Method of preparing heterocyclic derivatives of guanidine or their salts

专利摘要:

公开号:SU795471A3
申请号:SU772462806
申请日:1977-03-18
公开日:1981-01-07
发明作者:Ройс Расмуссен Крис
申请人:Макнейл Лабораториз Инкорпорейтед(Фирма)；
IPC主号:

专利说明:

The invention relates to the field of obtaining new guanidine derivatives possessing biological activity and which can be used in medicine. The patent literature describes uanidine derivatives x, in which The thermocyclic nucleus is five or six membered saturated with 1, 3-diazacarbocycle-2-ylidene. These derivatives have no substituent on the nitrogen atom of the iminogroup of guanidine. No data on the preparation of the proposed guanidine derivatives is absent. The aim of the invention is to expand the existing arsenal of means of influence on the body. The removed target is achieved by the described guanidine derivatives of the general formula (1): Bsr (CBbJ J "Bp-u-ir-ii-hydrogen, alkyl with Cy-Cd, cycloalkyl with Cj-Cg, alkene-2yl group with, hydroxy-lower alkyl group, aralkyl or aryl group; 1,2,3-, hydrogen, alkyl group with Cf-C or aryl group; hydrogen, alkyl group G or aryl group; hydrogen, methyl or ethyl group; alkyl group, cycloalkyl group c, ars1lkyl or aryl groups; taken together, they represent 5 both saturated heterocyclic rings of 3–7 members, subject to if the group is a sixth ring, then the said ring is interrupted by an oxygen atom
or a sulfur atom or an additional nitrogen atom, the additional nitrogen atom of the mochset being substituted by a lower alkyl group, a phenyl group or a benzyl group, or the indicated ring may be seen by a lower alkyl group at a carbon atom different from that which is in close proximity to the atom nitrogen associated with a carboximidamide group such as, for example, aziridinyl; azetidinyl, pyrrolidinyl, piperidino, 2,3,4,5,6, 7-hexahydro-azepinyl, morpholino, thiamorpholino, thiamorpholino-1-oxide, thiamorpholino 1, 1-di ksid, 2, b-di-lower alkylmorpholine (preferably, 2,6-dimethylmorpholino), 4-lower alkyl-piperazinyl (preferably 4-metilpiperazinyl), 4-phenylpiperazinyl, 4-benzylpiperazinyl, 2, b-di-lower-piperazinyl;
R is an alkyl group with a cycloalkyl group with Cj-Cg, a bicycloalkyl group with, o, a bicycloalkenyl group with, a tricyclealkyl group with, 1-admethyl group, a tricycloalkenyl group with an arylalkyl group in which the aryl radical is a member of a member, a member of a member, a member of a member, a member of a member, a member of a member, a member of a member of a the state consists of phenyl or naphthyl radicals, and the alkyl radical contains, o, o; 7 tetramethylene-phenethyl group, diphenylalkyl group in which is alkyl; the radical contains, a naphthyl group, a condensed diarylcycloalkenyl group, a condensed diarylcycloalkyl group, a phenylcycloalkyl group in which the cycloalkyl radical contains a C -C, cycloalkylcycloalkyl group, in which each cycloalkyl radical contains a phenyl group, a methylenedioxyphenyl group a phenyl group substituted by 1–3 substituents each of which is selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group; or a phenyl group substituted by a member selected from the group consisting of amino, dimethylamino, methylethylamino, diethylamino lower alkanoylamino group, thio-lower alkyl, sulfinyl-lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, lower alkyl alkanoyl or nitro group; an unsubstituted 3-pyridyl group or a 3-pyridyl group substituted on the ring carbon atoms by 1 to 2 members selected from the group consisting of a halogen atom, lower alkyl and lower alkoxy.
These compounds are obtained by the interaction of compounds of formula (II):
(111
is chlorine, megdec X, or ethoxy; is either BJ4, C1 CHjOSOs, or
at
OSOj5 with the proviso that h is only C1, when X is C1, with a compound of the general formula (III):
NT - (in)
where R, RJ.RS above, in an anhydrous organic solvent, at a temperature, and the resulting compound of formula (IV):
MR
H
сNR4R5-HI UV)
where rg
have the above values
treated with alkali and the desired product is isolated as a base or converted into salt.
