NZ189977A - Substituted n-iminomethyl piperidines - Google Patents
Substituted n-iminomethyl piperidinesInfo
- Publication number
- NZ189977A NZ189977A NZ189977A NZ18997779A NZ189977A NZ 189977 A NZ189977 A NZ 189977A NZ 189977 A NZ189977 A NZ 189977A NZ 18997779 A NZ18997779 A NZ 18997779A NZ 189977 A NZ189977 A NZ 189977A
- Authority
- NZ
- New Zealand
- Prior art keywords
- diphenylmethyl
- addition salts
- acid addition
- piperidine
- toxic acid
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number 1 89977
189977
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Priority Dzzs{&): . |
Speoffica&lcn Cia.sCp.-WMKP^^J^ttP
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Patents Form No. 5
nj>2^ 23W^W19 "^CEN®-
PATENTS ACT 195 3
COMPLETE SPECIFICATION
Substituted N-iminomethylpiperidines
We, McNEILAB, INC., a corporation of the State of Pennsylvania, United States of America, of Camp Hill Road, Fort Washington, Pennsylvania, United States of America do hereby declare the invention for which -i/we pray that a Patent may be granted to »e/us, and the method by which it in to be performed, to be particularly described in and by the following statement:
1 - (followed by page la)
t)
189977
McC „
1 ,v-v- 11
1 a
SUBSTITUTED N-IMINOMETHYLPIPERIDINES-REIATED APPLICATION
—This application is a continuation-in-part ■ application of our copending application Serial No->
801,410, filed March 20, 197S.
BACKGROUND OF THE INVENTION Unsubstituted N-iminomethylpiperidine is disclosed in United States Patent No. 2,615,023, but said (compound does not inhibit gastric acid secretion even 10 at doses four times or greater than those at which the subject compounds are active. It has now surprisingly been discovered that certain substituted N-iminomethyl-piperidines are effective inhibitors of gastric acid secretion.
SUMMARY OF THE INVENTION
Description of the Compounds
The present invention comprises substituted N-iminomethylpiperidines of Formula CI):
R-, "
■ D
=NR,
(I)
<
wherein:
R1 taken individually is a member selected from the group consisting of hydrogen; phenyl;
phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, lower-25 alkoxy, hydroxy and halo;, phenyl(C^-C^)loweralkyl; 1-phenyl(C^-Cg)-loweralkyl; phenyl CC^-C^loweralkyl and 1-phenyl CC?-C9)-loweralkyl in which said phenyl is substituted with from
^ 189977
one to three members each selected from the group con-"
sisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; diphenyl(C^-C^)loweralkyl; dipheny1)loweralkyl wherein at le'ast one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and radicals of formulae:
ICH0)
and wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected frcrn the group consisting of hydrogen, acetyl, and phenyl, provided that when A is acetyl or phenyl, is a member selected from the group consisting of phenyl or phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy and halo;
R^ and A taken together is a member selected from the group consisting of benzhydrylidene and radicals of formulae:
CCH-)
and
Hooa*81
wherein n is 0, 1, or 2;
b mtv ^ J J
3 »w,/ / a ,,
R^' taken individually is a member selected frcm the group consisting of hydrogen; methyl; dipheny Imethyl; diphenyl- -methyl wherein at least one of the phenyl groups is substituted with from one to three members each selected m
from the group consisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; diphenylhydroxymethy1; diphenyl-hydroxymethyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy,
halo, hydroxy, and phenyl, provided that no more than one member is phenyl; and a radical of formula:
CCIU)
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
R^' and B taken together is a member selected from the group consisting of benzhydrylidene and a radical of formulae:
(CH
wherein n is 0, 1, or 2.
r£' taken individually is a member selected frcm the group consisting of hydrogen, diphenylmethyl; diphenyImethy 1 wherein at least one of said phenyls is substituted with frcm one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is phenyl; diphenyl-hydroxymethyl; diphenylhydroxymethy1 wherein at least
189977
4
one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and radicals m
of formulae:
CCH.
and
WW
13 MOV 1981
wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R£*and D taken together is benzhydrylidene;
is a member selected from the group consisting of hydrogen and loweralkyl; and is a member selected from the group consisting of hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenyllower-alkyl in which said phenyl is substituted with from one to three 15 members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, and halo; dipheny 1 (C-^-C^) loweralkyl; diphenyl (C^-C^) - loweralkyl in which at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, 20 hydroxy, halo, and phenyl, provided that no more than one member is phenyl; alkenyl; and alkynyl;
provided that at least one of said R^, R^', and R^" is other than hydrogen and further provided that when R^" is other than hydrogen R^, and R^'* anc^ A are each hydrogen; when R^1 is 25 hydrogen only one of R^ and R^" is other than hydrogen; when
R^' is methyl R^ is other than hydrogen and R^" is hydrogen; and when R^' is other than hydrogen or methyl R^, R^" and A are each hydrogen.
As used herein, loweralkyl and loweralkoxy may 30 be straight or branched chain saturated aliphatic hydrocarbons having from one to eight carbon atoms, such as for example, methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, pentyl, and the like loweralkyls, and, respectively,
the corresponding loweralkoxys, e.g. methoxy,
s 189977.
ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and the like. The term loweralkyl" includes those lower-
alkyls having from one to four carbon atoms, such as for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, and the like. The terms "phenyl-(Ci~C4)loweralkyl" and "diphenyl(C^-C4)loweralkyl" include only those compounds where the phenyl group(s) are bonded to the terminal carbon atom of a straight chain loweralkyl, such as 2-phenethyl, 4-phenylbutyl, 4,4-diphenylbutyl, 3,3-diphenylpropyl, and the like. The term "1-phenyl-(C7~Cg)loweralkyl" includes groups having the following general formula:
CH3
where m is 5, 6, -or 7. The term "alkyl" includes straight or branched chain saturated aliphatic hydrocarbons having up to sixteen carbon atoms, such as for example, the above mentioned loweralkyls and further such radicals as hexyl, heptyl, octyl, nonyl, decyl, dodecyl, hexadecyl, and the like. The term "cycloalkyl" includes mono-, bi-, and tricyclic saturated and unsaturated aliphatic hydrocarbons having up to ten carbon atoms, such as for example, cyclohexyl, adamantyl, 1-adamantyl-methyl, exo-norbornyl, endo-norbornyl, noradamantyl, anti-7-norbornenyl, and the like. The terms "alkenyl" and "alkynyl" include straight and branched chain hydrocarbons having from two to about eighteen carbon atoms and at least one double or triple bond, respectively,
such as for example, allyl, methallyl, 1-propargyl (1-propynyl), 2-pentenyl, and the like. The term "halo" includes fluoro, chloro, bromo and iodo.
Methods of Preparation
The compounds of Formula I may generally be prepared by reacting together: a) an appropriately-substituted piperidine of Formula (II) with an appropriate activated amide (Formula III) , or b) an appropriate primary amine of Formula (VII) with an activated
1899 7 7
o piperidine of Formula (VI), said activation in either case having been achieved by treatment of the respective amide with a suitable activating agent selected from,
-L. _ -f _
for example# phosgene, Me^O BF^ , Et30 BF4 , (MeOjSOj* Me0S02F, POCl^, PC15 and the like.
Included in the terms "amide" and "N-acyl-piperidine" as used herein are the corresponding thio derivatives in which the carbonyl oxygen has been replaced by sulfur. In the case of the thio derivatives,
there are additional suitable activating agents which may be employed, such as for example, loweralkyl halides (methyl halide being preferred), methyl tosylate, methyl sulfonic acid esters (e.g., methyl methanesulfonate)
methyl trifluoromethylsulfonate, and the like.
The activated reactant of Formula (III) may be in either free base or acid addition salt form.
Specific preparative routes are given below:
A) The compounds of Formula (I) may be prepared by reacting the appropriately-substituted piperidine of Formula (II) with an appropriate imidate ester of Formula (III). The methyl and ethyl esters are preferred. The substituted piperidine and the imidate ester (which may be present in either free base or acid addition salt form* the latter being shown) are stirred together in a suitable organic solvent such as, for example, a halo-carbon (e.g., carbon tetrachloride, chloro'form, 1,2-dichloroethane, and the like), a loweralkanol (e.g.,
methanol, ethanol, isopropanol, and the like), an aromatic hydrocarbon (e.g., benzene, xylene, toluene, and the like), dimethylsulfoxide, and the like., The temperature of the Yreaction is preferably from about 0° to about 25°C, and in some cases may be carried out as high as 50°C, but in any event the temperature of the reaction must not be high enough to decompose significant amounts of the imidate ester. The resulting product may be isolated and purified by techniques known in the art, e.g., by stripping off the solvent and recrystallizing the desired product in the free base or acid addition salt form.
The above reaction scheme may be illustrated by the
189977
following, wherein A, 3, D, ^1' ^1' ^2' ^3 as previously defined, Z is selected from the group consisting of loweralkoxy (preferably methoxy and ethoxy), loweralkyl-S- (preferably methylthio), chloro, and Cl2(0)PO-, and X is a member selected from the group consisting of halide, BF^, FSO^r and CH^OSO-j. Additionally, when Z is loweralkyl-S-, X may also be a member selected from the group consisting of (4-methylphenyl)S03, CH^SO^, and CF^SO-j.
