NO791026L - SUBSTITUTED N-IMINOMETHYL PIPERIDINES - Google Patents

Description

Substituted N-iminomethylpiperidines and methods for

their production..

It is in the U.S. patent no. 2,615,023 described unsub- . substituted N-iminomethylpiperidine, but the compound does not inhibit gastric acid secretion even at doses four times greater or more than the doses at which the present compounds are active. It has now surprisingly been found that certain substituted N-iminomethylpiperidines are effective facilitators of gastric acid secretion.

The present invention thus relates to substituted N-iminomethylpiperidines with formula (I):

where

R-1 is selected from the group consisting of hydrogen, phenyl, phenyl substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy and halogen; phenyl(C^-C^)lower alkyl, 1-phenyl(Cy-Cg)lower alkyl, phenyl-(C-^-C^)lower alkyl and 1-phenyl(Cy-Cg)lower alkyl where said phenyl group is substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy, halogen and phenyl, provided that no more than one group is phenyl, diphenyl (C-^-C^) lower -alkyl, dif enyl (C-^- C^) lower-alkyl, where.

at least one of the mentioned phenyl groups is substituted with from 1 -

3 groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy and phenyl, provided that no more than one of the groups is phenyl; diphenylhydroxymethyl, diphenylhydroxymethyl wherein at least one of the phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy, halogen and phenyl, provided that no more than one of the groups is phenyl; ,s'amt compounds with the formulas:

where n is 0, 1 or 2 and E is H or 0H.

. A is selected from the group consisting of hydrogen, acetyl

and phenyl, provided that when A is acetyl or phenyl, then R-^ is selected from the group consisting of phenyl or phenyl substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy and halogen.

R-^ and A may together be selected from the group consisting of benzhydrylidene and compounds of the formulas:

where n is 0, 1 or 2.

R^ is selected from the group consisting of hydrogen, methyl, diphenylmethyl, diphenylmethyl where at least one of the phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy, halogen and phenyl, provided that no more than one of the groups is phenyl; diphenylhydroxymethyl, diphenylhydroxymethyl where at least one of the phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy and phenyl, provided that no more than one of the groups is phenyl; and.a compound with the formula: ,f

where n is 0, 1 or 2 and E. is H or OH;

B is hydrogen;

R-j.' and B together may be selected from the group consisting of. benzhydrylidene and a compound of the formula:

where n is 0, 1 or 2.

Rj" is selected from the group consisting of hydrogen, diphenylmethyl, diphenylmethyl where at least one of the phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower-ralkyl, lower-alkyl, halogen, hydroxy and phenyl, provided that not more than one of the groups is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl where at least one of said phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy, halogen and phenyl, provided that no more than one of the groups is phenyl, as well as compounds with the formulas:

where n is 0, 1 or 2;

D is individual hydrogen;

R-^" and D together are benzhydrylidene, provided that when R-^" is different from hydrogen, then R-^, R-^<1> and A are each hydrogen, and when R-^' is different from hydrogen, then R-^" is hydrogen, and when R^' is different from hydrogen or methyl, then R-^ and A are each hydrogen;

R 2 is selected from the group consisting of hydrogen and C 1 -C 4 -lower alkyl; and

R^ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, phenyl-lower-alkyl, phenyl-lower-alkyl where said phenyl group is substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy and halogen, diferiyl(C^-C^) lower-alkyl, diphenyl (C-^-C^)-lower-alkyl where at least one of said phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen and phenyl, provided that no more than one of the groups is phenyl; alkenyl; and alkynyl; provided that at least one of the said groups R-p R^', R-^", R 2 and R-^ is different from hydrogen.

With the terms lower-alkyl and lower-alkoxy are understood here straight or branched, saturated, aliphatic hydrocarbons with from 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl and similar lower alkyl groups, and respectively the corresponding lower alkoxy groups, i.e. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy etc. The term "C-^-C^-lower alkyl" means the lower alkyl groups which have from 1-4 carbon atoms, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, etc. The terms "phenyl(C-^-C^)lower alkyl" and "diphenyl(C-^-C^)lower alkyl" mean only those compounds where the phenyl group(s) is bound to the terminal carbon atom in a straight chain lower alkyl group, such as 2-phenethyl, 4-phenylbutyl, 4,4-diphenylbutyl, 3,3-diphenylpropyl etc. The term "1-phenyl(Cy-Cg)-lower-alkyl" means groups with the following general formula:

where m is 5, 6 or 7. The term "alkyl" includes both straight and branched, saturated, aliphatic hydrocarbon groups of up to 16 carbon atoms, such as e.g. those mentioned under lower alkyl groups above and radicals such as hexyl, heptyl, octyl, nonyl, decyl, dodecyl, hexadecyl and the like. The term "cycloalkyl". includes mono-, di- and tricyclic, saturated and unsaturated, aliphatic hydrocarbons with up to 10 carbon atoms, such as e.g. cyclohexyl, adamantyl, 1-adamantyl-methyl, exo-norbornyl, endo-norbornyl, noradamantyl, anti-7-norbornenyl, etc. The terms "alkenyl" and "alkynyl" include straight and branched hydrocarbons having from 2-18 carbon atoms and at least one double or triple bond, respectively, e.g. allyl, methallyl, 1-propargyl (1-propynyl), 2-pentenyl, etc. The term "halogen" includes fluorine, chlorine, bromine and iodine.

Compounds of formula I can generally be prepared by reacting: a) a suitable substituted piperidine of formula (II) and a suitable activated amide (formula III), or a suitable primary amine of formula (VII) and an activated • N-acyl -piperidine of formula (VI), where the activation in each case has been achieved by treating the respective amide with a suitable activating agent selected from the group, for example, consisting of phosgene, Me^O+BF^~, Et^BF ^<->, (MeO) 2 SO 2 , MeOSO 2 F, POCl 2 , PCl 2 , and the like.