In connection with the presence of the tertiary nitrogen atom in the compounds (D), salts formed upon the addition of an acid and quaternary salts can be obtained. The target compound (I) can be converted to therapeutically active, non-toxic salts formed upon the addition of an acid by treatment with an appropriate acid, such as, for example, an inorganic acid, such as a hydrohalic acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acid, for example acetic acid, propionic acid, glycolic acid, pamonic acid, pyruvic acid, malonic acid, succinic acid, ma leic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic,; acid, cinnamic acid; almond acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, para-aminobipicyclic acid. At the same time, the salt form can be converted by treatment with alkali into the free base form.
Therapeutically active quaternary ammonium salts can be obtained by carrying out the reaction between compound (I) and alkylation agents, for example alkyl, alkenyl or aralkyl halides, sulfate esters or sulfonates, such as for example methyl iodide, ethyl bromide, propyl bromide; allyl chloride, benzyl chloride, or di-n-alkyl alkyl sulfate-dimethyl sulfate, diethyl sulfate lower alkyl sulfonates of methyl-para-toluene sulfone atom; methyl fluorosulfonate.
The reaction to obtain the quaternary salts can be carried out in the presence or absence of a solvent, depending on whether the quaternary salt formation agent itself is capable or incapable of conducting itself, moreover, as a solvent at room temperature or under cooling, at atmospheric pressure or in a closed container, under pressure. Suitable organic solvents for the reaction are ethers, such as diethyl ether and tetrahydrofuran, hydrocarbons.
dyes, such as benzene and heptane, ketones, such as acetone and butanone, lower alkanols, such as ethanol, propanol, butanol or organic acid amides, taKHe, such as formamide or dimethylformamide. The anionic group of the quaternary salt can be easily exchanged by using appropriate ion exchange methods.
The target compounds described by formula (I), and their salts formed upon the addition of an acid, and quaternary salts possess valuable pharmacological characteristics, in particular, as anti-secretory and hypoglycemic agents.
The anti-secretory activity of the test compound was studied on female Sprague-Duly rats, after the intraduodenal administration of compound (i, d) with doses ranging between 2.5 and 40 mg / 1 kg of body weight. The rats were codified 24 hours before the experiments and they were given water and kept in individual cages. On the day of testing, the rats were weighed and selected so that the rats consumed in each experiment had a weight / divergence within + 20g.
Surgical intervention was performed with anesthesia with diethyl ether. As soon as the rats were anesthetized, their teeth were removed with small tweezers. A section was made along the midline of the abdominal cavity, about 1 1/2 cm long, and the stomach and the duodenal bone were exposed.
the colon. If at this point in time the stomach was filled with food or feces, the rat was not used for the experiments. Using the stitching of 4-0 sutures, a suture was placed in the longest part of the stomach close to the buttocks, being careful not to damage the blood vessels in this area. In the center of the suture, a small slot was made located in the center of the suture and a cannula consisting of a small
0 vinyl tube with a flange at one end, and after this cannula was inserted into the stomach, sutures were applied in close proximity to the flange. Immediately after this, the test compound was administered intraduodenally in a volume of 0.5 ml per 100 g of rat weight. Typically, three rats were consumed for each dose tested. Control rats received the solvent of the test compound, usually a 0.5% aqueous solution of methylcellulose.
After the test compound was infused, the abdominal cavity walls and the skin were closed successively, with
5 assisted by 3-4 18-mm clips and a tube used for sampling was inserted into the cannula. Then each rat was placed in a crate in which was
a slit is made in order