^ NH + ZC=NR3 HX > y\ /n?=nr3
r2
(II) (III) (I)
The compounds of Formula (I) wherein R2 is hydrogen may also be prepared by an analogous route by substituting an appropriate compound of Formula (IIIA) or (IIIB) for the imidate ester of Formula (III). If 15 the former is used, the resulting thiourea is then reduced (e.g., with Raney nickel) to give the desired compound. If the latter is used, silver chloride is employed as catalyst. These reaction schemes are illustrated by the following:
m 335
.1 899 7 7
8
B) The compounds of Formula CI) may also be prepared by reacting a suitably-substituted piperidine of Formula (II) with acetic formic anhydride or N,N-diloweralkylthioformamide (for H2=H^ or a cl~c4 low^alkyl anhydride (for R2=Cl"C4 l°weralky1)' the anhydride preferably being present in excess. The piperidine and anhydride or thioformamide are combined with cooling and are allowed to stir for about 18 hours. The resulting reaction mixture, either dissolved in an organic solvent selected from the aforementioned halocarhon and aliphatic hydrocarbon solvents or without the addition of solvent, is then treated with, an aqueous solution of a weak, base te.g%, sodium bicarbonate! until the aqueous layer is neutral Cfor the anhydride routel or is washed with.
water Cfor the amide route!. The organic layer is separated and any solvent present is removed to obtain the respective intermediate amides CIV1, CEVAl, and CVl * The intermediate amide is treated either neat or in the presence of an organic solvent such asf for example, a halocarbon CCHCl^, CEjC^) or a hydrocarbon (benzene,
toluene) at 25° to 100®C with a suitable activating agent, as described previously, for about two to three hours, to produce the activated derivative (.VI), after which the reaction mixture is allowed to cool. Addition of the appropriate primary amine CVII) yields the desired product of Formula CI) which may be isolated and purified by known methods discussed above.' The above reaction scheme may be illustrated by the following,
wherein. R^, R^', R^", R2, R3, A, B, D, Z, and X are as originally defined:
IW J J J
,1 89977
* v3</-
vii x "a kc-nr,
a \ /a,
When Z is Cloweralkyll-S-, the compounds of Formula CIl wherein may also be obtained by reacting the activated intermediate CVI) with, the appropriate isocyanate of Formula (VIII), preferably at the reflux temperature of the solvent (e.g., toluene) for about nine days. This reaction scheme is illustrated by the following:
loweralkyl
N=C"
VI
a
R3N=C=0
VIII
I CR2=H1
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 am appropriate acid, as for example an 15 inorganic acid such as a hydrohalic acid, i*e«, hydrochloric, hydrobromic or hydriodic acid; sulfuric or nitric acid; phosphoric acid; an organic acid such as acetic, propionic, glycolic, pamoic, pyruvic, oxalic, malonic, succinic, maleic, picric, fumaric, malic, 20 tartaric, citric, benzoic, cinnamic, mandelic, methane-
sulfonic, ethanesulfonic, benzenesulfonic, g^-toluenesulfonic,
18 9977
salicylic, 2-naphthalenesulfonic or £-aminosalicylic acid. The therapeutically active,, non-toxic acid addition salts of subject compounds (I) are included within the scope of the present invention.
The'starting materials of Formulas (II), (III), (IV), (IVA), (V), (VI), (VII), and (VIII) are known or may be prepared by known methods. See generally R. C. Elderfield, Heterocyclic Compounds, Vol. 1, Ch. 9, pp 617-77 (1950). Preparative methods for compounds (II) are described in, for example, articles by F. Ravenna, Farmaco (Pavia) Ed. Sci., 1£, 473-82 (1959) and E. Sury and K. Hoffman, Helv. Chim. Acta., 248, 2133 (1954). Preparative methods for compounds (III) and (IV) are described in, for example, articles by R. Ohme and E. Schmitz, Angew. Chem. Intern. Ed., £, 566 (1967), F. Snydam,
et al., J. Org. Chem., 34, 292 (1969), and K. Sechinger, Helv. Chim. Acta., 56, 776 (1973). Preparative methods for compounds (V) and (VI) are described in, for example, C. A. Buehler and D. E. Pearson, Survey of Organic Syntheses , Ch. 18, p 894 (1970).
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 of ± 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 1 1/2 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
" MN 335
.1 899 7 7
11
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
0
compound is administered either intraduorionally (i,d.l -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 pH7 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/1) equals amount of 0.01 N sodium hydroxide needed to titrate the acid to pH7; and Total Acid Output equals Titratable Acid times Volume. Results are reported as the ED5Q dose (mgAg 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
12 189977-
i.d. and p.o. at less than 80 mg/kg, with preferred com- ^
pounds having an ED^q p.o. less than 20 mg/kg. In contrast, the prior art N-iminomethylpiperidine demonstrates no inhibition whatsoever at a dose of 100 mg/kg p.o. or at 5 80 mg/kg i.d.
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 10 an aid in the prevention and amelioration of distress occasioned by high concentrations of stomach acid.
Description of the Preferred Embodiments
Preferred compounds of the invention are those of Formula (I) wherein:
is a member selected from the group consisting of phenyl; phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy and halo; .
~ phenyl(C^-C^)loweralkyl; phenyl-20 (C^-C^)loweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy and halo; diphenyl-(C-^-C^) loweralkyl and diphenyl(C^-C^)loweralkyl wherein at least one of said phenyls is substituted with from 25 one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo, and phenyl,
provided that no more than one member is phenyl;
R2 is a member selected from the group consisting of hydrogen and methyl;
R^ is a member selected from the group consisting of hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenyl-loweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; alkenyl, and 35 alkynyl; and
R^' , A, B, and D are each hydrogen.
More preferred compounds of the invention are those of Formula (.1) wherein: —
■
1899 7 7
13
is a member selected from the group consisting of diphenylmethyl and diphenylmethyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo?
R2 is hydrogen;
R^ is a member selected from the group consisting of hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; alkenyl; and alkynyl; and
R^1, A, B, and D-are hydrogen.
Most preferred compounds of the invention are those of Formula (I) wherein R^ is a member selected from the group consisting of diphenylmethyl and diphenylmethyl wherein one of said phenyls is substitued in the para-position with a member selected from the group consisting of loweralkyl, loweralkoxy, and halo; R2 is hydrogen; R^ is a member selected from the group consisting of hydrogen, straight chain alkyl, and phenylloweralkyl; and Rl"'
A, B, and D are all hydrogen.
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 (I), 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 nontoxic. Pharmaceutical compositions comprising a subject compound (I) 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 (I) or an acid addition salt thereof is combined
MN 335
189977
14
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 five hundred milligrams of the active ingredient, and preferably from about fifteen to about two hundred fifty milligrams .
The following examples are intended to illustrate but not to limit the scope of the present invention.
189977
EXAMPLE I
4-Diphenylmethy1-1-iminomethylpiperidine hydrochloride hydrate
A suspension of 27.39g (0.25 mole) of ethyl formimidate hydrochloride [prepared by the method of Ohme, et al., Angew. Chem. Intl. Ed., 6, 566(1967)] and 52.71g (0.20 mole) of diphenyl-4-piperidylmethane in 80 ml of freshly-opened absolute ethanol was stirred magnetically under a calcium chloride tube overnight. The suspension was filtered and diethylether was added to the filtrate. The filtrate was stripped to dryness and the resulting oil was crystallized from isopropanol. The solid was then suspended in boiling ethyl acetate to obtain a higher melting form. Two recrystallizations from ethanol-ether yielded pure 4-diphenylmethyl-l-iminomethyl-piperidine hydrochloride hydrate; m.p. 220-221°C.
EXAMPLE II
Following the procedure of Example If but substituting for the ethyl formimidate hydrochloride and diphenyl-4-piperidylmethane used therein, equivalent amounts of the appropriate starting materials, there are prepared the following:
NC=NR- • Salt
/ 1 / R2
Salt m.p. (°C)
diphenylmethyl
HC1
H
H
271.5-277.5
a- (4-methaxypheaiyl) benzyl fumarate
H
H
E
189.5-192.5
a- (1,4-biphenyl) -a-hydroxybenzyl
BC1
H
H
H
216 -218
phenyl
HC1
H
H
H
204 -205
benzyl
BC1
0 H
H
H
199 -201.5
phenyl
HC1
H
H
172 -175
a- (4-chlarophenyl)
fumarate
H
H
H
192.5-194.5
benzyl
16
EXAMPLE III
1 8997
4-(Diphenylmethyl)-1-N-ethyliminomethyl-piperidine oxalate hemihydrate
A mixture of 8.00g (0.029 mole) of N-formyl-4-diphenylmethylpiperidine and 3.61g (2.67 ml, 0.029 mole) of dimethylsulfate was heated on a steam bath for two hours to give a clear thick syrup. To this material was then added 1.38g (2.00 ml, 0.031 mole) of ethylamine in 15 ml of methylene chloride. The resulting solution was stirred for 1.5 hours at 25°, stripped, slurried in ether, and treated with 28 ml of 3 N sodium hydroxide solution. The ethereal layer was dried over potassium carbonate, filtered through diatomaceous earth filter aid and evaporated to give 8.77g of yellow liquid. Treatment of this material in isopropanol with 3.26g of oxalic acid dihydrate afforded 5.0g of white solid m.p. 165-175°C. Recrystallization from isopropanol afforded pure 4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate hemihydrate as a white solid; m.p. 185-187°C.
EXAMPLE IV
Following the procedure of Example III, but substituting for the N-formyl-4-diphenylmethylpiperidine and ethylamine used therein, equivalent amounts of the appropriate starting materials, there are prepared the following:
diphenylmethyl
?2 H
H H H H H H H
i-propyl n-butyl rv-hexyl n-heptyl n-octyl t-octyl n-nonyl
NC=NR, • Salt I 3
/R2
Salt cyclohexane sulfamate fumarate m.p. (°C) 179.5-181
175 -178 193.5-195
179 -181.5
175 -178
157 -159
227 -229
142 -144.5
1 8 9977
h h.
Salt m.p
>. (°C)
diphenylmethyl
H
iv-decyl succinate
106
-109
II
H
n-dcdecyl fumarate hydrate
143
-145.5
It
H
1-adamantyl fumarate
275
-276
II
H
benzyl cyclohexane sulfamate
164.
-166.5
It
H
phenethyl
IV
141
-144
n
H
g-chlorobenzyl
2-naphthalene sulfonate
222
-224
tt
H
£-methaxybenzyl
If
110.
-112.5
a-(4-methaxyphenyl) H benzyl n-octyl
(E)-2-butene-dioate
154.
-156
a- (4-methylpbeny 1) benzyl
H
n-octyl
IV
161
-163.5
diphenylmethyl
H
4-methylbenzyl perchlorate
242
-244
n
H
phenyl
4-toluene-
285
-286
sulfonate EXAMPLE IVA
A mixture of 4-[(4-methoxyphenyl)phenylmethy1]-1-[(octylimino)methyl]piperidine (1.90g, 0.0045 mole) and 42 ml of 47-49% hydrobromic acid was refluxed one hour, cooled, and the aqueous portion decanted from a thick oil. The oil was dissolved in methylene chloride, rendered neutral with aqueous sodium bicarbonate, dried and evaporated. The residue, 4-[(4-hydroxyphenyl)-phenylmethyl]-1-[.(octylimino)methyl]piperidine was converted to its 2-naphthalenesulfonic acid salt, m.p. 177.5-180°C.
