IE47898B1 - Substituted n-iminomethylpiperidines - Google Patents
Substituted n-iminomethylpiperidinesInfo
- Publication number
- IE47898B1 IE47898B1 IE650/79A IE65079A IE47898B1 IE 47898 B1 IE47898 B1 IE 47898B1 IE 650/79 A IE650/79 A IE 650/79A IE 65079 A IE65079 A IE 65079A IE 47898 B1 IE47898 B1 IE 47898B1
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- phenyl
- diphenylmethyl
- loweralkyl
- addition salt
- acid addition
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- 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
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- 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
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- 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
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- 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
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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
- C07D211/20—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
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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
- C07D211/68—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
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- 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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Abstract
Substituted N- iminomethylpiperidines of Formula (I): wherein R1, A, R1, B, R1'', D, R2 and R3 represent certain specified substituent groups are disclosed. These compounds are useful for the inhibition of gastric acid secretion.
Description
The present invention relates to substituted N-iminomethylpiperidines which are useful for the inhibition of gastric acid secretion.
Unsubstituted N-iminomethylpiperidine is disclosed in United States Patent No. 2,615,023, but this compound does not inhibit gastric acid secretion even 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-iminomethylpiperidines are effective inhibitors of gastric acid secretion.
The present invention provides substituted N-iminomethylpiperidines of Formula (I):
wherein:
IC=HR, (I)
7 8 9 8
-3 R^ taken individually is hydrogen; phenyl; phenyl substituted with from one to three loweralkyl, loweralkoxy, hydroxy or halo; phenyl loweralkyl; 1-phenyl (C^Cg) loweralkyl; phenyl(C^-C^)lower alkyl and 1-phenyl(Cy-Cg)5 loweralkyl in which the phenyl is substituted with from one to three loweralkyl,loweralkoxy,hydroxy,halo, phenyl, provided that no more than one substituent is phenyl; diphenylloweralkyl; diphenyl)loweralkyl wherein at least one of the phenyls is substituted with from one to three 1oweralkyl, loweralkoxy,halo, hydroxy, or phenyl, provided that no more than one substituent is phenyl; diphenylhydroxymethyl; diphenylhydroxymethyl wherein at least one of the phenyls is substituted with from one to three loweralkyl, loweralkoxy, hydroxy, halo or phenyl, provided that no more than one member is phenyl; or a group of the formula:
E or
E wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is hydrogen, acetyl, or phenyl provided that when A is acetyl or phenyl, R^ is phenyl
7 8 9 8 '4 or phenyl substituted with from one to three loweralkyl, loweralkoxy, hydroxy or halo;
Rj and A taken together form a benzhydrylidene group or group of the formula:
wherein n is 0, 1, or 2; .
H'l· taken individually is hydrogen; methyl; diphenylmethyl; diphenyImethyl wherein at least one of the phenyl groups is substituted with from one to three loweralkyl, loweralkoxy, hydroxy, halo or phenyl, provided that no more than one substituent is phenyl;
diphenyIhydroxymethyl; diphenylhydroxymethyl wherein at least one of the phenyls is substituted with fr.om one to three loweralkyl, loweralkoxy, halo, hydroxy, or phenyl, provided that no more than one substituent is phenyl; or a group of the formula:
wherein n is Ο, 1, or 2 and E is Ii or OH;
B taken individually is hydrogen;
Rj1 and B taken together from a benzhydrylidene group or a group of the formula:
wherein n is 0, 1, or 2.
R3 taken individually is hydrogen, diphenyImethyl; diphenyImethyl wherein at least one of the phenyls is substituted with from one to three lower’alkyl, loweralkoxv, halo, hydroxy, or phenyl, provided that no more than one substituent is phenyl; diphenylhydroxymethyl;
diphenylhydroxymethyl wherein at least one of the phenyls is substituted with from one to three loweralkyl, loweralkox'y, hydroxy, halo or phenyl, provided that no more than one substituent is phenyl; or a group of the formula:
if or
-6 wherein n is 0, 1. or 2;
D taken individually is hydrogen;
R and D taken together form a benzhydrylidene group;
R2 is hydrogen or C^-C^ loweralkyl; and is hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenylloweralkyl in which the phenyl is substituted with from one to three loweralkyl, loweralkoxy, hydroxy or halo; diphenyl (C^-C^)loweralkyl; diphenyl(C^-C^)loweralkyl in which at least one of the phenyls is substituted with from one to three loweralkyl, loweralkoxy, hydroxy, halo or phenyl, provided that no more than one substituent is phenyl; alkenyl; or alkynyl; provided that at least one of feaid R^,R',R^,R2, and R^ is other than hydrogen and further'provided that when Ry is other than hydrogen R^, and R'^, and A are each hydrogen; when R1^ is hydrogen then one of R^ and R^ is other than hydrogen; when R'i is methyl R^ is other than hydrogen and R^ is hydrogen; and when R^' is other than hydrogen or methyl Rl'Kl an<1 & are each hydrogen.
By the term loweralkyl and loweralkoxy as used herein is meant straight or branched chain saturated aliphatic hydrocarbons having from one to eight carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and pentyl, as loweralkyls, and respectively, the corresponding loweralkoxys, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy. By the term C^-C^ loweralkyl is meant those loweralkyls having from one to
7 8 9 8 _7_ four carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl. By the terms phenyl(C^-C^)loweralkyl and diphenyl(C^-C^)loweralkyl are meant 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 or 3,3-diphenylpropyl. The term 1-phenyl(C^-Cg)lower alkyl includes groups having the following general formula; / k
wherein m is 5,6 or 7. The term “alkylincludes straight or branched chain saturated aliphatic hydrocarbons having up to about sixteen carbon atoms, such as the above mentioned loweralkyls and further such radicals as hexyl, heptyl, octyl, nonyl, decyl, dodecyl and hexadecyl. The term cycloalkyl includes mono- bi-, and tricyclic saturated and unsaturated aliphatic hydrocarbons having up to about ten carbon atoms, such as, cyclohexyl, adamantyl, 1-adamantyl-methyl, exo-norbornyl, endo-norbornyl, noradamanthyl and anti-7-norborneyl. The terms alkenyl and alkynyl include straight and branched chain hydrocarbons having from two to about eighteen carbon atoms
7 8 9 8
-8and at least one double or triple bond, respectively, such as allyl, methallyl, 1-propargyl (1-propynyl) and 2-pentenyl. By the term halo is meant fluoro, chloro, bromo and iodo.
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 N-.’acyl 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, for example, phosgene, Mc3° BF4 , Et3O BF4 , (Me0)2S02, MeOSOjF, POC13 and PC15·
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 loweralkyl halides (methyl halide being preferred), methyl tosylate, methyl sulfonic acid esters (e.g.,methyl methanesulfonate) and methyl trifluoromethylsulfonate.
The activated reactant of Formula (III) may be in either free base or acid addition salt form.
Specific preparative routes are given below:
Λ) 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 a:;, a halocarbon (e.g. carbon y0 tetrachloride, chloroform or 1,2-dichloroethane, a loweralkanol (e.g., methanol , ethanol' or'isopropanol an aromatic hydrocarbon, (e.g., bi-nzene , xylene, or toluene or dimethylsulfoxide. The temperature of the reaction 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
7 8 9 8
- 10 fallowing, wherein A, B, D, R^, R£, R£, Rj» R3 are as previously defined, Z is selected from the group consisting of loweralkoxy (preferably methoxy and ethoxy), loweralkyl-S- (preferably methylthio), chloro, and
C12(O)PO-, and X is a member selected from the group consisting of halide, BF^, FSOj, and CHjOSOj. Additionally, when Z is loweralkyl-S-, X may also be a member selected from the group consisting of (4-methylphenyl)SO3, CHjSOj, and CFjSOj.
