Method for preparing derivatives of n-(4-piperidinyl)-bicyclic condensed 2-imidazolamine, their phar

专利摘要:
Novel N-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives of formula <CHEM> wherein: A<1>=A<2>-A<3>=A<4> is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH or -CH=CH-CH=N-; R is hydrogen or C1-6alkyl; R<1> is furanyl substituted with C1-6alkyl, pyrazinyl, thiazolyl, or imidazolyl optionally substituted with C1-6alkyl; L is C3-6alkenyl optionally substituted with Ar<3>, or L is a radical of formula -Alk-R<3>, -Alk-O-R<4>, -Alk-N-(R<5>)-R<6>, -Alk-Z-C(=O)-R<7> or -CH2-CH(OH)-CH2-O-R<9>; the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are anti-histaminic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1644717A3
申请号:SU884355903
申请日:1988-06-14
公开日:1991-04-23
发明作者:Эдуард Жанссенс Франс；Лео Гисланус Торреманс Жозеф；Станислас Марселла Диелс Гастон
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

a suitable acid addition salt by treatment with a suitable acid or, conversely, converting the salt into
free base with alkali treatment. 2 tab.
The invention relates to the field of heterocyclic compounds, in particular, to a process for the preparation of derivatives of No.- (4-piperidinyl) bicyclic fused 2-imidazolamine of the general formula (I)
AlK-R
h
R
) -N-y
- - I x
HN
their pharmaceutically acceptable acid addition salts or stereoisomers thereof, wherein A1 A is a bivalent
yl
ICD:
g
by the radical —CH — CH — CH — CH- (a-1); -N CH-CH CH- (a-2), (a-CH CH-N CH- (a-4) or CH CH-CH-N- (a-5);
R is a hydrogen atom or alkyl
R furanyl, substituted alkyl with C-C f;
L is alkenyl (J3- (J6, which may be substituted by phenyl or is a radical of the formulas -Alk - R (b-1), -Alk-0-Ke (b-2), -Alk -ZC (0) -R4 (b-4) or -ai2-CH (OH) -CHz-0-R5- (b-5), where R- is hydrogen, phenylthio, phenylsulfonyl, 4,5-dihydro-5 oxo-1H-tetra-el -1-yl, optionally substituted in the 4th position with alkyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 4-morpholinyl or 1-piperidinyl, or if R is furanyl, substituted C is C-alkyl and A is a bivalent radical of the formula (a-1) or (a-2); R2 can also be thienyl, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl or phenyl which m Jet be substituted by (C -SfE-alkyloxy;
R 3-alkyl C, -C4 or phenyl, which may be substituted by one or two, identical or different substituents from the group (.) -Alkyloxy or alkyl
R. - alkyl With, -C, () -alkyl-amino group, (C -C-alkyloxy group
0
five
0
25
0
35 5 50
or phenyl, which may be substituted by one or two, identical or different substituents from the group: halogen, (C -C-alkyloxy or alkyl);
Z is an oxygen atom, an NH group or a simple bond;
R $ is phenyl with the proviso that A A - A A4 is a radical of the formula (a-1) or (a-2) if L is a radical of the formula (L-4), having antihistaminic activity
The aim of the invention is to develop a method for producing new compounds with higher antihistamine activity.
Compounds of the invention in which Z is C-Cg-alkenyl, optionally substituted by Ar, may be present in E- and Z-WarHo
Pure stereochemical isomeric forms of the compounds of formula (I) can be obtained by known methods.
Diastereoisomers can be separated by physical separation methods; selective crystallization and chromatographic techniques, for example, distribution in countercurrent, and enantiomers can be separated from each other by selective crystallization of their di-stereoisomeric salts with optically active acids
Pure stereoisomeric forms can also be obtained from the corresponding pure stereoisomeric forms of suitable starting materials, provided that these reactions occur stereochemically.
The cis- and trans-diastereoisomeric rematets can be further divided into their optical isomers, cis (+), cis (-), trans (+), trans (-) „
Stereoisomeric forms of the compounds of formula (I) are obtained by the proposed method.
The compounds of formula (I), their pharmaceutically acceptable acid addition salts, and possible stereoisomeric forms possess useful pharmacological properties. They're in
3164
Active anthistamine agents In addition to their antihistamine properties, some of the target compounds also show serotonin antagonism.
In addition, the compounds of formula (I), pharmaceutically acceptable acid addition salts and their stereoisomeric forms, are particularly attractive due to their favorable pharmacological profile. In particular, some compounds exhibit such a rapid reaction that their anti-histamine effect appears almost instantly.
Considering their antihistamine properties, the compounds of formula (I) and their acid addition salts are very useful in treating such allergic diseases as, for example, allergic rhinitis, allergic conjunctivitis, chronic fever, allergic asthma
Given their pharmacologically beneficial properties, the target compounds can be prepared in various pharmaceutical forms for administration. To prepare the proposed pharmaceutical compositions, an effective amount of the specific compound as a base or an acid addition salt as the active ingredient is combined with a pharmaceutically acceptable carrier, the carrier being in a wide variety of forms depending on the form of preparation required for administration. Such pharmaceutical compositions are desirably in unit dosage adapted for oral, rectal, parenteral administration or for injection. For example, in preparing the compositions in doses for oral administration, any conventional pharmaceutically acceptable medium can be used, for example, water, glycols, oils, alcohols; in the case of oral liquid preparations, suspensions, syrups, elixirs and solutions,
or solid carriers — starch, sugar, kaolin, lubricants, binders, disintegrating agents — in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules in single doses for oral administration are most advantageous, in which case solid pharmaceutical carriers are usually used. For parenteral compositions