EXAMPLE V
4-(Diphenylmethyl)-1-[(octylimino)methyl]- piperidine Fumarate Hydrate
A solution of triethyl oxonium fluoroborate [prepared from 104.6g (0.737 mole) of boron trifluoride etherate and 56.04g (47.37 ml, 0.606 mole) of epichloro-hydrin] was dissolved in 800 ml of anhydrous methylene chloride and the resulting solution treated with 81.Og (0.516 mole) of N-(n-octyl) formamide and stirred overnight at 25°. 4-Diphenylmethylpiperidine (130g, 0.518 mole) was added and the mixture was stirred for four hours. A small amount of white solid was filtered off,
""HN-J35
189977
18
the filtrate made basic with 3 N sodium hydroxide solution, separated, dried over potassium carbonate and evaporated to a yellow oil. This material was dissolved in isopropanol and treated with 60g of fumaric acid with 5 warming. Addition of an equal volume of acetone followed by ether caused a solid to form affording two crops of material m.p. 152-157°C. These were combined and re-crystallized from ethanol-water to give two crops of 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine 10 fumarate hydrate; m.p. 157-159°C.
EXAMPLE VI
4-(Diphenylmethyl)-1-piperidinecarbothioaldehyde
A solution of 20.Og (0.08 mole) of 4-dipheny1-methylpiperidine, 14.2g (0.16 mole) of N,N-dimethylthio-15 formamide and 50 ml of toluene was 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 afforded a white crystalline solid, 4-(di-20 phenylmethy1)-1-piperidinecarbothioaldehyde, m.p. 152-154*
EXAMPLE VII
Following the above procedure, but substituting for 4-diphenylmethylpiperidine used therein, an equivalent amount of an appropriate piperidine, there are pre-
pared the following: r t
«s ,
"ix f \s
NCH
\ /
A
m.p.
(°C)
9-fluorenyl
H H
142 -
146
H
H Ph2CH
115 -
120
benzyhydrylidene
H
131 -
134
diphenylhydroxymethyl
H H
200 -
203
EXAMPLE VIII
4-(Diphenylmethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate
A solution of 5.54g (0.019 mole) of 4-(diphenyl methyl) -1-piperidinecarbothioaldehyde in 20 ml of
1899 7 7
chloroform was treated with 2.65g (1.16 ml, 0.019 mole) of methyl iodide and refluxed for one hour. The resulting solution was treated with 3.49g (0.019 mole) of n-dodecylamine, refluxed one and one half hours, cooled,
treated with aqueous sodium hydroxide and the organic layer separated. After drying, evaporation yielded an oil which was converted to the fumarate to yield 4-(diphenylmethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate; m.p. 143-145.5°C.
EXAMPLE IX
Following the above procedure, but substituting for the 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde and n-dodecylamine used therein, equivalent amounts of the appropriate starting materials, there are prepared the following:
V
\
NCH=NRq /
h
A
h
Salt m.p. C9C)
H H \ / -CCH^gOC-
m2)1cR3
diphenylmethyl
H
H
fumarate hydrate
(sinter 125°) 131 -135
diphenylmethyl
H
H
-CH2CZCR
HC1
117 -119
9H-fluoren-9-yl
H
H
2^8*17
HC1
174 -177
H
H
diphenylmethyl
fumarate hydrate
(sinter 68.5°) 70 -72
-benzyhydrylidene-
H
2^17
fumarate
167 -170
diphenylhydraxyraethyl H
H
-^^17
fumarate
(sinter 145°) 155 -161
H
H
diphenylmethyl
H
fumarate
185.5-187.5
EXAMPLE X
Alternate Preparative Routes Illustrated for 4-(Diphenylmethyl)-1-[(octylimino)methyl]piperidine
1) A mixture of 2.90g (0.01 mole) of 4-(dipheny lmethy1)-1-piperidinecarbothioaldehyde, 12 9g (0.01 mole) of n-octylamine, 0.60g (0.01 mole) of glacial acetic acid and 20 ml of toluene was heated with stirring at 60° for two days. The reaction mixture was made basic
189977
and concentrated to give an oil which was identified as 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine by vapor phase chromatography.
2) A mixture of 2.0g (0.0068 mole) of 4-(diphenylmethyl )-1-piperidinecarbothioaldehyde, 0.9g (0.0069 mole) of n-octylamine, 2.16g (0.010 mole) of mercuric oxide and 15 ml of isopropanol was refluxed overnight/ filtered and concentrated. The residue was treated with fumaric acid to give 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (E)-2-butenedioate (1:1) hydrate which was identified by comparison with em authentic sample by thin layer chromatography.
3) A solution of l.Og (0.0034 mole) of 4-(diphenylmethyl) -1-piperidinecarbothioaldehyde , 0.59g (0.0038 mole) of n-octyl isocyanate and 6 ml toluene were refluxed nine days. Vapor phase chromatography in conjunction with mass spectral analysis showed 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine in the amount of 17% in the reaction mixture.
4) A solution of l.Og (0.0034 mole), of 4-(diphenylmethyl) -1-piperidinecarbothioaldehyde , 0.45g (0.0034 mole) of n-octylamine, and 6.0 ml isopropanol was refluxed overnight. Vapor phase chromatography analysis of the reaction mixture showed 4-(diphenylmethyl)-1-[ (octylimino)methyl]piperidine to be present.
) A solution of 6.0g (0.035 mole) of n-octyl-isothiocyanate was dissolved in 25 ml of toluene, treated with 8.80g (0.035 mole) of 4-diphenylmethylpiperidine and stirred at 25° for twelve hours. The mixture was cooled, filtered and evaporated. Chromatography of the residue through silica gel using chloroform as an eluent afforded a brown oil, 4-(diphenylmethyl)-N-octyl-1-piperidinecarbothioamide. A mixture of l.Og (0.0024 mole) of this material, 3g of Raney Nickel and 15 ml of isopropanol was refluxed three hours, cooled, and filtered. Evaporation of the filtrate afforded an oil which was converted to a fumarate identified as 4-(diphenylmethyl)-1-[ (octylimino)methyl]piperidine (E)-2-butenedioate
(1:1) hydrate by thin layer chromatography.
189977
21
6) A solution of N-formyl-4-diphenylmethyl piperidine 40.Og (0.143 mole) and 50 ml of methylene chloride was treated with phosgene until gas evolution ceased. After refluxing for one hour, the excess phosgene 5 was removed under reduced pressure, the reaction was diluted with 50 ml of methylene chloride and 24.8 ml (0.145 mole) of n-octyl amine in 25 ml of methylene chloride was introduced at such a rate as to maintain mild reflux. Triethyl amine (28 ml) was added slowly, 10 the reaction stirred for ten minutes, and then poured into water. The organic phase was separated, washed with 20% sodium hydroxide solution, dried, and stripped to an oil which was converted to 4-(diphenylmethyl)-1-[(octylimino) methyl] piperidine (E)-2-butenedioate (1:1) hydrate, 15 identified by thin layer chromatography.
phenylmethylpiperidine, 3.50g (0.022 mole) of n-octyl-isonitrile, 0.26g (0.002 mole) of silver chloride, and 10 ml of toluene was stirred 48 hours at 25°, filtered, 20 stripped, and the residue dissolved in methylene chloride. Extraction with 10% sodium hydroxide, drying and filtration of the organic layer followed by evaporation afforded 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine isolated as the fumarate salt, which was identified by 25 thin layer chromatography.
cribed, the following compounds were tested for their antisecretory activity. The ED^g values for p.o. 30 administration and the percent inhibition for i.d.
administration at 20 mg/kg are tabulated below (R^* = H except where noted):
7) A mixture of 5.60g (0.022 mole) of 4-di
EXAMPLE XI
Following the test procedure previously des-
3
• #
h
A
h.
: h diphenylmethyl h
h h
•1
11
II
ethyl
II
II
II
-ch2ch=ch2
II
II
It
-a^cach
It
VI
II
i-prcpyl
II
It
It n-butyl
•9
tl
•
n-ftexyl m
w v
n-heptyl n
n
*
n-octyl it it n
t-octyl it tt
H
n-nonyl ii ii n
n-decyl ii ii it n-dodecyl it
H
ii l-adanantyl it it ii
-(ch2) 8cb=ch (ch2) ?ch n
ii ii benzyl ii n
n phenethyl it ii n
g-chlorobenzyl it ii ethyl h
n ii h
g-methoxybenzyl
• •
m
ED_-50
jAg po)
Percent Inhibition at 20 mg/kg id
0.7
100
4.3
100
.2
100
6.07
100
9.8
. 96
8.6
100
8.7
96
11.6
72
9.8
64
28*
19.6
93
8.2
79
53
80
37.0
0**
66
78.9
3.3
100
3.7
100
.7
94
>40
75
<40
63
to
KJ
CD SO O
s ^
0 VJ
• •
?L - ?1
*
a- (p-iriethoxyphenyl) benzyl H H
n ii ii a-(4-chlorophenyl)benzyl " "
a- (1,4-biphenyl) -a-hydraxybenzyl " "
phenyl n "
9-fluorenyl " "
benzyl " "
a-{4-methylphenyl)benzyl " "
diphenylmethyl " methyl ft II TV
<?
phenyl -CCH^ "
benzhydry 1 idene "
H H "
H n „
a-(4-hydroxyphenyl)benzyl " "
a-(phenyl)-a-hydroxybenzyl " "
H .. ..
* 98% inhibition at 80 nig/kg i.d.
** 52% inhibition at 80 mgAg i.d*
*** Prior art cxxrpound
+ Rj1 = diphenylmethyl ++ ccnpound administered intraperitoneally ph Percent
50 Inhibition at
R3 QngAg po) 20 mgAg Id
H 12.1 100
n-octyl 16.9 62
H 2.32 100
H >80 72
H Ca 40 77
n-octyl 15.9 48
H 114 98
n-octyl - 73
n-octyl 14 98
(a,2> 4* © 8J 82
H - 71
n-octyl 0.625 68.2
n-octyl 18.3 92,2+
H 7** 68+
n-octyl 2** -
.. 5++
H Inactive 0***
at 80
4 ©*9 7Z.
24
EXAMPLE XII
Following tlie procedure described by Buehler and Pearson [Survey of Organic Syntheses, Ch. 18, p 894 (1970)] and using the appropriate substituted piperidine and anhydride, there are prepared the following piperidine amides, wherein the following substituents are in the two CR^n), three (R^') or four (R^) position:
R, '
Substituent diphenylmethyl a-(4-chlarcphenyl)benzyl a-(4-methylphenyl)benzyl or (4-methoxypheny 1) benzyl or (4-chlaraphenyl)benzyl
9-fluorenyl diphenylmethyl phenyl phenyl
4-chlarqphenyl
4-chlarophenyl
4-methoxyphenyl
4-methaxyphenyl
4-chlarabenzyl phenyl phenyl a-(1,4-biphenyl) benzyl or (1,4-biphenyl) benzyl or (1,4-biphenyl) benzyl
2,2-diphenylethyl
2,2-diphenylethyl
2,2-diphsnylethyl
, U-dihydro-5H-dibenzo [a,d] • cycloheptene-5-yl
Position of Substituent
4
n n
if
3
II ft
4
It
If It h.