The compounds of Formula (I) wherein Rj is hydrogen may also be prepared by an analogous route by substituting an appropriate compound of Formula (IIIA) or (IXIB) for the imidate ester of Formula (III). If 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:
R3N«c«s-^thiourea·16^^) (I) (Rj=H) (XXXA) r3N5C ) (X) (HIB)
- 11 B) The compounds of Formula (I) may also be prepared by reacting a suitably-substituted piperidine of Formula (II) with acetic formic anhydride or N,Ndiloweralkylthioformamide (for R2*H) or a cl-c4 loweralkyl anhydride (for R2Cy-C4 loweralkyl), the anhydride preferably being present in excess. The piperidine and anhydride or thLofocmmide 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 halocarbon and aliphatic hydrocarbon solvents or without the addition of solvent, is then treated with an aqueous solution of a weak base (e.g., sodium bicarbonate! until the aqueous layer is neutral (for the anhydride route! 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 (IV1, ClVAl, and (Vi *
The intermediate amide is treated either neat or in the presence of an organic solvent such as, for example, a halocarbon (CHC13, CH^Clj) or a hydrocarbon (benzene, toluene) at 25s to 100’C with a suitable activating agent, aa 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 (VIII yields the desired product of Formula (I) which may be isolated and purified by known methods discussed above.' The above reaction scheme may be illustrated by the following, wherein.^, R^, Rj, R2, R3, A, B, D, Z, and X are as originally defined:
When Z is (loweralkyll-S-, the compounds of Formula CH wherein R2»H: ““Y also be obtained by reacting the activated intermediate (VI) 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
. loweralkyl S +
H
R3N»C-0-» ItR2»H)
VIII
Because the subject compounds CIl possess a basic amidine group, they may be converted into the corresponding acid addition salts.
The acid addition salts may be prepared by reaction with an appropriate acid, as for example an inorganic acid such as a hydrohalic acid, i.e., hydrochloric, hydrobromic or 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, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, g-toluenesulfcnic, salicylic, 2-naphthalenesul£onic or j>-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 (IX), (III), (IV), (TVA), (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., 14, 473-82 (1959) and E. Sury and X. 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., 6, 566 (1967), F. Snydam, et al., J. Org. Chem., 34, 292 (1969), and K. Seehinger, 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 Synthases, 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 into the stomach in the center of the purse string, and a cannula, consisting of a small vinyl tube with a flange on one end, is put into the stomach, and the purse string stitch is closed tightly around the flange. The test compound is administered either intraduodonally (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 ED5Qdoae (wAg required to produce an average of 50% inhibition in Total Acid Output versus controls in all the animals tested for a particular compound) and as percent inhibition. The compounds of the invention all demonstrate a significant inhibition both
i.d. and p.o, at less than 80 mg/kg, with preferred compounds having an 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 80 mg/kg i.d.
It is well-known that excessive secretion of gastric hydrochloric acid leads to unneeded peptic activity and endangers the mucos lining of the stomach. The use of gastric antisecretory agents is thus desirable as an aid in the prevention and amelioration of distress occasioned by high concentrations of stomach acid.
Preferred compounds of the invention are those of Formula (I) wherein;
Rj is a phenyl; phenyl substituted with from one to three loweralkyl, loweralkoxy, halo or phenyl, provided that no more than one substituent is phenyl; phenyl(C^-C^) loweralkyl;phenyl(Cj-C^)loweralkyl in which the phenyl is substituted with from one to three loweralkyl, loweralkoxy or halo; diphenyl-(C^C^)loweralkyl and diphenyl(C^-C^)loweralkyl wherein at least one of the phenyls is substituted with from one to three loweralkyl, loweralkoxy, halo or phenyl, provided that no more than one substituent is phenyl;
R2 is hydrogen or methyl;
R3 is hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenyl-loweralkyl in which the phenyl is substituted with from one to three loweralkyl, loweralkoxy, or halo; alkenyl or alkynyl; and
4788 8 kJ' Rl ' Λ’ B' and D nrc enc1’ hydrogen.
More preferred compounds of the invention are those of Formula (1) wherein:
is diphenylmethyl or diphenylmethyl wherein at least one 5 of the phenyls is substituted with from one to three loweralkyl, loweralkoxy or halo;
R2 is hydrogen;
R3 is hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl in which the phenyl is substituted with from one to three loweralkyl, loweralkoxy or halo; alkenyl; or alkynyl; and R1'' Rl' Λ' B' and D are hydrogen.
Most preferred compounds of the invention are those of Formula (1) wherein is diphenylmethyl or diphenylmethyl wherein one of the phenyls is substituted in the para15 position with a loweralkyl, loweralkoxy or halo; R2 is hydrogen; R^ is hydrogen, straight chain alkyl or phenylloweralkyl; and R^1, R^ 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, a method of inhibiting gastric acid secretion 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 non-toxic. Pharmaceutical compositions comprising a subject compound (I) are also considered- a further aspect of the present invention.
To prepare the pharmaceutical compositions of the 5 present invention, a substituted N-iminomethylpiperidine of Formula (I) or an acid addition salt thereof is combined
7 8 9 8
I
- 18 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 prepara5 tion 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 prefer30 ably 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.
- 19 EXAMPLE X
4-Diphenylmethyl-l-iminomethylpiperidine hydrochloride hydrate_
A euepeneion of 27.39g (0.25 mole) of ethyl formimidate hydrochloride [prepared by the method of Ohme, et al., Angew. Chem. Inti. Ed., £, 565(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-irainomethylpiperidine hydrochloride hydrate; m.p. 220-221’C.
EXAMPLE II
Following the procedure of Example I, 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:
Salt A h. ^3 m.p. (eC) diphenylnethyl HC1 H <^5 H 271.5-277.5 ct- (4-metbcxypfeenyl) benzyl fvnarate H H H 189.5-192.5 a- {l,4-biphenyl}-oehydroxyhenzyl aci H H H 216 -218 phenyl BC1 H H H 204 -205 benzyl aci qH H H 199 -201.5 phenyl aci c-ot3 H H 172 -175 or (4-chlarophenyl) funarate H H H 192.5-194.5
benzyl
- 20 EXAMPLE III
4-(DiphenyImethyl)-1-N-ethyliminomethylplperidine oxalate hemihydrate
A mixture of 8.00g (0.029 mole) of N-formyl-4diphenylmethylpiperidine 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. 165175°C. Recrystallization from isopropanol afforded pure 4-(diphenyImethyl)-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;
h. Salt m.p. (“O diphenylmethyl 3 -CHjCBaC^ cyclohexane sulfamate 179.5-181 1» H i-pcopyl fumarate 175 -178 n H n-butyl n 193.5-195 H H n-hexyl R 179 -181.5 19 H n-heptyl π 175 -178 11 H n-octyl it 157 -159 Π H t-cctyl n 227 -229 Π H n-nonyl « 142 -144.5
Salt sup. (*C) diphenylmethyl H n-deqyl succinate 106 -109 N H n-dodecyl fmarate hydrate 143 -145.5 H H 1-edsmanfcyl fumarate 275 -276 «1 H benzyl cyclohexane sulfanate 164.5-166.5 K H phenethyl M 141 -144 «1 H g-cfalcaxbsnzyl 2-naphthalene sulfonate 222 -224 H H M 110.5-112.5 a-(4-methoKSphenyl) benzyl H n-octyl (E)-2-butene- dioate 154.5-156 a- (4-tnethylphenyl) benzyl H n-octyl N 161 -163.5 diphenyImethyl H 4-methylbenzyl perchlorate 242 -244 M H phenyl 4-toluene- sulfonate 285 -286
EXAMPLE IVA
A mixture of 4-[(4-methoxyphenyl)phenylmethyl]~ l-[(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]-l-[.{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 epichlorohydrin] 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 25s. 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, 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 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 recrystallized from ethanol-water to give two crops of 4-(diphenyImethyl)-1-[(octylimino)methyl]piperidine fumarate hydrate? m.p. 157-159’C.