0 so that the cannula freely hangs and the rat moves to a certain extent. After the rat had stabilized for 30 minutes, the sampling tube was removed and replaced with a clean tube to obtain gastric juice. Gastric juice was sampled for 1 hour. At the end of the study, the cannula was removed and the rat was destroyed.
0
A sample of stomach contents was placed in a centrifuge tube and centrifuged in order to settle the solids. The volume was recorded and aliquots of the upper layer of liquid with a volume of 1 ml were placed in a beaker containing 10 ml of distilled water and titrated to pH with 0.01 n. sodium hydroxide solution. The results obtained were noted as volume, titrated acid and total acidity, where volume is the total number of milliliters of gastric juice minus sediment; titrated acid (milliequivalents / liter) amount
5 0.01 n. sodium hydroxide solution required for titration of the acid to pH 7; total acidity titrated acids x vol. The results were expressed as percentage inhibition relative to the results of the control experiment, and a minimum of 5% inhibition indicated anti-secretory activity.
In addition, the target compounds (I) and their salts have been established.
five
have the ability to reduce the sugar content in the blood (i.e., have glycemic activity), as indicated by experiments to determine the telerantivity of rats, especially with the compounds described by formula (I i).
Determination of the rat telerancy to glucose is a standard M and extremely sensitive cnocci6oM used in the diagnosis of diabetes and hypoglycemic diseases,
Male Sprague-Dewali rats (Charles River 134-250 g) drank water and were tied up 24 hours before the experiment. Blood samples (0.1 ml) were taken from the tail of rats without anesthesia after 0.30.60.90.020.150 and 180 minutes after oral administration of 1 g of glogose per 1 kg of body weight in 1 ml of water. Blood samples were immediately freed from proteins using an aqueous solution of barium oxide hydrate and zinc sulfate and the glucose level was determined by the glucose oxidase method.
Two to five rats were consumed in each experiment. In addition, they used a control group. Test compounds (1–200 mg / kg, subcutaneously or intraperitoneally) were introduced into a suspension in 0.5 ml or –1.0 ml (preferably, 0.5 ml) O, 5–1.0% methylcellulose solution. Control rats received the same amount of solvent subcutaneously. The blood glucose levels at each time point were expressed in mg% (mg glucose per 100 ml of blood). The average glucose levels in the control experiments were compared statistically using the method. The student's average value obtained for the experimental group for each experimental time point. If the compounds significantly reduced the glucose content in the blood at any time with a probable limit of 95%, then the compound was considered to have hypoglycemic activity.
PRI mme p.1. Z - (- 1 -) - N- (1 methyl-2-pyrrolidene) -N-phenyl-1-pyrrolidinecarboxyl imidamide tartrate,
To 1.84 g (0.013 mol) of boron trifluoride in anhydrous diethyl ether, under nitrogen, add 1.02 g (0.011 mol) of epichlorohydrin with rapid stirring, for 3 hours. The resulting crystalline triboxyloxy is washed with fresh anhydrous diethyl ether, decantation J under nitrogen. The crystals are dissolved in anhydrous C nrc l. To the solution was added 1.09 g (0.011 mol of 1-methyl-2-pyrolidinone and the mixture was stirred for 2 hours. To the resulting solution was added 0.01 mol of N-phenyl-1-pyrrolidinecarboxymylamide while cooling in an ice-water bath.
The reaction mixture is stirred overnight (approximately 16 hours). The mixture is evaporated to dryness in vacuo and then diluted with diethyl ether, causing the crude crystalline salt of HBFj 1- (1-methyl-2-pyrrolidinylidene) -N-phenyl-1-pyrrolidinecarboximidamide to crystallize. The crystals are recrystallized from acetone to obtain the purity of the fluoroborate salt, melting at a temperature of 164-1bb C. The fluoroborate salt is converted into the free base in medium 1 2 with a 20% sodium hydroxide solution, in ice. The organic layer is dried over anhydrous potassium carbonate, filtered and evaporated to dryness in vacuo to obtain a free base. An equimolar amount of g (+) - tartaric acid is added to the free base in methanol. The resulting solution is concentrated by adding isopropanol until all the methanol is not evaporated, with the formation of solitartrate upon cooling. After recrystallization from isopropanol with a small amount of methanol, a pure product is obtained, Z - (- I -) - N- (1-methyl-2-pyrrolidinylidene) -N-phenyl-1-pyrrolidinecarboximidamide tartrate, melting at 153, 5-156 C .