H
methyl n-butyl H
methyl iv-butyl H
methyl n-butyl
H
H
ff ff It phenyl H
phenyl H
phenyl H
phenyl phenyl H
ff
1 899
Substituent
^ Position of Substituent
%
A
, ll-dihydxo-5ft-dibenzo [a,d] -eye loheptene-5-y 1
2
methyl
H
«l ft n-butyl ft
" .
4
H
It n
ft methyl ff n
ff n-butyl ff
4,4-diphenyl-n-butyl
4
H
ft
4 , 4-d iphenyl-n-butyl ff methyl ff
4,4-diphery 1-nrbuty1
ff n-butyl ft
4-metboxybenzyl ff
H
If benzyl ft ff
If
9-fluorenyl
If ff tf diphenylmethyl tf methyl ft dipfaenylmethylene tf ff tf a- (4-chlorophenyl) benzyl ft
It ff a- (4-methylphenyl) benzyl ft ff tt a- (4-raethaxyphenyl) benzyl tf ff ff diphenylmethyl
3
It tt
9-fluorenyl ff
H
It a-(4-chlorophenyl)benzyl tf
It ff phenyl
4
tf tf
9-fluorenyl tf tf ff
4-chlorophenyl ff tt
If
4-methaxyphenyl ff ff ff
4-chlorobenzyl ft
It ft
4-methaxybenzyl ff
It tt benzyl tf ft ff diphenylmethyl tf n-butyl ff diphenylnethylene ft ff ft a- (4-chlorophenyl) benzyl tf
If
If a- (4-methoxyphenyl) benzyl tf ft tf a- (4-methy lphenyl) benzyl ff ff ff diphenylmethyl
3
ft
II
9-fluorenyl ft ft tt
9-fluorenyl
4
•t
II
a- (4-chlorophenyl) benzyl
3
ff tf
mi J o a l89977
26
Position of
Substituent
Substituent
A
5ft-dibenzo [a,d] cyclohepten-5-yl
2
H
H
19
ft methyl tt tt
It n-butyl
11
,11-dihydro[a,d]cyclohepten-5-yl
It
H
tt
It tt methyl tf n
tf n-butyl ff phenyl (octyl) methyl
4
H
It m
If methyl
It it tt n-butyl
II
phenyl (hexyl) methyl
It
H
It tt
It methyl
It tt
It n-butyl tt phenyl
It
It ft
4-chlorophenyl tl
It ft
4-raetboxyphenyl ft
It ft benzyl
If n
tf
4-chlorobenzyl
•f n
n
4-methoxybenzyl
It it n
diphenylmethyl
2
H
tt diphenylmethyl
It methyl tt diphenylmethyl
It n-butyl n
5H-dibenzo [a,d] cyclohepten-5-yl
4
H
tt
5H-dibenzo [a,d] cyclohepten-5-yl tf methyl it
5Ehdibenzo [a,d] cyclohepten-5-yl tt n-butyl tt
EXAMPLE XIII Following the procedure described by Buehler and Pearson [Survey of Organic Syntheses, Ch. 18, p 894 (1970)] and using the appropriate substituted piperidine and anhydride, there are prepared the following piperidine amides:
27
189977
(CH2>n
NC=0
I
*2
Position of Substituent
3
tf
n 0
1
ff ff
2
If ff
0
If tf
1.
ff tf
2
ff h
ch3 n-butyl h ch3
n-butyl h ch3 n-butyl h ch3
n-butyl h ch3
n-butyl h
CH3 n-butyl
28
1 899 7 7
EXAMPLE XIV
Following the procedure of Example XIII, there are prepared the following piperidine amides:
wherein R2 = hydrogen, methyl, or n-butyl.
EXAMPLE XV
Following the procedure of Example XIII, there are prepared the following piperidine amides:
(c6h5)2c
\
NC=0
J *2
Position of Substituent
4
tl tl
3
tt
IV
2
a h
CH3 n-butyl h
ch3
n-butyl h ch3
n-butyl
29
EXAMPLE XVI
MN 335
189977
Following procedures described in the references given above for compounds of Formula (III), the following are prepared: 0 H
II I R-C-NR,
h.
h
-<CH2>11CH3
h
-(CH2)7CH3
h
-<CH2>14CH3
h
-(CH2)4CH=CHCH2CH3
h cis-(CH2)5CH=CH(CH2)1qCH.
h
-(CH2)6C=CH
h
4-ClPh-
h
4-MeOPh-
H
4-MePh-
h
-ch2c=ch
H
exo-2-norborny1
h endo-2-norborny1
h
1-decahydronaphthyl
h
1-adamantyl
H
2-bicyclo[2.2.2]octyl
h anti-7-norbornenyl
H
endo-bicyclo[3.2.1]octyl
h
1-adamantylmethy1
Me h
Me
~C2H5
Me
-(ch2)5ch3
Me
-(ch2)7ch3
Me
-(ch2)14ch3
Me
-(ch2)4ch=chch2ch3
Me cis-(CH2)5CH=CH(CH2)1qCH
Me
-CH2C=CH
Me
(CH2)6C=CH
Me
Ph
Me
4-ClPh-
Me
4-MeOPh-
Me
4-MePh-
Me
PhCH2-
Me
4-ClPhCH2-
Me
4-MePhCH2-
MN 335
Me Me Me M6 Me Me Me Me Me Me n-Butyl
T"Bu")
Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu Bu BU Bu Bu BU H Me BU H Me Bu
18 99
ii
4-MeOPhCH2-PhCH2CH2-exo-2—norbornyl endo-2-norbornyl 1-decahydronaphthyl 1-adamantyl 2-bicyclo[2.2.2]octyl anti-7-norbornenyl endo-bicyclo[3.2.1]octyl 1-adamantylmethyl H
C2H5
-ch2ch=ch2 (ch2)7ch3 (ch2)14ch3 -(ch2)4ch=chc2h5
cis-(CH2)5CH=CH(CH2)1qCH3
-ch2c=ch (ch2)6c=h
4-ClPh 4-MeOPh 4-MePh Ph phCH2
4-ClPhCH2-4-MePhCH2-4-MeOPhCH2-PhCH2CH2 exo-2-norbornyl endo-2-norborny1 1-decahydronaphthyl 1-adamantyl 2-bicyclo[2.2.2]octyl anti-7-norborneny1 endo-bicyclo[3.2.1]octyl 1-adamantylmethyl diphenylmethyl diphenylmethyl diphenylmethyl 3,3-diphenyl-n-propyl 3,3-diphenyl-n-propyl 3,3-diphenyl-n-propyl
31
EXAMPLE XVII
Following the procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and dipheny1-4-piperidylmethane or N-formyl-5 4-diphenylmetKylpiperidine and ethylamine, respectively, used therein, equivalent amounts of the appropriate starting materials such as described in Examples XII and XVI, there are prepared the following, wherein the following substituents are in the two (R^n), three (R^'), 10 or four (R1) positions:
Position of
Substituent Substi-
(^1' ^l*' 000 ^l"^ uent R2 R^ A
diphenylmethyl 2 H H H
diphenylmethyl 3 " H "
9-fluorenyl "
o-( 4-chlorophenyl) benzyl " " " "
diphenylhydraxyraethy 1 4 " " "
,ll-dihydro-5H-dibenzo "
[a,d]cyclohepten-5-yl
4-chlorobenzyl " " " "
4-methoxyphenyl " " " "
diphenylmethyl " "
n
4-chlorophenyl " "
a- (4-nethylphenyl) benzyl " " "
4-chlorobenzyl " " "
a-(4-chlorophenyl)-a- " " "
hydraxybenzyl a-(4-chlorophenyl)benzyl 3 " "
9-fluorenyl
4-methaxybenzyl 4 " -(CH2)7CH3
9-fluorenyl 3
diphenylhydraxyirethy 1 2 " "
a-(4-chlorophenyl)benzyl 3 " "
32
Substituent R^, or R^)
Position of Substi-uent diphes^lhyaroxymethyl 4
SH-dihenzo[a,d] " cycloheptimr5-yl phenyl "
diphenylmethyl "
ct- (4-chlorophenyl) -a- " hydraxybenzyl a- C4-chloropheryl)benzyl 3
9-fluorenyl 4
ct- (4-raethylphenyl) benzyl "
4-chlorophenyl "
4-methoxybenzyl H
diphenylmethyl "
cr-W-methaxyphenyl) benzyl "
diphenylmethyl 3
10, ll-dihydro-5-hydraxy- "
5H-dibenzo[a,d]cyclohepten-5-yl
9-fluorenyl "
dipheny lhydraxynethyl 4
phenyl "
4-chlorobenzyl "
diphenylmethyl "
cc- (4-chlorophenyl) benzyl 3
9-hydraxy- 9-fluorenyl 4
a-(4-chlorophenyl)-ct- " hydraxybenzyl
4-methoxyphenyl "
benzyl "
ct- (4-methylphenyl) benzyl "
diphenylmethyl "
a- (4-ch 1 orophertyl) benzyl "
a-{4-methoKyphenyl)-a- " hydraxybenzyl
9-fluorenyl 3
a- (4-chlorophenyl) benzyl "
diphenylmethyl 2
H
tf
189977
h.
