (2-nitrophenyl) amino-isomethyl (phenylmethyl) a1 gyno-pi-pyridinecarboxylate and 600 h, methane saturated with ammonia, hydrogenate n
50 at a normal pressure and at 30 ° C using 15 parts of the catalyst (palladium on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered,
(3- (4-fluorophenyl) methyl 55 start it through Hyflo, and the filtrate
amino-4-pyridinyl aminothioxomethyl amino -1-piperidinecarboxylate as residual product (intermediate 23);
evaporated, resulting in 47 hours, (00% yield) ethyl 4- - G (2-aminophenyl) amino thioxomethyl (phenylmethyl) amino - - piperacine carbo
ethyl 4 2- (2-pyridinylmethyl)
amino-3-pyridinyl aminothioxomethyl amino 1-piperidinecarboxylate as a residue (intermediate 24);
ethyl 4- 2- (2-thienkmethyl) amino-phenyl-amino-thioxomethyl} amino -1-piperidinecarboxylate as residual, product (intermediate 25),
ethyl 4- 2- (3-furansh1metil) amino} phenyl aminothioxomethylamino 1-piperidinecarboxylate as a residue (intermediate 26);
ethyl 4-g 2- (5-methyl-2-furanyl) methyl amino;) phenyl aminothioxomethyl amino - piperidinecarboxylate as a residue (intermediate 27);
ethyl 4- 2- (4-methoxyphenyl) methyl amino (hetinn amino acid to methyl omethyl amino - piperidinecarboxylate as a residue (intermediate 28);
Ztil-4- 1 - (4-fluorophen-1-sh) methyl-6-methoxy-H-benzimidazol-2-yl amino - -piperidinecarboxylate (intermediate 29), I
EXAMPLE 6 A mixture of 42.5 hours, ethyl 4- (phenylmethyl) amino - -piperidine-carboxylate, 30 hours, -isothiocyanate-2-nitrobenzene and 270 hours, tetrahydrofuran is stirred for 3 h with KONfflaTHOu tetra-teratura, In the mixture
2,2-oxybiopropane was added and stirring continued overnight. The precipitated product is filtered and dried, resulting in 48.5 hours, (68.5%) of methyl 4-2-nitrophenyl amino thioxomethyl (phenylmethyl) amino-β-piperidinecarboxylate with m.p. 40 ° C (intermediate compound 30),
45 Example7, Mix 48.5 h,
ethyl 4-gg (2-nitrophenyl) amino thioxomethyl (phenylmethyl) a1 gyno-piperidinecarboxylate and 600 h, methanol, saturated with ammonia, is hydrogenated at
50 at normal pressure and at 30 ° C using 15 parts of catalyst (10%) palladium on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered, evaporated, resulting in 47 hours, (00% yield) ethyl 4- - G (2-aminophenyl) amino thioxomethyl (phenylmethyl) amino - -piperac carboxylate as a residual evaporation product intermediate 3 i
I .I
Example A mixture of 74 parts of ethyl- -4-f 2- (2-phenylmethyl) amino-3-pyridine amino aminomethyl aminoJ -1 - piperidinecarboxylate, 96 parts of mercuric oxide (divalent), 0.1 parts of sulfur and 800 hours. the ethanol is stirred and heated under reflux for 3 hours. The reaction mixture is filtered, passed through Hyflo and the filtrate is evaporated. The residue after evaporation crystallizes from aceto
nitrile, in
resulting in getting
stirred and heated for a week at. This reaction mixture is cooled and poured into water.
20
52.5 parts (70% yield) ethyl-4- 3- (2-fu-) The resulting product was twice extraranylmethyl) -ZH-imidazo 4,5-b pyridine-2-yl-amino} -1-piperidinecarboxylate from m.p. 149.2 ° C (intermediate 32).
By performing the process in the same manner, the following compounds were also prepared:
ethyl 4- 1- (2-furanylmethyl) -1H- -benzimidazol-2-yl amino 1-piperidinecarboxylate, m.p. 135.8 ° C (intermediate 33);
ethyl 4-1- (4-fluorophenyl) methyl -1 -1H-imidazo 4,5-b pyridin-2-yl amino -1-piperidinecarboxylate, m.p.
25
212.5 ° C (intermediate 34). 30 connections:
are treated with methylbenzene. The combined extracts are dried, futted and evaporated. The residue after evaporation crystallizes from a mixture of 2-propanone with 2,2-oxybispropane. The product is filtered and dried, whereby 1 3.4 parts (62.1%) of ethyl 4-5 (6) -fluoro-1 - (4-fluorophenylmethyl) -1H-benzimidazol-2-yl amino -1- piperidinecarboxylate, so pl. 182.5t (intermediate 43).
Having carried out the process in a similar way, the following are also obtained.
ethyl 4- 1- (4-fluorophenyl) methyl -1 -1H-imidazo 4,5-c pyridin-2-yl amino -1-piperidinecarboxylate, hydrochloride monohydrate (intermediate 35);
ethyl 4- 3- (4-fluorophenyl) methyl-β-ZK-imidazo 4,5-c pyridin-2-yl. amino -1-piperidinecarboxylate, dihydrochloride monohydrate, m.p. 168.6 ° C (intermediate 36);
ethyl 4- 3- (2-pyridinylmethyl) -ZH- -imidazo 4,5-b pyridin-2-yl amino -1 -1 piperidinecarboxylate, m.p. 141.3 ° C (intermediate 37)
ethyl 4- 1- (2-thienylmethyl) -1H- -benzimidazol-2-yl amino-piperidinecarboxylate, m.p. .142.7 ° C (intermediate 38);
ethyl 4- - (3-furanylmethyl) -1H- -benzimidazol-2-yl amino-J-1-piperidinecarboxylate, m.p. 150.7 ° C (intermediate 39);
ethyl 4 1- (5-methyl-2-furanyl) methyl J -1 -H-benzimidazol-2-yl amino} -1 - piperidinecarboxylate, hemihydrate, so pl. 150.1 ° C (intermediate 40); I
ethyl 4- 1- (4-methoxyphenyl) methyl -1 1 -benzimidazol-2-yl-amino - |
five
77288
piperidinecarboxylate, m.p., 157, (intermediate, compound 41);
ethyl 4- (1H-benzimidazol-2-yl) (phenylmethyl) amine -1-piperidinecarboxylate (intermediate 42).
PRI me R 9. A mixture of 15.03 parts of ethyl 4- (5-fluoro-1H-benzigadazol-2-yl-amino) -piperidinecarboxylate, 9 parts 1- (chloromethyl) -4-fluorobenzene, 5.3 parts of sodium carbonate, 0.2 parts of potassium iodide and 117 parts of H, N-dimethylformamide
ten
stirred and heated for a week at. This reaction mixture is cooled and poured into water.
The resulting product is twice extra-
are treated with methylbenzene. The combined extracts are dried, futted and evaporated. The residue after evaporation crystallizes from a mixture of 2-propanone with 2,2-oxybispropane. The product was filtered and dried, whereby 1 3.4 parts (62.1%) of ethyl 4-5 (6) -fluoro-1 - (4-fluorophenylmethyl) -1H-benzimidazol-2-yl amino were obtained. -1- piperidinecarboxylate, so pl. 182.5t (intermediate 43).
Having carried out the process in a similar manner, the following are also obtained.
ethyl 4-fl- (2-pyridinyl) methyl - - 1H-benzim1-dazol-2-yl amino - 1-piperidinecarboxylate, m.p. 1 6 1, 5 C (intermediate compound 44); ethyl 4- - (3-pyridinylmethyl) -1H- -benzimidazol-2-yl amino -1-piperiynylcarboxylate, i.e. 191.4 ° C (intermediate 45);
ethyl 4- 1- (2-pyrazinylmethyl) -1H-benzimidazol-2-yl amino -1-piperidinecarboxylate, hydromhydrate monohydrate, m.p. 178, 3 C (intermediate 46);
ethyl 4- - (4-thiazolylmethyl) -1H- -benzimidazol-2-yl amino -1-piperidinecarboxylate, dibromo-hydrate monohydrate; m.p. I78.5-179.3 ° C (intermediate 46);
ethyl 4-l- (4-thiazolylmethyl) -1H-benzimidazol-2-yl amino} -1-piperidinecarboxylate, m.p. 156.2 ° C (intermediate 47);
ethyl 4- I- (4-fluorophenyl) methyl-1-1H-benzimidazol-2-yl-methylmethylamino-1-piperidinecarboxylate as a residue (intermediate 48);
ethyl 4-t Cl - (5-methyl-1H-imidazol-4-yl) methyl -1H-benzimidazol-2-yl
amino - piperidinecarboxylate, dichloride idrat, m.p. 233.7 C (intermediate compound 49).
PRI me R 10. A mixture of 50 hours ethyl- -A- 3- (2-furanylmethyl) -ZH-imidazo
A, 5 β1-pyridin-2-yl amino -1-piperidinecarboxylate, 50 parts of potassium hydroxide, 400 hours of 2-propanol and 20 drops. stir and heat under reflux for 5 hours. The reaction mixture is evaporated and water is added to the evaporation residue. The product is extracted twice with 4-metsh-2-pentanone. The combined extracts are dried, filtered and scrubbed. The solid residue is stirred in 1,1-oxybisbisethane. This product is filtered and dried, resulting in 34 parts (85%) of 3- (2-furanylmethyl) -M- (4-piperidinyl) -ZH-imidazo 4,5-b pyridine-2-amine5 t .pl. 159.0 ° C (intermediate compound 50) ..