Included in the terms "amide" and "N-acyl-piperidine" as they are used here are the corresponding thioderivatives where the carbonyl oxygen atom has been replaced with sulphur. In connection with the thioderivatives there are also other suitable activating agents that can be used, e.g. .eg lower alkyl halides (methyl halide is preferred), methyl tosylate, methyl sulfonic acid esters (eg methyl methane sulfonate), methyl trifluoromethyl sulfonate and the like.

The activated reactant of formula (III) can either be in the form of the free base or in the form of an acid addition salt.

Specific routes of synthesis are indicated below:

A) The compounds of formula (I) can be prepared

by reacting a suitable substituted piperidine of formula (II) and a suitable imidate ester of formula (III). The methyl and ethyl esters are preferred. The substituted piperidine and the imida ester (which may be present either in the form of a free base or in the form of an acid addition salt, the latter compound being shown) can be stirred together in a suitable organic solvent such as e.g. 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, xylene, toluene etc.), dimethyl sulphoxide

. and such. The temperature of the reaction is preferably kept between 0 and 25°C, but can in certain cases be carried out up to 50°C, but in any case the temperature of the reaction mixture must not be so high that significant amounts of the imidate ester are decomposed. The resulting product can be isolated and purified in a well-known manner, e.g. by distilling off the solvent and recrystallizing the precipitated product either in the form of a free base or in the form of an acid addition salt. The above synthesis route can be illustrated as shown below-

for, where A, B, D, R-^R-^, R-^", R 2 and R^ are as defined above, Z is selected from the group consisting of lower-alkoxy, (preferably methoxy and ethoxy), lower-alkyl -S- (preferably methylthio), chlorine and C12(0)P0-, and X is selected from the group consisting of halide, BF^, FSO^ and CH^OSO^ When Z is lower-alkyl-S-, then X may also be selected from the group consisting of (4-methylphenyl)SO^, CH^SO^ and CF^.SOj.

Compounds of formula (i) where R 2 is hydrogen can also be prepared in an analogous manner by using a suitable compound of formula (HIA) or (UIB) instead of the imidatester of formula (III). If the former is used, the resulting thiourea will be reduced (e.g. with Raney nickel) to the phoronsed compound. If the latter compound is used, solv chloride can be used as a catalyst. These synthesis pathways are shown below:

B) Compounds of formula (I) can also be prepared by reacting a suitable substituted piperidine of formula (II) with acetic formic anhydride or N,N-dilavere-alkylthioform-amide (for R ? = H) or a C^-C ^-lower alkyl anhydride (for R 2 = C-j^-C^-lower alkyl), and the anhydride is preferably used in an excess. The piperidine and the anhydride or thioform amide are combined and decoupled and stirred for approx. 18 hours. The resulting reaction mixture, e.g. dissolved in an organic solvent selected from the aforementioned group consisting of halocarbons and aliphatic hydrocarbon solvents, or without the use of solvents, is then treated with an aqueous solution of a weak base (e.g. sodium bicarbonate) until, the aqueous layers are neutral (for the anhydride synthesis) or washed with water (for the amide synthesis). The organic layer is then separated, and any solvent present is removed, whereby the intermediate amides (IV), (IVA) and (V) are obtained. The intermediate amide is treated either as such or in the presence of an organic solvent, e.g., a halocarbon (CHCl^, CH^C^) or a hydrocarbon (benzene or toluene), at 25 - 100 C with a suitable activating agent as indicated earlier, for from 2-3 hours, whereby the activated derivative of formula (VI) is produced, after which the reaction mixture is allowed to cool. Addition of a suitable primary amine (VII) gives the forex product of formula (I) which can then be isolated and purified in a known manner. The above synthesis is shown below where R-^, R]_'>^2'^3'A, B, D, Z and X are as previously defined:

When Z is (Laveré-alkyl)-S-, then the compounds of formula I where R2=Hogso can be prepared by reacting the activated intermediate (VI) with a suitable isocyanate of formula (VIII), preferably by refluxing in a suitable , suitable solvent (e.g. toluene) for approx. 9 dogn.. This synthesis pathway is shown below:

As the present compounds of formula (I) have a basic amidine group, they can be converted into their corresponding acid addition salts.

The acid addition salts can be prepared by a reaction with a suitable acid, e.g. an inorganic acid such as a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or nitric acid, phosphoric acid or an organic acid such as acetic acid, propionic acid, -acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p.-toluenesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid or p-aminosalicylic acid. The therapeutically active, non-toxic acid addition salts of the phoronized compounds (i) are part of the present invention. -'

The starting compounds with the formulas (II), (III), (IV), (IVA), (V), (VI), VII) and (VIII) are known or can be prepared by known methods. See generally R.C. Elderfield, "Heterocyclic Compounds", Volume 1, Chapter 9, Pages 617 - 677

(1950). Preparative methods for compounds of formula (II) are e.g. described in articles by F. Ravenna, Farmaco (Pavia) Ed. Sei., 14, 473 - 482 (1959) and E. Sury and K. Hoffmann, Heiv. Chim. Acta, 248, 2133 (1954). Preparative methods for compounds of formula (III) and (IV) are described e.g. in articles by R. Ohme and E. Schmitz, Angew. Chem. Intern. Ed., 6, 566 (1967), F. Snydam, et al., J. Org. Chem., 34, 292 (1969) and K. Sechinger, Heiv. Chem. Acta, 56, 776 (1973). Preparative methods for compounds of formula (V) and (VI) are e.g. described by CA. Buehler and D.E. Pearson, Survey of Organic Synthesis, Chapter 18, page 894 (1970).

Sample methods

Compounds according to the present invention can be used to inhibit the secretion of stomach acid as this can be measured using the following test. Female Sprague-Dawley rats were fasted for 24 hours before being prSwet, and were given water ad libidum while housed in individual cages. On the test day itself, the rats were weighed and selected so that the rats in each

sample did not vary more in weight than 20 grams.