EXAMPLE VI
4-(DiphenyImethyl)-1-piperidinecarbothioaldehyde
A solution of 20.Og (0.08 mole) of 4-dipheny1methylpiperidine, 14.2g (0.16 mole) of Ν,Ν-dimethylthioformamide 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-(dipheny Imethyl) -1-piperidinecarbothioaldehyde, m.p. 152-154’C.
EXAMPLE VII
Following the above procedure, but substituting for 4-diphenylmethylpiperidine used therein, an equivalent amount of an appropriate piperidine, there are prepared the followings
9-fluorenyl
H
—.—benzyhydrylidenediphenylhydroxymethyl
Ph2CH H ' H
m.p. (°C)
142 - 146 115 - 120 131 - 134 200 - 203
EXAMPLE VIXI
4-(Diphenylmethyl)-1-N(n-dodecyliminomethyl)piperidine fumarate
A solution of 5.54g (0.019 mole) of 4-(diphenylmethyl) -1-piperidinecarbothioaldehyde in 20 ml of 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 ndodecylamine, refluxed one and one half hours, cooled, 5 treated with aqueous sodium hydroxide and the organic layer separated. After drying, evaporation yielded an oil which was converted to the furaarate to yield 4(diphenyImethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate; m.p. 143-145.5C.
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;Ri< NCH-NR3 A Salt m.p. C°C) Η H diphenylmethyl a B -taygcc- fimarate hydrate (sinter 125°) 131 -135 diphenylmethyl H H -eHjesa BC1 117 -119 9H-fluoren-9-yl H H 2% HC1 174 -177 H H diphenylmethyl 2^17 furaarate hydrate (sinter 68.5°) 70 -72 -benzyhydrylidene- H 2^17 fumarate 167 -170 diphenyHydroxymethyl H H 2^17 furaarate (sinter 145°) 155 -161 H B diphetyl- H furaarate 185.5-187.5
methyl
EXAMPLE X
Alternate Preparative Routes Illustrated for 4-(Diphenylmethyl)-1-[(octylimino)methyl]piperidine
1) A mixture of 2.90g (0.01 mole) of 4-{diphenylmethyl) -1-piperidinecarbothioaldehyde, 129g (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 609 for two days. The reaction mixture was made basic
- 24 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 an 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-octylisothiocyanate 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-octy1-1piperidinecarbothioamide. 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.
6) A solution of N-formyl-4-diphenylmethylpiperidine 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 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, 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-(diphenyImethyl)-1-((octylimino) methyl] piperidine (E)-2-butenedioate (1:1) hydrate, identified by thin layer chromatography.
7) A mixture of 5,60g (0.022 mole) of 4-diphenylmethylpiperidine, 3.50g (0.022 mole) of n-octylisonitrile, 0.26g (0.002 mole) of silver chloride, and 10 ml of toluene was stirred 48 hours at 25°, filtered, 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)-l-[(octylimino)methyl3piperidine isolated as the fumarate salt, which was identified by thin layer chromatography.
EXAMPLE XX
Following the test procedure previously described, the following compounds were tested for their antisecretory activity. The ED5Q values for p.o. administration and the percent inhibition for i.d. administration at 20 mg/kg are tabulated below (R^ »
A
go & ο δ q q
« ex * « go rt ex 0 e eo Π Ο Γ» 03 ο»
s rt
r* rt N o a ca • xo e P* SO 00 so « CM e • rt • r*» • f* < o •sf o S0 9% 00 GO rt 91 in ex co rt P* xo rt rt o o o fH rt rt r-f in rt so N V V Λ V
<1
SC
*3
ΙΊ
98% Inhibition at 80 mg/kg i.d. 52% inhibition at 80 mg/kg i.d.
89 8
- 28 EXAMPLE XIX
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, wherein the following substituents are in the two
CR^n), three (R^1) or four s (Rp position: Ii _/R1 W NC=°A \ _Λ Substituent Position of Substituent «2 A diphsiylmethyl 4 H H a- (4-chlacophenyl)benzyl R R rt cr (4-raethylpheryl) benzyl n R tt or (4-methoxyphenyl) benzyl π n R or (4«chlaraphenyl)benzyl 3 n R 9-fluorenyl n R tt diphenylmethyl R n It phenyl 4 n ft phenyl H tl phenyl 4-chlorophenyl IT tt H 4-chlorophe3^1 n n phenyl 4-rasthaxyphenyl n π H 4-methoxyphenyl rt R phenyl 4-chlorobenzyl R H B phenyl R methyl phenyl phenyl w n-butyl phenyl a- (1,4-biphenyl) benzyl M H H or (1,4-bipbenyl)benzyl n methyl R cr (1,4-biphenyl) benzyl R n-butyl tt 2,2-diphenylethyl R B rt 2,2-diphenylethyl ft methyl tl 2,2-diphenylethyl R n-butyl n 10, ll-dihydro-5g-dihenzo [a,d] cycloheptene-5-yl ~ ” 2 H R
-2947898
A
Β
Substituent Position of Substituent 10,U-dihydro-ffi-dibeezo[a,d]cycloheptmne^S-yl ~ 2 methyl Ν w n-butyl « · 4 B Ν w methyl η 1« rt-butyl 4,4-diphetiyl-n-feutyl 4 B 4,4-dipteiyl-jHxrtyl H methyl 4,4-diphenyl-n-butyl tt iHwtyl 4-methcaybenzyl M B benzyl rt tt 9-fluorenyl rt tt diphenylmethyl tt methyl diphenylmethylene rt tt a- (4-chlcraphenyl) benzyl N tt a- (4-mefchylphenyl)benayl rt tt a- (4-methoocyphenyl) benzyl rt tt diphenylmethyl 3 tt 9-fluorenyl tt N a- (4-chloEopheryl) benzyl N It phenyl 4 tt 9-fluorenyl tt tt 4-chlorofhenyl N tt 4-methoxyphenyl tt tt 4-chlorcbenzyl N tt 4-methaxybenzyl N N benzyl W diphenylmethyl N n-butyl diphenylmethylene tt tt a-(4-chlorophenyl)benzyl H N a-(4-methoxyphenyl)benzyl tt « a-(4-methylphenyl)benzyl tt diphenylmethyl 3 N 9-fluorenyl tt tt 9-fluarenyl 4 tt a-(4-chlorophenyl)benzyl 3 tt
η
Ν
Ν η
Η η
w
Μ
Μ
1*
Ν
Μ η
η w
η η
η η
η
Ν η
η
Μ
Ν *2
Position of Substituent
Substituent