-(CK2)7ai3
H
phenyl H
- (CHj) 4CH=aCH2CH3
cxs-
(a^) 5ch=CH (ay 10CH3
(a^jgCscH
Substituent 0^, , or R^")
phenyl 4
4-methoxybenzyl "
diphenylmethyl "
a- (4-methaxyphenyl) benzyl a-(4-methylphenyl) -a- " hydraxybenzyl a- (4-chlorophenyl) benzyl 3
9-fluorenyl 4
, ll-dihydro-5H-dibenzo " [a,d] cyclohepten-5-yl
4-methoxyphenyl "
4-chlorobenzyl "
diphenylmethyl "
a- (4-methy lphenyl) benzyl "
a- (4-methaxyphenyl) -a- " hydrcoq^benzyl
diphenylmethyl 3
9-fluorenyl "
phenyl 4
4-chlorobenzyl "
a-(4-chloraphenyl)benzyl "
diphenylmethyl "
dipheny lhydroxymethy 1 "
or- (4-chlorophenyl) benzyl 3
9-fluorenyl "
4-methaxyphenyl 4
benzyl "
diphenylmethyl "
a- (4-methoxyphenyl) benzyl "
a-(4-methy lphenyl)-a- " hydraxybenzyl diphenylmethyl 3
9-fluarenyl "
phenyl 4
4-chlorobenzyl "
a- (4-methoxyphenyl) benzyl "
33
Position of Substi-uent
H
If n
it it n
iv
189977
*3
(aygcrch
«t
-o^cech h
ff ff tf fl If phenyl exo-2-norbomyl
H
If endo-2-norbornyl tt If If ff
1-decahydranaphthyl
It rt l-adamantyl
34
Substituent (R^ R^, or R^)
Position of Substi-uent
, ll-dihydro-5-hydroxy- 4 5H-dibenzo [ a, dT cyclohepten-5-y1
a- (4-chlorophenyl) -ct- " hydraxybenzyl a- (4-chlorophenyl) benzyl 3
9-fluarenyl "
4-chlorophenyl 4
benzyl "
diphenylmethyl "
a- (4-methaxyphenyl)benzyl "
dipheny Ihydraxymethyl N
diphenylmethyl 3
9-fluorenyl 4
phenyl "
4-methaxybenzyl "
diphenylmethyl "
a-(4-chlorophenyl)benzyl "
a- (4-methylphenyl )-ct- " hydraxybenzyl diphenylmethyl 3
9-fluorenyl "
phenyl 4
4-chlorobenzyl "
diphenylmethyl "
a- (4-methy lphenyl) benzyl "
diphenylliydraxyinethyl "
a-(4-chlorophenyl) benzyl
9-fluorenyl diphenylhydraxymsthyl
4-methoxyphenyl benzyl "
diphenylmethyl "
<*- (4-methaxyphenyl) benzyl "
a-(4-chlorophenyl)-a- " hydraxybenzyl ct-(4-chlorophenyl) benzyl 3
■h
H
189977
1-adamantyl
A H
3
ft
2
4
phenyl
2-bicyclo [2.2.2] octyl
H
it It tl 19 tt anti-7-norbornenyl endo-bicyclo [3.2.1] octyl
1-adamantylmethyl
1 89977
Position of
Substituent Substi-
(R,, R,*, or R,") uent
*2
*3
A
9-fluorenyl
3
H
1-adamantylmethyl
H
phenyl
4
fl
If
It
4-methaxybenzyl
19
If
If
If diphenylmethyl n
methyl
H
ft a- (4-methaxyphenyl) benzyl
19
19
tf tt a- (4-chlorophenyl) -a-hydraxybenzyl a
• II
n fl
-hydraxy-5&-dibenzo [a,d] cyclohepten-5-yl vi
If n
tf a- (4-chlorophenyl) benzyl
3
II
n tl
9-fluorenyl tl tf it
If diphenylmethyl
2
ff ii tl
4-chlorophenyl
4
ff it
II
benzyl ff ff if ff diphenylmethyl tf ff
II
a- (4-methoxyphenyl) benzyl
If tf
19
If a- (4-methylphenyl) -a-hydraxybenzyl tf
If it
II
diphenylmethyl
3
tf
19
N
9-hydraxy-9-fluorenyl
4
tf
19
tf
4-methoxyphenyl tf tf
19
It
,ll-dihydro-5H-di benzo [a,d] cyclohepten-5-yl tf
II
19
II
benzyl tf
If
!9
II
a- (4-methylphenyl) benzyl
If tt
-(012)7(213
If diphenylhydraxymethyl
If
II
If
II
a-(4-chlorophenyl)benzyl
3
tf tl
II
9-fluorenyl fl
II
t«
n phenyl
4
If tl n
benzyl tl
If tf n
diphenylmethyl
II
If
- (CF^) 14^3
n ct- (4-chlarapbenyl) benzyl tl
II
II
n a- {4-methoxyphenyl) -a-hydraxybenzyl tf
If ii tt diphenylmethyl
3
II
II
n
9-fluarenyl
II
tt
11
n
MN 335
36
1 899 7r~
Substituent (1^, 1^', or I^")
Position of Substi-uent
4
It
4-nethaxyphenyl .
4-chlorobenzyl diphenylmethyl "
a- {4-methaxyphenyl) benzyl"
phenyl "
dipherylhydraxynethyl "
a- (4-chlaraphenyl) benzyl 3
9-fluorenyl "
4-chlarophenyl 4
benzyl "
diphenylmethyl "
ct- (4-methylphenyl) benzyl "
ct- C4-chlaropheny1) -ct- " hydraxybenzyl diphenylmethyl 3
9-fluarenyl "
phenyl 4
4-chlorobenzyl "
diphenylmethyl "
a- (4-nethasQ>phenyl) benzyl"
diphenylhydraxymethyl "
9-fluorenyl 3
ct- (4-chlaropbenyl) benzyl "
4-irethaxypbenyl 4
benzyl "
diphenylmethyl "
a-(4-methylphenyl)benzyl "
a- (4-chlorophenyl) -a- " hydraxybenzyl diphenylmethyl 3
9-hydroxy-9-fluorenyl 4
phenyl "
4-methaxybenzyl "
diphenylmethyl "
a-(4-chlorophenyl)benzyl "
diphenylhydraxymethyl "
methyl tt h.
it
■CHjOKHJ
H
ff phenyl H
- (CHL,) 4CS=CHZH2CH3
cis- (O^) 5CH=CH (CHj ) 1QCH3
-a^crch
-(a^jgcach
Substituent (B^ R^, or R^)
37
Position of Substi-uent Rj
2 4
diphenylmethyl m
9-fluorenyl diphenylhydraxyniethyl
4-chlorqpbenyl
4-chlorobenzyl "
diphenylmethyl "
a-(4-chlorophenyl)benzyl "
diphenylhydraxymethyl "
diphenylmethyl 3
,ll-dihydro-5-hydraxy- "
5a-dibenzo [a,d] cyclohepten-5-yl
9-fluorenyl "
a-(4-methoxyphenyl)benzyl 4
4-chlorobenzyl "
diphenylmethyl "
a- (4-iaethylphenyl) benzyl "
phenyl "
diphenylhydraxymethyl "
diphenylmethyl phenyl
9-fluorenyl benzyl
,11-dihydro- 5lfr-d i benzo [a, d]cyclohepten-5-yl diphenylmethyl a- (4-chlorophenyl) benzyl a- (4-methylphenyl) -a-hydraxybenzyl diphenylmethyl
9-fluorenyl
4-methoxyphenyl 4
4-chlorobenzyl "
diphenylmethyl "
a-(4-methoxyphenyl)benzyl "
dipheny lhydroxymethy 1 "
or (4-chlorcphenyl) benzyl 3
methyl
3
4
3
4
1 89977
-(ch^gcsch
3
It benzyl 4-chlarobenzyl 4-metboxybenzyl 4-methylbenzyl
4-chlorobenzyl benzyl exo-2-norbornyl g>do-2-norbornyl l-decahydronaphthyl
A H
it tt tf If tf tf tf tf tf
If tf phenyl H
MN 335
38
t 89977
Substituent
^rl/ *1'' ^ *1"*
9-fluorenyl
4-chlorophenyl
4-methaxybenzyl
diphenylmethyl a- (4-chlorophenyl) benzyl a-(4-methylphenyl) -a-hydraxybenzyl diphenylmethyl
9-fluorenyl
phenyl benzyl diphenylmethyl a- (4-nethaxyphenyl) benzyl diphenylhydroxymethyl 15 a- (4-chlorophenyl) benzyl 9-fluorenyl 4-chloraphenyl 4-raethoxybenzyl diphenylmethyl 20 a- (4-methylphenyl) benzyl diphenylhydraxymethyl diphenylmethyl a- (4-chloraphenyl)benzyl phenyl 25 9-fluorenyl
4-methaxybenzyl diphenylmethyl phenyl a- {4-chlorophenyl) benzyl 30 diphenylhydraxymethyl diphenylmethyl 9-fluorenyl 4-chlorophenyl benzyl 3 5 diphenylmethyl
Position of Substi-uent
3
4
methyl it
1-decahydronaphthyl
1-adamantyl
2-bicyclo [2.2.2] octyl anti-7-norbornenyl endo-bicyclo [3.2.1] octyl h
ft phenyl h ft
1-adamantylmethyl
Substituent V or R^")
39
Position of Substi-uent R2
a- (4-methylphenyl) benzyl 4
a- (4-chloropfaenyi) -a- " hydraxybenzyl diphenylmethyl 3
9-fluarenyl "
4-methoxyphenyl 4
4-chlorobenzyl "
diphenylmethyl "
ct- (4-methoxyphenyl) benzyl "
diphenylhydraxymethyl "
diphenylmethyl 3
9-fluorenyl "
phenyl 4
4-chlorobenzyl "
diphenylmethyl "
phenyl "
a- (4-methoxyphenyl) benzyl "
a- (4-chlarophenyl) -a- " hydraxybenzyl diphenylmethyl 2
a- (4-chlarqphenyl) benzyl 3
9-fluorenyl "
4-methaxyphenyl 4
benzyl "
diphenylmethyl "
a- (4-chlorophenyl) benzyl "
diphenylhydroxymethy1 "
diphenylmethyl 3
9-fluorenyl ."
phenyl 4
benzyl "
diphenylmethyl "
a-(4-methylphenyl) benzyl "
diphenylhydraxymethyl "
a-(4-chlorophenyl)benzyl 3
9-fluorenyl "
methyl xt-butyl
1 8997
*3
1-adamantylmethyl
H
n n tt vt
B
h
If 19
n if ft IV 91
phenyl
H
ii
MN 335
40
Substituent
®1' *1*' 030 bl"*
Position of Substi-uent
189977
3
n
4
n
, ll-dihydro-5-hydraxy- 3 nrbutyl 5Khdibenzo [a,d] cyclchepten-5-yl~
4-nethaxyphesnyl 4 "
4-chlorabenzyl " " 5 diphenylmethyl " "
a-(4-chlorcphenyl)benzyl " "
diphenylhydraxymethyl " "
a- (4-chlarophenyl) benzyl 9-fluorenyl 10 4-chlorophenyl benzyl diphenylmethyl
-hydraxy-5H-dibenzo [a,d]cyclohepten-5-yl a- (4-methylphenyl) benzyl
a-(4-methaxyphenyl)-a-hydraxybenzyl diphenylmethyl
9-fluorenyl phenyl
4-chlorobenzyl
2 0 diphenylmethyl a- (4-methylphenyl) benzyl diphenylhydraxymethyl a- (4-chlorophenyl) benzyl
9-fluorenyl
phenyl
4-methoxybenzyl diphenylmethyl a- (4-methylphenyl) benzyl diphenylhydraxymethyl
10,11-dihydro- 5H-d i henzo [a,d]cyclohepten-5-yl diphenylmethyl
9-fluorenyl
4-methoxyphenyl h.