An operation was performed under light ether anesthesia. As soon as the rats were anaesthetized, the teeth were removed and a midline incision was made on the abdomen approx. 3.75 cm in length, and the stomach and duodenum were exposed. If the stomach sac at this time was filled with food or faecal material, the rats were discarded. If the condition of the stomach was acceptable, then a number of stitches were placed in a circle on the fundus part of the stomach with the help of a needle, being careful to avoid puncturing any of the blood vessels in the area. A small incision in the stomach was then made in the center of the sutured area, and a cannula consisting of a small vinyl tube with a flange at one end was inserted into the stomach sac, after which the stitches were pulled tightly around the flange. The PrSve compound was administered either intraduodenal (i.d.) immediately after the operation or orally (p.o.) 1 hour before the operation in doses varying from 0.25 to 160 mg per kg of body weight in a volume of 0.5 ml per 100 g body weight. The control rats were only fed the liquid itself, i.e. 0.5% aqueous methylcellulose. After the operation (and in connection with the intra-duodenal administration) and after administration of the test compound, the abdominal wall and skin were closed simultaneously with three or four 18 mm wound clips and a collection tube was placed on the cannula. Each rat was then placed in a box where there was a longitudinal slot so that the cannula could hang down freely and so that the rat could move without too much difficulty. After the rat had been stabilized for approx. half an hour, the collection tube on the canayle was thrown away and replaced with a clean tube for collecting the stomach acid. The collections were made in increments of 1 hour. After the experiment was finished, the cannula was removed and the rats necropsied. The sample of stomach acid that had been collected was poured into a centrifuge and centrifuged to collect any sediment. The volume was read, and a 1 ml sample of the overlying liquid was quickly transferred to a beaker containing 10 ml of distilled water and titrated to pH 7 using 0.01N sodium hydroxide. The results were determined for volume, titratable acid and total acid production, where volume corresponds to the total number of ml of stomach acid minus sediment; titratable acid (meq/l) corresponds to the amount of 0.01N sodium hydroxide that was required to titrate the acid to pH 7, and total acid production is equal to titratable acid times the volume. The results are given as the ED^Q dose (mg per kg body weight; which is required to produce a mean of 50% inhibition of the total acid production in relation to the control animals, in all the animals tested for a particular compound ) and as percent inhibition. The compounds according to the present invention all showed a significant inhibition both i.d. and p.o. at less than 80 mg per kg, and the preferred compounds had an ED^q p.o. of less than 20 mg per kg. In contrast, the previously known compound N-iminomethylpiperidine has no inhibition at all at a dose of 100 mg per kg p.o. or at a dose of 90 mg per kg i.d. It is well known that excessive secretion of hydrochloric acid in the stomach leads to unnecessary peptic activity and can be dangerous for the mucous membranes in the stomach. The use of agents that inhibit the secretion of stomach acid is therefore necessary to relieve and prevent the damage that may occur due to high concentrations of stomach acid. Preferred compounds according to the invention are those of formula (I) where: R is selected from the group consisting of phenyl; phenyl substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy, halogen and phenyl, provided that no more than one group is phenyl; phenyl (C 1 -C 2 ) lower alkyl; phenyl(C-3-C4) lower alkyl where said phenyl group is substituted with from 1-3 groups from the group consisting of lower alkyl, lower alkoxy and halogen; diphenyl (C-^-C^) lower-alkyl and diphenyl(C^-C^)lower-alkyl, where at least one of the phenyl groups is substituted with from 1-3 groups selected each from the group consisting of lower-alkyl, lower alkoxy, halogen and phenyl, provided that no more than one of the groups is phenyl; ;R 2 is selected from the group consisting of hydrogen and methyl; R 1 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; phenyl-lower alkyl; phenyl-lower-alkyl where said phenyl group is substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy and halogen; alkenyl and alkynyl; and ;Rl'' A' B°&D is nver hydrogen. The most preferred compounds according to the invention are those of formula (I) where R-^ is selected from the group consisting of diphenylmethyl and diphenylmethyl of which at least one of the said phenyl groups is substituted with from 1-3 groups selected from the group consisting of lower alkyl, lower alkoxy and halogen; R 2 is hydrogen; R 1 is selected from the group consisting of hydrogen; alkyl; phenyl-lower alkyl; phenyl-lower-alkyl where said phenyl group is substituted with from 1-3 groups selected from the group consisting of lower-alkyl, lower-alkoxy and halogen; alkenyl and alkynyl; and ;R]_', R]_", A, B and D are each hydrogen. ;The most preferred compounds are those of formula (I) wherein R-j^ is selected from the group consisting of diphenylmethyl and diphenylmethyl of which at least one of the said phenyl groups are substituted in the para position by a group selected from the group consisting of lower-alkyl, lower-alkoxy and halogen; R2 is hydrogen; R^ is selected from the group consisting of hydrogen, straight-chain alkyl and phenyl-lower-alkyl; and R1', R]_">A» B ; and D are all hydrogen. ;Given the fact that the present compounds inhibit the secretion of gastric acid, the present invention provides a method for inhibiting gastric acid secretion which includes internally administering to a patient, be it human or animal, who has excessive secretion of gastric acid, an inhibitory amount of a substituted N-iminomethylpiperidine of formula (I), either in the form of a base or in the form of an acid addition salt, preferably in mixture with a pharmaceutically acceptable carrier or diluent. If the compound is used in the form of an acid addition salt, said salt must of course be pharmaceutically acceptable and non-toxic. Furthermore, the invention relates to pharmaceutical preparations containing a compound of formula (I). To prepare pharmaceutical preparations according to the present invention, a substituted N-iminomethylpiperidine of formula (I) or an acid addition salt thereof can be combined as the active ingredient in an intimate mixture with a pharmaceutical carrier according to commonly known pharmaceutical technique, and the carrier can have a number of different forms, all depending on the preparation that is desired, e.g. oral or parenteral. When preparing preparations in oral dosage form, different pharmaceutical media can be used, such as water, glycols, oils, alcohols, flavourings, preservatives, dyes etc., and in connection with oral liquid preparations such as suspensions, elixirs and solutions, you use substances such as starch, sugars, diluents, granulating agents, spreading agents, binders, disintegrants etc., and oral solid preparations can e.g. be in the form of powders, capsules or tablets. Because they are so easy to administer, tablets and capsules will represent the most advantageous oral dosage unit form, and in such cases solid pharmaceutical carriers are of course used. If desired, the tablets can be coated using standard techniques. For parenteral preparations, the carrier will normally include sterile water, although other ingredients can also be used to facilitate solubility or for preservative purposes. Injectable suspensions can also be prepared, and in this case liquid carriers, suspending agents etc. will be used. The pharmaceutical preparations will per dose unit, e.g. in the form of a tablet, capsule, powder, injection, ete., contain from 10 - 500 mg of active ingredient, preferably from approx. 15 - approx. 