0
one
Q 5
0 5 o 5
0
five
7
the carrier usually includes sterile water, at least in large part, although other ingredients may be included, for example, to increase solubility, Injection solutions can be prepared on the basis of carriers containing saline solution, glucose solutions, or mixtures of salt and glucose solutions. Injectable suspensions can be prepared, in which case suitable liquid carriers, suspending agents and the like can be used. In compositions suitable for surface application, the carrier optionally contains a permeability enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in small amounts, and these additives should not have a noticeable harmful effect on the skin. Said additives may facilitate the application of the preparation to the skin and / or may facilitate the preparation of the desired compositions. These compositions may be applied in various ways, for example, skin patching, application of n a patch of skin or ointment. It is generally convenient to use acid addition salts for the preparation of aqueous compositions due to their higher solubility in water compared to the corresponding bases.
For ease of administration and for dose uniformity, it is particularly convenient to prepare these pharmaceutical compositions in the form of unit doses. The proposed unit dosage form refers to physically discrete units suitable for single dosages, each dosage containing a predetermined amount of active ingredient calculated for a particular therapeutic effect in combination with the desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including coated tablets), capsules, pills, powders, cachets, solutions or suspensions for injection, doses in a teaspoon or tablespoon, and their individual packages.
The compounds of formula (I) are used in a method of treating allergic diseases in warm-blooded animals by administering an effective antiallergic amount of the compound
ly (l) or a pharmaceutically acceptable acid addition salt thereof.
When treating allergic diseases in warm-blooded animals, it is easy to determine the effective amount based on the tests presented. The effective amount is 0.001-100 mg / kg live weight, more preferably 0.01-1 mg / kg live weight o
Preparation of derivatives “Example 1. AO A mixture of 12.9 parts of 4-methyl-2-furancarboxaldehyde, 9.1 parts of hydroxylamine hydrochloride, 11.9 parts of pyridine and 160 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is placed in water. All this is acidified with concentrated hydrochloric acid and the product obtained is extracted with 1,1-sibisethane. The extract obtained was washed with water, dried, filtered and evaporated, yielding 14 parts (95.6%) of 4-methyl-2-furancarboxaldehyde oxime as a residue (intermediate 1).
B. A mixture of 14 parts of 4-methyl-2-furancarboxaldehyde oxime, 400 parts of methanol and 40 parts of 2-propanol, saturated with hydrogen chloride, is hydrogenated at normal pressure at room temperature for 4 hours of catalyst 10%. Palladium on coal. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the resulting filtrate is evaporated at 30 ° C. The residue is placed in water and saturated with potassium carbonate. The resulting product is extracted with 1,1-oxybisethane. The resulting extract is dried, filtered and evaporated. The residue is purified on a chromatographic column over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, resulting in 8 parts (64.2%) of 4-methyl-2-furanmethanamine being obtained as a residue (intermediate 2).
C. A mixture of 10.4 parts of 2 chloro-3-nitropyridine, 8 parts of 4-methyl 2-furanethanes per 7.6 parts of sodium bicarbonate and 120 hours of ethanol is stirred during the time of the Kochi at reflux. The reaction mixture is evaporated and the residue is placed in water. The resulting product is extracted with 1,1-oxybisethane.
The extract obtained is dried, filtered and evaporated. The residue is purified on a silica gel chromatography column using trichloromethane as eluent. Pure fractions are collected, the eluent is evaporated, resulting in 14.9 parts (91.2%) of M- (4-methyl-2-furanyl) methyl (-3-nitro-2-pyridinamine) as a residue (intermediate 3) .
D. A mixture of 14.9 parts of N- (4-methyl-2-furanyl) methyl-3-nitro-2-pyridinamine, 2 hours, 4% solution of thiophene in methanol and 320 parts of methanol is hydrogenated at normal pressure at room temperature with 2 hours of catalyst 5% palladium on carbon. After the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated, resulting in 14.2 parts (100%) of N g of X4-methyl-2-furanyl) methyl -2,3-pyridinediamine in residue type (intermediate 4).
In a similar way, the following is obtained: N - Ј (5-methyl-2-furanyl) methyl -1,2-benzenediamine as a residue (intermediate 5);
 X5-methyl-2-furanyl) methyl -2,3-pyridinamine as a residue (intermediate 6);
N - (2-methyl-3-furanyl) methyl -2,3-pyridinamine as a residue (intermediate 7);
N g- Ј (5 ethyl-2-furanyl) methyl -2,3-pyridinediamine as a residue (intermediate 8);
 Ј (5-methyl-2-furanyl) methyl | -3,4-pyridinamine as residue (intermediate 9);
 (H-methyl-2-furanyl) methyl -2,3-pyridinamine as residue (intermediate 10);
N - ((5-methyl-2-furanyl) methyl 3,4-pyridinamine g as residue (intermediate 11);
Ne- (1-methylatil) -2-furanyl - methyl} -2,3-pyridine diamnn as residue (intermediate 12).
Example 2. A. A mixture of 68.5 parts of ethyl-4-isocyanato-1-piperidinecarboxylate, 58.0 parts of N - (5-ethyl-2-furanyl) methyl -2,3-pyridinediamine and 450 h . the tetrahydrofuran is stirred overnight at reflux. After evaporation, the residue is purified on a silica gel column chromatography using
916
a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is stirred in 1,2-hydroxy bisethane.
