JPS6217588B2 - - Google Patents

Description

[Detailed description of the invention]

Unsubstituted N-iminomethylpiperidines are described in U.S. Pat.
Even doses more than double the dose do not suppress gastric acid secretion. Surprisingly, it has now been discovered that certain substituted N-iminomethylpiperidines are effective inhibitors of gastric acid secretion. The present invention is based on the formula (): It consists of substituted N-iminomethylpiperidines, where R ₁ is independently hydrogen; phenyl; phenyl (C ₁ -C ₄ ) lower alkyl; diphenyl (C ₁ -C ₄ ) lower Alkyl; at least one of the phenyls is selected from the group consisting of lower alkyl, lower alkoxy, halo, hydroxy and phenyl;
Diphenyl (C ₁ -C ₄ ) lower alkyl substituted with ~3 members, provided that more than one member is not phenyl; diphenylhydroxymethyl; at least one of the phenyls is lower alkyl , lower alkoxy, hydroxy, halo and phenyl.
It is replaced with 3 members, but there is a condition that 1
diphenylhydroxymethyl such that more than one member is not phenyl; and the formula

[Formula] and

A member selected from the group consisting of compounds of the formula
where n is 0 and E is H; A is independently a member selected from the group consisting of hydrogen; acetyl, with the proviso that when A is acetyl, R ₁ is phenyl R ₁ and A together are benzhydrylidene; R ₁ ′ is independently hydrogen; diphenylmethyl; B is independently hydrogen; R ₁ ″ is independently is hydrogen; D is independently hydrogen; _R2 is a member selected from the group consisting of hydrogen and _C1 - _C4 lower alkyl; and _R3 is hydrogen; alkyl; cycloalkyl; phenyl lower alkyl; phenyl lower alkyl substituted with 1 to 3 members each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halo; selected from the group consisting of alkenyl and alkynyl; provided that at least one of R ₁ , R ₁ ′, R ₁ ″, R ₂ and R ₃ is other than hydrogen. As used herein, lower alkyl and lower alkoxy are straight chain or branched saturated aliphatic hydrocarbons having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl. and similar lower alkyls and the respective corresponding lower alkoxys, such as methoxy, ethoxy, propoxy, butoxy, pentoxy and the like. The term " _C1 - _C4 lower alkyl" includes lower alkyls having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and the like. “Phenyl (C ₁ - _{C 4} ) lower alkyl” and “Diphenyl (C ₁
~ _C4 ) Lower alkyl" includes only compounds in which a phenyl group is bonded to the terminal carbon atom of a straight chain lower alkyl, such as 2-phenethyl, 4-phenylbutyl, 4,4-diphenylbutyl, 3,3
-Includes diphenylpropyl, etc. The term "alkyl" includes straight-chain or branched saturated aliphatic hydrocarbons of up to about 16 carbon atoms, such as the lower alkyls listed above and others such as hexyl, heptyl, octyl, nonyl, decyl, dodecyl. ,
Included are groups such as hexadecyl and the like. The term "cycloalkyl" includes mono-, di- and tri-cyclic saturated and unsaturated aliphatic hydrocarbons having up to about 10 carbon atoms, such as cyclohexyl, adamantyl, 1-adamantyl-methyl, exo- These include norbornyl, endo-norbornyl, noradamantyl, anti-7-norbornenyl, and the like. The terms "alkenyl" and "alkynyl" include straight-chain and branched hydrocarbons having from 2 to about 18 carbon atoms and at least one double or triple bond, such as allyl, methallyl, respectively; 1-propargyl (1-propynyl),
Includes 2-pentenyl. The term "halo" includes fluoro, chloro, bromo and iodo. Methods of Preparation Compounds of formula are generally prepared by combining (a) a suitably substituted piperidine of formula () with a suitably activated amide (formula), or (b) a suitable primary amine of formula (). _{Activated N- (} ^{acylpiperidines} _of ^{the formula -} ,
It is obtained by treatment with a suitable activator selected from (MeO) ₂ SO ₂ , MeOSO ₂ F, POCl ₃ , PCl ₅ and the like. The terms "amide" and "N-acylpiperidine" herein refer to the corresponding thio derivatives in which the carbonyl oxygen is replaced by sulfur.
In the case of thio derivatives, other suitable activators such as lower alkyl halides (preferably methyl halides), methyl tosylate, methyl sulfonic acid esters (for example methyl methanesulfonate),
Methyl trifluoromethyl sulfonate and the like can be used. The activated reactant of formula () can be in free base or acid addition salt form. The specific manufacturing steps are as follows: (A) Compounds of formula () are prepared by reacting a suitably substituted piperidine of formula () with a suitable imidate ester of formula (). Methyl and ethyl esters are preferred.
Substituted piperidine and imidate esters, which can exist in free base or acid addition salt form;
(the latter is indicated) in a suitable organic solvent such as a halocarbon (e.g. carbon tetrachloride, chloroform, 1,2-dichloroethane, etc.), a lower alkanol (e.g. methanol, ethanol, isopropanol, etc.), an aromatic hydrocarbon (e.g. benzene, etc.). , xylene, toluene, etc.), dimethyl sulfoxide, etc.). The reaction temperature is preferably from about 0° to about 25°C, and in some cases can be carried out as high as 50°C, but in all cases the reaction temperature is sufficiently high to decompose a significant amount of the imidate ester. Must not be. The resulting product can be isolated and purified by techniques known in the art, such as by removing the solvent and recrystallizing the desired product in free base or acid addition salt form.
The above reaction formula is shown below, where A, B,
D, R ₁ , R ₁ ′, R ₁ ″, R ₂ and R ₃ are as defined above, and Z is lower alkoxy (preferably methoxy and ethoxy), lower alkyl-S- (preferably is methylthio), chloro and _Cl2
(O)PO-, and X
is a member selected from the group consisting of halides, BF ₄ , FSO ₃ and CH ₃ OSO ₃ . Furthermore, when Z is lower alkyl-S-, X is (4
_{-methylphenyl} ) _SO3 , _{H3SO3 and CF3SO3}
It can also be a selected member of the group consisting of. Compounds of formula () in which R ₂ is hydrogen can also be prepared by a similar process by replacing the imidate ester of formula () with a suitable compound of formula (A) or (B). If the former is used, the thiourea formed is then reduced (eg with Raney nickel) to give the desired compound. If you use the latter,