250 mg. The following examples illustrate the invention. ;Example 1 ;4-diphenylmethyl-1-iminomethylpiperidine hydrochloride hydrate;A suspension of 27.39 g (0.25 mol) of ethylformimidate hydrochloride (prepared by the method of 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 freshly opened absolute ethanol were stirred magnetically under calcium chloride overnight. The suspension was filtered, and diethyl ether was added to the filtrate. This was distilled to dryness, and the resulting oil was crystallized from isopropanol. The solid was then suspended in boiling ethyl acetate, whereby a higher-melting form was obtained. Two recrystallizations from ethanol-ether gave pure 4-diphenylmethyl-1-iminomethylpiperidine hydrochloride hydrate, mp 220-221°C. ;Example 2;By using the method from example 1, but by;replacing the aforementioned ethyl formidate hydrochloride and diphenyl-4-piperidylmethane with equivalent amounts of suitable starting compounds, the following compounds were prepared: ; ; Example 5; 4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate hemihydrate; A mixture of 8.00 g (0.029 mol) N-formyl-4-diphenylmethylpiperidine and 3.61 g (2.67 ml, 0.029 mol) of dimethyl sulfate was heated on a steam bath for 2 hours, whereby a clear, thick syrup was obtained. To this was then added 1.38 g (2.00 ml, 0.031 mol) of ethylamine in 15 ml of methylene chloride. The resulting solution was stirred for 1.5 hours at 25°C, distilled off, dried in ether and treated with 28 ml of 3N sodium hydroxide solution. The ether layer was dried over potassium carbonate, filtered through diatomaceous earth and then evaporated to give 8.77 g of a yellow liquid. This was treated in isopropanol with 3.26 g of oxalic acid dihydrate, and gave 5.0 g of a white solid with a melting point of 165 - 175°C. Recrystallization from isopropanol gives pure 4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate -hemihydrate as a white solid, melting point.185<->187°C.. ;Example 4;The same procedure as in example 3 was used, but starting compounds other than N-formyl-4-diphenylmethylpiperidine and ethylamine were used, and one obtained produced the.fSuggesting compounds: ; Example 4A; A mixture of 4-(14-methoxyphenyl)phenylmethyl7-1-j/'(octylimino)methyl7piperidine (1.90 g, 0.0045 mol) and 42 mL of 4? - 49% hydrobromic acid was refluxed for 1 hour, cooled, after which the aqueous part was decanted from a thick oil. The latter was dissolved in methylene chloride, neutralized with aqueous sodium bicarbonate, dried and evaporated. The residue, 4-(14-hydroxyphenyl)phenylmethyl7-1-(octylimino^ethyl^piperidine) was converted to its 2-naphthalenesulfonic acid salt, melting point 177.5 - 180°X. Example 5 4-(diphenylmethyl)- l -/ Toctylimino) methyl 7piperidine fumarate hydrate; A solution of triethyloxonium fluoroborate (prepared from 104.6 g (0.737 mol) boron trifluoride etherate and 56.04 g (47.37 ;ml, 0.606 mol) epichlorohydrin) was dissolved in 800 ml of anhydrous methylene chloride and the solution was treated with 81.0 g (0.516 mol) of N-(n-octyl)formamide and stirred overnight at 25°C. 4-Diphenylmethylpiperidine (130 g, 0.518 mol) was added and the mixture stirred for 4 hours. A small amount of a white solid was filtered off, the filtrate was made basic with 3N sodium hydroxide solution, separated, dried over potassium carbonate and evaporated to a yellow oil. This was dissolved in isopropanol and treated with 60 g of fumaric acid under heating. Addition of an equal volume of acetone followed by ether gave a solid in the form of two yields, mp 152-157°C. The yields were combined and recrystallized from ethanol and water, whereby two yields of 4-(diphenylmethyl)-!-/! octylimino)methyl 7-;piperidine fumarate hydrate, melting point 157 - 159°C; Example 6-;4-(diphenylmethyl)-1-piperidinecarbothioaldehyde; A solution of 20.0 g (0.08 mol) 4-diphenylmethylpiperidine, 14 .2 g (0.16 mol) of N,N-dimethylthioformamide and 50 ml of toluene were refluxed for 12 hours, cooled and washed with water. The organic layer was separated, dried and purified from solvents to give an oil which was treated with diethyl ether and this gave a solid. Recrystallization of this gave a white crystalline substance, i.e. 4-(diphenylmethyl)-l- piperidine carbutioaldehyde, melting point 152 - 154°C. ;Example 7;Using the same procedure as above, but using a suitable amount of another suitable piperidine, the following compounds were prepared:; ; Example 8; 4-(diphenylmethyl)-1-N-(n-dodecyliminomethyl) piperidine fumarate; A solution of 5.54 g (0.019 mol) 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde in 20 ml of chloroform was treated with; .2.65 g (1.16 ml, 0.019 mol) of methyl iodide and refluxed for 1 hour. The resulting solution was treated with 3.49 g (0.019 mol) of n-dodecylamine, refluxed for 1.5 hours, cooled, treated with aqueous sodium hydroxide, after which the organic layer was separated. After evaporation and evaporation, you got an oil which was converted to the fumarate, and 4-(diphenylmethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate was obtained, melting point 143 - 145.5°C. . Example 9 Using the same procedure as mentioned above, but using equivalent amounts of other suitable starting compounds, the following compounds were prepared: ; Example 10; Alternative preparative synthesis routes for ;4-(diphenylmethyl)-1-^Ioctylimino)methyl7piperidine; 1) A mixture of 2.90 g (0.01 mol) 4-(diphenylmethyl)-1-piperidinecarbutioaldehyde, 129 g (0.01 mol) n-octylamine, 0.60 g (0.01 mol) glacial acetic acid and 20 ml toluene were heated with stirring at 60°C for 2 dbgn. The reaction mixture was basified and concentrated to an oil which was identified as 4-(diphenylmethyl)-1-((Xoctylimino)methyl)piperidine by vapor phase chromatography. 2) A mixture of 2.0 g (0.0068 mol) 4-(diphenylmethyl)-1-piperidinecarbutioaldehyde, 0.9 g (0.0069 mol) n-octylamine, 2.16 g (0.010 mol) mercuric oxide and 15 ml of isopropane was refluxed overnight, filtered and concentrated. The residue was treated with fumaric acid and 4-(diphenylmethyl)-1-^Xoctylimino)methyl-7-piperidine (E)-2-butenedioate (1:1) hydrate was obtained which was identified by comparison with an authentic sample by means of thin layer chromatography. ;3) A solution of 1.0 g (0.0034 mol) of 4-(diphenylmethyl)-1-piperidinecarbutioaldehyde, 0.59 g (0.0038 mol) of n-octyl isocyanate and 6 ml of toluene was refluxed for 9 days. Vapor phase chromatography together with mass spectral analysis showed that 4-(diphenylmethyl)-1-(Xoctylimino)methyl-7piperidine was present in an amount of 17% in the reaction mixture. ;4) A solution of 1.0 g (0.0034 mol) 4-(diphenylmethyl)-l-piperidinecarbutioaldehyde, 0.45 g (0.0034 mol) n-octylamine and 6.0 ml isopropanol was refluxed over the night. Vapor phase chromatography analysis of the reaction mixture showed that 4-(diphenylmethyl)-1-((Xoctylimino)methyl)piperidine was present. ;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 stirred at 25°C for 12 hours . The mixture was then cooled, filtered and evaporated. Chromatography of the residue through silica gel using chloroform as an eluent gave a brown oil, ie 4-(diphenylmethyl)-N-octyl-1-piperidinecarbothioamide. A mixture of 1.0 g (0.0024 mol) of the latter compound, 3 g Raney nickel and 15 ml isopropanol was refluxed for 3 hours, cooled and filtered. Evaporation of the filtrate gave an oil which was converted to a fumarate which was identified as 4-(diphenylmethyl)-1-(Xoctylimino)methyl-7-piperidine (E)-2-butenedioate (1:1) hydrate by thin layer chromatography. ;6) A solution of N-formyl-4-diphenylmethylpiperidine 40.0 g (0.143 mol) and 50 ml of methylene chloride was treated with. phosgene until gas evolution stopped. After refluxing for 1 hour, the excess phosgene was removed under reduced pressure, the mixture was then diluted with 50 ml of methylene chloride, after which 24.8 ml (0.145 mol) of n-octylamine in 25 ml of methylene chloride was added in such. amount to maintain a gentle simmer. 28 ml of triethylamine was added slowly, and the mixture was stirred for 10 minutes and then poured into water. The organic phase was separated, washed with 20% sodium hydroxide solution, dried and distilled to an oil which was converted to 4-(diphenylmethyl)-1-(1-octylimino)methyl 7piperidine (E)-2-butenedioate (1:1) hydrate, identified by thin layer chromatography. 7) A mixture of 5.60 g! * (0.022 mol) 4-diphenylmethyl-piperidine, 3.50 g (0.022 mol) n-octyl isonitrile, 0.26 g (0.002 mol) solv chloride and 10 ml toluene were stirred for 48 hours at 25°C, filtered, distilled off and the residue dissolved in methylene chloride. Extraction with 10% sodium hydroxide, drying and filtration of the organic layer followed by evaporation gave 4-(diphenylmethyl)-l-(roctylimino)methyl 7piperidine isolated as the fumarate salt, and this was identified by thin layer chromatography .