Carried out the process in the same way, get:
1 - (2-furanylmethyl) -M- (4-piperidinyl) -1H-benzimidazol-2-amine, m.p. 211.0 C (intermediate compound 51
N- (4-piperidsh-1yl) -1- (2-thienylmethyl) -1Y-benzimidazol-2-amine (intermediate compound 52);
1- (3-furanylmethyl) -M- (4 piperidine-1) 1I-benzimidazol-2-amine (intermediate 53);
1 -C (5-methyl-2-furanyl) methylJ-N- - (4-piperidinyl) -1H-benzimidazole-2- -amine as an residue (intermediate 54);
1 - (4-methoxyphenyl) methylJ-N- (4-piperidinyl) -H-benzimidazol-2-amine m.p. 78.1 C (intermediate compound 55);
1- (4-fluorophenyl) methyl-5-methoxy- -N- (4-piperidine 1-w) -1H-benzimide-azole--2-amine (intermediate 56 1- (4-fluorophenyl) methyl -H- methyl-L- - (4-pyperidinyl) -1H-benzi1-1 Idazole-2-α-ytin, monohydrate, dihydrochloride, mp 222.2 ° C (interm. 57);
1- (4-fluorophenyl) methyl-6-methoxy--N- (4-piperidinyl) -1H-benzimidazol-2-amnn (intermediate compound.The compound 58 N (phenylmethyl) -K- (4 piperidinyl) -1.5 beximidazole-2-amine (intermediate compound 59).
Example 11. A mixture of 30 h, ethyl- (2-pyridinyl) methyl -1H-benzimidazol-2-yl: amino -1-piperidinylcarboxylate and 300 h. 48% aqueous solution of hydrobromic acid is stirred and heated for 3 hours at 80 ° C. The reaction mixture is evaporated, the evaporation residue is crystallized from methanol, resulting in 41 parts (93.2% yield) of N- (4-piperidinyl) -l- (2-pyridinyl) methyl -1H-benzimidazol-2-0. -amine, tribromhydrate, so pl. 295.9 ° C (intermediate compound 60),
By performing the process in the same manner, the following compounds were also prepared:
5 N- (4-piperidinyl) -1 - (3-pyridinyl-methyl) -.1 H-benzimidazol-2-amine, tribrobromide, m.p. 260 ° C (intermediate 61);
N- (4-piperidinyl) -1- (2-pyrazinyl-0 methyl) - H-benzimidazol-2-amine, tribromohydrate (intermediate compound 62);
1 - (4 fluorophenyl) mett lI-N- (4-piperidinyl) - 1P-imidazo 4,5-L1 pyridine-5 -2-amine, dibromohydrate, etc. 300.6 ° C (intermediate 63);
1-G (4-fluorophenyl) methyl-N (4-piperidinyl) -1 H-imidazo 4, 5-c pyridine-2-aM iH, dibromohydrate, m.p. 279.4 ° C 0 (intermediate 64);
N- (4-piperidinyl) 3- (2-pyridinyl-methyl) -ZN-imidazo 4,5-ЗZpyridin-2- -amine, tribromhydrate, m.p. 265.5 ° C (intermediate compound 65); 5 (4-fluorophenyl) methyl -Y- (4-piperidinyl) -ZN-imidazo 4, 5-c pyridine-2- -amine, dibromohydrate monohydrate, so pl. 291.6 ° C (Intermediate 66);
0 N- (4-piperidinyl) -1- (4-thiazolylmethyl) - H-benzimidazol-2-amine, dibromohydrate monohydrate, mp, 223.5 ° C (Intermediate 67);
1 E (5-methyl-III-n-schazol-4-yl) methyl 45 -Y- (4-piperidipyl) -H-benzimidazol-2-amine, tribromhydrate, m.p. 272.1 ° C (intermediate compound 68).
Example 12. K2h. thiophene in 40 parts of ethanol was added 15 parts of ethyl- 50 -4-oxo-1-piperidinecarboxylate, 25 parts of 1- (4-fluorophenylmethyl) -N- (4-pyperidinyl) -lH-benzimidazol-2- amine and 200 parts of methanol. The entire mixture is hydrogenated at normal pressure and at room temperature using 5 parts of catalyst (5%) gshatin on charcoal. After uptake of the calculated amount of hydrogen, the catalyst is filtered, the filtrate is evaporated. Residual 11
The evaporation product is purified by passing through a chromatographic column filled with silica gel using a mixture of three chloromethane and methanol (in a volume ratio of 90:10) as eluent. Pure fractions are collected and the eluent is evaporated. The evaporation residue is converted to the hydrochloride salt in 2-propanol and 2-propanone. The salt is filtered and dried, resulting in 13.6 parts of dihydrochloride - (4-fluorophenylmethyl) -1H-benzimide sol-2-yl-amino - 1, 4-bipiperidine - -1-carboxylate monohydrate, mp. 260 ° C (intermediate compound 69).
A mixture of 25 parts of 1- (phenylmethyl) -3-piperidininone hydrochloride, 55 parts of 1 -C (4-fluorophenyl) methyl J- -K- (4-piperidinium.n) -1H-benzimidazole- 2-amine, 1 part of a solution of thiophene in ethanol (4%), 50 parts of potassium agate and 500 parts of 2-methoxyethanol are hydrogenated at normal pressure and at 50 ° C using 5 parts of catalyst (10%) palladium on wood coal After the calculated amount of hydrogen was taken up, the catalyst was filtered and the filtrate was evaporated. The residual product is evaporated, dissolved in water and the mixture is made alkaline with sodium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue was evaporated twice with cristoplication from acetonitrile. The resulting product is filtered and dried, resulting in 9.75 h of 1- (4- -fluoroLenyl) metsh1 -H- (G-phenylmethyl), 3-bipiperidin-4-yl -1H-benzimidazol-2-amine, t .pl. 174.6 ° C
(intermediate 70). I. .
Example 13. A mixture of 21 hours ethyl 4-C1 - (4-fluorophenylmethyl) -1H-benzimidazol-2-yl-amino 1,4-bipiperidine -1-carboxylate and 450 parts of a 48% aqueous solution of hydrobromic acid stirred and heated under reflux for 16h. This reaction mixture is evaporated. The free base is separated from the residual product by a conventional method using an aqueous solution of sodium hydroxide, extracted with dichloromethane. The extract is dried and evaporated, resulting in 8 hours (yield 50%) - (4-fluorophenylmethyl) t-1H-benzimidazol--2-ylZ-11,4-bipiperidin-4-amine as
9772812
residual product evaporation (intermediate 71).
Example 14. A mixture of 11.3 parts of 1- - (4-fluorophenyl) methyl -K- | 1 - (feng метил methyl-1,3-bipiperidin-4-yl -1H-benzimidazol-2-amine and 200 parts of methanol is hydrogenated at normal pressure and at room temperature using 2 parts of catalyst 10 (10%), palladium on charcoal.
After the calculated amount of hydrogen was taken up, the catalyst was filtered and the filtrate was evaporated. The evaporation residue is suspended in
15 2,2-oxibispropane. The product is filtered and dried, resulting in 8.5 parts (91.5%) of N- (1,3-β-biperidin-4-yl) -1-f (4-fluorophenylmethyl-H-benzimidazol-2 -amine (interstitial compound 72).
Example 15. A mixture of 2.7 parts of 2- chloroacetonitrile, 19.5 parts of H- (4-piperidinyl) tribromhydrate (3-pyridinylmethyl) - H-benzimidazole-2-amine,
25 13 parts of sodium carbonate and 135 parts of N, N-dimethylformamide are stirred and heated for 3 hours at 50 ° C. The reaction mixture is poured into water and extracted with dichloromethane. The extract is dried, filtered and evaporated. The evaporation residue is crystallized from acetonitrile, whereby 6 hours (50% yield) of 4- 1- (3-pyridinylmethyl) -1H-benzimidazol-2-yl-amino--1-piperidineacetonitrile are obtained. hemihydrate, so pl. 204.5 ° C (intermediate 73).
35
Carried out the process in a similar way and using equivalent
40 quantities of the corresponding starting materials are also listed in table. I connection
Carrying out the process in the same way, (cis-trans) is obtained (145 - (4-fluorophenylmethyl -1H-benzimide-ZOL-2-IL-amino-3-methyl-1-piperidine-acetonitrile, mp 150.1 ° С (intermediate compound 100).
Example 16. K mixed
50 mixtures of 3.14 parts of 3-furancarboxylic acid, 6 parts of N, K-dimethyl ethane are added 1.2 parts of 2-chloro-1-methylpyridine iodide. After stirring for 10 minutes at room temperature, 7 hours are added.
55 4- (1-benzimidazol-2-yl) aminoZ-1-pyperidine-tetonitrile, the whole mixture is stirred for 1 h at room temperature. The reaction mixture is washed with water. The organic phase is dried, fertilized and implanted. The evaporation residue crystallizes from acetonitrile to give 7 hours, (74% yield) (3-furanylcarbonyl) -1 -1H-benzimidazol-2-ylZamino -1-pyperidine acetonitrile (intermediate 101).
PRI me R 17. A mixture of 17h. (2-pyridinylmethyl) -ZH-them, 4,5-L-pyridin-2-yl-amino-β-piperidine acetonitrile and 400 parts of methanol, saturated with ammonia, are hydrogenated under normal pressure and at room temperature using 3 hours of catalyst based on nickel wounded. After the calculated amount of hydrogen was taken up, the catalyst was filtered and the filtrate was evaporated. The evaporation residue crystallizes from acetonitrile, resulting in 15 parts (90% yield) of (2-α-amino-ethyl) -4-piperidinyl-3- (2-pyrididylmethyl) -ZH-imidazo 4,5-L1 pyridine. -2-amine, so pl. 151.1 ° C (intermediate 102).
