Antisecretory 4-diphenylmethyl-1-[(oxoalkyl)imino]methyl-piperidines and their derivatives

4-Diphenyl-1-[(oxo and oxo-related alkyl)imino]methyl-piperidine derivatives are disclosed which are useful for the inhibition of gastric acid secretion.

BACKGROUND OF THE INVENTION 
This invention relates to 
4-diphenylmethyl-1-[(oxoalkyl)-imino]methyl-piperidine derivatives and 
more particularly to those compounds of Formula II below and their 
pharmaceutically acceptable acid addition salts, which are inhibitors of 
gastric acid secretion. 
PRIOR ART 
The compounds of the present invention are the oxo or related derivatives 
of certain compounds disclosed in U.S. Pat. No. 4,251,655, such as 
4-diphenylmethyl-1-[octylimino]methyl piperidine which has the formula: 
##STR1## 
SUMMARY OF THE INVENTION 
The present invention is concerned with 
4-diphenylmethyl-1-[(oxoalkyl)-imino]methylpiperidines and their 
derivatives of the following Formula II, and pharmaceutically acceptable 
acid addition salts thereof: 
##STR2## 
wherein: n is an integer from 1-10, inclusive 
m is an integer from 0-9, inclusive 
n+m=1-10 
Z is selected from the following: 
##STR3## 
The compounds of the present invention all have an oxo or ketone function, 
or a function related thereto such as an --OH (which may be considered as 
a reduced ketone), or an oxime.dbd.N--OH, or a ketal 
##STR4## 
or thioketal 
##STR5## 
or acetal (OR.sub.1).sub.2. 
As used herein, the term "loweralkyl" refers to both straight chain and 
branched chain alkyls, e.g., methyl, ethyl, propyl, isopropyl, t-butyl, 
hexyl, and the like. 
METHODS OF PREATION 
The compounds of the present invention may be prepared by the following 
reaction scheme: 
##STR6## 
An appropriately activated derivative (IV) of 
N-formyl-4-(diphenylmethyl)piperidine (III), prepared from III and an 
activating agent chosen from, for example, phosgene (preferred), Me.sub.3 
O.sup.+ BF.sub.4.sup.-, Et.sub.3 O.sup.+ BF.sub.4.sup.-, (MeO).sub.2 
SO.sub.2, MeOSO.sub.2 F, POCl.sub.3, PCl.sub.5 and the like may be treated 
with an appropriate primary amine of general structure V to give an 
amidine of general structure VI. Amidine VI is treated with aqueous acid 
to obtain a keto amidine of general structure VII. Reduction of VII to the 
alcohol of general structure VIII may be accomplished with sodium 
borohydride as the reducing agent. Oximes of general structure IX are 
prepared by treating VI with hydroxylamine hydrochloride. 
Because the subject compounds (II) possess a basic amidine group, they may 
be converted into the corresponding acid addition salts. 
The acid addition salts may be prepared by reaction with an appropriate 
acid, as for example an inorganic acid such as a hydrohalic acid, i.e., 
hydrochloric, hydrobromic or hydroiodic acid; sulfuric or nitric acid; 
phosphoric acid; an organic acid such as acetic, propionic, glycolic, 
pamoic, pyruvic, oxalic, malonic, succinic, maleic, picric, fumaric, 
malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, 
ethanesulfonic, benzenesulfonic, p-toluenesulfonic, salicylic, 
2-naphthalenesulfonic or p-aminosalicylic acid. The therapeutically 
active, nontoxic acid addition salts of subject compounds (II) and their 
hydrates or solvates are included within the scope of the present 
invention. 
The starting materials may be prepared by known methods or as illustrated 
in detail in the Preparations section. 
METHOD OF TESTING 
The compounds of the invention are useful for inhibition of gastric acid 
secretion as measured by the following test. Female Sprague-Dawley rats 
are fasted twenty-four hours before testing and are given water ad libidum 
while being kept in individual cages. On the day of testing, the rats are 
weighed and are selected so that the rats in each test weigh within a 
range .+-.20 grams. 
Surgery is carried out under light ether anesthesia. As soon as the rat is 
anesthetized its teeth are removed and a mid-line incision is made on the 
abdomen about 11/2 inches in length and the stomach and duodenum are 
exposed. If at this point the stomach is filled with food or fecal 
material, the rat is discarded. If the condition of the stomach is 
acceptable, a purse string stitch is placed on the fundic portion of the 
stomach with a suture, taking care not to pierce any blood vessels in the 
area. A small nick is then made into the stomach in the center of the 
purse string, and a cannula, consisting of a small vinyl tube with a 
flange on one end, is put into the stomach, and the purse string stitch is 
closed tightly around the flange. The test compound is administered either 
intraduodenally (i.d.) immediately after surgery or orally (p.o.) one hour 
prior to surgery at doses generally ranging from about 0.25 to about 160 
mg/kg in a volume of 0.5 ml/100 grams rat. Control rats receive the test 
vehicle, 0.5% aqueous methyl cellulose. 