The product is filtered off to dry, resulting in 50 hours (44.4%) of ethyl-4 - //// 2 - /// 5-ethyl-2-FU-ranyl / methyl / -amino / -3-pyridinyl (amino) thioxomethyl / amino / -1-piperidinecarb oxylate (intermediate 13).
In "A mixture of 50 parts of ethyl-4 - //// 2 - /// 5- ethyl-2-furanyl / methyl / -amino / -3-pyridinyl / amino / thioxomethyl / amino / -1-pin redinecarboxylate, 32 , 4 parts of mercury (II) oxide and 480 parts of ethanol are stirred for 1 hour at reflux. The reaction mixture was filtered over diatomaceous earth and the resulting filtrate was evaporated. The residue is stirred in 1,1-oxybis ethane. The crystalline product is filtered and dried, resulting in 38 parts (83.1%) of egil-4- // 3 - // 5-ethyl-2-furanyl / methyl / -ZN-imidazo 4, pyridin-2-yl / -amino / - 1-piperidinecarboxylate. T „pl. 111.1 C (intermediate 14).
Similar compounds are prepared in the same way:
ethyl 4 - // 1 - // 5-methyl-2-furanyl / methyl / -1H-benzimidazol-2-yl / -amino / - 1-piperidinecarboxylate, hemihydrate, so pl. 150.1 ° C (intermediate 15);
ethyl 4 - // 3 - // 5-methyl-2-furanyl / methyl / -ZH-imidazo 4, S-b pyridin-2-yl / amino / -1-piperidinecarboxylate as a residue (intermediate 16);
ethyl 4 - // 3 - // 2-methyl-3-furanyl / methyl / -ZH-imidazo 4,5-bj pyridin-2-yl / amino / -1-piperidinecarboxylate, t, pl. 153.7 ° C (intermediate 17);
ethyl 4 - // 1 - // 5-methyl-2-furanyl / methyl / -1H-imide zo 4,5-c pyridin-2-yl / amino / -1-piperidinecarboxylate, mp. 155.2 &amp; C (Intermediate 18);
ethyl 4 - // 3 - // 3-methyl-2-furanyl / methyl / -ZH-imidazo 4,5-bJpyridin-2-yl / amino / -1-piperidinecarboxylate as a residue (intermediate 19);
ethyl 4 - // 3 - // 5-methyl-2-furanyl / methyl / -ZH-imidazo G4,5-e pyridin-2-yl / amino / -1-piperidinecarboxylate (intermediate 20);
ethyl 4 - // 3 - // 5- / 1-methylethyl / -2-furanyl / methyl / -ZH-imidazo 4,5-bJ pyridine-2-yl / amino / -1-piperidinecarboxy - lat in the form of residue (intermediate 21)
1710
ethyl 4 // 3 - // 4-methyl-2-furanyl / methyl / -ZH-imidazo 4,5-b pyridin-2 yl / amino / -1-piperidinecarboxylate as a residue (intermediate 22) j
Example 3. To a stirred mixture, 4.6 parts. 50% sodium hydride dispersion and 450 parts. P, M-methyl forms and 57.6 parts of ethyl 4 - // 1H benzimidazol-2-yl were added in portions. / amino / -1-peridinecarboxylate under nitrogen atmosphere. After the addition is complete, stirring is continued for 30 minutes at room temperature. Then 27.0 parts of 3- (chloromethyl) -2-methylLurane are added dropwise with cooling. After the addition is complete, stirring is continued for 1 hour. Water is added dropwise to this mixture and the product is extracted with 4-methyl-2-pentanone. The extract obtained is dried, filtered and evaporated. The residue is stirred in 1.11-oxybisethane. The solid product is filtered and purified on a chromatographic column with silica gel, using gc mixture of trichloromethane and methanol (95: 5 by volume) as eluene. Pure fractions are collected and the eluent is evaporated. The residue is stirred in 1.11-oxybisethane. The resulting product is filtered and dried, resulting in 37.5 parts (19.0%) of ethyl-4 - // 1 - // 2-methyl / -3-furanyl / methyl-1H-benimidaeol-2- yl / amino / - 1-piperidnncarboxylate. M.p. 150.4 ° C (intermediate 23).
In a similar manner, ethyl 4- (1-4-thiazolylmegyl) -1 -1-benzimndazol-2-yl / amino-1-piperidinecarboxyl is obtained. M.p. 156.2 С (intermediate 24).
i
PRI me R 4. A mixture of 20.5 hours ethyl 4 - // 1 - // 5-methyl-2-furanyl / methyl / -1H-imidazo 4,5-cj pyridin-2-yl / amino / - 1-piperidinecarboxylate, 40, h. Potassium hydroxide and 240 parts of 2-propanol are stirred overnight at reflux. After evaporation, the residue is taken up in water and the product is extracted with dichloromethane. The extract obtained is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The resulting product is filtered and dried, yielding 15h. (88%) 1 - // 5-methyl-2-furanyl / methyl / - H- / 4-piperidinyl / -1K-imido, 5-cJ pyridin-2-amine. m.p. 185.6 ° C (intermediate 25).
Similarly, receive:
1 - // 5-methyl 2-furanyl / methyl / -N- / 4-piperidinyl / -1H-benzimidazol-2-amine as a residue (intermediate 26);
N / 4-piperidinyl / -1t / 4-thiazolylmethyl / -1H-benzimidazole-2-amine dihydrobromide monohydrate; m.p. 223.5 ° C (Intermediate 27);
3 - // 5-methyl-2-furanyl / methyl / N- / 4200 parts of methanol, saturated with ammonia, is hydrogenated at normal pressure and room temperature with 2 parts of catalyst Rane nickel. After the calculated amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is evaporated to give 6 h, M (1- (2-aminoethyl) -4-pipiperidinyl) / 3H-imidazo 4, 5-bJ pyridine-10 peridin-yl / - 1 // 5-methyl-2-furanyl / Me-2-amine; m.p. 120 ° C (intermediate 28);
3 - // 2-methyl-3-furanyl / methyl / -N- (4-piperidinyl) -ZH-imidazo 4,5-b pyridin-2-amine; m.p. 165 C (intermediate 15% 29);
3 - // 5-ethyl-2-furanyl / methyl / -N- / 4-piperidinyl / -ZH-imidazo 4,5-bJ pyridine-2-amine; m.p. 106 ° C (intermediate 30);
1 - // 2-methyl-3-furanyl / methyl / -H- / 4-piperidinyl / -1H-benzimidazol-2-amine; m.p. 168 ° C (intermediate 31);
3 - // 3-methyl-2-furanyl / methyl / -N- / 420
piperidinyl / -ZH-imidazo 4,5-b pyridine-2-amine; m.p. 160 ° C (intermediate 32);
3 - // 5-methyl-2-furanyl / methyl / -N- / 4-piperidinyl / -ZH-imidazo 4,5-cJ pyridine-2-amine hemihydrate; m.p. 146 C (intermediate 33);
3 - // 5- / 1-methylethyl / -2-furanyl / methyl / -H- / 4-piperidinyl / -ZH-imidazo 4,5-ЗZpyridin-2-amine dihydrochloride, m.p. 235 ° C (intermediate 34);
3 // 4-methyl-2-furanyl / methyl / -N- / 4-piperidinyl / 3N-imidazo 4,5-bJ pyridinyl / 1H-benzimidazol-2-amine as a residue (intermediate 37)