Carrying out the process in the same way and using the appropriate starting materials, the compounds listed in Table 2 are obtained 2
35
40
Carrying out the process in a similar manner, one obtains tax (cis + trans) - (2-aminoethyl) -3-methyl-4-piperidinyl -1- (4-fluorophenyl) methyl} - I-benzimidazole-2-amine, t. pp 132.2 ° C (intermediate compound 128).
Example 18. In 180 parts of tetrahydrofuran, 2.4 parts li-were carefully added. in the atmosphere of nitrogen. Then a solution of 7 parts of (3-fluoroalkylbonyl) -lH-benzimidazol-2-yl amine-1-piperidine acetoetonyl-propyl in tetrahydrofuran is added in a tetrahydrofuran: the temperature rises to. After this addition is complete, stirring is continued overnight at reflux temperature. The reaction mixture is then cooled in an ice bath, then it decomposes as a result of the sequential addition of 3 hours, water, 9 parts of a 15% sodium hydroxide solution and 9 parts of water. The whole mixture is filtered, passes through Hyflo, and the filtrate is evaporated. The evaporation residue is filtered, 55 passes through silica gel, using as eluent a mixture of trichloromethane and methanol (volume ratio 80:20), sat.;
Q
45
50
ammonia. Pure fractions are collected and the eluent is evaporated. The evaporation residue was crystallized from acetonitrile, which resulted in 3.6 parts (2-aminoethi1) -4-piperidinyl -1H-benzimidazole-2-amine (yield 69.5%), m.p. 99.8 ° C (intermediate 129).
PRI me R 19. A mixture of 9.25 parts of 1- -chloro-2-propanone, 48.6 parts of dibromohydrate 1- (4-fluorophenylmethyl) -K- (4-piperidinyl) -1H -benzimidazole-2-amine, 32 parts of sodium carbonate and 135 parts of N, N-dimethylformamide are stirred and heated overnight at. Then this reaction mixture is poured into water, and the product is extracted with 4-methyl -2 -2-pentanone. The extract is dried, filtered and evaporated. The evaporation residue crystallizes from 4-methyl-2-pentanone, resulting in 15 hours, (39.5% yield) of (4-fluorophenyl) methyl -1H-benzimidazol-2-yl amino -1-piperidinyl- -2-propanone (intermediate compound 130).
A mixture of 5.7 parts of (4-fluorophenyl) methyl-1H-benzimidazol-2-yl amino-1-piperidine 1-2-propacone, 2.1 h.
Hydroxylamine hydrochloride Q, 20 parts of pyridine, 10 parts of ethanol and 12.5 parts of water are mixed for 3 hours at 65 ° C. The reaction mixture is then vlive0
five
35
40
55
The mixture is alkalified with sodium hydroxide. Product
filtered and dried, resulting in 5.5 parts (93% yield) of okrim I C (4-fluorophenyl) methyl -1 -1 H-bepzimidazol-2-yl 1-amino-1-piperidinyl 2-propanone, t .pl. 202 ° C (intermediate compound 131).
A mixture of 4 parts of the oxime (4- -fluorophenyl) methyl -1H-benzimidazol-, -2-yl -1 -piperidinyl-2-propano45 for and 120 parts of methanol, saturated with ammonia, is hydrogenated at normal pressure and at room temperature using 2 parts of the catalyst based on Rane nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered and the filtrate was evaporated. The evaporation residue is crystallized from acetonitrile, which results in 1.3 hours (34% yield) of K- (1- (2-aminopropyl-1) -4-piperidinyl -1- (4-fluorophenyl) methyl -1 N- benzimidazole-2-ag.1Ina, m.p. G78, (intermediate compound 132).
15.
P p and m ep 20. A mixture of 5.4 parts of etyp (2-chloroethyl) carbamate, 19 parts of monohydrate of N- (4-piperidinyl) tribromhydrate (4-thiazolylmethyl) -1H-benzimidazol-2- amine, 15 parts sodium carbonate, 0.2 parts sodium iodide and 90 hours. The N, N-dimethyl acetamide was stirred at 75 ° C overnight. Water was added and the product was extracted with 4-methyl -2-pentanone. The extract is dried, filtered and evaporated, resulting in 14 hours of ethyl 2-4-l- - (4-thiazolylmethyl) -H-benzimidazol-2-yl amino -1-piperidinyl ethyl carbamate in the form of an oily residual product (intermediate compound 133).
A mixture of 14 parts (4-thiazolylmethyl) -1 H-benzimidazol-2-yl j amino-β-piperidinyl methyl carbamate and 300 hours. The 48% aqueous solution of hydrobromic acid is stirred and heated under reflux for 30 minutes. The reaction mixture is evaporated. The sticky evaporation residue is left out in a mixture of ethanol and acetonitrile. The product is filtered and dried, resulting in 14 parts of tribromhydrate, - (2-aminoethyl) -4-piperidinyl -1- (4-thiazolylmethyl) -1H-benzimidazol-2-amine (intermediate 1 34).
Example 21. To 1h. a solution containing 2 parts of thiophene in 40 parts of ethanol was added 11.3 parts of 1- (4-fluoro-phenylmethyl) -H-1 2- (phenylmethyl) amino-ethyl-4-piperidinyl-1H-benzimidazole -2-amine, 2 h. paraformaldehyde, 10 parts of potassium acetate and 120 h. methanol. The whole mixture is hydrogenated at normal pressure and at room temperature using 2 hours; a catalyst (10%) of platinum on charcoal. After the calculated amount of hydrogen has been absorbed by the catalyst, the mash is filtered, it is passed through Hyflo and the filtrate is evaporated, resulting in 9.4 parts of 1- (4-α-fluorophenyl) methyl -N-1-2-methyl (phenylmethyl) amino ethyl -4-piperidine -1H-benzimidazol-2-amine as a evaporation residue (compound 135).
A mixture of 9.4 parts of 1- (4-fluorophenyl) methyl-N-1-2-methyl (phenylmethyl) amino ethyl -4-piperidine 1 -1H-benzimidazol-2-amine and 120 parts of methanol is hydrogenated at normal pressure and at
9772816
Koshshtnoy TeNmepaType using 2 h, catalyst (10%) palladium on charcoal. After the NIN is consumed, the calculated amount of hydrogen is filtered and the filtrate is evaporated. The residual evaporation product is converted to its trichlorohydrate salt in 2-propanol. This salt is filtered and dried, resulting in a yield of 6.3 parts (64% yield) of 1-C (4-fluorophenyl) me- (methylamino) ethyl -4-pyrididinyl -1H-benzimidazole trichloride hydrate 2-amine, m.p. 232.4 ° C (intermediate connection 136).
Example 22. For I h through a stirred mixture consisting of 6 parts of 1- (2-furanylmethyl) -H- (4-piperidinyl) -1Y-benzimidazole-2-amine and
20 40 parts of methanol, gaseous ethylene oxide is passed in the whole bubbles. Stirring is continued for 3 hours at room temperature. The reaction mixture is then evaporated, and the volatile residue of evaporation is reduced to the salt of (E) -2-butandioate in ethanol and 2-propanol. This salt is filtered and suctioned, in the reagent of which 6.5 parts are obtained. Monohydra3Q and 4-1- (2-furan1-shmethyl) -1H-benzimidazol-2-yl amino-i-piperidinylethanol ( E) butanedioate (2: 3), so pl. 183, (intermediate compound 137), - (4-fluoro-enylmethyl) -1 -H-benzimidazol--2-ylamino-1-piperidineethanol, m.p. 138, 7 ° C (intermediate. Compound 1 38) Example 23. A mixture of 7, .5 h. - (2-aminoethyl) -4-piperidinyl -1- (4. „-Methoxyphenyl) methyl - P-benzimidazole- 2-amine and 225 parts of a 48% aqueous solution of hydrobromic acid are stirred and heated for a week. After cooling out
., the precipitate the product is filtered and dried, resulting in a yield of 7.3, h. (yield 57%) tribromhydrin: 1 - (2-aminostil) -4-piperidinyl amino-1H-benzimidazole-1-sh: methyl phenol monohydrate, so pl. 250 ° C
35
50
exact connection 139).
EXAMPLE 24 A mixture of 12 parts of N- (2-aminoethyl) -4-piperidinyl -1- - (4-fluorofensch1) methyl-5-methoxy-1H-55-benzimidazol-2-amine and 150 hours The 40% aqueous solution of hydrobromic acid is stirred and heated for 48 hours at 80 ° C. The reaction mixture is then evaporated, and os17
The final evaporation product is suspended in 2-propol. This product is filtered and dried, resulting in 18.5 hours, (yield 95.7%) of monohydrate 2- 1- (2-α-amino-ethyl) 4 piperidipyl | -amino -1 -1 (4-ft o rf of peel) I get Tyl-1H-b e n 3 and mid a-zol-3-ol, mp, 250 ° С (intermediate compound 40),
Example 25. To a mixture of chilled and cooled (10 ° C) mixtures of 5.04 parts of carbon disulfide, 2.06 hours,, H - methane-tetraylbis (cyclohexanamine) and 45 parts of tetrahydrofuran are added dropwise a solution of 3.7 hours . - (2-aminoethyl) -4-p: iperid: P-n-1 - (4- -foprophenylmethyl) -lH benzy eddazo, p-2-- -amine in tetrahydrofuran. After the Bepme HiiH of this addition, the stirring continues during the first night and at the same time the sub, ep; -; There is one room sperypa in the mix. Then the reaction mixture is evaporated, the residual product is evaporated; 4-1 I will be cleaned, passing through a chromatographic column filled with a sl-gel. with t-tc-use as an eluent a mixture of trichloromethane and methanol (in a total ratio of 98: 2). The pure fraction is collected and the eluent is extracted, resulting in 4 hours (yield 1 00%) 1 - (4-fluorophenyl methyl) -N 1.1 - - (2-isothiocyanatoethyl) -4 Pigleridi-nyl 1H-benzi shdazol -2-amyp as an evaporation residue (intermediate 141),
Similarly, the following compounds are prepared:
I - (2-furanylmethyl) - M- AND - (2-iso:: and: o cyanoetch1) -4-piperidrnn-sh -1I - benz-imindazol-2-amine (intermediate / short with; 2) 142);
  (4 fluorophenyl) methyl j-N- (1 - (2- - iso thiocyanato ethyl) -4-piperidinyl - - 1 H-imidazo 4, 5b pyridin-2-amine as a evaporation residue (intermediate 143);
(2-nzothiodianatoethyl) 4-pyperidinyl - 3 (2-pyridip and im. Til) - ZI
| t
,. (iridin-2-am1-p {.. intermediate compound 144);
3- (4-fluorophenyl) methyl | --M ™ 1- (2- -isothiocyanatoeth. L) -4-piperidinyl-imidazo 455-bZiridin-2-amine as a evaporation product (intermediate compound 145),
Preparation of the final compounds. EXAMPLE 26. First method.