a H
4
19
3
•i
-(ch2)4cb<3x:2h5
cis- (O^) 5C3KH (O^) 1qCH3
-CHjCSCH
Substituent (1^, or I^")
41
Position of Substi-uent R2
benzyl * 4
diphenylmethyl "
ct- (4-chlorophenyl) benzyl "
phenyl a- (4-methaxyphenyl) -a- " hydraxybenzyl a-(4-chlorophenyl)benzyl 3
9-fluarenyl "
phenyl 4
4-methaxybenzyl "
diphenylmethyl "
a- (4-methylphenyl) benzyl "
a- (4-chlarophenyl)-ct- " hydraxybenzyl diphenylhydraxymethyl 2
diphenylmethyl 3
9-fluorenyl "
phenyl 4
4-methaxybenzyl "
diphenylmethyl "
a-(4-methoxyphenyl) benzyl "
diphenylhydraxyrnethyl "
diphenylmethyl 3
9-hydraxy-9-fluorenyl 4
phenyl "
4-chlorobenzyl "
diphenylmethyl "
a- (4-methylphenyl) benzyl n diphenylhydraxyrnethyl "
a- (4-chlarophenyl) benzyl 3
3 0 9-fluorenyl "
4-methaxyphenyl 4
benzyl "
diphenylmethyl "
a- (4-chlcaropheanyl) benzyl "
n-butyl
189977
-chjcha -(ch^^csch fl n
benzyl 4-chlorobenzyl 4-methylbenzyl ff
4-methaxybenzyl tt benzyl 4-methy lbenzyl phenethyl ff tt n
exo—2-norbornyl ft ft ft endo-2-norbornyl
H
ft phenyl ff
If ff
If It ft II
MN 335
1 89977
42
Substituent
(R^ R^, or Y)
Position of Substi-uent
4
3
tt
4
It a-(4-methylphenyl) -a-hydraxybenzyl diphenylmethyl
9-fluorenyl
phenyl
4-methaxybenzyl diphenylmethyl "
a-(4-chlorophenyl) benzyl "
a-(4-methoxyphenyl) -a- " hydraxybenzyl
phenyl "
a- (4-chlarophenyl) benzyl 3
9-fluorenyl "
phenyl 4
benzyl "
diphenylmethyl "
a-(4-methaxyphenyl)benzyl "
diphenylhydraxymethyl "
diphenylmethyl 3
9-fluorenyl "
4-chlorophenyl 4
4-chlorobenzyl "
diphenylmethyl "
a- (4-methylphenyl) benzyl "
a- (4-chlarophenyl) -a- " hydraxybenzyl
a-(4-chlarophenyl) benzyl 3
9-fluorenyl "
phenyl
4-methaxybenzyl diphenylmethyl 30 a- (4-methylphenyl) benzyl diphenyIhydraxyiiiethyl diphenylmethyl 9-fluorenyl diphenylmethyl
4
n h h.
n-butyl endo-2-norbornyl
A H
1-decahydronaphthyl phenyl h
1-adamantyl
2-bicyclo [ 2.2.2 ] octy1
anti-7-norbornenyl
ruv j j
43
189977
Substituent
®1' ^l'' ^ *4."*
Position of Substi-uent
4-methoxyphenyl ^ 4
4-chlorctenzyl "
diphenylmethyl "
a- (4-methoBOTbenyl) benzyl "
a- (4-methylphenyl) -a- " hydraxybenzyl ct- (4-chlorophenyl) benzyl 3
9-fluorenyl "
phenyl 4
4-methaxybenzyl "
diphenylmethyl "
a- (4-methaxyphenyl)benzyl "
diphenylhydroxymethy 1 "
diphenylmethyl 3
9-fluorenyl "
phenyl 4
benzyl "
cc— (1,4-biphenyl) benzyl "
a- (1,4-biphenyl)benzyl "
a-(1,4-biphenyl)benzyl "
2,2-diphenylethyl "
2,2-diphenylethyl "
2,2-diphenylethyl "
4,4-dipheny 1-n-butyl "
4,4-dipheny 1-n-butyl "
4,4-dipheny1-n-butyl "
diphenylmethyl "
phenyl 3
9-fluorenyl 4
4-chlorobenzyl "
diphenylmethyl 3
dipheny lhydraxyraethyl 4
n-butyl anti-7-norbornenyl endo-bicyclo [3.2.1] octyl ff ft ff tt If If if tf If If
H
n-butyl H ch3 n-butyl H ch^ n-butyl H
®3 n-butyl
H
ch3
n-butyl
1-adamantylmethyl
-(c2!2)7^3
H
if II If If
If 11 tf If If ff
H
7®-phenethyl
H
phenethyl H
-(chjiTchJ phenethyl diphenylmethyl
3,3-diphenyl-n-propyl if ii
MN 335
44
18 9977
Substituent (1^, 1^' , or 1^")
phenyl (octyl)methyl
, U-dihydro-5H-ri ibenzo [a,d] cyclohepten-5-yl
5H-dibenzo[a,d] cycloheptenr5-yl phenyl (hexyl) methyl phenyl (hexyl) methyl
, ll-dihydro-5E-^iibenzo [a,d] cyclohepten^5-yl
5H-dibenzo [a,d] cycloheptS]r5-yl
,ll-dihydro-5ff-dibenzo [a,d] cyclohepten-5-yl
5H-d ibenzo [a,d] cyclohepten^5-yl phenyl (octyl)methyl
Position of Substi-uent
4
2
h.
H
methyl tt rt-butyl h.
H
(ch^gcszh (CH2)4C3f=CHC2J2CH3 -(c^jgcach
-chjca phenethyl
A H
mn 335
45
18 9977
Example XVril Following the procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively, used therein, equivalent amounts of the appropriate starting materials such, as described in Examples XIII and XVI, there are prepared the following:
Position of Substituent
3 3
3
4 4 4 3 3
3
4 4 4 3 3
3
4 4 4
n
0 0 0 0 0 0
2 2 2 2 2 2
nc=nr.
h h h h ch3
n-butyl b h h h
CH3
n-butyl h h h h
CH3 n-butyl h
n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl
raw jjj
46
example xix
1 89977
Following the procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively, used therein, equivalent amounts of the appropriate starting materials such as described in Examples XIV and XVI, there are prepared the following:
__2 h h h h ch3
n-butyl h h h h ch3
n-butyl h h h h ch3 n-butyl
!!
h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl
MN-335
189977
example xx
Following the procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively,
used therein, equivalent amounts of the appropriate starting materials such as described in Examples XV and XVI, there are prepared the following:
(C6HS)2C.
\
NC=NR,
. i 3
/ r2
Position of Substituent
2
2
3
3
4 4 2
2
3
3
4 4 2
2
3
3
4 4
n
0 0 0 0 0 0
2 2 2 2 2 2
h h h h ch3 n-butyl h h h h ch3
n-butyl h h h h ch3
n-butyl
_3 h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl h n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl
MN 335
48
EXAMPLE XXI
n8 99 77
N-[4-(Diphenylmethyl)-1-piperidinyl]
methylene benzenebutanamine (E)-2-Butenedioate Hydrate
A mixture of 4.40g (0.016 mole) of N-formyl-4-(diphenylmethyl)piperidine and 1.47 ml (2.00g, 0.015 mole) 5 of dimethyl sulfate was heated in a steam bath for three hours at 100°C under anhydrous conditions until homogeneous. The mixture was cooled, dissolved in 30 ml of methylene chloride and treated with 2.50 ml (2.36 g, 0.016 mole) of phenylbutylamine. The resulting solution 10 was stirred for three hours and treated with 6 ml 3 N
sodium hydroxide solution with vigorous stirring at 0°. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to an oil. This material was dissolved in isopropanol, treated with 15 1.84g of fumaric acid and cooled. There was filtered off a white crystalline solid which was recrystallized from ethanol to give N-[4-(diphenylmethyl)-1-piperidinyl]-methylene benzenebutanamine (E)-2-butenedioate hydrate as a white crystalline solid, m.p. 207-208.5°C.
EXAMPLE XXII
4-(Diphenylmethyl)-1-[1-(octylimino)ethyl]- piperidine Monoperchlorate
A mixture of the fluoroborate salt of N-octyl-acetimidic acid ethyl ester (.generated from 5.68g [Q.Q4 mole] of boron trifluoride etherate, 2.77g [0.03 mole] 25 of epichlorohydrin, and 5,80g [0.034 mole] of N-octyl acetamide) and 50 ml of ether was treated with. 4 ml C2.92g, 0.029 mole) of triethyl amine. Filtration and evaporation of the filtrate afforded a liquid residue which was dissolved in 120 ml dry toluene. To this 30 solution was added 6.00g (.0.024 mole) of glacial acetic acid and the resulting solution was stirred at 50°C over 4A molecular sieves under a nitrogen atmosphere for four days. The reaction mixture was cooled and neutralized by shaking with. 3 N sodium hydroxide solu~ 35 tion. The organic layer was separated, dried over K2C03, filtered and stripped to an oil which was distilled.
MN 335
189977
49
The pot residue was dissolved in ether and perchloric acid and methanol added. Cooling the solution produced a solid fraction. Filtration afforded a crystalline solid which was recrystallized three times from methanol to give 4-(Diphenylmethyl)-1-[1-(octylimino)-ethyl]piperidine Monoperchlorate as a white crystalline solid, m.p. 119-121.5°C.
EXAMPLE XXIII a-(4-Methylphenyl)-g-pheny1-4-pyridine Methanol A solution of 0.05 mole of 4-methylphenyl magnesium bromide in 500 ml of anhydrous ether was treated with 4-benzoylpyridine in 500 ml anhydrous ether.