The results of example 2 are shown in table 1.
Example 2
B
 M
five
B / I N-C-M.EB BI.
table j
Ph
H H 0 1.2: 1
H H 1: 1
-CHPh Me
H H -M (Me) - / n 1.08: 1
Me
Ph
H H 1, / - 1
1 p-MePh Me H) 1-17: 1
I 2, 4-CH Me H
/ -
Fumarat
208-210
146-148,5
Tartrate
(120) 128.5-13
umarat 176-178
Ut-lie
HI
Example 3. N- (2, 6-dimethylfenyl) 11 -methyl-2-pyrro-lidilidene) -1-pyrrolidinecarboximidamide fumarate.
To a solution of 3.47 g (0.035 mol) of anhydrous 1-methyl-2-pyrrolidinone in an anhydrous atmosphere, in a dry nitrogen atmosphere, add 3.99 g (0.035 mol) of methyl fluorosulfonate. After 2 hours at room temperature, with stirring, at a time, a solution of 6.52 (0.03 mol) of the free base of N- (2,6-di-methylphenyl) -1-pyrrolidinecarboximidamide is added. After stirring overnight at rounding temperature, the reaction mixture was basified with an excess of cold 20% sodium hydroxide solution. The organic layer is separated and the aqueous phase is extracted with two portions of fresh CHjijiClj, 50 ml each. The combined organic extracts, after drying over anhydrous potassium carbonate, are filtered and rast-2 norbornyl
85.4; "2C; J Ph, N (
i-MePh N O
Me
Continued tab. one
the solvent is removed in vacuo, the residual oil is dissolved in diethyl ether and the solution is filtered through diatomaceous earth. After treating the filtrate with a hot solution of fumaric acid in isopropanol until neutral reaction, the product is obtained in the form of a fumarate salt. After recrystallization from isopropanol (filtering, not cooling), a pure product is obtained, fumarate M- (2,6-dimethylphenyl) -N- (1-methyl-2-pyrrolidinylene) -t-pyrrrolidine carboximidamide, melting at a temperature of 182-184 0 (with a slight decomposition). The results of example 4 are shown in table 2.
Example 4
- (bn2) lt
I I ((
N N - 1
table 2
161-174
Fumarat (decomp.) HI
1.90-191
(decomp.) "-Meph -I $ -1 Me -O 3-MePh -K S -CHjCH-CHj, 17: 1 3-OMePh M (Me) / | -CflaCH CHj, 1, 17: 1 3-MePh -U O 2 Me 1.2: 1
Example 5: This example illustrates methods for the preparation of quaternary salts of the compounds described by the foil 1 (1).
A.M- (2,6-Dichlorophenyl) -K - (1-methyl-2-pyrrolithio-i-iden-1-pyrrolidinecarboximidomidinyl) methofluorosulfonate
To 6.83 g (0.02 mol) M- (2,6-DICHLORPHENYL) (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide in anhydrous, 11 add 2.70 g; o, p23 mol) methyl fluorosulfonate with stirring under nitrogen. The mixture is stirred overnight and then evaporated to dryness in vacuo to an oily residue, which is triturated with diethyl ether to obtain crystals. After recrystallization from acetone, and then a pure product is obtained from ethyl acetate, N- (2,6-dichlorophenyl) -N - (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidomidinyl, methyl fluorosulfonate, is obtained. melting at temperature G48-150C.
B. N- (1-methyl-6-pyrrolidinylidene) -N-phenyl-1-pyrrolidinecarboxymidamidine, metoiodide
A solution of 0.05 mol of N- (1-methyl-2-pyrrlidinylidene) -N-phenyl-1-pyrrolidinecarboximidamide (Example 1-2), in the form of a free base, is treated with 0.05 mol of methyl iodide in 30 ml of acetone. After 2 days, the crystals are collected and recrystallized from acetone to obtain the pure N- (1-methyl-2-pyrrolidinylidene) -N-phenyl-1-pyrrolidinecarboximide ideine metoiodide, melting at 162-164 ° C.
The results of the analysis are as follows:
Continued table. 2 1, 2: 1 Fumarat -1/8 Fumarat
Calculated: C 49.52} H 6.11;
5 13.59.
N
Spn25
C 49.58} H 6.11;
Found%:
N 13.59.