Silver chloride is used as a catalyst. These reaction formulas are expressed by the following formulas: (B) Compounds of formula () are prepared by combining a suitably substituted piperidine of formula () with acetic anhydride, formic acid or N.
N-di-lower alkylthioformamide (R ₂ =
H) or _C1 - _C4 lower alkyl anhydride ( _R2
= _C1 - _C4 lower alkyl), where the anhydride is preferably present in excess. piperidine and anhydride or thioformamide are combined with cooling;
and stir for about 18 hours. The resulting reaction mixture is dissolved in an organic solvent selected from the halocarbon and aliphatic hydrocarbon solvents mentioned above or without the addition of a solvent, and then treated with a weak base (e.g. carbonic acid) until the aqueous phase is neutral. (sodium hydrogen) (for the anhydride process) or washed with water (for the amide process). The organic layer is separated and the solvent present is removed to obtain the corresponding intermediate amides (), (A) and (). The intermediate amide is reacted neat or in the presence of an organic solvent such as a halocarbon (CHCl ₃ , CH ₂ Cl ₂ ) or a hydrocarbon (benzene, toluene) at 25° to 100° C. with a suitable activator as described above. The activated derivative () is prepared by processing for 2-3 hours, after which the reaction mixture is left to cool. Addition of the appropriate primary amine () gives the desired product of formula (), which is isolated and purified by the known methods described above. The above reaction formula is expressed by the following formula, where R ₁ , R ₁ ′, R ₁ ″, R ₂ , R ₃ , A,
B, D, Z and X are as originally defined: When Z is (lower alkyl)-S-, the activated intermediate product () has the formula ()
R ₂ = R 2 =
A compound of formula () which is H is obtained. This reaction equation is explained by the following equation: Since the subject compounds () have a basic amidine group, they can also be converted into the corresponding acid addition salts. Acid addition salts are prepared using suitable acids such as inorganic acids such as hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid; sulfuric acid or nitric acid; phosphoric acid; organic acids such as acetic acid, propionic acid, glycolic acid,
pamoic acid [4,4'-methylenebis(2-hydroxy-2-naphthoic acid)], pyromic acid, oxalic acid, malonic acid, succinic acid, maleic acid, picric acid, fumaric acid, malic acid , tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
It can be produced by reaction with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid or p-aminosalicylic acid. Therapeutically active non-toxic acid addition salts of the subject compounds () are also included within the scope of this invention. Formula (), (), (), (A), (), (
),
Are the starting materials of () and () known?
Alternatively, it can be manufactured by a known method. In general, RC Elderfield (RC
Elderfield), “Heterocyclic Compounds”, vol. 1, 9.
See Chapter, pp. 617-77 (1950). The method for producing compounds () is, for example, F.Ravenna.
Literature by Farmaco (Papia)
(Pavia), Ed.Sci. 14 , 473-82 (1959) and E. Sury and K. Hoffman, Helv.
Chim.Acta.), 248 , 2133 (1954). Methods for producing compounds () and () are described, for example, in the literature by R. Ohme and E. Schmitz, Angew.Chem.Intern.Ed. ), 6 , 566 (1967),
F.Snydam and other journals
Of the Organic Chemistry (J.Org.
Chem.), 34 , 292 (1969) and K. Sechinger, Helv.
Chim.Acta.), 56, 776 (1973). The methods for producing compounds () and () are described in, for example, "Survey of Organic Syntheses" by CA Buehler and DEPearson,
Chapter 18, page 894 (1970). Test Methods The compounds of the present invention are useful for inhibiting gastric acid secretion as measured by the following test. Female Sprague-Dawley mice are fasted for 24 hours prior to testing and are given water ad libitum while kept in individual cages. On the day of the test, weigh the mice and choose the weight of each test mouse to be within ±20 grams. The surgery is performed under light ether anesthesia. Once the mouse is anesthetized, the teeth are removed and an incision approximately 11/2 inches long is made in the middle of the abdomen and the stomach and duodenum are exposed. If the stomach is full of food or fecal material at this point, discard the mouse. If the stomach is in good condition, the fundic portion of the stomach should be sewn with a purse string.
stitch), being careful not to puncture the blood vessel in that area. Next, a small incision is placed in the center of the purse string in the stomach, a cannula consisting of a small vinyl tube with a flange at one end is placed into the stomach, and the purse string is placed around the flange. Tighten the sutures. Test compounds are administered intraduodenumally immediately after surgery or orally 1 hour before surgery, typically at approximately
0.5ml/with a dosage within the range of 0.25 to approximately 160mg/Kg
Administer in a mouse volume of 100 g. Control mice receive the test vehicle, 0.5% aqueous methylcellulose. After surgery and (in the case of intraduodenal administration) after administration of the test compound, the abdominal wall and skin are
Close simultaneously using two wound clamps and place the collection tube over the cannula. Each mouse is then placed in a box with vertical slits so that the cannula can hang freely and the mouse can move about undisturbed. 30 mice
After a minute of rest, the collection tube on the cannula is discarded and replaced with a clean tube to collect gastric fluid. Collect every hour. At the end of the study remove the cannula and kill the mouse. A sample of the collected stomach contents is drained into a centrifuge tube and centrifuged to solidify the sediment. Measure the volume and place a 1 ml portion of the supernatant into a beaker containing 10 ml of distilled water, and
Titrate to pH 7 using 0.01N sodium hydroxide. Results are measured in terms of volume, titratable acid and total acid flux, where volume is gastric fluid minus sediment; titratable acid (meq/).