SE-dibsao [a, d] cyclchectan-5-yl 2 H H A n methyl If tk a n-butyl tt 10,H-dihydco[a,d]cyclahspten-5-yl A H w A n methyl tt ft «I n-butyl It phenyl (octyl)methyl 4 H It n n methyl ft n n n-butyl n phenyl (heyl)methyl It H A * A IT methyl M n n-twtyl It phenyl a tt A 4-chlcrophenyl It n It 4-fflSthaxyphenyl n n n benzyl It « n 4-chlcrobenzyl π tt tt 4-methoxybenzyl It n A diphenylmethyl 2 H A diphenylmethyl n methyl A diphenylmethyl It n-butyl A 5H-dibenzo [a,d] cyclohepten-5-yl 4 H · A 55-dibenzo [a ,d] cyclohepten-5-yl It methyl A SH-dibenzo [a,d] cyclohepten-5-yl n n-butyl A
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:
Β ch3 n-butyl
Β cb3 n-butyl
B
CB3 n-butyl
B cb3 n-butyl
B ca3 n-butyl
B ca3 n-butyl
EXAMPLE XIV
Following the procedure of Example XIII, there are prepared the following piperidine amides:
wherein R2
EXAMPLE XV
Following the procedure of Example XIII, there are prepared the following piperidine amides:
(C6H5>2C
NC-0 *2
Position of Substituent R2 n
n
H n
H ch3 n-butyl
H • ch3 n-butyl
B ca3 n-butyl
EXAMPLE XVI
Following procedures described in the references given above for compounds of Formula (III), the following
prepared: • R2C-NR3 ^2R3 H -(CB2)nCB3 H -(CB2)7cb3 H -2)14ch3 S -(CH2)4ch-chch2cb3 B cis-(CB2)5CB-CB(CB2)10CB B -(CH2)gCSCH B 4-ClPh- B 4-MeOPh- H 4-MePh- H -CHjCHCH B exo-2-norbornyl a endo-2-norbornyl B 1-decahydronaphthyl H 1-adamantyl H 2-bicyclo[2.2.2]octyl H anti-7-norbornenyl B endo-bicyclo[3.2.1]octyl H 1-adamantyImethyl Me H MeC2H5 Me -(cb2)5cb3 Me -(CB2)7CB3 Me -(CH2)14CB3 Me -(CB2)4ch-chcb2ch3 Me cis-(CH2)5CH»CH(CH2)10CH. Me -CBjCSCB Me (CH2)gC5CH Me Ph Me 4-ClPh- Me 4-MeOPh- Me 4-MePh- Me PhCB2- Me 4-ClPhCH2- Me 4-MePhCH2-
R2 Me 4-MeOPhCH2- Me PhCH2CH2- Me exo-2-norbornyl 5 M6 endo-2-norbornyl Ms 1-decahydronaphthyl Me l-adamantyl Me 2-bicyclo[2.2.2]octyl Me anti-7-norbornenyl 10 Me endo-bicyclo[3.2.1]octyl Me 1-adamantyImethyl n-Butyl TBu) H BuC2H5 Bu -CH2CH«CH2 15 Bu (CH2)7CH3 Bu 2)14ch3 Bu -(CH2)4CH»CHC2Hs Bu cis—(CH2)5CH»CH(CH2)1oCH3 Bu -ch2c=ch 20 Bu (ch2)6c=h BU 4-ClPh Bu 4-MeOPh Bu 4-MePh BU Ph 25 BU PhCH2 Bu 4-ClPhCH2- Bu 4-MePhCH2- BU 4-MeOPhCH2- BU PhCH2CH2 30 Bu exo-2-norbornyl Bu endo- 2 -norbornyl BU 1-decahydronaphthyl Bu l-adamantyl BU 2-bicyclo[2.2.2]octyl 35 Bu anti-7-norbomenyl BU endo-bicyclo[3.2.1]octyl Bu 1-adamantylmethyl 1 H diphenylmethyl Me diphenyImethyl 40 Bu diphenylmethyl H 3,3-diphenyl-n-propyl Me 3,3-diphenyl-n-propyl Bu 3,3-diphenyl-n-propyl
EXAMPLE XVII
Following the procedure of either Example I or
Example III, but substituting for the ethyl formimidate hydrochloride and diphenyl-4-piperidylmethane or N-formyl4-diphenylmetliylpiperidine 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^“), three or four (Rj) positions:
(Rf),
Position of
Substituent Subeti(®1' 8/' Y’ uent diphenylmethyl 2 diphenylmethyl 3
9-fluorenyl a- (4-chlarophenyl)benzyl diphenyllydroKymethyl 4 «2
H
N
N
,H-dihyta>-5S-dibenzo [a,d] cyclchepten-5-yl
4-chlorohenzyl
4-methoxyphenyl diphenylmethyl
4-chlorophenyl a- (4-methylphenyl) benzyl 4-chlorobenzyl a-(4-chlorophenyl)-a- hydraxybenzyl a- (4-chlorophenyl) benzyl 3
9-fluorenyl 4-methaxybenzyl 4 9-fluorenyl 3 diphenylbydroxymethyl 2 «w n
a- (4-
898
Substituent «ρ car Rj.)
Position of Substiuent *2 *3 diphenylhydraxymethyl 4 H
5H~dibenzo[a,d] cyclohept5]r5“yl phenyl ’ diphenylmethyl cr-(4-chlorophenyl)-a- hydroxybenzyl cr (.4-chlarophenyl) benzyl 3
9-fluarenyl 4 a-(4-methylphenyl) benzyl
4-chlaroghenyl
4-methoxybenzyl diphenylmethyl a- (4-methaxypbenyl) benzyl diphenylmethyl 3 lO.ll-dihydro-5-hydroxy-
5B-dibenzo [a ,d] cyclahepten-5-yl
9-fluorenyl diphenylhydraxymethyl 4 phenyl 4-cHlorobenzyl diphenylmethyl a-(4-chlorophenyl)benzyl 3 9-hydroxy-9-fluaremyl 4 cr(4-chlarophenyl)-a- hydxoxybenzyl
4-metboxyphenyl benzyl cr (4-methylphenyl) benzyl diphenylmethyl cr (4-chlarophenyl) benzyl a- (4-methoxyphenyl) -a- hydraxybenzyl
9-fluorenyl 3 a-(4-chlorophenyl)benzyl diphenylmethyl 2
-((¾)^ H n « phenyl
-^140¾ H
-(CHj) 42CH3 n cis- (CH,) gCBCH (CEL,) j pCg, η n r w » « ti « π n ti tt (CH^gCaCH η n η n tt h n R π R
Position of
Substituent SubetiORjy R^, or R^) uent phenyl 4
4-methcxybenzyl ” diphenylmethyl ” a-(4-methoocyphenyl)benzyl or(4-methylphenyl)-cr hydamybenzyl cr (4-chlorophenyl)benzyl 3
9-fluorenyl 4
,ll-dihydro-5B-dibenzo [a,d] cyclobeptian-5-yl
4-methcayphenyl
4-chlarobenzyl diphenylmethyl or (4-raethylphenyl) benzyl cr (4-raethcacypfcenyl)-a- hydracybenzyl diphenylmethyl 3
9-fluorenyl phenyl 4
4-chlotobenzyl cr (4-chlaraphenyl)benzyl diphenylmethyl diphenylhydrcstymethyl or (4-chloropbenyl) benzyl 3 9-fluorenyl
4-methCKyphenyl 4 benzyl diphenylmethyl cr (4-methagphenyl) benzyl cr (4-raefchylphenyl) -cr hydzoxybenzyl diphenylmethyl 3
9-fluorenyl phenyl 4
4-chlarobenzyl cr {4-methoxyphenyl) benzyl
-¾
H (CHjJgCHCH
A
-CHjCSCH
A exD-2-ncrbomyl endo-2-norfcognyl
A l-decahydronephthyl l-aianantyl phenyl
H
7 8 9 8
Substituent (Rj., R^', or R^)
Position of Substiuent «2
,U-dihydro«5-bydxootf- 4 H 5H-dibenzo(a,dTcyclohepten-5-yl a-(4-chlorcphenyl) -a- hydraxybenzyl a- (4-chlarcphenyl) benzyl 3 9-fluorenyl
4-Chlarophenyl 4 benzyl diphenylmethyl a-(4-methaxyphenyl) benzyl diphenylhydraxymethyl diphenylmethyl 3
9-fluorenyl 4 phenyl
4-methcKybenzyl diphenylmethyl a-(4-chlarophenyl)benzyl a-(4-fnethylphenyl)-a- hydraxybenzyl
Rg A l-adamantyl H w n η «ι
Fhenyl
H
2-bicyclo[2.2.2]octyl n w « « anti-7-norbornenyl » « w « diphenylmethyl 3 9-fluorenyl phenyl 4 4-chlorobenzyl diphenylmethyl a-(4-methylphenyl) benzyl diphenylhydraKymethyl a- (4-chlarcphenyl) benzyl 3
9-fluorenyl diphenylhydraxymethyl 2 4-metbajqiphenyl 4 benzyl diphenylmethyl a-(4-metbaxyphenyl)benzyl a-(4-chlarophenyl) -a- hydraxybenzyl a-(4-chlaraphenyl)benzyl 3 endo-bicyclo[3.2.1]octyl η n n it η n n ti n n η n η n