C. Similarly, by treating the product described in Example 1D, in the form of a free base (0.05 mol) in diethyl ether (anhydrous) with methyl fluorosulfonate (0.05 mol), an oily residue is quickly obtained
5 which crystallizes. After recrystallization from tert-butanol, the product is obtained in the form of the corresponding methyl fluorosulfonate salt, melting at a temperature of 135.5-137 0
PRI me R 6. Hydroiodide N-feOnyl-N- (2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide.
A solution of 0.07 mol of triethyloxon fluoroborate in anhydrous CHjCl is prepared in the usual way, to which 6.08 g (0.079 mol) of 2-pyrrolidinone are added to the thief. After stirring for 2 1/2 hours, the mixture is falsified with 50% sodium hydroxide solution while cooling in a bath.
O with ice water. The organic layer is separated and dried over potassium carbonate. Thereafter, 12.28 g (0.065 mol) of H-phenyl-1-pyrrolidinecarboximidamine is filtered and treated.
5 The solvent is evaporated; it is tert-tubanol, and the resulting solution is heated for 22 hours at reflux temperature.
L The reaction mixture is allowed to cool to room temperature and thereafter, it is not hydrolyzed with hydrogen iodide (47%), resulting in the release of rts crude hydroiodide crystals.
5 roles. After recrystallization from 166-168 (rael.) 158-160 (decomp.) 120-122 ()) 8-151
tert-butanol gives the pure salt, N-phenyl-N- (2-pyrry Lidinylidene) hydronodide, 1-pyrrolidinecarboximidamide, which melts at 223-225 ° C (with decomposition).
PRI me R 7. Z - (+) - tartrate of N- (1-methyl-2-pyrrolidinylidene) -N-phenyl-1-pyrrolidinecarboximidamide.
To 0.99 g (0.01 mol) of 1-methyl-2-pyrrolidone in anhydrous benzene is slowly added with stirring, heating, at reflux temperature, 1.26 g (O, 01 mol) of dimethyl sulfate. The reaction mixture is stirred for another 5 hours. 1.89 g (0.01 mol) of M-phenyl-1-pyrrolidinecarboximidamide was slowly added to the mixture. The resulting mixture was stirred overnight at room temperature. The mixture is evaporated to dryness in vacuo and the residue is dissolved with CHjCl, after which the product is converted into the free base by treating with 50% sodium hydroxide solution in ice. The organic layer is dried over potassium carbonate, filtered and evaporated to dryness in vacuo to obtain 2.7 g oils. The oil is dissolved in methanol, and then 1.5 g (0.01 mol) of Z - (+) - tartaric acid is added. After recrystallization from methanol and isopropanol, the product, Z - () - TapTrate of N- (1-methyl-2-pyrpolidinylidene-) -N-phenyl-1-pyrrolidinecarboximidamide, is melted at 153-15 hbs.
Example Z- (+) -tartrate N- (1-methyl-2-pyrrolidinylidene) -N-phenyl-1-pyrrolidinecarboximidamide.
To a cooled solution of 1.98 g (0.02 mol) of 1-methyl-2-pyrrolidone in anhydrous toluene was added 3.95 g (0.04 mol) of phosgene. The resulting mixture was stirred under nitrogen at room temperature for 45 minutes to obtain white crystals. Excess phosgene and solvent are removed with a filter stick (under nitrogen). Fresh toluene is added, which is then removed in vacuo to remove residual phosgene. The crystals are washed with fresh toluene twice more and then dissolved in anhydrous CH., After which 1.89 g (0.01 mol) of M-phenyl-1-pyrrolidinecarboximidamide and 1.01 g (0.01 mol) of triethylamine are added. The resulting mixture was stirred overnight under a nitrogen atmosphere. The mixture is evaporated to dryness in vacuo and the residue is dissolved in, the solution is treated with 50% sodium hydroxide solution in ice. The organic layer, containing the product in the form of the free base, is separated, dried over anhydrous potassium carbonate, filtered and evaporated to dryness in vacuo to obtain an oily residue. They are dissolved in isopropanol and Z - (- f) tartaric acid is added to about pH 6-7. The resulting crystals are recrystallized from isopropanol to obtain the pure product, Z (+) - tartrate, N- (1-methyl-2-pyrrolidinylidene) -M-phenyl-1-pyrrolidine. carboximidamide, melted at 155-156s.
Q PRI me R 9. N- (1-methyl-2-pyrrolidiylidene) -N-phenyl-1-pyrrolidicarboximidamide; converted into the following pharmaceutically acceptable salts, resulting from the addition of inorganic and organic acids, by the usual treatment with the acid of the acids listed below:
Fumarate, melting point i56-157 Cf
0 phosphate, melting point 200-201C (with decomposition);
hydrobromide, melting point (206) 207-209 ° C;
oxalate, melting point
5 129-131s
pamoat, melting point 253-256 ° C
nitrate, melting point 170-171 ° C (with slight decomposition);
Q maleate, melting point 115-117-C; paraoxybenzoate, melting point 179-1BO C.
An example. N - (-aminophenyl) -N - (1 -methyl-2-pyrolidinidelidene) - 1-pyrrolidincarboximidamide hydrobromide.
N-- (1 -Methyl-2-pyrrolidinylidene) -N-C-nitrophenyl) - 1-pyrrolidinecarboximidamide 2.46 g (0.0078 mol) in 50 ml of absolute ethanol is subjected to hydrogenation (approximately 3 atmospheres) in a Parr mixture, on the skeletal nickel catalyst Rene. The hydrogen uptake is complete after about 0.5 hours. The catalyst is separated by filtration and the precipitate is washed with ethanol. The combined filtrates are evaporated in vacuo. The residue is dissolved in ethanol and neutralized with one quivalent aqueous hydrogen bromide solution (48% solution). The resulting solid is recrystallized from ethanol and diethyl ether to obtain pure hydrobromide N - (((- amnophenyl) (1 methyl 2-pyrrolidinylidene) - 1-pyrrolidinecarboximide 1 id, melted at
temperature 241-241, 5s.
The results of the analysis are as follows:
Calculated,%: C, 52.46; H 6.60; N.19,12.
1b HmM-NZch.
Found,%: C 52.44; H 6.60; 5 N 19.09.
Example. N- (acetylaminophenyl) -N - {) - methyl-1-pyrrolidinylidene) t hydrobromide - pyrrolidinecarboximidamide,
N- ((-aminophenyl) -N- {1 -methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide in free base form, 3.4 g (0 mol) heated on a steam bath with 25 ml of acetic anhydride for about h After this time, the reaction mixture was diluted with ethanol and heated for another 1 hour. The volatile components were removed in vacuo and the residue was treated with dilute aqueous solution of sodium hydroxide and extracted with methylene chloride.
After drying the extract over anhydrous potassium carbonate, filtering and removing the solvent, a residual oil is obtained which is converted to the corresponding salt, which is formed by the addition of acid, hydrobromic acid. In the medium of diethyl ether, the pure product -N- (A-acetylaminophenyl) -N- (1- methyl 2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide, melting at 246-247 C.
. EXAMPLE 12 N- (1-methyl-2-pyrrolidinylidene) -m - ((-methylsulfonylphenyl} -4-morpholino carboxymethyl amide.
To 1.98 g (0.0006 mol) of N- (4-methylthiophenyl) -N - (1-methyl-2-pyrrolidinylidene) - 4-morpholine-carboximidamide in the form of a free base in anhydrous methylene chloride, cooled to, is added, with stirring , 3.6 g (0.018 mol) of metachloro peroxybenzoic acid, and the temperature should not rise higher. The mixture is stirred at this temperature for 0.5 h, after which it is washed successively with saturated solutions of sodium bicarbonate (three portions of 40 ml) and sodium chloride (three portions of 35 ml) The organic layer is dried over carbon. potassium oxide, then filtered (using fine-grained material used to form the filter layer), then evaporated almost to dryness under vacuum. After dilution with methanol, some amount of insoluble material is formed, which is filtered and discarded. The filtrate is evaporated almost to dryness on a steam bath. After melting with diethyl ether, pure N- (1-methyl-2-pyrrolidinylidene) -N -, {-methylsulfonylphenyl) - (-morpholine-carboxy-amidamide, melting at (165) b7-170 ° C is obtained
The results of the analysis are as follows:
Calculated,%: C 56.03; H 6.64.
  ъ Found,%: C 56.05; H 6.69.
Example 3. N- (1-Methyl-2-pyrrolidi11idene) -N - (4-methylsulfinylphenyl) -t-morpholinecarboximidamide.