After stirring the resulting mixture for 1.5 hours at 25°, an aqueous solution of arrtnonium chloride was *^<*3 causing a »">! to form which was filtered. Recrystallization of this material from 95% ethanol afforded the desired a-(4-methylphenyl)-a-phenyl-4-pyridine methanol, m.p. 192-195°C. The corresponding 4-chlorophenyl (m.p. 198-202°C) and 4-methoxyphenyl (m.p. 204-206°C) derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
example xxiv a-(4-Methylphenyl)-a-phenyl-4-piperidine
A solution of 25.Og (0.09 mole) g-(4-methyl-phenyl)-g-pheny1-4-pyridine methanol, 55 ml of 47-51%
hydriodic acid and 180 ml of acetic acid was refluxed overnight, cooled, and poured into aqueous sodium bisulfite. This solution was made basic with sodium hydroxide and extracted with methylene chloride. From the organic layer there was isolated an oil which was reduced at 40 psi over platinum oxide at 60-65°C in acetic acid following the method of United States Patent No. 3,267,108. The excess acid was removed and the residue made basic to give g-(4-methylphenyl)-g-phenyl-4-piperidine which was characterized as its fumarate salt, m.p. 157.5-161.5°C (Hoover). The corresponding 4-chlorophenyl (m.p. 175-178°C; fumarate salt) and
• raw jj3
i89977
4-methoxyphenyl (m.p. 94-98°C; free base) derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
EXAMPLE XXV
a-(1,4'-Biphenyl)yl-g-phenyl-4-pyridinemethanol
A solution of lll.Og (0.50 mole) of 4-biphenyl bromide in 200 ml of dry tetrahydrofuran (THF) was added slowly to a mixture of 12.10g (0.5 gram-atom) of magnesium, 2 ml of ethylenedibromide and 200 ml of THF at 10 such a rate as to maintain reflux. After addition the mixture was refluxed for 0.5 hours, cooled and treated over 0.5 hours with a solution of 82.3g (0.45 mole) of 4-benzoylpyridine in 600 ml THF. The resulting slurry was stirred 0.5 hours at 25°C and treated with 1000 ml 15 20% ammonium chloride solution. The organic layer was separated, filtered, the filtrate dried, filtered and stripped. The residue was triturated with ether and filtered. This solid was recrystallized from ethanol, chloroform, and finally toluene to give a-(1,4'-biphenyl)-20 yl-a-phenyl-4-pyridinemethanol as a white solid, m.p.
after drying in vacuo at 70°C; 173.5-175.5°C.
EXAMPLE XXVI
a- (.1,4' -Biphenyl) yl-g-phenyl-4-piperidinemethanol
A solution of lO.OOg (0.030 mole) of g-(l,4'-25 biphenyl)yl-g-phenyl-4-pyridine and 160 ml of acetic acid was hydrogenated in the presence of platinum oxide (l.Og) at 25-35 psi at 70-90° on a Paar shaker. After hydrogen uptake ceased, the mixture was filtered through dicalite and evaporated to a solid residue. This residue 30 was slurried in water, made basic with 3 N 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 recrystal-35 lized from toluene to give g-(1,4'-biphenyl)yl-g-phenyl-4-piperidinemethanol as a white solid; m.p. 185-186.5°C.
Claims (22)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 55 189977 R2 is a member selected from the group consisting of hydrogen and C^-C4 loweralkyl; and R.j is a member selected from the group consisting of hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenylloweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, and halo; diphenyl(C^-C^)loweralkyl; diphenyl)loweralkyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is phenyl; alkenyl; and alkynyl; provided that at least one of said R^, R^\ R^", R2, and R3 is other than hydrogen, and further provided that when R-^" is other than hydrogen Rlf and Rx', and A are each hydrogen; when ' is hydrogen only one of ^ and R1" is other than hydrogen; when ^' is methyl R1 is other than hydrogen and R^" is hydrogen; and when r^* is other than hydrogen or methyl R-^, R^" and A are each hydrogen.
2) The substituted N-iminomethylpiperidine of Claim 1 wherein: R^ is a member selected from the group consisting of phenyl; phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy and halo; phenyl(C^-C^)loweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; diphenyl (C^-C4) loweralkyl and diphenyl (C^-C^j) loweralkyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo, and phenyl, provided that no more than one member is ph "■ phenyl (C^-C4) loweralkyl; • 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 11 12 189977 56 Rj is a member selected from the group consisting of hydrogen and methyl; R^ is a member selected from the group consisting of hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenylloweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; alkenyl; and alkynyl; and Rj.*' A, B, and D are each hydrogen.
3). The substituted N-iminomethylpiperidine of Claim 2 wherein: R^ is a member selected from the group consisting of diphenylmethyl and diphenylmethyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; R2 is hydrogen; R^ is a member selected from the group consisting of hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy; and halo; alkenyl; and alkynyl; and R^', RA, B, and D are each hydrogen.
4) The substituted N-iminomethylpiperidine of Claim 3 wherein: R^ is a member selected from the group consisting of diphenylmethyl and diphenylmethyl wherein one of said phenyls is substituted in the para-position with a member selected from the group consisting of loweralkyl, loweralkoxy , and halo; R2 is hydrogen; R^ is a member selected from the group consisting of hydrogen; straight chain alkyl; and phenylloweralkyl; 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 189977 57
5) A member selected from the group consisting of 4-diphenylmethyl-l-iminomethylpiperidine and the nontoxic acid addition salts thereof.
6) A member selected from the group consisting of 4-(diphenylmethyl)-1-[(isopropylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
7) A member selected from the group consisting of 1-[N-(benzyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof.
8) A member selected from the group consisting of 1-[N-(phenethyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof.
9) A member selected from the group consisting of 1-[N-(n-decyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid additions salts thereof.
10) A member selected from the group consisting of 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
11) A member selected from the group consisting of 4-(diphenylmethyl)-1-[(ethylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
12) A member selected from the group consisting of 1-[N-(n-butyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof.
13) A member selected from the group consisting of 4-(diphenylmethyl)-l-[(hexylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
14) A member selected from the group consisting of 4-(diphenylmethyl)-1-[(heptylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
15) A member selected from the group consisting of 4- (diphenylmethyl) -1- [ (t-octylimino)methyl] pipe^jjiin^^ and the non-toxic acid addition salts thereof. —"""" 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 4 189977 58
16) A member selected from the group consisting of 4-(diphenylmethyl)-1-I(nonylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
17) A member selected from the group consisting of 4-(diphenylmethyl)-1-[(dodecylimino)methyl]piperidine and the non-toxic acid addition salts thereof.
18) A member selected from the group consisting of 1-[(1-adamantylimino)methyl]-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof.
19) A member selected from the group consisting of 1-[(4-chlorobenzylimino)methyl]-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof.
20) A member selected from the group consisting of 1-[(allylimino)methyl]-4-diphenylmethyl)piperidine and the non-toxic acid addition salts thereof. of 4-(diphenylmethyl)-1-[(2-propynylimino)methyl]-piperidine and the non-toxic acid addition salts thereof. of 4-(diphenylmethyl)-1-[(9-octadecen-l-ylimino)methyl]-piperidine and the non-toxic acid addition salts thereof. 23) A member selected from the group consisting of 4-(diphenylmethyl)-1-[ethyl(imino)methyl]piperidine and the non-toxic acid addition salts thereof. 24) A member selected from the group consisting of 4(9-fluorenyl)-l-[ (octylimino)methyl]piperidine and the non-toxic acid addition salts thereof. 25) A member selected from the group consisting of 4-(diphenylmethyl)-1-[methyl(octylimino)methyl]-piperidine and the non-toxic acid addition salts thereof. 26) A member selected from the group consisting of N-[4-(diphenylmethyl)-1-piperidinyl]methylene benzenebutanamine and the non-toxic acid addit
21) A member selected from the group consisting
22) A member selected from the group consisting thereof. 189977 59 2 7. A member selected from the group consisting of 4-acetyl-l-(iminomethyl)-4-phenylpiperidine and the nontoxic acid addition salts thereof. 2 8. A member selected from the group consisting of 4-benzhydrylidene-l- ["(octylimino)methyl jjpiperidine and the non-toxic acid addition salts thereof. 29 . A member selected from the group consisting of 3- (diphenylmethyl)-1-t(octylimino)methyljpiperidine and the non-toxic acid addition salts thereof. 30... A member selected from the group consisting of 3-(diphenylmethyl)-1-(iminomethyl)piperidine and the non-toxic acid addition salts thereof. 31 . A member selected from the group consisting of 4- (diphenylhydroxymethyl)-1- £ (octylimino)methyl) -piperidine and the non-toxic addition salts thereof. 32 . A member selected from the group consisting of 4- (hydroxydiphenylmethyl) -1- £ (octylimino)methyl^ «• piperidine(E) 2-butenedioate . 33 . A member selected from the group consisting of 3-(diphenylmethyl)-1-(iminomethyl)piperidine(E) 2-butenedioate hydrate. 34 . An agent useful for the inhibition of gastric acid secretion, characterized by the fact that it comprises a compound of the formula (I) herein and a pharmaceutically acceptable carrier therefor. 