1-adamantylmethyl η n η n
Π II
Substituent (R^, R^’» or RjD
9-fluorenyl phenyl
4-methtaybenzyl dipheny Imethyl
Foei-f tion of Subetiuant Rj
H a-(4-wetboxypbenyl) benzyl l-edamentylmethyl methyl a-(4-chlcraphenyl) -ahytaotybenzyl
-hyiraxy-5&-dibenzo [a,d] cyclchepten-5-yl a- (4-dilazophenyl) benzyl 3
9-fluotenyl diphenylmethyl 2 4-chlarophenyl 4 benzyl diphenylmethyl a-(4-methcaypbenyl) benzyl a-(4mettiylphenyl)-a- hydxaxybenzyl diphenylmethyl 3
9-hydraxy-9-fluorenyl 4 4-toethoxyphenyl
,ll-dihydro-5H-dibenzo [a,d] cydoheptien-5-yl benzyl a-(4iaethylpbenyl)benzyl diphenylhytaocymethyl ®-(4-chloeqphenyl)benzyl 3 9-fluorenyl phenyl 4 benzyl diphenylmethyl »-(4-ohlorapbenyl) benzyl o- (4-rartheayphenyl) -a- hydraxybenzyl diphenylmethyl 3
9-fluatenyl ^2¾
N
A
Substituent (F^, R^, ar R^)
Position of Substiuent Rj
4-methoxypheriyl, 4 4-chlorobenzyl diphenylmethyl a- (4-nethc«yphenyl)benzyl phenyl diphenylhydraxymethyl a-(4-cblarophenyl)henzyl 3 9-fluorenyl 4-chloraphenyl 4 benzyl diphenylmethyl ” a- (4-methylphenyl) benzyl a- (.4-chlorqpbenyl) -a- hydroxybenzyl diphenyhnethyl 3 9-fluorenyl phenyl 4 4-chlarobenzyl diphenylmethyl a- (4-methoxyphenyl) benzyl diphenylhydraxymethyl 9-fluorenyl 3 a-(4-chlarophenyl) benzyl 4-methaxyphenyl 4 benzyl diphenylmethyl a-(4-methylphenyl)benzyl a- (4-chlorophenyl) -a- hydroxybenzyl diphenylmethyl 3 9-hydraxy-9-fluorenyl 4 phenyl 4-methoxybenzyl n diphenylmethyl a-(4-chloraphenyl) benzyl diphsnylhydraxymethyl methyl
R
-¾
-
-OLCB“CH-(^4(30¾¾ phenyl cis- (¾) SCB=CH (¾) 1QCT3
-¾^ •(CHjJgCSCH
Position of A Substituent ί (Bp R^', or Rj) Subeti- uent diphenylmethyl 3 methyl -«X^gSCB. H 9-fluorenyl N N M tt diphenylhydroo^methyl 2 M tt tt 4-chlorophenyl 4 tl tt H 4-chlorobenzyl tt N tt tt diphenylmethyl tt N benzyl tt a- (4-chloroph±nyl)benzyl tt M 4-chlorobenzyl tt diphenylhydroxymethyl tt tt 4-methoxybenzyl tl diphenylmethyl 3 tt 4-nethyIbenzyl N 10, H-dihydro-5-hydraxy- tt tt tt N
5H-dibenao [a,d] eyclohepten-5-yl
9-fluorenyl a- (4-methoxypheryl)benzyl 4-chlorabenzyl It 4 w tt tt M tt 4-chlorobenzyl benzyl tt tt N 15 diphenylmethyl tt N eap-2-narfaomyl M a- (4-methylpfaenyl) benzyl N tt tt It phenyl tt tt N phenyl diphenylhydraxyraethyl tt tt tt H diphenylmethyl 3 R II N 20 phenyl 4 N tt tt 9-fluorenyl 3 N tt tt benzyl 4 tt tt tt 10,ll-dihydro-5H-dibenzo tt tt N It [a,d] cyclohepten-5-yl diphenylmethyl tt tt endo-2-norbomyl tt 25 a-(4-chlorophenyl) benzyl M N tt 11 a- (4-methylphenyl)-a- II tt tt If
hydraybenzyl diphenylmethyl 3
9-fluorenyl
4-methowyphenyl 4
4-chlorobenzyl diphenylmethyl a-(4-methoacyphenyl)benzyl diphenylhydroxymethyl a- (4-chlarophenyl)benzyl 3
1-decahydronaphthyl
Substituent (Rj/ Sj/, or Rj) 9-fluorenyl 4-chlorophenyl
4-raethcBtybensyl « diphenylmethyl « a (4-chlorophenyl)benzyl a“ (4-methylphenyl)-a- hydraxybenzyl diphenylmethyl 3
9-fluorenyl « phenyl 4 benzyl n diphenylmethyl a- (4-methoxyphenyl)benzyl diphenylhydnaymethyl a- (4-chloraphenyl)benzyl 3 9-fluorenyl 4
4-chlorophenyl
4-methoxybenzyl diphenylmethyl a-(4-methylphsnyl) benzyl diphsnylhydroxymethyl diphenylmethyl 2 a-(4-chlorophenyl)benzyl 3 phenyl 4
9-fluorenyl 3
4-methoxybenzyl 4 diphenylmethyl n phenyl ” a-(4-chlorophenyl) benzyl diphenylhydraxymethyl diphenylmethyl 3
9-fluorenyl nethyl 1-decahydronapfathyl
Π B 1-adamantyl
2-bicyclo[2.2.2]octyl anti-7-norbornenyl endo-bicyclo [ 3.2.1] octyl phenyl
H
4-chlorophenyl 4 benzyl diphenylmethyl n
1-adamantylmethyl
Position of Substituent Substi- (1^, R^', or Rj) J jent a- (4-raethylphenyl) benzyl 4 methyl l-edementylraethyl o- (4-chlarophenyi) -ahydrcocybenzyl R N tt diphenylmethyl 3 N tt 9-fluorenyl M tt N 4-methcocyphenyl 4 tt R 4-chlorobenzyl N N tt diphenylmethyl tt m-butyl H cc- (4-rasthaxyphenyl) benzyl M N tt diphenylhydroxymethyl «V tt N diphenylmethyl 3 ft tt 9-fluorenyl tt tt tt phenyl 4 tt H 4-chlorobenzyl tt tt N diphenylmethyl tt tt ^2¾ phenyl tt R N a- (4-methoxyphenyl)benzyl tt R R cc- (4-chloraphenyl) -cchydraxybenzyl tt R It diphenylmethyl 2 R tt a- (4-chlorcphenyl) benzyl 3 R tt 9-fluorenyl tt R tt 4-methoxyphenyl 4 tt tt benzyl tt N N diphenylmethyl tt R -(CHj)^ cc- (4-chlorcphenyl) benzyl N tt M diphenylhydroxymethyl tt tt H diphenylmethyl 3 tt tt 9-fluorenyl tt R N phenyl 4 R R benzyl tt tt H diphenylmethyl tt R -«=2>14®3 a- (4-methylphenyl) benzyl tt R R diphenylhydroxyraethyl tt R H a- (4-chlarophenyl)benzyl 3 tt H 9-fluorenyl tt « N
phenyl
Η η
Position of
Substituent Substi(Rp 1^', or RjO uent Sj
,U-dihydro-5-hydroxy- 3 re-butyl 5H-dibenzo [a,d] cyclchepten-5-yl-
4-wethaxyphenyl 4
4-chlorobenzyl diphenylmethyl a- (4-chlnrophenyl)benzyl diphenylhydraxymethyl a-(4-chlorophenyl)benzyl 3
9-fluarenyl
4- chlaraphenyl 4 benzyl diphenylmethyl °
- hydraxy-5H-dibenzo [a,d]cyolohepten-S-yl a-(4-methylphenyl) benzyl ”
-¾
-(¾)^
R n
n a-(4-methaxyphenyl)-a- hydroxybenzyl diphenylmethyl 3
9-fluorenyl phenyl 4
4-chlorobenzyl diphenylmethyl a- (4-metbylphenyl)benzyl dipherylhydraxymethyl a-(4-chlorophenyl)benzyl 3
9-fltcrenyl phenyl 4
4-methoxybenzyl diphenylmethyl a- (4-methylphenyl) benzyl diphenylhydroxymethyl
,ll-dihydro-5H-dibenzo [a ,d] cyclohepten-5-yl cis- (¢3¾) SCS-CH (¾)
-CHjCSCH
II diphenylmethyl 3 S-fluarenyl 4-methoxyphenyl 4
Substituent CR^r R^', or P^w)