297728 18
S. 1,14 h, 2-hlo) 1pp1 eimidine, 3.7 h. N- (2 Am1: noe p-l) -4-nineridi- (4 fluorophenylmethyl) -1H-beisimindazol-2-amine5 1.06 parts of carbonate
five
0
sodium, Ujl h, potassium iodide and 1 ee h., K-d1 methyl form; 1mda nere; watered and heated during 70.degree. C., the reaction mixture was poured into water, and the product was extracted with 4-methyl-2-pept - non. Extract v.shutyvayut, filtered and vypriyvayut. The evaporation residue is purified by passing it through a chromatographic column filled with silica gel, using trichloromethane and methanol (in a volume ratio of 96: 4), saturated with ammonia, as a solvent. Pure facacies are collected} and the eluent is evaporated. The residue of the digestion crystallizes from acetonitrile, resulting in 1.5 hours (34%) of 1- (4fluorophenyl) methyl -Y- 1 (2-pyrimidinyl) amino ethyl -4- .piperidipyl -1 -I-And- bepzim1-dazol-2-s 5 ia, so pl. 168.4 ° C (compound 1),
The second way. A mixture of 34.5 parts of 2-chloro pry DgPIa5 PO h, (2-amino-ethyl) -4-piper11DIN1-1L -1 - (4-fluorophene) n) methyl-1 - benzimidazol-2- ag-ina, 25 hours of oxygen, sodium carbonate, and 1200 hours of distilled agitation and heating. reflux overnight. The regakpion mix is given and filtered, passing through Hyflo. The filtrate is evaporated. The residual product of evaporation is determined by the method of liquid chro - atot-raf1-p1 of high concentration using sil1-psagel. and smssn of trichloromethane with methanol (volume ratio 95: 5), saturated with .a1; ohm, as SJHO-peppe. The pure fractions are collected and the eluent evaporated. C) Cl-evaporating atom crystallizes from acetonitrile and jiy4a OT 82 parts (61% yield) - (4-fluorophenyl) methi. - 2 (2 pirk: midin) amino-ethyl-4-piperidipyl -1H-benzimidazol-2-amine, mp, 168.4 ° C (compound).
0
0
five
50
55
Carried out npoi ecc as described in method 1 and using equivalent amounts of starting materials, the compounds shown in table 3 are obtained.
Carrying out the processes in the same manner as described in method 1, the following compounds are obtained:
3- (4-fluorophenyl) methyl -N- 1-1.2- - (2-pyridinyl) amino ethyl -4-pipefO
f5
Ridinyl-ZN-imidazo 4, 5-b pyr1schin-2- -amin, t, pl. 181, (compound 23);
2- 2-C4- 3- (4-fluorophenyl) methyl-β-3H-imidazo 4,3-b pyridin-2-yl amino -1 -1-piperidinyl ethyl amino-3-pyridine carboxamide, m.p. 205, (compound 24);
j (4-fluorophenyl) methyl-N-l-2-- (2-pyrimidinyl) amino-ethyl-4-piperidinyl - H-imidazo 4,5-b pyridine-2-amino, m.p. 165, (compound 25);
1-C4-fluorophenyl) methyl -N- - (2-pyridinyl) amino ethyl -4-piperidinyl -1H-imidazo 4,5-c pyridin-2- -amin, m.p. 203.1 ° C (compound 26);
3- (2-pyridinylmethyl) (2-pyrimidinyl) amino ethyl -4-piperidine-1-ZI-imidazo 4,5-b1-pyridin-2-amine (E) butandioate (2: 3), mp. 181.2 ° C (compound 27);
3- (2-furanylmethyl) (2-pyrimidinylamino) ethyl-4-piperidinyl i -ZH-imidazo 4,5-b3 pyridin-2-amine, m.p. 139.9 ° C (compound 28);
3- (4-fluorophenyl) methyl-N-1- 2- (2-pyrimidinyl) amino ethyl-4-piperidinyl-3H-imidazo 4,5-c pyridine-2- -amine (E) -2- butendioate (1: 2), so pl. 198, O ° C (compound 29);
3- (5-chloro-2-pyridinyl) amino-propyl-4-piperidinyl-1-L (4-fluorophenyl) methyl -1H-benzimidazol-2-amine trichlorohydrate monohydrate, m.p. 196.5 ° C (compound 30);
6-chloro-K-2- 4-C 1- (4-fluorophenyl) methyl -1 H-benzimide az ol-2-yl amino - -1-piperidinyl ethyl-4,5-pyrimidine diamine, mp. 216.7 C (compound 31),
8-chloro-y-2-4-C- (4-fluorophenyl) methyl -1H-benzimndazol-2-yl amino -1 -1-piperidinyl ethyl 3-phthalazinamine -2 -2-propanolate (1: 1), t. square 139.7 ° C (compound 32).
Example 27. Carried out the process as described in method I of the example, from in methanol, saturated with ammonia.
tetrahydrofuran at this temperature. After stopping this addition, the temperature in the mixture is slowly dated to room temperature and stirring is continued overnight at room temperature. The precipitated product is filtered and the filtrate is evaporated. The evaporation product is purified by passing it through a chromatographic column filled with gel or gel using a mixture of trichloromethane and methanol (in a 90:10 volume ratio) saturated with ammonia as eluent. Pure fractions are collected and the eluent is evaporated. The residual product is converted to the hydrochloride salt in 2-propanol. This salt is filtered, dried and as a result 1.7 parts of N-1-t2- (2-chloro-4-pyrimidinyl) amino ethyl-4-pi-pyridinyl - - (4-fluorofensh1) -methyl-1H monohydrate monohydrate are obtained. -be imidazole-2-amine, so pl. 287.4 ° C (compound 60). Carrying out the procedure in the same way, the following compounds are obtained:
 (2-chloro-6-methyl-4-pyrimidinyl) amino ethyl -4-piperidinyl - -1 - (4-fluorophenyl) methyl -1 H-benzimy-dazol-2-amine, mp. 124.4 ° C (Comp. 61);
N-C1 - 2-. (4-chloro-6-methyl-2-pyrimidinyl) amino ethyl -4-piperidinyl - (4-fluorophenyl) methyl - H-benzimidazole-2-amine, m.p. 151.9 ° C. (compound 62).
 And p and me R 29. A mixture of 3.4 h. 6-chloro-3-nitro-3-pyridinamine, 7.4 h (2-aminoethyl) -4-piperidinyl -1 40 (4-fluorophenyl) methyl - 1H-benzimidazole-2-amine and 10 h. 1-methyl-2-pyrrolidinone is stirred and heated for 2 hours at 150 C. Then the reaction mixture is cooled and the solution
20
25
thirty
35
.
26 and using K, L-dimethylacetamide as a solvent, the compounds are prepared, in Table. four.
Carrying out the process in the same way, the compounds listed in Table 2 are obtained five.
PRI me R 28. A mixture of 3.7 parts of N- (2-aminoethyl) -4-piperidinyl -1- - (4-fluorophenyl1methyl) - H-benzimidazol-2-amine, 1 h. K, Ы -diethylethanamine and 45 parts of tetrahydrofuran are stirred at -20 ° C and a solution of 1.5 hours is added dropwise to it. 2,4-dichloropyrimidine in
The whole mixture is evaporated and water is added to the evaporation residue. The resulting product is extracted three times with 4-methyl-2-penta.
5Q non. The combined extracts are dried, filtered and embedded in a vacuum. The evaporation residue is purified by passing it through a chromate graphic column filled with sy
 using a mixture of trichloromethane and methanol (in a volume ratio of 95: 5) as eluent. Pure fractions are collected and the eluent is evaporated. Residual product evaporation
O
five
, from in methanol, saturated with ammonia.
tetrahydrofuran at this temperature. After stopping this addition, the temperature in the mixture is slowly brought to room temperature and stirring is continued overnight at room temperature. The precipitated product is filtered and the filtrate is evaporated. The evaporation residue is purified by passing it through a chromatographic column filled with nickel, using as eluent a mixture of trichloromethane and methanol (in a volume ratio of 90:10) saturated with ammonia. Pure fractions are collected and evaporated. The residual product is converted to the hydrochloride salt in 2-propanol. This salt is filtered, dried, and 1.7 parts of N-1-t2- (2-chloro-4-pyrimidinyl) amino ethyl-4-pyperidinyl - - (4-fluorofensh1) -methyl- monohydrate monohydrate are obtained. 1H-benzimidazole-2-amine, m.p. 287.4 ° C (compound 60). Carrying out the process in the same way, the following compounds are obtained:
 (2-chloro-6-methyl-4-pyrimidinyl) amino ethyl -4-piperidinyl - -1 - (4-fluorophenyl) methyl -1 H-benzimy-dazol-2-amine, mp. 124.4 ° C (compound 61);
N-C1 - 2-. (4-chloro-6-methyl-2-pyrimidinyl) amino ethyl -4-piperidinyl 1 - - (4-fluorophenyl) methyl - H-benzimidazole-2-amine, m. square 151.9 ° C. (compound 62).