is the amount of 0.01N sodium hydroxide required to titrate the acid to pH 7; and total acid flow is the volume of titratable acid. ED RESULTS ₅₀
dose (in all animals tested for a particular compound, an average of 50% in total acid efflux vs. control)
The dose required to produce % inhibition (mg/Kg) and % inhibition rate are reported. All compounds of the invention are
80 for both intraduodenal and oral administration.
Significant inhibition was shown below mg/Kg. In comparison, prior art N-iminomethylpiperidine showed no inhibition at a dose of 100 mg/Kg for oral administration or even at a dose of 80 mg/Kg for duodenal administration. It is well known that excessive secretion of hydrochloric acid in the stomach results in excessive digestive activity and poses a risk to the gastric mucosa. Therefore, it is desirable to use gastric acid secretion inhibitors as an adjunct to prevent and improve the suffering caused by high concentrations of gastric acid. Description of Preferred Embodiments Preferred compounds of the present invention are preferred compounds of the present invention, in which R ₁ is phenyl; phenyl (C ₁ -C ₄ ) lower alkyl; at least one of the phenyls is lower alkyl, lower alkoxy, halo, and phenyl. a member selected from the group consisting of diphenyl (C ₁ -C ₄ ) lower alkyl substituted with 1 to 3 members each selected from the group, provided that more than one member is not phenyl; R ₂ is a member selected from the group consisting of hydrogen and methyl; R ₃ is each selected from the group consisting of hydrogen; alkyl; cycloalkyl; phenyl lower alkyl; phenyl is each selected from the group consisting of lower alkyl, lower alkoxy and halo; phenyl lower alkyl substituted with 1 to 3 members; a member selected from the group consisting of alkenyl and alkynyl; and R ₁ ′, R ₁ ″, A, B, and D are each hydrogen; Further preferred compounds of the present invention are those of formula () in which R ₁ is diphenylmethyl and at least one of the phenyls is selected from the group consisting of lower alkyl, lower alkoxy and halo, respectively. Ta1~
a member selected from the group consisting of diphenylmethyl substituted with 3 members; R ₂ is hydrogen; R ₃ is hydrogen; alkyl; phenyl lower alkyl; phenyl consists of lower alkyl, lower alkoxy and halo 1-3 each selected from the group
phenyl lower alkyl substituted with 2 members;
a member selected from the group consisting of alkenyl; and alkynyl; and R ₁ ′, R ₁ ″, A, B and D are hydrogen. The compound is a member in which R ₁ is a member selected from the group consisting of diphenylmethyl and diphenylmethyl in which at least one of the phenyls is substituted in the para position with a member selected from the group consisting of lower alkyl, lower alkoxy and halo; R ₂ is hydrogen; R ₃ is a member selected from the group consisting of hydrogen, straight chain alkyl and phenyl lower alkyl; and R ₁ ′, R ₁ ″, A,
It is of the formula () where B and D are all hydrogen. Description of Treatment Methods and Pharmaceutical Compositions In terms of the secretion-suppressing activity of the compounds of the present subject matter, the substitution of formula ( Further provided is a method for suppressing gastric acid secretion, which comprises internally administering the N-iminomethylpiperidine, preferably mixed with a pharmaceutically acceptable carrier. If acid addition salt forms are used, the salts must, of course, be pharmaceutically acceptable and non-toxic. Pharmaceutical compositions containing the subject compounds () are also considered to be another aspect of the invention. To prepare the pharmaceutical composition of the present invention, a substituted N-iminomethylpiperidine of formula () or an acid addition salt thereof is used as an active ingredient and combined with a pharmaceutical carrier according to common pharmaceutical compounding techniques. Mix thoroughly. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral administration. For preparing compositions for oral dosage forms, the usual pharmaceutical vehicles can be used, such as oils, alcohols, flavoring agents, preservatives in the case of oral liquid preparations, such as suspensions, elixirs and solvents. or, in the case of oral solid preparations such as powders, capsules and tablets, carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants, etc. may be used. can. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are of course employed. If desired, tablets may be sugar-coated or enteric-coated by conventional techniques. For parenteral use, the carrier is usually sterile water, but may also contain other ingredients, eg, to aid solubility or for preservative purposes. Injectable suspensions may also be prepared, in which case a suitable liquid carrier,
Suspending agents etc. can be used. Here, the pharmaceutical composition is
Each dosage unit, such as a tablet, capsule, powder, injection, scoop, etc., contains from about 10 to about 500 mg of active ingredient, preferably from about 15 to about 250 mg of active ingredient. The following examples are illustrative and are not intended to limit the scope of the invention. Example 1 4-Diphenylmethyl-1-iminomethylpiperidine hydrochloride hydrate 27.39 g (0.25 mol) of ethylformimidate hydrochloride [Ohme et al., Angew.Chem. Intl.Ed.) 6 , 566 (1967)] and 52.71 g (0.20 mol) of diphenyl-4-piperidylmethane in 80 ml of fresh absolute ethanol were placed under a calcium chloride tube. Stir magnetically overnight. Strain the suspension;
Then diethyl ether was added to the liquid. The liquid was evaporated to dryness and the resulting oil was crystallized from isopropanol. The solid is then suspended in boiling ethyl acetate to obtain the higher melting point form. Two recrystallizations from ethanol-ether gave pure 4-diphenylmethyl-1-iminomethylpiperidine hydrochloride hydrate.
Melting point 220-221℃. Example 2 By repeating the method of Example 1, but substituting equivalent amounts of the appropriate starting materials in place of the ethylformimidate hydrochloride and diphenyl-4-piperidylmethane used therein, the following materials were obtained: manufactured:

【table】

[Table] Example 3 4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate hemihydrate 8.00 g (0.029 mol) of N-formyl-4-diphenylmethylpiperidine and 3.61 g (2.67 ml,
A mixture of 0.029 mol) dimethyl sulfate was heated on a steam bath for 2 hours to give a clear thick syrup. To this material was then added 1.38 g (2.00 ml, 0.031 mole) of ethylamine in 15 ml of methylene chloride. The resulting solution was stirred at 25° for 1.5 hours, stripped, slurried in ether, and treated with 28 ml of 3N sodium hydroxide solution. The ether layer was dried over potassium carbonate and passed through a diatomaceous earth filter material.
It was then evaporated to give 8.77g of yellow liquid.
This material was treated with 3.26 g of oxalic acid dihydrate in isopropanol to give 5.0 g of a white solid. Melting point 165-175℃. Recrystallization from isopropanol gives pure 4-(diphenylmethyl)-
1-N-ethyliminomethylpiperidine oxalate hemihydrate was obtained in the form of a white solid. Melting point 185
~187℃. Example 4 If the method of Example 3 is repeated but equivalent amounts of the appropriate starting materials are used in place of the N-formyl-4-diphenylmethylpiperidine and ethylamine used therein, the following is prepared: Was:

【table】

[Table] Example 4A A mixture of 4-[(4-methoxyphenyl)phenylmethyl]-1-[(octylimino)methyl]piperidine (1.90 g, 0.0045 mol) and 42 ml of 47-49% hydrobromic acid. The mixture was refluxed for 1 hour, cooled, and the aqueous portion was decanted from the thick oil. The oil was dissolved in methylene chloride, neutralized with aqueous sodium bicarbonate, dried and evaporated. The residual 4-[(4-hydroxyphenyl)phenylmethyl]-1-[(octylimino)methyl]piperidine was converted to its 2-naphthalenesulfonate salt. Melting point 177.5-180℃. Example 5 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine fumarate hydrate A solution of triethyloxonium fluoroborate [104.6 g (0.737 mol) of boron trifluoride etherate and 56.04 g (47.37 ml) , 0.606 mol) of epichlorohydrin] was dissolved in 800 ml of anhydrous methylene chloride, and the resulting solution was treated with 81.0 g (0.516 mol) of N-(n-octyl)formamide, and Stir overnight at 25°. 4-diphenylmethylpiperidine (130g,
0.518 mol) was added and the mixture was stirred for 4 hours. A small amount of white solid was separated and the liquid was made basic with 3N sodium hydroxide solution, separated, dried over potassium carbonate and evaporated to give a yellow oil. This material was dissolved in isopropanol and treated with 60 g of fumaric acid while warming. Addition of an equal volume of acetone followed by ether produced a solid that gave two groups of materials. Melting point 152-157℃. When these were combined and recrystallized from ether-water, two groups of 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine fumarate hydrate were obtained. Melting point 157-159℃. Example 6 4-(Diphenylmethyl)-1-piperidinecarbothioaldehyde A solution of 20.0 g (0.08 mol) of 4-diphenylmethylpiperidine, 14.2 g (0.16 mol) of N.N-dimethylthioformamide and 50 ml of toluene is prepared.
Refluxed for 12 hours, cooled and washed with water.
The organic layer was separated, dried and stripped to an oil which was treated with diethyl ether to give a solid. Recrystallization of this material yields a white crystalline solid, 4-(diphenylmethyl)-
1-Piperidinecarbothioaldehyde was obtained. Melting point 152-154℃. Example 7 If the above procedure was repeated but the 4-diphenylmethylpiperidine used therein was replaced by an equivalent amount of the appropriate piperidine, the following was prepared:

[Table] Cymethyl Example 8 4-(diphenylmethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate 5.54 g (0.019 mol) of 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde,
2.65 g (1.16 ml,
0.019 mol) of methyl iodide and 1
Refluxed for an hour. 3.49 g (0.019
molar) of n-dodecylamine, refluxed for 1.5 hours, cooled, treated with aqueous sodium hydroxide, and the organic layer was separated. After drying and evaporation an oil was obtained which was converted to fumarate to give 4-(diphenylmethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate. Melting point 143-145.5℃. Example 9 The above procedure is repeated, but substituting equivalent amounts of the appropriate starting materials for the 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde and n-dodecylamine used here. Things were manufactured:

Table Example 10 Alternative manufacturing process described for 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (1) 2.90 g (0.01 mol) of 4-(diphenylmethyl)-1-piperidine carbothioaldehyde,
129 g (0.01 mol) n-octylamine,
A mixture of 0.60 g (0.01 mol) glacial acetic acid and 20 ml toluene was heated at 60° with stirring for 2 days. The reaction mixture was made basic and concentrated to give an oil, which was identified by gas phase chromatography as 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine. (2) 2.0 g (0.0068 mol) of 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde,
0.9 g (0.0069 mol) n-octylamine,
A mixture of 2.16 g (0.010 mole) mercury oxide and 15 ml isopropanol was refluxed overnight, filtered, and concentrated. Treatment of the residue with fumaric acid yielded 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine(E)-2-butenedioate (1:1) hydrate, which was analyzed by thin layer chromatography. It was identified by comparing it with samples certified by B. (3) 1.0 g (0.0034 mol) of 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde,
A solution of 0.59 g (0.0038 mol) n-octyl isocyanate and 6 ml toluene was refluxed for 9 days. Gas phase chromatography and mass spectrometry showed an amount of 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine in the reaction mixture of 17%. (4) 1.0 g (0.0034 mol) of 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde,
A solution of 0.45 g (0.0034 mol) n-octylamine and 6.0 ml isopropanol was refluxed overnight. Gas phase chromatographic analysis of the reaction mixture showed the presence of 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine. (5) A solution of 6.0 g (0.035 mol) of n-octyl-isothiocyanate was dissolved in 25 ml of toluene, treated with 8.80 g (0.035 mol) of 4-diphenylmethylpiperidine and heated at 25° for 12 hours. Stirred. Cool the mixture, strain
and evaporated. The residue was chromatographed through silica gel using chloroform as eluent to give 4-(diphenylmethyl)-N-octyl-1-piperidinecarbothioamide as a brown oil. 1.0 g (0.0024 mol) of this substance, 3 g of Raney nickel and 15
The mixture of ml isopropanol was refluxed for 3 hours, cooled and filtered. Evaporation of the liquid yields an oil converted to fumarate, which is determined by thin layer chromatography to 4-(diphenylmethyl)-1-[(octylimino)methyl]
Piperidine (E)-2-butenedioate (1:
1) Identified as a hydrate. (6) 40.0g (0.143mol) N-formyl-4-
A solution of diphenylmethylpiperidine and 50 ml of methylene chloride was treated with phosgene until gas evolution ceased. After refluxing for 1 hour, excess phosgene was removed under reduced pressure, the reaction was diluted with 50 ml of methylene chloride, and the reaction was dissolved in 25 ml of methylene chloride.
24.8 ml (0.145 mol) of n-octylamine was added at a rate to maintain a gentle reflux. Triethylamine (28 ml) is added slowly and the reaction is stirred for 10 minutes, then poured into water. The organic phase was separated, washed with 20% sodium hydroxide solution, dried and stripped to give an oil, which was identified by thin layer chromatography as 4-(diphenylmethyl)-1.
−[(octylimino)methyl]piperidine(E)−
It had been converted to 2-butenedioate (1:1). (7) A mixture of 5.60 g (0.022 mol) 4-diphenylmethylpiperidine, 3.50 g (0.022 mol) n-octylisonitrile, and 0.26 g (0.002 mol) silver chloride was stirred at 25° for 48 hours,
Filtered, stripped and the residue was dissolved in methylene chloride. Extraction with 10% sodium hydroxide, drying and filtration of the organic layer followed by evaporation yielded 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine isolated in the fumarate salt form; It was identified by thin layer chromatography. Example 11 The following compounds were tested for their antisecretory activity according to the test procedure described above. The ED ₅₀ values for oral administration and % inhibition for intraduodenal administration of 20 mg/Kg are shown in the table below (R ₁ '=H unless otherwise noted):