Position of Sdsstiuent «2 *3 benzyl * 4 diphenylmethyl a-(4-chlorophenyl) benzyl phenyl a- (4-methcocyphenyl) -a- bydraxybenzyl a- (4-chloraphenyl) benzyl 3 9-fluca?enyl phenyl 4 4-methOKybenzyl diphenylmethyl a- (4-methylphenyl) benzyl a-(4-chlorophenyl)-a- hydreocybenzyl diphenylhydroKymethyl 2 diphenylmethyl 3 9-flucrenyl phenyl 4 4-mathcocybenzyl diphenylmethyl a-(4-iaBthcetyphenyl) benzyl diphenylhydroocymethyl diphenylmethyl 3 9-hydrcoty-9-fluorenyl 4 phenyl * 4-chlarobenzyl * diphenylmethyl ” a- (4-methylphenyl) benzyl diphenylhydroocymethyl a-(4-chlotopbenyl)benzyl 3 9-fluarenyl 4-methoxyphenyl 4 benzyl diphenylmethyl a- (4-chlcrcphenyl)benzyl nrbutyl w
-CHjCECH
-(CHjJgCaCH n
H phenyl
H benzyl
4-chlarobenzyl
4-raethylbenzyl
4-raethaxybenzyl
N benzyl
4-methylbenzyl phenethyl «oo-2-norbornyl
N endo-2-norbornyl
N
Substituent (1^, ΐγ, or Rf) a- (4-methylphenyl) -ahydrcKybenzyl diphenylmethyl
Position of Substiuent Kj irbutyl endo-2-norbomyl
9-fluorenyl phenyl 4
4-nBthajgbaizyl diphenylmethyl a-M-chlarophenyl) benzyl ** a- (4-methoxyphenyl) -a- hydraxybenzyl phenyl a-(4-chlorophenyl)benzyl 3
9-fluorenyl phenyl 4 benzyl diphenylmethyl a- (4-methaxyphenyl) benzyl dipbenylhydrasymetbyl diphenylmethyl 3
9-fluorenyl
4-chlorophenyl 4
4-chlarobenzyl diphenylmethyl a- (4-methylptenyl)benzyl a-(4-chlarcphenyl)-a- hydraxybenzyl a-(4-chlarophenyl)benzyl 3 9-fluorenyl phenyl '4
4-methcxybenzyl diphenylmethyl a- {4-methylphenyl)benzyl diphenylhydroxymethyl diphenylmethyl 3
9-fluorenyl diphenylmethyl 2 κ
tl tt
1-decahydronaphthyl tt n
n n
η «
n l-adamantyl
If
It n
n n
ti
2-bicyclo[2.2.2]octyl n
N tt n
n n
anti-7-norbornenyl tt n
n tt n
A
H (I tt
It tt n
n n
phenyl
H
It tt
It n
» n
η n
tt π
n n
n n
n cr tt n
tt n
n ti n
Substituent (Rg, 1^', or Rg)
Position of Substiuent
4-methaxyphanyl . 4
4-chlorobenzyl diphenylmethyl oH4-mBthaxyphenyl) benzyl a-(4methylpbenyl)-o- hydraxybenzyl a-(4-dilarophenyl)benzyl 3
9-fluorenyl phenyl 4
4-methaxybenzyl diphenylmethyl ot-(4-methaxyphenyl) benzyl * diphenylhydraxyraethyl diphenylmethyl 3
9-fluarenyl phenyl 4 benzyl a- (1,4-biphenyl) benzyl a-(l,4-biphenyl)benzyl a-(1,4-biphenyl)benzyl
2,2-diphenylethyl
2,2-diphenylethyl
2,2-diphenylethyl
4.4- dipbenyl-n-butyl M
4,4-diphenyl-n-butyl
4.4- diphenyl-n-butyl diphenylmethyl phenyl 3
9-fluorenyl 4
4-chlorobenzyl diphenylmethyl 3 diphenylhydraxyraethyl 4 n-butyl anti-7-norfaomenyl endo-bicyclo [3.2.1]octyl
1-adecantyImethyl
H
CHg n-butyl a
% n-butyl a
CHg n-butyl a
CHg n-butyl a
CHg n-butyl a
-7®3 phenethyl
H phenethyl
H
-(0¾)^ phenethyl diphenylmethyl
3,3-diphenyl-n-propyl
89 8
Substituent (1^, , or RjD Position of Substi- uent - «? A phenyl(octyl)methyl 4 a B a 10, H-dihydxo-5S-dibenzo [a,d] cyclchepten-5-yl 2 n -(CHjJtC^ R 5g-dibenzo[a,d] ”cycloheptanr5-yl R It R R phenyl (hexyl)methyl 4 R (oygCscB R phenyl (heayl) methyl R methyl -(CH2)4C9<3CH2CH3 M 10, ll-dihydro-5S-dibenzo [a,d] cyclohepten-5-yl 2 R -(CHjJgCCT R 5H-dihenzo[a,d] “cyoloheptfflr5-yl N n Π R 10, ll-dihydro-5H-dibenzo [a,d]cyclohepten-5-yl H n-butyl -CHjCS R 5H-dibenzo[a,d] “cycloheptfflirS-yl n R n R pheryl (octyl)methyl 4 n phenethyl R
Example XVIII
Following the procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl4-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: (CH2)n\ \ NC-NR, >-( r2 Position of Substituent n R, 3 0 H H 3 0 H n-octyl 3 0 H n-dodecyl 4 0 H n-hexadecyl 4 0 ch3 n-octyl 4 0 n-butyl n-octyl 3 1 H H 3 1 H n-octyl 3 1 H n-dodecyl 4 1 H n-hexadecyl 4 1 ch3 n-octyl 4 1 n-butyl n-octyl 3 2 H H 3 2 H n-octyl 3 2 H n-dodecyl 4 2 H n-hexadecyl 4 2 ch3 n-octyl 4 2 n-butyl n-octyl
EXAMPLE XIX
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 ethy lamine, respectively, used therein, equivalent amounts of the appropriate starting materials such as described in Examples XIV and XVI, there are prepared the following:
H
B
H
B ch3 n-butyl
B
H
H
B ca3 n-butyl
H
B
B
B cb3 n-butyl
B n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl
B n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl
B n-octyl n-dodecyl n-hexadecyl n-octyl n-octyl
EXAMPLE XX
Following the procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-idiphenylmethylpiperidine or N-formyl4-diphenylmetbylpiperidine and ethylamine, respectively, used therein, equivalent amounts of the appropriate starting materials such as described in Examples XV and
XVI, there are prepared tbe following: W6h5)2c Position of Substituent n ^3 2 0 H H 2 0 H n-octyl 3 0 H n-dodecyl 3 0 H n-hexadecyl 4 0 ch3 n-octyl 4 0 n-butyl n-octyl 2 1 H H 2 1 H n-octyl 3 1 H n-dodecyl 3 1 H n-hexadecyl 4 1 ch3 n-octyl 4 1 n-butyl n-octyl 2 2 H H 2 2 H n-octyl 3 2 H n-dodecyl 3 2 H n-hexadecyl 4 2 ch3 n-octyl 4 2 n-butyl n-octyl
898
EXAMPLE XXI
Η-[4-(Diphenylmethyl)-1-piperidinyl3 methylene~benzenebutanaroine (E)-2-Butenedioate Hydrate
A mixture of 4.40g (0.016 mole) of N-formyl-4(diphenyImethyl)piperidine and 1.47 ml (2.00g, 0.015 mole) 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 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 1.84g of fumaric acid and cooled. There was filtered off a white crystalline solid which was recrystallized from ethanol to give N-[4-(diphenyImethyl)-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-octylacetimidic acid ethyl ester (generated from 5.68g [0.04 mole] of boron trifluoride etherate, 2.77g [0.03 mole] of epichlorohydrin, and 5,80g [0.034 mole] of N-octyl acetamide) and 50 ml of ether was treated with 4 ml (2.92g, 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 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 solution. The organic layer was separated, dried over KjCOj, filtered and stripped to an oil which was distilled.