To the stirred solution, 98 g (0.006 mol) of N- (-methylthiophenyl) 5 -N - (1-methyl-2-pyrrolidinylidene) -4-morpholine-carboxyimidamide as a free base in methylene chloride, at a temperature, 1.22 g ( 0.006 mol) methachlorperoxyQ benzoic acid, so that the temperature is maintained at 5c. After that, the reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. The organic layer is sequentially saturated with sodium bicarbonate solution (three portions of 30 ml) and saturated sodium chloride solution (two portions of 30 ml) and dried over anhydrous potassium carbonate. After filtration, the solvent is removed in vacuo and after treatment of the residue with DIETHYL. EXAMPLE With ether and hexane, a crude product is obtained, which is recrystallized from diethyl
5 ether and hexane to obtain pure N- (1-methyl-2-pyrrolidinylidene) -N- ((-methylsulfinylphenyl) - (- morpholinecarboximidamide, melting at a temperature of (5) 7-120 C.
Q The results of the analysis are as follows.
Calculated.%: C 58.60; H 6.94.
C.7.
Found,%: C 58.58; H 6.91.
 Example14. Hydroiodide N-Ct-hydroxyphenyl) (1-methyl-2-pyrrolidinylidene) - -pyrrolidine carboxyme Damide.
A solution of 26.6 g (0.07 mol) of M- (1-methyl-2-pyrrolidinylidene) -m - (i (0-benyleyloxyphenyl) -1-pyrrolidinecarboxymidamide in the form of a free base in 50 ml of acetic acid) is placed in tr bitch Perra and hydrogenated under hydrogen pressure of about
5 3 atm over 10% palladium on carbon for about 2 hours, or until the absorption of hydrogen is complete, at room temperature. The reaction mixture is filtered and
The Q solvent is removed in vacuo to give a viscous oil, which is dissolved in acetone and treated with one equivalent of hydroiodic acid (concentrated aqueous acid).
The crystals of the crude product are recrystallized from methanol, acetone and diethyl ether to obtain the pure hydroiodide M- (-oxo-phenyl) -N- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide melting at 174-178 ° C
The results of the analysis are as follows.
Calculated,%: C 46.49; H 5.60; N 13.52.
 H .N 0. H.
Found,%: C 46.62; H 5.59; N 13.63,
PRI me R 15. Hydroiodide N-C-acetoxyphenyl) -N- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide,
12 g (0.20 mol) of glacial acetic acid are slowly added to a solution of 5.15 g (0.0124 mol) of the N- (4-hydroxyphenyl) -N- (1-methyl-2-pyrrolidinyl-ilidene) hydride in -1- pyrrolidinecarboximidamide and 41.2 g (0.20 mol of N, N-dicyclohexylcarbodiimide in 400 ml of acetone. The reaction mixture is stirred at room temperature, under nitrogen, for 3 days, the NN-dicyclohexyl urea is removed by filtration and the filtrate is concentrated in vacuo to give obtaining an amber oil. After several triturations with diethyl ether, a solid yellow substance is obtained. After recrystallization from acetone and diethyl ether, a white solid is obtained, melting at a temperature of (188) 195-197 ° C. Subsequent recrystallization from acetone, methanol and diethyl ether yields a pure hydroxyhydrogen N-Ct-aueTO Xphenyl) -N - (1 -methyl-2-pyrrolidinyldenide) -1-pyrrolidinecarboximidamide, in the form of a white solid, melting at a temperature of 196199 ° C.
The results of the analysis are as follows.
Calculated,%: C 47.38; H 5.52; N 12.28.
  Nj, 0r
Hi
Found,%: C 47.31; H 5.57; 12.26.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining heterocyclic guanidine derivatives of general formula (I)
f
yk
U1
and,
de R.
hydrogen, alkyl group with C, cycloalkyl group with Cj-Cy, alkene-2yl group with C.-C ", hydroxy-lower alkyl group, and aryl alkyl or aryl group} 1,2,3;
n R,
hydrogen, alkyl group with a C j -Cj or aryl group;
H
hydrogen
an alkyl group c-c .f-Cg or aryl group.
hydrogen, methyl group or ethyl group; an alkyl group with a Su-C, cycloalkyl group with a Cj-Cif aralkyl or aryl group
0
taken together, they represent a 37-member saturated heterocyclic ring; provided that in the event that the group
.four
N
is a six-membered ring, then said ring may be interrupted by an oxygen atom or a sulfur atom or an additional nitrogen atom, and the additional nitrogen atom may be substituted by a lower alkyl group, a phenyl group or a benzyl group, or the specified ring may be replaced by a lower alkyl group, on the atom carbon other than in the immediate vicinity of the nitrogen atom associated with the carboximidamide group, such as, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperid ino, 2,3,4,5,6,7-hexahydro-azepinyl, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino, 1-dioxide, 2,6, di-lower alkyl morpholino (preferably 2,6 dimethyl- morpholino) 4-lower alkyl-piperazinyl (preferably 4-methyl piperazinyl), 4-phenyl piperazinyl, 4-benzyl piperazinyl, 2,6-di-lower piperazinyl;
