Method for preparation of imidazoline or pyrimidine derivatives or theirs physiologically tolerated

专利摘要:
New pharmacologically active heterocyclic derivatives as muscarinic receptor blocking agents, useful for the treatment of gastrointestinal disorders of the following formula whereinR is hydrogen atom or C₁₋₉ alkyl optionally substituted by 2 or 3 radicals, which may be identical or different from each other, selected from aryl, cycloalkyl, hydroxy and carboxamide;R₁ may be any group indicated for R, or NHR₄, in which R₄ is hydrogen atom, C₁₋₄ alkyl substituted by -OOCR₅, in which R₅ is methyl sub­stituted by 2 or 3 radicals, which may be identical or different from each other, selected from aryl, cycloalkyl and hydroxy, or a cycloalkyl substituted by another cycloalkyl;R₂ is hydrogen atom, C₁₋₄ alkyl, a radical -OOCR₅, in which R₅ is as hereinbefore defined;R₃ is hydrogen atom or C₁₋₄ alkyl;n is 0, 1 or 2provided that at least one among R, R₁, R₂ and R₃ is different from hydrogen atom. The tautomers of the compounds of formula (I) and acid addition salts thereof, as well as the processes for their preparation and pharmaceu­tical compositions containing them are also described
公开号:SU1676446A3
申请号:SU884356369
申请日:1988-09-09
公开日:1991-09-07
发明作者:Никола Массимо；Донетти Артуро；Цереда Энцо；Туркони Марко；Скиави Жованбаттиста；Микеллетти Розамария
申请人:Институто Де Анджели С.П.А. (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of novel chemical compounds, imidazoline derivatives or pyrimidine of the general formula
BUT

R, -C- (CH2VNfN
G (sn2) n
where R is hydrogen or methyl;
RJ and RЈ are selected from the group: phenyl or cycloalkyl with 3-6 carbon atoms;
p-0 or 1;
w, integer, which can be used in medicine.
The purpose of the invention is to find a method for producing new derivatives in the imidaeoline and pyrimidine series, which are highly antistatic.
Example 1: 1- (3-Phenyl-3-cyclehexyl-3-hydroxy) -propyl--1,4,5,6-tetrahydropyrimidine hydrochloride.
A mixture of 1.26 g of 1-phenyl-1-cyclohexyl-3-chloro-1-propanol and 0.42 g of 3,4,5,6-tetrahydropyrimidine in 15 ml
Os
v | Os
fc
ABOUT

WITH
anhydrous dimethylformamide is heated at 75-80 ° C for 30 hours. The solvent is evaporated in vacuo and the residue is purified by column chromatography (eluent: methanol-acetic acid-aqueous ammonia in a ratio of 100: 2: 3). The combined fractions are evaporated, the residue is taken up in methylene chloride and washed with water. After evaporation of the solvent, the desired product is obtained as a free base, which is treated with ethanolic hydrochloric acid. Obtain 0.5 g of 1- (3-phenyl-3-cyclohexyl-3- -oxy) -propyl-1,4,5,6-tetrahydropyrimidine hydrochloride, mp 203-205 ° С (compound 1) Mass Spectrum : 301 m / e m + n Calculated,%: C 67.74; H 8.68; N 8.32.
with „ngvmgo
HC1
Found,%: C 67.51; H 8.62; N 8.38.
In the manner described above, 1- (3-phenyl-3-cyclohexyl-3-hydroxy) -propnl-2-methyl-2-imidazoline hydrochloride (compound 2) is obtained, m.p. 231- 233 ° C. +
Mass spectrum: 301 m / e m + Hj.
Calculated,%: C 67.74; H 8.68; N 8.32.
C b 7,74; H 8.68;
CnH7gN20 HC1
Found,%: C 67.59; H 8.70; N 8.36.
EXAMPLE 2 1- (4- -Phenyl-4-cyclohexyl-4-hydroxy) -butyl--2-methyl-2-imidazoline hydrochloride.
a) To a stirred and cooled with ice solution of 60 mmol of cyclohexyl magnesium chloride in 23.2 ml of dry ether is added 5.5 g of 4-chlo-butyrophenone in 17 ml of ether. The mixture is stirred at 0 ° C for
2 h, then an aqueous solution of sodium chloride is carefully added. The organic phase is separated and dried. The solvent is removed and the residue is purified by column chromatography (eluant: hexane-ether in a ratio of 98: 2). 5 g of 1-phenyl-1-cyclohexyl-4-chloro-1-butanol are obtained in the form of an oil (compound 3).
Mass spectrum: 267 m / e M + Hj.
b) A mixture of 1-phenyl-cyclohexyl-4-chloro-1-butanol and 2-methyl-2-imidazoline in dimethylformamide is treated in the manner described in example 1 to obtain 1- (4-fe0
five
0
five
0
five
0
five
0
nyl-4-cyclohexyl-4-hydroxy) -butyl-2-mr-2-imidazoline, mp 185-188 ° C.
Mass spectrum: 315 m / e Јm + n.
Calculated,%: C 68.45; H 8.90; N 7.98.
sgon30y2onns1.
Found,%: C 68.40, H 8.88; N 8.01.
In the manner described above, 1- (4-phenyl-4-cyclohexyl-4-hydroxy) -butyl-1,4,5,6-tetrahydropyrimidine hydrochloride, m.p. 227-229 ° C (compound 4), is obtained.
Mass spectrum: 315 m / e m + Hj.
Calculated,%: C 68.45; H 8.90; N 7.98.
C2oH3oNzO .. HC1.
Found,%: C 68.37; H 8.87; N 8.02.
PRI me R 3. Antispastic action.
The antispastic effect of the compounds is determined on the guinea pig isolated gut, using the betan chol as a spasmogenic agent.
Guinea pigs (450-455 g) are killed by cutting off the head, then immediately cut a 2 cm long rectum. The fabric is placed in a bath (10 ml) containing a solution of the following composition, mmol: sodium chloride 137; potassium chloride 2.68; calcium chloride 1.82; sodium bicarbonate 5.9; magnesium chloride 1; sodium hydrogen phosphate 0.42; Glucose, 5.6. Test run at 37 ° C, residual voltage 800 mg. By cumulative addition of 0.3-30 µmol of betan-chol, contractions are excited, with the maximum response surviving after each addition. 60 minutes before repeating agonist stimulation, antagonists are added.
The antagonist-induced change in the curve of response to different concentrations of betanol is used to create a dose / response curve (DR).
Kv (dissociation constant) is determined by linear regression analysis:

TO
at
DR - 1
where B is the concentration of the antagonist under investigation.
The results of the experiment are presented in the table.
Compound
nmol
 A comparison of the data in the table indicates a higher antispastic activity of new compounds in comparison with atropine.
The novel compounds are classified as medium toxic substances.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining imidaeolin derivatives or pyrimidine of the general formula
night {CHjh
Rl-C-CCHz -N N K2R
where R is hydrogen or methyl;
R f and R are selected from the group phenyl or Cj-C-cycloalkyl;
n 0 or 1;
m 1-5 (integer), or their physiologically tolerable acid addition salts, characterized in that the compound of the general formula
the night
) m-x
V
where t, K and R, have the indicated meanings;
X is a removable group, reacted with a compound of the general formula
. HN-f N
where R and p have the indicated meanings, in an inert organic solvent medium, followed by isolation of the desired product in free form or as a salt.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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IT8721976A|IT1231237B|1987-09-21|1987-09-21|HETEROCYCLIC DERIVATIVES|

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