【table】

[Table] Example 12 N-[4-(diphenylmethyl)-1-piperidinyl]methylenebenzenebutanamine (E)-2-
Butenedioate hydrate 4.40 g (0.016 mol) N-formyl-4-(diphenylmethyl)piperidine and 1.47 ml (2.00 mol)
g, 0.015 mol) of dimethyl sulfate was heated in a steam bath for 3 hours at 100° C. under anhydrous conditions until homogeneous. Cool the mixture;
Dissolved in 30ml methylene chloride, and 2.50ml
(2.36 g, 0.016 mol) of phenylbutylamine. The resulting solution was stirred for 3 hours and treated with 6 ml of 3N sodium hydroxide solution at 0° with vigorous stirring. Separate the organic layer;
Dry over potassium carbonate, filter and evaporate to give an oil. This material was dissolved in isopropanol, treated with 1.84 g of fumaric acid, and cooled. A white crystalline solid was separated and recrystallized from ethanol to give N-[4-(diphenylmethyl)-1-piperidinyl]methylenebenzenebutanamine (E)-2-butenedioate hydrate as a white product. was obtained in the form of a crystalline solid. melting point
207-208.5℃. Example 13 4-(diphenylmethyl)-1-[1-(octylimino)ethyl]piperidine monoperchlorate N-octylacetimidic acid ethyl ester (5.68 g [0.04 mole] boron trifluoride etherate, 2.77 g [0.03 mol] of epichlorohydrin,
and 5.80 g (0.034 mol) of N-octylacetamide) and 50 ml of ether was treated with 4 ml (2.92 g, 0.029 mol) of triethylamine. Filtration and evaporation gave a liquid residue, which was dissolved in 120 ml of dry toluene. 6.00 g (0.024
mol) of glacial acetic acid, and the resulting solution was diluted with 50 mol of glacial acetic acid.
under nitrogen atmosphere on 4A molecular sieves at 4°C.
The mixture was stirred for several days. Cool the reaction mixture and add 3N
Neutralized by shaking with sodium hydroxide solution. Separate the organic layer, dry over K ₂ CO ₃ , filter and strip to give an oil,
Distilled it. The vessel residue was dissolved in ether and perhydrochloric acid and methanol were added. The solution was cooled to give a solid fraction. Upon filtration, a crystalline solid was obtained which was recrystallized three times from methanol to give 4-(diphenylmethyl)-1-
[1-(octylimino)ethyl]piperidine monoperchlorate was obtained in the form of a white crystalline solid. Melting point 119-121.5℃. Example 14 α-(4-methylphenyl)-α-phenyl-4
- Pyridine methanol 500 ml of a solution of 0.05 mol of 4-methylphenylmagnesium bromide in 500 ml of anhydrous ether
of 4-benzoylpyridine in anhydrous ether. After stirring the resulting mixture at 25° for 1.5 hours, an aqueous solution of ammonium chloride was added to form a solid, which was filtered. this substance
Recrystallization from 95% ethanol yields the desired α-(4-methylphenyl)-α-phenyl-4
-pyridinemethanol, melting point 192-195°C was obtained. The corresponding 4-chlorophenyl (melting point 198-202
°C) and 4-methoxyphenyl (melting point 204-206
C) derivatives were also prepared by the same method using equal amounts of the appropriate starting materials. Example 15 α-(4-methylphenyl)-α-phenyl-4
-piperidine 25.0 g (0.09 mol) α-(4-methylphenyl)-α-phenyl-4-pyridinemethanol,
A solution of 55 ml of 47-51% hydroiodic acid and 180 ml of acetic acid was stirred overnight, cooled, and poured into aqueous sodium hydrogen sulfate. The solution was made basic with sodium hydroxide and extracted with methylene chloride. An oil was isolated from the organic layer and it was reduced over platinum oxide at 40 psi at 60-65°C in acetic acid according to the method of US Pat. No. 3,267,108. Removal of excess acid and basification of the residue gives α-