R is an alkyl group with, a cycloalkyl group with Cj-Cg, a bicycloalkyl group with
C-r-d- o
bicycloalkenyl group with
tricyloalkyl group with
,about,
1-adamantylmethyl group, tricycloalkenyl group with Cg-Cjo,
an aralkyl group in which the aryl radical is a member selected from the group consisting of phenyl or naphthyl radicals and the alkyl radical contains,
ff, fOi is a tetramethylene-phenethyl group, a diphenylalkyl group in which the alkyl radical contains a C-c f naphthyl group, a condensed diarylcycloalkenyl group, a condensed diarylcycloalkyl group, a phenylcyclo-loalkyl group in which a cycloalkyl radical contains a Cfi alkyl group that contains a cycloalkyl radical and a cycloalkyl group contains a cycloalkyl radical and a cycloalkyl group contains a cycloalkyl radical and a cycloalkyl group contains a cycloalkyl radical; A cycloalkylcycloalkyl group in which each cycloalkyl radical contains a Cg-C: phenyl group, a methylenedioxyphenyl group, a phenyl group substituted by 1 substituents, each of which is selected from the group consisting of a halo atom, a lower alkyl group, and a lower alkoxy group; or a phenyl group substituted with a member selected from the group consisting of Aminogen, dimethylamino, methylethylamino, diethylamino, lower alkanoylamino groups, thio-nizshegralkila, sul finil-lower alkyl-sulfonyl bottom Sheha alkyl, trifluoromethyl, gydroksila, benzyloxy, lower alkanoyloxy , a lower alkanoyl or nitro group, an unsubstituted 3-pyridyl group or a 3-pyridyl group substituted on the ring carbon atoms. 1-2 members selected from the group consisting of a halogen atom, a lower ahgkyl, and a lower alkoxy or their salts, characterized in that the compound of the general Formula (II): Il is a chloro, methoxy or ethoxy group; is either Bj, C1, CHjOSOj or OSOjf with the proviso that V is only C 1 when x - C t is reacted with a compound of general formula (III) NR e anhydrous organic melt at the temperature of the compound form IV) Bj .-.) p and c S-HBiBe-HI-Rj- have the aforementioned substances with alkali and the target product is isolated as a base and converted into salt. Sources of information, taken into account when examining Patent of England 1409768, 2 C, published. 1975.

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公开号 | 公开日

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ZA771644B|1978-10-25|

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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CA1201119A|1978-09-18|1986-02-25|Mcneilab, Inc.|Diaza-cyclic derivatives of guanidine|

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AU5263779A|1978-11-29|1980-05-29|Beecham Group Limited|Derivatives of thiazolidin-2-ylidene and oxazolidin-2-ylidene with hypoglycaemic acitivity|

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AT2075T|1979-04-20|1983-01-15|Beecham Group Plc|OXAZOLINE AND THIAZOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.|

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EP0018134B1|1979-04-21|1984-03-14|Beecham Group Plc|Dihydropyridine derivatives, processes for their preparation and pharmaceutical compositions containing them|

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EP0020304A1|1979-05-29|1980-12-10|Ciba-Geigy Ag|Guanidines, process for their preparation, pharmaceutical preparations containing such compounds and their application|

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JPS55160764A|1979-05-29|1980-12-13|Ciba Geigy Ag|Guanidine its manufacture and pharmaceutic medicine containing same|

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US4269837A|1980-02-19|1981-05-26|Pfizer Inc.|Hypoglycemic guanylamidines, compositions and use|

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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US66838676A| true| 1976-03-19|1976-03-19|

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