 And p and me R 29. A mixture of 3.4 hours of 6-chloro-3-nitro-3-pyridinamine, 7.4 parts of (2-aminoethyl) -4-piperidinyl -1-0 (4-fluorophenyl) methyl -1H-benzimidazole-2-amine and 10h. 1-methyl-2-pyrrolidinone is stirred and heated for 2 hours at 150 C. Then the reaction mixture is cooled and solution 0
five
0
five
.
All of this mixture is evaporated, and water is added to the residue, the exact product of evaporation. The resulting product was extracted three times with 4-methyl-2-penta5Q non. The combined extracts are dried, filtered and embedded in a vacuum. The evaporation residue is purified by passing it through a chromatographic column filled with silica gel, using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. Residual product evaporation
211297728-22
crystallized from 4-methyl-2-penta-1H-benzimidazol-2-ami 1 (E) butenioate
non, get 5 hours (yield 50%) N - (1: 2), mp, 173.9 ° C (compound 72),
 1 (4-fluorophenyl) methyl -1H-4C 2-1 C2- (2-pyrimidinylimino)
-benzimidazol-2-yl amino 1-pineridi-ethylZ 4-nineridinyl amino -1 H-benzyl ethyl-3-nitro-2,6-pyridinediamine imidazol-1-yl methyl phenol, e.g. mp, 205.7 ° C (compound 63).
PRI me R 30. A mixture of 1.7 h. 2-chloro-pyridine, 9.66 parts of tribromo-hydrate - (2-aminostil) -4-piperidinyl with lmino-l- (4-fluorophenyl) methyl -. fO -amine, m.p. 200.1 ° C (compound 74) ;, -1H-benzimidazol-5-ol, 5 parts acidic 1- (4-fluorophenyl) methyl -H-methyl-N- 1 2- (2-pyrimidinylamino) -piperidinyl -1H -benzimidazole-2-amine, so pl. 101.3 ° C (compound 75); 15K- (phenylmethyl) -M-C1- 2- (2-pyrimidinylamino) ethyl-4-piperidinyl - -1H-benzimidazol-2-amine, m.p. 207, Gs (compound 76).
230.8 ° C (compound 73);
1 -C4-fluorophenip) methyl-6-methoxy- (2-pyrimidinylamino) -4-piperidinyl -1H-benzimidazole-225
sodium carbonate and 80 parts of ethanol are stirred and heated under reflux overnight. Reakldona mixture is evaporated, and the rest
the exact product of evaporation 5 is dissolved in chloromethane. The organic phase is washed with water, dried,
Filter and evaporate. Residual „„,, g ,, ,,
Example 31. 5.5 h. 4-Ll- (4- the evaporation product crystallizes 20G,
, -fluorophenylmethyl) 1H-benzimidazole-2- from a mixture of acetonitrile and methanol,
resulting in a gain of 5.2 hours, (yield 83%) 1- (4-fluorophenyl) methyl - (2-pyrimidinylamino) -4-piperidinylZ amino -1H-benimide- .. sol-5-ol, so pl. 194.4 ° C (compound 64). I.
By carrying out a process similar to 1M, the following compounds are also prepared:
l- (phenylmethyl) (2-pyrimidinyl) amino ethyl -4-piperidinyl - -1H-benzimidazol-2-amine, m.p., 188.3 ° C (compound 65);
1-methyl-N-O-C2- (2-pyrimidinyl) amino 3 ethyl -4 piperidinyl -1 H-benzimidazol-2-amine, hemihydrate, m.p. 20.9 ° C (compound 66);
1- (4-methylphenyl) methyl-K--1-2- (2-pyrimidinyl) amino ethyl-4-pyrididinyl -1 H-benzimidaz ol-2-amine, mp. 123.6 ° C (compound 67);
1- (4-chlorophenyl) methyl -K- 1- 2- - (2-pyrimidinylamino) ethyl | -4-piperi 30
 -lamino-1-piperidine zanol and 135 hours of N, N-dimethylformamide was adjusted to room temperature and 0.75 parts of the 50% sodium hydride dispersion was added to the mixture. After stirring for 1 hour at room temperature, 2.5 hours of 2-chloroquinoline was added to the mixture and the mixture was stirred overnight at room temperature. The reaction mixture is poured into water, and the resulting product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residual product evaporated crystallizes from acetonitrile, resulting in 4.3 hours, (yield 58%) -H (4-fluorophenyl) -methyl} -Y-1- 2- (2-quinol-1-oxy) ethyl 4-piperidinyl - 1H-Benzimide 40 sol-2-amine5 mp, 149.9 ° C (compound 77).
Carrying out the process in a similar way, also receive:
dinyl -1H-benzimidazol-2-amine5 m.p. 45 N-Ll- 2- (5-bromo-2-pyridine) ok137, 8 ° C (compound 68)
1 - 1 (4-methoxyphenyl) methyl (2-pyrimidinylamino) ethyl-4-pyrididinyl - H-benzimidazol-2-amine, m.p. 160, (compound 69);
(2-Pyrimidinylamino) -4-piperidinyl -1H-benzimidazol-2s ethyl -4-piperidinylJ-1 - (2-furanyl-methyl) - H-benzimidazol-2-amine, t, pl. 160, 5 ° С (compound 78);
1- (4-fluorophenyl) methyl-N- - 2 - 50 (methylthio) -4-pyrimidinyl oxy ethyl-4-piperidinyl -1H-benzimidazole-2-amine, m.p. 120.6 ° C (compound amine, mp. 208.6 ° C (compound 70); reduction 79);
1 - (4-fluorophenyl) methyl 3-5-methoxy-1- (4-fluorophenyl) methyl-M-1-2-N-I- 2- (2-pyrimidinylamino) ethyl - 55 - (3-methyl-2- quinoxalinyl) oxy ztil-4-piperine scinil-lH-benzimidazol-2--4-piperidinyl -1H-benzimidazole-2-a№1H, so pl. 160.7 ° C (compound 71); - gmin, so pl. 168, (compound 80);
N- 1 - 2- (2-pyrimidinylamino) methyl-1-C (4-fluorophenyl) methyl -N- - 2-4-11 Iperidinyl -1 - (4-thiazopylmethyl) - pyrimidinyloxy ethyl-4-piperidiethyl 3-nineridinyl amino -1H-benzimidazol-1-yl methyl phenol, t.s.
-amin, m.p. 200.1 ° C (compound 74); 1- (4-fluorophenyl) methyl -N-methyl230, 8 ° C (compound 73);
1 -C4-fluorophenip) methyl-6-methoxy- (2-pyrimidinylamino) -4-piperidinyl -1H-benzimidazole-25
, -fluorophenylmethyl) 1H-benzimidazole-2-
0
 -lamino-1-piperidine zanol and 135 hours of N, N-dimethylformamide was adjusted to room temperature and 0.75 parts of the 50% sodium hydride dispersion was added to the mixture. After stirring for 1 hour at room temperature, 2.5 hours of 2-chloroquinoline was added to the mixture and the mixture was stirred overnight at room temperature. The reaction mixture is poured into water, and the resulting product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residual product evaporated crystallizes from acetonitrile, resulting in 4.3 hours, (yield 58%) -H (4-fluorophenyl) -methyl} -Y-1- 2- (2-quinol-1-oxy) ethyl 4-piperidinyl - 1H-benzimide-2-amine5 mp, 149.9 ° C (compound 77).
Carrying out the process in a similar way, also receive:
45 N-Ll- 2- (5-bromo-2-pyridine) oxy ethyl-4-piperidinylJ-1 - (2-furanyl-methyl) - H-benzimidazol-2-amine, t, pl. 160, 5 ° С (compound 78);
1- (4-fluorophenyl) methyl-N- - 2 - 50 (methylthio) -4-pyrimidinyl oxy ethyl-4-piperidinyl -1H-benzimidazole-2-amine, m.p. 120.6 ° C (compound 23129772824
Nile - H-benzimidazol-2-amine, m.p., - (1H) -pyrimidinone, m.p. 134.5 ° C; 133.8 ° C (compound 81); (compound 89);
  C (5-bromo-2-pyridinyl) o - - (4-fluoro-phenyl) methyl-Si ethyl-4-piperidinyl - - (4-fluoro-1H-6-benzimidazol-2-yl amino - -piphenyl) methyl -1H-6enzimidazol-2-amine, ridinyl ethyl amino-6-methyl-4- (H) - mp, 161.5 ° C (compound 82); pyrimidinone, tnl. 143.6 ° C (com (1-2-furanylmethyl) (2-90).
rimidinyloxy) ethyl-4-piperidinyl - Example 33, Mixture of 1.12 parts of 2-1 H-benzimidazol-2-amine (E) butandioate-pyrimidine thiol, 4.6 parts of dichlorohydra- (1: 2), mp 180.4 ° C (compound 83); W ta (2-chloroethyl) -4-piperidinyl} 1- (4-fluorophenyl) methyl-N-1- 2- (2- -1- (4-fluorophenylmethyl) -1H-benzimide- -pyridinylmethyl) methyl -4- piperidisol-2-amine, 4 parts of potassium carbonate and kil} -1H-benzimidazol-2-amine (E) -2-bu-80 h, 2-propanone is stirred in tendioate (1: 2), t , pl. 162 ° C (compounds of 3 days at room temperature 84) ./ 5 re.