Example. 11

Using the method described earlier, the following compounds were tested for their anti-secretory activity. The ED^Q values for p.o. administration and percent inhibition for i.d. administration at 20 mg per kg body weight is given below (R-^' = H if nothing else is stated).: Example 12 N-^4-(diphenylmethyl)-1-piperidinyl7-methylene-benzenebutanamine (E)-2- butenedioate- hydrate

A mixture of 4.40 g (0.016 mol) N-formyl-4-(diphenylmethyl)piperidine and 1.47 ml (2.00 g, 0.015 mol) dimethyl sulfate was heated on a steam bath for 3 hours at 100°C under anhydrous conditions until the mixture became homogeneous. It was then cooled, dissolved in 30 ml of methylene chloride and treated with

2.50 mL (2.36 g, 0.016 mol) of phenylbutylamine. The solution was stirred for 3 hours and then treated with 6 ml of 3N sodium hydroxide solution under vigorous stirring at 0°C. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to an oil. This was dissolved in isopropanol, treated with 1.84 g of fumaric acid and cooled. A white crystalline solid was filtered off which was recrystallized from ethanol, and N-(4"-(diphenylmethyl)-1-piperidinyl7-methylene-benzenebutan-amine (E)-2-butenedioate hydrate was obtained as a white, crystalline solid - ' substance, melting point 207 - 208.5° C. Example 13

4-(diphenylmethyl)-1-(1-(octylimino)ethyl7-piperidine-monoper-

chlorate 2_

A mixture of the fluoroborate salt of N-octylacetimidine acid ethyl ester (developed from 5.68 g (0.04 mol) boron trifluoride etherate, 2.77 g (0.03 mol) epichlorohydrin and 5.80 g (0.034 mol) N-octylacetamide). and 50 ml of ether was treated with 4 ml (2.92 g, 0.029 mol) of triethylamine, Filtration and evaporation of the

the funnel gave a liquid residue which was dissolved in 120 ml of dry toluene. To the solution was added 6.00 g (0.024 mol) of glacial acetic acid,

and the resulting solution was stirred at 50°C over 4 Ångstrbm molecular sieves under a nitrogen atmosphere for 4 days. The reaction mixture was then cooled and neutralized by shaking with 3N sodium hydroxide solution. The organic layer was separated, dried over K 2 CO 3 , filtered and solvent distilled off to give an oil which was distilled.