Preparation of the target compounds. EXAMPLE 6 Mixture 3.32 part of 1- / 2-bromoethyl / -4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 4.65 h „1 - // 5-methyl-2-furanyl / methyl / -Y- / 4-piperidinyl / -1H-benzimidazol-2-amine, 1.6 parts of sodium carbonate and 45 parts of M, H-dimethylacetamide are mixed in overnight at 80 ° C. The reaction mixture is poured into water and the product obtained is extracted with 4-methyl-2-pentanone. The extract obtained is dried, filtered and evaporated. The residue is purified on a chromatographic column with silica gel, using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the ethanedioate salt in methanol. The resulting salt is filtered off and dried, yielding 5.2 parts (55%) of 1-ethyl-1,4-dihydro-4- / 2- / 4 - // 1 - // 5 -methyl-2-furanyl / methyl / -1H- 35 benzimidazol-2-yl / -amino / -1-piperidinyl / ethyl / -5H-tetrazole-5-one-ethanedio 25
thirty
2-amine; m.p. 143 ° C (intermediate 35).
at (1: 2) 17).
Т „p 190.5 С (compound Example 5. А„ Mixture 2 parts 2-chloroacetonitrile, 8 parts 1 - // 5-methyl-40 2-furans / methyl / -M- / 4-piperidinyl / - 1H-benzimidazole -2-amine, 3.1 parts of sodium carbonate and 90 hours M, K of dimethyl phosphate are stirred and heated overnight at 45 ° C. The reaction mixture is drunk into water and the resulting product is extracted with dichloromethane. filtered and evaporated. The residue is crystalline Example: A mixture of 3.9 parts of 2,3-dihydro-1,4-benzodioxy-2-methanol-methanesulfonate (ester), 7.4 h 3 - // 5-methyl 2-furanyl / methyl / - - / 4-piperidinyl / -ZN-imidazo 4,5-b pyridin-2-a mine, 3.3 parts of sodium carbonate and 90 parts of M, N of dimethylacetamide are stirred overnight at 80 ° C.
The mixture is poured into water and
The product is extracted from a mixture of acetonitrile and the 2.2-50% is extracted with 4-mesibispropane, giving 7.3 parts (80.4%)
4 - // 1 - // 5-methyl-2-furanyl / -methyl / -1N-benzimidazol-2-yl / amino / -1-piperidineacetonitrile. exact 36)
Mp-177.3 C (intermediate
thyl-2-pentanone. The extract obtained is dried, filtered and evaporated. The residue is purified on a chromatographic column with silica gel, using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the ethanedioate salt in methanol. This salt is filtered. A mixture of 6 h. 4 - // 1 - // 5-methyl-2-furanyl / methyl / -1H-benzimidazol-2-yl / amino / -1-piperidineacetonitrile and
200 parts of methanol, saturated with ammonia, are hydrogenated at normal pressure and room temperature with 2 parts of Rane's nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the resulting filtrate is evaporated, yielding 6 h, M / 1- / 2-aminoethyl / -4-piperidine-yl / -1 // 5-methyl-2-furanyl / me -
0 peridin-yl / -1 // 5-methyl-2-furanyl / me
five
0
thyl / 1H-benzimidazol-2-amine as residue (intermediate 37) o
Preparation of the target compounds. EXAMPLE 6 Mixture 3.32 part of 1- / 2-bromoethyl / -4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 4.65 h „1 - // 5-methyl-2-furanyl / methyl / -Y- / 4-piperidinyl / -1H-benzimidazol-2-amine, 1.6 parts of sodium carbonate and 45 parts of M, H-dimethylacetamide are mixed in overnight at 80 ° C. The reaction mixture is poured into water and the product obtained is extracted with 4-methyl-2-pentanone. The obtained ex, the tract is dried, filtered and evaporated. The residue is purified on a chromatographic column with silica gel, using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the ethanedioate salt in methanol. The resulting salt is filtered off and dried, yielding 5.2 parts (55%) of 1-ethyl-1,4-dihydro-4- / 2- / 4 - // 1 - // 5 -methyl-2-furanyl / methyl / -1H- 5 benzimidazol-2-yl / -amino / -1-piperidinyl / ethyl / -5H-tetrazole-5-one-ethanedio5
0
.
at (1: 2) 17).
T „p 190.5 C (connection
Example. A mixture of 3.9 parts of 2,3-dihydro-1,4-benzodioxy-2-methanol-methanesulfonate (ester), 7.4 h 3 - // 5-methyl 2-furanyl / methyl / -i- / 4- piperidinyl / -ZH-imidazo 4,5-b pyridine-2-amine, 3.3 parts sodium carbonate and 90 hours M, H dimethylacetamide are stirred overnight at 80 ° C.
The mixture is poured into water and
Ny product is extracted with 4-me
thyl-2-pentanone. The extract obtained is dried, filtered and evaporated. The residue is purified on a chromatographic column with silica gel, using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the ethanedioate salt in methanol. This salt is filtered 1 J164
emerge and dry, yielding 2.2 parts (23%) of K- / 1 - // 2,3-dihydro-1,4-benzodioxin-2-yl - / - methyl / -4-piperidinyl / -3- / / 5 methyl-2-furanyl / methyl / -ZN-imidazo-4,5-b pyridine-2-amnthanthioate (1: 2). M.p. 222.3 ° C (compound 10),
Example 8. A mixture of 1.2 parts of 1-chloro-2-ethoxyethane 3.1 parts of 3 - // 2-me type-3-furanyl / methyl / - 1- / 4-piperidnnil / -ZN-imidazoЈ4 , 5-bJ pyridin-2-amine, 1.6 parts of sodium carbonate and 45 parts of M, M-dimethylformamide are measured overnight at 70 ° C. The reaction mixture is drunk in 50 parts of water. Petroleum ether is added and, after stirring, the crystalline product is filtered off, washed with water and petroleum ether and stirred in 1.1 oxybisethane. The resulting product
filter and sugaat at room temperature, obtaining 1.6 h. (38.1%) N- / 1- / 2-ethoxyethyl / -4-piperidinyl / -3 - // 2-methyl-3-furanyl / methyl / 3N-imidazo 4,5-b pyridin-2-amine dihydrate. M.p. 84.5 ° C (compound 24).
II p and me R 9. A mixture of 1.82 h. 3-bromo-1-propeca, 7.4 h. 3 - // 5-methyl-2-furanyl / methyl / -M- / 4-piperidinyl / - The 3N-imidazo 4,5-bJ pyridine-2-amino-phase dioato (2: 1), 4.7 parts of sodium bicarbonate and 120 parts of ethanol are stirred overnight at reflux. The reaction mixture is filtered and the resulting filtrate is evaporated. The residue is placed in water and extracted with trichloromethane. The extract obtained is dried, filtered and evaporated. The residue is purified on a chromatographic column with a silcagel, using trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to (E) -2-butanedioate salt in a mixture of 2-propanol and methanol. This salt is filtered off and dried, yielding 2 parts (23%) of 3 - // 5-methyl-2-furanyl / methyl / -M- (1- / 2-propenyl) -4-piperidinyl / -ZN-imidazo 4, 5-bj pyridine-2-amine (E) -2-butendioag (1: 2).