PRI me R 32, Mixture 2.7 h, 5- The reaction mixture was filtered and - (4-fluorophenyl) methyl -2- (methylthio) -4- the filtrate was evaporated. The residual pro- (1H) -pyrimidinone and 3.67 h, the evaporation product is purified, passes- (2-aminoethyl) -4-piperidinyl -1- (4- through chromatographic column, na-fluorophenyl) methyl -1H- The benzimidazole-2-20 filled with silica gel, using an amine, is stirred and heated to a mixture of trichloromethane and methanol (for 4 hours at 140 ° C. The reaction is applied in a volume ratio of 95: 5). The mixture is cooled and dissolved in trifluoroethylene. ,
chloromethane. The solution is purified, skip- The pure fractions are collected and the eluent is chromatographed through a chromatographic column-25. The residual precipitate, filled with silica gel, using crystallizes from a mixture of 2, a mixture of trichloromethane and methanol-propanol with 2,2-oxybispropane, (in a volume ratio of 96: 4), all of which results in 1.7 h ammonia, as eluent. (yield 35.8%) 1- (4-fluorophenyl) methyl} - The pure fractions are collected and the eluent VES (2-pyrimidinylthio) is evaporated, the Residual product is evaporated by -piperidinyl - H-benzimidazole-2-amine suspended in 1, I-hydroxybenzene, t, nn. 146.1-147.7 ° C (compound, resulting in 4.5 hours, value 91).
(yield 76.8%) monohydrate 5- (4-chloro- By carrying out a process similar to phenyl) methyl -2-2-4-4- (4-fluoro-25), get the monohydrate nile) methyl} -1H-benzimidazol-2 -yl, 1 - (4-fluorophenyl) methyl2-1H-ben amino - piperidinyl ethyl amino-4 zimidazol-2-yl} amino -1-piperidinyl (1H) -pyrimidinone, m.p. 150,6-ethylthio-4- (1H) -quinazoline, m.p. 158.7 ° C (compound 85) .133.4 ° C. (Compound 92).
Carried out a process similar to 40
using the equivalent Example 34. According to the amounts of the corresponding starting materials and the procedures described in the example materials, the following pe 26 are also prepared, the following compounds were also prepared:. compounds:
 - (4-fluorophenyl) methyl-45 - (4-fluorophenyl) methyl} -1 -1-benzimidazol-2-yl amino -1-pi-1H-benzimidazol-2-yl amino -1-pi-. Ridinyl Ethyl Amino-6-propyl-4-pyrimi peridinyl, 3-pyridinediamine-dinol, m.p. 164.8 ° C (compound 86); trihydrochloride, so pl. 256.5 C (so2-2-4- (4-fluorophenyl) methylZ - dylenie 93);
-1H-Benzimidazol-2-yl amino -1-pipo-50 1- (4-fluorophenyl) methyl-C-1-2-ridinyl ethyl amino-4- (1H) -pyrimidi-; - (4-pyrimidinamino) ethyl-4-piperinone, m.p. 150.4 ° C (compound 87); dinyl7-1H-benzimidazol-2-aminghemi2- 1- (4-fluorophenyl) methyl - hydrate, so pl. 133.9 ° C (compound 94). -1H-benzimidazol-2-yl amino -1-pipene-N-2-C4-t l- (4-fluorofensh1) methyl) -rididylZethyl amino-4- (1H) -quinazol-55 -1I-benzimidazol-2- sul Amino -1 - pipanone, m.p. 264, (compound 88); Ridinyl Ethyl -1-Phthalazinamine, m.p.
(4-fluorophenyl) methyl - 178.1 ° C (compound 95); -1H-benzimidazol-2-yl amino11-piperi-; N - |. l- (4-fluorophenyl) -medinyl ethyl} amino-6- (phenylmethyl) -4-thyl -1H-benzimidazol-2-sh1 amino} -1-piperidish-ethyl-4, 3-pyrimidine-amine, mp, 207, (compound 96); (4-ft6rphenyl) methylI-1H-benzimnidazol-2-yl-G - (2-pyridinyl) -, 4-bipiperidine-4-amine (E) -2-butendoate (2: 3 monohydrate, t. mp, 226.1 ° C (compound 97);
1- (4-fluorophenyl) methyl -M- - (6-methoxy-4-pyrimidinyl) amino ethyl -4-piperidinyl -IH-benzimidazole -2-amine, mp.145.8 ° C (compound 98); (4-Fluorophenyl) methyl-1H-benzimidazole 2-yl amino-α-piperidinyl methyl-N- (2-pyrimidinyl) acetamide (E) -2-byterate (1: 2), m.p. 191.1 ° C (compound 99);
  4 (1-fluorophenyl) methyl - -1H-benzimidazol-2-yl amino -1-pipidylnyl ethyl-H- (2-pyrimidinyl) benzamide (E) -2-butandioate (i: 2), mp . 201.8 ° C (compound 100);
(4-fluorophenyl) -1 -1H-benzimidazol-2-yl} amino -1-pipedinidyl methyl -N- (3-pyridinylmethyl) thiourea, m.p. 147.2 ° C (compound 102);
 1- (4-fluorophenyl) methyl-1H-benzimidazol-2-yp amino-1-piperidinyl ethyl-N- (2-pyridinylmethyl) thiourea, m.p. 182 C (Compound 103);
(4-Fluorophenide) methyl - - H-benzimidazol-2-yl amnno -1-piperidinyl ethyl-H - (3-pyri; :( ynyl) -tourea, mp 11 3, 5-1 17, 7 C (compound 104);
 - (4-fluorophenyl) methyl - -1H-bepzimidazol-2-yl amino | 1 -PiperidinylZethyl-K- (2-pyridinyl) thiourea, m.p. 192.6 ° C (compound 105);
N- (4-amino-3-pyridinyl) -K (4 fluorophenyl) methyl} -1H-benzimy /, dazol-2-yl 1-amino} - -piperidinyl
ethyl thiourea (compound 106);
M- (3-amino-2-pyridinesh1) -C C1-C (4-fluorophenyl) methyl J-1H-benzimy dazol-2-yl amino -niperidinyl ethyl thiourea (compound 107);
.N- (4-amino-3-pyridinyl) -N (2-furanylmethyl) -1H-benzimidazol-2-yl amino - -piperidinyl ethyl thiourea (compound 108);
H- (4-Al-shcho-3-pyridinyl) C Cl (4-fluorophenyl) methyl -1H-imidazole 455-b pyridine 2-yl amino - pipad P1adinyl ethyl thiourea (compound 109);

N- (4-amino-3-pyridinyl-K-C2-4- (2-pyridinylmethyl) -ZH-imidazo 4,5-b pyridin-2-yl amino-β-piperidinyl ethyl thiourea (PO compound);
N- (4-amino-2-pyridinyl) -N - 3- (4-fluorophenyl) methyl-3H-imidazole 4,5-b pyridin-2-yl ag-1ino - -piperidinyl ethylthiourea (compound);
1 (4-fluorophenyl) methyl-N- - 2-, 6-DIHYDRO-4H-1, 3-thiazin-2-yl amino ethyl 4-piperidinyl - H-benz-imidazole-2-amino monohydrate 5 m.p. 2.4 C (compound 12). Comparative testing. The advantages of the proposed compounds in comparison with the known can be seen from. comparative data presented in Table. 6
The in vitro histamine receptor effect of a known compound and proposed is illustrated in a test with strips of guinea pig small intestine. The in vitro antagonistic effect of serotonin is illustrated by a test for the caudal artery.
Test with strips of small guts guinea pig. Guinea pig small intestine strips are suspended in a 00 ml thyroid bath at 37.5 ° C pre-loaded with 0.75 g and aerated with 95% Of, and
five
0
3
0
5% COj
The spasms caused by the hysta with the auger (.0.5 mg / l) are recorded kimotraphic with an isotonic level, with a 5-fold increase. The interaction of the compound to be tested (5 minute incubation period) with the antagonist is studied. In the first column of the table. 6, the effective concentration (in mg / l) of various compounds is given, whereby a significant inhibition (50%) of the compression caused by histamine is measured (value).
Test for caudal artery in rats.
Astral arteries of hungry samod rats (210-235 g) were used in the test. Spiral strips 5–6 cm long and 2 mm thick were obtained from each artery and placed vertically in a 00 ml bath containing an oxidized Krebs – Genselei – 5 ta solution. Submaximal arterial contraction of the strips was caused by the addition of single doses of serotonin (40 mg / kg) to the bath for 2 minutes at an interval of 10 minutes each time. The compression tightness was measured before and after 5 minutes after the addition of the drug. After washing, the antagonist was added again three times in order to see the contraction restored or normalized. The first column of the table. 6 shows the values of U (effective dose) in mg / l.
In this regard, the ED values are the minimum concentrations of the above mentioned drugs, which reduce the amplitude of compression to at least 50% of its normal: onset.
As an analogue in structure, having the same type of biological activity, 1-4-phenylmethyl-1-2-2 (4-methoxyphenyl ethyl 4-piperidinyl-1H-benzimidazole-2-amine (astemizole) was chosen).
For comparative tests, guinea pig strips and small intestine strips were selected and tested for caudal artery in rats, since it is known that these in vitro tests are very selective for histamine and, accordingly, serotonin antagonistic activity. I
Protecting rats from death caused by 48/80.
Compound 48/80, a mixture of oligomers obtained by condensation of 4-methoxy-L-methylbenzenethanamine and formaldehyde, is described as a strong histamine releasing agent.