After the surgery and (in the case of i.d. administration) after 
administration of the test compound, the abdominal wall and skin are 
closed simultaneously with three or four 18 mm wound clips and a 
collecting tube is placed on the cannula. Each rat is then placed in a box 
in which a longitudinal slit has been made to allow the cannula to hang 
freely and to allow the rat to move about unencumbered. After the rat has 
been allowed to stabilize for thirty minutes, the collection tube on the 
cannula is discarded and replaced with a clean tube to receive the gastric 
juice. Collections are made at one hour. At the end of the study, the 
cannula is removed and the rat is sacrificed. 
The sample of gastric contents collected is drained into a centrifuge tube 
and centrifuged to pack down the sediment. The volume is read and a 1 ml 
aliquot of the supernatant is put into a beaker containing 10 ml distilled 
water and is titrated to pH 7 using 0.01 N sodium hydroxide. Results are 
determined for Volume, Titratable Acid and Total Acid Output, where Volume 
equals total ml of gastric juice minus sediment; Titratable Acid (meq/l) 
equals amount of 0.01 N sodium hydroxide needed to titrate the acid to pH 
7; and Total Acid Output equals Titratable Acid times Volume. Results are 
reported as the ED.sub.50 dose (mg/kg required to produce an average of 
50% inhibition in Total Acid Output versus controls in all the animals 
tested for a particular compound) and as percent inhibition. The compounds 
of the invention all demonstrate a significant inhibition both i.d. and 
p.o. at less than 80 mg/kg, with preferred compounds having an ED.sub.50 
p.o. less than 20 mg/kg. 
It is well-known that excessive secretion of gastric hydrochloric acid 
leads to unneeded peptic activity and endangers the mucous lining of the 
stomach. The use of gastric antisecretory agents is thus desirable as an 
aid in the prevention and amelioration of distress occasioned by high 
concentrations of stomach acid. 
The results obtained for representative compounds of the invention by the 
above test for inhibition of gastric secretion are shown in Table I: 
TABLE I 
______________________________________ 
##STR7## 
ED.sub.50 Acute Gastric 
Compound of Fistula, Rat 
Example No. n X (mg/kg p.o.) 
______________________________________ 
1 4980-46-98 
6 O(CH.sub.2).sub.2 O 
3.14 
2 4955-46-98 
6 O 14.74 
3 4978-71-98 
6 H,OH 78.08 
4 5085-71-98 
6 NOH 12.31 
5 5066-46-98 
8 O 4.76 
6 5020-11-98 
1 O 6.07 
______________________________________ 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The compounds within the scope of the invention are those of Formula II 
wherein: 
n is 1-10 
m is 0-9; n+m is 1-10 
Z is selected from the following: 
##STR8## 
The preferred compounds are those of Formula II wherein: 
n is 1-10 
m is 0-9; n+m is 1-10 
Z is selected from the following: 
##STR9## 
and the most preferred compounds are those in Table I. 
DESCRIPTION OF THE METHOD OF TREATMENT AND PHARMACEUTICAL COMPOSITIONS 
In view of the antisecretory activity of the subject compounds, there is 
further provided herein a method of inhibiting gastric acid secretion 
which comprises internally administering to a gastric hyperacidic subject 
(man or animal) an effective gastric acid secretion inhibiting amount of a 
substituted N-iminomethylpiperidine of Formula (II), in base or acid 
addition salt form, preferably in admixture with a pharmaceutically 
acceptable carrier. If an acid addition salt form is used, said salt must 
of course be pharmaceutically-acceptable and non-toxic. Pharmaceutical 
compositions comprising a subject compound (II) are also considered a 
further aspect of the present invention. 