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 whi'Ch was recrystallized three times from methanol to give 4-(Diphenylmethyl)-1-[1-(octylimino)ethyl]piperidine Monoperchlorate as a white crystalline solid, m.p. 119-121.5SC.
EXAMPLE XXIII a-(4-Methylphenyl)-a-phenyl-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 25s, an aqueous solution of anssniun chloride wee added causing a solid to farm which was filtered. Recrystallization of this material from 95% ethanol afforded the desired a-(4-methylphenyl)a-phenyl-4-pyridine methanol, m.p. 192-195SC. The corresponding 4-chlorophenyl (m.p. 198-202sC) and 4methoxyphenyl (m.p. 204-206*0 derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
EXAMPLE XXIV
4- f (4-(methylphenyl)phenylmethy ljpiperidine
A solution of 25.Og (0.09 mole) a-(4-methylphenyl)-a~phenyl-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 4-/(4-methylphenyl)phenylrnethyl/ 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
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 α-(1,4'-Biphenyl)yl-a-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 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 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)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- (.1,41 -Biphenyl) yl-g-phenyl-4-piperidinemethanol
A solution of lO.OOg (0.030 mole) of
EXAMPLE XXVII
9-(41-piperidinyl)-9-fluorenol
A solution of 13. Og (0.05 sole) of 9-(4'pyridyl)-9-fluorenol in 200 ml of glacial acetic acid was hydrogenated over 0.8g of platinum oxide at 40 psi.
The mixture was filtered, stripped, and the residue made basic affording 9-(4*-piperidinyl)-9-fluorenol.
EXAMPLE XXVIII 4-Fluorenylidenepiperidine
A suspension of 13.Og (0.05 mole) of 9-(4'piperidinyl)-9-fluorenol in 70 ml of 48% sulfuric acid was heated on a steam bath for seven hours and poured on to ice. The resulting solid was filtered, made basic with sodium hydroxide solution and extracted with methylene chloride. The organic layer was separated, dried over potassium carbonate, filtered and stripped to give 4fluorenylidenepiperidine.
EXAMPLE XXIX 9-(4'-Pyridyl)fluorene
A solution of 1.35g (0.005 mole) of α,α-diphenyl4-pyridine methanol in 18.5 ml of 97% formic acid was treated dropwise with 8 ml of concentrated sulfuric acid. The reaction was refluxed ten minutes, cooled and made basic with 6 N sodium hydroxide solution causing a solid to separate. This material was filtered and recrystallized from methanol to give 9-(4'-pyridyl)fluorene, m.p. 141143°C (Hoover).
EXAMPLE XXX
9-(41-Piperidyl) fluorene fumarate
A solution of 54.75g (0.225 mole) of 9-(4'pyridyl)fluorene in 600 ml of acetic acid was hydrogenated over 5.0g of platinum oxide at 40 psi and 25°C.
The mixture was filtered, stripped and made basic, affording 9-(4’-piperidyl)fluorene, which was crystallized as the fumarate salt, m.p. 228-230°C (dec).
Claims (5)
1. A substituted N-iminomethylpiperidine of formula (I, R A Ί '3 NC=NR. (I) or a corresponding non-toxic acid addition salts thereof, 5 wherein: taken individually is hydrogen; phenyl; phenyl substituted with from one to three loweralkyl, loweralkoxy, hydroxy or halo; phenyl (C^-C^)loweralkyl;
2. A substituted N-iminomethylpiperidine as claimed in claim 1 wherein: R^ is a phenyl; phenyl substituted with from one to three loweralkyl, loweralkoxy, halo or phenyl, provided that no more than one substituent is phenyl; phenyl loweralkyl; phenyl(Cj-C^)loweralkyl in which the phenyl is substituted with from one to three loweralkyl, loweralkoxy or halo; diphenyl (C^-cploweralkyl and diphenyl (C^-C^)loweralkyl wherein at least one of the phenyls is substituted with from one to three loweralkyl, loweralkoxy, halo or phenyl,
3. ' 3. A substituted N-iminomethylpiperidine as claimed in claim 2 wherein: 10 is diphenylmethyl or diphenylmethyl wherein at least one of the phenyls is substituted with from one to three loweralkyl, loweralkoxy or halo; R 2 is hydrogen; R 3 is hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl 15 in which the phenyl is substituted with from one to three loweralkyl, loweralkoxy or halo; alkenyl; or alkynyl; and R l' an< 3 D are each hydrogen.
