• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The method of obtaining the substituted N-imiomethylpiperidine, the general formula D) 1 "W A, R2 / where R is a hydrogen atom, o (-
    公开号:SU1158042A3
    申请号:SU792745899
    申请日:1979-03-28
    公开日:1985-05-23
    发明作者:Скотт Малькольм；Расмуссен Крис
    申请人:Макнейлэб Инк (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new substituted N-iminomethylpiperidine of the general formula -) I A RZ where R is a hydrogen atom, (X - (, 4-labels syphenyl) benzyl, fluorenyl, diphenyl C, | -C4. Alkyl, diphenyloxymethyl, (X -methylphenyl) benzyl; A is a hydrogen atom, or A together with RI is benzhydrylidene, a hydrogen atom or diphenylmethyl; „a hydrogen atom,. -alkyl EZ - a hydrogen atom,. alkyl phenyl (.) - alkyl, adamantyl, halo phenyl (C-C4.) - alkyl, Cz-Ce-alkenyl alkynyl, phenyl, or methoxybenzyl, or their salts with acids, which can be used to suppress gastric secretion The compounds obtained by the proposed method can be used in medicine. There is a known method for producing amidine by reacting amines with salts of imidoesters, imidothioethers lj or imidohalides .2 and p. The reaction is usually carried out in an organic solvent medium room temperature or heating. Derivatives of piperidine N-iminomete AJ are known. However, they are not inhibitors of gastric acid secretion. The purpose of the invention is the development of a method for producing new N-imino methylpiperidine derivatives with valuable pharmacological properties based on a known method. This goal is achieved by the fact that according to the method of obtaining new. substituted N-iminomethylpiperidine of the general formula I or their salts with acids, comprising the fact that. The compound of general formula Y-LF 22 where the values of the radicals R 1 J RI R have the indicated values, Z lower alkoxy, lower alkylthio or chlorine atom, X atom of halogen, OSO.CH, CHjCOO provided lower alkylthio, X iodine atom; is reacted with an amine of the general formula Rj has the indicated values and the target product is isolated in free form or as a salt with an acid. The reaction of a compound of general formula II with an amine of general formula III is carried out without a solvent or in the presence of an organic solvent (e.g., SPSl3, CHjCl) or a hydrocarbon (e.g. benzene, toluene) at 25-100 C. The desired products can be isolated as salts with acids such as hydrohalic acid, for example hydrobromic or hydroiodic acid; sulfuric acid, nitric acid, phosphoric acid, organic acids, for example, acetic acid, propionic acid, glycolic acid, pyravic acid, oxalic acid, malonic acid, succinic acid, malonic acid, malonic acid, succinic acid, maleic acid, picrinic acid, fumaric acid, almond acid, tartaric acid, malonic acid, malonic acid, malonic acid, malonic acid, propylene, oxalic acid α-toluene sulfonic acid, salicylic acid, 2-naphthalenesulfonic acid or para-aminosalicilic acid. . Example 1. Synthesis of 4- (diphenylmethyl) -1-N-ethyliminomethylpiperidinoxalate hemihydrate. Over a steam bath, a mixture of 8.00 g (0.29 mol) of H-frmyl-4-diphenylmethylpiperidide and 3.61 g (2.67 mg, 0.029 mol) of dimethyl sulfate is heated for 2 hours, resulting in a clear thick syrup , which is a compound of the formula bNz axis, OSOJOCH, CbN3. Then, to the obtained substance is added. 1.38 g (2.00 MP, 0.031 mol) of these amines in 15 ml of methylene chloride. The resulting solution was stirred for 1.5 hours at 25 ° C, distilled off, triturated in sulfuric ether and treated with 28 ml of Zn. sodium hydroxide. The ether layer was dried over ali carbonate, filtered through a filter with diatomaceous earth, and evaporated to give 8.77 g of a yellow liquid. By treating this liquid with isopropyl alcohol of 3.26 g of oxalic acid dihydrate, 5.0 g of a white substance are obtained with a melting point of 165-175 C. A recrystallization from isopropanol yields pure 4- (diphenylmethyl) -1-K-these iminomethyl- piperidinoxalate as a