To prepare the pharmaceutical compositions of the present invention, a 
substituted N-iminomethylpiperidine of Formula (II) or an acid addition 
salt thereof is combined as the active ingredient in intimate admixture 
with a pharmaceutical carrier according to conventional pharmaceutical 
compounding techniques, which carrier may take a wide variety of forms 
depending on the form of preparation desired for administration, e.g., 
oral or parenteral. In preparing the compositions in oral dosage form, any 
of the usual pharmaceutical media may be employed, such as for example, 
water, glycols, oils, alcohols, flavoring agents, preservatives, coloring 
agents, and the like in the case of oral liquid preparations such as for 
example, suspensions, elixirs, and solutions; or carriers such as 
starches, sugars, diluents, granulating agents, lubricants, binders, 
disintegrating agents, and the like in a case of oral solid preparations, 
such as for example, powders, capsules, and tablets. Because of their ease 
in administration, tablets and capsules represent the most advantageous 
oral dosage unit form, in which case solid pharmaceutical carriers are 
obviously employed. If desired, tablets may be sugar coated or enteric 
coated by standard techniques. For parenterals, the carrier will usually 
comprise sterile water, although other ingredients, for example, to aid 
solubility or for preservative purposes, may be included. Injectable 
suspensions may also be prepared, in which case appropriate liquid 
carriers, suspending agents, and the like may be employed. The 
pharmaceutical compositions herein will contain, per dosage unit, e.g., 
tablet, capsule, powder, injection, teaspoonful, and the like, from about 
ten to about 500 milligrams of the active ingredient, and preferably from 
about fifteen to about 250 milligrams. 
The following preparations, showing how to prepare various starting 
materials and examples are intended to illustrate but not to limit the 
scope of the present invention. 
PREATION OF STARTING MATERIALS 
Preparation 1 
##STR10## 
N-[7-Oxo(6-carboethoxy)octyl]phthalimide 
A solution of sodium ethoxide in ethanol, prepared by dissolving 23.69 g 
(1.03 moles) of sodium in 800 ml of absolute alcohol, was treated slowly 
with ethyl acetoacetate. To this solution was added, in one portion, 308 g 
(1.04 moles) of N-(5-bromopentyl)phthalimide and the resulting mixture was 
refluxed for two hours and stirred overnight at 25.degree.. The ethanol 
was stripped, 1500 ml of water was added to the residue, and the resulting 
mixture was extracted with 3.times.400 ml of ether. The ether layers were 
combined, dried over anhydrous sodium sulfate, filtered and stripped to 
give 350 g of light brown oil. This material was used in the next step 
without purification. 
Preparation 2 
##STR11## 
N-(7-Oxooctyl)phthalimide 
A mixture of 350 g of crude N-[7-oxo(6-carboethoxy)octyl]phthalimide and 
1000 ml of acetic acid, concentrated hydrochloric acid, and water was 
refluxed for three hours. The reaction mixture was stripped, the residue 
dissolved in methylene chloride and basified with 2 N NaOH solution. The 
organic layer was separated, dried over anhydrous sodium sulfate, filtered 
and stripped to an orange oil, 73% pure by gc (SE-30, 
90-280.degree.@16.degree./min). This material was used without further 
purification in Preparation 3. 
Preparation 3 
##STR12## 
N-[6-(2-Methyl-1,3-dioxolan-2-yl)hexyl]phthalimide 
A mixture of 142.0 g (0.52 mole) of N-(7-oxooctyl)phthalimide, 60 ml of 
ethylene glycol, 5.80 g of p-toluenesulfonic acid and 290 ml of benzene 
was refluxed overnight using a Dean-Stark trap to collect the azeotrope. 
The reaction was cooled, treated with 2 N NaOH solution, the organic layer 
separated, dried over anhydrous potassium carbonate, filtered and stripped 
to give 125.25 g of orange oil, 76% pure by gc (SE-30, 
90.degree.-280.degree.@16.degree./min). 
Preparation 4 
##STR13## 
N-[6-(2-Methyl-1,3-dioxolan-2-yl)hexyl]amine 
A mixture of 125.25 g (0.395 mole) of 
N-[6-(2-methyl-1,3-dioxolan-2-yl)hexyl]phthalimide, 23 ml of 85% hydrazine 
hydrate, and 370 ml of 95% ethanol was refluxed for four hours, cooled, 
filtered and stripped. The residue was mixed with 500 ml of water, 
basified with 2 N NaOH solution and extracted with methylene chloride. The 
organic layer was separated, dried over anhydrous potassium carbonate, 
filtered, and stripped to an orange oil. This material was distilled to 
give 35.70 g (64%) of clear oil bp 80.degree.-83.degree. (0.100 mm). 