The remaining residue was dissolved in ether and perchloric acid

and added methanol. Quenching the solution gave a solid. Filtration gave a crystalline substance which was recrystallized

3 times from methanol and 4-(diphenylmethyl)-!-/!-(octyl-imino)-ethyl 7-piperidine monoperchlorate was obtained as a white crystalline substance, melting point 119 - 121.5°C.

Example 14

oe-(4-methylphenyl)-α-phenyl-4-pyridine-methanol

A solution of 0.05 mol of 4-methylphenylmagnesium bromide in 500 ml of anhydrous ether was treated with 4-benzoylpyridine in 500 ml of anhydrous ether. After stirring the mixture for 1.5 hours at 25°C, an aqueous solution of ammonium chloride was added, giving a solid which was filtered off. 4-methylphenyl)-α-phenyl-4-pyridine-methanol

with melting point 192 - 195°C. The corresponding 4-chlorophenyl (melting point 198 - 202°C) and 4-methoxyphenyl (melting point 204 - 206°C) derivatives were also prepared in the same way using equivalent amounts of suitable starting materials.

Example 15

oe-(4-methylphenyl)-q-phenyl-4-piperidine

A solution of 25.0 g (0.09 mol) o-(4-methylphenyl)-α-phenyl-4-pyridine-methanol, ~55 mL of 47-51% hydroiodic acid and 180 mL of acetic acid was refluxed overnight , cooled and poured into aqueous sodium bisulphite. The solution was basified with sodium hydroxide and extracted with methylene chloride. An oil was isolated from the organic layer, which was reduced by approx. 3 kg/cm 2 over platinum oxide at 60 - 65°C in acetic acid using the method from the U.S. Patent No. 3,267,108. The excess of acid was removed, and the residue was made basic, whereby α-(4-methylphenyl)-α-phenyl-4-piperidine was obtained which was characterized as the fumarate salt, melting point 157.5 - 161.5°C (Hoover). The corresponding 4-chlorophenyl (m.p. 175-178°C, fumarate salt)' and 4-methoxyphenyl (m.p. 94-98°C, free base) derivatives were also prepared in the same manner using equivalent amounts of the appropriate starting compounds.

Example 16

q-(1,4'-bif.enyl)yl-α-4-pyrimidinemethanol

A solution of 111.0 g (0.50 mol) 4-biphenyl bromide in 200 ml dry tetrahydrofuran (THF) was slowly added to a mixture of 12.10 g (0.5 gram atom) magnesium, 2 ml ethylene dibromide bg 200 ml of tetrahydrofuran at such a rate that gentle boiling was maintained. After the addition, the mixture was refluxed for half an hour, cooled and treated for half an hour with a solution of 82.3 g (0.45 mol) of 4-benzoylpyridine in 600 ml of tetrahydrofuran. The resulting suspension was stirred for half an hour at 25°C and treated with 1000 ml of 20% ammonium chloride solution. The organic layer was separated, filtered, the filtrate dried, filtered and freed of solvent. The residue was treated with ether and filtered. The solid was recrystallized from ethanol, chloroform and finally from toluene to give α-(1,4'-biphenyl)-yl-α-phenyl-4-pyridinemethanol as a white solid, m.p. after drying in vacuo at 70 °C, 173.5 175.5°C Example 17

q-(1,4'-biphenyl)yl-q-phenyl-4-piper. idine methanol

A solution of 10.0 g (0.030 mol) α-(L,4'-biphenyl)-yl-α-phenyl-4-pyridine and 160 ml of acetic acid was hydrogenated in the presence of platinum oxide (1.0 g)" at a hydrogen pressure varying from about 2 to about 3 kg/cm2 at temperatures from 70 - 90°C

in a Paar hydrogenator. After the hydrogen uptake had stopped, the mixture was filtered through dicalite and evaporated to a solid residue. This was carried out in water, made basic with 3N NaOH and extracted with chloroform. The chloroform layer was dried over potassium carbonate, filtered through dicalite and evaporated. The residue was dissolved in toluene and, cooled. The resulting solid was filtered and recrystallized from toluene to give α-(1,4'-biphenyl)yl-α-phenyl-4-piperidine methanol as a white solid, mp 185-186.5°C Example 18

9-(4'-piperidinyl)-9-fluorenol

A solution of 13.0 g (0.05 mol) of 9-(4'-pyridyl)-9-fluorenol in 200 ml of glacial acetic acid was hydrogenated over 0.8 g of platinum oxide at 3 kg/cm p. The mixture was filtered , purified from solvent and the residue made basic, whereby 9-(4'.-piperidinyl')-9-fluorenol was obtained.

Example 19

4-fluorenylidene piperidine

A suspension of 13.0 g (0.05 mol) of 9-(4'-piperidinyl)-9-fluorenol in 70 ml of 48% sulfuric acid was kept on a steam bath for 7 hours and then poured into ice. The resulting solid

was filtered off, basified with sodium hydroxide solution and extracted with methylene chloride. The organic layer was separated, dried over potassium carbonate, filtered and purified to 4-fluorenylidene piperidine.

Example 20

9- ( 41 - pvridvl) fluorene

A solution of 1.35 g (0.005 mol) of α,α-diphenyl-4-pyridinemethanol in 18.5 ml of 97% formic acid was treated dropwise with 8 ml of concentrated sulfuric acid. The reaction mixture was refluxed for 10 minutes, cooled and basified with 6N sodium hydroxide solution, whereby a solid was separated. This was filtered off and recrystallized from methanol, whereby 9-(4'-pyridyl)fluoroene was obtained, melting point 141 - 143°C (Hoover).