white solid with m. pl. 185-187 ° C. Example 2. Following the procedure of Example 1, but replacing N formyl-4-diphenylmethylpiperidine and ethylamine, which were used in Example 1 with equivalent amounts of the corresponding starting materials, the following products are obtained (Table 1): Example 3. Synthesis of 4- (diphenyl methyl) - 1-S -, (n-dodecyliminomethyl) -pi-peridinfumarate. A solution of 5.34 g (0,, 019 mol) of 4- (di-phenylmethyl) -1-piperidinecarbotialdehyde in 20 ml of chloroform is treated with 2.65 g (1.16 MP, 0.019 mol) of t-ylide and boiled under reflux for 1 hour. . The resulting solution of the compound of the formula "-CH- N C J 3" CHH5 is treated with 3.49 g (0.019 mol) of n-dodecylamine, boiled for 5 hours under reflux, cooled and treated with sodium hydroxide. The organic layer is separated. After drying, evaporation, an oil is obtained, which is converted to fumarate, yielding 4- (diphenylmethyl) -1-N- (n-dodecylyminomethyl) -pyperidine fumarate, m.p. square 143-145.6 C. Yield 2.75 g (25%). Example 4. Following the procedure described in Example 3, but the 4- (diphenylmethyl) -1-piperidine 1) botoaldehyde and n-dodecylamine substitutions used in this example, with equivalent amounts of the corresponding starting materials, synthesize the following compounds (Table 2): EXAMPLE 5. Alternative methods for the preparation of 4- (diphenylmethyl) -1-5 (octylimino) methyl piperidine, 1) A mixture of 2.90 g (0.01 mol) of 4- (diphenylmethyl) -1-piperidine carbothio. aldehyde, 129 g (0.01 mol) of n-octylamine, 0.60 g (0.01 mol) of glacial acetic acid and 20 ml of toluene are heated while stirring SRI two days at 60 C. The reaction mixture was concentrated and basified to give an oil which was identified by gas chromatography as the 4- (diphenylmethyl) -1- (oktilimino) methyl piperidine. 2) A solution of 1.0 g (0.0034 mol) of 4- (diphenylmethyl) -1-piperidine-carbobioaldehyde, 0.45 g (0.0034 mol) of n-octylamine and 6.0 ml of isopropyl alcohol is boiled in reverse by refrigerator for 8 hours. Using vapor chromatography, it was shown that 4- (diphenylmethyl) -1 (octylamino) methyl piperidine is present in the reaction mixture. 3) A solution of 40.0 g of M-formyl-4-diphenylmethylpiperidine (O, 143 mol) and 50 MP of methylene chloride is treated with phosgene until the gassing stops. After refluxing for 1 hour, the excess phosgene is distilled off under reduced pressure, the reaction mixture is diluted with 50 ml of methylene chloride and 24.8 mp (0.145 mol) of n-octylamine and 25 ml of methylene chloride are added at a rate such that maintain a gentle reflux. 28 ml of triethylamine are slowly added, the reaction mixture is stirred for 10 minutes and then poured into water. The organic phase is separated, washed with 20% sodium hydroxide solution, dried and distilled to obtain an oil, which is converted to 4- (diphenylmethyl) -1- (octlimino) methyl piperidine (E) -2-buta (yioat (1: 1) TLC-established hydrate Example 6, (Diphenylmethyl) -1-piperidinyl} methylenebenzenebutanamine (E) -2-butandioate hydrate Mixture 4.40 g (0.016 mp) N-forylethl-4- (difonylmethyl) piperidine and 1.47 ml (2.00 g, 0.015 mol) of dimethyl sulfate is heated on a steam bath for 3 hours at 100 s under anhydrous conditions until homogeneity is obtained. The resulting compound of the formula OGH, HS n is cooled They are dissolved in 30 ml of methylene chloride and treated with 2.50 ml (2.36 g, 0.16 mol) of phenylbutylamine. The resulting solution is stirred for 3 hours and treated with 6 ml of sodium hydroxide solution while stirring at OC. The organic layer is separated, dried over potassium carbonate, filtered, and evaporated to an oil. This substance is dissolved in isopropanol, treated with 1.84 g of fumaric acid and cooled, and solid be filtered. crystals that recrystall from ethanol. N-0 + - (diphenylmethyl) -1-piperidinyl} -methylenebenzo-Lbytanamine (E) -2-butandioate hydrate is obtained in the form of solid white