Preparation 5 
Following the procedure described in Preparation 1 and using the 
appropriate N-bromoalkylphthalimides and .beta.-ketoesters, the following 
can be prepared: 
______________________________________ 
##STR14## 
n m 
______________________________________ 
5 4 
4 3 
3 2 
2 1 
9 0 
7 0 
4 0 
3 0 
2 0 
______________________________________ 
Preparation 6 
Following the procedure described in Preparation 2 the following can be 
prepared: 
______________________________________ 
##STR15## 
n m 
______________________________________ 
6 4 
5 3 
4 2 
3 1 
10 0 
9 0 
7 0 
5 0 
4 0 
3 0 
______________________________________ 
Preparation 7 
Following the procedure described in Preparation 3 the following can be 
prepared: 
______________________________________ 
##STR16## 
n m 
______________________________________ 
6 4 
5 3 
4 2 
3 1 
10 0 
9 0 
7 0 
5 0 
4 0 
3 0 
______________________________________ 
Preparation 8 
Using the procedure described in Preparation 7, but substituting various 
carbinols for ethylene glycol, the following acetals may be prepared: 
______________________________________ 
##STR17## 
n m R.sub.1 
______________________________________ 
6 4 CH.sub.3 
5 3 CH.sub.3 
4 2 CH.sub.3 
3 1 CH.sub.3 
10 0 CH.sub.3 
9 0 CH.sub.3 
8 0 CH.sub.3 
7 0 CH.sub.3 
6 0 CH.sub.3 
5 0 CH.sub.3 
4 0 CH.sub.3 
3 0 CH.sub.3 
6 4 CH.sub.3 CH.sub.2 
5 3 CH.sub.3 CH.sub.2 
4 2 CH.sub.3 CH.sub.2 
3 1 CH.sub.3 CH.sub.2 
10 0 CH.sub.3 CH.sub.2 
9 0 CH.sub.3 CH.sub.2 
8 0 CH.sub.3 CH.sub.2 
7 0 CH.sub.3 CH.sub.2 
6 0 CH.sub.3 CH.sub.2 
5 0 CH.sub.3 CH.sub.2 
4 0 CH.sub.3 CH.sub.2 
3 0 CH.sub.3 CH.sub.2 
______________________________________ 
Preparation 9 
Following the procedure described in Preparation 4, the following can be 
prepared: 
______________________________________ 
##STR18## 
n m 
______________________________________ 
6 4 
5 3 
4 2 
3 1 
10 0 
9 0 
7 0 
5 0 
4 0 
3 0 
1 6 
1 5 
1 3 
______________________________________ 
Preparation 10 
Using the procedure described in Preparation 4, the following amino ketals 
can be prepared: 
______________________________________ 
##STR19## 
n m R.sub.1 
______________________________________ 
6 4 CH.sub.3 
5 3 CH.sub.3 
4 2 CH.sub.3 
3 1 CH.sub.3 
10 0 CH.sub.3 
9 0 CH.sub.3 
8 0 CH.sub.3 
7 0 CH.sub.3 
6 0 CH.sub.3 
5 0 CH.sub.3 
4 0 CH.sub.3 
3 0 CH.sub.3 
1 6 CH.sub.3 
1 5 CH.sub.3 
1 3 CH.sub.3 
1 0 CH.sub.3 
6 4 CH.sub.3 CH.sub.2 
5 3 CH.sub.3 CH.sub.2 
4 2 CH.sub.3 CH.sub.2 
3 1 CH.sub.3 CH.sub.2 
10 0 CH.sub.3 CH.sub.2 
9 0 CH.sub.3 CH.sub.2 
8 0 CH.sub.3 CH.sub.2 
7 0 CH.sub.3 CH.sub.2 
6 0 CH.sub.3 CH.sub.2 
5 0 CH.sub.3 CH.sub.2 
4 0 CH.sub.3 CH.sub.2 
3 0 CH.sub.3 CH.sub.2 
1 6 CH.sub.3 CH.sub.2 
1 5 CH.sub.3 CH.sub.2 
1 3 CH.sub.3 CH.sub.2 
1 0 CH.sub.3 CH.sub.2 
______________________________________ 
Preparation 11 
Following the method of Fieser, J. Am. Chem. Soc., 76, 1945 (1954) and 
using the compounds of Preparations 2 and 6 and ethanedithiol the 
following may be prepared: 
______________________________________ 
##STR20## 
n m 
______________________________________ 
6 4 
5 3 
4 2 
3 1 
1 0 
10 0 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
1 6 
1 5 
1 4 
1 3 
______________________________________ 
Preparation 12 
Using the method of Preparation 9, the following can be prepared: 
______________________________________ 
##STR21## 
n m 
______________________________________ 
6 4 
5 3 
4 2 
3 1 
1 0 
10 0 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
1 6 
1 5 
1 4 
1 3 
______________________________________