169977 35. A process for preparing a compound of claim 1 and the corresponding non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying examples I-V, VIII-X and XVII-XXII. 36. A process for preparing a compound of claim 2 and the corresponding non-toxic acid addition salts thereof substantially as hereinbefore described with reference to the accompanying examples I-IV, V, VIII-X, XVII, XX and XXI. 37. A process for preparing a compound of claim 3 and the corresponding non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying examples I-IV, V, VIII-X, XVII, XX and XXI. 38. A process for preparing a compound of claim 4 and the corresponding non-toxic acid addition salts thereof substantially as hereinbefore described with reference to the accompanying examples I-IV, V, VII-X, XVII, XX and XXI. 39' A process for preparing 4-diphenylmethyl-1-iminomethylpiperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example I. 40- A process for preparing 4-(diphenylmethyl)-1-£(isopropylimino)methyl^piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 41. a process for preparing 1-£n-(benzyl)iminomethyl] -4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 42. a process for preparing 1-[n-(phenethyl) iminomethyl^ -4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with -reference to the accompanying example IV. 43. A process for preparing 1-[n-(n-decyl)iminomethyl^ -4-diphenylmethylpiperidine and the non-toxic acid additions salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 189977 61 44. A process for preparing 4-(diphenylmethyl)-1- ^(octylimino)methyl}piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying examples IV, V and X. 45. A process for preparing 4-(diphenylmethyl)-1- f(ethylimino)methyl}piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example III. 46. A process for preparing 1-^N-(n-butyl)iminomethyl^ -4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 47. A process for preparing 4-(diphenylmethyl)-1-^(hexylimino)methyl^ piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 48. a process for preparing 4-(diphenylmethyl)-1-((heptylimino)methyl}piperidine and the no n-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 49. A process for preparing 4-(diphenylmethyl)-1-f(t-octylimino)methyl}piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 5.0. a process for preparing 4-(diphenylmethyl)-1-[(nonylimino)methyl] piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 5jl. a process for preparing 4-(diphenylmethyl) -1-^(dodecylimino)methyl} piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying examples IV, VIII and XVII. 62 189977 52. A process for preparing 1-£(1-adamantylimino)-methyl]-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 53. A process for preparing l-£(4-chlorobenzylimino)-methyl]-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 54. A process for preparing 1- [" (allylimino)methyl] -4-diphenylmethyl)piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IV. 55. A process for preparing 4-(diphenylmethyl)-1-[(2-propynylimino)methyl] -piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying examples IX and XVII. 56. A process for preparing 4-(diphenylmethyl)-1- £ ethyl(imino)methyl] piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example II. 57. A process for preparing 4 (9-fluorenyl)-1- [(octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IX. 58. A process for preparing 4-(diphenylmethyl)-1-^methyl(octylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described . <yid with reference to the accompanying example XX. j ' 59. a process for preparing n-[4-(diphenylmethyl) -,1-piperidinyl^ methylene benzenebutanamine and the non-toxic acid addition salts thereof, substantially as hereinbefore 189977 63 described and with reference to the accompanying example XXI. 60. A process for preparing 4-benzhydrylidene-l-(octylimino)methyl)piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IX. 61. A process for preparing 3-(diphenylmethyl)-1- £(octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IX. 62. A process for preparing 3-(diphenylmethyl)-1-(iminomethyl)piperidine and the non-toxic acid addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IX. 63. A process for preparing 4-(diphenylhydroxymethyl) -1-[ (octylimino)methyl]-piperidine and the non-toxic addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example XVII. 64. A process for preparing 4- [(4-hydroxyphenyl)-phenylmethyl] -1- [ (octylimino) -methyl] piperidine and the non-toxic addition salts thereof, substantially as hereinbefore described and with reference to the accompanying example IVA. 65. A process for preparing 4-[(4-hydroxyphenyl)-phenylmethyl]-1-((octylimino)methyl]piperidine 2-naphthalenesul-fonate substantially as hereinbefore described and with reference to the accompanying example IVA. 66. A compound of claim 1 and the corresponding nontoxic acid addition salts thereof, whenever prepared according to the process claimed in claim 35. 189977 64 67. A compound of claim 2 and the corresponding non-toxic addition salts thereof, whenever prepared according to the process claimed in claim 35. 68. A compound of claim 3 and the corresponding non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 37. 69. A compound of claim 4 and the corresponding non-toxic addition salts thereof, whenever prepared according to the process claimed in claim 3,8. 7Q . 4-Diphenylmethyl-l-iminomethylpiperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 3 9. 71. 4-(Diphenylmethyl)-1-[(isopropylimino)methyl}~ piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim -40,. 72. 1-[n-(Benzyl) iminomethyl]-4-diphenylmethyl piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 41. 73. l-^N-^henethyl)iminomethyl]-4-diphenylmethyl-piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 42. 74. 1-[n-(n-Decyl)iminomethyl]-4-diphenylmethylpiper-idine and the non-toxic acid additions salts thereof, whenever prepared according to the process claimed in claim 43 . 75. 4-(Diphenylmethyl)-l-[ (octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 44. ic o o7 7 1 o / / I ' 65 76. 4-(Diphenylmethyl)-1-(ethylimino)methyl]piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 45. 77 . 1-[n-(n-Butyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 46. 78. 4-(Diphenylmethyl)-1- [ (hexylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 47 - E9 . 4- (Diphenylmethyl)-1- ^(heptylimino)methylj piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 4&.. 80.. 4- (Diphenylmethyl)-1- [(t-octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 4 9 • 81. 4-(Diphenylmethyl)-1- [(nonylimino)methyljpiperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 50 . f 82,. 4- (Diphenylmethyl)-l-[ (dodecylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 51.. 83. 1-[(1-Adamantylimino)methylj-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 52. 84. 1- f (4-Chlorobenzylimino)methyl]-4-(diphenylmethyl) — piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 53. >34 85. l-[(Allylimino)methyl]-4-diphenylmethyl)piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 54. . 189977 66 86 . 4- (Diphenylmethyl) ~1~["(2-propynylimino)methylj -piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 55. 8V . 4-(Diphenylmethyl)-1-[ethyl(imino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 56. 88. 4(9-Fluorenyl)-1-£(octylimino)methylj piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 57 • 89.. 4- (Diphenylmethyl)-l-["methyl (octylimino )methylj -piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 58. 90 . N-[4-(Diphenylmethyl)-1-piperidinyl] methylene benzenebutanamine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 5 9.. -51.. 4-Benzhydrylidene-l-[ (octylimino) methyl) piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 60. .92. 3-(Diphenylmethyl)-1-[(octylimino)methyljpiperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 6H. 93. 3-(Diphenylmethyl)-1-(iminomethyl)piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 6 2. 94. 4-(Diphenylhydroxymethyl)-1-^(octylimino)methyl] -piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 63;. 189977 67 95 . 4-[(4-Hydroxyphenyl)phenylmethyl^-1-^(octylimino) • methyl^piperidine and the non-toxic acid addition salts thereof, whenever prepared according to the process claimed in claim 64. 96. 4-£(4-Hyroxyphenyl)phenylmethyl^-1-f(octylimino)-methyl} piperidine 2-naphthalenesulfonate whenever prepared according to the process claimed in claim €5. WEST-WALKER, McCABE per: ATTORNEYS f OFi THE APPLICANT
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89141978A | 1978-03-29 | 1978-03-29 | |
| US1020979A | 1979-02-08 | 1979-02-08 |
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| NZ189977A true NZ189977A (en) | 1984-05-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ189977A NZ189977A (en) | 1978-03-29 | 1979-03-23 | Substituted n-iminomethyl piperidines |
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| JP (1) | JPS54132580A (en) |
| AT (1) | AT372081B (en) |
| AU (1) | AU523867B2 (en) |
| CA (1) | CA1140118A (en) |
| CH (1) | CH639071A5 (en) |
| DE (1) | DE2912026A1 (en) |
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| GR (1) | GR65192B (en) |
| IE (1) | IE47898B1 (en) |
| IL (1) | IL56962A (en) |
| IT (1) | IT1116525B (en) |
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| NZ (1) | NZ189977A (en) |
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| PT (1) | PT69383A (en) |
| SE (1) | SE7902724L (en) |
| SU (1) | SU1158042A3 (en) |
| YU (1) | YU73179A (en) |
| ZW (1) | ZW6479A1 (en) |
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| IL117149A0 (en) * | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
| US5889006A (en) * | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
| SE508513C2 (en) * | 1997-02-14 | 1998-10-12 | Ericsson Telefon Ab L M | Microstrip antenna as well as group antenna |
| TWI245763B (en) * | 1998-04-02 | 2005-12-21 | Janssen Pharmaceutica Nv | Biocidal benzylbiphenyl derivatives |
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| CH563109A5 (en) * | 1972-03-17 | 1975-06-30 | Ciba Geigy Ag |
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1979
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- 1979-03-23 NZ NZ189977A patent/NZ189977A/en unknown
- 1979-03-27 JP JP3516879A patent/JPS54132580A/en active Granted
- 1979-03-27 SE SE7902724A patent/SE7902724L/en not_active Application Discontinuation
- 1979-03-27 YU YU00731/79A patent/YU73179A/en unknown
- 1979-03-27 DK DK124979A patent/DK124979A/en not_active Application Discontinuation
- 1979-03-27 DE DE19792912026 patent/DE2912026A1/en active Granted
- 1979-03-28 IT IT48515/79A patent/IT1116525B/en active
- 1979-03-28 ZW ZW64/79A patent/ZW6479A1/en unknown
- 1979-03-28 PH PH22331A patent/PH15760A/en unknown
- 1979-03-28 CA CA000324324A patent/CA1140118A/en not_active Expired
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- 1979-03-28 FI FI791035A patent/FI791035A/en not_active Application Discontinuation
- 1979-03-28 ES ES479033A patent/ES479033A1/en not_active Expired
- 1979-03-28 AT AT0230979A patent/AT372081B/en not_active IP Right Cessation
- 1979-03-28 NO NO791026A patent/NO791026L/en unknown
- 1979-03-29 GR GR58719A patent/GR65192B/en unknown
- 1979-03-29 FR FR7907919A patent/FR2421169A1/en active Granted
- 1979-03-29 NL NL7902465A patent/NL7902465A/en not_active Application Discontinuation
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- 1979-08-08 IE IE650/79A patent/IE47898B1/en unknown
Also Published As
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| GR65192B (en) | 1980-07-29 |
| DE2912026A1 (en) | 1979-10-11 |
| NL7902465A (en) | 1979-10-02 |
| PT69383A (en) | 1979-04-01 |
| JPS54132580A (en) | 1979-10-15 |
| IL56962A (en) | 1983-03-31 |
| IE47898B1 (en) | 1984-07-11 |
| DK124979A (en) | 1979-09-30 |
| SU1158042A3 (en) | 1985-05-23 |
| DE2912026C2 (en) | 1990-04-05 |
| JPS6217588B2 (en) | 1987-04-18 |
| GB2017689B (en) | 1982-09-02 |
| ATA230979A (en) | 1983-01-15 |
| AU523867B2 (en) | 1982-08-19 |
| GB2017689A (en) | 1979-10-10 |
| IT1116525B (en) | 1986-02-10 |
| ES479033A1 (en) | 1980-06-16 |
| SE7902724L (en) | 1979-09-30 |
| PH15760A (en) | 1983-03-22 |
| IT7948515A0 (en) | 1979-03-28 |
| FR2421169B1 (en) | 1983-05-27 |
| CH639071A5 (en) | 1983-10-31 |
| IL56962A0 (en) | 1979-05-31 |
| CA1140118A (en) | 1983-01-25 |
| FR2421169A1 (en) | 1979-10-26 |
| YU73179A (en) | 1983-12-31 |
| ZW6479A1 (en) | 1980-11-26 |
| IE790650L (en) | 1979-09-29 |
| AU4532279A (en) | 1979-10-04 |
| NO791026L (en) | 1979-10-02 |
| FI791035A (en) | 1979-09-30 |
| AT372081B (en) | 1983-08-25 |
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