crystals, mp. 20,208.5 ° C. Yield 2.80 g (34%). Example 7. Methods for determining suppression of the gastric juice. Compounds of general formula I are tested for inhibition of gastric acid according to the following procedure. Sprague-Doli rats (females) were fed for 24 hours before the start of the experiment and were given plenty of water when kept in individual cages. On the day of the experiment, the rats were weighed and selected so that the curts in each weight group did not exceed more than +20 g. Surgical intervention was performed under light ether anesthesia. After anesthesia occurred in the rat, its teeth were removed and an incision was made along the midline of the animal's abdomen about 38.1 mm in length and the stomach and duodenum were examined. If at that moment the rat's stomach was filled with food or fecal matter, the rats were rejected. If the stomach was in an acceptable condition, the cannula was implanted into the bottom of the stomach, paying special attention to not piercing the blood vessels in the area of operation. The cannula had a small vinyl tube with a flange at one end. The test compound was administered either into the duodenum (ID) immediately after the surgery, or via the pioT (p.o.) one hour before the surgery, in doses usually varying from about 0.25 to 160 mg / kg in a volume of 0.5 ml / 100 g rat. The control animals received a 0% aqueous solution of methylcellulose used in the experiments. After surgery and (in the case of ID injection) after insertion of the used compound, the walls of the peritoneum and skin were fastened simultaneously with three - 18 mm clamps and a test tube was placed on the cannula. Each rat was then placed in a box in which there was a slit for freeing the cannula and for free moving the rat. After the rat had calmed down for 30 minutes, the tube on the cannula was removed and replaced with a clean tube for collecting gastric juice. The juice was taken for 1 hour. At the end of the experiment, the cannula was removed and the rat was killed. l did .. Selected samples of gastric juice were placed in centrifuge tubes and turned on to obtain a precipitate. The volume was measured and 1 MP aliquots of the supernatant liquid were poured into the chemical composition, 10 ml of distilled water were in the beaker, and titrated to pH 7 0.01 n. sodium hydroxide. The results were determined by volume, titrated acid and total acid output, where the volume is equal to the number of millimeters of gastric juice minus sediment, the titrated acid is equal to the amount of 0.01 n. The sodium hydroxide required to titrate the acid to pH 7. The total acid output equals the product of the titratable acid by volume. The results are presented as the ED5 dose (mg / kg) required to achieve, on average, 50% inhibition of the total acid output against controls for all animals for a particular type of compound and as a percentage of inhibition. All compounds of the invention show significant suppression, both when administered inside the duodenum, and when administered through the 7 mouth in an amount of less than 80 mg / Kg with preferred compounds that have an ED 50 when administered orally in an amount of less than 20 mg / kg. In contrast to these data, the known L-im1Nometylpiperidine does not have an inhibitory effect in doses up to 100 mg / kg when administered through the mouth (oral administration) and in doses up to 8 mg / kg when administered in the duodenum. Following the experimental procedure described, the following
    -ABOUT
    Table 1
    Nli SALT 2 compounds for their antisecretory activity. The values of ED $ 0 should be for oral administration and the percentage of inhibition when administered to the duodenum at a dosage of 30 mg / kg is summarized in Table 3-5 (Rj is a hydrogen atom, except where otherwise indicated). The compounds of general formula I obtained according to the proposed method with a high inhibitory ability of gastric juice cleavage.