Protection against fatal collapse due to disorder of circulation caused by compound 48/80 is an easy way to quantify the activity of the test compounds. For the experiment, male rats of an inbred Wistar strain weighing 240-260 g were used. After fasting overnight, the rats were transferred to conditioned laboratory conditions (temperature 21 ± 1 ° C, relative humidity 65 ± 5%). The test compound is injected subcutaneously or orally into the rat or alternatively with the solvent (in the case of a solvent, a NaCl solution with a concentration of 0.9% is used). After 1 h after such treatment, the body was injected by intravenous injection of 48/80 compound, freshly dissolved in water, at a dose of 0.5 mg per kg of body weight (0.2 ml / 100 g of weight). In control experiments in which an organism
250 solvent-treated rats administered a standard dose of 48/80, no more than 2.8% of the animals survived after 4 hours. Survival by g of 4 h is considered as a safety criterion or as a protective effect of drug administration.
The values of the EU of the compounds of formula 11 and of the intermediate compounds when O are given in the first column of the table. 7 and 8. The indicated ED units are those values, expressed in mg per kg of body weight, at which test compounds i protect 50% of the test animals from death caused by compound 48/80.
The compounds of formula I, intermediate compounds and pharmaceutically suitable acid addition salts thereof.
0 are also strong serotonin si antagonists.
The activity of the proposed compounds as serotonin antagonists is well shown in the results obtained in the following tests, which investigated the antagonistic activity of these compounds on
action of serotonin. I
Antagonistic effect on serotonin-induced effects in the stomach.
Disruption caused by connection 48/80.
Compound 48/80 (a mixture of oligomers obtained by condensation of 4- -methoxy-N-methylbenzeneethanamine and formaldehyde) is a powerful agent that promotes the release of active amines from endogenous substances such as histamine and serotonin. Rats injected with compound 48/80 show a consistent change in blood flow in various vascular organs: cyanosis of the ears and extremities manifested within 5 minutes after the injection of the compound; rats die of shock within 30 minutes. I fok with subsequent killing could be eliminated,
0 if rats are pretreated with a classic H 1 antagonist.
However, the stimulatory effects on gastric secretion are not suppressed, so that rats treated with compound
5 48/80, and protected from shock by the H 1 antagonist, can show all signs of intense activity of the gastric gland; macroautopsi shows dilated stomachs with excessively high so291
holding uneven bright red spots, all over; -n1C | .ch) and sheath, which correspond to the region of the separated glands. A number of ssrotonintazh antagonstop5 such as metisergid, cyprogentate nt, cnnappser -: ,,
Inanerpne, nipamneron, CHiiriep: jH ,: nn-1,
dotfen and ms T M I iiijiiai, rio: viot; yrbiu yc i wound iU; 4 li koiech) yus ;; ;; И5 as well as under the rivers:, e1i1 in l; e. ITK:; ol; .1с; t x stomachs and ttpesMepiioe gastric distension,
 Method / Face
Rats sai: Dov inbred Histar pggamma weighing but 220-25Q: В1.и1ер} are hungry for: but n :, | 1, only zod, H (: ii: -r ye:; i-: e soe h ,. dt th:) Echo po ii; ogd; suitable for rchsgno-ra or sus-nsizii. In Ogm lnizm Kosii-olmpkh py (D:;::; p Kolchos:;: ;; - ta, -yul, p r iicni-vvy: - / - :::: .tir:; i pg-cia, later 1 hr Ti cipi aifn jb riccx |; | -; with chickpea 11Doq (inrr, ojauii ppod 5-; - - (d, P (leni.) Met1-i1) - - ;; 11eraz: -glpl. 1 - MeTHj - 111-oenzi.pdazol-2-metha) 1 doaop 2,; f T / Ki. Chg rp: 2 h: -; oh yes I Oi or g-ucm j cyuxO- TicP jin j-.
SKDII ISP - TueMO J lj GOSGIARPYA,, v f1; well, 1D) I1 CH1yu 1- AND G | Ptssiii lgt1: T | - g; crir: - iizm dog ;: RAT ciC CyiHicinic А8 / ЬО (h psch ... ekdni g; (back ia e.i; h B / Vk k} .y s 5e -: -: chapBjnilKUOT I: U ;;, 1 YAYU; AI HliX ke, Lu / us1., For
so these acorn. luJOi.ici nioT m plant -} 1s. ia s; e,; and. KIMIIII.I, Li.uch- CTHj ginzi and T1pd; word and; and: we are from the Macroscopic and Firming one ..-- 15 1kkale from O to ++ n-. iir ti4CM O matches niojHtoMy o- X; io: pi-- DNM1.1X damage, and sa.mse high knockout; 11; 1L corresponds: there is a newer unevenness, covered - Gojiee with half of the glandular.
In the column / tab. 7 and H ii o cauldrons for a number of compounds of the frmsy (I) and intermediate compounds. harp, noe (in mg per kg of body weight) 5 of which 1 are gastric distension, as well as damage to the glandular zone. A half of a rat is absent in 50% of isthus rats. (the value of AU
Columns. 7 and 8 oboanale ;; and eat a N buttress missing1): e or ny by the presence of N and aromatic rings and place N in the specified ring "
772830
1) Table 7 and 8 (-1 means hydrocarbon |; odd b e rad1i; aly with branching n.yooo
(Oed.in.eng, not listed in Taol. 7 and 8, do not restrict oobeN of the invention and give. Legs: as an example of empty headlamps; its name: their actions: all connections: O) L-; and G, denoted by formula (1), n of all rhpo; e / kyrol: our compounds f In view of a: tigi :: ta l-nyu X and serotininanthagoistic properties of compounds of the formula (l) j of intermediate compounds and nx acidotr: o additive Salts of these compounds are as follows: 5 iievu.je for 1H of allergic diseases, such as 1.ac, nalimer, allergic pHinrr ,, hell, in; rical conjunctiva of the chronyleka K eapivpa ia, alle. G 1h Skye acT ;. ia n etc.
P n ....
.15.13И11. Y: lyl) l en 1T GLtami; o1eoi i-T srotrol; and: -lg.1 and x foxes; And 41.: Sky active-:; wasp. and .h; connected; l - - can be l; 1G caught; ogm p VIL.S); -3jlichnykh pharma- p.evt; -ghes |;: and}; irelaratov., iredtgaza hslya x; (. l B1 here in ortism. For nri- I about (ollt1 (;; a) m; ii; itllusky; ch-) many L efls1spg kolicchevo connection- | n; g ; (JjOpMt was delighted with i; .aii KfU.: Otlo lg lpt1 V1toy (:: oli, p.puzhpgesoo, cialis akti: zgkp o.l1grediyelta, CMeuinea with pharmaceutical liposk. 5yr; : .yu; ke1 namevatfnogo; tv species of the headset; symo from the desire: -Kl1 fs) | vrelarat a, and the average value for the input p
 ; i headlights: -accessible-; e komlozidii 5kela1 elvlo nrri otavl lzat ::. in the form of single (single) doses, recommended for oral administration into opraHiisM, through
 If you are sick or nenateralvically, for example, you should be able to take a composition that has been added to the dosage form by mouth and can usually be used in a 45 ml dietary environment, in a medium, like water, , p-icols, oils, alcohols, and so on, in the introduction through the mouth in the form of liquid non-drugs, for example suspensions, snrones, elixirs
50 and solutions; or solid carriers such as starch may be used; sugars, kaolin, oils, binders, two agents, and so on, in the case of holes, caps sul, and tablets, From the point of view of ease of administration, tablets and Kansul are most desirable to be administered in a single dosage form through the mouth and in this case solid pharmaceutical carriers are not used. In the case of parenterally administered compositions, the carrier usually comprises sterilized water, which constitutes at least the largest part of the composition, although other ingredients that contribute to solubility can be used. . For example, injection solutions can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline solution with glucose solution. Injectable suspensions may be prepared, and suitable liquid carriers, suspending agents, and so on may be used. Acid addition salts of the formula (.1) due to their increased solubility in water compared with the corresponding basic forms of the compounds are more suitable for the preparation of aqueous compositions.
Especially preferably prepared. These pharmaceutical positions are given in the form of a single dosage form for ease of administration and uniformity of dosage. The unit dosage form of the invention relates to discrete discrete preparations in the form of a single dose, each of which contains a predetermined amount of the active ingredient, calculated in such a way as to provide the desired therapeutic effect when used in a mixture With the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including coated tablets), capsules, pills, bags of powders, wafers, injection solutions or suspensions, tea spoons, tablespoons, and so on, and combinations thereof.
The proposed compounds are used in the method of treating allergic diseases in warm-blooded animals by introducing into the body an effective antiallergic amount of a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof.
The dosages administered daily to the body are in the range of 0.1-100 mg 55, preferably 1-50 mg.