4. A substituted N-iminomethylpiperidine as claimed in claim 3 wherein: 20 R^ is diphenylmethyl or diphenylmethyl wherein one of the phenyls . is substituted in the para-position with a loweralkyl, loweralkoxy or halo; R 2 is hydrogen; R 3 is hydrogen; straight chain alkyl; or phenylloweralkyl; 25 and R' 1 ,R*' 1 , Λ,Β, and D are each hydrogen. 5. 4-Diphenylmethyl-l-iminomethylpiperidine or a nontoxic acid addition salt thereof. 6. 4-(Diphenylmethyl)-1- Jjisopropyliminojmethyl] 5 piperidine or a non-toxic acid addition salt thereof. 7. 1-Jn-(Benzyl)iminomethyl]-4-diphenylmethylpiperidine or a non-toxic acid addition salt thereof. 8. 1—(N-(Phenethyl)iminomethyl]-4-diphenylmethylpiperidine or a non-toxic acid addition salt thereof. 10 9. 1-Jn-(n-Decyl)iminomethylJ-4-diphenylmethylpiperidine or a non-toxic acid addition salt thereof. 10. 4-(Diphenylmethyl)-1-[\octylimino)methyi] piperidine or a non-toxic acid addition salt thereof. 11. 4-(Diphenylmethyl)-1- [(ethylimino) methyl] 15 piperidine or a non-toxic acid addition salt thereof. 12. 1-[n-(n-Butyl)iminomethylj-4-diphenylmethylpiperidine or a non-toxic acid addition salt thereof. ν. 478 98 13. 4-(Diphenylmethyl)-1-£(hcxylimino)methyljpiperidine or a non-toxic acid addition salt thereof. 14. 4-(Diphenylmethyl)-1- ((heptylimino)methyl]piperidine or a non-toxic acid addition salt thereof. 15. 4-(Diphenylmethyl)-1-((t-octylimino)methyl]piperidine or a non-toxic acid addition salt thereof. 16. 4-(Diphenylmethyl)-l-((nonylimino)methyl3piperidine or a non-toxic acid addition salt thereof. 17. 4- (Diphenylmethyl)-l-(_(dodecylimino)methyljpiperidine or a non-toxic acid addition salt thereof. 18. l-Q(l-Adaroantylimino)methyl3-4-(diphenylmethyl)piperidine or a non-toxic acid addition salt thereof. 19. 1- ((4-Chlorobenzylimino)methyl]-4-(diphenylmethyl)piperidine or a non-toxic acid addition salt thereof. 20. 1- QAllylimino)methyl3-4-diphenylmethyl)piperidine of a non-toxic acid addition salt thereof. 21. 4- (Diphenylmethyl)-l-C.(2-propynylimino)methyl] piperidine or a non-toxic acid addition salt thereof. 22. 4- (DiphenyImethyl)-1- £(9-octadecen-l-ylimino)methylJ piperidine or a non-toxic acid addition salt thereof. 5 23. 4- (Diphenylmethyl)-1-fethyl(iminolmethyl]piperidine or a non-toxic acid addition salt thereof. 24. 4- [g- (4-Methoxyphenyl)benzyl]-1-iminomethylpiperidine or a non-toxic acid addition salt thereof. 25. 4 [a-(4-Methoxyphenyl)benzyl]-l- £(octylimino)methylj~·· 10 piperidine or a non-toxic acid addition salt thereof. . 26. 4p-(4-Chlorophenyl)benzyl]-1-iminomethylpiperidine or a non-toxic acid addition salt thereof. 27. 4 (9-Fluoroenyl)-1-Qoctylimino)methyl}piperidine or a non-toxic acid addition salt thereof. 15 28. 4 (a- ¢4ethylphenyl)benzyl} -l-[_(octylimino)methyl] piperidine or a non-toxic acid addition salt thereof. 29. 4- diphenylmethyl)-1-Qnethyl(octylimino)methyljpiperidine or a non-toxic acid addition salt thereof. 30. Ν- β-(Diphenylmethyl)-l-piperidinyl]methylene bcnzencbutanamine or a non-toxic acid addition salt thereof. 31. 4-Acetyl-l-(iminomethyl)-4-phenylpiperidine or a 5 non-toxic acid addition salt thereof. 32. 4-Benzydrylidene-l- |\octylimino) methyl jjpiperidine or a non-toxic acid addition salt thereof. 33. 3-(Diphenylmethyl)-1- [(octylimino)methyl] piperidine or a non-toxic acid addition salt thereof. 4 7 8 9 8 provided that no more than one substituent is phenyl; R 2 is hydrogen or methyl; R^is hydrogen; alkyl; cycloalkyl; phenylloweralkyl; phenylloweralkyl in which the phenyl is substituted with 5 from one to three loweralkyl, loweralkoxy or halo; alkenyyl or alkynyl; and R, 1' R 1' and D are eac h hydrogen.
5. Claimed in claim 47 substantially as described herein.
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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE790650L IE790650L (en) | 1979-09-29 |
| IE47898B1 true IE47898B1 (en) | 1984-07-11 |
Family
ID=26680913
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE650/79A IE47898B1 (en) | 1978-03-29 | 1979-08-08 | Substituted n-iminomethylpiperidines |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS54132580A (en) |
| AT (1) | AT372081B (en) |
| AU (1) | AU523867B2 (en) |
| CA (1) | CA1140118A (en) |
| CH (1) | CH639071A5 (en) |
| DE (1) | DE2912026A1 (en) |
| DK (1) | DK124979A (en) |
| ES (1) | ES479033A1 (en) |
| FI (1) | FI791035A (en) |
| FR (1) | FR2421169A1 (en) |
| GB (1) | GB2017689B (en) |
| GR (1) | GR65192B (en) |
| IE (1) | IE47898B1 (en) |
| IL (1) | IL56962A (en) |
| IT (1) | IT1116525B (en) |
| NL (1) | NL7902465A (en) |
| NO (1) | NO791026L (en) |
| NZ (1) | NZ189977A (en) |
| PH (1) | PH15760A (en) |
| PT (1) | PT69383A (en) |
| SE (1) | SE7902724L (en) |
| SU (1) | SU1158042A3 (en) |
| YU (1) | YU73179A (en) |
| ZW (1) | ZW6479A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5889006A (en) * | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
| IL117149A0 (en) * | 1995-02-23 | 1996-06-18 | Schering Corp | 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH563109A5 (en) * | 1972-03-17 | 1975-06-30 | Ciba Geigy Ag |
-
1979
- 1979-03-19 AU AU45322/79A patent/AU523867B2/en not_active Ceased
- 1979-03-20 GB GB7909671A patent/GB2017689B/en not_active Expired
- 1979-03-22 PT PT69383A patent/PT69383A/en unknown
- 1979-03-23 NZ NZ189977A patent/NZ189977A/en unknown
- 1979-03-27 SE SE7902724A patent/SE7902724L/en not_active Application Discontinuation
- 1979-03-27 DE DE19792912026 patent/DE2912026A1/en active Granted
- 1979-03-27 YU YU00731/79A patent/YU73179A/en unknown
- 1979-03-27 JP JP3516879A patent/JPS54132580A/en active Granted
- 1979-03-27 DK DK124979A patent/DK124979A/en not_active Application Discontinuation
- 1979-03-28 SU SU792745899A patent/SU1158042A3/en active
- 1979-03-28 PH PH22331A patent/PH15760A/en unknown
- 1979-03-28 ZW ZW64/79A patent/ZW6479A1/en unknown
- 1979-03-28 CA CA000324324A patent/CA1140118A/en not_active Expired
- 1979-03-28 IL IL56962A patent/IL56962A/en unknown
- 1979-03-28 AT AT0230979A patent/AT372081B/en not_active IP Right Cessation
- 1979-03-28 IT IT48515/79A patent/IT1116525B/en active
- 1979-03-28 NO NO791026A patent/NO791026L/en unknown
- 1979-03-28 ES ES479033A patent/ES479033A1/en not_active Expired
- 1979-03-28 FI FI791035A patent/FI791035A/en not_active Application Discontinuation
- 1979-03-29 FR FR7907919A patent/FR2421169A1/en active Granted
- 1979-03-29 CH CH292779A patent/CH639071A5/en not_active IP Right Cessation
- 1979-03-29 GR GR58719A patent/GR65192B/en unknown
- 1979-03-29 NL NL7902465A patent/NL7902465A/en not_active Application Discontinuation
- 1979-08-08 IE IE650/79A patent/IE47898B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK124979A (en) | 1979-09-30 |
| GR65192B (en) | 1980-07-29 |
| PH15760A (en) | 1983-03-22 |
| GB2017689B (en) | 1982-09-02 |
| YU73179A (en) | 1983-12-31 |
| NL7902465A (en) | 1979-10-02 |
| CH639071A5 (en) | 1983-10-31 |
| NZ189977A (en) | 1984-05-31 |
| JPS6217588B2 (en) | 1987-04-18 |
| PT69383A (en) | 1979-04-01 |
| NO791026L (en) | 1979-10-02 |
| IT7948515A0 (en) | 1979-03-28 |
| IL56962A0 (en) | 1979-05-31 |
| DE2912026A1 (en) | 1979-10-11 |
| DE2912026C2 (en) | 1990-04-05 |
| AU523867B2 (en) | 1982-08-19 |
| ATA230979A (en) | 1983-01-15 |
| FR2421169A1 (en) | 1979-10-26 |
| ZW6479A1 (en) | 1980-11-26 |
| FI791035A (en) | 1979-09-30 |
| FR2421169B1 (en) | 1983-05-27 |
| IE790650L (en) | 1979-09-29 |
| AT372081B (en) | 1983-08-25 |
| GB2017689A (en) | 1979-10-10 |
| CA1140118A (en) | 1983-01-25 |
| AU4532279A (en) | 1979-10-04 |
| SU1158042A3 (en) | 1985-05-23 |
| JPS54132580A (en) | 1979-10-15 |
| IL56962A (en) | 1983-03-31 |
| ES479033A1 (en) | 1980-06-16 |
| IT1116525B (en) | 1986-02-10 |
| SE7902724L (en) | 1979-09-30 |
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