Example 21

9-(41-piperidyl)fluorene fumarate

A solution of ..54.75 g (0.225 mol) of 9-(4'-pyridyl)-fluorine in 600 ml of acetic acid was hydrogenated over 5.0 g of platinum oxide at 3 kg/cm and at 25 C The mixture was filtered, purified from solvent and made basic, whereby 9-(4'-piperidyl)fluorene was obtained, which was crystallized as its fumarate salt, melting point 228 - 230°C (decomposition).

Claims (21)

1. Process for the preparation of compounds selected from the group consisting of a substituted N-iminomethylpiperidine of formula (I): and the corresponding non-toxic, acid addition salts wherein: R-^ taken individually is selected from the group consisting of hydrogen, phenyl, phenyl substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, "hydroxy and halogen; phenyl(C^ -C^ )lower alkyl; 1-phenyl-(Cy-Cg)lower alkyl; phenyl(C^ -C^ )lower alkyl and 1-phenyl-(Cy-Cg)lower -alkyl, wherein said phenyl group is substituted with from 1 to 3 groups each selected from the groups consisting of lower-alkyl,' lower-alkoxy, hydroxy, halogen and phenyl, provided that no more than one of the groups is phenyl; diphenyl (C^ -C^ ) lower-alkyl; diphenyl (C-^-C^) lower-alkyl where at least one of the phenyl groups is substituted with from 1 - 3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy and phenyl, provided that no more than one of the groups is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl of which at least one of the said phenyl groups is substituted with from 1-3 groups each selected from the group be consisting of lower alkyl, lower alkoxy, hydroxy, halogen and phenyl, provided that no more than one of the groups is phenyl; as well as compounds with the formulas: where n is 0, 1 or 2,' and E is H or OH; A individually is a group selected from the group consisting of hydrogen, acetyl, and phenyl, provided that when A is acetyl or phenyl, then R^ is selected from the group consisting of phenyl or phenyl substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy and halogen; R-^ and A together are selected from the group consisting of benzhydrylidene and compounds with the formulas: where n is 0, 1 or 2; R1<I> taken individually is selected from the group consisting of hydrogen, methyl, diphenylmethyl, diphenylmethyl where at least one of the phenyl groups is substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy, halogen < p > g phenyl, provided that no more than one group is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl wherein at least one of said phenyl groups is substituted with from 1-3 groups each selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy and phenyl, provided that no more than one of the groups is phenyl; as well as a connection with the formula: where n is 0, 1 or 2 and E is H or OH; B taken individually is hydrogen; 1 and B together are selected from the group consisting of benzhydrylidene and a compound of the formula: where n is 0, 1 or 2; R^" taken individually is selected from the group consisting of hydrogen, diphenylmethyl; diphenylmethyl of which at least one of said phenyl groups is substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy and phenyl, provided that no more than one of the groups is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl where at least one of the said phenyl groups is substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower alkoxy, hydroxy, halogen and phenyl, provided that no more than one group is phenyl; as well as compounds of the formulas: where n is 0, 1 or 2; D taken individually is hydrogen; R-^ " and D taken together are benzhydrylide, provided that when R-^" is different from hydrogen, then R-^ , R-^1 and A . each hydrogen, and when R^' is different from hydrogen, then is . R-1" is hydrogen, and when R-^' is different from hydrogen or methyl, then R-^ and Y are each hydrogen; R 2 is selected from the group consisting of hydrogen and C 1 -C 1 -lower alkyl; and R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, phenyl-lower alkyl; phenyl-lower-alkyl where said phenyl group is substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, hydroxy and halogen; diphenyl (C 1 -C 1 -C 1 ) lower alkyl; diphenyl-(C-^ -C^ )lower-alkyl where at least one of the said phenyl groups is substituted with from 1-3 groups each selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy and phenyl, provided that no more than one group is phenyl; alkenyl; and alkynyl; provided that at least one of said R^ , Ri'» R-^", R 2 and R^ is different from hydrogen, characterized in that mana) i) reacts a compound with the formula with a compound of the formula or the acid addition salt form of the latter compound, namely in a suitable organic solvent at a temperature between 0 and 50°C, and where A, B, D, R-^ R-^, R- ^', R 2 and R ^ is as defined previously, Z is selected from the group consisting of lower-alkoxy, lower-alkyl, lower-alkyl-S-, chlorine and C12 (0)P0-, and X is selected from the group consisting of halide, BF^ , FSO^ , CH^OSO^ and furthermore when Z is lower-alkyl-S-, then X can also be selected from the group consisting of (4-methylphenyl)SO^ , CH^ SO^ and CF^SO^, in order to thereby obtain a compound of formula (I); or ii) reacts a compound of the formula (II) with a compound of the formula: under the same reaction conditions as stated under step a) i), thereby producing the corresponding thiourea which is then reduced to produce a compound of formula (i) where R2 is hydrogen; or iii) reacts a compound of formula II with a compound of formula: in the presence of solv chloride as a catalyst, whereby a compound of formula (I) is produced, where R 2 is hydrogen; orb) i) reacts a compound of the formula with a compound of the formula: where R-p R-l', R-j^ ", R 2 , R^ , A, B, D Z and X are as defined previously, in order thereby to produce a compound of formula (i); or ii) in the case where Z in compound (VI) is (Lower- alkyl)-S- and R2 is H,. react said compound with the formula with a compound of the formula: in a suitable solvent, preferably by refluxing, to thereby prepare a compound of formula (I), wherein R 2 is hydrogen, and, if desired, to prepare non-toxic acid addition salts of the compounds prepared. 