(4-Methylphenyl)-α-phenyl-4-piperidine was obtained, which was identified as the fumarate salt. Melting point 157.5-161.5℃ (Hoover). The corresponding 4-chlorophenyl (melting point 175-178°C, fumarate salt) and 4-methoxyphenyl (melting point 94
˜98° C., free base) derivatives were also prepared by the same method using equal amounts of the appropriate starting materials. Example 16 α-(1,4′-biphenyl)yl-α-phenyl-4-pyridinemethanol 111.0 g (0.50 mol) of 4-biphenyl bromide in 200 ml of dry tetrahydrofuran (THF)
The medium solution was mixed with 12.10 g (0.5 gram atom) of magnesium, 2 ml of ethylene dibromide and 200 ml of
Add THF slowly to the mixture at a rate that maintains reflux. After the addition, the mixture was refluxed for 0.5 h, cooled, and 82.3 g (0.45 mol)
of 4-benzoylpyridine in 600 ml of THF.
Treated for more than 0.5 hours. The generated slurry was heated to 25℃
Stirred for 0.5 hour at room temperature and treated with 1000 ml of 20% ammonium chloride solution. The organic layer was separated, filtered, and the liquid was dried, filtered, and stripped. The residue was triturated with ether and filtered. This solid was recrystallized from ethanol, chloroform and finally toluene to obtain α-(1,4'-biphenyl)-yl-α-phenyl-4-pyridinemethanol in the form of a white solid. Melting point after drying at 70°C in vacuo, 173.5-175.5°C. Example 17 α-(1,4′-biphenyl)yl-α-phenyl-4-piperidinemethanol 10.00 g (0.030 mol) of α-(1,4′-biphenyl)yl-α-phenyl-4-pyridine and 160
A solution of ml of acetic acid was hydrogenated on a Parscher in the presence of platinum oxide (1.0 g) at 25-35 psi and 70-90°. After hydrogen uptake ceased, the mixture was passed through dicalite and evaporated to give a solid residue. The residue was slurried in water, made basic with 3N NaOH, and extracted with chloroform. The chloroform layer was dried over potassium carbonate, passed through dicalite and evaporated.
The residue was dissolved in toluene and cooled.
The resulting solid is filtered and recrystallized from toluene to give α-(1,4'-biphenyl)yl-
α-phenyl-4-piperidine methanol was obtained in the form of a white solid. Melting point 185-186.5℃. Example 18 9-(4'-Piperidinyl)-9-fluorenol 13.0 g (0.05 mol) of 9-(4'-pyridyl)-9
- 0.8 g of a solution of fluorenol in 200 ml of glacial acetic acid
hydrogenated over platinum oxide at 40 psi. The mixture was filtered, stripped, and the residue made basic to yield 9-(4'-piperidinyl)-9-fluorenol. Example 19 4-fluorenylidenepiperidine 13.0 g (0.05 mol) of 9-(4'-piperidinyl)
A suspension of -9-fluorenol in 70 ml of 48% sulfuric acid was heated on a steam bath for 7 hours and poured onto ice. The resulting solid was filtered, made basic with sodium hydroxide solution and extracted with methylene chloride. Separate the organic layer, dry over potassium carbonate, filter, and strip.
4-fluorenylidenepiperidine was obtained. Example 20 9-(4′-pyridyl)fluorene 1.35 g (0.005 mol) α・α-diphenyl-
A solution of 18.5 ml of 4-pyridine methanol in 97% formic acid was treated dropwise with 8 ml of concentrated sulfuric acid. 10 reactants
Reflux for minutes, cool and basify with 6N sodium hydroxide solution to separate the solids. This material was filtered and recrystallized from methanol to yield 9-(4'-pyridyl)fluorene. Melting point 141-143°C (Hoover). Example 21 9-(4'-Piperidyl)fluorene fumarate A solution of 54.75 g (0.225 mol) of 9-(4'-pyridyl) fluorene in 600 ml of acetic acid was heated with hydrogen at 40 psi and 25°C over 5.0 g of platinum oxide. It became. The mixture was filtered, stripped, and made basic to give 9-(4'-piperidyl)fluorene, which crystallized as the fumarate salt. Melting point 228-230℃ (decomposition).