M.p. 172.7 ° C (compound 2).
The remaining compounds obtained in accordance with Examples 6-9 are listed in Table. one"
Pharmacological examples. Useful antihistamine properties of compounds of formula (I) can be used17
14
as an active ingredient in compositions.
Example 10. Protection of rats from mortality caused by the connection 48/80.
Compound 48/80 is a mixture of oligomers obtained by condensation of 4-methoxy-M methylbenzeneethanamine and formaldehyde, a potential agent that releases histamine. Protection against lethal circulatory collapse caused by 48/80 is a simple way to quantify the antihistamine activity of test compounds. In the experiments, male rats of an inbred Wistar strain weighing 240–260 g were used. After an overnight fasting, the rats were transferred to a lab-conditioned laboratory (temperature, relative humidity 65 ± 5-0.
The rats are subcutaneously or orally administered a test compound or vehicle (paciBop NaCl, 0S9%). After 1 hour after administration, they injected intravenously the 48/80 compound, freshly dissolved in water at a dose of 0.5 mg / kg (0.2 ml per 100 g of live weight). In control experiments in which 250 solvent treated animals were administered a standard dose of 48/80, no more than 2.8% of animals survived after 4 hours. Therefore, survival after 4 hours is considered as a reliable criterion of the synthetic effect of the administered drug. The ED 50 values of the compounds of formula (I) are listed in Table. 2 and represent live weight values at which the test compounds protect 50% of the test animals from death caused by the 48/80 compound.
Compounds of formula (I) can be read as toxic. Test compounds are administered to rats at doses of at least 40 mg / kg. Mortality was not found for compounds 2 - 7,9,11,13, 15,17,27 - 31, 39, 46 and 47.
Therefore, the ED value for the above compounds is significantly higher than 40 mg / kg body weight. Therefore, the compounds of formula (I) can be defined as perfectly safe5 considering that the average safety limit is above 1300.
Examples of pharmaceutical compositions in unit doses suitable for
systematic reception of animals or humans by the proposed method.
The active ingredient (All) used in these examples refers to a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
Example 11. Drops for oral administration.
50 g of All is dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of polyethylene glycol at 60-80 ° C. After cooling to 30-40 ° C, 35 L of polyethylene glycol is added and the mixture is thoroughly mixed. Then, a solution of 1750 g of sodium saccharin in 2.5 liters of purified ode is added and, with stirring, 2.5 g of cocoa flavor and polyethylene glycol are added to a volume of 50 liters, resulting in a solution for oral drops containing 10 mg of AI per 1 ml. . The resulting solution is filtered and filled into suitable containers.
Example 12. Solutions for oral administration.
9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 liters of boiling purified water. 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of All are first dissolved in 3 l of this solution. The resulting solution is combined with the remaining portion of the first solution and 12 L of 1,2,3-propantriol and 3 L of 70% sorbitol solution are added. Then 40 g of sodium saccharin are dissolved in 0.5 l of water and 2 ml of raspberry and gooseberry essence are added. This solution is combined with the first, water is added to a volume of 20 liters, and an oral solution is prepared containing 20 mg AI per teaspoon (5 ml). The resulting solution is filled into suitable containers.
Example 13. Capsules.
20 g of AI, 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate are mixed vigorously. The resulting mixture is filled with 1000 suitable hard gelatin capsules, each containing 20 mg of AI.
Example 14. Film-coated tablets
To obtain a tablet core, a mixture of 100 g of AI, 570 g of lactose and 200 g of starch is thoroughly mixed and moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in about 200 ml of water. The wet powder is sieved, dried and sieved again. Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are added to it. All this is well mixed and compressed tablets. 10,000 tablets are obtained, each containing 10 mg of an AI.
Coating.
To a solution of 10 g of methylcellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in i 150 ml of dichloromethane. Then 75 ml of dichloromethane and 1.5 ml of 1,2,3-propantriol are added, 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the first one, and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated color suspension are added, and all this is done with comfort.
The cores of the tablets are coated with the mixture thus obtained in coating systems.
Example 15. Solution for injection.
1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in about 0.5 l of boiling water for injection. After cooling to 50 ° C, 4 g of lactic acid, 0.05, is added with stirring g propylene glycol and 4 g AI. The solution is cooled to room temperature and supplemented with water for injection to a volume of 1 l, resulting in a solution containing 4 mg AI per 1 ml. The solution is sterilized by filtration and filled into sterile vials.
Example 16. Suppositories.
3 g of AI are dissolved in a solution of 3 g of 2,3-dihydroxybutanedioic acid in 25 ml of polyethylene glycol-400. 12 g of surfactant and triglycerides up to 300 g are melted together. The resulting mixture is thoroughly mixed with the first solution, poured into molds at a temperature of 37-38 ° C and get 100 suppositories, each of which
contains 300 mg AI.
li
Thus, the proposed method allows to obtain compounds with a higher antihistamine activity than the known ones.