Thus, a method has been proposed for the preparation of N-heteroalkyl-4-piperidinamine derivatives of the general formula ()
five
0
five
0
D
0
five
possessing valuable pharmacological properties.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining N-heterocyclyl-4-piperidinamine general formula
R,
) CA
five
0
R3
where L is the divalent radical of the formula
-sn spn-sn-n CH-CH CH- or
-CH CH-CH N,
where one of the hydrogen atoms may be substituted with a halogen, hydroxy or.-alkoxy group;
R is hydrogen or alkyl; Rj is hydrogen, C.-C-alkyl, unsubstituted or substituted by phenyl (unsubstituted or monosubstituted by halogen, C-C-alkyl or C -C-alkoxygroup, pyridinyl, 2-pyrazinyl, thienyl, furanyl (unsubstituted or monosubstituted by C - With alkyl), 4-thiazolyl or 3- - (2-methylimidazolyl);
RJ is hydrogen, C-C-alkyl or benzyl;
L is a K- (2-pyridinyl) -4- -piperdinyl radical, unsubstituted or monosubstituted in the pyridine ring by chlorine or nitro,
or L is a radical of the formula
bc
or L is a radical of the general formula
Geth With C YC K - m am t 2g1
where or 1;
, 1,2,3 or 4,
Y is a bond, an oxygen atom, a sulfur -COO-, -CONH-, -NHCONH-, -№1CSNH-, -N group (CnpCSNKshti group in which R is hydrogen. go zoil and radical;
33
Geth - shestilennye
A single ring, with one and two nitrogen atoms in the cycle, linked to the chain C H at the carbon atom, unsubstituted, one or 5 or disubstituted by halogen, OXI, amino or nitro, C, -C-alkyl, C, -C-alkoxy C, C-C-alkylthio, C-C - alkylamino, aminocarbonyl, fO benzyl, halogen-substituted benzyl or (halogen-substituted benzyl) amino group, or condensed with a benzene ring, J5
or their pharmaceutically acceptable
salts, characterized in that
what is piperidine of the general formula
1297728 34
heterocyclic radicals such as
alkyl or C-C-alcorac furanyl (unsubstituted C, -C-alkyl or 2-pyrazinyl lower alkyl or benz N- (Y-pyridinyl) -4-pip) or substituted by pyridine with chlorine or a radical of the formula
FS
or radical common form
GETS N YC N - 1 Zhn .fi IZM
where, 1-4, yes
Y
-No
"- OY-CX
Q is a radical of the formula
or the radical NUS, R .. K „, Riv A, p:
- /
. ,, 2 Y have specified
values are alkylated with a compound of the general formula
Geth W, t 2t
where p and Geth have the indicated W-halogen, w-lower alkoxy or lower alkylthio group, in the medium of a reaction-inert solvent, isolating the desired product in free form or in the form of a pharmaceutically acceptable salt.
Priority signs: 12.07.82 with A - a bivalent radical of the formula
-CH CH-CH CH- -N CH-CH CH- or
-CH CH-CH N - where one of the atoms. Hydrogen may be substituted by a halogen atom, a lower alkoxy or hydroxy group, Rj, hydrogen, Rj hydrogen, a C.-Cj-alkyl, unsubstituted or substituted by phenyl which may be substituted by one
radical, such as
halogen, Cj alkyl or C-C-alkoxyl, thienyl, furanyl (unsubstituted or monosubstituted With C, -C-alkyl), pyridinyl or 2-pyrazinyl, Ri is hydrogen, lower alkyl or benzyl, L is an N- radical ( Y-pyridinyl) -4-piperidinyl, which is unsubstituted or substituted in the pyridine ring by chlorine or nitro, the radical of the formula
FSU
or radical of the general formula
0
GETS N YC N - 1 Zhn .fi IZM
where, 1-4, yes
Y atom is oxygen in which
sulfur or group / NP,
hydrogen, C-G, -alkyl,
R. stands for
five
0
benzyl, acetyl or benzoyl; Get means a pyridinyl radical which may be substituted by one or two substituents, such as halogen, amino, nitro, lower alkyl, lower alkoxy, lower alkylthio or oxy, benzyl or halo-substituted benzyl, quinolinyl radical, may be substituted by lower alkyl, pyrimidinyl, which may be one or disubstituted by a group independently selected from groups such as halogen, amino, oxy, lower alkyl, lower alkoxy, nizalkylthio, benzyl or halo-substituted benzyl, hina zolyl ra-, dical, which may be substituted by hydroxy or - lower alkyl group, pyri -. a dasinyl radical, which may be substituted by lower alkyl, a quinoxaline radical, which may be substituted by lower alkyl, a pyrazinyl radical, which may be replaced by halogen or lower alkyl
five
0
scrap;
04/22/83 when A is a bivalent radical of the formula.
—CH — CH — CH — CH — —N CH — CH CH — —CH CH — CH N where one of the hydrogen atoms may be replaced by halogen, lower alkoxy-55 si or oxy group, R ,, is hydrogen or lower alkyl, R / is hydrogen C — C— is alkyl unsubstituted or substituted by phenyl (unsubstituted or monosubstituted with halogen, C — C alkyl, or
351297728.36
C-C-alkoxygroup), pyridinyl, -CONH-, -NHCONH-, -NHCSNII-,
2-pyrazinyl, thienyl, furanyl-N (CHJCSNH- or group) NP-, in which (unsubstituted or monosubstituted by the second R - hydrogen, -alkyl,
C -Ci-alkyl), 4-thiazolyl or 3-benzyl, acetyl or benzoyl, Geth
- (2-methylimidazolyl), R, hydrogen, denotes six-membered heterocyclyC-C-alkyl or benzyl, L is a single ring with one or two
em is a radical of the formula N- (2-pyri-nitrogen atoms in the cycle, associated with
Dinil) -4-piperidinyl, unsubstituted With R, at the carbon atom, not it
or mono-substituted in the ring pyridium-substituted, one or disubstituted by chlorine or nitro, radical fO by a radical independently selected from
formul / / -C.
N or radical of formula
GetS R YC N - w 2t n 2p
where or 1,, 1-4, Y is a bond, an oxygen atom, sulfur, the -СОО- group,
groups: halogen, hydroxy, amino, nitro, C.-C-alkyl, C, -C-alkoxy, C-C-alkylthio, C, -C, alkylamino, aminocarbonyl, benzyl, halo-amine f5 meHHbfe benzyl, (halo benzyl amino group, or may be condensed with a benzene ring.
groups: halogen, hydroxy, amino, nitro group, C.-C-alkyl, C, -C-alkoxy, C-C-alkylthio, C, -C, alkylamino, aminocarbonyl, benzyl, halo-methylHHbfe benzyl, ( a halo-substituted benzyl amino group, or may be condensed with a benzene ring.
Table 1
NC-CnH2n-N:
H RI
N / Nz
.
R,
 sn sn sn sn sn sn
N CH-CH CH
sun night night
CH CH-CH-N
sun night night
N CH-CH CH
N CH-CH CH
(2-Pyridinyl) -CH N
4-F-C H CHN
S 4 2
4-FC C N.N.
64 2
(2-pyrazinyl) SI N
4-F-C, And ,, SI, N
6 h 1
(2-Furansh1) SNN
4-F-C H CH ,, N
(2-11iridinsh1) CH, H
(2-Furanil) CH „H
39
H R
%
k 1297728
40 Table 2
2 CH CH-CH CH 4-CH 0-С
2 CH CH-CH CH 4-F-CgH CH
2 CH CH-CH CH 4-F-C H CH
64 2
2 CH CH-CH CH 4-F-C, H CH
642
2 CH CH-CH CH (5-CH, -4-imidasojiVin) CH,
127 2 CH CH-CH CH N
H Basing 129.8
H 5-CHj O Foundation of N 6-CH, O Foundation
Foundation Foundation 190
Foundation 182.8
T b b 3
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4- (2-ipidimidinyl) -butyl
2- (3-Sh2-2-Pyridinyl) KN-ethyl
3- t (2-Pyrimidinyl (-propyl
2-1 (6-C1-4-Pyrimidinyl) KN-ethyl
1 - (2- Pyrimidinyl) -4- -piperidinyl
2- (2-Pyrimidinyl) -propyl
2- (Phenylmethyl) - (4-F-C
6 4 2
4-F-C H.CH
 H, CH
64 4
4-F-C. H CH e h 2
4-F-C H CH-G A i
.H.CH 64 2
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2- (5-NO. -2-Pyridine) NH propyl
-F-C,
Base150.0
Foundation148.1
Foundation143,8
,9
Ground158.7
Base1,60,8
Base148.7
2HС1 Е / 2 229.3 НО
10 (2-pyrimidinyl)
4-F-C N.SK
l- (3-NO -2-pyridinyl) -4-piperidinyl 4-F-C H CH
1 - (2-Pyrimidinyl) -3- -piperidinyl
2-E (5-M02-2-pyrvdinil)
4-F-a H CH e 4 2
4-F-C H CH
S h 2
2- (4-Shn, M-oxide-3-pyridinyl MH ethyl 4-F-Cg,
2- (2-pyrimidinyl) NH - (2-Pyridnyl) -ethylCH, j
2- (2-Pyrimidinyl) MN
ethyl4-F-C H CH
6 A g
2- (2-Pyrimidinyl) UN ethyl
2- (3-Pyrimidinyl) NH ethyl
2-L (2-Pipy Radinyl) NH ethyl
2- (2-Gryrimidinyl) LHH1 ethyl
2- (2-Pyrimidinyl) No. 1 ethyl
5-G (2-Pyrimidinyl) ET Pentyl
(Z-Pyridiyl) CH,
(2-Pyrazin1sh)
CH 2
(2-thienyl) CH „
(Z-Furanil) CH
(5-CH -2-furanyl) CH.
4-F-C H CH 6-1 2
H Base 167.2
H 108-123
Basis 177.1
Ground 1 75.7
Basis 199.0
Basis 150,8
Base 180.9
2 (or 3) F
Foundation218.9
Base 185,8
Base 181,5
Foundation213.5
Base143,7
Base136,5
Al --NH-CH2 CH2-l
NILE
gu
-Lt
(2-Furanyl) CH Basis 246.2
R i
-O | ti
HO ethyl
CHj 4-F-C H CHj H CH-CH-; CH "CH
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Editor H, Kistoulinets
Compiled by N.Naryshkova Tehred N.Glushchenko
Order 1674 Circulation 372, Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow,, Raushsk nab., 4/5
Pronzvodstvenno} 1o-printing company, Uzhgorod, st. Project, 4
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Proofreader S.Mekmar

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法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US39762682A| true| 1982-07-12|1982-07-12|

---

US06/487,774|US4556660A|1982-07-12|1983-04-22|N--4-piperidinamines|

---