Claims (1)

[Claims] 1 Formula () In the formula (), R ₁ independently represents hydrogen; phenyl; phenyl (C ₁ -C ₄ ) lower alkyl; diphenyl (C ₁ -C ₄ ) lower alkyl; at least one of phenyl is lower alkyl, lower 1 to 1 respectively selected from the group consisting of alkoxy, halo, hydroxy and phenyl
It is replaced with 3 members, but there is a condition that 1
substituted diphenyl (C ₁ -C ₄ ) lower alkyl in which more than one member is not a phenyl substituent; diphenylhydroxymethyl; at least one of the phenyls is from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo and phenyl, respectively; Substituted diphenylhydroxymethyl substituted with 1 to 3 members selected, with the proviso that more than one member is not a phenyl substituent; and where: n is 0, and E is H, a member selected from the group consisting of; A is independently a member selected from the group consisting of hydrogen and acetyl, with the proviso that As a condition, when A is acetyl, R ₁ is phenyl, R ₁ and A together are benzhydrylidene, R ₁ ' is independently hydrogen; diphenylmethyl, and B is independently is hydrogen; R ₁ ″ is independently hydrogen; R ₂ is a member selected from the group consisting of hydrogen and C ₁ -C ₄ lower alkyl; and R ₃ is hydrogen ; alkyl; cycloalkyl; phenyl lower alkyl; phenyl lower alkyl substituted with 1 to 3 members each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halo; alkenyl; and a group consisting of alkynyl; A substituted N-iminomethylpiperidine which is a member selected from the following, with the proviso that at least one of R ₁ , R ₁ ′, R ₁ ″, R ₂ and R ₃ is other than hydrogen. and its corresponding non-toxic acid addition salts. 2. A compound according to claim 1 selected from the group consisting of 4-diphenylmethyl-1-iminomethylpiperidine and its non-toxic acid addition salts. 3. A compound according to claim 1 selected from the group consisting of 4-(diphenylmethyl)-1-[(isopropylimino)methyl]piperidine and non-toxic acid addition salts thereof. 4 1-[N-(benzyl)iminomethyl]-4-
A compound according to claim 1 selected from the group consisting of diphenylmethylpiperidine and non-toxic acid addition salts thereof. 5 1-[N-(phenethyl)iminomethyl]-4
- Diphenylmethylpiperidine and non-toxic acid addition salts thereof. 6 1-[N-(n-decyl)iminomethyl]-4
- Diphenylmethylpiperidine and non-toxic acid addition salts thereof. 7. A compound according to claim 1 selected from the group consisting of 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine and non-toxic acid addition salts thereof. 8. The compound of claim 1 selected from the group consisting of 4-(diphenylmethyl)-1-[(ethylimino)methyl]piperidine and non-toxic acid addition salts thereof. 9. The compound of claim 1 selected from the group consisting of 4-(diphenylmethyl)-1-[(hexylimino)methyl]piperidine and non-toxic acid addition salts thereof. 10. The compound of claim 1 selected from the group consisting of 1-[(4-chlorobenzylimino)methyl]-4-(diphenylmethyl)piperidine and non-toxic acid addition salts thereof. 11. The compound of claim 1 selected from the group consisting of 4-(diphenylmethyl)-1-[(2-propynylimino)methyl]piperidine and non-toxic acid addition salts thereof. 12 selected from the group consisting of 4-[1-(4-methoxyphenyl)benzyl]-1-[(octylimino)methyl]piperidine and non-toxic acid addition salts thereof; Compound. 13. The compound of claim 1 selected from the group consisting of 4-[1-(4-chlorophenyl)benzyl]-1-iminomethylpiperidine and non-toxic acid addition salts thereof. 14. The compound of claim 1 selected from the group consisting of 4-(9-fluorenyl)-1-[(octylimino)methyl]piperidine and non-toxic acid addition salts thereof. 15. The compound of claim 1 selected from the group consisting of 4-(diphenylmethyl)-1-[methyl(octylimino)methyl]piperidine and non-toxic acid addition salts thereof. 16. The compound of claim 1 selected from the group consisting of 16 N-[4-(diphenylmethyl)-1-piperidinyl]methylenebenzenebutanamine and non-toxic acid addition salts thereof. 17. A compound according to claim 1 selected from the group consisting of 4-benzhydrylidene-1-[(octylimino)methyl]piperidine and non-toxic acid addition salts thereof. 18. The compound of claim 1 selected from the group consisting of 3-(diphenylmethyl)-1-[(octylimino)methyl]piperidine and non-toxic acid addition salts thereof. Claim 1 selected from the group consisting of 19 4-[(4-hydroxyphenyl)phenylmethyl]-1-[(octylimino)methyl]piperidine 2-naphthalene sulfonate or its non-toxic acid addition salts. Compounds described.