权利要求:
Claims (1)
[1]
Invention Formula
Method for preparing N- (4-piperidinyl) -bicyclic fused 2-imidazolamine derivatives of general formula (I)
AlK-R,
R
h
Ln
uYt
,one /
 .N
their pharmaceutically acceptable salts
the addition of acids or their stereoisomers,
where A zA2-A ggA is a bivalent radical -CH CH-CH CH-, -N CH-CH CH-,,, -CH CH-CII N-;
R is hydrogen or Cj-Cg-alkyl;
Rj - furanyl, keel;
substituted C-C-al-Cz-Sb alkenyl, which may be substituted with a phenyl or a radical of the formula -Alk-R, where 30 R is hydrogen, phenylthio or phenylsulfonyl, 4,5-dihydro-5-oxo-14-tetrazole -1-yl, optionally substituted in 4 position by C -C-alkyl, 2,3-Cc dihydro-1,4-benzodioxin-2-yl, 4-morpholinyl or 1-pyridinyl, or if R, is furanyl substituted with C, -Cg-alkyl, and A A - 40 -CH CH-CH CH- or -N CH-CH CH-: then Rj is thienyl, 2,3-dihydro-2-oxo-1H-benzimidazole -1-yl or phenyl, which may be substituted with a C -C-alkoxy group or 45 of the formula -Alk-OR, where R $ C -Sf-alkyl or phenyl l that can be substituted by one
five
five
0
or two identical and different substituents of the group of () alkyloxy or apyl; or of the formula Alk-Z-CC O) -R, where C is -C alkyl, C-C4-alkylamino, alkyl-hydroxy or phenyl, which may be substituted by one or two identical or different substituents from the group halogen, С Сф- alkyloxy or C -C4 alkyl; Z is an oxygen atom, the group NH kpc is a simple bond, or the formula -CH -SHSON), where RЈ is phenyl, provided that A A2l-A3 A is -CH CH-CH SI-, -N CH-CH CH -, if L is a radical -Alk-ZC (0) -R, where Z, R have the indicated meanings,
characterized in that
piperidine of general formula (II)
R
AlK-Rj
HN
W4
1-D
where R, R, A have the indicated meanings;
N - alkylate with a reagent of general formula (III)
L-W, where W is easily detachable
L has the indicated values in an inert organic solvent and, if necessary, transform the compounds of formula (I) into a pharmaceutically acceptable acid addition salt by treatment with a suitable acid or, conversely, convert the acid addition salt to the free base by alkali treatment.
ABOUT
/
rarCHz- 1Lngsn-g
 iMl