    .N para-Methoxybenzyl
    oi, - (4-MethoxyfeN n-Octyl Nile) benyl
    - (4-Methylphenyl)
    H Ng-Octyl benzyl
    H 4-MethylbenDiphenylmethyl zil
    H Phenyl
    R 1
    ; fc
    110.5-112.5 23
    27
    154.5-156
    31
    161-163,5
    32
    242-244
    285-286
    table 2
    , Nr,
    H - (CH,) C-CH
    (CHj CH,
    H-CHj
    H
    H n-CflH, j
    H
    Dife- n-GftH,
    H
    nnl
    methyl
    N p-se-i
    H
    H p-Sdsch
    Dife-N
    nilmetkp
    H N
    fu-caking HC1 at 125 ° С 131-135
    17 38 35
    117-119 174-177
    Hydrate fuma-cakes at rata68,5 ° C
    70-7263
    43
    Fumarat 167-170
    46
    Sintering at 145 with 155-161
    Fumarate 185.5-187.5 30
    "
    12
    Table 3
    CH (CHj) rn - (para-methoxyphenyl) benzyl. H - (para-methoxyphenyl) benzyl H (4-Chlorophenyl) benzyl - H - (1,4-Diphenyl)) 98% inhibition at 80 mg / kg i.d. #) 52% inhibition at 80 mg / kg i.d. ) Known compound.
    a +) R is a diphenylmethyl radical. .
    ) The compound was administered intraperitoneally. Benzyl 3,3 Fenetil. 3,7 para-Chlorobenzyl20,7 Hydrogen 40 para-Methoxybenzene n-Octyl
    2 (X - (- p-Methoxyphenyl) benzyl
    4 9-Fluorophenyl
    2 o -SA-Methylphenyl) benzyl
    6 Same
     4 Bönzgidrililiden
     H
    H
    - (4-Oxyphenyl) benzyl
    - (Phenyl) -a-hydroxybenzyl
    H Level
    Table "
    H n-Octil 16.9
    62 48 n-Octyl 15.9
    73
    82
    68.2
    92.2
    + +
    68
    + +
    Not active o
    H at 80 equipment: x) 98% inhibition at the initial dose, 1) 52% inhibition at the initial dose of 80 mg / kg,) Compound of the prior art. ) R - diphenylmethyl. ++) The compound was administered intracellularly. ..: Table5
    权利要求:
    Claims (1)
    [1]
    The method of obtaining substituted N-iminomethylpiperidine, General formula
    A, R. £ / where R 4 is a hydrogen atom, <X - (4-methoxyphenyl) benzyl, fluorenyl, diphenyl C ^ -C * -alkyl, diphenylvch; simethyl, bC- (4-methylphenyl) benzyl;
    A is a hydrogen atom or A together with R 4 - ( benzhydrylidene,
    R <is a hydrogen atom or diphenylmethyl;
    R 2 is a hydrogen atom, C f -C ^ -alkyl,
    R 3 is a hydrogen atom, C -C ^ -alkyl, phenyl (C! -C *) is alkyl, adamantyl, halogenophenyl (C, -C4.) Is alkyl, C 3 -C is alkenyl, alkynyl, phenyl or methoxybenzyl, or their salts with acids, from which a combination of the general formula wherein R 4 , A, R 4 , R 2 have the indicated meanings;
    Z is lower alkoxy, lower thio alkyl, or a chlorine atom;
    X is a Halogen atom, 0S0 3 CH 3 *, CH 3 COO provided that Z is lower alkylthio, '
    X is an iodine atom; . are reacted with an amine of the general formula R NH where R 3 are as defined and the desired product is isolated in the free form or as a salt with an acid.
    Prize priority:
    03/29/78 at R 3 - a hydrogen atom, <X- (4-methoxyphenyl) benzyl, fluorenyl, diphenyl C <-C ί, -alkyl, diphenyloxymethyl-0b- (4-methylphenyl) benzyl, A - a hydrogen atom, or A together with R 4 means benzhydrylidene, · R 2 is a hydrogen atom, C, -C * -alkyl, Rj is a hydrogen atom, C, -C f2- alkyl, phenyl (C 4 -C 4 ) -alkyl, adamantyl, halogenophenyl ( Cf-C <,) is alkyl, C, -Ce-alkenyl, alkynyl or methoxybenzyl, phenyl.
    02/08/79 at Rj - dodecyl.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US89141978A| true| 1978-03-29|1978-03-29|
    US1020979A| true| 1979-02-08|1979-02-08|
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