2. Process for the production of a chemical compound selected from the group consisting of 4-diphenylmethyl-1-iminomethylpiperidine and its non-toxic acid addition salts, characterized in that ethylformimidate is reacted with diphenyl-4*-piperidylmethane. 3. Process for the preparation of a chemical compound selected from the group consisting of 4-(diphenylmethyl)-1-(iso- . propylimino)methyl7piperidine and its non-toxic acid addition salts, characterized in that one reacts N-formyl-4-diphenylmethylpiperidine with dimethylsulphate, and then reacts the reaction product with isopropylamine. 4.. Process for the preparation of a chemical compound selected from the group consisting of 1-/N-(benzyl)iminomethyl7-4-diphenylmethylpiperidine and its non-toxic acid addition salts, characterized in that N-formyl-4-diphenylmethylpiperidine is reacted with dimethyl sulfate and then the reaction product reacts with benzylamine. 5. Process for the preparation of a chemical compound selected from the group consisting of 1-/N-(phenethyl)iminomethyl7-4-diphenylmethylpiperidine and its non-toxic acid addition salts, characterized in that N-formyl-4-diphenylmethylpiperidine is reacted with/'dimethylsulphate, and then the product reacts with phenethylamine. 6. Process for the preparation of a chemical compound selected from the group consisting of l-/N-(n-decyl)iminomethyl7- .4-diphenylmethylpiperidine and its non-toxic acid addition salts, characterized by reacting N-formyl-4-diphenylmethylpiperidine with dimethylsulphate and then reacting the product with n-decylamine. 7. Process for the preparation of a chemical compound selected from the group consisting of 4-(diphenylmethyl)-1-(Xoctyl-imino)methyl-7piperidine and its non-toxic acid addition salts, characterized in that N-formyl-4-diphenylmethylpiperidine is reacted with phosgene and then reacts the product with octylamine. . 8. Process for the preparation of a chemical compound selected from the group consisting of 4-(diphenylmethyl)-1-^X2-propynylimino)methyl7piperidine and its non-toxic acid addition salts, characterized in that one reacts .4-(diphenylmethyl)-1-piperidinocarbothioaldehyde with methyl iodide and then the product reacts with 2-propynylamine. 9. Process for the preparation of a chemical compound selected from the group consisting of 4-benzhydrylidene-1-((Xoctyl-imino)methyl-7piperidine and its non-toxic acid addition salts, characterized in that 4-benzhydrylidene-1-piperidinecarbothioaldehyde is reacted with methyl iodide and then reacts the product with n-octylamine. 10. Process for the preparation of a chemical compound selected from the group consisting of 4-(diphenylmethyl)-1-(Xethylimino)methyl7piperidine and its non-toxic acid addition salt, characterized in that ethylpropionimidate hydrochloride is reacted with diphenyl-4-piperidylmethane . 11. Process for the preparation of a chemical compound selected from the group consisting of 4-(diphenylmethyl)-1-(Xhexyl-imino)methyl-7piperidine and its non-toxic acid addition salts, characterized in that N-formyl-4-* diphenylmethylpiperidine is reacted with. dimethyl sulfate and then the product reacts with hexylamine. 12. Process for the preparation of a chemical compound selected from the group consisting of 1-(X4-chlorobenzylimino)-methyl7-4-(diphenylmethyl)piperidine <p> and its non-toxic acid addition salts, characterized in that one reacts N-formyl- 4-diphenylmethylpiperidine with dimethyl sulfate and then the product reacts with 4-chlorobenzylamine. 13. Process for the preparation of a chemical compound selected from the group consisting of 4^1-(4-methoxyphenyl)-benzyl7-1-(Toctylimino)methyl7piperidine and its non-toxic acid addition salts, characterized in that one reacts N-formyl-4/ I-(4-methoxyphenyl)benzyl7piperidine with dimethyl sulfate and then the product reacts with octylamine. 14. Process for the preparation of a chemical compound selected from the group consisting of (4-chlorophenyl)benzyl7-1-iminomethylpiperidine and its non-toxic acid addition salts, characterized in that one reacts ethyl- formidate hydrochloride with k~ ia-(4-chlorophenyl)benzyl7piperidine. 15. Process for the preparation of a chemical compound selected from the group consisting of 4(9-fluorenyl)-1-(1-octyl-imino)methyl-7-piperidine and its non-toxic acid addition salts, characterized in that 4(9-fluorenyl)-1-piperidinecarbutioaldehyde is reacted with methyl iodide and then the product reacts with octylamine. 16. Procedure for the production of chemical compounds ■ else selected from the group consisting of 4-(diphenylmethyl)-l-^inethyl-(octylimino)methyl7piperidine and its non-toxic acid addition salts, characterized in that triethyloxonium fluoborate is reacted with N-(n-octyl)acetamide and the product is reacted with 4- diphenylmethylpiperidine. 17. Process for the preparation of a chemical compound selected from the group consisting of N-(4-(diphenylmethyl)-1- piperidinyl7methylene-benzenebutanamine and its non-toxic acid addition salts, characterized in that reacts N-formyl-4-diphenylmethylpiperidine with dimethyl sulfate and then reacts the product with phenylbutylamine. 18.. Process for the preparation of a chemical compound selected from the group consisting of 3-(diphenylmethyl)-1-/Xoctyl-imino)methyl7piperidine and its non-toxic acid addition salts, characterized in that one reacts 3, (diphenylmethyl)-1-piperidinecarbutioaldehyde with methyl iodide and then the product reacts with octylamine. 19. Process for the production of 4-(hydroxydiphenylmethyl)-1-((Xoctylimino)methyl 7piperidine(E)^2-butenedioate, characterized by reacting 4-(hydroxydiphenylmethyl)-1-piperidinecarbothioaldehyde with methyl iodide and then the product reacts with octylamine. 20. Process for the production of 3-(diphenylmethyl)- . 1-iminomethyl)piperidine(E)-2-butenedioate hydrate, characterized By reacting ethyl formidate hydrochloride with diphenyl-3-piperidylmethane. 21. Process for the production of 4-(4-hydroxy-phenyl)phenylmethyl-7-1-(1-octylimino)methyl-7-piperidine-2-naphthalene-sulfonate, characterized by . that one treats with hydrobromic acid.