7 6
7
7 6
s -CH2-CH2 vv
sg
4-SI30-C6N CIS
AxCH2-sn2-sp3-cng-o-sn2-sngHCH-S-CH -Z-djypaSKii-N CH-CH CHCHH-3-SND-a-fura yl-CH CH-CH CH
HCH2-5 CH3-2 furanyl-CH CH-CH CHNSNg-5-CH3-2-furanyl N CH-CH CHHCNg-5-SYa3-2-furansh1-L CH-CH CHHCHt-5-CH3-2-d ypaHrai- SI SP-CH2 CH2 (COOH);
194.1
m
about
a a
&
O O OOOOCOOOVD yiCT
N
N
d HI
PS
ZZ
GO
ABOUT
S
f
N5.
Yu
N - - - - N9
O - sao ooo-vo
NJ | OC N J - JOO
tfVV "4VV44V
About UiUiOC UiUJO ho (ji
Zz
o
o
O g o
r
Ol
h:
well
OOP N N m
I I I
1L U1 1L
OOP

W) 41 U1
I I I
NJ N N5
& -i 4
3 3 3
p w w
W)
P
II o

o ii o
g and
0o II II
SQ
tO4t-M
1I
oo

II II O
oo
Ya i
3
II
HCH
N X-
about

I
oh oh
п о ш (and К
about
(ABOUT
-v you - /
u o o o
about
N
3
i
Yu - -
. To) vЈ
- Oi O
Co
n
fa ol th
Iz
Dioat (1: 2)
27
1644717
Table 2
28

类似技术:

---

公开号 | 公开日 | 专利标题

---

AU751486B2|2002-08-15|Fused pyridine inhibitors of cGMP phosphodiesterase

---

US7410966B2|2008-08-12|Use of and some novel imidazopyridines

---

US5204346A|1993-04-20|Pyrazolopyridine compounds

---

EP1289985B1|2003-12-10|Beta-carboline derivatives useful as inhibitors of phosphodiesterase

---

JP2008509953A|2008-04-03|4-[[| -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl] amino] -3-methoxy-N- | benzamide hydrates and polymorphs, processes for their preparation and their use as drugs

---

EP3271362B1|2020-04-22|Heterocyclic compounds useful as inhibitors of tnf

---

CN105518005A|2016-04-20|Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors

---

WO2003074525A1|2003-09-12|Nitrogen-containing heterocyclic compound

---

PL192397B1|2006-10-31|Derivatives of piperidine substituted at their position 4 with 1,2-substituted 1-piperidinyl radical a antagonists of tachykinin receptor

---

CA2555176A1|2005-08-25|Hiv integrase inhibitors

---

JP2007528394A|2007-10-11|HIV integrase inhibitor

---

EP1497292B1|2006-06-14|Azaindolylpiperidine derivatives as antihistaminic and antiallergic agents

---

KR20110082189A|2011-07-18|Modulators of amyloid beta

---

SU1644717A3|1991-04-23|Method for preparing derivatives of n-|-bicyclic condensed 2-imidazolamine, their pharmaceutically acceptable acid-addition salts or stereoisomers thereof

---

AU703634B2|1999-03-25|Novel crystalline forms of anhydrous 7-{|-6-amino-3-azabicyclo|hex-3-y1}-6-fluoro-1- |-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid, methanesulfonic acid salt.

---

HU201553B|1990-11-28|Process for producing tetrahydrofuro- and -thieno|pyridines and pharmaceutical compositions comprising same

---

JP2010505747A|2010-02-25|Selective antagonist of A2A adenosine receptor

---

EP2935262A1|2015-10-28|Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders |

---

JP6585718B2|2019-10-02|New benzimidazole derivatives as antihistamines

---

DE60319254T2|2009-02-12|PYRAZOLAMIDES FOR THE TREATMENT OF HIV INFECTIONS

---

US4940789A|1990-07-10|10,11-dihydro-5-alkyl-12-substituted-10,5-|-5H-dibenzo[a,d]cycloheptenes as neuroprotectant agents

---

KR910005854B1|1991-08-05|Process for the preparation of imidazoquinolines containing other heterocyclic groups

---

CN102459278A|2012-05-16|Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones

---

CA2141366A1|1995-08-02|Treatment of heart rhythm disorders by administration of 3-phenylsulfonyl-3,7-diazabicyclo[3.3.1]nonane compounds

---

JP2006516144A|2006-06-22|Thiazole compounds as integrin receptor antagonist derivatives

同族专利:

---

公开号 | 公开日

---

DE3874013D1|1992-10-01|

---

GR3006205T3|1993-06-21|

---

FI882909A|1988-12-20|

---

CN1029964C|1995-10-11|

---

US4897401A|1990-01-30|

---

PT87742B|1992-10-30|

---

AU600144B2|1990-08-02|

---

KR890000484A|1989-03-15|

---

IE61728B1|1994-11-30|

---

DE3874013T2|1993-01-07|

---

JPS6425776A|1989-01-27|

---

ZA884346B|1990-02-28|

---

FI90233C|1994-01-10|

---

HU201755B|1990-12-28|

---

EP0295742A1|1988-12-21|

---

NZ224928A|1990-04-26|

---

PH25532A|1991-07-24|

---

IL86788D0|1988-11-30|

---

NO882641L|1988-12-20|

---

EP0295742B1|1992-08-26|

---

PT87742A|1988-07-01|

---

HUT48628A|1989-06-28|

---

DK333288A|1988-12-20|

---

IE881849L|1988-12-19|

---

NO167803C|1991-12-11|

---

CN88103784A|1988-12-28|

---

FI90233B|1993-09-30|

---

DK169761B1|1995-02-20|

---

IL86788A|1992-08-18|

---

DK333288D0|1988-06-17|

---

JP2609464B2|1997-05-14|

---

CA1324133C|1993-11-09|

---

NO882641D0|1988-06-15|

---

ES2045083T3|1994-01-16|

---

AT79878T|1992-09-15|

---

KR970001158B1|1997-01-29|

---

AU1810988A|1988-12-22|

---

FI882909A0|1988-06-17|

---

NO167803B|1991-09-02|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4219559A|1979-01-10|1980-08-26|Janssen Pharmaceutica N.V.|N-Heterocyclyl-4-piperidinamines|

---

US4556660A|1982-07-12|1985-12-03|Janssen Pharmaceutica N.V.|N--4-piperidinamines|

---

US4634704A|1983-10-06|1987-01-06|Janssen Pharmaceutica, N.V.|Anti-allergic five membered heterocyclic ring containing N--4-piperidinamines|

---

US4695569A|1983-11-30|1987-09-22|Janssen Pharmaceutica N.V.|Bicyclic heterocyclyl containing N--4-piperidinamines|

---

US4588722A|1984-01-09|1986-05-13|Janssen Pharmaceutica N.V.|N- bicyclic condensed 2-imidazolamine derivatives|

---

EP0232937B1|1986-02-03|1992-08-19|Janssen Pharmaceutica N.V.|Anti-histaminic compositions containing n-heterocyclyl-4-piperidinamines|

---

CA1317939C|1987-07-01|1993-05-18|Janssen Pharmaceutica Naamloze Vennootschap|¬methyl and -hetero| substituted hexahydro-1h-azepines and pyrrolidines|GB8716313D0|1987-07-10|1987-08-19|Janssen Pharmaceutica Nv|2-imidazopyridines|

---

GB8900380D0|1989-01-09|1989-03-08|Janssen Pharmaceutica Nv|2-aminopyrimidinone derivatives|

---

PH30434A|1989-04-07|1997-05-09|Janssen Pharmaceutica Nv|Hydroxyalkylfuranyl derivatives|

---

US5272150A|1989-04-07|1993-12-21|Janssen Pharmaceutica N.V.|Hydroxyalkylfuranyl derivatives|

---

KR100190299B1|1990-07-19|1999-06-01|디르크 반테|Novel oxazolyl derivatives|

---

US5217980A|1990-07-19|1993-06-08|Janssen Pharmaceutica N.V.|Oxazolyl and piperidinyl substituted benimidazolyl compounds|

---

NZ238863A|1990-07-19|1993-03-26|Janssen Pharmaceutica Nv|Substituted thiazolyl and pyridinyl derivatives|

---

FR2725986B1|1994-10-21|1996-11-29|Adir|NOVEL PIPERIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

EE04590B1|1999-06-28|2006-02-15|Janssen Pharmaceutica N.V.|Respiratory Syncytial Virus Replication Inhibitors, Their Use and Method of Preparation, Pharmaceutical Composition and Method of Preparation, and Product|

---

WO2001000612A2|1999-06-28|2001-01-04|Janssen Pharmaceutica N.V.|Respiratory syncytial virus replication inhibitors|

---

TR200500707T2|1999-06-28|2005-04-21|Janssen Pharmaceutica N.V.|Inhibitors of replication of respiratory system syncytial virus.|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US6389987A| true| 1987-06-19|1987-06-19|

---